Patent Application
20240175027
The sequence listing of the present application is submitted electronically as an ASCII formatted sequence listing with a file name “11282seqlist”, creation date of Oct. 28, 2022, and a size of 112 Kb. This sequence listing submitted is part of the specification and is herein incorporated by reference in its entirety.
The field of the present disclosure relates to co-formulations and combination therapies that include an RNA and an antibody or antigen-binding fragment thereof along with methods for stabilizing RNA in a composition including beta-hexosaminidase.
Complement component C5 is target for several rare diseases, including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome, neuromyelitis optica, and generalized myasthenia gravis. Uncontrolled complement activation in PNH patients, for example, results in the primarily clinical manifestation of chronic hemolysis, as well as an increased risk of thromboembolism, leading to target organ damage and death.
Complement 5 is a validated target in the treatment of complement-mediated diseases such as generalized myasthenia gravis (gMG) as was established by the approval of Eculizumab (Ecu) for the treatment of patients with gMG. Anti-C5 antibody, Pozelimab, monotherapy has been shown to be effective in blocking C5 activity in another disease (paroxysmal nocturnal hemoglobinuria [PNH]) that is highly sensitive to complement mediated effects.
A great degree of complement inhibition is necessary to provide rapid and pronounced disease suppression and attain complete and uninterrupted inhibition of C5 throughout the entire C5-inhibitor dosing interval. Current C5-inhibitor monotherapies have not achieved a sufficient level of inhibition.
Therapies targeting C5 for PNH, such as Eculizumab and Ravulizumab (Soliris and Ultomiris, Alexion Pharmaceuticals), have demonstrated efficacy. However, in rare instances, Eculizumab and Ravulizumab are ineffective due to polymorphic variation in the gene encoding C5 such that the C5 protein is not bound by Eculizumab or Ravulizumab (Nishimura et al., Genetic variants in C5 and poor response to Eculizumab. N Engl J Med 2014; 370(7):632-639). In addition, treatment is burdensome as the drugs are generally administered chronically by IV infusion Q2W or Q8W, respectively, to maintain efficacy. Moreover, it has been reported that as many as 20% of patients with PNH on Eculizumab treatment at the labeled maintenance dose (900 mg Q2W IV) require significant increases in dose or dose frequency due to breakthrough hemolysis secondary to incomplete inhibition of C5 (Peffault de Latour et al., Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving Eculizumab. Blood 2015; 125(5):775-783) (Hillmen et al., Long-term safety and efficacy of sustained Eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria. Br J Haematol 2013; 162(1):62-73). While the regulatory approval of Ravulizumab has provided an agent with an IV dosing frequency of Q8W, patients still experience some hemolytic breakthrough (Lee et al., Ravulizumab (ALXN1210) vs Eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood 2019; 133(6):530-539).
A regimen of 30 mg/kg IV loading dose followed by 800 mg SC weekly was effective in a phase 2 study in complement treatment naïve patients with PNH (R3918-PNH-1852) at reducing serum LDH to <1.5×ULN in all patients and <1.0 ULN in most patients. However, the regimen represents relatively high doses for a biologic agent.
The requirement for such high anti-C5 mAb doses is driven by the need for 100% inhibition which is achieved with complete target engagement (Peffault de Latour, 2015) and C5 levels are high; and in order to achieve 100% inhibition on a population basis, inter- and intra-patient variability of C5 concentrations and instances of enhanced complement activation (which may occur with intercurrent illness) must be considered.
Cemdisiran is a synthetic small interfering ribonucleic acid (siRNA) targeting C5 messenger ribonucleic acid (mRNA) that is covalently linked to a triantennary N-acetylgalactosamine (GalNAc) ligand. Cemdisiran is designed to suppress liver production of C5 protein, when administered via SC injection. C5 is encoded by a single gene and is expressed and secreted predominantly by hepatocytes. Through the ribonucleic acid (RNA) interference pathway, Cemdisiran leads to the degradation of C5 mRNA by RNases, thereby reducing C5 protein production, leading to reduced levels of circulating C5 protein. Cemdisiran monotherapy has been found to be insufficiently effective as a monotherapy treatment for PNH. Badri et al., Clin Pharmacokinet. 2021; 60(3):365-78-Epub 2020/10/14.
Combining Cemdisiran with recombinant antibodies in a co-formulation that can conveniently be administered in a common injection raises the risk of contaminants from the antibody degrading the Cemdisiran molecule.
Moreover, treating patients suffering from a condition such as PNH raises the likelihood that a substantial portion of such patients will either be currently receiving another anti-C5 antibody or have recently received such an antibody and, thus, have detectable blood concentrations thereof. Experiments suggest that antibodies having the sequence of Eculizumab and Pozelimab, in combination, were able to form high molecular weight heteromeric complexes with C5, thus posing the risk of formation of such complexes in vivo when both antibodies are present in the circulation.
Results of a previous clinical study reported adverse reactions (e.g., serum sickness-like reactions, skin rash) upon switching from one C5 mAb to another, specifically, upon switching from eculizumab to crovalimab (SKY59/RO7112689/RG6107), a therapeutic C5 antibody that binds a different epitope than Eculizumab. These reactions were attributed to the formation of DTD immune complexes comprising C5 and the two C5 antibodies (Röth et al., The complement C5 inhibitor crovalimab in paroxysmal nocturnal hemoglobinuria. Blood 2020; 135(12):912-920; Röth et al., The SMART Anti-hC5 Antibody (SKY59/RO7112689) Shows Good Safety and Efficacy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Blood 2018a; 132(Suppl 1):535; United States Patent Publication US2009/0220508). The size of such immune complexes has been related to the occurrence of adverse events. For example, in a study where anti-drug-antibody (ADA)-positive patients were injected with infliximab, an antibody with specificity for a target unrelated to the complement system, a severe infusion reaction was observed when immune complexes larger than 1000 kDa (>6 antibodies) were detected for 1 patient, but not when only smaller immune complexes were detected (<1000 kDa) in 2 patients (van der Laken et al., Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Ann Rheum Dis 2007; 66(2):253-256), suggesting that large DTD immune complexes are more likely to be associated with adverse events. Furthermore, small DTD immune complexes are expected to be clinically insignificant based on extrapolation from other autoimmune disease states such as systemic lupus erythematous, whereby small immune complexes are inefficient in complement activation and interactions with Fc gamma receptor and do not deposit in tissues (Wener et al., Immune Complexes in Systemic Lupus Erythematosus (Chapter 19). Systemic Lupus Erythematosus. Academic Press; 2010).
Reducing the likelihood of such adverse events is difficult. In the COMMODORE-1 clinical trial, had two arms wherein patients were treated with the anti-C5 antibody, Crovalimab or Eculizumab during a 24 week primary treatment period. After the primary treatment period, patients in the Eculizumab had the option to switch to Crovalimab treatment. Sixteen percent of patients switching from Eculizumab to Crovalimab experienced type 3 hypersensitivity (T3H) reactions. T3H reactions and injection-related reactions were not applicable to the eculizumab arm as they were related to large DTD complex formation and subcutaneous administration, respectively, which are exclusive to the crovalimab arm. Scheinberg et al., Phase III Randomized, Multicenter, Open-Label Commodore 1 Trial: Comparison of Crovalimab vs Eculizumab in Complement Inhibitor-Experienced Patients With Paroxysmal Nocturnal Hemoglobinuria, European Hematology Association, Frankfurt, Germany; Virtual (Hybrid) 9 Jun. 2023.
The present invention includes a co-formulation including a C5 iRNA which is conjugated to a ligand that comprises one or more terminal amino sugars, such as N-Acetylgalactosamine (GalNAc) and/or N-acetylglucosamine (GlcNAc) residues; an antibody or antigen-binding fragment thereof that binds specifically to C5 (anti-C5) which is isolated from a mammalian host cell; having a pH of greater than or less than about 6 (e.g., about 6.5); and a pharmaceutically acceptable carrier. For example, in an embodiment of the invention, the co-formulation includes a C5 iRNA; an antibody or antigen-binding fragment thereof that binds specifically to C5; a buffer (e.g., histidine-based buffer, a citrate-based buffer, a phosphate-based buffer and/or an acetate-based buffer, for example, at a concentration of about 10-35, 35-45, 20-50, 20, 25, 30, 35, 40, 45 or 50 mM); a stabilizer (e.g., a polyol, a sugar, trehalose, sorbitol, mannitol, taurine, propane sulfonic acid, L-proline, sucrose, glycerol, threitol, maltitol, polyethylene glycol (PEG), and/or PEG3350; for example, at a concentration of about 0.8-3.6, 0.8, 0.9, 1.0, 1.25, 1.50, 2.0, 2.25, 2.50, 2.75, 3.00, 3.1, 3.2, 3.3, 3.4, 3.5 or 3.6% (w/v)); a viscosity reducer, and a non-ionic surfactant (e.g., a polyoxyethylene glycol alkyl ether; glucoside alkyl ether; polyoxyethylene glycol octylphenol ether; polyoxyethylene glycol alkylphenol ether; glycerol alkyl ester; polyoxyethylene glycol sorbitan alkyl ester; sorbitan alkyl ester; block copolymer of polypropylene glycol; block copolymer of polyethylene glycol; a polysorbate, octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; polyoxypropylene glycol alkyl ether; decyl glucoside, lauryl glucoside, octyl glucoside; triton X-100; nonoxynol-9; glyceryl laurate; cocamide MEA, cocamide DEA, dodecyldimethylamine oxide; poloxamer; polyethoxylated tallow amine (POEA); polysorbate-20 (PS20) and/or polysorbate-80 (PS80); for example, at a concentration of about 0.025, 0.05, 0.075, 0.1, 0.125, 0.15, 0.175% (w/v)), and pH of greater than or less than about 6 (e.g., within not less than 0.5 of 6.0) (e.g., about 6.5).
In an embodiment of the invention, the viscosity reducer (e.g., a dicarboxylic acid, an inorganic salt, an ester of citric acid, a xanthine, adipic acid; NaCl; caffeine; triethyl citrate, an amino acid, (D- or L-) arginine, L-arginine HCl, (D- or L-) alanine, (D- or L-) histidine, proline, (D- or L-) valine, glycine, (D- or L-) serine, (D- or L-) phenylalanine, (D- or L-) lysine, and (D- or L-) glutamate, and salts thereof; pyridoxamine; L-Ornithine; thiamine phosphoric acid ester chloride dihydrate, benzenesulfonic acid and/or pyridoxine; for example at a concentration of about 20-140, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135 or 140 mM)) is at a concentration of about 5 mM to about 100 mM (e.g., 50-75 mM) each. If the viscosity reducer is an amino acid, it can be the L-enantiomer thereof or the D-enantiomer thereof. The viscosity reducer may be the conjugate base or salt thereof of an acid specified herein. In an embodiment of the invention, the co-formulation is characterized by about 96% or more anti-C5 antibody or antigen-binding fragment purity as assessed by size exclusion chromatography after about 1 month at 2-8° C.; and/or about 94% or more C5 iRNA purity as assessed by anion exchange chromatography after about 1 month at 2-8° C. In an embodiment of the invention, the co-formulation has a 1:1 ratio of milligrams per milliliter concentration of C5 iRNA and anti-C5 antibody or antigen-binding fragment; and, optionally, a viscosity reducer which is arginine, adipate, NaCl, lysine, aspartate, proline, histidine, caffeine, phenylalanine and/or triethyl citrate, e.g., at a concentration of about 75 mM arginine, 75 mM adipate, 75 mM NaCl, 75 mM lysine, 75 mM aspartate, 75 mM proline, 50 mM histidine (wherein, if the buffer is histidine based, then the total histidine concentration of the co-formulation is 50 mM), 50 mM caffeine, 50 mM phenylalanine and/or 75 mM triethyl citrate. In an embodiment of the invention, the co-formulation has a 1:2 ratio of milligrams per milliliter concentration of C5 iRNA and anti-C5 antibody or antigen-binding fragment; and, optionally, a viscosity reducer such as is arginine, adipate, NaCl, lysine and/or aspartate, e.g., at a concentration of about 75 mM arginine, 75 mM adipate, 75 mM NaCl, 75 mM lysine and/or 75 mM aspartate.
In an embodiment of the invention, the co-formulation includes an antibody or antigen-binding fragment thereof that binds specifically to C5 (anti-C5) including: a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 26; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 58; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 66, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 74; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 154, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 162; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 170, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 178; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 186, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 194; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 202, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 210; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 218, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 226; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 234, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 242; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 250, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 266, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 274, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 282; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 290, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 298; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 306, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 314; a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 322, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 330; and/or a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 338, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 346. For example, in an embodiment of the invention, the antibody or antigen-binding fragment thereof that binds specifically to C5 (anti-C5) includes a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 4, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 6, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 8, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 12, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 14, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 16; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 20, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 22, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 24, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 28, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 30, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 32; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 36, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 38, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 40, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 44, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 46, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 48; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 52, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 54, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 56, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 60, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 62, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 64; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 68, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 70, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 72, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 76, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 78, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 80; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 84, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 86, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 88, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 92, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 94, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 96; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 100, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 102, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 104, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 100, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 102, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 104, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 116, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 118, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 120; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 124, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 126, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 128, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 100, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 102, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 104, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 140, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 142, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 144, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 148, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 150, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 152, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 108, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 110, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 112; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 124, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 126, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 128, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 148, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 150, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 152, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 116, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 118, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 120; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 148, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 150, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 152, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 140, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 142, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 144, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 132, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 134, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 136; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 156, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 158, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 160, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 164, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 166, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 168; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 172, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 174, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 176, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 180, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 182, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 184; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 188, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 190, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 192, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 196, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 198, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 200; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 204, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 206, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 208, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 212, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 214, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 216; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 220, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 222, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 224, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 228, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 230, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 232; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 236, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 238, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 240, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 244, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 246, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 248; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 252, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 254, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 256, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 260, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 262, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 264; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 268, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 270, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 272, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 260, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 262, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 264; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 276, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 278, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 280, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 284, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 286, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 288; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 292, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 294, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 296, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 300, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 302, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 304; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 308, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 310, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 312, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 316, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 318, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 320; a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 324, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 326, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 328, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 332, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 334, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 336; or a heavy chain variable region comprising an HCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 340, an HCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 342, an HCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 344, and a light chain variable region comprising an LCDR1 that comprises the amino acid sequence set forth in SEQ ID NO: 348, an LCDR2 that comprises the amino acid sequence set forth in SEQ ID NO: 350, an LCDR3 that comprises the amino acid sequence set forth in SEQ ID NO: 352. In an embodiment of the invention, the antibody or antigen-binding fragment thereof that binds specifically to C5 (anti-C5) includes a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 2, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 10; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 18, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 26; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 34, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 42; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 50, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 58; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 66, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 74; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 82, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 90; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 98, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 106; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 98, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 114; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 122, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 106; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 98, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 138, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 106; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 146, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 106; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 122, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 146, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 114; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 146, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 138, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 130; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 154, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 162; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 170, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 178; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 186, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 194; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 202, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 210; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 218, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 226; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 234, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 242; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 250, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 258; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 266, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 258; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 274, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 282; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 290, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 298; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 306, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 314; a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 322, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 330; or a heavy chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 338, a light chain variable region that comprises the amino acid sequence set forth in SEQ ID NO: 346. For example, in an embodiment of the invention, the co-formulation includes about 90 to about 275 mg/ml; or about 90; 91; 92; 93; 94; 95; 96; 97; 98; 99; 100; 101; 102; 103; 104; 105; 106; 107; 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123; 124; 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140; 141; 142; 143; 144; 145; 146; 147; 148; 149; 150; 151; 152; 153; 154; 155; 156; 157; 158; 159; 160; 161; 162; 163; 164; 165; 166; 167; 168; 169; 170; 171; 172; 173; 174; 175; 176; 177; 178; 179; 180; 181; 182; 183; 184; 185; 186; 187; 188; 189; 190; 191; 192; 193; 194; 195; 196; 197; 198; 199; 200; 211, 220, 242, or 274 mg/ml; or at least about 150 mg/ml, at least about 175 mg/ml, at least about 200 mg/ml, at least about 211 mg/ml, at least about 220 mg/ml, at least about 242 mg/ml or at least about 274 mg/ml of the antibody or antigen-binding fragment that specifically binds to C5 (anti-C5).
In an embodiment of the invention, the co-formulation includes a C5 iRNA that is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises a region of complementarity comprising at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5′-UAUUAUAAAAAUAUCUUGCUUUU-3′ (SEQ ID NO: 364), and wherein the dsRNA agent comprises at least one modified nucleotide. In an embodiment of the invention, the co-formulation includes a C5 iRNA that is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO: 406) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO: 369), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; s is a phosphorothioate linkage; and wherein the sense strand is conjugated at the 3′-terminus to the ligand
(e.g., wherein the C5 iRNA is Cemdisiran). In an embodiment of the invention, the co-formulation includes a C5 iRNA which is Cemdisiran and one or more of Cemdisiran impurity 1, Cemdisiran impurity 2 and Cemdisiran impurity 3 as discussed herein. In an embodiment of the invention, the C5 iRNA is at a concentration of about 20-100, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 115, 120, 130, 140, 150, 155, 160, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215, 220, 225, 230, 235, 240, 245, 250, 255, 260, 265, 270, 275, 280, 285, 290, 295, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370, 375, 380, 385, 390, 395, or 400 mg/ml.
In an embodiment of the invention, the co-formulation is characterized by a viscosity <30 cP at 20° C.; and/or an osmolality of 240-450 mOsm/kg; e.g. a viscosity ≤20 cP at 20° C.
The present invention includes a co-formulation including any of the following:
The present invention includes a co-formulation including a C5 iRNA which is Cemdisiran; an antibody or antigen-binding fragment which is Pozelimab; a viscosity reducer, which is L-arginine; a buffer which is a histidine-based buffer; a stabilizer which is sucrose; a non-ionic surfactant which is polysorbate 80; and a pH of about 6.5.
In an embodiment of the invention, the co-formulation includes a C5 iRNA that is conjugated to a ligand that comprises one or more terminal N-Acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc) residues; has a pH that is within no less than about 0.5 of about 6; and/or a pH that is about 6.5.
In an embodiment of the invention, the co-formulation is characterized by one or more of: comprises beta-hexosaminidase; comprises the antibody of antigen-binding fragment thereof which was expressed and isolated from a mammalian host cell that contains beta-hexosaminidase; comprises the antibody of antigen-binding fragment thereof which was expressed and isolated from a Chinese hamster ovary cell; comprises no more than about 1% Cemdisiran Impurity 1 relative to total Cemdisiran; comprises no less than about 80% Cemdisiran, relative to total Cemdisiran, after 2 years storage at 2-8° C.; has about 91% Cemdisiran before storage (at t=0); has no less than about 80% Cemdisiran after 1, 1%, 2, 2% or 3 years storage at 2-8° C.; has about 80% to about 91% Cemdisiran; exhibits a Cemdisiran Purity (%) by dIPRP of about 90.5% at t=0; 91.1% after 1 month storage at 2-8° C.; 90.8% after 3 months storage at 2-8° C.; 90% after 6 months storage at 2-8° C.; 88.8% after 9 months storage at 2-8° C.; 88.7% after 12 months storage at 2-8° C.; 89% after 18 months storage at 2-8° C.; and/or 89.4% after 24 months storage at 2-8° C.; exhibits a Cemdisiran Purity (%) by dIPRP of about 90.8% at t=0, 90.6% after 1 month storage at 2-8° C.; 90.5% after 3 months storage at 2-8° C.; 89.4% after 6 months storage at 2-8° C.; 88.3% after 9 months storage at 2-8° C.; 87.8% after 12 months storage at 2-8° C.; 87.8% after 18 months storage at 2-8° C.; and/or 89.4% after 24 months storage at 2-8° C.; exhibits a Cemdisiran Single Strand Purity (%) by dIPRP of about 90.5% at t=0; 90.2% after 1 month storage at 25° C. and 60% RH; 87.8% after 3 months storage at 25° C. and 60% RH; 85.1% after 6 months storage at 25° C. and 60% RH; 90% after 0.5 months storage at 40° C. and 75% RH; 88.9% after 1 month storage at 40° C. and 75% RH; 85.8% after 3 months storage at 40° C. and 75% RH; exhibits a Cemdisiran Purity (%) by dIPRP of about 90.8% at t=0; 88.8% after 1 month storage at 25° C. and 60% RH; 85.9% after 3 months storage at 25° C. and 60% RH; 82.3% after 6 months storage at 25° C. and 60% RH; 88.9% after 0.5 months storage at 40° C. and 75% RH; 87.3% after 1 month storage at 40° C. and 75% RH; 82.3% after 3 months storage at 40° C. and 75% RH; exhibits a Cemdisiran purity (%) by dIPRP of about 90.9% at t=0; about 90.1% after 1 month of storage at 25° C., 60% RH; about 90.9% after 3 months of storage at 25° C., 60% RH; about 90.4% after 6 months of storage at 25° C., 60% RH; about 89.9% after 0.5 months of storage at 40° C., 75% RH; about 89.7% after 1 month of storage at 40° C., 75% RH; and/or about 89.5% after 3 months of storage at 40° C., 75% RH; exhibits a Cemdisiran purity (%) by dIPRP of about 90.8% at t=0; about 90.2% after 1 month of storage at 25° C., 60% RH; about 90.8% after 3 months of storage at 25° C., 60% RH; about 90.3% after 6 months of storage at 25° C., 60% RH; about 89.5% after 0.5 months of storage at 40° C., 75% RH; about 89.6% after 1 month of storage at 40° C., 75% RH; and/or about 89.1% after 3 months of storage at 40° C., 75% RH; exhibits a Cemdisiran purity (%) by dIPRP of about 90.5% at t=0; about 89.9% after 1 month of storage at 25° C., 60% RH; about 90.8% after 3 months of storage at 25° C., 60% RH; about 90.4% after 6 months of storage at 25° C., 60% RH; about 90.1% after 0.5 months of storage at 40° C., 75% RH; about 89.6% after 1 month of storage at 40° C., 75% RH; and/or about 89.9% after 3 months of storage at 40° C., 75% RH; and/or exhibits a Cemdisiran purity (%) by dIPRP of about 91.1% at t=0; about 90% after 1 month of storage at 25° C., 60% RH; about 91% after 3 months of storage at 25° C., 60% RH; about 90.7% after 6 months of storage at 25° C., 60% RH; about 90% after 0.5 months of storage at 40° C., 75% RH; about 89.7% after 1 month of storage at 40° C., 75% RH; and/or about 89.9% after 3 months of storage at 40° C., 75% RH. In an embodiment of the invention, the co-formulation is characterized by one or more of no more than about 2.1 parts per million (ppm) molar ratio of beta-hexosaminidase to antibody or antigen-binding fragment; include no more than about 0.170 micrograms/ml beta-hexosaminidase, include no more than about 0.04 micrograms/ml beta-hexosaminidase; and/or about 0.04; 0.05; 0.06; 0.06; 0.0605; 0.0605; 0.0605; 0.063; 0.07; 0.07; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17 micrograms/ml beta-hexosaminidase; or no more than any of such concentrations.
The present invention also includes a method for administering a co-formulation as set forth herein to a subject comprising introducing the co-formulation into the body of the subject, for example, by injecting the co-formulation into the body of the subject; e.g., by intramuscular, subcutaneous, intravenous, intraocular and/or intravitreal injection.
The present invention also includes a method for treating or preventing a C5-associated disease or disorder (e.g., a disorder of inappropriate or undesirable complement activation; a hemodialysis complication; a lung disease or disorder; a neurological disorder; a parasitic disease; a post-ischemic reperfusion condition; a proteinuric kidney disease; a renal disorder; adult respiratory distress syndrome (ARDS); age-related macular degeneration (AMD); allergy; Alport's syndrome; Alzheimer's disease; an autoimmune disease; an immune complex disorder; an inflammatory disorder; an ocular disease; an organic dust disease; angiopathic thrombosis and protein-losing enteropathy; asthma; atherosclerosis; bronchoconstriction; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; CHAPLE disease (CD55 deficiency with hyperactivation of complement; chemical injury due to irritant gasses and/or chemicals; chronic obstructive pulmonary disease (COPD); complement activation due to burn; complement activation due to frostbite; complement activation due to obesity; complement activation due to sepsis; Crohn's disease; diabetes; diabetic macular edema (DME); diabetic nephropathy; diabetic retinopathy; dry AMD; dyspnea; emphysema; epilepsy; fibrogenic dust diseases; geographic atrophy (GA); glomerulopathy; Goodpasture's Syndrome; Guillain-Barre Syndrome; hemolytic anemia; hemoptysis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; immune complex-associated inflammation; infectious disease; inflammation of an autoimmune disease; inherited CD59 deficiency; injury due to inert dusts and/or minerals; interleukin-2 induced toxicity during IL-2 therapy; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; mesenteric artery reperfusion after aortic reconstruction; multiple sclerosis; myasthenia gravis; myocardial infarction; neuromyelitis optica; ocular angiogenesis; Parkinson's disease; pneumonia; progressive kidney failure; psoriasis; pulmonary embolisms and infarcts; pulmonary fibrosis; pulmonary vasculitis; renal ischemia; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; smoke injury; stroke; systemic inflammatory response in post-pump syndrome due to cardiopulmonary bypass or renal bypass; systemic lupus erythematosus (SLE); thermal injury; traumatic brain injury; uveitis; vasculitis; wet AMD; paroxysmal nocturnal hemoglobinuria (PNH); and/or xenograft rejection) in a subject in need thereof comprising administering a therapeutically effective amount of a co-formulation as set forth herein to the subject. In an embodiment of the invention, the subject is administered one or more further therapeutic agents, such as, for example, an androgen, an anti-coagulant, an anti-inflammatory drug, an antihypertensive, an immunosuppressive agent, a fibrinolytic agent, a lipid-lowering agent, an anti-CD20 agent, an anti-TNF alpha agent, a C3 inhibitor, an anti-thrombotic agent, a corticosteroid, a non-steroidal anti-inflammatory drug, an angiotensin-converting enzyme inhibitor, an inhibitor of hydroxymethylglutaryl CoA reductase, an anti-seizure agent, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, and thrombin inhibitors such as argatroban, lepirudin, bivalirudin, dabigatran, vincristine, cyclosporine A, methotrexate, ancrod, ε-aminocaproic acid, antiplasmin-a1, prostacyclin, defibrotide, rituximab, infliximab and/or magnesium sulfate.
The present invention provides a method for increasing the stability of RNA, or for reducing beta-hexosaminidase activity, in a composition, comprising the RNA which is conjugated to a ligand that comprises one or more terminal N-Acetylgalactosamine (GalNAc) residues and/or N-acetylglucosamine (GlcNAc) residues; and beta-hexosaminidase comprising (i) adding GalNAc and/or GlcNAc to the composition and/or (ii) increasing or decreasing the pH of the composition from about 6; for example, wherein the composition comprises the RNA, which is a C5 iRNA; an antibody or antigen-binding fragment thereof that was expressed and isolated from a mammalian host cell (e.g., Chinese hamster ovary (CHO) cell) that comprises the beta-hexosaminidase; and, optionally, a buffer; a viscosity reducer; a stabilizer; and a non-ionic surfactant. In an embodiment of the invention, the RNA is a double stranded RNA, optionally comprising an overhang of 1 or 2 nucleotides on one or both ends, for example, wherein the RNA was chemically synthesized.
The present invention includes a method for making a co-formulation including combining the RNAi and the antibody or antigen-binding fragment, and (i) adding GalNAc to the co-formulation and/or (ii) adjusting the pH of the co-formulation to about or below about 6. Co-formulations, which are the product of the method form part of the present invention.
The present invention provides a method for administering, to a subject, an antibody or antigen-binding fragment thereof that binds specifically to C5 (anti-C5) in combination with a C5 iRNA comprising introducing the antibody or fragment and the iRNA into the body of the subject. In an embodiment of the invention, the antibody or fragment and the iRNA are introduced by a subcutaneous injection or intravenous infusion of a co-formulation that comprises both the antibody or fragment and the iRNA; or subcutaneous injections or intravenous infusions of separate formulations that each comprises either the antibody or fragment or the iRNA.
The present invention provides a method for treating or preventing a C5-associated disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an antibody or antigen-binding fragment thereof that binds specifically to C5 in combination with a C5 iRNA which are in a single co-formulation or are in separate formulations. In an embodiment of the invention, the method further includes administering, to the subject, one or more initial intravenous or subcutaneous loading doses of the antibody or antigen-binding fragment and/or the iRNA. For example, in an embodiment of the invention, the method includes administering one or more doses of both (1) about 400 mg of the anti-C5 antibody or antigen-binding fragment; and (2) about 200 mg of the C5 iRNA; e.g., about 400 mg of the anti-C5 antibody or antigen-binding fragment is administered about every 2, 3 or 4 weeks (±3 days); and about 200 mg of the C5 iRNA is administered about every 4 weeks (±3 days). In an embodiment of the invention, the method includes administering (i) about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously about every 2 weeks (±3, 4, 5, 6 or 7 days), and about 200 mg of the C5 iRNA subcutaneously about every 4 weeks (±3, 4, 5, 6 or 7 days); (ii) about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously about every 4 weeks (±3, 4, 5, 6 or 7 days), and about 200 mg of the C5 iRNA subcutaneously about every 4 weeks (±3, 4, 5, 6 or 7 days); (iii) an intravenous loading dose of anti-C5 antibody or antigen-binding fragment, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of the C5 iRNA subcutaneously; and then, about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of the C5 iRNA subcutaneously; (iv) an intravenous loading dose of about 30 or 60 mg/kg anti-C5 antibody or antigen-binding fragment, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of the C5 iRNA subcutaneously; and then, about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of the C5 iRNA subcutaneously; (v) an intravenous loading dose of about 30 or 60 mg/kg anti-C5 antibody or antigen-binding fragment followed by one or more weekly subcutaneous doses of about 800 mg anti-C5 antibody or antigen-binding fragment, then, after an optional 1 week period, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of the C5 iRNA subcutaneously; and then, about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of the C5 iRNA subcutaneously; (vi) (a) a dose of Eculizumab intravenously and about 200 mg C5 iRNA subcutaneously; (b) a dose of the Eculizumab up to about 14 days (±3, 4, 5, 6 or 7 days) later; and (c) about another 14 or 15 days (±3, 4, 5, 6 or 7 days) later, an anti-C5 antibody or antigen-binding fragment dose of 30 or 60 mg/kg body weight intravenously, an anti-C5 antibody or antigen-binding fragment about 400 mg subcutaneously and C5 iRNA about 200 mg subcutaneously and (d) about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, a dose of anti-C5 antibody or antigen-binding fragment about 400 mg subcutaneously and C5 iRNA about 200 mg subcutaneously; or (vii) (a) about a 200 mg SC dose of C5 iRNA; (b) about 28 days (±3, 4, 5, 6 or 7 days) later, a 30 or 60 mg/kg IV loading dose of anti-C5 antibody or antigen-binding fragment, a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and a 200 mg SC dose of C5 iRNA; and (c) about another 29 days (±3, 4, 5, 6 or 7 days) later and about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, about a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and about a 200 mg SC dose of C5 iRNA; or (viii) (a) about 4 weeks (±3, 4, 5, 6 or 7 days) after an administration of Ravulizumab, a 200 mg SC dose of C5 iRNA; (b) about another 28 days (±3, 4, 5, 6 or 7 days) later, a 30 or 60 mg/kg IV loading dose of anti-C5 antibody or antigen-binding fragment, a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and a 200 mg SC dose of C5 iRNA; and (c) about another 29 days (±3, 4, 5, 6 or 7 days) later and about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and a 200 mg SC dose of C5 iRNA. In an embodiment of the invention, the anti-C5 antibody or antigen-binding fragment and C5 iRNA are administered about every 4 weeks (±3, 4, 5, 6 or 7 days) subcutaneously in a single injection of a co-formulation that comprises the anti-C5 antibody or antigen-binding fragment and C5 iRNA; and about every 4 weeks (±3, 4, 5, 6 or 7 days) a further injection of the anti-C5 antibody or antigen-binding fragment is administered subcutaneously; the anti-C5 antibody or antigen-binding fragment and C5 iRNA are administered about every 4 weeks (±3, 4, 5, 6 or 7 days) subcutaneously in separate injections of separate formulations wherein one comprises the anti-C5 antibody or antigen-binding fragment and the other comprises the C5 iRNA; and about every 4 weeks (±3, 4, 5, 6 or 7 days) a further injection of the anti-C5 antibody or antigen-binding fragment is administered subcutaneously; the anti-C5 antibody or antigen-binding fragment and C5 iRNA are administered about every 4 weeks (±3, 4, 5, 6 or 7 days) subcutaneously in a single injection of a co-formulation that comprises the anti-C5 antibody or antigen-binding fragment and C5 iRNA; and about every 2 weeks (±3, 4, 5, 6 or 7 days) a further injection of the anti-C5 antibody or antigen-binding fragment is administered subcutaneously; and/or the anti-C5 antibody or antigen-binding fragment and C5 iRNA are administered about every 4 weeks (±3, 4, 5, 6 or 7 days) subcutaneously in separate injections of separate formulations wherein one comprises the anti-C5 antibody or antigen-binding fragment and the other comprises the C5 iRNA; and about every 2 weeks (±3, 4, 5, 6 or 7 days) a further injection of the anti-C5 antibody or antigen-binding fragment is administered subcutaneously.
In an embodiment of the invention, the subject has previously received Ravulizumab (e.g., administered intravenous or subcutaneous) and/or Eculizumab (e.g., intravenously administered, e.g., 900 mg intravenously) therapy; and/or Pozelimab monotherapy. In an embodiment of the invention, the subject is complement inhibitor naïve.
The present invention includes a method for treating or preventing a C5-associated disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and C5 iRNA, wherein the subject has previously received Eculizumab wherein the subject is administered: (i) a dose of Eculizumab intravenously and 200 mg C5 iRNA subcutaneously; (ii) a dose of the Eculizumab up to about 14 days (±3, 4, 5, 6 or 7 days) later (about day 15); (iii) about 14 or 15 days (±3, 4, 5, 6 or 7 days) later (about day 29), the anti-C5 antibody or antigen-binding fragment at a dose of about 60 mg/kg body weight intravenously, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of the C5 iRNA subcutaneously; and (iv) starting about 28 days (±3, 4, 5, 6 or 7 days) later (about day 57) and about every about 28 days (±3, 4, 5, 6 or 7 days) thereafter, about 400 mg of the anti-C5 antibody or antigen-binding fragment subcutaneously and about 200 mg of the C5 iRNA subcutaneously.
The present invention provides a method for treating or preventing a C5-associated disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the subject has previously received Ravulizumab wherein the subject is administered: (i) about 28 days (±3, 4, 5, 6 or 7 days) after the last administration of Ravulizumab, about a 200 mg SC dose of C5 iRNA; (ii) about 28 days (±3, 4, 5, 6 or 7 days) later (about day 29), about a 60 mg/kg IV dose of anti-C5 antibody or antigen-binding fragment, about a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and about a 200 mg SC dose of C5 iRNA; (iii) starting about 28 days (±3, 4, 5, 6 or 7 days) later (about day 57) and about every about 28 days (±3, 4, 5, 6 or 7 days) thereafter, about a 400 mg SC dose of anti-C5 antibody or antigen-binding fragment and about a 200 mg SC dose of C5 iRNA.
The present invention provides a method for treating or preventing a C5-associated disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the subject has not previously received complement inhibitor treatment or not received complement inhibitor treatment recently, wherein the subject is administered (i) on about day 1, an intravenous dose of about 30 mg/kg anti-C5 antibody or antigen-binding fragment, about a 400 mg subcutaneous (SC) dose of the antibody or fragment, and about a 200 mg SC dose of the C5 iRNA; and (ii) starting about 28 days later (±3, 4, 5, 6 or 7 days) and about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, about 400 mg SC of the anti-C5 antibody or antigen-binding fragment and about 200 mg SC of the C5 iRNA.
The present invention provides a method for treating or preventing a C5-associated disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA, wherein the subject has previously received anti-C5 antibody or antigen-binding fragment monotherapy (i) starting about 7 to 8 (±3 days) days after the last dose of anti-C5 antibody or antigen-binding fragment monotherapy or when the next dose of the monotherapy is due and about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter, about a 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment and about a 200 mg SC dose of the C5 iRNA; or (ii) starting about 7 to 8 (±3 days) days after the last dose of anti-C5 antibody or antigen-binding fragment monotherapy or when the next dose of the monotherapy is due: about a 400 mg SC dose of the anti-C5 antibody or antigen-binding fragment and another the dose about every 2 weeks (±3, 4, 5, 6 or 7 days) thereafter; and about a 200 mg SC dose of the C5 iRNA and another the dose about every 4 weeks (±3, 4, 5, 6 or 7 days) thereafter.
The present invention further provides a method for treating or preventing a C5-associated disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an anti-C5 antibody or antigen-binding fragment thereof in combination with a C5 iRNA, wherein the subject has received one or more doses of a non-competing anti-C5 antibody or antigen-binding fragment (N/C Ab) (e.g., wherein the subject has detectable blood levels of N/C Ab when treatment is initiated): (1) a dose of C5 iRNA and the non-competing antibody or fragment on the day the dose of N/C Ab is due; (2) the next dose of non-competing anti-C5 antibody or antigen-binding fragment on the day such dose is due; (3) after about 1-2 half-lives of the N/C Ab, Pozelimab 60 mg/kg IV loading dose, Pozelimab 400 mg SC and Cemdisiran 200 mg SC; (4) starting 4 weeks thereafter, Pozelimab 400 mg SC Q4W and Cemdisiran 200 mg SC Q4W; or (1) following about 1-2 half-lives of the non-competing anti-C5 antibody or antigen-binding fragment from the last dose thereof, a dose of C5 iRNA; (2) following about another 1-2 half-lives of the N/C Ab, Pozelimab 60 mg/kg IV loading dose, Pozelimab 400 mg SC and Cemdisiran 200 mg SC; and (3) starting 4 weeks thereafter, Pozelimab 400 mg SC Q4W and Cemdisiran 200 mg SC Q4W. In an embodiment of the invention, the C5 iRNA is Cemdisiran; the anti-C5 antibody or antigen-binding fragment thereof is Pozelimab; the non-competing anti-C5 antibody or antigen-binding fragment is Eculizumab; the non-competing anti-C5 antibody or antigen-binding fragment is Ravulizumab; the half-life of the non-competing antibody is about 11 days; and/or the half-life of the non-competing antibody is about 32 days.
In an embodiment of the invention, during treatment, the subject achieves or achieves and maintains any one or more of: hemoglobin stabilization; does not receive a red blood cell transfusion; has no decrease in hemoglobin ≥2 g/dL; does not experience breakthrough hemolysis; CH50 levels in blood are fully suppressed relative to baseline (at 0 klU/L) before treatment and/or during any breakthrough hemolysis event; lack of treatment emergent adverse events; Improvement in fatigue, relative to before treatment; >5 point improvement in FACIT-Fatigue score relative to before treatment; improvement in physical functioning score on the European; organization for Research and Treatment of Cancer: Quality-of-Life Questionnaire; core 30 items (EORTC QLQ-C30)) relative to before treatment; improvement in GHS/QoL (global health status/QOL scale (GHS)), relative to before treatment; reduction in lactate dehydrogenase (LDH) levels relative to before treatment; achievement of LDH≤1.5× upper limit of normal (ULN) relative to before treatment achievement and maintenance of LDH≤1.0×ULN; a reduction in blood bilirubin levels relative to before treatment; a reduction in reticulocyte count relative to before treatment; a reduction in alternative pathway hemolytic activity assay (AH50) relative to before treatment; a reduction in PNH erythrocytes and/or granulocytes relative to before treatment; improvement in fatigue, shortness of breath, muscle weakness, headache, abdominal, pain, pain in back/legs, chest discomfort, difficulty sleeping, difficulty thinking clearly, and/or difficulty swallowing relative to before treatment; improvement in renal function as measured by estimated glomerular filtration rate (eGFR) relative to before treatment; reduction in blood free hemoglobin relative to before treatment; reduction in total C5 blood levels relative to before treatment; reduction in PNH clone size relative to before treatment; and/or increase in haptoglobin level relative to before treatment.
In an embodiment of the invention, the C5-associated disease or disorder is a disorder of inappropriate or undesirable complement activation; a hemodialysis complication; a lung disease or disorder; a neurological disorder; a parasitic disease; a post-ischemic reperfusion condition; a proteinuric kidney disease; a renal disorder; adult respiratory distress syndrome (ARDS); age-related macular degeneration (AMD); allergy; Alport's syndrome; Alzheimer's disease; an autoimmune disease; an immune complex disorder; an inflammatory disorder; an ocular disease; an organic dust disease; angiopathic thrombosis and protein-losing enteropathy; asthma; atherosclerosis; bronchoconstriction; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; CHAPLE disease (CD55 deficiency with hyperactivation of complement; chemical injury due to irritant gasses and/or chemicals; chronic obstructive pulmonary disease (COPD); complement activation due to burn; complement activation due to frostbite; complement activation due to obesity; complement activation due to sepsis; Crohn's disease; diabetes; diabetic macular edema (DME); diabetic nephropathy; diabetic retinopathy; dry AMD; dyspnea; emphysema; epilepsy; fibrogenic dust diseases; geographic atrophy (GA); glomerulopathy; Goodpasture's Syndrome; Guillain-Barre Syndrome; hemolytic anemia; hemoptysis; hereditary angioedema; hyperacute allograft rejection; hypersensitivity pneumonitis; immune complex-associated inflammation; infectious disease; inflammation of an autoimmune disease; inherited CD59 deficiency; injury due to inert dusts and/or minerals; interleukin-2 induced toxicity during IL-2 therapy; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; mesenteric artery reperfusion after aortic reconstruction; multiple sclerosis; myasthenia gravis; myocardial infarction; neuromyelitis optica; ocular angiogenesis; Parkinson's disease; pneumonia; progressive kidney failure; psoriasis; pulmonary embolisms and infarcts; pulmonary fibrosis; pulmonary vasculitis; renal ischemia; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; smoke injury; stroke; systemic inflammatory response in post-pump syndrome due to cardiopulmonary bypass or renal bypass; systemic lupus erythematosus (SLE); thermal injury; traumatic brain injury; uveitis; vasculitis; wet AMD; paroxysmal nocturnal hemoglobinuria (PNH); and/or xenograft rejection.
In an embodiment of the invention, the C5 iRNA and the anti-C5 antibody or antigen-binding fragment are co-formulated into a co-formulation and both the antibody or fragment and the C5 iRNA are administered by way of a single injection of the co-formulation.
In an embodiment of the invention, the co-formulation has a pH of about 6.5. In an embodiment of the invention, the C5 iRNA and the anti-C5 antibody or antigen-binding fragment are co-formulated into a co-formulation comprising 100 mg/ml Cemdisiran and 100 mg/ml Pozelimab; or 50 mg/ml Cemdisiran and 100 mg/ml Pozelimab.
In an embodiment of the invention, the co-formulation includes Cemdisiran; Pozelimab that was expressed and isolated from a mammalian host cell that includes beta-hexosaminidase; a buffer; a viscosity reducer; a stabilizer; a non-ionic surfactant and an optional viscosity reducer; at a pH of about 6.5.
In an embodiment of the invention, the subcutaneous injection is performed with a pre-filled syringe or an autoinjector.
In an embodiment of the invention, the subject suffers from aplastic anemia and/or myelodysplastic syndrome.
In an embodiment of the invention, the subject has previously received or which further comprises administering, before (optionally, which is any of 1, 2, 3, 4, 5, 6, 7, 8, 9 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 or 30 days before), after or during the administering of 400 mg subcutaneous Pozelimab and 200 mg subcutaneous Cemdisiran, to the subject: one or more doses of subcutaneous or intravenous Pozelimab; one or more 400 mg subcutaneous doses of Pozelimab; one or more doses of subcutaneous or intravenous anti-C5 antibody or antigen-binding fragment; one or more doses of subcutaneous or intravenous Eculizumab; one or more doses of subcutaneous or intravenous Ravulizumab; one or more doses of subcutaneous or intravenous Cemdisiran; one or more doses of subcutaneous or intravenous C5 iRNA; one or more subcutaneous doses of 800 mg Pozelimab; one or more subcutaneous doses of 800 mg anti-C5 antibody or antigen-binding fragment; one or more intravenous doses of 30 mg/kg body weight Pozelimab; one or more intravenous doses of 30 mg/kg body weight anti-C5 antibody or antigen-binding fragment; one or more intravenous doses of about 60 mg/kg body weight of Pozelimab; one or more intravenous doses of about 60 mg/kg body weight of anti-C5 antibody or antigen-binding fragment; one or more subcutaneous doses of about 800 mg of Pozelimab; one or more subcutaneous doses of about 800 mg of anti-C5 antibody or antigen-binding fragment; one intravenous dose of about 60 mg/kg body weight of Pozelimab and then one or more subcutaneous doses of about 800 mg of Pozelimab; one intravenous dose of about 60 mg/kg body weight of anti-C5 antibody or antigen-binding fragment and then one or more subcutaneous doses of about 800 mg of anti-C5 antibody or antigen-binding fragment; one or more doses of ≥300, ≥600, ≥900 or 1200 mg of Eculizumab intravenously; one or more doses of 200 mg of Cemdisiran subcutaneously; and/or one or more doses of 200 mg of C5 iRNA subcutaneously.
In an embodiment of the invention, intravenous administration of anti-C5 antibody or antigen-binding fragment is separated from subcutaneous administration of anti-C5 antibody or antigen-binding fragment or C5 iRNA by about 30 minutes; subcutaneous administration of anti-C5 antibody or antigen-binding fragment and C5 iRNA is followed by an observation period of about 30 minutes, 1 hour or 2 hours; and/or subcutaneous administration of C5 iRNA is followed by an observation period of about 30 minutes, 1 hour or 2 hours.
In an embodiment of the invention, if the subject exhibits one or more of the criteria: breakthrough hemolysis that is not due to a complement activating condition; and/or LDH increase ≥2×ULN due to a complement activating condition, then the subject receives an intensified treatment further comprising one or more 30 mg/kg IV doses of anti-C5 antibody or antigen-binding fragment.
In an embodiment of the invention the subject exhibits one or more of the criteria: breakthrough hemolysis that is not due to a complement activating condition; and/or LDH increase ≥2×ULN due to a complement activating condition, then the subject receives an intensified treatment wherein: (1) if the subject had received a treatment regimen comprising about 400 mg of the anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 4 weeks (±3, 4, 5, 6 or 7 days), and about 200 mg of the C5 iRNA administered subcutaneously about every 4 weeks (±3, 4, 5, 6 or 7 days); then administering a single 30 mg/kg IV dose of anti-C5 antibody or antigen-binding fragment on the day of intensification and an intensified regimen of about 400 mg of the anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 2 weeks (±3, 4, 5, 6 or 7 days), and about 200 mg of the C5 iRNA administered subcutaneously about every 4 weeks (±3, 4, 5, 6 or 7 days) is administered starting on the day of intensification; or (2) if the subject had received a treatment regimen comprising about 400 mg of the anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 2 weeks (±3, 4, 5, 6 or 7 days), and about 200 mg of the C5 iRNA administered subcutaneously about every 4 weeks (±3, 4, 5, 6 or 7 days); then administering a single 30 mg/kg IV dose of anti-C5 antibody or antigen-binding fragment on the day of intensification and re-initiation of the treatment regimen comprising about 400 mg of the anti-C5 antibody or antigen-binding fragment administered subcutaneously about every 2 weeks (±3, 4, 5, 6 or 7 days), and about 200 mg of the C5 iRNA administered subcutaneously about every 4 weeks (±3, 4, 5, 6 or 7 days) starting on the day of intensification.
In an embodiment of the invention, the anti-C5 antibody or antigen-binding fragment or Pozelimab is expressed in a mammalian host cell (e.g., Chinese hamster ovary cell) and the iRNA or Cemdisiran is chemically synthesized.
In an embodiment of the invention, the anti-C5 antibody or antigen-binding fragment and C5 iRNA are co-formulated into a co-formulation that comprises no more than about 2.1 parts per million (ppm) molar ratio of beta-hexosaminidase to antibody or antigen-binding fragment; include no more than about 0.170 micrograms/ml beta-hexosaminidase, include no more than about 0.04 micrograms/ml beta-hexosaminidase; and/or about 0.04; 0.05; 0.06; 0.0605; 0.063; 0.07; 0.0765; 0.078; 0.08; 0.14; 0.141; 0.15; 0.1525; 0.166; or 0.17 micrograms/ml beta-hexosaminidase; or no more than any of such concentrations.
In an embodiment of the invention, the anti-C5 antibody or antigen-binding fragment thereof is (1) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 2, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 10; (2) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 18, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 26; (3) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 34, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 42; (4) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 50, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 58; (5) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 66, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 74; (6) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 82, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 90; (7) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; (8) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114; (9) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; (10) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 98, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; (11) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; (12) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 106; (13) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 122, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; (14) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 114; (15) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 146, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; (16) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 138, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 130; (17) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 154, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 162; (18) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 170, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 178; (19) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 186, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 194; (20) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 202, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 210; (21) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 218, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 226; (22) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 234, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 242; (23) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 250, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258; (24) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 266, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 258; (25) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 274, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 282; (26) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 290, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 298; (27) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 306, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 314; (28) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 322, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 330; and/or (29) a heavy chain variable region (HCVR) that comprises the HCDR1, HCDR2 and HCDR3 of a HCVR that comprises the amino acid sequence set forth in SEQ ID NO: 338, and a light chain variable region (LCVR) that comprises the LCDR1, LCDR2 and LCDR3 of a LCVR that comprises the amino acid sequence set forth in SEQ ID NO: 346.
In an embodiment of the invention, the C5 iRNA comprises an RNA strand that is complementary to an mRNA transcribed from the C5 gene sense strand DNA sequence AAGCAAGATATTTTTATAATA (nucleotides 782-802 of SEQ ID NO: 360). In an embodiment of the invention, the C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the antisense strand comprises a region of complementarity comprising at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5′-UAUUAUAAAAAUAUCUUGCUUUU-3′ (SEQ ID NO: 364), and wherein the dsRNA agent comprises at least one modified nucleotide. In an embodiment of the invention the C5 iRNA is a double-stranded ribonucleic acid (dsRNA) agent comprising a sense strand and an antisense strand, wherein the sense strand comprises 5′-asasGfcAfaGfaUfAfUfuUfuuAfuAfaua-3′ (SEQ ID NO: 406) and the antisense strand comprises 5′-usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT-3′ (SEQ ID NO: 369), wherein a, g, c and u are 2′-O-methyl (2′-OMe) A, G, C, and U, respectively; Af, Gf, Cf and Uf are 2′-fluoro A, G, C and U, respectively; dT is a deoxy-thymine nucleotide; s is a phosphorothioate linkage; and wherein the sense strand is conjugated at the 3′-terminus to the ligand
In an embodiment of the invention, the C5 iRNA and the antibody or antigen-binding fragment thereof that binds specifically to C5 are in a co-formulation that is specifically set forth herein.
In an embodiment of the invention, wherein the C5 iRNA and the anti-C5 antibody or antigen-binding fragment thereof are in a single co-formulation which, when administered subcutaneously, is administered in 1 or 2 or more (e.g., 2) injections of said co-formulation.
Preferably, the C5 iRNA is Cemdisiran; and/or the anti-C5 antibody or antigen-binding fragment thereof is Pozelimab.
SUMMARY: Complement inhibitor naïve: On day 1: Pozelimab in a single loading dose of 30 mg/kg intravenous (IV) and 400 mg subcutaneous (SC), and Cemdisiran 200 mg SC (the combination maintenance dose); Starting on day 29: Pozelimab 400 mg SC every 4 weeks (q4W) and Cemdisiran 200 mg SC q4W (e.g., in a Cemdisiran/Pozelimab co-formulation). Switch from Pozelimab monotherapy to Pozelimab+Cemdisiran combination therapy: the last dose of Pozelimab monotherapy) or, when the next dose of Pozelimab monotherapy is due, subjects start receiving Pozelimab 400 mg SC every 4 weeks (q4W) and Cemdisiran 200 mg SC q4W; Switch from Eculizumab therapy to Pozelimab+Cemdisiran combination therapy: On day 1 (the day of subject's scheduled Eculizumab administration): Cemdisiran 200 mg SC and Eculizumab >900 mg IV (subject's usual dose); On day 15, for subjects on Eculizumab q14 days (labeled dose regimen): Labeled Eculizumab dose [for subjects on Eculizumab more frequently than q14 days: patients are dosed within 2 days of their usual planned dose; On day 29 (or when the next Eculizumab is due (if on Eculizumab doses more frequent than q14w) or 2 weeks later): Pozelimab 60 mg/kg IV loading dose, and Pozelimab 400 mg SC and Cemdisiran 200 mg SC; and Starting on day 57 (or 4 weeks later): Pozelimab 400 mg SC and Cemdisiran 200 mg SC q4W; Switch from Ravulizumab therapy to Pozelimab+Cemdisiran combination therapy: On day 1 (4 weeks after the last administration of Ravulizumab): Cemdisiran 200 mg SC; On day 29 or 4 weeks later: Pozelimab 60 mg/kg single IV loading dose, and Pozelimab 400 mg SC and Cemdisiran 200 mg SC; and Starting on Day 57 or 4 weeks later: Start Pozelimab 400 mg SC q4W and Cemdisiran 200 mg SC q4W.
While combining two C5-inhibitor therapies with complementary mechanisms of action (Pozelimab and Cemdisiran) offers the advantages of fully suppressing the C5 pathway at a (relatively) low level of C5 expression, various technical issue must be overcome in order to reach a suitable dosing regimen and delivery vehicle for the agents.
The superior C5 suppression offered by the compositions and methods of the present disclosure results in the need for less Pozelimab, which, in turn, leads to a reduced SC volume of antibody injection, a reduced dosing frequency, a window of drug administration that is wider for the combination than the Pozelimab monotherapy, and the potential for reduced injection site reactions. In patients requiring chronic and long-term administration, the combination offers the potential for improved compliance and quality of life compared to Pozelimab monotherapy, while still providing for maximal inhibition of C5 activity in a greater percentage of patients than Eculizumab therapy. Moreover, as discussed herein, the dosing regimens of the present disclosure avoid the danger of adverse events caused by the formation of large drug-target-drug complexes (e.g., Eculizumab-C5-Pozelimab). The co-formulation of both agents also offers the convenience of only a single subcutaneous injection in order to administer both agents together.
The present disclosure provides a stable co-formulation that comprises an antibody or antigen-binding fragment thereof, e.g., Pozelimab and a C5 iRNA, e.g., Cemdisiran. Co-formulating an antibody expressed from a mammalian host cell and an iRNA molecule conjugated to ligand having a terminal N-acetylgalactosamine (GalNAc) and/or N-acetylglucosamine (GlcNAc) presents technical challenges. Small amounts of an enzyme from such host cells which frequently contaminates antibodies preparations, beta hexosaminidase, has been shown to catalyze the removal of terminal GalNAc residues from such iRNA ligands. The present disclosure provides stable co-formulations that include such antibodies and iRNA molecules which overcome this issue, for example, by adjustment of pH from 6 (e.g., 6.5), the addition of GalNAc and/or GlcNAc; and/or the addition of arginine (e.g., L-arginine such as L-arginine HCl).
The administration of anti-C5 antibody and C5 iRNA in the methods of the present disclosure have been designed to rapidly and continuously suppress concentrations of C5 to pharmacologically inactive levels. Typically, anti-C5 monotherapies call for relative high doses in patients with PNH. The requirement for such high anti-C5 mAb doses is driven by 2 factors. First, C5 levels are high and there is a need for 100% inhibition which can only be achieved with complete target engagement (Peffault de Latour R et al., Assessing complement blockade in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab. Blood 2015; 125(5):775-83); second, in order to achieve 100% inhibition on a population basis, inter- and intra-patient variability of C5 concentrations and instances of enhanced complement activation (which may occur with intercurrent illness) could be employed. Combinations of Pozelimab and Cemdisiran achieve high complement inhibition with a relatively lower dose of the antibody. Combining Pozelimab and Cemdisiran also offers the advantages achieving the low complement levels while administering less Pozelimab (relative to Pozelimab monotherapy), thereby leading to a reduced SC volume of injection, reduced dosing frequency, a window of drug administration that is wider than that of Pozelimab monotherapy, and the potential for reduced injection site reactions.
The present disclosure includes dosing regimens for switching from a prior anti-C5 antibody therapy (e.g., Eculizumab or Ravulizumab) to a C5 iRNA+anti-C5 antibody or antigen-binding fragment thereof therapy of the present disclosure (e.g., Pozelimab+Cemdisiran). Pozelimab has been shown to bind C5 non-competitively with antibodies having the amino acid sequence of Eculizumab (Eculizumab*), and thus has the potential to form heteromeric complexes including large DTD immune complexes, for example, in patients switching from Eculizumab to Pozelimab therapy. Large DTD immune complexes are known to cause adverse events such as serum sickness-like reactions, skin rash. The dosing regimens of the present disclosure have been designed to reduce the danger of the formation of the large DTD complexes and the occurrence of such adverse events.
The term “antibody”, as used herein, refers to immunoglobulin molecules comprising four polypeptide chains, two heavy chains (HCs) and two light chains (LCs), inter-connected by disulfide bonds (e.g., IgG)—for example H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; crovalimab; Eculizumab, tesidolumab, mubodina or Ravulizumab; preferably, Pozelimab. In an embodiment of the disclosure, each antibody heavy chain (HC) comprises a heavy chain variable region (“HCVR” or “VH”) (e.g., SEQ ID NO: 2; 18; 34; 50; 66; 82; 98; 98; 122; 98; 138; 146; 122; 146; 146; 138; 154; 170; 186; 202; 218; 234; 250; 266; 274; 290; 306; 322; or 338; or a variant thereof) and a heavy chain constant region; and each antibody light chain (LC) comprises a light chain variable region (“LCVR or “VL”) (e.g., SEQ ID NO: 10; 26; 42; 58; 74; 90; 106; 114; 106; 130; 106; 106; 130; 114; 130; 130; 162; 178; 194; 210; 226; 242; 258; 258; 282; 298; 314; 330; or 346; or a variant thereof) and a light chain constant region (CL). The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL comprises three CDRs and four FRs. Preferably an antibody or antigen-binding fragment thereof in a co-formulation of the present disclosure was expressed and isolated from a mammalian host cell such as a Chinese hamster ovary (CHO) cell.
Antibodies as set forth herein include, for example, monoclonal, recombinant, chimeric, human and/or humanized antibodies.
In an embodiment of the disclosure, the assignment of amino acids to each framework or CDR domain is in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883. Thus, the present disclosure includes antibodies and antigen-binding fragments including the CDRs of a VH and the CDRs of a VL, which VH and VL comprise amino acid sequences as set forth herein (or a variant thereof), wherein the CDRs are as defined according to Kabat and/or Chothia.
In an embodiment of the disclosure, an anti-C5 antigen-binding protein, e.g., antibody or antigen-binding fragment, comprises a heavy chain constant domain, e.g., of the type IgA (e.g., IgA1 or IgA2), IgD, IgE, IgG (e.g., IgG1, IgG2, IgG3 and IgG4 (e.g., comprising a S228P and/or S108P mutation)) or IgM. In an embodiment of the disclosure, an antigen-binding protein, e.g., antibody or antigen-binding fragment, comprises a light chain constant domain, e.g., of the type kappa or lambda. The present disclosure includes antigen-binding proteins comprising the variable domains set forth herein (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; crovalimab; Eculizumab, tesidolumab, mubodina or Ravulizumab; preferably, Pozelimab) which are linked to a heavy and/or light chain constant domain, e.g., as set forth above.
“Isolated” antigen-binding proteins (e.g., antibodies or antigen-binding fragments thereof), polypeptides, polynucleotides and vectors, are at least partially free of other biological molecules from the cells or cell culture from which they are produced. Such biological molecules include nucleic acids, proteins, other antibodies or antigen-binding fragments, lipids, carbohydrates, or other material such as cellular debris and growth medium. An isolated antigen-binding protein may further be at least partially free of expression system components such as biological molecules from a host cell or of the growth medium thereof. Generally, the term “isolated” is not intended to refer to a complete absence of such biological molecules (e.g., minor or insignificant amounts of impurity may remain) or to an absence of water, buffers, or salts or to components of a pharmaceutical formulation that includes the antigen-binding proteins (e.g., antibodies or antigen-binding fragments).
In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to complement factor 5 (C5) protein, interacts with one or more amino acids contained within NMATGMDSW (SEQ ID NO: 353) (or at least 1, 2, 3, 4 or 5 amino acids therein); or WEVHLVPRRKQLQFALPDSL (SEQ ID NO: 354) (or at least 1, 2, 3, 4 or 5 amino acids therein), as determined by hydrogen/deuterium exchange. In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to complement factor 5 (C5) protein interacts with one or more amino acids contained within the alpha chain and/or the beta chain of C5, as determined by hydrogen/deuterium exchange. For example, in an embodiment of the disclosure, the antibody or antigen-binding fragment does not interact with an amino acid of the C5a anaphylatoxin region of C5, as determined by hydrogen/deuterium exchange. In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to complement factor 5 (C5) protein interacts with an amino acid sequence selected from the group consisting of
The sequence of anti-C5 antibodies and antigen-binding fragments thereof (e.g., LCVRs and HCVRs or LCDRs and HCDRs thereof) that may be included in a co-formulation or used in a method are set forth below.
Polynucleotides encoding the chains set forth in Table A are set forth below in Table B.
In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to C5, which is in a co-formulation of the present disclosure comprises:
(1)
In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to C5, which is in a co-formulation of the present disclosure comprises:
(a)
In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to C5, which is in a co-formulation of the present disclosure comprises:
(i)
In an embodiment of the disclosure, an antibody or antigen-binding fragment thereof that binds specifically to C5, which is in a co-formulation of the present disclosure comprises a heavy chain comprising the amino acid sequence:
QVQLQESGPGLVKPSETLSLTCTVS
GDSVSSSY
WTWIRQP
PGKGLEWIGY
IYYSGSS
NYNPSLKSRATISVDTSKNQFSL
KLSSVTAADTAVYYC
AREGNVDTTMIFDY
WGQGTLVTVSS
AIQMTQSPSSLSASVGDRVTITCRAS
QGIRND
LGWYQQKP
GKAPKLLIY
AAS
SLQSGVPSRFAGRGSGTDFTLTISSLQP
EDFATYYC
LQDENYPWT
FGQGTKVEIKRTVAAPSVFIFPP
such an antibody may be referred to herein as Pozelimab or REGN3918 (variable regions and CDRs underscored).
“H2M11683N”; “H2M11686N”; “H4H12159P”; “H4H12161P”; “H4H12163P”; “H4H12164P”; “H4H12166P”; “H4H12166P2”; “H4H12166P3”; “H4H12166P4”; “H4H12166P5”; “H4H12166P6”; “H4H12166P7”; “H4H12166P8”; “H4H12166P9”; “H4H12166P10”; “H4H12167P”; “H4H12168P”; “H4H12169P”; “H4H12170P”; “H4H12171P”; “H4H12175P”; “H4H12176P2”; “H4H12177P2”; “H4H12183P2”; “H2M 11682N”; “H2M11684N”; “H2M 11694N” or “H2M 11695N”, unless otherwise stated, refer to anti-C5 antigen-binding proteins, e.g., antibodies and antigen-binding fragments thereof (including multispecific antigen-binding proteins), that bind specifically to C5, comprising an immunoglobulin heavy chain or variable region thereof (VH) comprising the amino acid sequence specifically set forth herein corresponding, in Table A herein or Table 1 of WO2017/218515 (and the sequences set forth therein), to H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N or H2M11695N (e.g., SEQ ID NO: 2; 18; 34; 50; 66; 82; 98; 98; 122; 98; 138; 146; 122; 146; 146; 138; 154; 170; 186; 202; 218; 234; 250; 266; 274; 290; 306; 322 or 338) (or a variant thereof), and/or an immunoglobulin light chain or variable region thereof (VL) comprising the amino acid sequence specifically set forth herein corresponding, in Table A herein or Table 1 of WO2017/218515 (and the sequences set forth therein), to H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N or H2M11695N (e.g., SEQ ID NO: 10; 26; 42; 58; 74; 90; 106; 114; 106; 130; 106; 106; 130; 114; 130; 130; 162; 178; 194; 210; 226; 242; 258; 258; 282; 298; 314; 330 or 346) (or a variant thereof); and/or that comprise a heavy chain or VH that comprises the CDRs thereof (CDR-H1 (or a variant thereof), CDR-H2 (or a variant thereof) and CDR-H3 (or a variant thereof)) and/or a light chain or VL that comprises the CDRs thereof (CDR-L1 (or a variant thereof), CDR-L2 (or a variant thereof) and CDR-L3 (or a variant thereof)). In an embodiment of the disclosure, the VH is linked to an IgG constant heavy chain domain (e.g., IgG1 or IgG4 (e.g., IgG4 (S228P mutant))) and/or the VL is linked to a lambda or kappa constant light chain domain.
An “anti-C5” antibody or antigen-binding fragment or antibody or antigen-binding fragment that “binds specifically” to C5 binds to human C5 with a KD of at least 1 nM (i.e., 1 nM or a higher affinity), e.g., about 0.1 or 0.2 nM.
In an embodiment of the invention, an anti-C5 antibody or antigen-binding fragment is missing the C-terminal Lysine from the heavy chain.
The present disclosure provides a co-formulation that includes an anti-C5 antibody or antigen-binding fragment thereof (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; crovalimab; Eculizumab, tesidolumab, mubodina or Ravulizumab; preferably, Pozelimab); and an iRNA which effects the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a C5 gene (C5 iRNA), e.g. Cemdisiran (e.g., Cemdisiran/Pozelimab). The C5 gene may be within a cell, e.g., a cell within a subject, such as a human. The present disclosure provides iRNA agents for inclusion in a co-formulation of the disclosure which effect the RNA-induced silencing complex (RISC)-mediated cleavage of RNA transcripts of a complement component C5 gene.
Cemdisiran is a chemically synthesized double-stranded oligonucleotide glycoconjugate that is covalently linked to a ligand containing 3 GalNAc residues to facilitate targeted delivery to the liver. See e.g.,
The sense strand (A-125167) contains 21 nucleotides and the antisense strand (A-125647) contains 25. The 3′-end of the sense strand is conjugated to a triantennary GalNAc moiety (referred to as L96) through a phosphodiester linkage.
The antisense strand (A-125647) contains four phosphorothioate linkages, two consecutive phosphorothioate linkages at the 3′ end and two at the 5′ end. The sense strand (A-125167) contains two phosphorothioate linkages at the 5′ end. The 21 nucleotides of the sense strand hybridize with the complementary 21 nucleotides of the antisense strand, thus forming 21 nucleotide base pairs duplex with a 4-base overhang at the 3′-end of the antisense strand. The bases involved in base pair formation are connected with a center dot. Cemdisiran is preferably in a salt form, e.g., the Na+ salt form, but the present disclosure includes embodiments including Cemdisiran in the free acid form as well as in other salt forms, e.g., Ca2+ salts.
When expressing, herein, the concentration of RNAi in a composition, such as a co-formulation of the present disclosure, in terms of mass per volume (e.g., mg/ml), the RNAi is in a salt form or a free acid form. Preferably, when referring to Cemdisiran as such, the Cemdisiran is in salt form, preferably Na+ salt form. Na+ counter-ions are present due to the net-negatively charged ribonucleotide phosphate backbone. The quantity of Cemdisiran free acid form can be obtained by multiplying the Cemdisiran Na+ salt form concentration by 0.9443.
The structure of Cemdisiran Sodium (ALN-62643) is shown below wherein A-125167 is on top (5′-3′) and A-125647 is on bottom (3′-5′):
The C5 iRNAs that can be included in co-formulations of the disclosure include an RNA strand (e.g., the antisense strand) having a region which is about 30 nucleotides or less in length, e.g., at least 15, 15-30, 15-29, 15-28, 15-27, 15-26, 15-25, 15-24, 15-23, 15-22, 15-21, 15-20, 15-19, 15-18, 15-17, 18-30, 18-29, 18-28, 18-27, 18-26, 18-25, 18-24, 18-23, 18-22, 18-21, 18-20, 19-30, 19-29, 19-28, 19-27, 19-26, 19-25, 19-24, 19-23, 19-22, 19-21, 19-20, 20-30, 20-29, 20-28, 20-27, 20-26, 20-25, 20-24, 20-23, 20-22, 20-21, 21-30, 21-29, 21-28, 21-27, 21-26, 21-25, 21-24, 21-23, or 21-22 nucleotides in length, which region is substantially complementary to at least part of an mRNA transcript of a C5 gene.
In an embodiment of the disclosure, a C5 iRNA is a glycoconjugate that includes a double stranded RNA complementary to a region of C5 which is conjugated (e.g., by a linker) to a terminal mono-, or bi-, tri-antennary N-acetylgalactosamine (GalNAc) group, preferably triantennary N-acetylgalactosamine.
In an embodiment of the disclosure, an iRNA agent which may be included in a co-formulation of the present disclosure, includes a single stranded RNA that interacts with a target RNA sequence, e.g., a C5 target mRNA sequence, to direct the cleavage of the target RNA. Without wishing to be bound by theory, it is believed that long double stranded RNA introduced into cells is broken down into siRNA by a Type III endonuclease known as Dicer (Sharp et al. (2001) Genes Dev. 15:485). Dicer, a ribonuclease-III-like enzyme, processes the dsRNA into 19-23 base pair short interfering RNAs with characteristic two base 3′ overhangs (Bernstein, et al., (2001) Nature 409:363). The siRNAs are then incorporated into an RNA-induced silencing complex (RISC) where one or more helicases unwind the siRNA duplex, enabling the complementary antisense strand to guide target recognition (Nykanen, et al., (2001) Cell 107:309). Upon binding to the appropriate target mRNA, one or more endonucleases within the RISC cleave the target to induce silencing (Elbashir, et al., (2001) Genes Dev. 15:188). Thus, in one aspect the disclosure relates to a single stranded RNA (siRNA) generated within a cell and which promotes the formation of a RISC complex to effect silencing of the target gene, i.e., a C5 gene. Accordingly, the term “siRNA” is also used herein to refer to an iRNA as described above.
In another embodiment, the iRNA agent which may be included in a co-formulation of the present disclosure may be a single-stranded siRNA that is introduced into a cell or organism to inhibit a target mRNA. Single-stranded iRNA agents bind to the RISC endonuclease, Argonaute 2, which then cleaves the target mRNA. The single-stranded siRNAs are generally 15-30 nucleotides and are chemically modified. The design and testing of single-stranded siRNAs are described in U.S. Pat. No. 8,101,348 and in Lima et al., (2012) Cell 150: 883-894, the entire contents of each of which are hereby incorporated herein by reference. Any of the antisense nucleotide sequences described herein may be used as a single-stranded siRNA as described herein or as chemically modified by the methods described in Lima et al., (2012) Cell 150:883-894.
In another embodiment, an iRNA for use in the compositions, uses, and methods of the disclosure is a double-stranded RNA and is referred to herein as a “double stranded iRNA agent,” “double-stranded RNA (dsRNA) molecule,” “dsRNA agent,” or “dsRNA”. The term “dsRNA”, refers to a complex of ribonucleic acid molecules, having a duplex structure comprising two anti-parallel and substantially complementary nucleic acid strands, referred to as having “sense” and “antisense” orientations with respect to a target RNA, i.e., a C5 gene. In some embodiments of the disclosure, a double-stranded RNA (dsRNA) triggers the degradation of a target RNA, e.g., an mRNA, through a post-transcriptional gene-silencing mechanism referred to herein as RNA interference or iRNA.
In an embodiment of the disclosure, the iRNA is a double-stranded ribonucleic acid (dsRNA) wherein the dsRNA comprises a sense strand and an antisense strand, wherein the sense strand comprises nucleotides (e.g., at least 15 contiguous nucleotides) differing by no more than 3 nucleotides from the nucleotide sequence of C5 (open reading frame underscored):
tatatccgtg gtttcctgct acctccaacc atgggccttt tgggaatact ttgtttttta
atcttcctgg ggaaaacctg gggacaggag caaacatatg tcatttcagc accaaaaata
ttccgtgttg gagcatctga aaatattgtg attcaagttt atggatacac tgaagcattt
gatgcaacaa tctctattaa aagttatcct gataaaaaat ttagttactc ctcaggccat
gttcatttat cctcagagaa taaattccaa aactctgcaa tcttaacaat acaaccaaaa
caattgcctg gaggacaaaa cccagtttct tatgtgtatt tggaagttgt atcaaagcat
ttttcaaaat caaaaagaat gccaataacc tatgacaatg gatttctctt cattcataca
gacaaacctg tttatactcc agaccagtca gtaaaagtta gagtttattc gttgaatgac
gacttgaagc cagccaaaag agaaactgtc ttaactttca tagatcctga aggatcagaa
gttgacatgg tagaagaaat tgatcatatt ggaattatct cttttcctga cttcaagatt
ccgtctaatc ctagatatgg tatgtggacg atcaaggcta aatataaaga ggacttttca
acaactggaa ccgcatattt tgaagttaaa gaatatgtct tgccacattt ttctgtctca
atcgagccag aatataattt cattggttac aagaacttta agaattttga aattactata
aaagcaagat atttttataa taaagtagtc actgaggctg acgtttatat cacatttgga
ataagagaag acttaaaaga tgatcaaaaa gaaatgatgc aaacagcaat gcaaaacaca
atgttgataa atggaattgc tcaagtcaca tttgattctg aaacagcagt caaagaactg
tcatactaca gtttagaaga tttaaacaac aagtaccttt atattgctgt aacagtcata
gagtctacag gtggattttc tgaagaggca gaaatacctg gcatcaaata tgtcctctct
ccctacaaac tgaatttggt tgctactcct cttttcctga agcctgggat tccatatccc
atcaaggtgc aggttaaaga ttcgcttgac cagttggtag gaggagtccc agtaacactg
aatgcacaaa caattgatgt aaaccaagag acatctgact tggatccaag caaaagtgta
acacgtgttg atgatggagt agcttccttt gtgcttaatc tcccatctgg agtgacggtg
ctggagttta atgtcaaaac tgatgctcca gatcttccag aagaaaatca ggccagggaa
ggttaccgag caatagcata ctcatctctc agccaaagtt acctttatat tgattggact
gataaccata aggctttgct agtgggagaa catctgaata ttattgttac ccccaaaagc
ccatatattg acaaaataac tcactataat tacttgattt tatccaaggg caaaattatc
cactttggca cgagggagaa attttcagat gcatcttatc aaagtataaa cattccagta
acacagaaca tggttccttc atcccgactt ctggtctatt acatcgtcac aggagaacag
acagcagaat tagtgtctga ttcagtctgg ttaaatattg aagaaaaatg tggcaaccag
ctccaggttc atctgtctcc tgatgcagat gcatattctc caggccaaac tgtgtctctt
aatatggcaa ctggaatgga ttcctgggtg gcattagcag cagtggacag tgctgtgtat
ggagtccaaa gaggagccaa aaagcccttg gaaagagtat ttcaattctt agagaagagt
gatctgggct gtggggcagg tggtggcctc aacaatgcca atgtgttcca cctagctgga
cttaccttcc tcactaatgc aaatgcagat gactcccaag aaaatgatga accttgtaaa
gaaattctca ggccaagaag aacgctgcaa aagaagatag aagaaatagc tgctaaatat
tgtgagcagc gagctgcacg gattagttta gggccaagat gcatcaaagc tttcactgaa
tgttgtgtcg tcgcaagcca gctccgtgct aatatctctc ataaagacat gcaattggga
aggctacaca tgaagaccct gttaccagta agcaagccag aaattcggag ttattttcca
gaaagctggt tgtgggaagt tcatcttgtt cccagaagaa aacagttgca gtttgcccta
cctgattctc taaccacctg ggaaattcaa ggcgttggca tttcaaacac tggtatatgt
gttgctgata ctgtcaaggc aaaggtgttc aaagatgtct tcctggaaat gaatatacca
tattctgttg tacgaggaga acagatccaa ttgaaaggaa ctgtttacaa ctataggact
tctgggatgc agttctgtgt taaaatgtct gctgtggagg gaatctgcac ttcggaaagc
ccagtcattg atcatcaggg cacaaagtcc tccaaatgtg tgcgccagaa agtagagggc
tcctccagtc acttggtgac attcactgtg cttcctctgg aaattggcct tcacaacatc
aatttttcac tggagacttg gtttggaaaa gaaatcttag taaaaacatt acgagtggtg
ccagaaggtg tcaaaaggga aagctattct ggtgttactt tggatcctag gggtatttat
ggtaccatta gcagacgaaa ggagttccca tacaggatac ccttagattt ggtccccaaa
acagaaatca aaaggatttt gagtgtaaaa ggactgcttg taggtgagat cttgtctgca
gttctaagtc aggaaggcat caatatccta acccacctcc ccaaagggag tgcagaggcg
gagctgatga gcgttgtccc agtattctat gtttttcact acctggaaac aggaaatcat
tggaacattt ttcattctga cccattaatt gaaaagcaga aactgaagaa aaaattaaaa
gaagggatgt tgagcattat gtcctacaga aatgctgact actcttacag tgtgtggaag
ggtggaagtg ctagcacttg gttaacagct tttgctttaa gagtacttgg acaagtaaat
aaatacgtag agcagaacca aaattcaatt tgtaattctt tattgtggct agttgagaat
tatcaattag ataatggatc tttcaaggaa aattcacagt atcaaccaat aaaattacag
ggtaccttgc ctgttgaagc ccgagagaac agcttatatc ttacagcctt tactgtgatt
ggaattagaa aggctttcga tatatgcccc ctggtgaaaa tcgacacagc tctaattaaa
gctgacaact ttctgcttga aaatacactg ccagcccaga gcacctttac attggccatt
tctgcgtatg ctctttccct gggagataaa actcacccac agtttcgttc aattgtttca
gctttgaaga gagaagcttt ggttaaaggt aatccaccca tttatcgttt ttggaaagac
aatcttcagc ataaagacag ctctgtacct aacactggta cggcacgtat ggtagaaaca
actgcctatg ctttactcac cagtctgaac ttgaaagata taaattatgt taacccagtc
atcaaatggc tatcagaaga gcagaggtat ggaggtggct tttattcaac ccaggacaca
atcaatgcca ttgagggcct gacggaatat tcactcctgg ttaaacaact ccgcttgagt
atggacatcg atgtttctta caagcataaa ggtgccttac ataattataa aatgacagac
aagaatttcc ttgggaggcc agtagaggtg cttctcaatg atgacctcat tgtcagtaca
ggatttggca gtggcttggc tacagtacat gtaacaactg tagttcacaa aaccagtacc
tctgaggaag tttgcagctt ttatttgaaa atcgatactc aggatattga agcatcccac
tacagaggct acggaaactc tgattacaaa cgcatagtag catgtgccag ctacaagccc
agcagggaag aatcatcatc tggatcctct catgcggtga tggacatctc cttgcctact
ggaatcagtg caaatgaaga agacttaaaa gcccttgtgg aaggggtgga tcaactattc
actgattacc aaatcaaaga tggacatgtt attctgcaac tgaattcgat tccctccagt
gatttccttt gtgtacgatt ccggatattt gaactctttg aagttgggtt tctcagtcct
gccactttca cagtgtacga ataccacaga ccagataaac agtgtaccat gttttatagc
acttccaata tcaaaattca gaaagtctgt gaaggagccg cgtgcaagtg tgtagaagct
gattgtgggc aaatgcagga agaattggat ctgacaatct ctgcagagac aagaaaacaa
acagcatgta aaccagagat tgcatatgct tataaagtta gcatcacatc catcactgta
gaaaatgttt ttgtcaagta caaggcaacc cttctggata tctacaaaac tggggaagct
gttgctgaga aagactctga gattaccttc attaaaaagg taacctgtac taacgctgag
ctggtaaaag gaagacagta cttaattatg ggtaaagaag ccctccagat aaaatacaat
ttcagtttca ggtacatcta ccctttagat tccttgacct ggattgaata ctggcctaga
gacacaacat gttcatcgtg tcaagcattt ttagctaatt tagatgaatt tgccgaagat
atctttttaa atggatgcta aaattcctga agttcagctg catacagttt gcacttatgg
actcctgttg ttgaagttcg tttttttgtt ttcttctttt tttaaacatt catagctggt
cttatttgta aagctcactt tacttagaat tagtggcact tgcttttatt agagaatgat
(SEQ ID NO: 360) and the antisense strand comprises nucleotides (e.g., at least 15 contiguous nucleotides) differing by no more than 3 nucleotides from the nucleotide sequence of:
In an embodiment of the disclosure the C5 iRNA (e.g., dsRNA) is characterized b the structure:
A-U-U-U-U-U-A-U-A-A-U-A-R1
See International Nonproprietary Names for Pharmaceutical Substances (INN) (Proposed INN: List 114), WHO Drug Information, Vol. 29, No. 4, 2015.
The present disclosure includes an iRNA which can be included in a co-formulation of the present disclosure that is a double-stranded ribonucleic acid (dsRNA) agent (e.g., having a complementarity region of 19-23 nucleotides in length and/or having a strand length of no more than 30 nucleotides) for inhibiting expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, the antisense strand comprising a region of complementarity which comprises at least 17 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of 5′-UAUUAUAAAAAUAUCUUGCUUUU-3′ (SEQ ID NO: 364), wherein one or more of the dsRNA nucleotides are modified. The dsRNA agent may include at least one modified nucleotide e.g., with 2′-deoxy, 2′-methoxy, and/or 2′-fluoro groups, for example, where substantially all of the nucleotides of the sense strand and antisense strand are modified nucleotides. Moreover, the sense strand can be conjugated to a ligand attached at the 3′-terminus, e.g., terminally modified with a triantennary GalNAc moiety.
The modified nucleotides that may be included in a dsRNA include a 3′-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, an abasic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a nucleotide comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group. The dsRNA may include a phosphorothioate and/or methylphosphonate internucleotide linkage.
A dsRNA is double stranded, but may include one or more overhangs, such as at the 3′ end of one or more strands (e.g., 2 or more nucleotides of overhang).
Double stranded RNAs of the present disclosure may include a ligand (e.g., a N-acetylgalactosamine (GalNAc) derivative,
In an embodiment of the disclosure, the ligand is conjugated to the 3′ end of the sense strand of the dsRNA.
In one aspect, the present disclosure provides a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5 which can be included in a co-formulation of the present disclosure, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence 5′-AAGCAAGAUAUUUUUAUAAUA-3′ (SEQ ID NO: 365) and wherein the antisense strand comprises the nucleotide sequence 5′-UAUUAUAAAAAUAUCUUGCUUUU-3′ (SEQ ID NO: 364), e.g., wherein one or more of the dsRNA nucleotides are modified; e.g., with 2′-deoxy, 2′-methoxy, and/or 2′-fluoro groups and/or terminally modified with a triantennary GalNAc moiety. In one embodiment, the dsRNA agent comprises at least one modified nucleotide, as described herein.
In one aspect, the present disclosure provides a double stranded iRNA agent, which can be included in a co-formulation of the present disclosure, for inhibiting expression of complement component C5 wherein the double stranded iRNA agent comprises a sense strand and an antisense strand forming a double-stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 365 and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 364, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, and wherein the sense strand is conjugated to a ligand attached at the 3′-terminus. In one embodiment, the dsRNA agent comprises at least one modified nucleotide, as described herein.
In one embodiment, substantially all of the nucleotides of the sense strand are modified nucleotides selected from the group consisting of a 2′-O-methyl modification, a 2′-fluoro modification and a 3′-terminal deoxy-thymine (dT) nucleotide. In another embodiment, substantially all of the nucleotides of the antisense strand are modified nucleotides selected from the group consisting of a 2′-O-methyl modification, a 2′-fluoro modification and a 3′-terminal deoxy-thymine (dT) nucleotide. In another embodiment, the modified nucleotides are a short sequence of deoxy-thymine (dT) nucleotides. In another embodiment, the sense strand comprises two phosphorothioate intemucleotide linkages at the 5′-terminus. In one embodiment, the antisense strand comprises two phosphorothioate intemucleotide linkages at the 5′-terminus and two phosphorothioate intemucleotide linkages at the 3′-terminus. In yet another embodiment, the sense strand is conjugated to one or more GalNAc derivatives attached through a branched bivalent or trivalent linker at the 3′-terminus.
In one embodiment, at least one of the modified nucleotides is selected from the group consisting of a 3-terminal deoxy-thymine (dT) nucleotide, a 2′-O-methyl modified nucleotide, a 2′-fluoro modified nucleotide, a 2′-deoxy-modified nucleotide, a locked nucleotide, a basic nucleotide, a 2′-amino-modified nucleotide, a 2′-alkyl-modified nucleotide, a morpholino nucleotide, a phosphoramidate, a non-natural base comprising nucleotide, a nucleotide 20 comprising a 5′-phosphorothioate group, and a terminal nucleotide linked to a cholesteryl derivative or a dodecanoic acid bisdecylamide group.
In another embodiment, the modified nucleotides comprise a short sequence of 3-terminal deoxy-thymine (dT) nucleotides.
In one embodiment, the region of complementarity is at least 17 nucleotides in length. In another embodiment, the region of complementarity is between 19 and 21 nucleotides in length. In one embodiment, the region of complementarity is 19 nucleotides in length. In one embodiment, each strand is no more than 30 nucleotides in length. In one embodiment, at least one strand comprises a 3′ overhang of at least 1 nucleotide. In another embodiment, at least one strand comprises a 3′ overhang of at least 2 nucleotides. In one embodiment, the dsRNA agent further comprises a ligand. In one embodiment, the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent. In one embodiment, the ligand is an N-acetylgalactosamine (GalNAc) derivative. In one embodiment, the ligand is
In one embodiment, the dsRNA agent is conjugated to the ligand as shown in the following schematic
and, wherein X is O or S. In one embodiment, the X is O.
In an embodiment of the present disclosure, the C5 iRNA includes an RNA strand that is complementary to an mRNA transcribed from the C5 gene sense strand DNA sequence AAGCAAGATATTTTTATAATA, for example, wherein the iRNA is a dsRNA that includes another hybridized RNA strand.
In another aspect, the present disclosure provides a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence 5′-AAGCAAGAUAUUUUUAUAAUA-3′ (SEQ ID NO: 366) and wherein the antisense strand comprises the nucleotide sequence 5′-UAUUAUAAAAAUAUCUUGCUUUUdTdT-3′ (SEQ ID NO: 367).
In another aspect, the present disclosure provides a double-stranded ribonucleic acid (dsRNA) agent for inhibiting expression of complement component C5, wherein the dsRNA agent comprises a sense strand and an antisense strand, wherein the sense strand comprises the nucleotide sequence asasGfcAfaGfaUfAfUfuUfuuAfuAfauaL96 (SEQ ID NO: 368) and wherein the antisense strand comprises the nucleotide sequence usAfsUfuAfuaAfaAfauaUfcUfuGfcuususudTdT (SEQ ID NO: 369).
In an embodiment of the disclosure, the sense or antisense strands of a dsRNA that can be included in a formulation of the present disclosure comprises sequences selected from the group consisting of A-118320, A-118321, A-118316, A-118317, A-118332, A-118333, A-118396, A-118397, A-118386, A-118387, A-118312, A-118313, A-118324, A-118325, A-119324, A-119325, A-119332, A-119333, A-119328, A-119329, A-119322, A-119323, A-119324, A-119325, A-119334, A-119335, A-119330, A-119331, A-119326, A-I119327, A-125167, A-125173, A-125647, A-125157, A-125173, and A-125127. In one embodiment, the dsRNA agent comprises at least one modified nucleotide.
In an embodiment of the disclosure, the dsRNA comprises the two following pairs of strands:
In an embodiment of the disclosure, the C5 iRNA (e.g., Cemdisiran) comprises one or more alactosamines e.g., 3, for example, represented by the structure:
wherein the wavy double helix-like structure represents the RNA portion of the molecule and X is O or X is S; e.g.,
However, in an embodiment of the disclosure, a co-formulation of the present disclosure further comprises degradation products represented by one or more of the following structures (wavy line represents double stranded RNA structure):
wherein 1, 2 or 3 of the terminal N-acetylgalactosamines (GalNAc) are missing.
iRNAs of the present disclosure can be chemically linked, by the RNA portion of the molecule, to one or more ligands, moieties or conjugates that enhance the activity, cellular distribution or cellular uptake of the iRNA. Such moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al., Proc. Natl. Acid. Sci. USA, 1989, 86: 6553-6556), cholic acid (Manoharan et al., Biorg. Med. Chem. Let., 1994, 4:1053-1060), a thioether, e.g., beryl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660:306-309; Manoharan et al., Biorg. Med. Chem. Let., 1993, 3:2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20:533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al., EMBO J, 1991, 10:1111-1118; Kabanov et al., FEBS Lett., 1990, 259:327-330; Svinarchuk et al., Biochimie, 1993, 75:49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654; Shea et al., Nucl. Acids Res., 1990, 18:3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14:969-973), or adamantane acetic acid (Manoharan et al., Tetrahedron Lett., 1995, 36:3651-3654), a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264:229-237), or an octadecylamine or hexylamino-carbonyloxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277:923-937).
A ligand can be a carbohydrate. A carbohydrate conjugated RNA is advantageous for the in vivo delivery of nucleic acids. As used herein, “carbohydrate” ligand refers to a compound which is either a carbohydrate per se made up of one or more monosaccharide units having at least 6 carbon atoms (which can be linear, branched or cyclic) with an oxygen, nitrogen or sulfur atom bonded to each carbon atom; or a compound having as a part thereof a carbohydrate moiety made up of one or more monosaccharide units each having at least six carbon atoms (which can be linear, branched or cyclic), with an oxygen, nitrogen or sulfur atom bonded to each carbon atom. Representative carbohydrates include the sugars (mono-, di-, tri- and oligosaccharides containing from about 4, 5, 6, 7, 8, or 9 monosaccharide units), and polysaccharides such as starches, glycogen, cellulose and polysaccharide gums. Specific monosaccharides include C5 and above (e.g., C5, C6, C7, or C8) sugars; di- and trisaccharides include sugars having two or three monosaccharide units (e.g., C5, C6, C7, or C8).
In one embodiment, a carbohydrate conjugate for use in the compositions and methods of the disclosure is a monosaccharide. In one embodiment, the monosaccharide is an N-acetylgalactosamine, such as
In some embodiments, the conjugate or ligand described herein can be attached to an iRNA oligonucleotide with various linkers that can be cleavable or non-cleavable. The term “linker” or “linking group” means an organic moiety that connects two parts of a compound, e.g., covalently attaches two parts of a compound. Linkers typically comprise a direct bond or an atom such as oxygen or sulfur, a unit such as NR8, C(O), C(O)NH, SO, SO2, SO2NH or a chain of atoms, such as, but not limited to, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylhereroaryl, which one or more methylenes can be interrupted or terminated by O, S, S(O), SO2, N(R8), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where R8 is hydrogen, acyl, aliphatic or substituted aliphatic. In one embodiment, the linker is between about 1-24 atoms, 2-24, 3-24, 4-24, 5-24, 6-24, 6-18, 7-18, 8-18 atoms, 7-17, 8-17, 6-16, 7-16, or 8-16 atoms. Linkers may comprise redox cleavable linking groups, phosphate-based cleavable linking groups, acid cleavable linking groups, ester-based linking groups and/or peptide-based cleaving groups.
wherein x=1-30, y=1-15 and z=1-20; when one of X or Y is an oligonucleotide, the other is a hydrogen. In certain embodiments of the compositions and methods of the disclosure, a ligand is one or more GalNAc (N-acetylgalactosamine) derivatives attached through a bivalent or trivalent branched linker.
The present disclosure provides pharmaceutical, preferably aqueous, co-formulations that comprise a pharmaceutically acceptable carrier and the separate components (i) an anti-C5 antibody or antigen-binding fragment thereof (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H-4H-12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; crovalimab; Eculizumab, tesidolumab, mubodina or Ravulizumab; preferably, Pozelimab) and; (ii) a C5 iRNA, preferably a glycoconjugate, such as Cemdisiran.
A co-formulation may be designated in the form: antibody/iRNA; for example, “Pozelimab/Cemdisiran” or “Cemdisiran/Pozelimab” denotes a co-formulation of the present disclosure including Pozelimab and Cemdisiran.
A co-formulation or pharmaceutical co-formulation, as used herein, refers to a formulation including an anti-C5 antigen-binding protein (e.g., antibody or antigen-binding fragment thereof), a C5 iRNA and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier includes, for example, one or more excipients. In an embodiment of the disclosure, a co-formulation of the present disclosure is aqueous, i.e., includes water.
Pharmaceutical formulations including anti-C5 antigen-binding proteins may be prepared by admixing the antigen-binding protein with one or more excipients (see, e.g., Hardman et al. (2001) Goodman and Gilman's The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY).
The present invention provides a method for making a co-formulation comprising combining a C5 iRNA (e.g., Cemdisiran or the Na+ salt thereof; e.g., wherein the C5 iRNA is reconstituted with water from a lyophilized composition thereof); an antibody or antigen-binding fragment thereof that binds specifically to C5 (e.g., Pozelimab); a buffer (e.g., Histidine); a viscosity reducer (e.g., L-arginine); a stabilizer (e.g., sucrose); and a non-ionic surfactant (e.g., polysorbate 80), and, optionally, adjusting the co-formulation pH to greater than or less than about 6 (e.g., about 6.5±0.2); and, optionally sterile filtering the co-formulation.
The present disclosure provides methods for making a co-formulation of the present disclosure including combining an RNAi (e.g., Cemdisiran) and the antibody or antigen-binding fragment (e.g., Pozelimab) (e.g., that includes detectable quantities of beta-hexosaminidase contaminant), and (i) adding GalNAc to the co-formulation and/or (ii) adjusting the pH of the co-formulation to about or below about 6 (e.g., within not less than 0.5). In an embodiment of the disclosure, other excipients are also combined, e.g., buffer, viscosity reducer, stabilizer and/or surfactant. Co-formulations (e.g., Cemdisiran/Pozelimab) produced by such methods are part of the present disclosure. In an embodiment of the disclosure, the antibody or fragment which is combined with the other components is initially in a lot that includes beta-hexosaminidase contaminant and is diluted by a factor of 0.25, 0.5 or 0.75 when incorporated into the co-formulation.
Various viscosity reducer are known in the art for use with co-formulations. viscosity reducer are agents that can reduce the viscosity of a formulation. Viscosity reducers may also function as tonicifiers that modulate the osmolality of the formulation. Such viscosity reducer include an adipic acid; an amino acid or salt thereof; (D- or L-) arginine; L-arginine HCl; (D- or L-) alanine; benzenesulfonic acid; caffeine; a dicarboxylic acid; an ester of citric acid; (D- or L-) glutamate; Glycine; (D- or L-) histidine; an inorganic salt; L-Ornithine; (D- or L-) lysine; Proline; (D- or L-) phenylalanine; (D- or L-) serine; NaCl; pyridoxamine; pyridoxine; thiamine phosphoric acid ester chloride dihydrate; triethyl citrate; (D- or L-) valine; and/or a xanthine. In an embodiment of the disclosure, the amino acid is an L-amino acid such as L-arginine. L-arginine acts both as a tonicifier as well as a stabilizer and viscosity reducer. Arginine HCl can decrease Cemdisiran degradation and allow for a near isotonic solution.
Stabilizers include agents, such as sugars or polyols, that aid in the reduction of degradation, for example, of antibodies or antigen-binding fragments, e.g., aggregation. Polyols are sugar alcohols having multiple hydroxyl groups. Stabilizers include a sugar or polyol, e.g., trehalose, sorbitol, mannitol, taurine, propane sulfonic acid, L-proline, sucrose, glycerol, threitol, maltitol, and/or polyethylene glycol (PEG; such as PEG3350).
Non-ionic surfactants contain molecules with head groups that are uncharged. Non-ionic surfactants include a non-ionic surfactant including a polyoxyethylene moiety; a sorbitan; a polyoxyethylene glycol alkyl ether, such as octaethylene glycol monododecyl ether; pentaethylene glycol monododecyl ether; polyoxypropylene glycol alkyl ether; glucoside alkyl ether, such as decyl glucoside, lauryl glucoside, octyl glucoside; polyoxyethylene glycol octylphenol ether, such as triton X-100; polyoxyethylene glycol alkylphenol ether, such as nonoxynol-9; glycerol alkyl ester, such as glyceryl laurate; polyoxyethylene glycol sorbitan alkyl ester, such as polysorbate; sorbitan alkyl ester, such as spans; cocamide MEA, cocamide DEA, dodecyldimethylamine oxide; block copolymer of polyethylene glycol and polypropylene glycol, such as poloxamer; and polyethoxylated tallow amine (POEA); poloxamer 188, polyethylene glycol 3350, a polyethylene glycol (e.g., PEG3350) or a polysorbate such as polysorbate 80 (PS80) or polysorbate 20 (PS20). In an embodiment of the disclosure, the non-ionic detergent is polysorbate-20 (PS20), polysorbate-80 (PS80).
A buffer is a mixture of a weak acid and its conjugate base or vice versa which resists changes in its pH and therefore keeps the pH at a nearly constant value. Various buffers may be used in the co-formulations of the present disclosure, for example, histidine-based buffer, phosphate buffer or citrate buffer. A histidine-based buffer is a buffer comprising histidine. Examples of histidine buffers include histidine chloride, histidine hydrochloride, histidine acetate, histidine phosphate, and histidine sulphate.
The present disclosure encompasses co-formulations having any of the specifically recited components, e.g., at the specifically recited concentrations, but wherein the pH of the co-formulation is about 6.5.
In an embodiment of the disclosure, the co-formulation contains the impurity, beta-hexosaminidase, e.g., in a quantity of about 0.04 to about 0.17 micrograms/ml, e.g., when pH of the co-formulation is less than or greater than about 6 (e.g., by at least 0.5), e.g., 6.5.
For example, the disclosure includes a pharmaceutical co-formulation (e.g., Cemdisiran/Pozelimab) comprising:
In an embodiment of the disclosure, a co-formulation (e.g., Cemdisiran/Pozelimab) comprises (e.g., for example, with detectable quantities of beta-hexosaminidase as discussed herein):
In an embodiment of the disclosure, a co-formulation of the present disclosure includes the antibody and iRNA and is in association with a further therapeutic agent, such as, for example, an anti-coagulant, warfarin, aspirin, heparin, phenindione, fondaparinux, idraparinux, a thrombin inhibitor, argatroban, lepirudin, bivalirudin, dabigatran, an anti-inflammatory drug, a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), an antihypertensive, an angiotensin-converting enzyme inhibitor, an immunosuppressive agent, vincristine, cyclosporine A, or methotrexate, a fibrinolytic agent ancrod, E-aminocaproic acid, antiplasmin-a1, prostacyclin, defibrotide, a lipid-lowering agent, an inhibitor of hydroxymethylglutaryl CoA reductase, an anti-CD20 agent, rituximab, an anti-TNFalpha agent, infliximab, an anti-seizure agent, magnesium sulfate, a C3 inhibitor and/or an anti-thrombotic agent.
The term “in association with” indicates that a co-formulation is provided along with (2) one or more further therapeutic agents, such as methotrexate, which can be formulated into a single composition, e.g., for simultaneous delivery, or formulated separately into two or more compositions (e.g., a kit including each component, for example, wherein the further therapeutic agent is in a separate formulation). Components administered in association with each another can be administered to a subject at the same time or at a different time than when the other component is administered; for example, each administration may be given simultaneously (e.g., together in a single composition or essentially simultaneously during the same administration session) or non-simultaneously at one or more intervals over a given period of time. Moreover, the separate components administered in association with each another may be administered to a subject by the same or by a different route. Thus, the present disclosure includes co-formulations which are in association with a further therapeutic agent as well as methods of treating or preventing a disease or disorder associated with C5 (e.g., PNH, MG or CHAPLE) in a subject by administering to a subject in need thereof a co-formulation of the present disclosure in association with a further therapeutic agent.
The present disclosure includes co-formulations described herein wherein the concentration of the antibody and/or iRNA is ±10% the value shown; the concentration of surfactant is ±50% the value shown; and/or any of the other excipient concentrations (e.g., viscosity reducer, buffer, stabilizer) or pH are ±20% the value shown.
In an embodiment of the disclosure, a co-formulation of the present disclosure,
Combination Therapy Dosing Regimens of Anti-C5 and C5 iRNA
The present disclosure includes methods that comprise administering to a subject in need thereof, with a disease or disorder or condition associated with C5, an anti-C5 antibody or antigen-binding fragment thereof in combination with a C5 iRNA (e.g., in the form of a co-formulation including both the antibody or fragment and the iRNA, e.g., as set forth herein) at a dosing amount and frequency that achieves a safe and effective therapeutic response (combination therapy of the present disclosure).
In some embodiments, the present disclosure relates to the administration of one or more doses of an anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) in combination with one or more doses of a C5 iRNA (e.g., Cemdisiran). Preferably, the administration is in a co-formulation of the present disclosure (as discussed herein), e.g., 100:100 or 50:100 (Cemdisiran mg/ml:Pozelimab mg/ml)), for example in an injection volume of about 2 ml.
Generally, herein, a co-formulation including Cemdisiran and Pozelimab may be referred to in the following format: 100:100, 75:150 or 50:100. In such notation, when referring to such a co-formulation, the first number indicates the mg/ml of Cemdisiran and the second number indicates the mg/ml of Pozelimab.
A “dosing regimen” or “combination therapy dosing regimen” refers to a method for treating or preventing a disease or disorder or condition associated with C5 (preferably, PNH) including administering amounts of a combination therapy of the present disclosure at the frequencies as discussed herein.
For example, the present disclosure encompasses methods for administering an anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA comprising introducing the agents into the body of a subject, e.g., by injection such as by subcutaneous injection or intravenous infusion, for example, under a schedule according to any of the dosing regimens discussed herein (e.g., about 400 mg of the anti-C5 antibody or antigen-binding fragment (e.g., Pozelimab) subcutaneously about every 2-4 weeks (±3, 4, 5, 6 or 7 days) and about 200 mg of the iRNA (e.g., Cemdisiran) subcutaneously about every 4 weeks (±3, 4, 5, 6 or 7 days)).
Thus, the present disclosure provides a method for treating or preventing a C5-associated disease or disorder (for example, dry AMD or MG; preferably, PNH) in a subject in need thereof comprising administering to the subject an anti-C5 antibody or antigen-binding fragment thereof (“the anti-C5 Ab”) and a C5 iRNA according to the following:
In an embodiment of the disclosure, the subject is administered, concurrently,
The present disclosure also includes embodiments wherein the subject is administered concurrently:
The present disclosure also includes embodiments wherein the subject is administered concurrently:
A dosing regimen, e.g., for treatment of a disease or disorder or condition associated with C5 such as PNH, including the anti-C5 and C5 iRNA, for a subject who has previously received Pozelimab monotherapy, e.g., as set forth herein, may be referred to herein as a “Pozelimab Monotherapy Switch” regimen.
In an embodiment of the invention, the regimen is as follows: On day 1 (7 to 8 days after the last dose of Pozelimab monotherapy) or, when the next dose of pozelimab monotherapy is due, subjects start receiving either
Pozelimab monotherapy include treatment of a disease or disorder or condition associated with C5 (preferably, PNH) with Pozelimab as the only C5-specific inhibitor or, more specifically, anti-C5 antibody or antigen-binding fragment (e.g., not with both Pozelimab and Eculizumab). In an embodiment of the present disclosure, before receiving a combination therapy as discussed herein, 400 mg anti-C5 antibody or antigen-binding fragment SC about every 2, 3 or 4 weeks and about 400 mg C5 iRNA SC about every 4 weeks, the subject has received a dosing regimen according to the following:
In an embodiment of the present disclosure, subcutaneous Pozelimab monotherapy doses are administered in a formulation comprising about:
Naïve or complement inhibitor naïve patients have not ever or not recently (e.g., not in the last 1, 2, 3, 4, 5 or 6 months or for at least about 4 or 5 half-lives of the last complement inhibitor they received) received complement inhibitor therapy (e.g., Eculizumab, Ravulizumab, Pozelimab).
In an embodiment of the disclosure, a complement inhibitor naïve subject is treated for a disease or disorder or condition associated with C5 (preferably, PNH) by a method including administering:
In an embodiment of the disclosure, a complement inhibitor naïve subject is treated for a disease or disorder or condition associated with C5 (preferably, PNH) by a method including administering:
During the transition of therapy from Eculizumab or Ravulizumab to a therapy including the anti-C5 Ab (e.g., Pozelimab) and C5 iRNA (e.g., Cemdisiran), an additional dose of Pozelimab (e.g., a dose of 30 or 60 mg/kg IV) can be administered, e.g., under circumstances such as if there is a suspicion that an adverse event (AE) potentially due to large drug-target-drug (DTD) immune complexes may occur or has occurred and/or if systemic corticosteroids are administered for a type III hypersensitivity reaction. This additional dose will establish conditions of Pozelimab excess in the circulation and thereby minimize the risk of further formation of immune complexes.
Switch from Eculizumab Therapy
A dosing regimen for a subject who has previously received Eculizumab, e.g., as set forth above, may be referred to herein as an “Eculizumab Switch” regimen. Preferably, the subject is being treated for a disease or disorder or condition associated with C5, such as PNH.
In an embodiment of the invention, the Eculizumab Switch regimen has a lead-in loading phase and a switch phase as follows:
Initially, subjects remain on Eculizumab background treatment at their usual dose/frequency, and Cemdisiran alone is introduced as follows:
In an embodiment of the invention, the Eculizumab half-life (e.g., in a subject having PNH) is about 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21 days, e.g., about 11 days (Wijnsma et al., Pharmacology, Pharmacokinetics and Pharmacodynamics of Eculizumab, and Possibilities for an Individualized Approach to Eculizumab. Clin Pharmacokinet. 2019 July; 58(7):859-874; AI-Ani et al., Eculizumab in the management of paroxysmal nocturnal hemoglobinuria: patient selection and special considerations. Ther Clin Risk Manag. 2016 Aug. 1; 12:1161-70).
In an embodiment of the present disclosure, the dosing regimen includes:
A prescribed dosing regimen (e.g., for subjects 18 years of age or older) for treatment of PNH with Eculizumab is as follows:
A prescribed dosing regimen for treatment of aHUS with Eculizumab is as follows:
A prescribed dosing regimen of Eculizumab for treatment of generalized myasthenia gravis or neuromyelitis optica spectrum is as follows:
In an embodiment of the present disclosure, Eculizumab is administered to a subject in a dose taken from a pharmaceutical formulation comprising 300 mg of Eculizumab, polysorbate 80 (6.6 mg) (vegetable origin), sodium chloride (263.1 mg), sodium phosphate dibasic (53.4 mg), sodium phosphate monobasic (13.8 mg), and Water for Injection, USP, at pH 7 and in a volume of 30 mL.
Switch from Ravulizumab Therapy
A dosing regimen for a subject who has previously received Ravulizumab, e.g., as set forth above, may be referred to herein as an “Ravulizumab Switch” regimen. Preferably, the subject is being treated for a disease or disorder or condition associated with C5 such as PNH.
In an embodiment of the disclosure, a Ravulizumab switch regimen is as follows:
In an embodiment of the invention, the Ravulizumab half-life (e.g., in a subject having PNH) is about 32 days (Stern et al., Ravulizumab: a novel C5 inhibitor for the treatment of paroxysmal nocturnal hemoglobinuria. Ther Adv Hematol. 2019 Sep. 10; 10:2040620719874728; Lee et al., Ravulizumab (ALXN1210) vs eculizumab in adult patients with PNH naive to complement inhibitors: the 301 study. Blood. 2019 Feb. 7; 133(6):530-539; Lee et al., Immediate, complete, and sustained inhibition of C5 with ALXN1210 reduces complement-mediated hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH): interim analysis of a dose-escalation study [abstract]. Blood. 2016; 128(22). Abstract 2428).
In an embodiment of the disclosure, a subject is treated for a disease or disorder or condition associated with C5 (preferably, PNH), where the subject previously received Ravulizumab (e.g., according to the prescribed dosing regimen) and is being switched to a treatment regimen with a different anti-C5 antibody or antigen-binding fragment (the anti-C5 Ab), preferably Pozelimab, and a C5 iRNA (the C5 iRNA), preferably Cemdisiran, is administered:
The day 1 Ravulizumab loading dose can be according to the patient's weight (>40 kg to <60 kg, 2400 mg IV; >60 kg to <100 kg, 2700 mg IV; 2100 kg, 3000 mg IV). The first maintenance dose that is administered 2 weeks after the loading dose as follows: (>40 kg to <60 kg, 3000 mg IV; >60 kg to <100 kg, 3300 mg IV; 100 kg, 3600 mg IV). Thereafter, the maintenance doses should be administered IV Q8W (±7 days).
A Ravulizumab subcutaneous maintenance dose is 490 mg once weekly in adult patients greater than or equal to 40 kg body weight, e.g., with PNH or aHUS. The subcutaneous dosing schedule is allowed to occasionally vary by ±1 day of the scheduled dose day, but the subsequent dose should be administered according to the original schedule.
A prescribed dosing regimen for treatment of PNH with Ravulizumab is as follows:
Subcutaneous Ravulizumab maintenance doses may be 490 mg once weekly in adult patients greater than or equal to 40 kg body weight with PNH. Patients not currently on Ravulizumab or Eculizumab treatment with a body weight of >40 kg at treatment start may initiate the subcutaneous doses of Ravulizumab about 2 weeks after the intravenous Ravulizumab loading dose. Patients currently treated with Eculizumab with a body weight of >40 kg at time of next scheduled Eculizumab dose may initiate the subcutaneous doses of Ravulizumab about 2 weeks after the intravenous Ravulizumab loading dose. Patients currently treated with Ravulizumab intravenous (IV) administration may initiate the subcutaneous doses of Ravulizumab about 8 weeks after the last intravenous Ravulizumab maintenance dose. In an embodiment of the present disclosure, the subject has previously received Ravulizumab treatment for at least 24 weeks.
As discussed, the subject may have been previously receiving Pozelimab monotherapy, e.g., at a dosage of about 800 mg subcutaneously (SC) every 1, 2, 3 or 4 weeks (which may have been preceded by a loading dose of Pozelimab, e.g., intravenously), or Ravulizumab or Eculizumab, e.g., according to a prescribed dosing regimen. Patients who have received Pozelimab monotherapy, Ravulizumab or Eculizumab previously may be in any phase of the prescribed dosing regimen of the antibody before switching to a combination therapy of the present disclosure. For example, the subject may have received one or more loading doses and/or one or more maintenance doses of Eculizumab. In an embodiment of the invention, prior to or on the same day as initiating treatment with a monthly regimen of 400 mg Pozelimab and 200 mg Cemdisiran, when the subject is switching from Eculizumab or Ravulizumab or another anti-C5 antibody or antigen-binding fragment thereof, the subject receives an intravenous loading dose of Pozelimab (e.g., 30 mg/kg or 60 mg/kg) and/or a single SC dose of Cemdisiran (e.g., 200 mg). The transition period mitigates the risk for the formation of large DTD (drug-target-drug) immune complexes of Eculizumab-C5-Pozelimab during the switch from Eculizumab or Ravulizumab-C5-Pozelimab during the switch from Ravulizumab to the Pozelimab+Cemdisiran combination.
Pozelimab binds C5 non-competitively with eculizumab, and thus has the potential to form heteromeric complexes including large DTD immune complexes. In vitro, neither Pozelimab nor Eculizumab individually form higher-order multimers larger than a 1:2 mAb:C5 complex with C5. Pozelimab was added to pre-formed in-house Eculizumab:C5 complexes under conditions of excess Pozelimab (5:1:1 Pozelimab:in-house eculizumab:C5) and equimolar amounts of total mAb to C5 (1:1:2 Pozelimab:in-house eculizumab:C5). Under conditions of Pozelimab excess, the majority of samples (˜86%) had free antibody and either trimeric or pentameric complexes (2:1 or 3:2 mAb:C5 molar ratios, respectively), with the remainder comprising large HMW complexes. At an equimolar ratio of total mAb and C5, the majority of the samples (˜86%) had large HMW complexes larger than pentamers. While Eculizumab and Pozelimab in combination were able to form heteromeric complexes with C5, the presence of excess Pozelimab reduced the formation of large higher order immune complexes relative to conditions where total mAb and C5 were present at equimolar concentrations.
When switching from a regimen that includes an antibody that does not compete significantly with Pozelimab for binding to C5 (a non-competing antibody or antigen-binding fragment thereof (N/C Ab), e.g., Eculizumab or Ravulizumab), a transition period is designed to mitigate the potential risk for the formation of large DTD immune complexes of, for example, Eculizumab-C5-Pozelimab during the switch from Eculizumab to the Pozelimab/Cemdisiran combination. The transition period can include a lead-in Cemdisiran dose followed by a high higher IV loading dose of Pozelimab (60 mg/kg) than is used in treatment naïve patients (30 mg/kg). The initial dose of Cemdisiran (e.g., occurring on day 1) reduces C5 production and, thereby, the circulating level of total C5 available for potential large DTD complex formation prior to the introduction of Pozelimab. To further minimize the risk, the 60 mg/kg IV loading dose of Pozelimab establishes a high Pozelimab:Eculizumab molar ratio. This excess concentration of Pozelimab reduces the formation of higher-order DTD immune complexes, relative to equimolar molar concentrations of total antibody and C5, by assuring saturation of the C5 binding sites by Pozelimab. This IV loading dose results in a molar ratio of Pozelimab to Eculizumab of approximately 17:1, based on a reported mean trough concentrations of Eculizumab of 97 mg/L (Soliris® Eculizumab (Prescribing information)) and the predicted concentration of Pozelimab.
An additional dose of anti-C5 antibody or antigen-binding fragment, preferably Pozelimab, of about 30 mg/kg IV, can be included in circumstances such as if there is a suspicion of an adverse event [AE] potentially due to large DTD (drug-target-drug) immune complexes and/or if systemic corticosteroids are administered for a type III hypersensitivity reaction. This additional dose will likely establish conditions of Pozelimab excess in the circulation and thereby minimize the risk of further formation of immune complexes.
Thus, the present disclosure includes:
Generally, the initial dose or doses that are non-recurring may be referred to as “loading” doses and subsequent doses that are recurring may be referred to as “maintenance” doses.
In an embodiment of the invention, a large DTD complex refers to a complex larger that an pentameric complex (e.g., 2:1 or 3:2::mAb:C5 molar ratio) or a complex having a molecular weight of 1000 kDa or more.
In an embodiment of the invention, an excess of Pozelimab relative to an N/C Ab such as Eculizumab or Ravulizumab refers to a molar excess of greater than 1:1::Pozelimab:N/C Ab (e.g., 17:1).
A dosing regimen including monthly doses of both anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab; e.g., about 400 mg) and C5 iRNA (e.g., Cemdisiran; e.g., about 200 mg) may be referred to as the q4w or Q4W regimen.
A dosing regimen including doses (e.g., of about 400 mg) of anti-C5 antibody or antigen-binding fragment thereof every 2 weeks and monthly doses (e.g., of about 200 mg) of C5 iRNA may be referred to as the q2w or Q2W regimen.
The term “4 weeks” or a “month”, in an embodiment of the invention, refers to about 28, 29 or 30 days (±3, 4, 5, 6 or 7 days).
The term “2 weeks”, in an embodiment of the invention, refers to about 14 days (±3, 4, 5, 6 or 7 days).
Anti-C5 antibody or antigen-binding fragment thereof 400 mg SC Q4W refers to administration of about 400 mg of the antibody or fragment (e.g., Pozelimab) subcutaneously about every month, 4 weeks or 28 days (±3, 4, 5, 6 or 7 days).
Anti-C5 antibody or antigen-binding fragment thereof 400 mg SC Q2W refers to administration of about 400 mg of the antibody or fragment (e.g., Pozelimab) subcutaneously about every 2 weeks or 14 days (±3, 4, 5, 6 or 7 days).
C5 iRNA 200 mg SC Q4W refers to administration of 200 mg of the iRNA (e.g., Cemdisiran) subcutaneously about every 4 weeks or 28 days (±3, 4, 5, 6 or 7 days).
As set forth herein, any dosing episode (e.g., which involves multiple doses of drugs), may be followed by a 30 minute to 2-hour observation period after the last administration or for however long, in the judgment of the treating physician, no adverse events are likely to occur acutely. Typically, on a given day when a subject receives an intravenous dose and one or more subcutaneous doses, the intravenous dose is given first; however, the scope of the present disclosure includes embodiments wherein the doses are given in any order, e.g., SC then IV then SC.
In an embodiment of the disclosure, a subject receiving the combination therapy of anti-C5 Ab and C5 iRNA achieves or achieves and maintains while receiving the therapy one or more of the following:
In an embodiment of the disclosure, a subject receiving the combination therapy of anti-C5 Ab and C5 iRNA achieves or achieves and maintains while receiving the therapy one or more of the following:
In an embodiment of the disclosure, in spite of treatment with a combination therapy of the present disclosure, a subject may be administered a transfusion with red blood cells (RBCs) for example, according to the following:
In an embodiment of the disclosure, a subject receiving a combination therapy of the present disclosure receives an “intensified” treatment, e.g., if the subject experiences breakthrough hemolysis that is not due to a complement activating condition (e.g., intercurrent infection) and/or if the subject experiences inadequate LDH response (i.e., LDH >1.5×ULN) that is sustained (e.g., on 2 consecutive measurements spanning at least about 2 weeks). Intensified treatment includes one or more doses of anti-C5 antibody or antigen-binding fragment, preferably Pozelimab and/or C5 iRNA, preferably Cemdisiran, in addition to the doses specified in a combination therapy as discussed herein, for example,
In an embodiment of the disclosure, a subject who receives intensified treatment (e.g., who was receiving the Eculizumab switch regimen), preferably for treatment of PNH, receives administration of 30 mg/kg Pozelimab IV on the day of initiation (e.g., which can be initiated from day 57 onward) in addition to a maintenance regimen with a shortened frequency of Pozelimab administration 400 mg SC Q2W (±3, 4, 5, 6 or 7 days) along with Cemdisiran 200 mg SC Q4W (±3, 4, 5, 6 or 7 days) e.g., for a period of 32 weeks starting on the day of initiation.
In some embodiments, the disclosed combination therapy includes administering the anti-C5 antibody or antigen-binding fragment thereof to a subject in need thereof in one or more doses administered about four times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every eight weeks, once every twelve weeks, or less frequently so long as a therapeutic response is achieved. In one embodiment, the disclosed anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) is administered to the subject once every two weeks or once every four weeks.
As used herein, the expression “in combination with” means that the anti-C5 antibody or antigen-binding fragment thereof is administered before, after, or concurrently with the C5 iRNA. This expression includes sequential or concurrent administration of the anti-C5 antibody or antigen-binding fragment thereof and a C5 iRNA.
In some embodiments, when the anti-C5 antibody or antigen-binding fragment thereof is administered “before” the C5 iRNA, the anti-C5 antibody or antigen-binding fragment thereof may be administered more than 12 weeks, about 12 weeks, about 11 weeks, about 10 weeks, about 9 weeks, about 8 weeks, about 7 weeks, about 6 weeks, about 5 weeks, about 4 weeks, about 3 weeks, about 2 weeks, about 1 week, about 150 hours, about 100 hours, about 72 hours, about 60 hours, about 48 hours, about 36 hours, about 24 hours, about 12 hours, about 10 hours, about 8 hours, about 6 hours, about 4 hours, about 2 hours, about 1 hour, about 30 minutes, about 15 minutes or about 10 minutes prior to the administration of the C5 iRNA.
In some embodiments, when the anti-C5 antibody or antigen-binding fragment thereof is administered “after” the C5 iRNA, the anti-C5 antibody or antigen-binding fragment thereof may be administered about 10 minutes, about 15 minutes, about 30 minutes, about 1 hour, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 10 hours, about 12 hours, about 24 hours, about 36 hours, about 48 hours, about 60 hours, about 72 hours, about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 5 weeks, about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about 11 weeks, about 12 weeks, or more than 12 weeks after the administration of the C5 iRNA.
As used herein, “concurrent” administration means that the anti-C5 antibody or antigen-binding fragment thereof (e.g., Pozelimab) and a C5 iRNA (e.g., Cemdisiran) are administered to the subject in a single dosage form (e.g., co- formulated) or in separate dosage forms administered to the subject during the same treatment episode, preferably within about 1 or 2 hours or 30 minutes or less of each other (i.e., before, after, or at the same time), such as about 15 minutes or less, or about 5 minutes or less. If administered in separate dosage forms, each dosage form may be administered via the same route (e.g., both administered intravenously, subcutaneously, etc.); or, alternatively, each dosage form may be administered via a different route. In any event, administering the components in a single dosage from, in separate dosage forms by the same route, or in separate dosage forms by different routes are all considered “concurrent” administration” for purposes of the present disclosure. In an embodiment of the disclosure, concurrent subcutaneous doses of anti-C5 antibody or antigen-binding fragment and C5 iRNA are administered by injection into separate arms.
As used herein, “sequential” administration means that each dose of a selected therapy is administered to the subject at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks, or months). For illustrative purposes, sequential administration may include administering an initial dose of the anti-C5 antibody or antigen-binding fragment thereof (or C5 iRNA), followed by one or more secondary doses the C5 iRNA (or anti-C5 antibody or antigen-binding fragment thereof), optionally followed by one or more tertiary doses of the anti-C5 antibody or antigen-binding fragment thereof (or C5 iRNA). For illustrative purposes, sequential administration may include administering to the subject an initial dose of the anti-C5 antibody or antigen-binding fragment thereof (or C5 iRNA), followed by one or more secondary doses of the C5 iRNA (or anti-C5 antibody or antigen-binding fragment thereof), and optionally followed by one or more tertiary doses of the C5 iRNA (or anti-C5 antibody or antigen-binding fragment thereof).
As used herein, “initial” dose, “secondary” dose, and “tertiary” dose refer to the temporal sequence of administration. Thus, the “initial” dose is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”); “secondary” doses are administered after the initial dose; and “tertiary” doses are administered after the secondary doses. The initial, secondary, and tertiary doses may all contain the same amount of the selected therapy or may contain different amounts of the selected therapy.
The co-formulations and/or combination therapy of the present disclosure (e.g., Cemdisiran/Pozelimab) are useful for the treatment or prevention of a disease or disorder or condition associated with C5 that includes the step of administering a therapeutically effective amount of anti-C5 antibody or antigen-binding fragment and a C5 iRNA, preferably in a co-formulation, e.g., by parenteral route, e.g., intramuscular (IM), subcutaneous (SC), intravenous (IV) or intravitreal (IVT) or intraocular injection. Preferably, about 400 mg of the antibody, preferably Pozelimab, is administered every about 2-4 (e.g., 2, 3 or 4) weeks whereas about 200 mg iRNA, preferably Cemdisiran, is administered about every 4 weeks.
In some embodiments, the disclosed co-formulation and/or combination therapy (e.g., Cemdisiran/Pozelimab) can be used for treating or preventing myasthenia gravis (MG), for example, a 100:100 co-formulation. Signs and symptoms of MG include, but are not limited to, weakness of the eye muscles (ocular myasthenia), drooping of one or both eyelids (ptosis), blurred or double vision (diplopia), a change in facial expression, difficulty swallowing, shortness of breath, impaired speech (dysarthria), weakness in the arms, hands, fingers, legs, and/or neck. Sometimes the severe weakness of myasthenia gravis may cause respiratory failure. Thus, the present disclosure includes methods for treating or preventing MG, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co-formulation of the present disclosure to the subject (e.g., by SC, IM or IV injection). In an embodiment of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of 400 mg Pozelimab SC and 200 mg Cemdisiran SC (e.g., every 4 weeks)).
In some embodiments, the disclosed co-formulations and/or combination therapy of the present disclosure (e.g., Cemdisiran/Pozelimab) are useful in treating or preventing atypical hemolytic uremic syndrome (aHUS). Signs and symptoms of aHUS include, but are not limited to, platelet activation, hemolysis, systemic thrombotic microangiopathy (formation of blood clots in small blood vessels throughout the body) leading to stroke, heart attack, kidney failure and/or death, end-stage renal disease, permanent renal damage, abdominal pain, confusion, edema, fatigue, nausea/vomiting, diarrhea, and microangiopathic anemia. Thus, the present disclosure includes methods for treating or preventing aHUS, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co-formulation of the present disclosure to the subject (e.g., by SC, IM or IV injection). In an embodiment of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of 400 mg Pozelimab SC and 200 mg Cemdisiran SC (e.g., every 4 weeks)).
In some embodiments, the disclosed co-formulation and/or combination therapy (e.g., Cemdisiran/Pozelimab) can be used for treating or preventing paroxysmal nocturnal hemoglobinuria (PNH), for example, a 50:100 co-formulation (Cemdisiran mg/ml:Pozelimab mg/ml). Signs and symptoms of PNH include, but are not limited to, destruction of red blood cells, thrombosis (including deep vein thrombosis, pulmonary embolism), intravascular hemolytic anemia, red discoloration of urine, symptoms of anemia such as tiredness, shortness of breath, and palpitations, abdominal pain and difficulty swallowing. Thus, the present disclosure includes methods for treating or preventing PNH, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co-formulation of the present disclosure to the subject (e.g., by SC, IM or IV injection). In an embodiment of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of 400 mg Pozelimab SC and 200 mg Cemdisiran SC (e.g., every 4 weeks)).
In some embodiments, the disclosed co-formulations and/or combination therapy are useful in treating PNH patients (including PNH patients who have transitioned from Pozelimab monotherapy) by, for example, controlling hemolysis without any breakthrough hemolysis events, achieving hemoglobin stabilization, and/or maintaining normalization of LDH for a sustained period of time (e.g., at least 28 weeks). In some embodiments, the disclosed co-formulations and/or combination therapy are useful in treating PNH patients (including PNH patients who have transitioned from Pozelimab monotherapy) by, for example, improving patient fatigue, improving global health status (GHS)/Quality-of-Life (QoL), and/or improving physical functioning as compared to baseline,
In some embodiments, the disclosed co-formulation and/or combination therapy (e.g., Cemdisiran/Pozelimab) can be used for treating or preventing CHAPLE disease (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis and protein-losing enteropathy). CHAPLE disease is characterized by symptoms such as inflammatory bowel disease, protein losing enteropathy (which can be associated with hypoalbuminemia), hypogammaglobulinemia, intestinal lymphangiectasia, and/or thrombotic events. Thus, the present disclosure includes methods for treating or preventing CHAPLE, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co-formulation of the present disclosure to the subject (e.g., by SC, IM or IV injection). In an embodiment of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of 400 mg Pozelimab SC and 200 mg Cemdisiran SC (e.g., every 4 weeks)).
In some embodiments, the disclosed co-formulation and/or combination therapy (e.g., Cemdisiran/Pozelimab) can be used for treating or preventing (including reducing or eliminating signs or symptoms thereof, or reducing complement activation associated therewith) a disease or disorder or condition associated with C5 such as a disorder of inappropriate or undesirable complement activation; systemic inflammatory response in post-pump syndrome due to cardiopulmonary bypass or renal bypass; a neurological disorder; a renal disorder; a hemodialysis complication; an inflammatory disorder; inflammation of an autoimmune disease; thermal injury; an immune complex disorder; an autoimmune disease or a proteinuric kidney disease. Thus, the present disclosure includes methods for treating or preventing any of such disorders, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co-formulation of the present disclosure to the subject (e.g., by SC, IM or IV injection). In an embodiment of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of 400 mg Pozelimab SC and 200 mg Cemdisiran SC (e.g., every 4 weeks)).
In some embodiments, the disclosed co-formulation and/or combination therapy (e.g., Cemdisiran/Pozelimab) can be used for treating or preventing (including reducing or eliminating signs or symptoms thereof, or reducing complement activation associated therewith) a disease or disorder or condition associated with C5 such as complement activation due to burn; inherited CD59 deficiency; renal ischemia; a post-ischemic reperfusion condition; adult respiratory distress syndrome; Alport's syndrome; Alzheimer's disease; atherosclerosis; bullous pemphigoid; C3 glomerulopathy; capillary leak syndrome; Crohn's disease; diabetes; diabetic nephropathy; epilepsy; glomerulopathy; Guillain-Barre Syndrome; hemolytic anemia; hyperacute allograft rejection; infectious disease; interleukin-2 induced toxicity during IL-2 therapy; lupus nephritis; membranoproliferative glomerulonephritis; membranoproliferative nephritis; mesenteric artery reperfusion after aortic reconstruction; multiple sclerosis; myasthenia gravis; myocardial infarction; neuromyelitis optica; complement activation due to obesity; Parkinson's disease; progressive kidney failure; psoriasis; renal ischemia-reperfusion injury; rheumatoid arthritis; schizophrenia; SLE nephritis; stroke; systemic lupus erythematosus (SLE); traumatic brain injury; vasculitis; xenograft rejection; CHAPLE disease/syndrome (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis and PLE); complement activation due to frostbite; complement activation due to sepsis. Thus, the present disclosure includes methods for treating or preventing any of such condition or disease, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co-formulation of the present disclosure to the subject (e.g., by SC, IM or IV injection). In an embodiment of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of 400 mg Pozelimab SC and 200 mg Cemdisiran SC (e.g., every 4 weeks)).
In some embodiments, the disclosed co-formulations and/or combination therapy of the present disclosure (e.g., Cemdisiran/Pozelimab) are useful for treating or preventing (including reducing or eliminating signs or symptoms thereof, or reducing complement activation associated therewith) a disease or disorder or condition associated with C5 such as a lung disease or disorder such as dyspnea, hemoptysis, ARDS, asthma, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary embolisms and infarcts, pneumonia, fibrogenic dust diseases, injury due to inert dusts and minerals (e.g., silicon, coal dust, beryllium, and asbestos), pulmonary fibrosis, an organic dust disease, chemical injury (due to irritant gasses and chemicals, e.g., chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia, and hydrochloric acid), smoke injury, thermal injury (e.g., burn or freeze), asthma, allergy, bronchoconstriction, hypersensitivity pneumonitis, a parasitic disease, Goodpasture's Syndrome, pulmonary vasculitis, hereditary angioedema, or immune complex-associated inflammation. Thus, the present disclosure includes methods for treating or preventing any of such condition or disease, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co-formulation of the present disclosure to the subject (e.g., by SC, IM or IV injection). In an embodiment of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of 400 mg Pozelimab SC and 200 mg Cemdisiran SC (e.g., every 4 weeks)).
In some embodiments, the disclosed co-formulations and/or combination therapy of the present disclosure (e.g., Cemdisiran/Pozelimab) are useful for treating or preventing (including reducing or eliminating signs or symptoms thereof, or reducing complement activation associated therewith) a disease or disorder or condition associated with C5 which is an ocular disease such as age-related macular degeneration (AMD), diabetic macular edema (DME), diabetic retinopathy, ocular angiogenesis (ocular neovascularization affecting choroidal, corneal or retinal tissue), geographic atrophy (GA), uveitis and neuromyelitis optica. The co-formulations of the present disclosure may be used to treat or to ameliorate at least one sign and/or symptom of dry AMD or wet AMD. Thus, the present disclosure includes methods for treating or preventing any of such condition or disease, in a subject in need thereof, including the steps of administering a therapeutically effective amount of co-formulation of the present disclosure to the subject (e.g., parenteral injection; or preferably, by intraocular or intravitreal injection). In an embodiment of the invention, such a therapeutically effective amount is any of the dosing regimens set forth herein (e.g., one or more doses of 400 mg Pozelimab SC and 200 mg Cemdisiran SC (e.g., every 4 weeks)).
“Treat” or “treating” means to administer a co-formulation of the present disclosure (e.g., Cemdisiran/Pozelimab) to a subject having a disease or disorder or condition associated with C5, such that one or more signs or symptoms thereof in the subject are reduced or eliminated, e.g., reducing complement activation associated therewith.
A therapeutically effective dose or amount of anti-C5 antibody and a C5 iRNA, in a co-formulation for treating a disease or disorder or condition associated with C5, is in the range of about 10-800 mg of each, administered once every 1, 2, 3, 4, 5, 6, 7, or 8 weeks.
A subject or patient—used interchangeably herein—refers to a mammal, preferably, a human. In an embodiment of the disclosure, the subject suffers from a disease or disorder or condition associated with C5, such as PNH or MG or aHUS or CHAPLE. In an embodiment of the disclosure, the subject is or was previously receiving a therapeutic agent for treating the disease or disorder (e.g., a complement inhibitor, such as crovalimab; Eculizumab, tesidolumab, mubodina and/or Ravulizumab) before switching to a co-formulation and/or combination therapy of the present disclosure that includes different agents (e.g., Cemdisiran/Pozelimab). In an embodiment of the present disclosure, the subject is treatment “naïve” having never previously received a complement inhibitor or not having recently received a complement inhibitor, e.g., with in 1, 2, 3, 4, 5 or 6 months. In an embodiment of the present disclosure, a subject has been diagnosed with paroxysmal nocturnal hemoglobinuria which has been confirmed by a history of high-sensitivity flow cytometry. In an embodiment of the present disclosure, the subject has a lactate dehydrogenase of at least 1.5×ULN (upper limit of normal). Sahin et al., Pesg PNH diagnosis, follow-up and treatment guidelines. Am J Blood Res 2016; 6(2):19-27. In an embodiment of the present disclosure, the subject or patient does not have any one or more of the following characteristics:
In an embodiment of the disclosure, the subject is receiving or has received a blood transfusion.
In an embodiment of the disclosure, a subject receiving a co-formulation of the present disclosure to treat a disease or disorder or condition associated with C5 achieve a reduction in intravascular hemolysis or blood lactate dehydrogenase (LDH) levels and/or a reduction in the receipt of blood transfusions compared to prior to the initiation of treatment.
The present disclosure also provides an injection device comprising the co-formulations of the present disclosure (e.g., Cemdisiran/Pozelimab). An injection device is a device that introduces a substance into the body of a patient via a parenteral route, e.g., intramuscular, subcutaneous, intravitreal, intraocular or intravenous. For example, an injection device may be a syringe (e.g., pre-filled or auto-injector) which, for example, includes a cylinder or barrel for holding fluid to be injected (e.g., the co-formulation), a needle for piecing skin and/or blood vessels for injection of the fluid; and a plunger for pushing the fluid out of the cylinder and through the needle bore. In an embodiment of the disclosure, an injection device that comprises a co-formulation is suitable for subcutaneous, intravitreal or intravenous (IV) injection. Such a device includes a co-formulation in a cannula or trocar/needle which may be attached to a tube which may be attached to a bag or reservoir for holding fluid (e.g., saline; or lactated ringer solution comprising NaCl, sodium lactate, KCl, CaCl2 and optionally including glucose) introduced into the body of the patient through the cannula or trocar/needle.
The co-formulation can, in an embodiment of the disclosure, be introduced into the device once the trocar and cannula are inserted into the vein of a subject and the trocar is removed from the inserted cannula. The IV device may, for example, be inserted into a peripheral vein (e.g., in the hand or arm); the superior vena cava or inferior vena cava, or within the right atrium of the heart (e.g., a central IV); or into a subclavian, internal jugular, or a femoral vein and, for example, advanced toward the heart until it reaches the superior vena cava or right atrium (e.g., a central venous line).
In an embodiment of the disclosure, an injection device is an autoinjector; a jet injector or an external infusion pump. A jet injector uses a high-pressure narrow jet of liquid which penetrate the epidermis to introduce a co-formulation to a patient's body. External infusion pumps are medical devices that deliver the co-formulation into a patient's body in controlled amounts. External infusion pumps may be powered electrically or mechanically. Different pumps operate in different ways, for example, a syringe pump holds fluid in the reservoir of a syringe, and a moveable piston controls fluid delivery, an elastomeric pump holds fluid in a stretchable balloon reservoir, and pressure from the elastic walls of the balloon drives fluid delivery. In a peristaltic pump, a set of rollers pinches down on a length of flexible tubing, pushing fluid forward. In a multi-channel pump, fluids can be delivered from multiple reservoirs at multiple rates.
The present disclosure provides methods for reducing the level of beta-hexosaminidase enzymatic activity in a composition, such as a pharmaceutical co-formulation, e.g., which comprises a molecule which is a substrate for the enzyme (e.g., a co-formulation of an antibody or antigen-binding fragment thereof (e.g., H2M11683N; H2M11686N; H4H12159P; H4H12161P; H4H12163P; H4H12164P; H4H12166P; H4H12166P2; H4H12166P3; H4H12166P4; H4H12166P5; H4H12166P6; H4H12166P7; H4H12166P8; H4H12166P9; H4H12166P10; H4H12167P; H4H12168P; H4H12169P; H4H12170P; H4H12171P; H4H12175P; H4H12176P2; H4H12177P2; H4H12183P2; H2M11682N; H2M11684N; H2M11694N; H2M11695N; crovalimab; Eculizumab, tesidolumab, mubodina or Ravulizumab; preferably, Pozelimab) isolated from a mammalian host cell and including beta hexosaminidase (beta hex) contaminants and an iRNA that includes a ligand having one or more terminal GalNAc and/or GlcNAc residues which are substrates of beta-hex). Typically, the beta-hexosaminidase is present in small, trace amounts that have carried over with the antibody or antigen-binding fragment after isolation from the host cell and/or host cell growth medium.
Evidence suggests that the amount of beta-hex in antibody compositions is dependent on the particular antibody. Most antibodies tested exhibited <2 ppm beta-hex. Pozelimab has been observed to have somewhat higher beta-hex levels than many other antibodies tested. Purification steps, however, may also affect the degree of antibody-to-antibody beta-hex content variability.
In an embodiment of the disclosure, the beta-hex is Chinese hamster beta-hex. In an embodiment of the disclosure, the beta-hex is characterized as mammalian beta-hex, e.g., mouse or human beta-hex. Beta-hex may, in an embodiment of the disclosure, be fungal, e.g., from yeast such as Candida albicans or Pichia (e.g., Pichia pastoris).
In an embodiment of the disclosure, the antibody or fragment binds specifically to C5, tumor necrosis factor alpha, PD-1, PD-L1, VEGF, VEGF receptor, HER2, CTLA4, Leptin receptor, CD3, CD28, CD20, IL-23 and/or EGFR. In an embodiment of the disclosure, the iRNA binds to a polynucleotide encoding any of such genes.
The present disclosure includes co-formulations that preferably include no detectable beta-hex. However, included within the scope of the present disclosure are co-formulations (e.g., Cemdisiran/Pozelimab) that:
In humans, lysosomal β-hexosaminidases catalyze the hydrolysis of β-glycosidically linked N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc) residues from the nonreducing end of a number of glycoconjugates (may be referred to herein in terms of a molecule conjugated to a ligand that comprises one or more terminal GlcNAc or GalNAc residues). Three different isoforms of the dimeric enzymes are known: β-hexosaminidase A (HexA), which represents the heterodimer of the noncovalently linked α and β chain, and the homodimeric isoenzymes β-hexosaminidase B (HexB, ββ) and β-hexosaminidase S (HexS, αα). β-hexosaminidases are particularly important for the lysosomal catabolism of glycosphingolipids, essential membrane components of eukaryotic cell surfaces. See Wendeler & Sandhoff, Hexosaminidase assays, Glycoconj J (2009) 26:945-952.
Assays for beta-hexosaminidases are commercially available. See β-Hexosaminidase Activity Assay, Tribioscience (Sunnyvale, CA). For example, a colorometric assay determines the conversion of p-Nitrophenyl N-acetyl-β-D-glucosaminide to and N-acetyl-D glucosamine and p-Nitrophenol which can be measured at absorbance (OD 405 nm).
The optimal pH for beta-hexosaminidase activity against Cemdisiran was measured to be about 6. Thus, such activity can be reduced by changing the pH to a value above or below 6, for example, 6.5. A pH higher than 6 led to greater Cemdisiran stability; however, in a co-formulation, an antibody such as Pozelimab, an increased pH leads to an increase in % Region1/acidic charge species for the antibody. Some co-formulations of the present disclosure have been formulated to reach a balance of conditions that lead to stable Cemdisiran while still maintaining stability in Pozelimab.
The present disclosure includes methods for reducing beta-hexosaminidase activity against a double stranded RNA (dsRNA) substrate (e.g., that includes a terminal GalNAc such as Cemdisiran) in a composition comprising adjusting the pH to a value above or below about 6, for example, to a value that is no closer than 0.5 to 6.
Beta-hexosaminidase activity has also been shown to be reduced in the presence of N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc). The present disclosure includes methods for reducing beta-hexosaminidase activity against a double stranded RNA (dsRNA) substrate (e.g., that includes a terminal GalNAc such as Cemdisiran) in a composition comprising adding N-acetylgalactosamine (GalNAc) or N-acetylglucosamine (GlcNAc) to the composition. For example, about 5% (w/v) GlcNAc and/or GalNAc can be added.
These examples are intended to exemplify the present disclosure are not a limitation thereof. Compositions and methods, including dosing regimens, set forth in the Examples form part of the present disclosure.
In this Example, an accurate and absolute quantification of the host cell protein, beta-hexosaminidase as a process-related impurity in Pozelimab antibody preparations was performed.
Recombinant beta-hexosaminidase protein and antibody drug substance were produced in-house. Tris-HCl, Tris(2-carboxyethyl)phosphine (TCEP HCl), iodoacetamide (IAM), and formic acid (FA) were from Thermo Fisher Scientific (Waltham, MA). Sequencing grade modified trypsin was from Promega (Madison, WI). LC/MS grade acetonitrile with 0.1% FA and water with 0.1% FA were purchased from Fisher Scientific (USA). Milli-Q water used in the experiments was generated.
Beta-hexosaminidase (‘beta-hex’) calibration standards were prepared by serially diluting recombinant beta-hex spiked in 5 mg/mL of Pozelimab antibody drug substance which was free of beta-hex. The beta-hex standard concentrations were 3.3, 8.2, 20.5, 51.2, 128, 320, and 800 ppm (in moles). Quality controls were prepared separately at 3.3, 7.5, 173, 588, and 800 ppm (in moles).
20 μL of beta-hex calibration standards, controls and samples were transferred to a 96 well plate and concentrated to dryness with a sample concentrator. Then the dried proteins were reconstituted in the denaturation and reduction solution (8 M urea and 10 mM TCEP-HCl) with brief mixing and incubated at 56° C. with shaking for 30 minutes. After cooling, the mixtures were alkylated in 10 mM of IAM at room temperature in the dark for 30 minutes. After alkylation, 10 μg of trypsin was added to the mixture (1:10 ratio of trypsin to substrate) and incubated at 37° C. with shaking overnight. At the end of digestion, 10% FA was added to quench the reaction.
The digested peptide mixture was injected into liquid chromatography (Agilent 1290 Infinity II LC Systems) coupled with the Agilent 6495B Triple Quadrupole mass spectrometer to perform MRM analysis. The separation was conducted by reversed-phase liquid chromatography using an ACQUITY UPLC BEH130 C18 column (2.1×50 mm, 1.7 μm; Waters). Mobile phase A was 0.1% FA in water, and mobile phase B was 0.1% FA in acetonitrile. The initial gradient started at 3% B for 0.5 min, then increased to 35% B over 10 min, and was followed by 90% B wash for 2.4 min and 3% B equilibration for 2.4 min. A flow rate of 0.4 mL/min was used in the gradient. The Agilent Jet Stream electrospray ionization (AJS ESI source) was applied with heated nitrogen as the sheath gas and drying gas at 400° C. and 180° C., respectively, at a flow rate of 12 L/min. The MS was operated in positive mode with capillary voltage at 3000 V, nozzle voltage at 300 V and nebulizer pressure at 35 psi. Pre-selected mass-to-charge ratio (m/z) of precursor and product ion pair of beta-hex peptides were fragmented with optimized collision energy and detected in the mass spectrometer. Agilent MassHunter Workstation Data Acquisition for 6400 Series Triple Quadrupole, version B.10.0, was used to run the LC/MS system. Agilent MassHunter Quantitative Analysis, version B.09.00, was used for data analysis.
The assay was performed in 5 mg/mL beta-hex free antibody drug substance and ranged from 3.3-800.0 ppm (in moles). Five known concentration samples, LLOQ, LQC, MQC, HQC, and ULOQ, always prepared in triplicate for evaluation during assay development process. Inter-assay accuracy and precision met acceptance criteria of QCs (±25% for LLOQ, ±20% for other QCs) except for one LQC (14/15 of QCs at Day 1) failed at accuracy (Table 1-2). Intra-assay accuracy and precision were calculated from the triplicate QC analysis prepared from single set experiment performed at Day 2 instead of duplicate preparations. Both intra-assay accuracy and precision met acceptance criteria of all QCs (Table 1-3). Mass to charge ratio of quantifier target peptide (‘TLDAMAFNK’; m/z transition: 505.9 >796.7) was specific to beta-hex in assay matrix and other components that might be present in digestion buffer. Dilution linearity evaluated using spiked standards showed that recovery of Beta-hex at 5, 10, 50, 100, 150 and 218 mg/mL antibody matrix was linear (
Eleven lots of Pozelimab were analyzed for beta-hex levels by the SRM-LC-MS/MS assay (see method section). The abundance of beta-hex in Pozelimab Lot A, Lot B and Lot 1 (282-332 ng/mL) were at least 2-times higher than in the Lot 2, Lot C, Lot D, Lot 4, Lot E, Lot F, Lot 3 and Lot G materials (120-156 ng/mL). See beta-hex levels measured in various lots in
Research studies were initiated to assess the long-term, accelerated, and stress stability for the co-formulation of Cemdisiran and Pozelimab in a single formulation. Co-formulations were manufactured and Cemdisiran was reconstituted in WFI (water for injection).
Glass vials were filled with filtered co-formulation (100:100 or 75:150 Cemdisiran mg/mL: Pozelimab (mg/mL)). The 100:100 co-formulation contains 100 mg/mL Cemdisiran, 100 mg/mL Pozelimab, 10 mM histidine, 50 mM arginine hydrochloride, 0.075% (w/v) polysorbate 80, 1% (w/v) sucrose, pH 6.0. The 75:150 co-formulation contains 75 mg/mL Cemdisiran, 150 mg/mL Pozelimab, 15 mM histidine, 75 mM arginine hydrochloride, 0.1125% (w/v) polysorbate 80, 1.5% (w/v) sucrose, pH 6.0.
A Cemdisiran only liquid formulation was also manufactured (100 mg/mL Cemdisiran in 50 mM Arg HCl, 10 mM His, 1% sucrose, 0.075% PS80, pH 6) and used as a control for this study.
Long-term, Accelerated, and Stress Stability Study. An outline of the long-term, accelerated, and stress stability conditions is presented in Table 2-1.
Results (Pozelimab: 24 month storage at 5° C.). No appreciable change in the physical or chemical stability of Pozelimab in co-formulations was observed in any of the monitored attributes after 24 months at 5° C. (see Table 2-2 and Table 2-3).
Results (Pozelimab: 3-6 month storage at 25° C. or 40° C.). Appreciable changes in the Pozelimab stability (e.g., formation of HMW and charge variants) in a liquid formulation after 25° C./60% RH and 40° C./75% RH storage (see Table 2-4 and Table 2-5) was similar to the Pozelimab only liquid formulation (data not shown).
Results (Cemdisiran: Storage at 5° C., 25° C. or 40° C.). There was a decrease in Cemdisiran purity (by dIPRP) in both co-formulations (100:100 and 75:100) at 5° C. and 25° C./60% RH and 40° C./75% RH (see Table 2-2 through Table 2-5,
Chromatograms from dIPRP analysis of 40° C./75% RH 3 month samples are shown in
aSample passes color and visual appearance assessment if it is clear to slightly opalescent, essentially free from visible particulates, and colorless to yellow.
bSilicone oil droplets and bubbles removed by removing particles with aspect ratio ≤0.85.
cImpurities 1, 2, and 3 result from loss of 1, 2, and 3 N-acetylgalactosamines (GalNAcs).
dRegion 1 corresponds to acidic species that elute before the main peak, Region 2 corresponds to the main peak, and Region 3 corresponds to basic species that elute after the main peak. dIPRP, denaturing ion pair reverse phase; DP, drug product; FDS, Formulated Drug Substance; FLR,
aSample passes color and visual appearance assessment if it is clear to slightly opalescent, essentially free from visible particulates, and colorless to yellow.
bSilicone oil droplets and bubbles removed by removing particles with aspect ratio ≤0.85.
cImpurities 1, 2, and 3 result from loss of 1, 2, and 3 N-acetylgalactosamines (GalNAcs).
dRegion 1 corresponds to acidic species that elute before the main peak, Region 2 corresponds to the main peak, and Region 3 corresponds to basic species that elute after the main peak. dIPRP, denaturing ion pair reverse phase; DP, drug product; FDS, Formulated Drug Substance; FLR, fluorescence; HMW, high molecular weight; iCIEF, imaging capillary isoelectric focusing; LMW, low molecular weight; Micro-Flow Imaging; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography
aSample passes color and visual appearance assessment if it is clear to slightly opalescent, essentially free from visible particulates, and colorless to yellow.
bSilicone oil droplets and bubbles removed by removing particles with aspect ratio ≤0.85.
cImpurities 1, 2, and 3 result from loss of 1, 2, and 3 N-acetylgalactosamines (GalNAcs).
dRegion 1 corresponds to acidic species that elute before the main peak, Region 2 corresponds to the main peak, and Region 3 corresponds to basic species that elute after the main peak. dIPRP, denaturing ion pair reverse phase; FLR, fluorescence; HMW, high molecular weight; iCIEF, imaging capillary isoelectric focusing; LMW, low molecular weight; Micro-Flow Imaging; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography
aSample passes color and visual appearance assessment if it is clear to slightly opalescent, essentially free from visible particulates, and colorless to yellow.
bSilicone oil droplets and bubbles removed by removing particles with aspect ratio ≤0.85.
cImpurities 1, 2, and 3 result from loss of 1, 2, and 3 N-acetylgalactosamines (GalNAcs).
dRegion 1 corresponds to acidic species that elute before the main peak, Region 2 corresponds to the main peak, and Region 3 corresponds to basic species that elute after the main peak. dIPRP, denaturing ion pair reverse phase; FLR, fluorescence; HMW, high molecular weight; iCIEF, imaging capillary isoelectric focusing; LMW, low molecular weight; Micro-Flow Imaging; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography
aSample passes color and visual appearance assessment if it is clear to slightly opalescent, essentially free from visible particulates, and colorless to yellow.
bSilicone oil droplets and bubbles removed by removing particles with aspect ratio ≤0.85.
cImpurities 1, 2, and 3 result from loss of 1, 2, and 3 N-acetylgalactosamines (GalNAcs). dIPRP, denaturing ion pair reverse phase; DP, drug product; NR, not required; UPLC, ultra-performance liquid chromatography
DIPRP was coupled with MS (mass spectroscopy) to identity the Cemdisiran impurities in co-formulations.
Results confirmed that impurity #1 and #2 in
Confirmation that Beta-Hexosaminidase is the Host Cell Protein (HCP) in Pozelimab Formulated Drug Substance is Responsible for Cemdisiran Degradation in Co-Formulations
Experiment 1. Co-formulations (100:100 and 75:150) were manufactured as set forth above using Pozelimab from lot 1. A quantitative method was developed by selected reaction monitoring (SRM)-LC-MS/MS, so that there was 2.5x higher beta-hexosaminidase concentration in lot 1 compared to lot 2 material.
Co-formulations manufactured with the lot 1 material were placed on stability at 5° C., 25° C./60% RH, and 40° C./75% RH. Cemdisiran purity (by dIPRP) for co-formulation manufactured from Pozelimab lot 1 and lot 2 at 40° C./75% are shown in
Experiment 2. A beta-hexosaminidase spiking study at accelerated conditions confirmed that the enzyme was responsible for Cemdisiran degradation in the liquid co-formulations. Cemdisiran formulations (100 mg/mL) (i.e., Cemdisiran reconstituted with WFI) with and without 10 μg/mL beta-hexosaminidase were manufactured. Glass vials were filled with formulation and stored at 40° C./75% RH.
Experiment 1 (pH Study). Another stability study was initiated (similar to the set-up described for the above study of Cemdisiran+Pozelimab) with two co-formulations, both containing 50 mg/mL Cemdisiran and 100 mg/mL Pozelimab, both manufactured from the same source material (e.g., Pozelimab). However, an additional 20 mM of histidine was added to one co-formulation so that the final pH would be higher, pH 6.6. Excipients and final concentrations in the co-formulations studied in this Experiment are shown below:
Experiment 2. Another research stability study was initiated (similar to Cemdisiran+Pozelimab) with the following co-formulations:
All co-formulations with GalNAc or GlcNAc showed no appreciable change in % total impurities 1-3 (i.e., loss of 1-3 GalNAcs from Cemdisiran) even after 6 months at 25° C. or 3 months at 40° C. See Tables 2-8-2-11.
aSample passes color and visual appearance assessment if it is clear to slightly opalescent, essentially free from visible particulates, and colorless to yellow.
bSilicone oil droplets and bubbles removed by removing particles with aspect ratio ≤0.85.
cImpurities 1, 2, and 3 result from loss of 1, 2, and 3 N-acetylgalactosamines (GalNAcs).
dRegion 1 corresponds to acidic species that elute before the main peak, Region 2 corresponds to the main peak, and Region 3 corresponds to basic species that elute after the main peak. dIPRP, denaturing ion pair reverse phase; FLR, fluorescence; GalNAc, N-acetylgalactosamine; GlcNAc, N-acetylglucosamine; HMW, high molecular weight; iCIEF, imaging capillary isoelectric focusing; LMW, low molecular weight; MFI, Micro-Flow Imaging; ndIPRP, nondenaturing ion pair reverse phase; NR, not required; SE, size exclusion; UPLC, ultra-performance liquid chromatography
aSample passes color and visual appearance assessment if it is clear to slightly opalescent, essentially free from visible particulates, and colorless to yellow.
bSilicone oil droplets and bubbles removed by removing particles with aspect ratio ≤0.85.
cImpurities 1, 2, and 3 result from loss of 1, 2, and 3 N-acetylgalactosamines (GalNAcs).
dRegion 1 corresponds to acidic species that elute before the main peak, Region 2 corresponds to the main peak, and Region 3 corresponds to basic species that elute after the main peak.
aSample passes color and visual appearance assessment if it is clear to slightly opalescent, essentially free from visible particulates, and colorless to yellow.
bSilicone oil droplets and bubbles removed by removing particles with aspect ratio ≤0.85.
cImpurities 1, 2, and 3 result from loss of 1, 2, and 3 N-acetylgalactosamines (GalNAcs).
dRegion 1 corresponds to acidic species that elute before the main peak, Region 2 corresponds to the main peak, and Region 3 corresponds to basic species that elute after the main peak.
aSample passes color and visual appearance assessment if it is clear to slightly opalescent, essentially free from visible particulates, and colorless to yellow.
bSilicone oil droplets and bubbles removed by removing particles with aspect ratio ≤0.85.
cImpurities 1, 2, and 3 result from loss of 1, 2, and 3 N-acetylgalactosamines (GalNAcs).
dRegion 1 corresponds to acidic species that elute before the main peak, Region 2 corresponds to the main peak, and Region 3 corresponds to basic species that elute after the main peak.
eSample result unavailable to due instrument issue
Concentration of beta-hex in Pozelimab formulated drug substance (FDS) directly impacts Cemdisiran degradation rates in liquid co-formulations
Pozelimab with the low and high measured concentrations of beta-hex (lot 3 and lot 4, respectively) was used to manufacturing additional two co-formulations and placed in storage for a study of stability.
The two co-formulations were:
Data also showed that the rate of Cemdisiran degradation was proportional to the beta-hexosaminidase content. Co-formulations manufactured with Pozelimab lot 3, (containing 30% higher beta-hex compared to lot 4), resulted in a 30-35% faster rate of Cemdisiran degradation for both co-formulations, compared to the co-formulations manufactured with Pozelimab lot 4.
To optimize pH and the concentrations of the selected excipients for Cemdisiran & Pozelimab co-formulations, a Design of Experiment (DOE) study was developed to characterize and explore the excipient design space (see Table 3-1). A 23 co-formulation study was designed that considered all main effects, as well as the identified secondary interactions and quadratics, as defined by a risk assessment. The design was created, evaluated, and confirmed using statistical JMP software to be sufficiently powered and able to cover >95% design space with good estimation capability (i.e., prediction variance <1.0). Each co-formulation also contained 0.15% PS80.
An outline of the long-term, accelerated, and stress stability conditions, and freeze-thaw conditions is presented in Table 3-2.
Excipients, excipient concentrations and pH were chosen based on the following desirability criteria:
Excipients, excipient concentrations and pH displayed of co-formulations evaluated in the DOE experiments are set forth in
A higher pH (relative to pH 6) resulted in significant reduction in Cemdisiran degradation at 2-8° C. At a higher pH, a higher rate of Pozelimab acidic charge formation was observed, but this effect was relatively small after 2-8° C. storage for 4 months.
For the 50:100 co-formulation, a higher arginine HCl concentration (e.g., 90 mM vs 50 mM) was observed to decreased Cemdisiran degradation and allowed for a near isotonic solution.
Once sucrose concentration, arginine HCl concentration, histidine concentration, and pH was selected for each co-formulation, an agitation stability study was performed to evaluate the concentration of PS80. Surfactant is necessary for preventing protein instability at air-liquid interface. The following co-formulations were manufactured with 0.025, 0.050, 0.075, 0.1 or 0.2% (w/v) PS80:
Glass vials were fill with co-formulation and placed on an orbital shaker in sideway orientation at 250 RPM for 48 hours. All co-formulations showed no change in any monitored quality attribute, including % HMW, as shown in
Research studies were initiated to assess the long-term, accelerated, and stress stability stress for the optimized co-formulations of Cemdisiran and Pozelimab in a single formulation. Glass syringes were filled with following co-formulation and placed in storage for a stability study:
Long-term, Accelerated, and Stress Stability Study. An outline of the long-term, accelerated, and stress stability conditions, and the agitation and freeze-thaw conditions is presented in Table 3-3.
No appreciable changes in the Pozelimab stability (e.g., formation of HMW and charge variants) or Cemdisiran stability (e.g., purity) after 6 months storage at 5° C. (see Table 3-4 and Table 3-5).
There was a decrease in Cemdisiran purity (by dIPRP) in both co-formulations at 4000/75% RH. However, the rate of Cemdisiran degradation was much lower in these co-formulations than in those of other studies (
aSilicone oil droplets and bubbles removed by removing particles with aspect ratio ≤0.85.
bImpurities 1, 2, and 3 result from loss of 1, 2, and 3 N-acetylgalactosamines (GalNAcs).
cRegion 1 corresponds to acidic species that elute before the main peak, Region 2 corresponds to the main peak, and Region 3 corresponds to basic species that elute after the main peak.
aSilicone oil droplets and bubbles removed by removing particles with aspect ratio ≤0.85.
bImpurities 1, 2, and 3 result from loss of 1, 2, and 3 N-acetylgalactosamines (GalNAcs).
cRegion 1 corresponds to acidic species that elute before the main peak, Region 2 corresponds to the main peak, and Region 3 corresponds to basic species that elute after the main peak.
PNH is an ultra-rare and life-threatening acquired genetic disease characterized by chronic intravascular hemolysis due to uncontrolled complement activation, and is associated with an increased risk of thrombosis. Patients with PNH often experience severe fatigue, which can negatively impact their physical functioning and health-related quality of life (QoL). Despite available treatments, patients may continue to experience episodes of breakthrough hemolysis due to insufficient complement inhibition. Cemdisiran and Pozelimab are therapeutic agents that act together to suppress terminal complement activity. Cemdisiran is an N-acetylgalactosamine-conjugated small interfering RNA (siRNA) that suppresses liver production of complement component C5, while Pozelimab is a fully human monoclonal antibody inhibitor of human C5. The combination of Pozelimab and Cemdisiran is being evaluated in an on-going phase 2, randomized, open-label, two-arm study (NCT04811716) that is designed to assess the safety and efficacy of Pozelimab and Cemdisiran combination therapy in PNH patients who have transitioned from Pozelimab monotherapy (30 mg/kg IV loading dose of Pozelimab, then 800 mg Pozelimab SC weekly) during an open-label extension trial (see NCT04162470). Safety and efficacy results are presented herein, along with patient-reported outcomes up to Week 16.
One objective of this study is to evaluate the safety and efficacy of two dosing regimens of Pozelimab and Cemdisiran combination therapy in patients with PNH who have transitioned from Pozelimab monotherapy. Another objective of this study is to report on patient-reported fatigue and impact on functioning and overall global health status (GHS)/QoL following treatment with Pozelimab and Cemdisiran combination therapy in patients with PNH who have transitioned from Pozelimab monotherapy.
an = 9
A patient must meet the following criteria to be eligible for inclusion in the study:
A patient who meets any of the criteria listed below will be excluded from the study. Patients may be re-screened up to 2 times after discussion between the investigator and the sponsor.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to the Clinical Trial Facilitation Group (CTFG) guidance (CTFG, 2020). Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
†Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study drugs. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient.
‡Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method (LAM) are not acceptable methods of contraception.
Note: The use of a female or male condom is not sufficient as a contraceptive measure but may be considered for the safety or prevention of sexually transmitted diseases. Female condom and male condom should not be used together
Methods: Patients (n=22) are randomized (1:1) into one of two treatment arms; both arms received subcutaneous (SC) Cemdisiran 200 mg every 4 weeks (Q4W) plus Pozelimab 400 mg SC at a frequency of either Q4W (arm 1) or every 2 weeks (Q2W; arm 2). The study consists of four periods:
The screening period is approximately 7 to 8 days. The duration of the OLTP (main study period) for a patient is a minimum of approximately 28 weeks. The duration will be longer for patients who require treatment intensification, which consists of a 28-week treatment regimen starting from the day of intensification. Patients who do not continue into the optional OLEP will be followed for an additional 52 weeks after the last dose of combination treatment. Patients opting to participate in the OLEP will continue open-label treatment for a 52-week period, to be followed by a 52-week safety follow-up period after the last dose of study treatment. Patients who complete the optional OLEP may be able to continue study treatment in a post-trial access program. Patients participating in the post-trial access program will therefore not be followed in the safety follow-up period.
Screening (7 to 8 days): The dose of Pozelimab is administered at the study site on the day of the screening visit in this study, which occurs on the day of a planned administration with Pozelimab monotherapy. Subsequently, the day 1 visit for the first combination treatment dosing occurs 7 to 8 days after the last dose of Pozelimab monotherapy.
As part of risk mitigation for this study, patients need to have documented vaccination against Neisseria meningitidis and receive updated meningococcal vaccination if needed. Daily oral antibiotic prophylaxis is recommended throughout the study. Patients are counseled regarding risk of infection with Neisseria gonorrhea, as applicable based on their risk level.
In addition to screening procedures to determine eligibility, patients are asked to complete a PNH Symptom-Specific Questionnaire daily for 7 consecutive days prior to the day 1 visit. Patients could choose to participate in the optional OLEP (open label extension period), optional future biomedical research, and/or optional pharmacogenomics component of the study by signing the respective optional informed consent forms.
Treatment Period (Day 1 to Week 28): Day 1 is scheduled 7 to 8 days after the last dose of Pozelimab monotherapy. On day 1, after confirming eligibility, patients are randomized in a 1:1 ratio to 1 of the 2 arms:
Optional Open-Label Extension Period (OLEP): All patients who complete the OLTP (including patients who receive intensified treatment) are offered the opportunity to continue in an optional 52-week OLEP, whereby the transition of the combination treatment from the OLTP to the OLEP is planned to be uninterrupted (i.e., day 1 visit of the OLE will correspond to the end of treatment (EOT) visit of the OLTP).
Patients whose treatment is not intensified during the main study period transition to the OLEP on a regimen of Pozelimab 400 mg SC Q4W and Cemdisiran 200 mg SC Q4W, regardless of their treatment assignment in the main treatment period. Patients whose treatment is intensified during the main study period transition to the OLEP and continue on the intensified treatment regimen of Pozelimab 400 mg SC Q2W and Cemdisiran 200 mg SC Q4W.
The OLEP ends 52 weeks after the first dose of study treatment in the OLEP, even if the patient requires intensified treatment during the OLEP. For patients who complete the optional OLEP, post-trial access to treatment may be available.
Combining pozelimab and Cemdisiran will rapidly and continuously suppress concentrations of C5 to pharmacologically inactive levels. A target-mediated drug disposition (TMDD) population PK model for Pozelimab and a population PK/PD model for Cemdisiran were developed based on respective data on healthy subjects. The models for Pozelimab and Cemdisiran were combined by introducing 05 production suppression effect of Cemdisiran to the synthesis rate of 05 in the TMDD model for Pozelimab. The unified model was used to perform simulations to inform dose selection of Pozelimab in combination with Cemdisiran. Based on simulations, Pozelimab 400 mg SC Q4W and Cemdisiran 200 mg SC Q4W will be sufficient to maintain the suppression of 05 to biologically inactive levels. In addition, at steady-state, the simulated total and free pozelimab concentration-time profiles are superimposable. This is consistent with the extremely low concentration of free 05 predicted by the unified population PK/PD model.
See the schedule of the various doses administered in Table 4-2 to 4-5 below.
Neisseria
gonorrhea
9
Neisseria
meningitidis
10
1Visits between week 6 and up to week 24 may be at the clinical site, or another preferred location, such as the patient's home. The location will be dependent on availability of home healthcare visiting professional as well as the preferences of the investigator and patient. In the event of travel restrictions due to a global pandemic, alternative mechanisms such as but not limited to telemedicine visits may be implemented to maintain continuity of study conduct.
2When multiple procedures are performed on the same day, the sequence of procedures is as follows: Clinical outcome assessments (COAs) → Electrocardiogram (ECG) → vital signs, physical examination, safety monitoring, lab collection → study treatment administration → any pre-specified post-dose sample collection.
3Patients who are re-started on an intensified treatment will undergo an adjustment to their scheduled visits. Patients may require unscheduled visit(s) as needed and should be subsequently followed per the Schedule of Events for Patients on Intensified Treatment in the OLTP.
4The day 1 visit should take place 7 to 8 days after the screening visit. Patients may be rescreened if they cannot schedule the screening visit and the day 1 visit over a period of 7 to 8 days.
5If the patient agrees to continue into the optional OLEP, the End of Treatment (EOT) visit of the OLTP will correspond to the day 1e visit of the OLEP (see Schedule of Events (Optional Open-Label Extension Period)). Any common assessments will be performed once for both visits.
6 Transfusions, breakthrough hemolysis history, and laboratory parameters for measurement of hemolysis (such as LDH, bilirubin, haptoglobin, reticulocyte count, and hemoglobin) should be obtained for the past 52 weeks, if possible. Prior history of thrombosis and Neisseria infections will be collected. Ongoing PNH symptoms and signs will also be collected. Information collected from parent studies may be used whenever possible.
7 Including Pozelimab administration.
8 Patients will have had previous documented vaccination for meningococcus (serotypes A, C, Y, W and serotype B if available) in the parent study, R3918-PNH-1868 (“An open-label extension study to evaluate the long-term safety, tolerability, and efficacy of REGN3918 in patients with paroxysmal nocturnal hemoglobinuria”), but may be revaccinated if prior vaccination is more than 5 years from screening. Alternatively, patients may be re-vaccinated in accordance with current national vaccination guidelines for vaccination use with complement inhibitors or local practice. Patients who require revaccination may be rescreened.
9 A risk factor assessment for Neisseria gonorrhea infection is recommended, and counseling is advised for at-risk patients.
10 A patient safety card will be distributed to patients at screening and risk information will be reviewed. Replacement cards may be given to the patient as needed.
11 During OLTP, the dose of Cemdisiran and Pozelimab SC should be given on the day of the corresponding study visit whenever possible. Study treatment administration should always be the last procedure after all blood sample collection and study assessments have been completed unless otherwise specified.
12Patients should be monitored for at least 30 minutes after completing the first Cemdisiran injection. A 30 minute monitoring period is not needed after the Pozelimab injection.
13 Injection training will be provided to patients who desire self-injection or injection by a designated person. Sites should observe patient self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be provided. SC injections may either be performed by the site personnel or another healthcare professional at the patient's home or preferred location, or be administered by the patient or a designated person who has successfully completed the injection training.
14 If study treatment is given by the patient or by a designated person, the patient will complete a diary for recording compliance with study treatment administration. If patient diary is provided to the patient, then it should be reviewed at each clinic visit and data collected into the case report forms (CRFs). On the final visit, the diary should be collected by the site.
15 At the screening visit, patient diary should be reviewed for the R3918-PNH-1868 (parent) study.
16 Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting on the first day of dosing with study treatment and continuing until 52 weeks after discontinuation of study treatment.
17 Patient will complete daily PNH Symptom-Specific Questionnaire for 7 consecutive days prior to day 1 visit. Patients should try to complete the PNH Symptom-Specific Questionnaire at the same time each day whenever possible.
18 Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough hemolysis event, then in addition to the required laboratory collection, additional samples will be collected unless already noted in the schedule of events for that visit. If the suspected event does not occur at a scheduled visit, then an unscheduled visit should occur with an evaluation of the patient and collection of samples for suspected breakthrough hemolysis assessment. Unscheduled blood collection for suspected breakthrough hemolysis events should include, at a minimum, CBC, reticulocyte count, chemistry, coagulation parameters, D-dimer, total C5, CH50, ADA (against Pozelimab), and drug concentrations of Pozelimab, as applicable.
19Clinical lab samples will be collected prior to any study drug administration (pre-dose) unless otherwise specified. The same methodology will be applied across study visits for lab sample collection, handling and processing, as best as possible, to preserve the quality of samples and minimize hemolysis. The coagulation blood sample (tube) must always be collected first, followed by the blood chemistry sample (tube).
20 Serum LDH, C-reactive protein (CRP), and bilirubin (total and direct) will be assessed as part of the blood chemistry analysis. Blood chemistry sample should be collected before study treatment administration (pre-dose). During lab collection, handling and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the lab result is not an accurate reflection of the patient's condition, the lab sample should be repeated.
21 Hematology sample should be collected before study treatment administration (pre-dose).
22 Blood samples for Pozelimab concentration analysis and total C5 analysis will be obtained on the specified days prior to any study treatment administration (pre-dose).
23 Blood samples for Cemdisiran concentration analysis and concentrations of its metabolites will be collected on the specified days prior to any study treatment administration (pre-dose) and 2 to 6 hours post Cemdisiran administration. The post-dose sample should be carefully coordinated with the dosing of Cemdisiran and may be collected at the clinic or by a visiting health care professional.
24Blood samples for immunogenicity will be collected on the specified days prior to any study treatment administration (pre-dose). At the visits where immunogenicity samples are to be taken, the sample should be collected with the sample for drug concentration. In the event of suspected treatment-related SAEs, such as anaphylaxis or hypersensitivity, additional samples for drug concentration and immunogenicity may be collected at or near the onset and the resolution of the event.
25 Blood samples for CH50 (efficacy endpoint) and AH50 will be obtained prior to any study treatment administration (pre-dose).
26 Whole blood samples for DNA extraction (optional) should be collected on day 1 (pre-dose) but can be collected at a later study visit. Patients who had consented to DNA testing in a prior study with Pozelimab and had provided a sample for analysis do not need to provide separate consent/sample for this study.
Neisseria
meningitidis
12
3The intensified treatment schedule will be anchored to the day of intensification (i.e., a reset occurs with the day of intensification becoming the day 1r visit and subsequent visits following the schedule of events for intensified treatment). Patients who receive intensified treatment will be considered to have complete the study once they finish the 28-week treatment period with the intensified treatment (i.e., after completing week 28r EOT assessments).
4During the intensified treatment period in the OLTP, the dose of Cemdisiran and Pozelimab SC should be given on the day of the corresponding study visit whenever possible. Study treatment administration should always be the last procedure after all blood sample collection and study assessments have been completed unless otherwise specified. If Pozelimab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 3 days before or up to 3 days after the planned dosing date provided that the dosing takes place after the corresponding study visit has been completed. For example, the day 29r (week 4r) visit can take place from day 26r to day 32r given the visit window of ±3 days for the week 4r visit. The dose of Pozelimab and Cemdisiran, therefore, can be given from day 26r to day 32r, but only on or after the week 4r visit assessments have been performed. Similarly, the day 113r (week 16r) visit can take place from day 106r to day 116r given the visit window of −7/+3 days for the week 16r visit. The dose of Pozelimab and Cemdisiran can be given from day 110r to day 116r, but only on or after the week 16r visit assessments have been performed. Care must be taken to coordinate dosing for visits where a post-dose sample is collected to measure concentration of Cemdisiran and its metabolites. For patients on intensified treatment in the OLTP, the final SC dose of Cemdisiran is at week 24r and the final SC dose of Pozelimab is at week 26r.
5For these visits, the dosing window (±3 days) is narrower than the study visit window (−7/+3 days).
6If the patient agrees to continue into the optional OLEP, the EOT visit of the OLTP will correspond to the day 1e visit of the OLEP. Any common assessments will be performed once for both visits.
7On day 1r, Pozelimab IV will be given first, with a 30-minute observation period before administration of SC doses. Subsequent Pozelimab SC dose will be administered Q2W and Cemdisiran SC dose will be administered Q4W. The SC injections may either be performed by the site personnel or another healthcare professional at patient's home or preferred location, or be administered by the patient or by a designated person who has successfully completed the injection training.
8Injection training will be provided to patients who desire self-injection or injection by a designated person. Site should observe patient self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be provided.
9If study treatment is given by the patient or by a designated person, the patient will complete a diary for recording compliance with study treatment administration. If patient diary is provided to the patient, then it should be reviewed at each clinic visit and data collected into the CRFs. On the final visit, the diary should be collected by the site.
10Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended until 52 weeks after discontinuation of study treatment.
11Patients should try to complete the PNH Symptom-Specific Questionnaire at the same time each day whenever possible.
12Patient safety card: Site should review the instructions on the safety card with the patient at each visit. Replacement cards may be given to the patient as needed.
13Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough hemolysis event, then, in addition to the required laboratory collection, additional samples for drug concentrations of Pozelimab will be collected unless already noted in the schedule of events for that visit. If the suspected event does not occur at a scheduled visit, then an unscheduled visit should occur with an evaluation of the patient and collection of coagulation, chemistry, and drug concentrations of Pozelimab.
14Clinical lab samples will be collected prior to any study drug administration (pre-dose) unless otherwise specified. During lab collection, handling and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis. The coagulation blood sample (tube) must always be collected first, followed by the blood chemistry sample (tube).
15Serum LDH, CRP, and bilirubin (total and direct) will be assessed as part of the blood chemistry analysis. Blood chemistry sample should be collected before study treatment administration (pre-dose). During lab collection, handling and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the lab result is not an accurate reflection of the patient's condition, the lab sample should be repeated.
16Hematology sample should be collected before study treatment administration (pre-dose).
17Pregnancy test for WOCBP: A urine test will be done at all visits indicated. Any positive urine pregnancy test should be confirmed with a serum pregnancy test.
18On day 1r, obtain blood sample for Pozelimab concentration and total C5 prior to IV administration of Pozelimab and also within 15 minutes after the end of the IV infusion. At subsequent timepoints, blood samples for Pozelimab drug concentration analysis and total C5 analysis will be obtained prior to any study treatment administration (pre-dose).
19Blood samples for Cemdisiran drug concentration analysis and concentrations of its metabolites will be collected on the specified days prior to any study treatment administration (pre-dose) and 2 to 6 hours post-Cemdisiran administration. The post-dose sample should be carefully coordinated with the dosing of Cemdisiran and may be collected at the clinic or by a visiting health care professional.
20Blood samples for immunogenicity will be collected on the specified days prior to any study treatment administration (pre-dose). At the visits where immunogenicity samples are to be taken, the sample should be collected with the sample for drug concentration. In the event of suspected treatment-related SAEs, such as anaphylaxis or hypersensitivity, additional samples for drug concentration and immunogenicity may be collected at or near the onset and the resolution of the event.
21Blood samples for CH50 (efficacy endpoint) and AH50 will be obtained prior to any study treatment administration (pre-dose).
Neisseria
meningitidis
9
3Day 1e of OLEP should be scheduled on the same day as week 28 (or week 28r for patients on intensified treatment) of the OLTP, and any common assessments will be performed once for both the OLTP and OLEP visits.
4For patients who did not receive intensified treatment during OLTP: At any time during the OLEP, patients who meet pre-specified criteria will receive intensified treatment of a Pozelimab 30 mg/kg IV loading dose followed 30 minutes later by the initiation of Pozelimab 400 mg SC Q2W and Cemdisiran 200 mg SC Q4W. Patients should be observed for 30 minutes in the interim between the IV and SC doses. Patients will continue their visit schedule at the next OLEP visit.
5During the OLEP, the dose of Cemdisiran and Pozelimab SC should be given on the day of the corresponding study visit whenever possible. Study treatment administration should always be the last procedure after all blood sample collection and study assessments have been completed unless otherwise specified:
6Injection training will be provided to patients who desire self-injection or injection by a designated person. Site should observe patient self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be provided.
7If study treatment is given by the patient or by a designated person, the patient will complete a diary for recording compliance with study treatment administration. If patient diary is provided to the patient, then it should be reviewed at each clinic visit and data collected into the CRFs. On the final visit, the diary should be collected by the site.
8Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended until 52 weeks after discontinuation of study treatment.
9 Patient safety card: Site should review the instructions on the safety card with the patient at each visit. Replacement cards may be given to the patient as needed.
10Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough hemolysis event, then in addition to the required laboratory collection, additional samples for drug concentrations of Pozelimab will be collected unless already noted in the schedule of events for that visit. If the suspected event does not occur at a scheduled visit, then an unscheduled visit should occur with an evaluation of the patient and collection of coagulation, chemistry, and drug concentration of Pozelimab.
11Clinical lab samples will be collected prior to any study drug administration (pre-dose) unless otherwise specified. During lab collection, handling and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis. The coagulation blood sample (tube) must always be collected first, followed by the blood chemistry sample (tube).
12Serum LDH, CRP, and bilirubin (total and direct) will be assessed as part of the blood chemistry analysis. Blood chemistry sample should be collected before study treatment administration (pre-dose). During lab collection, handling and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the lab result is not an accurate reflection of the patient's condition, the lab sample should be repeated.
13Hematology sample should be collected before study treatment administration (pre-dose).
14Pregnancy test for WOCBP: A urine test will be done at all visits indicated. Any positive urine pregnancy test should be confirmed with a serum pregnancy test.
15Blood samples for Pozelimab concentration analysis and total C5 analysis will be obtained on the specified days prior to any study treatment administration (pre-dose).
16Blood samples for Cemdisiran concentration analysis and concentrations of its metabolites will be collected on the specified days prior to any study treatment administration (pre-dose) and 2 to 6 hours post Cemdisiran administration. The post-dose sample should be carefully coordinated with the dosing of Cemdisiran and may be collected at the clinic or by a visiting health care professional.
17Blood samples for immunogenicity will be collected on the specified days prior to any study treatment administration (pre-dose). At the visits where immunogenicity samples are to be taken, the sample should be collected with the drug concentration sample. In the event of suspected treatment-related SAEs, such as anaphylaxis or hypersensitivity, additional drug concentration and immunogenicity samples may be collected at or near the onset and the resolution of the event.
18Blood samples for CH50 (efficacy endpoint) and AH50 will be obtained prior to any study treatment administration (pre-dose).
meningitidis
1
1Patient safety card: Site should review the instructions on the safety card with the patient at each visit. Replacement cards may be given to the patient as needed.
2Daily oral antibiotic prophylaxis against N. meningitidis is recommended until 52 weeks after discontinuation of study treatment.
Patients will be given intensified treatment if they meet both of the following criteria:
Patients' treatment will be intensified depending on their assigned treatment group as outlined below. An assessment of the patient's weight should be performed on the day of the IV Pozelimab load in order to calculate the appropriate dose.
Patients who undergo treatment intensification may require unscheduled visit(s) prior to intensification. During the OLTP, patients whose treatment is intensified should follow Table 4-3 (Schedule of Events for Patients on Intensified Treatment in the OLTP), with the day of intensification anchored to day 1r (RV1). Patients who restarted on an intensified treatment will be considered to have completed the OLTP once they receive 28 weeks of the intensified treatment and complete Week 28r assessments.
During the OLEP, patients who are not on intensified treatment who meet criteria for treatment intensification will receive a single administration of Pozelimab 30 mg/kg IV based on their current weight on the day of intensification+an intensified regimen of Pozelimab 400 mg Q2W along with Cemdisiran 200 mg Q4W starting on the day of intensification and for the remainder of the OLEP. Patients will continue their visit schedule at the next OLEP visit.
Patients who experience breakthrough hemolysis that is not due to a complement activating condition and meet criteria for treatment intensification are eligible to receive intensification of Pozelimab only once (whether during the main treatment period or the OLEP), beyond which no further intensification will be permitted.
Note: In the event of an LDH increase >2×ULN due to an acute complement activating condition during the OLTP or OLEP, an IV bolus of Pozelimab 30 mg/kg IV may be given. An assessment of the patient's weight should be performed on the day of the IV Pozelimab load in order to calculate the appropriate dose. This is not considered treatment intensification. No other changes will be made to the study treatment regimen (i.e., the regular dose and frequency of Pozelimab and Cemdisiran will proceed unchanged). Patients will continue onto the next visit of their current visit schedule.
Note: The IV dose should be administered first. The SC doses should be given at least 30 minutes after completion of the IV administration.
The primary objective of the study is to evaluate the safety and tolerability of 2 dosing regimens of Pozelimab and Cemdisiran combination therapy during the open-label treatment period (OLTP).
The secondary objectives of the study are:
The exploratory objectives of the study are:
The primary endpoint is the incidence and severity of TEAEs through week 28 of the OLTP.
The secondary endpoints for the OLTP are:
The exploratory endpoints for the OLTP are:
Patients who experience breakthrough hemolysis may receive intensified treatment as described herein. Breakthrough hemolysis is defined as an increase in LDH with concomitant signs or symptoms associated with hemolysis:
The signs or symptoms should correspond to those known to be associated with intravascular hemolysis due to PNH, limited to the following: new onset or worsening fatigue, headache, dyspnea, hemoglobinuria, abdominal pain, scleral icterus, erectile dysfunction, chest pain, confusion, dysphagia, new thrombotic event, anemia including hemoglobin value significantly lower (i.e., ≥2 g/dL decrease) as compared to patient's known baseline hemoglobin values.
Efficacy in this study is evaluated by the following laboratory assessments (Laboratory Variables for the Assessment of Efficacy):
These laboratory variables are relevant to the characterization and disease mechanisms of PNH (Brodsky, Paroxysmal nocturnal hemoglobinuria. Blood 2014; 124(18):2804-11).
Hemolytic anemia is a clinical manifestation of PNH, and patients often require blood transfusion for symptomatic management. The frequency of blood transfusion has been used in other studies of PNH to assess efficacy (Hillmen et al., The complement inhibitor Eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006; 355(12):1233-43) (Röth et al., Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Adv 2018; 2(17):2176-85).
Clinical Outcome Assessments (COAs) include the following:
Patients complete the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale and the European Organization for Research and Treatment of Cancer: Physical function assessments and QoL Questionnaire GHS/QoL. FACIT-Fatigue scores range from 0 to 52, with higher scores indicating less fatigue. EORTCQLQ-C30 scores range from 0 to 100; a high score for a functional scale represents a high/healthy level of functioning and a high score for the GHS/QoL represents a high QoL. These assessments are completed at baseline and intermittently throughout the OLTP. Higher scores indicate less fatigue or a better level of functioning or GHS/QoL. In this study, all baseline values and assessments are carried out before patients received the first dose of their assigned combination therapy. Pre-treatment baseline values are given for a previous phase 2 trial where all patients receive open-label Pozelimab monotherapy (see NCT03946748).
At the time of this analysis, all 22 randomized patients were ongoing in the study (median duration of 57 days), including one who had completed the OLTP and was continuing in the OLEP, and no patient required treatment intensification. At study baseline, patients were well controlled on Pozelimab monotherapy. Patient baseline demographics and characteristics from this study are summarized in Table 4-1.
Efficacy outcomes: Twenty-one patients (95.5%) maintained adequate control of hemolysis (LDH; ≤1.5×ULN) up until the data cut-off (
Treatment-emergent adverse events (TEAEs): There were no serious TEAEs or TEAEs leading to study drug discontinuation in any patient from either treatment group. Importantly, there were no meningococcal infections or TEAEs leading to death in this study. Six patients (27.3%; three from each treatment arm) experienced a total of 12 TEAEs. One patient (8.3%) in arm 1 experienced one adverse event of special interest, a mild injection-site reaction characterized by stinging lasting 30 minutes. All TEAEs were of mild-to-moderate intensity, except for a single severe TEAE of anemia occurring in one patient from the Pozelimab Q2W+Cemdisiran treatment group (arm 2). This same patient had previously experienced a moderate non-serious TEAE of breakthrough hemolysis, which was not considered related to the study treatment by the investigator.
Patient-reported outcomes: Before receiving Pozelimab monotherapy in the previous phase 2 trial (NCT03946748), mean (standard deviation [SD]) pre-treatment values were 32.3 (15.2) for FACIT-Fatigue scores, 70.9 (22.5) for physical functioning scores, and 60.6 (22.4) for GHS/QoL scores. For this study, baseline values were representative of the Pozelimab monotherapy that the patients were receiving prior to transitioning to the combination therapy. At study baseline, when patients transitioned from previous Pozelimab monotherapy, mean (SD) FACIT-Fatigue scores were 45.4 (5.5) and 45.0 (3.4) for arm 1 and arm 2, respectively (
aPre-treatment baseline values are given for the previous phase 2 trial where all patients received open-label Pozelimab monotherapy (NCT03946748).
bFACIT-Fatigue: scores range from 0 to 52, with higher scores indicating less fatigue.
cEORTC QLQ-C30: scores range from 0 to 100; a high score for a functional scale represents a high/healthy level of functioning, a high score for the GHS/QoL represents a high QoL.
The combination of Pozelimab and Cemdisiran was generally well tolerated in patients with PNH who transitioned from Pozelimab monotherapy (NCT04162470), regardless of the treatment arm. Over 90% of patients maintained adequate control of hemolysis and achieved hemoglobin stabilization. Furthermore, most patients maintained normalization of their LDH during the observation period. Accordingly, this combination therapy demonstrates significant efficacy in treating patients with PNH who transitioned from Pozelimab monotherapy.
Additionally, PNH patients who transitioned from Pozelimab monotherapy experienced meaningful improvements in pre-treatment fatigue (>5 point improvement in FACIT-Fatigue), and improvements in physical functioning, and GHS/QoL. Improvements in these scores were maintained by the combination treatment through to Week 16, particularly with the Pozelimab Q4W and Cemdisiran dose regimen. Despite the limited sample size, this evidence shows that Pozelimab and Cemdisiran combination therapy, especially the Q4W regimen, maintained improvements in patient fatigue, physical functioning, and GHS/QoL.
Prior to receiving Pozelimab monotherapy, mean (standard deviation [SD]) pre-treatment values were 32.3 (15.2) for FACIT-Fatigue scores (Table 4-13), 60.6 (22.4) for GHS/QoL scores (Table 4-23), and 70.9 (22.5) for physical functioning scores (Table 4-33; and Table 4-7). For the current trial, baseline values were representative of the effect of Pozelimab monotherapy that the patients were receiving prior to transitioning to the combination therapy. The mean (SD) FACIT-Fatigue score at baseline was 45.4 (5.6) for arm 1 (Pozelimab q4w and Cemdisiran q4w) and 45.6 (3.6) for arm 2 (Pozelimab q2w and Cemdisiran q4w) (Table 4-14; and Table 4-7). Over Weeks 2-28, the mean FACIT-Fatigue scores were 40.3-45.2 for arm 1 and 36.5-42.9 for arm 2 (Table 4-14-Table 4-22). The mean (SD) physical functioning score at baseline was 93.3 (8.8) for arm 1 and 94.2 (9.0) for arm 2 (Table 4-34). Over Weeks 2-28, the mean physical functioning scores were 90.0-95.0 for arm 1 and 82.0-90.9 for arm 2 (Table 4-35 Table 4-42; and Table 4-7). The mean (SD) GHS/QoL scores were well controlled and similar for both treatment arms at baseline (77.8 [14.4] for arm 1 and 80.2 [20.9] for arm 2) (Table 4-24). Over Weeks 2-28, the mean GHS/QoL scores were 69.2-77.3 for arm 1 and 66.7-75.8 for arm 2 (Table 4-24-Table 4-32; and Table 4-7).
At the time of this analysis, all patients had completed the OLTP; 23 entered the optional OLEP (Table 4-8). During the OLTP, 20 patients (83.3%) maintained control of lactate dehydrogenase (LDH; ≤1.5× upper limit of normal [ULN]) at all timepoints (most patients maintained an LDH<1.0×ULN) (
At data cut-off, 16 patients (66.7%; seven from arm-1 and nine from arm-2) experienced a total of 46 treatment-emergent adverse events (TEAEs); none leading to treatment discontinuation; 43 were of mild-to-moderate intensity (Table 4-11). Three severe TEAEs occurred in 2 patients, one patient had anemia, another patient had 2 events—gastroenteritis in association with an event of breakthrough hemolysis. Three patients in arm 2 had 1 serious TEAE each (COVID-19, upper respiratory tract infection, aforementioned gastroenteritis). No serious/severe TEAEs were considered related to study treatment, and all resolved. There were no meningococcal infections, thrombotic events, or deaths (Table 4-12 and Table 4-13).
Patients with PNH who transitioned from Pozelimab monotherapy had improved baseline scores compared with pre-treatment for their GHS/QoL, physical functioning, and fatigue scores. Improvements in these scores were maintained by the combination treatment through to Week 28, particularly with the Pozelimab Q4W and Cemdisiran dose regimen. Although further validation of these finding in a larger data set would be needed, this evidence suggests that Pozelimab and Cemdisiran combination therapy, particularly the Q4W regimen, improves and maintains improvements in patient fatigue, physical functioning, and QoL.
The combination of Pozelimab and Cemdisiran was generally well tolerated in patients with PNH, regardless of treatment arm. Overall, 83.3% maintained adequate control of hemolysis (Table 4-9), most maintaining normalization of LDH with 75% achieving hemoglobin stabilization during the OLTP. These findings support the ongoing development of this combination therapy in the treatment of patients with PNH.
aFACIT-Fatigue: scores range from 0 to 52, with higher scores indicating less fatigue.
bEORTC QLQ-C30: scores range from 0 to 100; a high score for a functional scale represents a high/healthy level of functioning, a high score for the GHS/QoL represents a high QoL.
cPre-treatment baseline values are given for the previous phase 2 trial where all patients received open-label Pozelimab monotherapy (NCT03946748).
dSeven patients in this study completed PRO instruments after receiving baseline treatment and thus were removed from analysis at this timepoint.
2 (16.7%)
67:100
87:100
80:100
47:100
80:100
47:100
73:100
40:100
40:100
At data cut-off, all 24 randomized patients completed the OLTP, and 23 entered the optional OLEP. No patient required treatment intensification.
At study baseline, patients were well controlled on Pozelimab monotherapy (Table 4-43).
an = 11.
The majority of patients achieved an LDH≤1.5×ULN at each visit throughout the OLTP (
Two patients (both from Arm 2) experienced an episode of moderate non-serious breakthrough hemolysis (one in association with a chlamydia infection, and one associated with gastroenteritis).
In total, four patients received blood transfusions from baseline through to Week 28 (Day 197; all patients from Arm 2). This includes the two patients with an event of breakthrough hemolysis (both patients continued to receive the combination therapy after receiving a blood transfusion).
At the time of this primary analysis, 75.0% (18 of 24) of patients met the criteria for hemoglobin stabilization (i.e., did not receive a red blood cell transfusion and had no decrease in hemoglobin ≥2 g/dL;
CH50, a measure of total complement hemolysis activity, remained fully suppressed at all post-baseline timepoints measured, including during the aforementioned breakthrough hemolysis events.
A total of 46 treatment-emergent adverse events (TEAEs) were reported in 16 patients (66.7%), none of which led to treatment discontinuation; 43 were of mild-to-moderate intensity.
Three severe TEAEs occurred in two patients: one patient had anemia, and another patient had two events (gastroenteritis in association with an event of breakthrough hemolysis).
Three patients in arm 2 had one serious TEAE each (COVID-19, upper respiratory tract infection, and the aforementioned gastroenteritis).
No serious or severe TEAEs were considered related to the study treatment, and all were resolved. There were no meningococcal infections, thrombotic events or deaths.
At the time of this primary analysis, Pozelimab and Cemdisiran combination treatment was generally well tolerated in patients with PNH who transitioned from Pozelimab monotherapy, regardless of the treatment arm.
The majority of patients maintained adequate control of hemolysis, most maintaining normalization of LDH (<1.0×ULN).
Most patients (75%) achieved hemoglobin stabilization during the OLTP.
These findings support the ongoing development of the combination of Pozelimab and Cemdisiran for the treatment of patients with PNH.
PNH is an ultra-rare, acquired disorder caused by a mutation in the phosphatidylinositol glycan class A (PIGA) gene, which leads to impaired expression of complement-regulating proteins on the surface of hematopoietic cells. Clinical presentation of PNH includes hemolytic anemia, hemoglobinuria, and thrombosis. Complement component C5 inhibitors such as Eculizumab are part of the current standard of care for PNH patients; however, this is an intravenous treatment which relies on nurse administration. In addition, some patients experience an incomplete response to therapy, and may still experience breakthrough hemolytic events. Pozelimab and Cemdisiran are therapeutic agents with a subcutaneous maintenance regimen that may be self-administered. Both agents act together to inhibit terminal complement through complementary mechanisms of action. The efficacy and safety of the combination of Pozelimab and Cemdisiran is being evaluated in an ongoing, phase 2, open-label single-arm study in patients with PNH who switch from Eculizumab therapy (NCT04888507).
The study has 4 periods: a screening period of up to 42 days, a 32-week open label treatment period (OLTP (main study period), longer for patients who are switched to treatment intensification), an optional 52-week OLEP (Open-label extension period (an optional period)), and a 52-week post-treatment safety follow-up period. The fourth period begins when a patient completes or permanently discontinues study treatment (e.g., at the time of premature study drug discontinuation, at the completion of study treatment in the OLTP for patients who decline the optional OLEP, or at the completion of study treatment in the optional OLEP). See the study flow diagram of
Safety and efficacy results are presented herein. Baseline characteristics of subjects is set forth in Table 5-1.
aPre-treatment LDH values.
bThree samples were missing from the central laboratory, so local laboratory pre-study PNH clone data were used.
A patient must meet the following criteria to be eligible for inclusion in the study:
A patient who meets any of the following criteria will be excluded from the study:
This phase 2 trial consists of a screening period (up to 42 days), a 32-week open-label treatment period (OLTP), an optional 52-week open-label extension period, and a 52-week post-treatment safety follow-up period. Patients transition from Eculizumab therapy to the combination of Pozelimab and Cemdisiran. An IV loading dose of Pozelimab is administered prior to the first dose of subcutaneous Pozelimab. The combination of subcutaneous Pozelimab and subcutaneous Cemdisiran are administered every 4 weeks.
Adequate control of hemolysis is defined as lactate dehydrogenase (LDH)≤1.5×ULN. Breakthrough hemolysis is defined as an increase in LDH (LDH≥2×ULN if pre-treatment LDH was <1.5×ULN, or LDH≥2×ULN after initial achievement of LDH≤1.5×ULN if pre-treatment LDH was >1.5×ULN) with concomitant signs or symptoms associated with hemolysis.
For the first approximately 2 weeks, patients remain on Eculizumab background treatment at their usual dose/frequency, and Cemdisiran alone is introduced. Lead-in Cemdisiran treatment and background concomitant treatment with Eculizumab Day 1 (the day of patient's scheduled Eculizumab administration): Cemdisiran 200 mg SC and Eculizumab ≥900 mg IV (at the patient's usual dose). Note: Eculizumab may be administered up to 2 days after Cemdisiran if not administered with Cemdisiran on day 1. Day 15: For patients on Eculizumab Q14 days (labeled dose regimen): day 15 (±2 days), i.e., day 13 to day 17; For patients on Eculizumab more frequently than Q14 days: patients are to be dosed within 2 days of their usual planned dose.
The following dosage regimen of Pozelimab/Cemdisiran combination therapy is administered during the switch from Eculizumab treatment: Pozelimab/Cemdisiran combination treatment: Day 29 (week 4): Pozelimab 60 mg/kg IV loading dose, followed (after a delay of at least 30 minutes) by Pozelimab 400 mg SC and Cemdisiran 200 mg SC; Day 57 (week 8) to day 197 (week 28): Pozelimab 400 mg SC and Cemdisiran 200 mg SC Q4W maintenance regimen (±7 days).
While the overall goal of the proposed dosing regimen is to prevent hemolysis, the transition period of the combination treatment initiation is also designed to mitigate the potential for the formation of large drug-target-drug (DTD) immune complexes of eculizumab-C5-pozelimab during the treatment switch. A lead-in cemdisiran dose plus a loading dose of pozelimab should minimize large DTD immune complex formation. A previous clinical study reported adverse reactions (e.g., serum sickness-like reactions, skin rash), upon switching from eculizumab to another anti-C5 mAb, crovalimab, attributed to the formation of immune complexes between C5 and the 2 non-competing C5 mAbs (Röth et al., Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies. Blood Adv 2018; 2(17):2176-85). See Nishidate et al., Validation of a method to analyze size distribution of crovalimab-complement C5-eculizumab complexes in human serum. Bioanalysis. 2022 July; 14(13):935-947-Epub 2022 Jul. 29; Nishimura et al., Mitigating Drug-Target-Drug Complexes in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Switch C5 Inhibitors. Clin Pharmacol Ther. 2023 April; 113(4):904-915-Epub 2023 Feb. 12. Similarly, pozelimab has been shown to bind C5 non-competitively with eculizumab (R3918-PH-19074), and thus has the potential to form higher-order immune complexes in the presence of eculizumab and C5. In vitro studies were conducted to simulate conditions that may occur when pozelimab is administered to a patient previously dosed with eculizumab. Neither pozelimab nor antibodies having the Eculizumab amino acid sequence (Eculizumab*) individually formed higher order multimers larger than a 1:2 mAb:C5 complex. Pozelimab was added to pre-formed eculizumab*:C5 complexes under conditions of excess pozelimab (5:1:1 pozelimab: eculizumab*:C5) and equimolar amounts of total mAb to C5 (1:1:2 pozelimab: eculizumab*:C5). Under conditions of pozelimab excess, the majority of complexes observed (˜86%) were either trimeric or pentameric (2:1 or 3:2 mAb:C5 molar ratios, respectively), with the remainder comprising large DTD immune complexes. At an equimolar ratio of total mAb and C5, the majority of the samples (˜86%) consisted of heterogeneous large DTD immune complexes larger than pentamers. In summary, while eculizumab* and pozelimab in combination were able to form heteromeric complexes with C5, the presence of excess pozelimab reduced the formation of higher-order immune complexes relative to conditions where total mAb and C5 were present at equimolar concentrations. In the current study, a 4-week lead-in period with a dose of cemdisiran 200 mg SC is provided. This is expected to reduce C5 production and consequently lower the total C5 (eculizumab*-C5 complexes plus free C5) level (about 86% reduction of total C5 on day 29 compared to day 1), before the initiation of the pozelimab/cemdisiran combination treatment. Consequently, the potential for the formation of the large DTD immune complexes should be significantly reduced. To further minimize the risk of formation of large DTD immune complexes upon initiating pozelimab/cemdisiran combination treatment, a loading dose of pozelimab 60 mg/kg IV is provided. Based on reported mean trough concentrations of eculizumab of 97 mg/L (Soliris, 2021) and predicted pozelimab concentration over time, the molar concentrations of pozelimab should be in excess of eculizumab following the IV loading dose with an estimated ratio of approximately 17:1. A lead-in cemdisiran dose plus a loading dose of pozelimab is considered the best solution to address this concern and provide rapid and sustained maximum C5 inhibition after the initiation of the combination treatment and throughout the dosing intervals. In addition to being part of the approach to mitigate the potential for the formation of large DTD immune complexes, the IV loading dose of pozelimab 60 mg/kg should ensure rapid and complete inhibition of C5 to avoid any breakthrough hemolysis that could occur during the treatment transition. Based on simulations, the dosage regimen of the IV loading dose followed by the SC maintenance dose of pozelimab/cemdisiran 400 mg/200 mg Q4W starting on day 29 should result in rapid and sustained suppression of C5 to biologically inactive levels.
See the schedule of the various doses administered in Table 5-2-5-5 below.
meningitidis
5
pneumoniae and
Haemophilus influenza type B (if needed)
meningitidis
8
1Study procedures: when multiple procedures are performed on the same day, the sequence of procedures is as follows: COA assessments, ECG and/or vital signs, blood collection, study treatment administration, and any pre-specified post-dose sample collection.
2Screening visit 1b can be combined with visit 1a, if LDH can be obtained one day before or on the day of Eculizumab administration. Visit 1b and additional interim visits may also be needed for repeat blood collection, vaccination, etc.
3Medical history: transfusions, breakthrough hemolysis history, and laboratory parameters for measurement of hemolysis (such as LDH, bilirubin, haptoglobin, reticulocyte count, and hemoglobin) should be obtained for the past 1 year, if possible. Prior history at any time of thrombosis and Neisseria infections will be collected if feasible. Ongoing PNH symptoms and signs will also be collected.
4Prior medications: including detailed Eculizumab administration history (past 26 weeks) and N. meningitidis vaccination (past 5 years); all other prior medications 12 weeks prior to screening.
5Patients will require administration with meningococcal vaccination unless documentation is provided of prior immunization in the past 5 years prior to screening, or less than 5 years if required according to national vaccination guidelines for vaccination use with complement inhibitors or local practice. For patients who require administration with meningococcal vaccination(s) during the screening period, administration should occur preferably at least 2 weeks prior to day 1, or at another time point according to local practice or national guidelines.
6Tuberculosis history and assessment. Screening by tuberculin skin test or T-cell interferon gamma release assay may be performed according to local practice or guidelines at the discretion of the investigator.
8Patient safety card: provide the patient safety card for N. meningitidis infection to the patient on day 1 or any other visit when needed. Site should review the instructions on the safety card with the patient at each visit.
9Cemdisiran administration: the first day of dosing of Cemdisiran will take place at the patient's usual schedule of administration for Eculizumab.
10Pozelimab IV administration: administration at day 29 should precede SC administration. After completion of IV administration, the patient should be observed for at least 30 minutes and if no clinical concern, then SC administration of the combination should proceed. Patients should be monitored for at least another 30 minutes after the first SC dosing.
11The SC doses of Pozelimab and Cemdisiran should be given Q4W (every 28 days) starting at day 29 (week 4). From day 57 (week 8) onward, Cemdisiran and Pozelimab SC administration may either be continued by the site personnel or another healthcare professional at the patient's home, or administration by the patient or designated person at the patient's preferred location after adequate training. The final SC dosing of the combination during the OLTP is at week 28. During the Q4W dose administration interval starting at day 57, the dose of Cemdisiran and Pozelimab SC should be given on the day of the corresponding study visit whenever possible. Study treatment administration should always be the last procedure after all blood sample collection and study assessments have been completed unless otherwise specified. If Pozelimab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 7 days before or up to 7 days after the planned dosing date, provided that the dosing takes place after the corresponding study visit has been completed. For example, the day 57 (week 8) visit can take place from day 54 to day 60 given the visit window. The corresponding dose of Pozelimab and Cemdisiran can be given from day 54 to day 64, but only after the week 8 visit assessments have been performed. Similarly, the day 113 (week 16) visit can take place from day 106 to day 120 given the visit window. The corresponding dose of Pozelimab and Cemdisiran can be given from day 106 to day 120, but only after the week 16 visit assessments have been performed. Pozelimab and Cemdisiran should be administered on the same day whenever possible. Care must be taken to coordinate dosing for visits where a post-dose sample is collected to measure the concentration of Cemdisiran and its metabolites.
12Eculizumab administration: continue patient's Eculizumab administration at the usual dose and dosing interval. Administration of Eculizumab at day 1 (when first dose of Cemdisiran is administered) may occur up to 2 days later.
13Injection training will be provided to patients who desire self-injection or injection by a designated person. Site staff should observe patient's self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be provided.
14If needed, based on patient self-administration/administration by a designated person, the patient will complete a diary for recording data on study treatment administration starting at the day 57 visit or a subsequent visit. If patient diary is provided to the patient, then it should be reviewed at each clinic visit and data collected into the case report forms (CRFs). On the final visit, the diary should be collected by the site.
15Daily oral antibiotic prophylaxis against N. meningitidis is recommended starting on the first day of dosing with study treatment and continuing until 52 weeks after discontinuation of Pozelimab/Cemdisiran. If vaccination for N. meningitidis occurs less than 2 weeks prior to day 1, then antibiotic prophylaxis must be administered for at least 2 weeks from the time of vaccination.
16Patients will complete the PNH Symptom-Specific Questionnaire on a daily basis for at least 14 days prior to the day 1 visit. Patients should try to complete the PNH Symptom-Specific Questionnaire at the same time each day whenever possible.
17Breakthrough hemolysis assessment: if a patient is suspected of having a breakthrough hemolysis event, then in addition to the required laboratory collection, additional samples for coagulation parameters, chemistry, hematology, reticulocyte count, D-dimer, total C5, CH50, ADA (against Pozelimab), and drug concentrations of Pozelimab and Eculizumab will be collected unless already noted in the Schedule of Events for that visit. If the suspected event does not occur at a scheduled visit, then an unscheduled visit should occur with an evaluation of the patient and collection of coagulation parameters, chemistry, hematology, reticulocyte count, total C5, CH50 and drug concentrations of Pozelimab and Eculizumab.
18During lab collection, handling, and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis. The coagulation blood sample (tube) must always be collected first, followed by the blood chemistry sample (tube). If the investigator or sponsor suspects that the lab result is not an accurate reflection of the patient's condition, the lab sample should be repeated.
19Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. The coagulation blood sample (tube) must always be collected first, followed by the blood chemistry sample (tube). During screening, obtain chemistry including LDH prior to Eculizumab administration on the day of (or if not possible, one day before) Eculizumab administration. On day 1 and all subsequent visits, obtain chemistry including LDH prior to any study treatment administration.
20Pregnancy test for WOCBP: a serum test will be done at the screening visit and a urine test will be done at all other visits indicated. Any positive urine test should be confirmed with a serum pregnancy test.
21Blood sample collection for concentrations of Pozelimab, Eculizumab, total C5, CH50 (efficacy endpoint), and AH50: obtain samples prior to any study drug administration (pre-dose). On day 29, obtain blood samples prior to IV administration of Pozelimab and also within 15 minutes after the end of the IV infusion.
22Blood samples for concentrations of Cemdisiran and its metabolites will be collected prior to any study treatment administration (pre-dose) and at 2 to 6 hours post-Cemdisiran administration. The post-dose sample should be carefully coordinated with the dosing of Cemdisiran and may be collected at the clinic or by a visiting healthcare professional.
23Blood samples for immunogenicity will be collected before the administration of any study drug (pre-dose). At the visits where immunogenicity samples are to be taken, the sample should be collected with the drug concentration sample. In the event of suspected SAEs, such as anaphylaxis or hypersensitivity, additional samples for drug concentration and immunogenicity may be collected at or near the event.
24Future research serum and plasma (optional): samples should be collected, as permitted by patient consent and local regulatory policies. They may be stored for up to 15 years or as permitted by local regulatory policies, whichever is shorter, for future biomedical research.
25Whole blood samples (optional) for DNA extraction should be collected on day 1 (pre-dose) but can be collected at a later study visit.
meningitidis
8
1Study procedures: When multiple procedures are performed on the same day, the sequence of procedures is as follows: COA assessments, ECG and/or vital signs, blood collection, study treatment administration, and any pre-specified post-dose sample collection.
2Patients should be monitored for at least 30 minutes after completion of Pozelimab 30 mg/kg IV. Subsequent SC doses will be administered Q2W (Pozelimab) and Q4W (Cemdisiran) and may either be performed by the site personnel or another healthcare professional at the patient's home, or administered by the patient or by a designated person. For patients on intensified treatment in the OLTP, the final SC dose of Cemdisiran is at day 197r, week 28r, and the final SC dose of Pozelimab is at day 211r (week 30r).
3Pozelimab and Cemdisiran SC administration: the dose of Pozelimab SC should be given Q2W (every 14 days) and Cemdisiran should be given Q4W (every 28 days) and on the day of the corresponding study visit whenever possible and as applicable. Study treatment administration should always be the last procedure after all blood sample collection and study assessments have been completed unless otherwise specified. If administration of Pozelimab or Cemdisiran cannot be administered on the day of the corresponding study visit, the dose may be administered up to 3 days before or up to 3 days after the planned dosing date as long as the dosing takes place after the corresponding study visit has been completed. For example, the day 29r (week 4r) visit can take place from day 26r to day 32r given the visit window. The dose of Pozelimab and Cemdisiran therefore can be given from day 26r to day 32r, but only on or after the week 4r visit assessments have been performed. Similarly, the day 113r (week 16r) visit can take place from day 106r to day 116r given the visit window. The dose of Pozelimab and Cemdisiran can be given from day 110r to day 116r, but only on or after the week 16r visit assessments have been performed. Whenever possible, the dose of Cemdisiran should be administered on the same day as the Q4W dose of Pozelimab. The final dose of Cemdisiran is at week 28r and the final dose of Pozelimab is at week 30r.
4Injection training will be provided to patients who desire self-injection or injection by a designated person. The site should observe patient self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be provided.
5If needed, based on patient self-administration/administration by a designated person, the patient will complete a diary for recording data on study treatment administration. If the patient diary is provided to the patient, then it should be reviewed at each clinic visit and data collected into the CRFs. On the final visit, the diary should be collected by the site.
6Daily oral antibiotic prophylaxis against N. meningitidis is recommended until 52 weeks after discontinuation of Pozelimab/Cemdisiran.
7Patients should try to complete the PNH Symptom-Specific Questionnaire at the same time each day whenever possible.
8Patient safety card: the site should review the instructions on the safety card with the patient at each visit.
9Breakthrough hemolysis assessment: if a patient is suspected of having a breakthrough hemolysis event, then in addition to the required laboratory collection, additional samples for coagulation parameters, chemistry, hematology, reticulocyte count, D-dimer, total C5, CH50, ADA (against Pozelimab), and drug concentrations of Pozelimab will be collected unless already noted in the Schedule of Events for that visit. If the suspected event does not occur at a scheduled visit, then an unscheduled visit should occur with an evaluation of the patient and collection of coagulation parameters, chemistry, hematology, reticulocyte count, total C5, CH50 and drug concentrations of Pozelimab.
11Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis.
12Pregnancy test for WOCBP: a urine test will be done at all visits indicated.
13Blood sample collection for concentrations of Pozelimab, total C5, CH50 (efficacy endpoint), and AH50: obtain samples prior to any study drug administration (pre-dose). On day 1, obtain blood sample for Pozelimab concentration and total C5 prior to IV administration of Pozelimab and also within 15 minutes after the end of the IV infusion.
14Blood samples for concentrations of Cemdisiran and its metabolites will be collected prior to any study treatment administration (pre-dose) and at 2 to 6 hours post-Cemdisiran dosing. The post-dose sample should be carefully coordinated with the dosing of Cemdisiran and may be collected at the clinic or by a visiting healthcare professional.
15Blood samples for immunogenicity will be collected before the administration of any study drug (pre-dose). At the visits where immunogenicity samples are to be taken, the sample should be collected with the drug concentration sample. In the event of suspected SAEs, such as anaphylaxis or hypersensitivity, additional samples for drug concentration and immunogenicity may be collected at or near the event.
Neisseria meningitidis
10
1Visits may be at the clinical site or another preferred location, such as the patient's home. The location will depend on the availability of a home healthcare visiting professional as well as the preferences of the investigator and patient. In the event of travel restrictions due to a global pandemic, alternative mechanisms such as but not limited to telemedicine visits may be implemented to maintain continuity of study conduct.
2Study procedures (visits): when multiple procedures are performed on the same day, the sequence of procedures is as follows: COA assessments, ECG and/or vital signs, blood collection, study treatment administration, and any pre-specified post-dose sample collection.
3Day 1e of OLEP should be scheduled on the same day as week 32 (or week 32r for patients on intensified treatment) of the OLTP, and any common assessments will be performed once for both the OLTP and OLEP visits.
4During the OLEP, the dose of Cemdisiran and Pozelimab SC should be given on the day of the corresponding study visit whenever possible. Study treatment administration should always be the last procedure after all blood sample collection and study assessments have been completed unless otherwise specified. If Pozelimab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 3 days before or up to 3 days after the planned dosing date for patients in an intensified treatment regimen (Pozelimab Q2W dosing) or up to 7 days before or 7 days after the planned dosing date for patients on a maintenance treatment regimen (Pozelimab Q4W dosing), provided that the dosing takes place after the corresponding study visit has been completed. Care must be taken to coordinate dosing for visits where a post-dose sample is collected to measure concentration of Cemdisiran and its metabolites.
5For patients who did not receive intensified treatment during OLTP: at any time during the OLEP, patients who meet pre-specified criteria will receive intensified treatment consisting of a Pozelimab 30 mg/kg IV loading dose followed 30 minutes later by the initiation of Pozelimab 400 mg SC Q2W and Cemdisiran 200 mg SC Q4W. Patients will continue their visit schedule at the next OLEP visit.
6Study treatment administration should always be the last procedure after all blood sample collection and study assessments have been completed unless otherwise specified. For patients whose treatment is not intensified during the OLEP, the last doses of Cemdisiran and Pozelimab are administered at week 52e. For patients whose treatment was intensified during the OLEP, the last doses of study treatment will be determined based on the time of treatment intensification.
7Injection training will be provided to patients who desire self-injection or injection by a designated person. The site should observe patient self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be provided.
8If study treatment is given by the patient or by a designated person, the patient will complete a diary for recording compliance with study treatment administration. If the patient diary is provided to the patient, then it should be reviewed at each clinic visit and data collected into the CRFs. On the final visit, the diary should be collected by the site.
9Daily oral antibiotic prophylaxis against N. meningitidis is recommended until 52 weeks after discontinuation of study treatment.
10Patient safety card: the site should review the instructions on the safety card with the patient at each visit.
11Breakthrough hemolysis assessment: if a patient is suspected of having a breakthrough hemolysis event, then in addition to the required laboratory collection, additional samples for coagulation parameters, chemistry, hematology, reticulocyte count, D-dimer, total C5, CH50, ADA (against Pozelimab), and drug concentrations of Pozelimab will be collected unless already noted in the Schedule of Events for that visit. If the suspected event does not occur at a scheduled visit, then an unscheduled visit should occur with an evaluation of the patient and collection of coagulation parameters, chemistry, hematology, reticulocyte count, total C5, CH50 and drug concentrations of Pozelimab.
12Clinical lab samples will be collected prior to any study drug administration (pre-dose) unless otherwise specified. The coagulation blood sample (tube) must always be collected first, followed by the blood chemistry sample (tube). During lab collection, handling, and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of the sample and avoid hemolysis.
13Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. The blood chemistry sample should be collected before study treatment administration (pre-dose). If the investigator or sponsor suspects that the lab result is not an accurate reflection of the patient's condition, the lab sample should be repeated.
14The hematology sample should be collected before study treatment administration (pre-dose).
15Pregnancy test for WOCBP: a urine test will be done at all visits indicated. Any positive urine pregnancy test should be confirmed with a serum pregnancy test.
16Blood samples for Pozelimab concentration analysis and total C5 analysis will be obtained on the specified days prior to any study treatment administration (pre-dose). If the patient receives treatment intensification during the open-label extension period, a PK sample should be obtained prior to IV Pozelimab administration and 15 minutes post-dose.
17Blood samples for Cemdisiran concentration analysis and concentrations of its metabolites will be collected on the specified days prior to any study treatment administration (pre-dose) and 2 to 6 hours post-Cemdisiran administration. The post-dose sample should be carefully coordinated with the dosing of Cemdisiran and may be collectedat the clinic or by a visiting healthcare professional.
18Blood samples for immunogenicity will be collected on the specified days prior to any study treatment administration (pre-dose). At the visits where immunogenicity samples are to be taken, the sample should be collected with the drug concentration sample. In the event of suspected treatment-related SAEs, such as anaphylaxis or hypersensitivity, additional drug concentration and immunogenicity samples may be collected at or near the onset and the resolution of the event.
Neisseria meningitidis2
1 Patients who discontinue study treatment in either the OLTP or the intensified OLTP will be asked to remain in the study until week 32 EOT (or week 32r EOT) and follow the original Schedule of Events as applicable. After the week 32 or week 32r EOT visit, the entry point into the safety follow-up schedule will depend on the number of weeks that have elapsed since patient's last dose (e.g., a patient who is 20 weeks after his/her final dose of study treatment at EOT will enter into the safety follow-up period at Visit FU-4 [26 weeks after last dose]). Patients who completed week 32r in the OLTP who choose not to continue treatment in the OLEP, patients who complete the optional OLEP but do not continue study treatment in a post-trial access program, and patients who permanently discontinue treatment during the OLEP will enter into the safety follow-up period at FU-1.
2Patient safety card: Site should review the instructions on the safety card with the patient at each visit. Replacement cards may be given to the patient as needed.
The primary objective of the study is to evaluate the safety and tolerability of Pozelimab and Cemdisiran combination therapy in patients with PNH who switch from Eculizumab therapy.
The secondary objectives of the study are:
The exploratory objectives of the study are:
The primary study endpoint is the incidence and severity of TEAEs through day 225 of the OLTP.
The secondary endpoints for the OLTP are:
The secondary endpoints for the optional OLEP are:
The exploratory endpoints for the OLTP are:
Laboratory Variables for the Assessment of Efficacy-Efficacy in this study is evaluated by the following laboratory assessments:
These laboratory variables are relevant to the characterization and disease mechanisms of PNH (Brodsky, Paroxysmal nocturnal hemoglobinuria, Blood 2014; 124(18):2804-11). Lactate dehydrogenase as a measure of intravascular hemolysis allows for an objective and precise means to gauge whether the control of intravascular hemolysis with Eculizumab is sustained when the patients are switched to Pozelimab and Cemdisiran combination treatment. The CH50 assay will be used to confirm complete inhibition of complement activity has been achieved throughout the dosing interval in patients with PNH.
Hemolytic anemia is a clinical manifestation of PNH, and patients often require blood transfusion for symptomatic management. The frequency of blood transfusion has been used in other studies of PNH to assess efficacy (Hillmen, 2006) (Röth, 2018).
The following clinical outcome assessments will be completed by the patient:
The safety variables in this study include:
The screening period will evaluate patients to establish their eligibility to enter the study.
The screening visit should take place up to 42 days prior to day 1 (a day that the patient is scheduled to be administered Eculizumab). An additional interim screening visit(s) may take place as needed, for instance, in order to obtain the LDH value for pretreatment assessment on the day of (or if not possible, one day before) Eculizumab administration, and prior to Eculizumab dosing.
Historical data will be collected including, but not limited to, Eculizumab administration, concomitant medications, hemolytic parameters, and transfusions. Data will also be collected on PNH signs and symptoms during the screening period.
Patients will require vaccination/revaccination for N. meningitidis unless documentation is provided of prior immunization in the past 5 years prior to screening, or less than 5 years if required according to current national vaccination guidelines for vaccination use with complement inhibitors or local practice. For patients who require meningococcal vaccination during the screening period, administration should occur preferably at least 2 weeks prior to day 1, unless local practice or national guidelines specify a different vaccination protocol. If vaccination precedes the initiation of study treatment by less than 2 weeks, then the patient must receive antibiotic prophylaxis for a minimum of 2 weeks from the date of vaccine administration
During screening, patients who have not been vaccinated against Streptococcus pneumoniae and Haemophilus influenza type B according to current national/local vaccination guidelines will be required to be vaccinated to be eligible for the study.
In addition to N. meningitidis, fatal or serious infections with N. gonorrhea have been reported in patients taking Eculizumab. Therefore, a risk assessment and counseling regarding the potential risk of N. gonorrhea infection will be conducted per local practice.
Patients will be assessed for active or latent tuberculosis infection based on local practice or applicable guidelines. Based on the risk assessment, the need for screening with either tuberculin skin test or T-cell interferon-gamma release assay will be made. The interpretation of these results, as applicable, will be made by the investigator. Further management and treatment will be the responsibility of the investigator.
In addition to screening procedures, patients will be asked to complete a PNH Symptom-Specific Questionnaire daily for at least 14 consecutive days prior to the day 1 visit.
Patients may choose to participate in the optional OLEP, optional future biomedical research, and/or optional pharmacogenomics component of the study by signing the respective optional informed consent forms (ICFs).
Patients who fulfill all the eligibility criteria will be enrolled in the study and receive their first dose of study drug on day 1, which should occur on the day of the patient's scheduled treatment with Eculizumab. As described herein, patients will be administered Cemdisiran with Eculizumab on day 1 (Note: Eculizumab may be administered up to 2 days after day 1 Cemdisiran in order to accommodate the logistical complexities associated with its administration). Eculizumab will be administered alone on day 15 (+2 days or earlier, according to the patient's usual dosing frequency. The first dose of combination SC therapy with Pozelimab and Cemdisiran without background Eculizumab will be administered on day 29 and continue Q4W thereafter. The first dose of combination SC therapy on day 29 will be preceded by an IV loading dose of Pozelimab to achieve high concentrations of Pozelimab rapidly in order to provide complete inhibition of C5, as soon as possible, during the switch from Eculizumab to Pozelimab. The SC doses should not be given until at least 30 minutes after completion of the IV administration, and the patient should be observed during the interval. Patients will also be monitored for at least 30 minutes after completing the first SC injections for the Pozelimab and Cemdisiran combination.
After the first SC dose of the Pozelimab and Cemdisiran combination on day 29, subsequent study treatment administrations may be continued by the site personnel, a healthcare professional if available, or administered by the patient or designated person at the patient's preferred location. These options for study treatment administration will depend on preference of the investigator and patient, local regulations, and availability of healthcare professional. If self-administration (or administration by a designated person) is undertaken, then sufficient injection training at the scheduled administration(s) with a Pozelimab and Cemdisiran maintenance regimen will be provided by the investigator or qualified study staff designee. After training, observation of self-administration (or administration by designated person) will be conducted by clinical site personnel and may be conducted in person at the patient's home or via telemedicine. Once this observation is considered satisfactory, the Pozelimab and Cemdisiran maintenance regimen can be subsequently administered independently by patient/designated person for the remainder of the study. A patient diary will be provided prior to initiation of self-administration for recording data on study treatment administration. The diary should be completed upon each study drug administration.
Breakthrough hemolysis is assessed by the investigator throughout the study and is as defined herein. During the study, a patient meeting criteria for breakthrough hemolysis or inadequate LDH response may qualify for treatment intensification as described herein.
Breakthrough hemolysis is defined as an increase in LDH with concomitant signs or symptoms associated with hemolysis:
The decision to transfuse with RBCs during the study should proceed according to the criteria herein.
Transfusions with RBCs during the screening period and while the patient is receiving study treatment may proceed according to the following predefined criteria that will trigger a transfusion as clinically indicated, however the actual number of units to be transfused is at the discretion of the investigator:
Patients should be closely monitored for the entire study for early signs and symptoms of meningococcal infection and evaluated immediately if an infection is suspected. Patients will be provided a patient safety card describing signs and symptoms of suspected meningococcal infection along with instructions to follow in case of a potential meningococcal infection as well as information for the non-investigator healthcare provider for awareness. Daily oral antibiotic prophylaxis is recommended.
During intravenous infusion of Pozelimab, due to concern of potential IV infusion reactions, patients should be observed for at least 30 minutes after the infusion. In addition, emergency equipment and medication for the treatment of infusion reactions must be available at the clinical site for immediate use. All infusion reactions must be reported as adverse events (AEs) and graded. Patients should also be observed for at least 30 minutes after completing the first SC injections of the Pozelimab and Cemdisiran combination.
During the transition of therapy from Eculizumab to Pozelimab, investigators should have heightened awareness for possible AEs as a result of the risk of formation of large multimers of complexes of Eculizumab-C5-Pozelimab (i.e., large drug-target-drug (DTD) immune complexes).
Study procedures in the treatment period include laboratory assessments of efficacy (LDH, hemoglobin, and CH50), transfusion record update, clinical outcome assessments, body weight, and routine safety assessments (vital signs, physical examination, ECG, safety laboratory testing). Treatment-emergent adverse events and concomitant medications will be monitored throughout the study. Patients will provide blood samples for biomarkers, drug concentration for potential PK and PD assessment, immunogenicity, and exploratory assessments. Study procedures are listed by visit in Table 5-2 and described herein. Study procedures, including sample collection for laboratory analysis, may be performed at the study clinic or at another location that is more convenient for the patient (including home visits), if this option is available and with approval. The last doses of study treatment for patients who do not receive dose intensification are administered on day 197 (week 28). Patients will return for safety, efficacy, and other assessments at the end of treatment (EOT) visit at week 32. For patients who restarted on intensified treatment during the study, the last dose of study treatment is administered at week 30. Patients will return for safety, efficacy, and other assessments at the EOT visit at week 32 (Table 5-3).
All patients who complete the OLTP study treatment, including patients who received the intensified regimen, will be offered the opportunity to continue in an optional 52-week OLEP, whereby the treatment with Pozelimab and Cemdisiran from the OLTP to the OLEP is planned to be uninterrupted (i.e., day 1e visit of the OLEP will correspond to the EOT visit in the OLTP, and any common assessments will be performed once for both visits). Study assessments and conduct for the optional OLEP are as described previously for the OLTP and are detailed in Table 5-4 (Schedule of Events for the optional OLEP).
During the optional OLEP, patients who are not on intensified treatment who meet criteria herein for treatment intensification will follow the dosing regimen as described herein with the new regimen starting on the day of intensification, and will continue their visit schedule at the next OLEP visit.
This means that starting the day of intensification (day pre-defined criteria have been met), the patient will receive a single administration of Pozelimab 30 mg/kg IV followed by SC administration of Pozelimab and Cemdisiran the same day. Thereafter, the patients will receive Pozelimab 400 mg Q2W and Cemdisiran 200 mg Q4W starting from the day of intensification (±3 days). The visit schedule for the OLEP will remain unchanged.
For patients who complete the optional OLEP, post-trial access to treatment may be available.
Patients who meet criteria for treatment intensification will receive a single administration of Pozelimab 30 mg/kg IV on the day of initiation (can be initiated from day 57 onward) in addition to a maintenance regimen with a shortened frequency of Pozelimab administration 400 mg SC Q2W along with Cemdisiran 200 mg SC Q4W (±3 days) for a period of 32 weeks starting on the day of initiation.
An intensified regimen is available to provide extra C5 suppression that some patients may need and which cannot be managed adequately by the standard dose regimen. Patients will receive intensification of their Pozelimab treatment from day 57 onward as described herein if they meet both criteria below:
During the OLTP, patients who undergo treatment intensification may require unscheduled visit(s) before initiation. The day of initiation of the intensified regimen should be re-anchored to baseline of the Intensified Treatment Period in the OLTP (day 1r) and thereafter following a similar schedule of subsequent visits and assessments as newly enrolled patients (see Table 5-3). Patients who are on intensified treatment will be considered to have completed the OLTP once they finish the 32-week treatment period on the intensified regimen.
During the optional OLEP, patients who are not on intensified treatment who meet criteria for treatment intensification will follow the dosing regimen described herein with the new regimen starting on the day of intensification and for the remainder of the OLEP. Patients will continue their visit schedule at the next OLEP visit (Table 5-4).
Patients are eligible to receive intensification of Pozelimab only once (whether during the main treatment period or the optional OLEP), beyond which no further intensification will be permitted. Note: After day 29, patients who have an LDH increase ≥2×ULN due to an acute complement activating condition during the OLTP, intensified OLTP or optional OLEP may receive an IV Pozelimab dose of 30 mg/kg IV at the discretion of the investigator. An assessment of the patient's weight should be performed on the day of the IV Pozelimab load in order to calculate the appropriate dose. This is not considered treatment intensification as there will be no change in regimen and no requirement to reset their schedule to day 1.
An assessment of the patient's weight should be performed on the day of the IV Pozelimab load in order to calculate the appropriate dose. The IV dose should be administered first. The SC doses should be given at least 30 minutes after completion of the IV administration. Note: Patients who experience breakthrough hemolysis that is not due to a complement-activating condition, and meet criteria for treatment intensification, are eligible to receive intensification of Pozelimab only once (whether during the main treatment period or the optional OLEP), beyond which no further intensification will be permitted.
In the event of an LDH increase ≥2×ULN due to an acute complement-activating condition (i.e., intercurrent infection) after day 29 in the OLTP, intensified OLTP or at any time in the optional OLEP, an IV loading dose of Pozelimab 30 mg/kg IV may be given at the discretion of the investigator and in consultation with the sponsor. An assessment of the patient's weight should be performed on the day of the IV Pozelimab load in order to calculate the appropriate dose. This is not considered treatment intensification. No other changes will be made to the study treatment regimen (i.e., the regular dose and frequency of Pozelimab and Cemdisiran will proceed unchanged). Patients will continue onto the next visit of their current visit schedule.
At the time of this data analysis, 6 patients were enrolled, 5 of whom were ongoing. While one patient discontinued after 29 days of treatment, the remaining 5 patients had a treatment duration of at least 169 days, with one completing the OLTP (Day 225).
Up to the time of data cut-off, no patient had a lactate dehydrogenase (LDH) level greater than 1.5×ULN (
There were no serious or severe TEAEs. Importantly, there were no meningococcal infections or adverse events due to potential large drug-target-drug immune complexes, or TEAEs leading to death, in this study. One patient discontinued study treatment due to two mild, non-serious TEAEs of headache at Days 2 and 16.
These results show that, in patients with PNH transitioning from Eculizumab treatment, including patients treated with higher than standard of care doses, the combination of Pozelimab and Cemdisiran was generally well tolerated, providing sustained control of intravascular hemolysis without any breakthrough hemolysis events. Accordingly, this combination therapy demonstrates significant efficacy in treating patients with PNH who transitioned from Eculizumab therapy.
Six patients were enrolled. Five patients completed the OLTP (Day 225); one patient discontinued treatment after 29 days due to a treatment-emergent adverse event (TEAE) (Table 5-12).
At baseline, lactate dehydrogenase (LDH) was well controlled on Eculizumab. In the year prior to enrollment, no patient had a history of a blood transfusion, but one patient had a history of breakthrough hemolysis. During the 32-week OLTP, no patient had an LDH greater than 1.5× the upper limit of normal (ULN;
One patient discontinued study treatment due to two mild, non-serious TEAEs of headache at Days 2 and 16. One subject experienced a serious TEAE of endometrial hyperplasia for long standing, intermittent post-menopausal bleeding that required hospitalization for pre-emptive hysterectomy/ovariectomy; the event was deemed not related to the study treatment by the investigator and sponsor (Table 5-9). There were no meningococcal infections, TEAEs due to potential large drug-target-drug immune complexes, thrombotic events or TEAEs leading to death (Table 5-10 and Table 5-11).
Results suggest that in patients with PNH transitioning from Eculizumab treatment (including patients receiving higher than standard doses), the combination of Pozelimab and Cemdisiran was generally well tolerated, providing sustained control of intravascular hemolysis without any breakthrough hemolysis events. Findings support the ongoing development of Pozelimab and Cemdisiran combination therapy.
Six patients were enrolled (Table 5-13), and five completed the OLTP (median [range] treatment duration: 229 [56-280] days). One patient discontinued study treatment after 29 days due to two mild, non-serious treatment-emergent adverse events (TEAEs) of headache at Days 2 and 16, both occurring prior to administration of the combination treatment at Day 29.
aPre-treatment values.
bThree samples were missing from the central laboratory, so local laboratory pre-study PNH clone data were used.
All patients had an LDH value of ≤1.5×ULN at all timepoints assessed; four out of the six patients maintained normal LDH values (≤1.0×ULN) at all time points evaluated (
No patients experienced a breakthrough hemolysis event, including the two patients who were previously treated with higher doses of eculizumab (1200 mg or 1500 mg every 2 weeks, respectively).
Individual patients' hemoglobin levels over time are shown in
CH50, a measure of terminal complement activity, remained fully suppressed at 0 klU/L throughout the study.
One patient experienced a serious and severe TEAE of endometrial hyperplasia for long standing, intermittent post-menopausal bleeding that required hospitalization for pre-emptive hysterectomy/ovariectomy; the event was deemed not related to study treatment.
The most common TEAEs were non-serious injection-site reactions (n=5, 83.3%; none led to treatment discontinuation), and headache (n=3, 50.0%). Importantly, there were no meningococcal infections, adverse events due to potential large drug-target-drug immune complexes, or TEAEs leading to death.
In patients with PNH transitioning from Eculizumab treatment, the combination of Pozelimab and Cemdisiran treatment was generally well tolerated and provided sustained control of intravascular hemolysis.
No patient experienced an event of breakthrough hemolysis.
Findings support the ongoing development of Pozelimab and Cemdisiran combination therapy.
Patients who completed the 32-week open-label treatment period (OLTP) were offered to participate in an optional 52-week OLEP. Patients were adults with PNH who had switched from stable Eculizumab therapy to the combination (pozelimab 400 mg and cemdisiran 200 mg) SC every 4 weeks in the OLTP. The study enrolled two patients who were previously treated with higher doses of Eculizumab (1200 mg or 1500 mg every two weeks).
All five patients who completed the OLTP were enrolled in and completed the OLEP. After completing the OLEP, all patients transitioned to an expanded access program to continue the combination of Pozelimab and Cemdisiran. At baseline of the OLTP, lactate dehydrogenase (LDH) was well controlled on Eculizumab and remained controlled during the 32-week OLTP. During the 52-week OLEP, no patient had an LDH greater than 1.5× the upper limit of normal (ULN; Figure) at any of the scheduled study visits or met the protocol criteria for breakthrough hemolysis (either by central or local laboratory values; defined as an increase in LDH [LDH≥2×ULN if pre-treatment LDH≤1.5×ULN, or LDH≥2×ULN subsequent to initial achievement of LDH≤1.5×ULN if pre-treatment LDH>1.5×ULN] with concomitant signs or symptoms associated with hemolysis). The two patients who previously received higher doses of eculizumab also maintained control of LDH levels throughout the OLTP and OLEP. Four of five patients remained transfusion free, but one patient required a blood transfusion while hospitalized with an acute complement-activating condition. This patient experienced two serious and severe treatment-emergent adverse events of respiratory infection and consequently acute hemolysis that did not meet the trial criteria for breakthrough hemolysis but was reported as an adverse event based on clinical judgement. The investigator and sponsor assessed these events as not treatment related. CH50, a measure of terminal complement activity at fixed time points, remained suppressed throughout the study in all patients. No other serious or severe adverse events were reported. There were no meningococcal infections, thrombotic events, or TEAEs leading to death.
Results suggest that, in patients with PNH transitioning from Eculizumab treatment, the combination of Pozelimab and Cemdisiran was generally well tolerated and provided long term sustained control of intravascular hemolysis without any breakthrough hemolysis events. Findings support the ongoing development of Pozelimab and Cemdisiran combination therapy.
This study is a randomized, open-label, Eculizumab and Ravulizumab-controlled, non-inferiority study. The study was terminated early due to recruitment issues.
Patients treated with Eculizumab will be eligible if they are taking Eculizumab at the labeled posology of 900 mg IV Q 14 days for at least 12 weeks prior to screening visit.
Patients treated with Ravulizumab will be eligible if they are taking IV Ravulizumab at the labeled posology Q8W based on body weight (BW) as follows: 3000 mg for BW≥40 kg to <60 kg, 3300 mg for BW≥60 kg to <100, 3600 mg for BW 100 kg for at least 24 weeks prior to screening visit.
The study (
The first screening visit should take place up to 6 weeks prior to day 1 (Table 6-1). Screening visit 1 should be scheduled based on the patient's Eculizumab or Ravulizumab dosing regimen prior to the study.
For patients taking Eculizumab at screening:
For patients taking Ravulizumab at screening:
Additional interim screening visit(s) may take place as needed, for instance, for repeat blood collection.
Historical data will be collected such as but not limited to Eculizumab or Ravulizumab administration, concomitant medications, hemolytic parameters, and RBC transfusions.
Due to the risk of Neisseria meningitidis infection, patients will require administration of meningococcal vaccination(s) in accordance with the local Eculizumab or Ravulizumab prescribing information, where applicable, and in accordance with current national vaccination guidelines for vaccination use with complement inhibitors or local practice and at the very least, within a period of 5 years prior to screening. For patients who require administration with meningococcal vaccination(s) during the screening period, administration should occur preferably at least 2 weeks prior to day 1, or at another time point according to local practice or national guidelines/local Eculizumab or Ravulizumab prescribing information (as applicable). If vaccination precedes the initiation of study treatment by less than 2 weeks, then the patient must receive antibiotic prophylaxis for a minimum of 2 weeks from the date of vaccine administration.
In addition to Neisseria meningitidis infection, fatal or serious infections with Neisseria gonorrhea have been reported in patients taking complement inhibitor therapy. Patients should therefore undergo a risk assessment and counseling regarding the potential risk of Neisseria gonorrhea as per local practice or national guidelines.
Patients who have not been vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type B may receive these vaccinations during the screening period or on the day of randomization, based on investigator discretion and taking into consideration the available national guidelines.
Patients will be assessed for active or latent tuberculosis (TB) infection based on local practice or applicable guidelines. Based on the risk assessment, the need for screening with either tuberculin skin test or T-cell interferon-gamma release assay will be made. The interpretation of these results, as applicable, will be made by the investigator. Further management and treatment of TB will be the responsibility of the investigator.
Day 1 (randomization) must take place on the day of the patient's scheduled Eculizumab administration or 4 weeks (i.e., 26 to 28 days) after the last administration of Ravulizumab, as applicable. If the day of randomization cannot be scheduled on the day of the patient's next Eculizumab dose or exactly 4 weeks after the last Ravulizumab dose, a window of 1 to 2 days is allowed such that the day of randomization may take place 1 to 2 days prior to the next scheduled Eculizumab dose or 26 to 28 days after the last Ravulizumab dose, as applicable.
Patients who fulfill all the eligibility criteria will be randomized in a 1:1 ratio to anti C5 standard of-care (i.e., continue existing treatment with Eculizumab or Ravulizumab) or treatment with Pozelimab and Cemdisiran.
Randomization will be stratified based on the criteria described herein:
Eligible patients will be randomized in a 1:1 ratio to receive either the combination treatment with SC Pozelimab 400 mg and Cemdisiran 200 mg Q4W or continue their anti C5 standard-of-care therapy with either Eculizumab 900 mg IV Q2W or IV Ravulizumab according to the labeled weight-based dosing algorithm according to a central randomization scheme provided by an Interactive Web Response System (IRWS) to the designated study pharmacist (or qualified designee). Randomization will be stratified according to the following factors:
The treatment period is 36 weeks. Treatment administration is based on a patient's PNH treatment prior to screening as well as their treatment assignment:
During IV infusion of Pozelimab, due to concern of potential IV infusion reactions, patients should be observed for at least 30 minutes after the infusion and prior to the administration of the first SC injections for Pozelimab and Cemdisiran.
A 2-hour observation period should be instituted following the first 3 administrations of Pozelimab and Cemdisiran, whether alone or in combination. For subsequent administrations after the third administration of each study treatment, the observation period can be reduced to 30 minutes, provided the combination is felt to be well tolerated by the patient, per investigator's discretion
While the overall goal of the proposed dosing regimen is to prevent hemolysis, the initiation of therapy is also designed to mitigate the potential for the formation of large drug-target-drug (DTD) immune complexes of eculizumab-C5-pozelimab or ravulizumab-C5-pozelimab during the treatment switch. As explained herein, a lead-in cemdisiran dose plus 60 mg/kg IV loading dose of pozelimab is included in order to minimize large DTD immune complex formation.
Patients who complete the OLTP (i.e., end of study [EOS] visit at day 253) will be offered the opportunity to enroll in another study, a follow-on OLE study. Screening for the next study may be conducted while the patient is in the OLTP, as described in Section 9.1.1.1 footnote #1.
For patients who complete the 36-week OLTP on the Pozelimab and Cemdisiran arm, the transition of treatment from the current study to the OLE is planned to be uninterrupted, whereby day 1 visit of the OLE will correspond to the EOT period/EOS visit in the current study.
Patients who complete the 36-week OLTP on the anti-C5 standard-of-care arm and plan to participate in the OLE study will undergo a transition period in order to switch to Cemdisiran and Pozelimab combination treatment in the same manner as those switching to the combination at study initiation as follows:
Patients treated with Eculizumab:
Patients treated with Ravulizumab:
This approach for patients randomized to the anti-C5 standard-of-care arm and who plan to enroll in the OLE study, ensures a consistent dosing approach when switching from Eculizumab or Ravulizumab to Pozelimab and Cemdisiran combination therapy and has no impact on study efficacy analysis for the randomized treatment period. Patients who discontinue treatment as well as patients who decline enrollment into the follow-on study of the OLE will undergo a safety off-treatment follow up period (FUP) of up to 52 weeks according to Table 6-4. Patients discontinuing the study treatment should be treated in accordance with local standards of care while continuing to be monitored in the 52-week off-treatment safety FUP. Investigators switching patients from the combination treatment to another anti-C5 mAb should have a heightened awareness for possible adverse events resulting from the formation of large DTD immune complexes.
The main study is considered finished, when all patients either complete the 36-week treatment period or prematurely discontinue the study. Additional data collected during the transition period and safety off-treatment FUP will be described separately.
Study assessments and procedures are presented by study period and visit in Table 6-1 (OLTP), Table 6-2 (transition period for Eculizumab arm), Table 6-3 (transition period for Ravulizumab arm), and Table 6-4 (FUP). See
meningitidis
6
pneumoniae and Haemophilus influenzae
X36
X11
X11
meningitidis
10
X34
X34
X34
X34
X34
meningitidis
6
pneumoniae and Haemophilus influenzae
X12
meningitidis
10
X29
meningitidis
6
pneumoniae and Haemophilus influenzae
X37
X37
X37
X37
X37
meningitidis
10
X32
X33
X33
1When multiple procedures are performed on the same day, the sequence of procedures is as follows: Clinical outcome assessments, electrocardiogram (ECG) and/or vital signs, blood collection, and study treatment administration. Patients who are being screened in this study (R3918-PNH-2022) who complete the R3918-PNH-2021 study will have all assessments performed as indicated in the SOE. This implies that the Screening Visit 1 in the R3918-PNH-2022 study may take place at week 24 of the R3918-PNH-2021 study and V2r of the R3918-PNH-2022 study take place at the time of week 26 of theR3918-PNH-2021 study prior to the Ravulizumab dose administration. Assessments that are common to both studies should not be duplicated.
2Screening visit 1 should be scheduled based on the patient's dosing regimen prior to the study. For patients taking Eculizumab, screening visit 1 should be scheduled on the day of or the day prior to an Eculizumab dose. For patients taking Ravulizumab, screening visit 1 should be scheduled about 6 weeks after the last Ravulizumab dose. Additional screening visits may be scheduled as needed.
3For patients taking Ravulizumab, the day 1 visit should occur 4 weeks (i.e., 26 to 28 days) after the last administration of Ravulizumab.
4Medical history including, transfusions, breakthrough hemolysis history, and laboratory parameters for measurement of hemolysis (such as LDH, bilirubin, haptoglobin, reticulocyte count, and hemoglobin) should be obtained for the past 52 weeks, if possible. Prior history of thrombosis and infections of the Neisseria spp. will be collected. Patients who have a C5 mutation confirmed while the study is ongoing should have the information included as part of the patient's medical history. Patients who are poor responders to Eculizumab or Ravulizumab treatment during the study may be asked for a mutation analysis to be conducted as part of the study, if the patient agrees to such testing.
5Including detailed Eculizumab or Ravulizumab administration history and Neisseria meningitidis vaccination and other vaccinations as applicable.
6Patients will require administration with meningococcal vaccination unless documentation is provided of prior immunization in the past 5 years, or less than 5 years if required according to current national vaccination guidelines for vaccination use with complement inhibitors/local Eculizumab or Ravulizumab prescribing information. For patients who require administration with meningococcal vaccination(s) during the screening period, administration should occur preferably at least 2 weeks prior to day 1, or at another time point according to local Eculizumab or Ravulizumab prescribing information/national guidelines.
7Vaccination for Streptococcus pneumoniae and Haemophilus influenzae type B should be initiated per current national/local vaccination guidelines.
8Tuberculosis history and assessment: Screening by tuberculin skin test or T-cell interferon gamma release assay may be performed according to local practice or guidelines at the discretion of the investigator
9A risk factor assessment for Neisseria gonorrhea will be performed in accordance with local practice/national guidelines, and regular testing and counseling is advised for at-risk patients.
10Patient safety card: provide the patient safety card for Neisseria meningitidis infection to the patient on day 1 and any other visit when needed. Site should review the instructions on the safety card with the patient at each visit.
11Eculizumab may be administered up to 2 days after day 1 visit or within 2 days of day 15 visit. If Eculizumab administration does not coincide with the day of clinic visit, as applicable, then the clinic visit should always precede the infusion of Eculizumab for patients on Q2W Eculizumab dosing.
12Pozelimab administration: administer study treatment to patients previously taking Eculizumab or Ravulizumab and randomized to Pozelimab/Cemdisiran arm.
13Cemdisiran administration: administer study treatment to patients randomized to Pozelimab/Cemdisiran arm.
14The dose of Pozelimab and Cemdisiran should be given Q4W (every 28 days) and on the day of the corresponding study visit whenever possible. Study treatment administration should always be the last procedure after all blood sample collection and study assessments have been completed. If Pozelimab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 7 days before or up to 7 days after the planned dosing date as long as the dosing takes place after the corresponding study visit has been completed. For example, the week 8 (day 57) visit can take place from day 54 to day 60 given the visit window. The dose of Pozelimab and Cemdisiran therefore can be given from day 54 to day 64 but only on or after the week 8 visit assessments have been performed. Similarly, the week 16 (day 113) visit can take place from day 106 to day 120 given the visit window. The dose of Pozelimab and Cemdisiran can be given from day 106 to day 120 but only on or after the week 16 visit assessments have been performed. Pozelimab and Cemdisiran should be administered on the same day whenever possible. A 2-hour observation period should be instituted following the first 3 administrations of Pozelimab and Cemdisiran, whether alone or in combination. For subsequent administrations after the third administration of each study treatment, the observation period can be reduced to 30 minutes, provided the combination is felt to be well tolerated by the patient, per investigator's discretion.
15Eculizumab administration: administer Eculizumab study treatment to patients previously taking Eculizumab and randomized to the anti-C5 standard-of-care arm. Time points at weeks 14, 18, 22, 26, 30, and 34 are not included in the schedule of events, nevertheless Eculizumab should be administered at these time points. If Eculizumab administration does not coincide with the day of clinic visit, as applicable, then the clinic visit should always precede the infusion of Eculizumab. Patients who opt to enroll in the OLE should follow the schedule of events for the transition period (Table 6-2) after completion of the end of OLTP.
16Only patients who plan to continue in the follow-on OLE study will receive a dose of study treatment at the EOS week 36 visit for the OLTP. In addition, patients who are taking Eculizumab or Ravulizumab during the OLTP should continue to follow the schedule of events for the transition period (Table 6-2) after completion of the end of OLTP.
17Intentionally left blank
18Intentionally left blank
19Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting on the first day of dosing with study treatment and continuing until up to 52 weeks after discontinuation of Pozelimab/Cemdisiran. For post-treatment prophylaxis for Eculizumab or Ravulizumab follow the local prescribing information/national guidelines/local practice. If vaccination for Neisseria meningitidis occurs less than 2 weeks prior to day 1, then antibiotic prophylaxis must be administered for at least 2 weeks from the day of vaccination.
20Patient will complete PNH Symptom-Specific Questionnaire daily for 14 days prior to day 1 visit and continuing through the OLTP.
21Vital signs include temperature, sitting blood pressure, and pulse. Vital signs will be obtained pre-dose after the patient has been sitting quietly for at least approximately 5 minutes, where applicable.
22Physical examination will include an evaluation of the head and neck, lungs, heart, abdomen, extremities, and skin. Care should be taken to examine and assess any abnormalities that may be present, as indicated by the patient's medical history.
23Breakthrough hemolysis assessment: If a patient is suspected of having a breakthrough hemolysis event, then in addition to the required laboratory collection, additional samples for CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations of Pozelimab/Cemdisiran/Eculizumab/Ravulizumab (depending on the patient's randomization/enrollment), ADA (against Pozelimab), and exploratory research serum and plasma will be collected unless already noted in the schedule of events for that visit. If the suspected event does not occur at a scheduled visit then an unscheduled visit should occur with an evaluation of the patient and collection of CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations of Pozelimab/Cemdisiran/Eculizumab/Ravulizumab, and ADA (against Pozelimab), as applicable, and exploratory research serum and plasma.
24During lab collection, handling and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the lab result is not an accurate reflection of the patient's condition, consideration should be given to repeat the lab sample if clinically warranted, and in all cases where an LDH is ≥2 × ULN in association with a potassium >6 mmol/L. Blood collection should always be obtained prior to study treatment administration, unless otherwise noted. The coagulation blood sample must always be collected first, followed immediately by the blood chemistry sample.
25Hemoglobin will be assessed as part of the hematology analysis. Hematology sample should be collected before study treatment administration.
26Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. During the screening period, obtain chemistry including LDH on the day of (or if not possible, one day before) Eculizumab or Ravulizumab administration. On day 1 and all subsequent visits, obtain chemistry including LDH prior to any study treatment administration, as applicable.
27Pregnancy test: A serum test will be done at screening visit and a urine test will be done at all other visits.
28Blood sample collection for concentrations of Pozelimab, Cemdisiran, Eculizumab, Ravulizumab, total C5, CH50, AH50, free hemoglobin, haptoglobin, sC5b-9, PNH erythrocytes, granulocytes, monocytes, and exploratory research serum and plasma sample: Obtain samples prior to any study drug administration (pre-dose). Sampling for PK and ADA is applicable to treatment received (i.e., drug conc for Pozelimab is obtained only in patients who receive Pozelimab). Eculizumab PK samples should be obtained in all patients taking Eculizumab at screening and Ravulizumab PK samples should be obtained in all patients taking Ravulizumab at screening.
29For patients who receive Pozelimab IV infusion: obtain blood samples where permitted, prior to IV administration of Pozelimab and also within 15 minutes after the end of the IV infusion.
30Blood samples for concentrations of Cemdisiran and its metabolites will be collected, where permitted, prior to any study treatment administration (pre-dose) and at 1 to 4 hours post dose. The post dose sample may be collected at the clinic or by a visiting health care professional (if available).
31Blood samples for ADA will be collected, where permitted, before the administration of any study drug (pre-dose). In the event of suspected SAEs, such as anaphylaxis or hypersensitivity, additional blood samples may be collected at or near the onset of the event for PK, ADA, and other analyses.
32Samples for the measurement of concentrations of Cemdisiran and its metabolites will be collected at this visit only for patients who are receiving Eculizumab treatment and willing to continue in the transition period and into the OLE
33Pozelimab and Cemdisiran ADA samples will also be collected pre-dose at this visit for patients who are received Eculizumab or Ravulizumab treatment and willing to continue in the transition period and into the OLE.
34All biomarkers collected specifically on V3/day 1 must be collected pre-dose.
35Whole blood samples for DNA extraction (optional) should be collected on day 1 (pre-dose) but can be collected at a later study visit.
36For patients on Ravulizumab, visit 2r procedures should be completed on the day of or up to 2 days prior to Ravulizumab dose administration. Day 1 must be scheduled 4 weeks after the Ravulizumab dose or within 26 to 28 days counting from the day of the Ravulizumab dose.
37Study treatment (Pozelimab/Cemdisiran, Eculizumab, or Ravulizumab) at week 36 is only for patients who intend to continue in the OLE. Patients who decline enrollment into OLE will not he dosed at week 36.
1 When multiple procedures are performed on the same day, the sequence of procedures is as follows: vital signs, blood collection (first coagulation draw then chemistry draw followed by all other labs) and study drug administration. It is particularly important that the scheduled blood draws are obtained prior to the administration of study treatment, especially efficacy parameters such as LDH (i.e., measurements reflect a time point at the end of the dosing interval).
2Transition period day 1 is the day of the week 36 Eculizumab dose given in the OLTP. During the transition period, Eculizumab may be administered within 2 days of all visits where Eculizumab administration applies. If Eculizumab administration does not coincide with the day of clinic visit, as applicable, then the clinic visit should always precede the infusion of Eculizumab.
3Patient safety card: provide the patient safety card for Neisseria meningitidis infection to the patient at any visit when needed. Site should review the instructions on the safety card with the patient at each visit.
4Patients randomized to the anti-C5 standard-of-care arm taking Eculizumab, who complete the 36-week OLTP and plan to enroll into the OLE study, will transition from Eculizumab to the combination treatment as follows: the patients will have received Cemdisiran 200 mg along with Eculizumab 900 mg IV on the week 36 End of Treatment Visit for the OLTP. Final Eculizumab 900 mg IV is on week 2t visit of the transition period, then Pozelimab 60 mg/kg IV along with Pozelimab 400 mg SC and Cemdisiran 200 mg SC on week 4t visit. Patients will transition to the OLE study after completing the week 4t visit.
5All study treatments (i.e., Pozelimab, Cemdisiran, and Eculizumab) should be administered as the last procedure after all blood sample collection and study assessments have been completed. A 2-hour observation period should be instituted following the administration of Cemdisiran on transition day 1 (week 36 of OLTP). On day 29 (week 4 of transition period), after completion of administration of Pozelimab 60 mg/kg IV, patients should be monitored for at least 30 minutes prior to administration of Pozelimab/Cemdisiran SC. A 2-hour observation period should be instituted after the last administration of study drug (whether Pozelimab or Cemdisiran SC).
7Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting on the first day of dosing with study treatment and continuing until up to 52 weeks after discontinuation of Pozelimab/Cemdisiran. For post-treatment prophylaxis for Eculizumab or Ravulizumab follow the local prescribing information/national guidelines/local practice.
8If a patient is suspected of having a breakthrough hemolysis event, then in addition to the required laboratory collection, additional samples for CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50 and drug concentrations of Pozelimab, Cemdisiran, Eculizumab or Ravulizumab, ADA (against Pozelimab), and exploratory research serum and plasma will be collected unless already noted in the schedule of events for that visit. If the suspected event does not occur at a scheduled visit then an unscheduled visit should occur to evaluate the patient and to collect CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50 and drug concentrations of Eculizumab or Ravulizumab/Pozelimab/Cemdisiran, and ADA (against Pozelimab) as applicable, and exploratory research serum and plasma.
9During lab collection, handling and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the lab result is not an accurate reflection of the patient's condition, consideration should be given to repeating the lab sample if clinically warranted and, in all cases, where an LDH is ≥2 × ULN in association with potassium ≥6 mmol/L. Blood collection should always be obtained prior to study treatment administration, unless otherwise noted.
10Hemoglobin will be assessed as part of the hematology analysis. Hematology sample should be collected before study treatment administration.
11Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. Obtain chemistry including LDH prior to any study treatment administration.
12Pregnancy test: A urine test will be done.
13For patients who receive Pozelimab IV infusion: obtain blood samples prior to IV administration of Pozelimab and also within 15 minutes after the end of the IV infusion.
14Blood sample for CH50 and total C5 will be collected pre-dose.
1 When multiple procedures are performed on the same day, the sequence of procedures is as follows: vital signs, blood collection (first coagulation draw then chemistry draw followed by all other labs) and study drug administration. It is particularly important that the scheduled blood draws are obtained prior to the administration of study treatment, especially efficacy parameters such as LDH (i.e., measurements reflect a time point at the end of the dosing interval).
2Transition period day 1 is the day of the week 36 Ravulizumab dose given in the OLTP.
3Patient safety card: provide the patient safety card for Neisseria meningitidis infection to the patient at any visit when needed. Site should review the instructions on the safety card with the patient at each visit.
5All study treatments (i.e., Pozelimab and Cemdisiran) should be administered as the last procedure after all blood sample collection and study assessments have been completed. A 2-hour observation period should be instituted following the administration of Cemdisiran on transition day 29 (week 4 of transition period). On day 57 (week 8 of transition period), after completion of administration of Pozelimab 60 mg/kg IV, patients should be monitored for at least 30 minutes prior to administration of the Pozelimab/Cemdisiran SC. A 2-hour observation period should be instituted after the last administration of study drug (whether Pozelimab or Cemdisiran SC).
6Patients randomized to the anti-C5 standard-of-care arm taking Ravulizumab, who complete the 36-week OLTP and plan to enroll into the OLE study will transition from Ravulizumab to the combination treatment as follows: the patients will have received the last dose of Ravulizumab at the week 36 End of Treatment Visit for the OLTP. They will enter into the transition period with the first visit at week 4t, 4 weeks after the last dose of Ravulizumab. At the week 4t visit, they will receive Cemdisiran 200 mg SC. At the week 8t visit they will receive Pozelimab 60 mg/kg IV along with Pozelimab 400 mg SC and Cemdisiran 200 mg SC. They will transition to the OLE study after completing the week 8t visit.
7Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting on the first day of dosing with study treatment and continuing until up to 52 weeks after discontinuation of Pozelimab/Cemdisiran. For post-treatment prophylaxis for Eculizumab or Ravulizumab follow the local prescribing information/national guidelines/local practice.
8If a patient is suspected of having a breakthrough hemolysis event, then in addition to the required laboratory collection, additional samples for CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50 and drug concentrations of Pozelimab, Cemdisiran, Eculizumab or Ravulizumab, ADA (against Pozelimab), and exploratory research serum and plasma will be collected unless already noted in the schedule of events for that visit. If the suspected event does not occur at a scheduled visit then an unscheduled visit should occur to evaluate the patient and to collect CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50 and drug concentrations of Eculizumab or Ravulizumab/Pozelimab/Cemdisiran, and ADA (against Pozelimab) as applicable, and exploratory research serum and plasma.
9During lab collection, handling and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the lab result is not an accurate reflection of the patient's condition, consideration should be given to repeating the lab sample if clinically warranted and in all cases where an LDH is ≥2 × ULN in association with potassium ≥6 mmol/L. Blood collection should always be obtained prior to study treatment administration, unless otherwise noted.
10Hemoglobin will be assessed as part of the hematology analysis. Hematology sample should be collected before study treatment administration.
11Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. Obtain chemistry including LDH prior to any study treatment administration.
12Pregnancy test: A urine test will be done.
13For patients who receive Pozelimab IV infusion: obtain blood samples prior to IV administration of Pozelimab and also within 15 minutes after the end of the IV infusion.
14Blood sample for CH50 and total C5 will be collected pre-dose.
1Antibiotics prophylaxis (recommended): Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting at FU-1 and continuing until up to 52 weeks after discontinuation of Pozelimab/Cemdisiran. For post-treatment prophylaxis for Eculizumab or Ravulizumab follow the local prescribing information/national guidelines/local practice.
2Patient safety card for Neisseria meningitidis: Patient safety card: provide the patient safety card for Neisseria meningitidis infection to the patient at FU-1 or any other visit when needed. Site should review the instructions on the safety card with the patient at each visit.
3Pregnancy testing: Monthly urine pregnancy testing will be conducted for WOCBP only. If performed via at-home testing kits, patients should be reminded to call the study staff each month with the results of their pregnancy test, and as soon as possible if their pregnancy test result is positive.
A patient must meet the following criteria to be eligible for inclusion in the study:
1. Male or female ≥18 years of age or legal age of majority, whichever is greater, at the time of consent
2. Diagnosis of PNH confirmed by a history of high-sensitivity flow cytometry from prior testing
3. (i) Ongoing treatment with Eculizumab* 900 mg IV Q 14 days for at least 12 weeks prior to screening visit.
or
Note: If a patient screen fails, and if the study is still ongoing, they may be rescreened (up to 2 times) if the Principal Investigator determines the patient may be eligible upon rescreening.
A patient who meets any of the following criteria will be excluded from the study:
1. Patients with a screening LDH>1.5×ULN who have not taken their C5 inhibitor within the labeled dose interval at the dose prior to the screening LDH assessment.
2. Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant.
3. Body weight <40 kilograms at screening visit.
4. Current plans for modification (initiation, discontinuation, or dose/dosing interval change) of the following background concomitant medications, as applicable, during screening and treatment period: erythropoietin, immunosuppressive drugs, corticosteroids, anti-thrombotic agents, anticoagulants, iron supplements, and folic acid.
5. Any use of complement inhibitor therapy other than Eculizumab or Ravulizumab in the 26 weeks prior to the screening visit or planned use during the study with the exception of study treatments.
6. Any of the following abnormalities at the screening visit (two repeat measurements are allowed per parameter during screening period):
The primary objective of the study is to evaluate the effect of Pozelimab and Cemdisiran combination therapy on hemolysis, as assessed by LDH, after 36 weeks of treatment, in patients with PNH who switch from Eculizumab or Ravulizumab therapy to the combination treatment versus patients who continue their Eculizumab or Ravulizumab therapy.
The secondary objectives of the study are to:
The exploratory objectives of the study are:
The primary endpoint is the percent change in LDH from baseline to EOT period at week 36 (day 253).
The key secondary endpoints are:
Other secondary endpoints are:
The exploratory endpoints are:
These laboratory variables are relevant to the characterization and disease mechanisms of PNH (Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood 2014; 124(18):2804-2811.).
Hemolytic anemia is a clinical manifestation of PNH, and patients often require blood transfusion for symptomatic management. The frequency of blood transfusion has been used in other studies of PNH to assess efficacy (Hillmen P, Muus P, Dührsen U, Risitano A M, Schubert J, Luzzatto L, et al. Effect of the complement inhibitor Eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria. Blood 2007; 110(12):4123-4128) (Röth A, Egyed M, Ichikawa S, Kim J S, Nagy Z, Gasl Weisinger J, et al. The SMART Anti-hC5 Antibody (SKY59/RO7112689) Shows Good Safety and Efficacy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Blood 2018; 132(Suppl 1):535).
Brief descriptions of COAs are provided in Section 9.2.3 and include the following:
Safety and anthropometric variables in this study include:
This study is a randomized, open-label, Ravulizumab-controlled, non-inferiority study. The study is planned to enroll patients with PNH who are complement inhibitor treatment-naive or have not recently received complement inhibitor therapy.
The study consists of the following periods: up to 6-week screening period and a 26-week OLTP with either Ravulizumab or the combination of Pozelimab and Cemdisiran (
The screening period of up to 6 weeks prior to day 1 will evaluate patients to establish their eligibility to enter the study. Historical data related to prior and concomitant medications, hemolytic parameters, and RBC transfusions as well as PNH symptoms will be collected.
Additional interim screening visit(s) may take place as needed, for instance repeat blood collection.
Due to the risk of Neisseria meningitidis infection, patients will require administration of meningococcal vaccination(s) in accordance with local Ravulizumab prescribing information, where applicable, and in accordance with current national vaccination guidelines for vaccination use with complement inhibitors or local practice and at a minimum, within a period of 5 years prior to screening. For patients who require administration with meningococcal vaccination(s) during the screening period, administration should occur preferably at least 2 weeks prior to day 1, or at another time point according to local practice or national guidelines/local Ravulizumab prescribing information (where available). If vaccination precedes the initiation of study treatment by less than 2 weeks, then the patient must receive antibiotic prophylaxis for a minimum of 2 weeks from the date of vaccine administration.
Patients who have not been vaccinated against Streptococcus pneumoniae and Haemophilus influenzae type B may receive these vaccinations during the screening period or on the day of randomization based on investigator discretion and taking into consideration the available national guidelines.
In addition to Neisseria meningitidis infection, fatal or serious infections with Neisseria gonorrhea have been reported in patients taking complement inhibitors. Therefore, patients should undergo a risk assessment and counseling regarding the potential risk of Neisseria gonorrhea infection as per local practice or national guidelines.
Patients will be assessed for active or latent tuberculosis (TB) infection based on local practice or applicable guidelines. Based on the risk assessment, the need for screening with either tuberculin skin test or T-cell interferon-gamma release assay will be made. The interpretation of these results, as applicable, will be made by the investigator. Further management and treatment of TB will be the responsibility of the investigator.
Patients who complete the screening assessments and are deemed eligible for enrollment will be randomized in a 1:1 ratio into the combination arm or the Ravulizumab arm. Randomization will be stratified based on the factors described herein-Patients will be randomized by an Interactive Web Response System (IWRS) in a 1:1 ratio to receive either the combination treatment with SC Pozelimab 400 mg and Cemdisiran 200 mg Q4W or IV Ravulizumab according to the labeled weight-based dosing algorithm. Stratified, blocked randomization will be performed using the following stratification factors:
Randomization blocking will be performed centrally.
The treatment period is 26 weeks (Table 7-1). Patients will receive the corresponding treatments according to their treatment assignment described below.
After day 1 dosing, subsequent administrations may be continued by the site personnel or a healthcare professional at the patient's home (if possible and approved by the sponsor) or for the combination of Pozelimab and Cemdisiran, administered by the patient or designated person at the patient's preferred location. These various options for administration will depend on preference of the investigator and patient, local regulations as well as availability of healthcare professional with sponsor endorsement. If self-administration/administration by designated person is undertaken for the combination of Pozelimab and Cemdisiran, then sufficient injection training at the scheduled administration(s) with Pozelimab and Cemdisiran maintenance regimen will be provided. After training, observation of self-administration/administration by designated person will be conducted by clinical site personnel or visiting healthcare professional/virtual visit (if available). Once this observation is considered satisfactory, the Pozelimab and Cemdisiran maintenance regimen can be subsequently administered independently by patient/designated person for the remainder of the study. Patients who self-administer/have the study drug administered by a designated person shall complete a patient diary to collect information on study treatment administration. They shall also be contacted by the study site to ensure study drug administration as planned.
All patients who complete the 26-week OLTP study treatment will be offered to participate in the long-term, OLE study of the combination treatment.
Patients randomized to the Ravulizumab arm who complete the 26-week OLTP and plan to enroll into the next study will be given an additional Ravulizumab dose at week 26 of the OLTP. These patients will first be offered to participate in the R3918 PNH 2022 study (a Pozelimab and Cemdisiran combination study in patients with PNH who are currently treated with Eculizumab or Ravulizumab). If recruitment for the R3918-PNH-2022 is open, the patient will proceed with screening as described for the R3918-PNH-2022 study.
If the patient does not meet eligibility requirements for the R3918-PNH-2022 study, or if recruitment is closed for R3918-PNH-2022, the patient may proceed into the OLE study. The transition from Ravulizumab to Cemdisiran and Pozelimab should be managed in the following manner (Table 7-2):
This approach for patients randomized to Ravulizumab and who plan to enroll in the OLE study directly is to ensure a consistent dosing approach when switching from Ravulizumab to Pozelimab and Cemdisiran combination therapy.
For patients who are randomized to the Pozelimab and Cemdisiran combination arm, day 1 visit of the OLE study will occur 2 weeks after the week 26 end of study (EOS) visit in the current study to ensure that there is no interruption of study treatment.
Patients who discontinue study treatment as well as patients who do not go on to participate in the R3918-PNH-2022 or decline enrollment into the OLE study will undergo a safety off-treatment follow-up period of up to 52 weeks according to Table 7-3. Patients discontinuing study treatment should be treated in accordance with local standards of care while continuing to be monitored in the 52-week off-treatment safety follow-up period. Investigators switching patients from the combination treatment to another anti-C5 mAb should have a heightened awareness for possible AEs resulting from the formation of large DTD immune complexes.
The main study is considered finished when all patients either complete the 26-week treatment period or prematurely discontinue the study. Additional data collected during the transition period and safety off-treatment follow-up period will be described separately.
In light of the public health emergency related to COVID-19, the continuity of clinical study conduct, and oversight may require implementation of temporary or alternative mechanisms. Examples of such mechanisms may include, but are not limited to, any of the following: phone contact, virtual visits, telemedicine visits, online meetings, non-invasive remote monitoring devices, use of local clinic or laboratory locations, and home visits by skilled staff. Additionally, no waivers to deviate from protocol enrollment criteria due to COVID-19 will be granted. All temporary mechanisms utilized, and deviations from planned study procedures are to be documented as being related to COVID-19 and will remain in effect only for the duration of the public health emergency.
Study assessments and procedures are presented by study period and visit in Table 7-1 (OTLP), Table 7-2 (Transition Period), and Table 7-3 (Safety Follow-up Period). See
meningitidis
5
X30
X12
X12
X31
X31
X26
X26
X28
X28
X28
X28
X28
X28
1Study procedure visits on days 15, 71, 113, 127, 141, and 169 may be at the clinical site, or another preferred location such as patient's home. The location will be dependent on availability (and if approved by the sponsor) of home healthcare visiting professional, and preferences of the investigator and patient. Visits may also be conducted at another preferred location depending on extenuating circumstances such as due to SARS-CoV-2 infection provided the assessments can be performed by the visiting healthcare professional.
2When multiple procedures are performed on the same day, the sequence of procedures is as follows: COA assessments; ECG/vital signs/physical examination; blood collection (first coagulation draw then chemistry draw followed by all other labs); and study drug administration. It is particularly important that the scheduled blood draws are obtained prior to the administration of Ravulizumab or Pozelimab and Cemdisiran, especially efficacy parameters such as LDH (i.e., measurements reflect a time point at the end of the dosing interval). During blood sample collection, handling, and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the lab result is not an accurate reflection of the patient's condition, consideration should be given to repeating the lab sample if clinically warranted and, in all cases, where an LDH is ≥2 × ULN in association with potassium ≥6 mmol/L. Specific instructions for avoiding hemolysis are provided in the relevant section of the protocol.
3Medical history including, transfusions, breakthrough hemolysis history, and laboratory parameters for measurement of hemolysis (such as LDH, bilirubin, haptoglobin, reticulocyte count, and hemoglobin) should be obtained for the past 52 weeks, if possible. Prior history of thrombosis and infections of the Neisseria spp. will be collected. Patients with a known C5 mutation (i.e., C5 variants R885H/C) are not eligible, however, if a C5 mutation is later suspected and confirmed while the study is ongoing, the information should be included as part of the patient's medical history. Patients who are poor responders to Ravulizumab treatment during the study may be asked for a mutation analysis to be conducted as part of the study, if the patient agrees to such testing.
4Including detailed medication history for PNH treatment and Neisseria meningitidis vaccination history and other vaccinations as applicable.
5Patients will require administration with meningococcal vaccination unless documentation is provided of prior immunization in the past 5 years or less than 5 years if required according to current national vaccination guidelines for vaccination use with complement inhibitors/local Ravulizumab prescribing information. For patients who require administration with meningococcal vaccination(s) during the screening/period, administration should occur preferably at least 2 weeks prior to day 1, or at another time point according to local Ravulizumab prescribing information/national guidelines.
6Vaccination for Streptococcus pneumoniae and Haemophilus influenzae Type B should be per current national/local vaccination guidelines.
7Screening by tuberculin skin test or T-cell interferon-gamma release assay may be performed according to local practice or guidelines at the discretion of the investigator.
8A risk factor assessment for Neisseria gonorrhea will be performed in accordance with local practice/national guidelines, and regular testing and counseling is advised for at-risk patients.
9Patient safety card for Neisseria meningitidis infection will be provided to the patient on day 1 or any other visit when needed. Site should review the instructions on the safety card with the patient at each visit.
10Patients who are randomized to Ravulizumab will receive Ravulizumab according to the labeled posology with the first dose of Ravulizumab administered on day 1 (or up to 2 days after the day 1 visit) according to the patient's weight (>40 kg to <60 kg, 2400 mg IV; ≥60 kg to <100 kg, 2700 mg IV; ≥100 kg, 3000 mg IV). The first maintenance dose should be administered 2 weeks after the loading dose as follows: (>40 kg to <60 kg, 3000 mg IV; ≥60 kg to <100 kg, 3300 mg IV; ≥100 kg, 3600 mg IV). Thereafter, the maintenance dose should be administered IV Q8W (+7 days). As the first maintenance dose is to be administered 2 weeks after the loading dose, the week 2 visit should proceed within the visit window, the day of or preceding the Ravulizumab administration. If Ravulizumab administration does not coincide with the day of clinic visit, as applicable, assuming that both the treatment and visit windows are respected, then the clinic visit should always precede the infusion of Ravulizumab dosing. A body weight should be performed prior to administration of Ravulizumab to allow for weight-based dosing. Patients who opt not to enroll into the follow on OLE study or who will not screen for the R3918-PNH-2022 study will have the last dose of Ravulizumab at week 18 (day 127).
11Patients who are randomized to Pozelimab and Cemdisiran combination arm will receive Pozelimab 30 mg/kg IV along with Pozelimab 400 mg SC and Cemdisiran 200 mg SC on day 1. Patients should be monitored for at least 30 minutes after completion of Pozelimab 30 mg/kg IV and should be monitored for at least another 30 minutes after the completion of the first Pozelimab and Cemdisiran SC dosing. Subsequent SC doses of the combination will be administered Q4W and may either be performed by the site personnel or another healthcare professional at patient's home (if available), or administration by patient or designated person at the patient's preferred location. The final dosing of the SC combination in the OLTP is at week 24. The dose of Pozelimab and Cemdisiran should be given Q4W (every 28 days) and on the day of the corresponding study visit whenever possible. Study treatment administration should always be the last procedure after all blood sample collection and study assessments have been completed. If Pozelimab or Cemdisiran cannot be administered on the day of the corresponding study visit, the combination may be administered up to 7 days before or up to 7 days after the planned dosing date as long as the dosing takes place after the corresponding study visit has been completed. For example, the week 8 (D57) visit can take place from D54 to D60 given the visit window. The dose of Pozelimab and Cemdisiran therefore can be given from D54 to D64 but only on or after the week 8 visit assessments have been performed. Similarly, the week 16 (D113) visit can take place from D106 to D 120 given the visit window. The dose of Pozelimab and Cemdisiran can be given from D106 to D120 but only on or after the week 16 visit assessments have been performed. Pozelimab and Cemdisiran should be administered on the same day whenever possible.
12If the sponsor has endorsed self-injection, injection training will be provided to patients who desire self-injection or injection by a designated person. Site should observe patient syringe preparation and self-injection or injection by a designated person and confirm adequacy. Patient instruction materials will be provided (or reviewed as needed).
13Patient diary: If needed, for self-administration or administration by a designated person with Pozelimab and Cemdisiran combination treatment only, a patient diary may be provided to collect information on study treatment administration. Patient diary may be provided at week 4 visit or a subsequent visit. If patient diary is provided to the patient, then it should be reviewed at each clinic visit and data collected into the case report forms (CRFs). On the final visit, the diary should be collected by the site.
14Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting on the first day of dosing with study treatment and continuing until up to 52 weeks after discontinuation of Pozelimab and Cemdisiran. For post-treatment prophylaxis for Ravulizumab, consult the local prescribing information/national guidelines/local practice. If vaccination for Neisseria meningitidis occurs less than 2 weeks prior to day 1, then antibiotic prophylaxis must be administered for at least 2 weeks from the day of vaccination.
15Patient will complete PNH Symptom-Specific Questionnaire daily for 14 days prior to day 1 visit and continuing through the OLTP.
16Vital signs include temperature, sitting blood pressure and pulse. Vital signs will be obtained pre-dose after the patient has been sitting quietly for at least approximately 5 minutes, where applicable.
17Physical examination will include an evaluation of the head and neck, lungs, heart, abdomen, extremities, and skin. Care should be taken to examine and assess any abnormalities that may be present, as indicated by the patient's medical history.
18If a patient is suspected of having a breakthrough hemolysis event, then in addition to the required laboratory collection, additional samples for CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations of Pozelimab/Ravulizumab/Cemdisiran, ADA (against Pozelimab) and exploratory research serum and plasma will be collected unless already noted in the schedule of events for that visit. If the suspected event does not occur at a scheduled visit, then an unscheduled visit should occur to evaluate the patient and to collect CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50 drug concentrations of Ravulizumab/Pozelimab/Cemdisiran, and ADA (against Pozelimab). In addition, an exploratory research serum and plasma sample should be collected.
19Clinical lab samples will be collected first before study drug administration. The coagulation blood sample must always be collected first, followed immediately by the blood chemistry sample. The same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis during sample processing.
20Hemoglobin will be assessed as part of the hematology analysis. Hematology sample should be collected before study treatment administration.
21Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. Blood chemistry sample should be collected before study treatment administration.
22Blood samples for Pozelimab PK will be obtained on the specified days prior to the Pozelimab dosing. On study visit day 1, obtain blood samples prior to IV administration of Pozelimab and also within 15 minutes after the end of the Pozelimab IV infusion.
23Cemdisiran and its metabolite PK samples will be collected on the specified days before and 1 to 4 hours post Cemdisiran administration. The post dose sample may be collected at the clinic or by a visiting health care professional (if available).
24Blood samples for Ravulizumab PK will be obtained prior to IV administration of Ravulizumab and also within 15 minutes after the end of Ravulizumab IV infusion.
25Blood samples for ADA will be collected on the specified days before the study drug administration. In the event of suspected SAEs, such as anaphylaxis or hypersensitivity, additional blood samples may be collected at or near the onset of the event for PK, ADA, and other analyses.
26For patients randomized to combination arm as well as patients in Ravulizumab arm who will be continuing in the transition period, blood samples are collected pre-dose to assess ADA of Pozelimab and Cemdisiran.
27Blood samples for total C5, free hemoglobin, haptoglobin, CH50, AH50, sC5b-9, and PNH erythrocytes, granulocytes, monocytes, and exploratory research serum and plasma will be obtained on the specified days prior to Ravulizumab or the combination administration.
28All biomarkers collected specifically on V3/day 1 must be collected pre-dose.
29Whole blood samples for DNA extraction (optional) should be collected on day 1 (predose) but can be collected at a later study visit.
30A Ravulizumab dose will be given at week 26 only if the patient intends to continue into OLE or R3918-PNH-2022. Patients who do not continue into a subsequent study with the Pozelimab/Cemdisiran combination will not receive a Ravulizumab dose at EOS.
31For patients planning to enroll in the OLE, day 1 of the R3918-PNH-2050 study must be scheduled 4 weeks after the week 24 dose of the combination treatment (i.e., 2 weeks after the week 26 EOS visit in the R3918-PNH-2021) to ensure no interruption in treatment administration.
1When multiple procedures are performed on the same day, the sequence of procedures is as follows: vital signs, blood collection (first coagulation draw then chemistry draw followed by all other labs), and study drug administration. It is particularly important that the scheduled blood draws are obtained prior to the administration of Ravulizumab or Pozelimab and Cemdisiran, especially efficacy parameters such as LDH (i.e., measurements reflect a time point at the end of the dosing interval). During blood sample collection, handling, and processing, the same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis during sample processing. If the investigator or sponsor suspects that the lab result is not an accurate reflection of the patient's condition, consideration should be given to repeating the lab sample if clinically warranted and, in all cases, where an LDH is ≥2 × ULN in association with potassium ≥6 mmol/L. Specific instructions for avoiding hemolysis are provided.
2Patients randomized to the Ravulizumab arm who complete the 26-week OLTP: If recruitment for the R3918-PNH-2022 is open and the patient has screened but was not eligible for the R3918-PNH-2022 study, the patient may instead proceed into the OLE study after completing the transition period. If recruitment for R3918-PNH-2022 is no longer open or the patient is not interested in participating in the R3918-PNH-2022, but is interested in participating in the OLE study, the patient may proceed directly into the transition period.
3Patient safety card for Neisseria meningitidis infection will be provided to the patient on any visit when needed. Site should review the instructions on the safety card with the patient at each visit.
4Patients randomized to the Ravulizumab arm, who complete the 26 weeks OLTP and plan to enroll into the OLE study, will transition from Ravulizumab to the combination treatment as follows: final Ravulizumab maintenance dose (per labeled weight-based dosing algorithm) will be administered IV at week 26 EOS visit in OLTP. Patients will receive Cemdisiran 200 mg SC on week 4t followed at week 8t by Pozelimab 60 mg/kg IV along with Pozelimab 400 mg SC and Cemdisiran 200 mg SC.
5All study treatments (i.e., Pozelimab, Cemdisiran, and Ravulizumab) should be administered as the last procedure after all blood sample collection and study assessments have been completed. After completion of administration of Pozelimab 60 mg/kg IV, patients should be monitored for at least 30 minutes. Patients should be monitored for at least 30 minutes after completion of the first Pozelimab SC dosing and the first Cemdisiran SC dosing.
6 Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended starting on the first day of dosing with study treatment and continuing until up to 52 weeks after discontinuation of Pozelimab and Cemdisiran. For post-treatment prophylaxis for Ravulizumab, consult the local prescribing information/national guidelines/local practice.
7If a patient is suspected of having a breakthrough hemolysis event, then in addition to the required laboratory collection, additional samples for CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50, drug concentrations of Pozelimab, Ravulizumab, and Cemdisiran, ADA (against Pozelimab), and exploratory research serum and plasma will be collected unless already noted in the schedule of events for that visit. If the suspected event does not occur at a scheduled visit, then an unscheduled visit should occur to evaluate the patient and to collect CBC, coagulation parameters (including D-dimer), chemistry, reticulocyte count, total C5, CH50 and drug concentrations of Ravulizumab/Pozelimab/Cemdisiran, and ADA (against Pozelimab). In addition, an exploratory research serum and plasma sample should be collected.
8Clinical lab samples will be collected first before study drug administration. The same methodology will be applied across study visits, as best as possible, to preserve the quality of sample and avoid hemolysis during sample processing.
9Hemoglobin will be assessed as part of the hematology analysis. Hematology sample should be collected before study treatment administration.
10Serum LDH, CRP, and bilirubin will be assessed as part of the blood chemistry analysis. Blood chemistry sample should be collected before study treatment administration.
11Blood samples for Pozelimab PK will be obtained on the specified days prior to the Pozelimab IV dosing and also within 15 minutes after the end of the Pozelimab IV infusion.
12All biomarkers and total C5 collected specifically on TV2 must be collected pre-dose.
The FUP is for patients who discontinue treatment for any reason, including those who complete the OLTP but decline enrollment into the next study.
Patients in the Ravulizumab arm who complete OLTP (i.e., last dose of study drug at week 18 and EOS at week 26) will enter FUP at visit FU-3 (i.e., 12 weeks after last dose of study drug)
Patients in the Pozelimab/Cemdisiran arm who complete OLTP (i.e., last dose of study drug at week 24 and EOS at week 26) will enter FUP at visit FU-1 (i.e., 4 weeks after last dose of study drug)
For patients who discontinue and do not complete OLTP, they will have an ET visit. Thereafter, their entry point into the FUP will depend on the number of weeks that have elapsed after their final dose of study treatment
meningitidis
2
1Antibiotics prophylaxis (recommended): Daily oral antibiotic prophylaxis against Neisseria meningitidis is recommended, continuing until up to 52 weeks after discontinuation of Pozelimab and Cemdisiran. For post-treatment prophylaxis for Ravulizumab, follow the local prescribing information/national guidelines/local practice.
2Patient safety card for Neisseria meningitidis: Patient safety card for Neisseria meningitidis infection will be provided to the patient at FU-1 or any other visit when needed. Site should review the instructions on the safety card with the patient at each visit.
3Pregnancy testing: Monthly urine pregnancy testing will be conducted for WOCBP only. If performed via at-home testing kits, patients should be reminded to call the study staff each month with the results of their pregnancy test, and as soon as possible if their pregnancy test result is positive.
The study population will consist of adult male and female patients with confirmed diagnosis of PNH along with active signs and symptoms with evidence of hemolysis and are either complement inhibitor treatment-naive or have not recently received complement inhibitor treatment. Method of treatment assignment and stratification factors are described herein:
Patients will be randomized by an Interactive Web Response System (IWRS) in a 1:1 ratio to receive either the combination treatment with SC Pozelimab 400 mg and Cemdisiran 200 mg Q4W or IV Ravulizumab according to the labeled weight-based dosing algorithm. Stratified, blocked randomization will be performed using the following stratification factors:
Randomization blocking will be performed centrally.
Note: Enrollment of patients who have had no RBC transfusion in the past 1 year prior to day 1 will be capped at 20% of the overall enrolled population.
A patient must meet the following criteria to be eligible for inclusion in the study.
Note: If a patient screen fails, and if the study is still ongoing, they may be rescreened (up to 2 times) if the investigator determines the patient may be eligible upon rescreening.
A patient who meets any of the following criteria will be excluded from the study:
1. Prior treatment with Eculizumab within 3 months prior to screening, Ravulizumab within 6 months prior to screening, or other complement inhibitors within 5 half-lives of the respective agent prior to screening.
2. Receipt of an organ transplant, history of bone marrow transplantation or other hematologic transplant.
3. Body weight <40 kilograms at screening visit.
4. Current plans for modification (initiation, discontinuation, or dose/dosing interval change) of the following background concomitant medications, as applicable, during screening and treatment periods: erythropoietin, immunosuppressive drugs, corticosteroids, antithrombotic agents, anticoagulants, iron supplements, and folic acid.
5. Planned use of any complement inhibitor therapy other than study drugs during the treatment period.
6. Any of the following abnormalities at the screening visit (two repeat measurements are allowed per parameter during screening period):
The primary objective of the study is to evaluate the effect on hemolysis and RBC transfusions over a 26-week treatment period of Pozelimab and Cemdisiran combination treatment versus Ravulizumab treatment in patients with active PNH who are complement inhibitor treatment-naive or have not recently received complement inhibitor therapy
The secondary objectives of the study are to:
The exploratory objectives of the study are to explore the effect of Pozelimab and Cemdisiran combination treatment versus Ravulizumab treatment on the following:
The co-primary endpoints are:
The key secondary endpoints are:
The other secondary endpoints are:
The exploratory endpoints are:
Efficacy in this study is evaluated by the following laboratory assessments:
These laboratory variables are relevant to the characterization and disease mechanisms of PNH (Brodsky RA. Paroxysmal nocturnal hemoglobinuria. Blood 2014; 124(18):2804-2811).
Hemolytic anemia is a clinical manifestation of PNH, and patients often require blood transfusion for symptomatic management. The frequency of blood transfusion has been used in other studies of PNH to assess efficacy (Hillmen P, Young NS, Schubert J, Brodsky RA, Socie G, Muus P, et al. The complement inhibitor Eculizumab in paroxysmal nocturnal hemoglobinuria. N Engl J Med 2006; 355(12):1233-1243) (Röth A, Egyed M, Ichikawa S, Kim J S, Nagy Z, Gasl Weisinger J, et al. The SMART Anti-hC5 Antibody (SKY59/RO7112689) Shows Good Safety and Efficacy in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). Blood 2018; 132(Suppl 1):535.).
COAs include the following:
In this study, initially designed to study treatment of complement inhibitor naïve patients with PNH with the combination using Ravulizumab as a comparator was redesigned to use Eculizumab as a comparator. Cohort A (n=40) enrolled patients (1:1 randomization) to receive either Pozelimab/Cemdisiran combination treatment or Ravulizumab. Cohort B (n=150) enrolled patients (1:1 randomization) to receive Pozelimab/Cemdisiran combination treatment or Eculizumab. See
Patients who received the combination treatment regimen (which may be referred to as “Pozelimab Q4W+Cemdisiran” or “combo” or “combination”) exhibited superior control over hemolysis, normalization of LDH and lack of breakthrough hemolysis, relative to patients who received only Ravulizumab monotherapy treatment regimen (“Ravulizumab”).
Adequate control of hemolysis refers to achievement of LDH≤1.5×ULN (considered clinically relevant threshold, ULN=upper limit of normal). Pharmacologic treatment is often initiated in symptomatic patients with LDH>1.5×ULN (LDH=lactate dehydrogenase). LDH s 1.5 xULN on complement inhibitor (CI) therapy correlates with improved symptoms, QoL and blood transfusions. Maintenance of adequate control of hemolysis refers to sustained reduction in LDH≤1.5×ULN at all visits from week 8 through week 26, inclusive, without an intervening event of breakthrough hemolysis. Normalization of LDH refers to achievement of LDH 51×ULN. Breakthrough hemolysis refers to an increase in LDH≥2×ULN after initial achievement of LDH≤1.5×ULN, plus signs or symptoms of hemolysis.
Twenty two patients completed the treatment period (11 in each arm) with 46 randomized at the time of the analysis (Table 7-4 and Table 7-5).
Baseline characteristics were generally similar in both arms (Table 7-6).
Hemoglobin (Hb) stabilization & transfusion avoidance was similar in week 26 completers among patients on combo vs Ravulizumab. See Tables 7-7 A-D.
Ninety-one % of the Combo patients vs 73% of the Ravulizumab patients maintained adequate control of hemolysis (LDH≤1.5×ULN) (Table 7-7). No patient (n=46) met the protocol criteria for breakthrough hemolysis. One patient had a bump in LDH levels on the combo due to viral fever D179 to 181 (LDH increase at D182, V13).
Transfusions can be driven by:
There was a higher proportion of Combo patients that achieved adequate control of hemolysis (LDH e 1.5×ULN By Visit) relative to Ravulizumab patients. The LDH measurements of each patient per visit are set forth in Table 7-8. LDH measurements that were above the reference range are indicated with an “(H)” and LDH measurements that were below the reference range are indicated with an “(L)”.
The mean percentage change from baseline in LDH among Combo patients and Ravulizumab patients is graphically summarized in
A comparison between the LDH and CH56 values of inadequate responders from each arm is set forth in
An inadequate responder in the Ravulizumab group (Subject ID. 158-001-101) normalized LDH after switching to the combo (first of 4 to cross over). See
As shown in
As set forth in Table 7-9 and 7-10, among Combo patients there was a higher proportion that achieved adequate control of hemolysis (i.e., achieved LDH≤1.5×ULN By Visit) and normalization of LDH (i.e., achieved LDH≤1×ULN By Visit) as compared to that of Ravulizumab patients. See
The majority of patients in both treatment groups (Combo and Ravulizumab) achieve control of LDH (below 1.5×ULN) by week 4 and maintained control through week 26 endpoint. See
Hemoglobin (Hb) was similar across treatment groups among week 26 completers. A summary of change from baseline of hemoglobin measurements over 26 weeks is set forth in Table 7-12. Individual hemoglobin measurements per visit are set forth in Table 7-13. See also
Transfusion avoidance was similar among week 26 completers. See Table 7-14. Transfusions can be driven by hemolysis (intravascular hemolysis, extravascular hemolytsis), bone marrow insufficiency and other factors such as blood loss. There may have been an imbalance in other factors given small sample size. See also, the summary of per protocol transfusions between groups in
Complement hemolytic assay (CH50) is an ex vivo functional assay measuring the activity of terminal complement in patient's blood and measures the ability of an individual's blood to lyse sensitized (antibody coated) sheep red blood cells (RBCs). Result are reported as the reciprocal of the dilution of serum required to lyse 50% of antibody coated sheep RBCs. If elevated, terminal complement activity is present. The assay is sensitive to reduction or absence of any component of the classical pathway (C1, C2, C3, C4) or terminal complement activity (C5 through 9). The CH50 assay results of individual patients per visit are set forth in Table 7-15. Out of range result flags (H=high and L=low) are included. CH50 data for Ravulizumab patients revealed a saw-tooth pattern that aligned with drug trough levels, while CH50 for Combo patients remained close to 100% inhibition at all timepoints. See
No new safety signals emerge based on treatment emergent adverse events comparing combo vs Ravulizumab:
This study was initiated to evaluate the effects of potential excipients on viscosity. Two base co-formulations, one containing 120 mg/mL Cemdisiran, 120 mg/mL Pozelimab, 15 mM histidine, pH 6.2 and another containing 75 mg/mL Cemdisiran, 150 mg/mL Pozelimab, 15 mM histidine, pH 6.2 were manufactured with a potential viscosity reducer. List of viscosity reducers and concentrations tested are shown below:
Co-formulations without additional excipient were also manufactured and used as a control for this study.
Viscosity at 20° C. was accessed by an automatic viscometer for all co-formulations. Table 8-1 shows the reduction of viscosity for each co-formulation compared to control. Maximum viscosity reduction observed was approximately a third. All excipients tested were effective viscosity reducers for co-formulations that contained 120 mg/mL Cemdisiran and 120 mg/mL Pozelimab, while only a subset was effective for co-formulations that contained 75 mg/mL Cemdisiran and 150 mg/mL Pozelimab. A common property of ineffective viscosity reducer was cyclic structure vs a effective viscosity reducer which was the salt form for co-formulations that contained 75 mg/mL Cemdisiran and 150 mg/mL Pozelimab. Intermolecular interactions possibly dominated by electrostatics, given effectiveness of sodium chloride and salt forms of amino acids (either Na+ or HCl) for both co-formulations.
Purity of both Pozelimab and Cemdisiran was measured after ≥1 month storage at 2-8° C. and compared to source material used for manufacturing co-formulations. Size exclusion ultra-performance liquid chromatography using a fluorescence detector was performed to access Pozelimab stability. See Table 8-2. Denaturing anion exchange ultra-performance liquid chromatography was performed to access Cemdisiran stability. See Table 8-3. All formulations showed no appreciable change in purity.
All references cited herein are incorporated by reference to the same extent as if each individual publication, database entry (e.g., Genbank sequences or GeneID entries), patent application, or patent, was specifically and individually indicated to be incorporated by reference. This statement of incorporation by reference is intended by Applicants to relate to each and every individual publication, database entry (e.g., Genbank sequences or GeneID entries), patent application, or patent, each of which is clearly identified in even if such citation is not immediately adjacent to a dedicated statement of incorporation by reference. The inclusion of dedicated statements of incorporation by reference, if any, within the specification does not in any way weaken this general statement of incorporation by reference. Citation of the references herein is not intended as an admission that the reference is pertinent prior art, nor does it constitute any admission as to the contents or date of these publications or documents.
The present disclosure is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the disclosure in addition to those described herein will become apparent to those skilled in the art from the foregoing description and accompanying figures. Such modifications are intended to fall within the scope of the appended claims.
| Number | Date | Country | Kind |
|---|---|---|---|
| 112141079 | Oct 2023 | TW | national |
The present application claims the benefit of U.S. Provisional Patent Appl. No. 63/381,450 filed Oct. 28, 2022, U.S. Provisional Patent Appl. No. 63/382,087 filed Nov. 2, 2022, U.S. Provisional Patent Appl. No. 63/382,264 filed Nov. 3, 2022, U.S. Provisional Patent Appl. No. 63/383,442 filed Nov. 11, 2022, U.S. Provisional Patent Appl. No. 63/385,909 filed Dec. 2, 2022, U.S. Provisional Patent Appl. No. 63/386,787 filed Dec. 9, 2022, U.S. Provisional Patent Appl. No. 63/495,767 filed Apr. 12, 2023, U.S. Provisional Patent Appl. No. 63/498,112 filed Apr. 25, 2023, U.S. Provisional Patent Appl. No. 63/505,011 filed May 30, 2023, and Taiwanese Patent Appl. No. 112141079 filed Oct. 26, 2023, each of which is herein incorporated by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 63505011 | May 2023 | US | |
| 63498112 | Apr 2023 | US | |
| 63495767 | Apr 2023 | US | |
| 63386787 | Dec 2022 | US | |
| 63385909 | Dec 2022 | US | |
| 63383442 | Nov 2022 | US | |
| 63382264 | Nov 2022 | US | |
| 63382087 | Nov 2022 | US | |
| 63381450 | Oct 2022 | US |
