Patent Application
20240368294
The contents of the electronic sequence listing (HOPA_034_03US_SeqList_ST26.xml; Size: 24,489 bytes; and Date of Creation: Mar. 25, 2024) are herein incorporated by reference in its entirety.
The present disclosure is related to compositions comprising a Tn3 scaffold and methods using the same in the treatment prevention of rheumatoid arthritis.
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that is associated with significant morbidity and mortality. The disease is characterized by inflammation of the synovial joints that can result in pain, swelling, and joint damage with secondary deformity and progressive disability. Worldwide, the prevalence of RA is estimated to be between 0.6-1.1% with variations across geographical regions. The incidence is 2-3 times higher in women than in men with a peak age of onset between 35-55 years of age. Uncontrolled active RA causes joint damage, disability, and decreased quality of life; comorbidities include cardiovascular disease and osteoporosis, and reduced life expectancy.
Despite the presence of existing therapeutic agents for the treatment of RA, there is a need for new treatments to reduce disease activity, because only a minority of subjects achieve clinical remission.
Provided are methods for treating rheumatoid arthritis in a subject in need thereof comprising administering a Tn3 scaffold comprising a CD40L-specific monomer subunit to the subject. In aspects, the Tn3 scaffold specifically binds to CD40L. In aspects, the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 1500 mg, and wherein the Tn3 scaffold is administered once about every 2 weeks for at least 2 doses, and is administered about once a month thereafter.
Provided are methods of treating rheumatoid arthritis in a subject in need thereof comprising: administering a Tn3 scaffold comprising a CD40L-specific monomer subunit to the subject; wherein the Tn3 scaffold specifically binds to CD40L; wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 1500 mg, and wherein the Tn3 scaffold is administered once about every 2 weeks for at least 3 doses, and is administered about once a month thereafter.
Provided are methods of treating rheumatoid arthritis in a subject in need thereof comprising: administering a Tn3 scaffold comprising a CD40L-specific monomer subunit to the subject; wherein the Tn3 scaffold specifically binds to CD40L; wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 1500 mg, and wherein the Tn3 scaffold is administered once about every 2 months for at least 2 doses.
Provided are methods for treating rheumatoid arthritis in a subject in need thereof comprising: administering a Tn3 scaffold comprising a CD40L-specific monomer subunit to the subject; wherein the Tn3 scaffold specifically binds to CD40L; wherein the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16, wherein the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 3000 mg, and wherein the Tn3 scaffold is administered about once, once a month, once about every two months, or once about every three months.
In aspects, the Tn3 scaffold is administered in combination with a second therapy. In aspects, the second therapy comprises an anti-inflammatory agent, an anti-pain agent, a Disease-modifying Antirheumatic Drug (DMARD), a corticosteroid, or an immune system modifying agent. In aspects, the DMARD is a conventional DMARD (cDMARD) or a biologic DMARD (bDMARD). In aspects, the DMARD is the cDMARD, and wherein the cDMARD is selected from the group consisting of: hydroxychloroquine, leflunomide, sulfasalazine, tofacitinib, and combinations thereof. In aspects, the DMARD is the bDMARD, and wherein the bDMARD is selected from the group consisting of: etanercept, infliximab, adalimumab, certolizumab, and golimumab. In aspects, the Tn3 scaffold is administered intravenously. In aspects, the intravenous administration comprises an infusion. In aspects, the Tn3 scaffold comprises two CD40L-specific monomer subunits connected in tandem. In aspects, the Tn3 scaffold binds CD40L and prevents binding of CD40L to CD40 and/or disrupts CD40 mediated signaling. In aspects, at least one CD40L-specific monomer subunit is fused or conjugated to a heterologous moiety selected from the group consisting of: a protein, a peptide, a protein domain, a linker, a drug, a toxin, a cytotoxic agent, an imaging agent, a radionuclide, a radioactive compound, an organic polymer, an inorganic polymer, a polyethylene glycol (PEG), biotin, an albumin, a human serum albumin (HSA), a HSA FcRn binding portion, an antibody, a domain of an antibody, an antibody fragment, a single chain antibody, a domain antibody, an albumin binding domain, an enzyme, a ligand, a receptor, a binding peptide, a non-FnIII scaffold, an epitope tag, a recombinant polypeptide polymer, and a cytokine. In aspects, at least one CD40L-specific monomer subunit is conjugated to PEG or is fused to HSA. In aspects, the HSA is a variant HSA comprising the amino acid sequence of SEQ ID NO: 4. In aspects, the Tn3 scaffold comprises the sequence of SEQ ID NO: 1. In aspects, a first dose of the Tn3 scaffold is administered at about 13 to about 25 mg/min, a second dose and third dose are administered at about 25 mg/min, and a fourth dose is administered at about 17 to about 33 mg/min. In aspects, a first dose of the Tn3 scaffold is administered at about 8 to about 17 mg/min, and a second dose and third dose are administered at about 13 mg/min. In aspects, a first dose of the Tn3 scaffold is about 1500 mg and subsequent doses are about 1500 mg or about 3000 mg. In aspects, the first and a second dose of the Tn3 scaffold are about 1500 mg and the subsequent doses are about 3000 mg. In aspects, a first dose is administered over 120 min or 180 min and subsequent doses are administered over 60 or 90 min. In aspects, a Tn3 scaffold is administered once. In aspects, a Tn3 scaffold is administered quarterly. In aspects, a quarterly administration of the Tn3 scaffold is equally efficacious or more efficacious than more frequent administrations of the Tn3 scaffold as determined by change from baseline in DAS28-CRP in a treated subject. In aspects, the change from baseline of the DAS28-CRP is determined quarterly. In aspects, the change from baseline of the DAS28-CRP is determined monthly. In aspects, the change from baseline of the DAS28-CRP is determined yearly. In aspects, the quarterly administration of the Tn3 scaffold confers sustained treatment efficacy in the subject in need as compared to an otherwise comparable subject undergoing more frequent administrations of the Tn3 scaffold as determined by a treatment assessment, and wherein the sustained treatment efficacy is of at least or at most about 15 days, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 8 months, 10 months, 1 year, or 1.5 years. In aspects, a treatment assessment is determined quarterly.
Provided herein are methods for treating RA in a subject in need thereof comprising administering a Tn3 scaffold comprising a CD40L-specific monomer subunit to the subject. In aspects, the Tn3 scaffold specifically binds to CD40L. In aspects, the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop SEQ ID NO: 16. In aspects, the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 1500 mg. In aspects, the Tn3 scaffold is administered once about every 2 weeks for at least 2 doses, and is administered about once a month thereafter.
Provided herein are methods for treating rheumatoid arthritis in a subject in need thereof comprising administering a Tn3 scaffold comprising a CD40L-specific monomer subunit to the subject. In aspects, the Tn3 scaffold specifically binds to CD40L. In aspects, the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16. In aspects, the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 1500 mg. In aspects, the Tn3 scaffold is administered once about every 2 weeks for at least 3 doses, and is administered about once a month thereafter.
Provided herein are methods for treating rheumatoid arthritis in a subject in need thereof comprising administering a Tn3 scaffold comprising a CD40L-specific monomer subunit to the subject. In aspects, the Tn3 scaffold specifically binds to CD40L. In aspects, the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16. In aspects, the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 1500 mg. In aspects, the Tn3 scaffold is administered once about every 2 months for at least 2 doses.
Provided herein are methods for treating rheumatoid arthritis in a subject in need thereof comprising administering a Tn3 scaffold comprising a CD40L-specific monomer subunit to the subject. In aspects, the Tn3 scaffold specifically binds to CD40L. In aspects, the monomer subunit comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop comprises SEQ ID NO: 16. In aspects, the Tn3 scaffold comprising the CD40L-specific monomer subunit is administered at a dose of about 3000 mg. In aspects, the Tn3 scaffold is administered about once a month, once about every two months, or once about every three months.
These and other aspects are described below.
The accompanying figures, which are incorporated herein and form a part of the specification, illustrate some, but not the only or exclusive, example aspects and/or features. It is intended that the aspects and figures disclosed herein are to be considered illustrative rather than limiting.
Provided herein are Tn3 scaffolds that are anti-cluster of differentiation (CD) 40 ligand (CD40L)—third fibronectin type III (Fn3) protein domain of human Tenascin C (Tn3) protein fusion proteins and methods of using the same in autoimmune disease. In aspects, compositions and methods provided are utilized for the treatment of B-cell dependent autoimmune diseases, such as rheumatoid arthritis (RA). Genome-wide association studies have identified a common variant in the CD40 locus that increases the risk of RA. The expression of CD40L on CD4+ T helper cells is also increased in subjects with active RA compared to healthy controls. Taken together, these observations suggest that inhibition of the CD40L/CD40 pathway may be beneficial in RA.
Also provided are methods comprising administering Tn3 scaffolds with TNF-α inhibitors (TNFi) for the treatment of autoimmune disease.
The following description includes information that may be useful in understanding the present disclosure. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed disclosures, or that any publication specifically or implicitly referenced is prior art.
While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.
All technical and scientific terms used herein, unless otherwise defined below, are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to techniques employed herein are intended to refer to the techniques as commonly understood in the art, including variations on those techniques and/or substitutions of equivalent techniques that would be apparent to one of skill in the art.
As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise.
The term “about” or “approximately” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, . . . ”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 52.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively to all values in the series, or the endpoints of the range.
As used herein, the term “subject” refers to any subject, e.g., a human or a non-human mammal, for whom diagnosis, prognosis, or therapy is desired. The term “subject” may mean a human or non-human mammal affected, likely to be affected, or suspected to be affected with a disease. The terms “subject” and “subject” are used interchangeably herein. In aspects, the subject is a mammal. A mammal includes primates, such as humans, monkeys, chimpanzee, and apes, and non-primates such as domestic animals, including laboratory animals (such as rabbits and rodents, e.g., guinea pig, rat, or mouse) and household pets and farm animals (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals, such as wildlife, birds, reptile; fish, or the like.
As used herein, the term “a subject in need thereof” includes subjects that could or would benefit from the methods described herein. Subjects in need of treatment include, without limitation, those already with the condition or disorder, those prone to having the condition or disorder, those in which the condition or disorder is suspected, as well as those in which the condition or disorder is to be prevented, ameliorated, or reversed.
As used herein, “treating” or “treat” describes the management and care of a subject for the purpose of combating a disease, condition, or disorder and includes the administration of a Tn3 scaffold used in the methods described herein to alleviate the symptoms or complications of a disease, condition or disorder, or to eliminate the disease, condition or disorder. Thus, the term “treat” or “treating” refers to both therapeutic measures and prophylactic or preventative measures, wherein the objective is to prevent, slow down (lessen), or ameliorate the progression of a disease (e.g., RA). Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishing the extent of the disease, stabilized (i.e., not worsening) state of the disease, delaying or slowing of disease progression, amelioration or palliation of the disease state, and reversing the disease (whether partial or total). The term “treat” can also include treatment of a cell in vitro or an animal model.
As used herein, “fused” refers to at least two polypeptides joined recombinantly. As used herein “conjugated” refers to formation of a bond between two components by chemical reaction. The bond may be covalent or non-covalent. Typically, two components that are conjugated to each other are chemically connected via a covalent bond.
When referring to a nucleic acid sequence or protein sequence, the term “identity” is used to denote similarity between two sequences. Unless otherwise indicated, percent identities described herein are determined using the BLAST algorithm available at the world wide web address: blast.ncbi.nlm.nih.gov/Blast.cgi using default parameters.
Described herein are methods for treating an autoimmune disorder using a Tn3 scaffold comprising a CD40L-specific monomer subunit. Also provided are compositions and methods of combining a Tn3 scaffold with a secondary therapy such as a TNFi.
In aspects, the Tn3 scaffold is used in methods of treating rheumatoid arthritis (RA). RA is a chronic systemic inflammatory disease that is associated with significant morbidity and mortality. RA comprises inflammation of the synovial joints that can result in pain, swelling, and joint damage with secondary deformity and progressive disability. In aspects, the methods comprise treating RA in a subject in need thereof by administering the Tn3 scaffold comprising a CD40L-specific monomer subunit. In aspects, the Tn3 scaffold specifically binds to CD40L. In aspects, the monomer subunit of the Tn3 scaffold comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises SEQ ID NO: 11, the BC loop comprises SEQ ID NO: 12, the CD loop comprises SEQ ID NO: 13, the DE loop comprises SEQ ID NO: 14, the EF loop comprises SEQ ID NO: 15, and the FG loop SEQ ID NO: 16. In aspects, a Tn3 scaffold comprises or consists of SEQ ID NO: 1.
The CD40 receptor is a member of the TNF family of receptors expressed on the plasma membrane of antigen-stimulated B cells, macrophage, and dendritic cells. The CD40 receptor functions to provide a co-stimulatory signal for B cells that have bound antigen. The cognate ligand for CD40 is CD40L (also known as CD154), which is expressed on the plasma membrane of T cells and other cell types, including platelets.
In aspects, subjects with RA comprise a common variant in the CD40 locus that increases the risk of RA. The RA risk allele is a gain-of-function allele that increases the amount of CD40 on the surface of at least primary human B-lymphocyte cells. In aspects, expression of CD40L on CD4+T helper cells is also increased in subjects with active RA compared to control subjects. Taken together, these observations suggest that inhibition of the CD40L/CD40 pathway may be beneficial in RA.
Provided herein are compositions that bind CD40L. In aspects, provided compositions comprise CD40L antagonists. In aspects, provided herein are compositions that comprise a Tn3 scaffold comprising a CD40L-specific monomer subunit (e.g., “Tn3 scaffold”). In aspects, provided herein are compositions that comprise a Tn3 scaffold comprising two CD40L-specific monomer subunits.
In aspects, a CD40L monomer subunit of a Tn3 scaffold comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG. In aspects, the Tn3 scaffold comprises a single CD40L-specific monomer subunit. In aspects, the Tn3 scaffold comprises two CD40L-specific monomer subunits. In aspects, the two CD40L-specific monomer subunits are connected in tandem. In aspects, the two CD40L-specific monomer subunits are connected by a linker. In other aspects, the linker comprises a peptide linker, which can be a flexible peptide linker. In aspects, the peptide linker comprises a (GmX)n sequence wherein X is Serine (S), Alanine (A), Glycine (G), Leu (L), Isoleucine (I), or Valine (V); m and n are integer values; m is 1, 2, 3 or 4; and, n is 1, 2, 3, 4, 5, 6, or 7.
In aspects, the Tn3 scaffold comprises a linker which comprises a functional moiety. In aspects, this functional moiety is an immunoglobulin or a fragment thereof. In aspects, this immunoglobulin or fragment thereof comprises an Fc domain. In aspects, this Fc domain fails to induce at least one FcγR-mediated effector function (e.g., Fc-deficient). In aspects, this at least one FcγR-mediated effector function is antibody-dependent cellular cytotoxicity (ADCC).
In aspects, the Tn3 scaffold comprises seven beta strands designated A, B, C, D, E, F, and G, and six loop regions designated AB, BC, CD, DE, EF, and FG, wherein the AB loop comprises or consists of SEQ ID NO: 11, the BC loop comprises or consists of SEQ ID NO: 12, the CD loop comprises or consists of SEQ ID NO: 13, the DE loop comprises or consists of SEQ ID NO: 14, the EF loop comprises or consists of SEQ ID NO: 15, and the FG loop comprises or consists of SEQ ID NO: 16. In aspects, the Tn3 scaffold comprises or consists of SEQ ID NO: 1. In aspects, beta strand A comprises or consists of SEQ ID NO: 5, beta strand B comprises or consists of SEQ ID NO: 6, beta strand C comprises or consists of SEQ ID NO: 17, beta strand D comprises or consists of SEQ ID NO: 18, beta strand E comprises or consists of SEQ ID NO: 19, beta strand F comprises or consists of SEQ ID NO: 20, and beta strand G comprises or consists of SEQ ID NO: 21.
In aspects, one or more CD40L-specific Tn3 monomers have a beta strand A comprising or consisting of IEV (SEQ ID NO: 5), RLDAPSQIEV (SEQ ID NO: 23), or SQIEV (SEQ ID NO: 24). In aspects, a Tn3 scaffold may comprise one or more CD40L-specific Tn3 monomers having the same or different beta strand A sequences. For example, a first CD40L-specific Tn3 monomer beta strand A may comprise or consist of IEV (SEQ ID NO: 5) and a second CD40L-specific Tn3 monomer beta strand A may comprise or consist of RLDAPSQIEV (SEQ ID NO: 23) or SQIEV (SEQ ID NO: 24).
The Tn3 scaffold may have the amino acid sequence as shown in SEQ ID NO: 1 and described above or it may have one or more amino acid residues changes relative to the amino acid sequence as shown in SEQ ID NO: 1. For example, if the Tn3 scaffold has amino acid sequence changes relative to those shown in SEQ ID NO: 1, the changes may be to one of the linkers. The Tn3 scaffold comprises a Gly15 linker separating two CD40L-specific monomers and a Gly10 linker separating a CD40L-specific monomer from an HSA sequence. Both or one of these linkers may be altered, and may be replaced with an amino acid sequence of (GmX)n wherein X is Serine (S), Alanine (A), Glycine (G), Leu (L), Isoleucine (I), or Valine (V); m and n are integer values; m is 1, 2, 3 or 4; and, n is 1, 2, 3, 4, 5, 6, or 7. For example, one or both linkers may be altered to have an amino acid sequence that comprises one of GGGGSGGGGS (SEQ ID NO: 7), GGGGSGGGGSGGGGS (SEQ ID NO: 8), GGGGGGGGGG (SEQ ID NO: 9) or GGGGGGGGGGGGGGG (SEQ ID NO: 10). If the Tn3 scaffold has an amino acid sequence relative to the amino acid sequence as provided in SEQ ID NO: 1, it may be due to a changes or changes in the HSA amino acid sequence fused to the two CD40L-specific monomers. The HSA fused to the two CD40L-specific monomers may be altered to relative to the HSA fused to the two CD40L-specific Tn3 monomers, except for at least one amino acid substitution, numbered relative to the position in full length mature HSA, at a position selected from the group consisting of 407, 415, 463, 500, 506, 508, 509, 511, 512, 515, 516, 521, 523, 524, 526, 535, 550, 557, 573, 574, and 580; wherein the at least one amino acid substitution does not comprise a lysine (K) to glutamic acid (E) at position 573.
Exemplary sequences for a Tn3 scaffold are shown in Table 1. In aspects, a Tn3 scaffold comprises at least about or at most about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or up to about 100% identity with any one of SEQ ID NO: 1-SEQ ID NO: 25 shown in Table 1. In aspects, any one of the sequences from Table 1 can be modified. In aspects, a modification comprises one or more truncations, deletions, insertions, and combinations thereof. A modification can occur at any of the residues provided in Table 1 and in any number of residues from Table 1. In aspects, a modification can comprise from 1-3, 1-5, 1-10, 1-20, 3-8, 3-10, 3-15, 5-8, 5-10, or 5-20 residues. In aspects, a modification can occur in up to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 30, 40, 50, 60, 70, 80, 90,100,200, 300, 400, or 450 residues.
AFAQYLQQSPFEDHVKLVNEVTEFAKTCVADESAENCDKSLHTLF
GDKLCTVATLRETYGEMADCCAKQEPERNECFLQHKDDNPNLPRL
VRPEVDVMCTAFHDNEETFLKKYLYEIARRHPYFYAPELLFFAKR
YKAAFTECCQAADKAACLLPKLDELRDEGKASSAKQRLKCASLQK
FGERAFKAWAVARLSQRFPKAEFAEVSKLVTDLTKVHTECCHGDL
LECADDRADLAKYICENQDSISSKLKECCEKPLLEKSHCIAEVEN
DEMPADLPSLAADFVESKDVCKNYAEAKDVFLGMFLYEYARRHPD
YSVVLLLRLAKTYETTLEKCCAAADPHECYAKVFDEFKPLVEEPQ
NLIKQNCELFEQLGEYKFQNALLVRYTKKVPQVSTPTLVEVSRNL
GKVGSKCCKHPEAKRMPCAEDYLSVVLNQLCVLHEKTPVSDRVTK
CCTESLVNRRPCFSALEVDETYVPKEFNAETFTFHADICTLSEKE
RQIKKQTALVELVKHKPKATKEQLKAVMDDFAAFVEKCCKADDKE
TCFAEEGKKLVAASQAALGL
In aspects, compositions of the disclosure may comprise any of the amino acid sequences as described in Int'l Appl. Nos. PCT/US2012/059477 and PCT/US2019/052997, which are incorporated herein by reference in their entireties. In aspects, provided compositions may comprise the amino acid sequence as shown in SEQ ID NO: 1 (referred to herein as VIB4920). VIB4920 comprises a bivalent CD40L-specific Tn3 protein fused to a HSA protein.
If the Tn3 scaffold has amino acid sequence changes relative to those shown in SEQ ID NO: 1, the changes may be to the amino acid sequence of one or both of the CD40L-specific Tn3 monomers, so long as it does not adversely effect in vivo efficacy of the Tn3 scaffold, e.g., change in amino acid sequence such that one or both CD40L-specific Tn3 monomers have the amino acid sequence as shown in SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 22, and SEQ ID NO: 25. In aspects, the first one or two N-terminal amino acid residues (SQ) may be absent and/or substituted with alternative amino acid residues.
In aspects, a Tn3 scaffold comprises at least one CD40L-specific monomer subunit bound to a heterologous moiety. In aspects, this heterologous moiety is selected from the group consisting of: a protein, a peptide, a protein domain, a linker, a drug, a toxin, a cytotoxic agent, an imaging agent, a radionuclide, a radioactive compound, an organic polymer, an inorganic polymer, a polyethylene glycol (PEG), biotin, an albumin, a HSA FcRn binding portion, an antibody or fragment thereof, an albumin binding domain, an enzyme, a ligand, a receptor, a binding peptide, a non-FnIII scaffold, an epitope tag, a recombinant polypeptide polymer, a cytokine, and a combination of two or more of said moieties. In aspects, the heterologous moiety is the albumin and the albumin comprises human serum albumin. In aspects, the heterologous moiety is an antibody. In aspects, the antibody is selected from the group consisting of: an Fc domain of an antibody, an antibody fragment, and a single chain antibody.
In aspects, the heterologous moiety is an imaging agent; for example, a radionuclide or biotin. In aspects, the heterologous moiety is a drug; for example, a cytotoxic agent or a radioactive compound.
In aspects, the heterologous moiety comprises PEG. In aspects, the Tn3 scaffold comprises at least one CD40L-specific monomer subunit fused or conjugated directly or via a linker to PEG. In aspects, both CD40L-specific monomer subunits are fused, conjugated, or connected via a linker to PEG. In aspects, the Tn3 scaffold comprises at least one (e.g., two) CD40L-specific monomer subunit fused or conjugated directly or via a linker to PEG.
In aspects, the heterologous moiety comprises albumin. In aspects, the Tn3 scaffold comprises at least one CD40L-specific monomer subunit fused or conjugated directly or via a linker to an albumin. In aspects, this albumin is HSA. In aspects, this HSA is a variant HSA. In aspects, the amino acid sequence of the variant HSA is SEQ ID NO: 4. In aspects, the variant HSA has at least one improved property compared with a native HSA or a native HSA fragment. In aspects, the amino acid sequence of the variant HSA is SEQ ID NO: 4 or a sequence having at least about 80%, 85%, 90%, 95%, 96%,97%, 98%, 99%, or up to 100% identity to SEQ ID NO: 4. In aspects, the improved property is an altered plasma half-life compared with the plasma half-life of a native HSA or a native HSA fragment. In aspects, the altered plasma half-life is a longer plasma half-life compared with the plasma half-life of a native HSA or a native HSA fragment. In aspects, the altered plasma half-life is a shorter plasma half-life compared with the plasma half-life of a native HSA or a native HSA fragment.
In aspects, any of the compositions comprising a Tn3 scaffold of the disclosure can be administered in any form. In aspects, a Tn3 scaffold is administered intravenously, subcutaneously, orally, intramuscularly, intrathecally, sublingually, rectally, vaginally, cutaneously, systemically, topically, transdermally, or by way of inhalation. In aspects, a Tn3 scaffold is administered intravenously. In aspects, a Tn3 scaffold is administered by intravenous infusion.
A Tn3 scaffold of the disclosure can be administered at any dose. In aspects, a Tn3 scaffold is administered at a dose from about: 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, 4500 mg, 4550 mg, 4600 mg, 4650 mg, 4700 mg, 4750 mg, 4800 mg, 4850 mg, 4900 mg, 4950 mg, or about 5000 mg. Any of the aforementioned dosages may be effective dosages for a method comprising treatment, reduction, or elimination.
In aspects, a Tn3 scaffold is administered at a dose of between about: 800-5000 mg, 900-4900 mg, 1000-4800 mg, 1100-4700 mg, 1200-4600 mg, or 1300-4500 mg. In aspects, a Tn3 scaffold is administered at a dose selected from the group consisting of: 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 mg, 3950 mg, 4000 mg, 4050 mg, 4100 mg, 4150 mg, 4200 mg, 4250 mg, 4300 mg, 4350 mg, 4400 mg, 4450 mg, and 4500 mg. In aspects, a Tn3 scaffold is administered at a dose selected from the group consisting of: 1500 mg and 3000 mg. In aspects, a Tn3 scaffold is administered at a dose of about 1500 mg. In aspects, a Tn3 scaffold is administered at a dose of about 3000 mg.
In aspects, a Tn3 scaffold of the disclosure is administered on a schedule that provides optimal results. In aspects, a Tn3 scaffold is administered to a subject in need thereof about once a week, about twice a week, about every two weeks, about once a month, about every two months, about every 3 months, about every 12 weeks, about every fifteen weeks, about every sixteen weeks, about every four months, about every five months, about every six months, or semiannually.
Any number of administrations may be provided to a subject in need thereof. In aspects, a subject is administered an effective dose on about every Day 1, Day 2, Day 3, Day 4, Day 5, Day 6, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4 years, or 5 years, or up to the lifetime of a subject, post treatment initiation. In aspects, a subject receives an effective dose on Day 1, Day 15, Day 29, and Day 57 post treatment initiation. In aspects, a subject receives an effective dose on week 0, week 2, week 4, week 8, and week 12 post treatment initiation. In aspects, a subject receives 1500 mg-3000 mg of a Tn3 scaffold on Day 1, Day 15, Day 29, and Day 57 post treatment initiation. In aspects, a subject in need thereof is administered 1500 mg of a Tn3 scaffold on Day 1, Day 15, Day 29, and Day 57 post treatment initiation.
In aspects, a subject in need thereof is administered 1500 mg of a Tn3 scaffold on day 1 and day 57 post treatment initiation. In aspects, a subject in need thereof is administered 3000 mg of a Tn3 scaffold on Day 1, Day 15, Day 29, and Day 57 post treatment initiation. In aspects, a subject in need thereof is administered 3000 mg of a Tn3 scaffold on Day 1 and Day 57 post treatment initiation, and then every 6 months thereafter as needed. In aspects, a subject in need thereof is administered 1500 mg of a Tn3 scaffold at weeks 0, 2, 4, 8, and 12 post treatment initiation. In aspects, the administering comprises an induction dose, for example the 1500 mg of a Tn3 scaffold at weeks 0, 2, 4, 8, and 12 post treatment initiation. Any of the aforementioned administrations can deviate by about 0-5 days, 0-4 days, 0-3 days, 0-2 days, or by about 1 day.
In aspects, the induction dose comprises administering a Tn3 scaffold once about every 2 weeks for at least 2, 3, 4, 5, 6, 7, 8, 9, or up to about 10 doses. In aspects, the induction dose comprises administering a Tn3 scaffold once about every 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks for at least about 2, 3, 4, 5, 6, 7, 8, 9, or up to about 10 doses. In aspects, the induction dose comprises administering a Tn3 scaffold once about every 2 weeks for at least 3 doses.
In aspects, a Tn3 scaffold is administered at a dose of about 3000 mg every three months or quarterly.
In aspects, a quarterly administration of any of the provided compositions can be as efficacious as more frequent dosing, at the same dosage, with the added benefit of requiring less interventions of a subject being treated. Indeed, quarterly administration regimens can confer extended treatment as compared to otherwise comparable regimens requiring more frequent dosing as determined by any of the methodologies provided herein (e.g., adjusted mean change from baseline and the like).
In aspects, an administration is a quarterly administration of about 3000 mg of a Tn3 scaffold.
In aspects, a maintenance dose comprises administering a Tn3 scaffold once about every 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks for at least 2, 3, 4, 5, 6, 7, 8, 9, or up to about 10 doses. In aspects, the maintenance dose comprises administering a Tn3 scaffold once about every 4 weeks for at least 4 doses.
In aspects, a subject receives an effective dose of a Tn3 scaffold on Day 1, Day 15 (±1 day), Day 29 (±3 days), and Day 57 (±3 days) post treatment initiation. In aspects, a subject in need thereof is administered 1500 mg of a Tn3 scaffold on Day 1, Day 15 (±1 day), Day 29 (±3 days), and Day 57 (±3 days) post treatment initiation, and then every 6 months thereafter as needed. In aspects, a subject in need thereof is administered 1500 mg of a Tn3 scaffold on Day 1, Day 15 (±1 day), and Day 29 (±3 days) post treatment initiation. In aspects, a subject in need thereof is administered 1500 mg of a Tn3 scaffold on Day 1 and Day 57 (±3 days) post treatment initiation. In aspects, a subject in need thereof is administered 3000 mg of a Tn3 scaffold on Day 1, Day 15 (±1 day), Day 29 (±3 days), and Day 57 (±3 days) post treatment initiation, and then every 6 months thereafter as needed. In aspects, a subject in need thereof is administered 3000 mg of a Tn3 scaffold on Day 1, Day 15 (±1 day), and Day 29 (±3 days) post treatment initiation. In aspects, a subject in need thereof is administered 3000 mg of a Tn3 scaffold on Day 1 and Day 57 (±3 days) post treatment initiation, and then every 6 months thereafter as needed. In aspects, 3000 mg of a Tn3 scaffold is administered every 3 months.
In aspects, a Tn3 scaffold is administered at a dose of about 1500 mg once about every 2 weeks for at least 2 doses, and is administered about once a month thereafter. In aspects, a Tn3 scaffold is administered at a dose of about 1500 mg once about every 2 weeks for at least 3 doses, and is administered about once a month thereafter. In aspects, a Tn3 scaffold is administered at a dose of about 1500 once about every month, once about every two months, or once about every three months. In aspects, a Tn3 scaffold is administered at a dose of about 3000 mg once about every month, once about every two months, or once about every three months. In aspects, a Tn3 scaffold is administered for two or more doses.
In aspects, a subject in need thereof is administered an effective dose of a Tn3 scaffold once every 2-4 weeks. In aspects, a subject in need thereof is administered an effective dose of a Tn3 scaffold once every 2 weeks or 4 weeks. In aspects, a subject in need thereof is administered 1500 mg of a Tn3 scaffold once every 2 weeks for at least 3 doses, once every 4 weeks for at least 4 doses, once every 4 weeks for at least 5 doses, or a combination thereof. In aspects, a subject in need thereof is administered 3000 mg of a Tn3 Scaffold once every 2 weeks for at least 3 doses, once every 4 weeks for at least 4 doses, once every 4 weeks for at least 5 doses, or a combination thereof. In aspects, a subject in need thereof is administered an effective dose of a Tn3 scaffold as an induction dose and as a maintenance dose thereafter.
In aspects, a Tn3 scaffold of the disclosure comprises SEQ ID NO: 1. The Tn3 scaffold comprising SEQ ID NO: 1 can be administered to a subject in need thereof at an effective dose of about 1500 mg every 2 weeks for at least 3 doses, once every 4 weeks for at least 4 doses, once every 4 weeks for at least 5 doses, or a combination thereof. In aspects, the Tn3 scaffold comprising SEQ ID NO: 1 can be administered to a subject in need thereof at an effective dose of about 3000 mg once every 2 weeks for at least 3 doses, once every 4 weeks for at least 4 doses, once every 4 weeks for at least 5 doses, or a combination thereof. In aspects, a subject in need thereof is administered an effective dose of a Tn3 scaffold comprising SEQ ID NO: 1 as an induction dose and as a maintenance dose thereafter.
In aspects herein, methods are directed to treat, reduce, or eliminate RA. In aspects, a method comprises administering a Tn3 scaffold of the disclosure. In aspects, a Tn3 scaffold is used to treat RA. In aspects, a Tn3 scaffold is administered to a subject in need thereof to treat RA using any dosing schedules disclosed herein. In aspects, a Tn3 scaffold is administered at a dose of about 1500 mg once about every 2 weeks for at least 2 doses, and is administered about once a month thereafter. In aspects, a Tn3 scaffold is administered at a dose of about 1500 mg once about every 2 weeks for at least 3 doses, and is administered about once a month thereafter. In aspects, a Tn3 scaffold is administered at a dose of about 1500 once about every month, once about every two months, or once about every three months.
In aspects, a Tn3 scaffold is administered at a dose of about 3000 mg once about every month, once about every two months, or once about every three months. In aspects, a Tn3 scaffold is administered for two or more doses.
In aspects of the methods disclosed herein, a subject in need thereof has been administered one or more standard of care therapies for the treatment of RA prior to the administration of a Tn3 scaffold.
In aspects, a standard of care therapy comprises an anti-inflammatory agent, an anti-pain agent, and a regimen to reduce disability associated with RA. In aspects, a subject continues on one or more prior treatment therapies while being administered a Tn3 scaffold. In aspects, a standard of care therapy is administered as a second therapy. In aspects, any of the below referenced therapies may be combined in a therapeutic regimen for the treatment of RA. In aspects, a subject is treated with both a Tn3 scaffold and a TNFi. In aspects, a Tn3 scaffold and a TNFi can be administered within one day of each other but are not administered on the same day.
In aspects, any of the referenced therapies are combined as part of a treatment regimen or combination therapy. For example, anti-inflammatory medications, including nonsteroidal anti-inflammatory drugs and systemic and intraarticular corticosteroids, may be used in combination with DMARDs. In aspects, a Tn3 scaffold is administered sequentially with any therapy disclosed herein. In aspects, a Tn3 scaffold may generally be administered concurrently with any second therapy disclosed herein. In aspects, a subject in need thereof has been administered any standard of care therapy for the treatment of RA prior to the administration of a Tn3 scaffold.
In aspects, a Tn3 scaffold is administered to a subject in need thereof. In aspects, a subject in need thereof has moderate disease activity RA. In aspects, a subject in need thereof has high disease activity RA. Moderate or high disease activity is defined as a subject having a Simplified Disease Activity Index (SDAI) greater than or equal to 17 despite prior treatment for at least 12 weeks with a TNFi. In aspects, a TNFi may be selected from a group consisting of, but not limited to, infliximab, golimumab, certolizumab, etanercept, and adalimumab. Advantageously, methods and compositions disclosed herein are effective in achieving low disease activity, defined an SDAI less than or equal to 11, by 16 weeks of treatment. In aspects, methods and compositions disclosed herein are effective in achieving sustained remission, defined by an SDAI less than or equal to 3.3 as measured between 16 and 40 weeks of treatment. In aspects, a method allows tapering of a TNFi during the course of a Tn3 scaffold treatment. In aspects, a TNFi treatment may be halted.
In aspects, a subject is administered an anti-inflammatory agent. In aspects, an anti-inflammatory agent comprises a nonsteroidal anti-inflammatory drug (NSAID). Exemplary NSAIDs are selected from the group consisting of: ibuprofen, naproxen, celecoxib, diclofenac, diflunisal, etodolac, indomethacin, ketoprofen, ketorolac, nabumetone, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, and combinations thereof.
In aspects, a subject is administered an anti-pain agent. Anti-pain agents comprise NSAIDs, acetaminophen, corticosteroid, opioid (e.g., codeine, fentanyl, Vicodin, morphine, oxycodone, Percocet), anti-depressant, anti-histamine (e.g., diphenhydramine or cetirizine, and the like), anti-convulsant, lidocaine, and combinations thereof. In aspects, an anti-pain agent is an anti-histamine. In aspects, an anti-pain agent is acetaminophen.
Disease-modifying Antirheumatic Drug (DMARD). NSAIDs may be used as anti-pain agents as well as anti-inflammatory agents. Corticosteroids may be used as anti-pain agents as well as anti-inflammatory agents.
In aspects, a subject is administered a regimen to reduce disability associated with RA. In aspects, a subject is administered a disease-modifying antirheumatic drug (DMARD). In aspects, a DMARD is cDMARD. In aspects, a DMARD is bDMARD. Exemplary bDMARDs may be a TNFi; for example, selected from the group consisting of: etanercept, infliximab, adalimumab, certolizumab, and golimumab. In aspects, a TNFi is etanercept or adalimumab.
Suitable cDMARDs are selected from the group consisting of: methotrexate (MTX), hydroxychloroquine (Plaquenil), leflunomide (Arava), sulfasalazine (Azulfidine), and combinations thereof. In aspects, a cDMARD is selected from the group consisting of: methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine. In aspects, a regimen to reduce disability comprises surgery. In aspects, a subject may undergo joint replacement surgery. Any body part may be subject of surgery including but not limited to hips, knees, shoulders, elbows, ankles, fingers, and combinations thereof. In aspects, joint fusion surgery is also performed. In aspects, a regimen comprises physical therapy. In aspects, a regimen comprises cognitive therapy. In aspects, a regimen comprises exercise.
In aspects, a subject is administered a corticosteroid. In aspects, a corticosteroid comprises a glucocorticoid. Glucocorticoids (GCs) are steroid hormones used for the treatment of inflammation, autoimmune diseases, and/or cancer. To exert their broad physiological and therapeutic effects, GCs bind to the GC receptor (GR) which belongs to the nuclear receptor superfamily of transcription factors.
In aspects, one or more GCs are administered to a subject in need thereof. In aspects, one or more GCs is selected from the group consisting of: triamcinolone, methylprednisolone, budesonide, dexamethasone, triamcinolone, prednisone, hydrocortisone, dexamethasone, betamethasone, prednisolone, deflazacort, and combinations thereof. In aspects, a GC is prednisone. In aspects, a GC is methylprednisolone.
In aspects, an immune system modifying agent comprises a cell-modifying agent, an interleukin, or a pathway modifier. In aspects, an immune system modifying agent is a cell-modifying agent. In aspects, a cell modifying agent modifies B cells or T cells. In aspects, a cell modifying agent modifies B cells and is selected from the group consisting of, but not limited to, rituximab, ofatumumab, obinutuzumab, and ibritumomab, and the like. In aspects, a cell modifying agent modifies B cells and comprises rituximab. In aspects, a cell modifying agent modifies T cells and is selected from the group consisting of, but not limited to, abatacept, belatacept, adalimumab, thymoglobulin, alemtuzumab, basiliximab, cyclosporine, sirolimus, tacrolimus, everolimus, and the like. In aspects, a cell modifying agent modifies T cells and comprises abatacept. In aspects, an immune system modifying agent binds an interleukin receptor selected from the group consisting of: IL-6R (tocilizumab), IL-2R, IL10R, IL-21R, and the like. In aspects, an immune system modifying agent is a pathway modifier that modifies a pathway such as Janus kinase (JAK; tofacitinib), and the like.
In aspects, a Tn3 scaffold of the disclosure is administered to a subject in need thereof in combination with a second therapy. In aspects, a second therapy comprises an anti-inflammatory agent, an anti-pain agent, a Disease-modifying Antirheumatic Drug (DMARD), a corticosteroid, or an immune system modifying agent. In aspects, a DMARD is a cDMARD or a bDMARD. In aspects, a cDMARD is selected from the group consisting of, but not limited to, hydroxychloroquine, leflunomide, sulfasalazine, tofacitinib, and combinations thereof. In aspects, a bDMARD is selected from the group consisting of, but not limited to, etanercept, infliximab, adalimumab, certolizumab, and golimumab.
In aspects, a Tn3 scaffold of the disclosure is administered to a subject in need thereof in combination with a TNF-α inhibitor. TNF-α plays a pro-inflammatory role in RA pathogenesis, with effects mainly on innate immunity. Among its many activities, it primes or directly mediates leukocyte activation, adhesion, and migration; endothelial activation and angiogenesis; chemokine expression; stromal cell activation; chondrocyte activation; and osteoclast differentiation in combination with receptor activator of NFκB ligand (RANKL). In contrast, IL-6 has prominent biological effects on both innate and adaptive immunity in RA. IL-6 promotes CD4+ T cells differentiation into T helper 17 (Th17) cells in combination with transforming growth factor-β (TGF-β) and inhibits TGF-β-driven T regulatory (Treg) cell differentiation, resulting in up-regulation of Th17/Treg balance and disruption of tolerance mechanisms. IL-6 also promotes T follicular helper cell differentiation and induces activated B cells differentiation of into antibody-secreting cells. Inhibition of the CD40-CD40L pathway by way of a Tn3 scaffold would be expected to specifically suppress the adaptive immune response. Combining a Tn3 scaffold with a TNF-α inhibitor provides an opportunity to determine if RA is driven by varied contributions of antigen-dependent (adaptive) and antigen-independent (innate) immune mechanisms.
Accordingly, combining TNF-α inhibition with blockade of the CD40-CD40L pathway by disclosed Tn3 scaffolds disrupts the pathologic innate and adaptive immune responses in a manner that restores normal tolerance mechanisms and promotes sustained disease control. In aspects, treatment with a TNFi in combination with a Tn3 scaffold will be more effective in controlling disease activity than maintaining a TNFi alone or replacing a partially effective TNFi with a Tn3 scaffold. In aspects, treatment with a TNFi in combination with a Tn3 scaffold is effective in reducing disease or a symptom in a subject in need thereof by at least about 1-fold, 10-fold, 50-fold, 100-fold, 200-fold, 500-fold, or up to about 1000-fold as compared to an otherwise comparable subject not administered a Tn3 scaffold. In aspects, treatment with a TNFi in combination with a Tn3 scaffold is effective in stabilizing disease than maintaining a TNFi alone or replacing a partially effective TNFi with a Tn3 scaffold.
In aspects, one or more standard of care therapies are administered for about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 20, about 25, about 30, about 35, about 40, about 52, about 52 weeks or more prior to the administration of a Tn3 scaffold.
A dose and dosing regimen of a Tn3 scaffold as disclosed herein may be such that any therapeutic effect achieved from administration of a Tn3 scaffold to treat any autoimmune/inflammatory disease or disorder, may be considered to be “long-lasting.” A “long-lasting” effect of a Tn3 scaffold in a treatment of an autoimmune/inflammatory disease or disorder is one in which a therapeutic effect achieved by a Tn3 scaffold is maintained (although the Tn3 scaffold is no longer administered) over at least 4 weeks, at least 6 weeks, at least 8 weeks, at least 10 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, or at least 24 weeks following administration of the last dose of a course of a Tn3 scaffold. In aspects, less frequent dosing of any of the compositions provided herein may be advantageous. Exemplary advantages of less frequent dosing include but are not limited to reduced frequency of side effects associated with an administered composition, reduced treatment-associated toxicity, increased quality of life for treated subjects, and the like. In aspects, a single administration of about 3000 mg of a Tn3 scaffold can be as equally efficacious or more efficacious than two or more administrations of the same composition as determined by the change from baseline in DAS28-CRP of a subject administered a Tn3 scaffold. In aspects, about 3000 mg once every 8 weeks (Q8W; administered twice) is about as efficacious as 1500 mg once every 4 weeks (Q4W). In aspects, provided are methods comprising a longer dosing interval as compared to otherwise comparable methods lacking administration of a Tn3 scaffold of the disclosure.
In aspects, a subject is assessed. An assessment can occur at any point before, during, or after administration with a Tn3 scaffold. In aspects, an assessment is performed before administration. In aspects, an assessment is performed during administration. In aspects, an assessment is performed post administration.
Any of the below-referenced assessments can occur at any time. In aspects, a subject is assessed by the minute, hourly, daily, weekly, monthly, quarterly, or yearly. In aspects, an assessment is completed twice daily, biweekly, bimonthly, or semiannually. In aspects, an assessment is performed from day −10, −9, −8, −7, −6, −5, −4, −3, −2, −1, 0, 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, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 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, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308 or up to about day 309 post treatment. Timing of assessments are further described below.
In aspects, a treatment regimen that comprises quarterly administrations of a composition that comprises a Tn3 scaffold is as efficacious as an otherwise comparable composition, at the same dosage, lacking the quarterly administration. In aspects, a treatment regimen that comprises administrations every 8 weeks of a composition that comprises a Tn3 scaffold is as efficacious as an otherwise comparable composition, at the same dosage, lacking the administration every 8 weeks. In aspects, a treatment regimen that comprises administrations every 12 weeks of a composition that comprises a Tn3 scaffold is as efficacious as an otherwise comparable composition, at the same dosage, lacking the administration every 12 weeks. In aspects, quarterly administration of a composition that comprises a Tn3 scaffold confers sustained treatment efficacy following a prior administration of a Tn3 scaffold as determined by an assessment provided herein. In aspects, treatment efficacy is determined by any of the following assessments. In aspects, sustained treatment efficacy is maintained for a period of about 5-10 days, 10-30 days, 15-40 days, 1 month-3 months, 1 month-2 months, 2 months-3 months, 3 months-5 months, 1 month-5 months, 1 year, 2 years, or up to about 5 years following a prior administration of a Tn3 scaffold. In aspects, sustained treatment efficacy is maintained for a period of about 5,7,9,11,13,15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, 65, 67, 69, 71, 73, 75, 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99,101,103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 123, 125, 127, 129, 131, 133, 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, 221, 223, 225, 227, 229, 231, 233, 235, 237, 239, 241, 243, 245, 247, 249, 251, 253, 255, 257, 259, 261, 263, 265, 267, 269, 271, 273, 275, 277, 279, 281, 283, 285, 287, 289, 291, 293, 295, 297, 299, 301, 303, 305, 307, 309, 311, 313, 315, 317, 319, 321, 323, 325, 327, 329, 331, 333, 335, 337, 339, 341, 343, 345, 347, 349, 351, 353, 355, 357, 359, 361, 363, 365, 367, 369, 371, 373, 375, 377, 379, 381, 383, 385, 387, 389, 391, 393, 395, 397, or up to about 400 days post treatment. The sustained treatment efficacy may be characterized by an adjusted mean score of −0.5, −1.0 from baseline as measured at the period post treatment.
In aspects, a subject undergoing quarterly administrations of a Tn3 scaffold has comparable or greater treatment efficacy as compared to an otherwise comparable subject lacking the quarterly administration or undergoing more frequent administration of the same Tn3 scaffold. In aspects, a subject undergoing administrations of a Tn3 scaffold every 8 or 12 weeks has comparable or greater treatment efficacy as compared to an otherwise comparable subject lacking the every 8 or 12 week administration or undergoing more frequent administration of the same Tn3 scaffold.
In aspects, a treatment of RA may be characterized by a reduction of at least about 10%, about 20%, about 30%, about 40%, about 50% or more of clinical symptoms of the disease or disorder, or by a reduction in inflammation, or by a reduction in biomarkers of the disease or disorder, relative to their levels prior to the treatment with a Tn3 scaffold. A reduction of any of these symptoms, or inflammation, or biomarkers, may be a reduction in the symptoms, or inflammation or biomarkers of at least about 25%, about 30%, about 40%, about 50%, about 60%, about 70%, about 75%, or more relative to their levels prior to the initiation of treatment with a Tn3 scaffold. A reduction may be such that the autoimmune disease or disorder is characterized as being in remission. If a Tn3 scaffold is used in a method of reducing inflammation in an inflammatory disease or disorder, an inflammatory disease or disorder may comprise RA.
In aspects, a sample of a subject is analyzed. In aspects, a sample of a subject is analyzed pre-treatment. In aspects, a sample of a subject is analyzed post-treatment. In aspects, a sample of a subject is analyzed pre-treatment and post-treatment. In aspects, a sample of a subject is analyzed pre-treatment for soluble factors. In aspects, a sample of a subject is analyzed post-treatment for soluble factors. In aspects, a sample of a subject is analyzed pre-treatment and post-treatment for soluble factors. In aspects, a sample of a subject is analyzed pre-treatment and post-treatment for soluble factors. The aforementioned soluble factors may include but are not limited to: levels of antibodies or autoantibodies, such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA); levels of sCD40L; levels of anti-drug antibodies targeting adalimumab, etanercept, and/or a Tn3 scaffold; levels of a Tn3 scaffold; levels of adalimumab or etanercept, as applicable; levels of CXCL13, sICAM, and/or any other relevant soluble mediators (e.g., IL-21, IL-10, IL-2, IL-17A, IFNγ, and the like.).
Levels of soluble immune parameters may be compared between a baseline value and time points following treatment with a composition disclosed herein. Comparisons may be made between treatment groups to evaluate an effect of the therapeutic intervention on changes in circulating levels of soluble immune parameters. In addition, a relationship between baseline sICAM and CXCL13 levels and treatment response can be determined. An impact of coadministration of a TNFi and a Tn3 scaffold on the drug levels of a Tn3 scaffold and adalimumab or etanercept may be assessed using parameters such as AUC, Cmax, and t1/2 (half-life). Finally, levels of soluble immune parameters may also be evaluated for associations with frequency, phenotype, and/or functional profile of circulating cells, such as T cell, B cell and myeloid populations.
In aspects, a treatment of RA may be a reduction of one or more of RF autoantibodies, anti-citrullinated peptide antibodies, Vectra DA biomarker score (Vectra DA biomarker score being a composite score of expression levels of interleukin-6, tumor necrosis factor receptor type I, vascular cell adhesion molecule 1, epidermal growth factor, vascular endothelial growth factor A, YKL-40, matrix metalloproteinase 1, MMP-3, serum reactive C protein (CRP), serum amyloid A, leptin, and resistin), plasma cell (PC) signature, CRP, DAS28-CRP, or clinical disease activity index (CDAI), or may be a reduction in number of tender joints, intensity of joint tenderness, number of swollen joints, or intensity of joint swelling, or any combinations thereof. In aspects, a treatment may be achievement of American College of Rheumatology (ACR) response criteria ACR20, ACR50, or ACR70.
In aspects, an assessment comprises determining a level of immunogenicity, if any, of a Tn3 scaffold of the disclosure. Immunogenicity comprises determining the presence of anti-drug antibodies (ADA) to a Tn3 scaffold. Immunogenicity may comprise determining the presence of anti-drug antibodies (ADA) to a TNFi. The presence of ADA can be evaluated using a plasma sample from a subject administered a Tn3 scaffold. In aspects, ADA are not detected post administration of a Tn3 scaffold and/or a TNFi. In aspects, ADA levels are reduced as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold; for example, the reduction may be about: 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% as compared to ADA levels in an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold.
In aspects, determining ADA levels to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, determining ADA levels to a Tn3 scaffold can be assessed on about Day 1, Day 15±1, Day 29±3, Day 85±3, Day 169 f 5, Day 253±7, Day 309±7 post treatment initiation.
In aspects, a method for treating, reducing, or eliminating RA may be characterized by an assessment comprises determining a level of autoantibodies in a subject. Autoantibodies comprise those that react with self-antigens. Exemplary autoantibodies comprise RF isotypes such as IgG, IgA, IgM, and combinations thereof. In aspects, an autoantibody can also be an anti-carbamylated protein antibody (anti-CarP) or antibodies against citrullinated protein and peptides (ACPA), or combinations thereof.
Exemplary methods of evaluating levels of autoantibodies may comprise EliA immunoassay, microarray, ELISA, or combinations thereof. In aspects, autoantibodies are not detected post administration of a Tn3 scaffold. In aspects, autoantibodies are not detected post administration of a Tn3 scaffold and a TNFi. In aspects, autoantibodies are detected at levels of at most about: 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, or 50-fold as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold. In aspects, treatment comprises reducing autoantibodies in a subject by about: 20%, 30%, 40%, 45%, 50%, 60%, 75%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% as compared to of the levels of autoantibodies in an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold.
In aspects, determining autoantibodies levels to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, determining autoantibodies levels to a Tn3 scaffold can be assessed on about Day 1, Day 15±1, Day 29±3, Day 57±3, Day 85±3, Day 113±5, Day 141±5, Day 169±5, Day 197±±, Day 225±±, Day 253±7, Day 281±7, Day 309±7 post treatment initiation.
In aspects, an assessment comprises determining a level of markers of inflammation post treatment with a Tn3 scaffold. Exemplary markers of inflammation include but are not limited to: IgM, IgG, IgA, C reactive protein (CRP), and combinations thereof. In aspects, suitable assays to assess a level of inflammation comprise: ELISA, hs-CRP test, CRP test, Luminex, and combinations thereof. In aspects, treated, reduced, or eliminated inflammation is detected in a subject administered a Tn3 scaffold. In aspects, a change as compared to a baseline is determined. In aspects, inflammation is reduced by at least about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 40-fold, 60-fold, 80-fold, 100-fold, 120-fold, 140-fold, 160-fold, 180-fold, 200-fold, 220-fold, 240-fold, 260-fold, 280-fold, or up to about 300-fold post administration as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold. In aspects, treatment comprises reducing markers of inflammation in a subject by about: 20%, 30%, 40%, 45%, 50%, 60%, 75%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% as compared to the levels of markers of inflammation in an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold.
In aspects, determining levels of markers of inflammation levels to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation.
In aspects, determining levels of markers of inflammation to a Tn3 scaffold can be assessed on about Day 1, Day 15 1, Day 29 3, Day 57 3, Day 85 3, Day 113 5, Day 141 5, Day 169±, Day 197±7, Day 225±7, Day 253±7, Day 281±7, Day 309±7 post treatment initiation.
In aspects, an assessment comprises determining duration of a response to a Tn3 scaffold by way of quantifying time to initiation of a rescue therapy. In aspects, rescue therapy comprises one or more of: administration of a new or intensified immunosuppressive, cDMARD, or bDMARD treatment for RA (e.g., initiation of or increase in dose of any cDMARD; initiation of a bDMARD therapy or JAK inhibitor therapy), increase in baseline corticosteroid dose, intraarticular steroid injection (e.g., methylprednisolone (or an equivalent)), or an intraarticular steroid injection of any dose. In aspects, an intraarticular steroid injection of any dose is administered at least once. In aspects, administration of a Tn3 scaffold is effective in treating, reducing, or eliminating initiation of a rescue therapy in a treated subject as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold. In aspects, administration of a Tn3 scaffold is effective at extending time to initiation of rescue therapy by at least about: 1 day, 6 days, 11 days, 16 days, 21 days, 26 days, 30 days, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 11 months, 1 year, 2 years, or up to about 5 years post administration.
In aspects, an assessment can comprise determining a level of a cytokine or an immune cell. In aspects, an immune cell comprises a leukocyte. In aspects, an immune cell comprises a lymphocyte. In aspects, an immune cell comprises a T cell or a B cell. In aspects, a level of a T cell is determined. Exemplary T cells comprise any of CD3, CD4, or CD8 positive cells. In aspects, levels of CD4+ T cells are determined including but not limited to: Th1, Th17, T reg, T helper, Th22, Th2, and combinations thereof. In aspects, levels of CD8 T cells are determined including but not limited to Tc1, Tc2, Tc9, Tc17, Tc22, and combinations thereof. In aspects, a cytokine level is determined. Exemplary cytokines include but are not limited to: CXCL13, free sCD40L, IL-6, interleukin-1 (IL-1), IL-12, and IL-18, tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ), interferon alpha (IFNα) granulocyte-macrophage colony stimulating factor (GM-CSF), and combinations thereof. In aspects, a change in level of any of the above referenced cytokines or immune cells is quantified and compared to a baseline level. In aspects, cytokine and/or immune cell levels are reduced by at least about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 40-fold, 60-fold, 80-fold, 100-fold, 120-fold, 140-fold, 160-fold, 180-fold, 200-fold, 220-fold, 240-fold, 260-fold, 280-fold, or up to about 300-fold post administration as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold. In aspects, cytokine and/or immune cell levels are reduced by about: 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold. Suitable methods to determine immune cell levels or cytokine levels may comprise flow cytometry, ELISA, Luminex, and combinations thereof by way of collecting blood and/or serum from a subject.
In aspects, determining levels of a cytokine and/or an immune cell to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation.
In aspects, determining levels of a cytokine and/or an immune cell to a Tn3 scaffold can be assessed on about Day 1, Day 15 1, Day 29±3, Day 57±3, Day 85±3, Day 113±5, Day 141±5, Day 169±5, Day 197±7, Day 225±7, Day 253±7, Day 281±7, Day 309±7 post treatment initiation.
In aspects, an assessment comprises quantifying expression levels of genes associated with disease activity by way of RNA and/or DNA analysis. In aspects, RNA testing may be performed to measure expression levels of genes associated with disease activity, specific cell types including plasma cells, T follicular helper cells, and pathways implicated in the pathogenesis of RA, including the CD40L/CD40 pathway. RNA may be isolated at baseline from blood to test for changes in expression levels of the aforementioned genes associated with disease activity. In aspects, transcriptome profiling is assessed by methods including, but not limited to, qPCR, RNAseq, and exome sequencing. In aspects, DNA testing may be performed. DNA may be isolated at baseline from blood to test for CD40/CD40L polymorphisms or polymorphisms in other genes relevant to the mechanism of action of a Tn3 scaffold.
In aspects, DNA epigenetics analysis may be performed. In aspects, DNA epigenetics analysis includes assessing changes in DNA methylation in immune-related genes. In aspects, changes are determined as compared to a baseline level. In aspects, epigenome profiling is assessed by methods including, but not limited to, ATACseq and DNA methylation sequencing.
In aspects, DNA may be collected for genotyping or sequencing of relevant disease- or immune-associated genes, such as HLA Class I/II alleles, genes with reported associations to RA, or genes related to the CD40L-CD40 pathway to investigate correlations with disease activity and therapeutic response. Similarly, whole blood may be used to examine epigenetic status of relevant disease- or immune-associated genes and to investigate relationships between epigenetics and disease activity or therapeutic response.
In aspects, whole blood can be collected and may be used to evaluate gene expression profiles before, during, and after treatment with any of the compositions provided herein. Gene expression of molecules found to be modulated by treatment in blood leukocytes may be analyzed in whole blood using quantitative methods. Samples may be used to examine gene expression signatures of various cell types and their changes over time, as well as to explore whether the circulating fibroblast and activated B cell gene signatures detected shortly before a disease flare as assessed by RAPID3.
In aspects, expression levels of genes associated with disease activity by way of RNA and/or DNA analysis may be reduced by at least about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 40-fold, 60-fold, 80-fold, 100-fold, 120-fold, 140-fold, 160-fold, 180-fold, 200-fold, 220-fold, 240-fold, 260-fold, 280-fold, or up to about 300-fold post administration as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold. In aspects, expression levels of genes associated with disease activity by way of RNA and/or DNA analysis may be reduced by at least about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold.
In aspects, determining expression levels of genes associated with disease activity by way of RNA and/or DNA analysis can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, determining expression levels of genes associated with disease activity by way of RNA and/or DNA analysis can be assessed on about Day 1, Day 15±1, Day 29 3, Day 57 3, Day 85 3, Day 113 5, Day 141 5, Day 169±, Day 253 7, and Day 309 f 7 post treatment initiation.
In aspects, a method provided herein can comprise determining a concentration of a Tn3 scaffold in a subject in need thereof post administration. In aspects, a method comprises a pharmacokinetic assessment. In aspects, a sample is a blood sample or a plasma sample, or a combination of both. In aspects, a suitable assay to measure pharmacokinetics may comprise electrochemiluminescence (ECL) assay, a bead-based assay, a cell-based assay, and combinations thereof. In aspects, a sample may comprise plasma and the plasma is assessed for a Tn3 scaffold concentration by measuring: maximum observed concentration (C.), area under the concentration-time curve (AUC), CL, and terminal elimination half-life (tim).
In aspects, a pharmacokinetic assessment to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, a pharmacokinetic assessment to a Tn3 scaffold can be assessed on about Day 1, Day 15±1, Day 29±3, Day 57±3, Day 85±3, Day 113±5, Day 141±5, Day 169±5, Day 197±7, and Day 225±7 post treatment initiation.
In aspects, a method comprises a pharmacodynamic assessment. In aspects, an assessment can occur over a period of time. In aspects, a method provided herein can comprise determining an amount of reduction or elimination of sCD40L by a Tn3 scaffold in a subject in need thereof post administration.
In aspects, a reduction of sCD40L may be detected as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold. In aspects, elimination of sCD40L may be detected as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold as compared to an otherwise comparable method lacking the administering of the Tn3 scaffold. In aspects, reduction of sCD40L comprises at least about or at most about: 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 15-fold, 20-fold, 25-fold, 30-fold, 35-fold, 40-fold, 45-fold, 50-fold, 55-fold, 60-fold, 65-fold, 70-fold, 75-fold, 80-fold, 85-fold, 90-fold, 95-fold, 100-fold, 105-fold, 110-fold, 115-fold, 120-fold, 125-fold, 130-fold, 135-fold, 140-fold, 145-fold, 150-fold, or up to about 200-fold reduction as compared to an otherwise comparable method lacking the administering.
The disclosure provides for a Tn3 scaffold containing compositions that efficiently reduce or deplete sCD40L in a subject. Because s Tn3 scaffold binds to and depletes sCD40L, the reduction or elimination can be used as a measure of treatment efficacy. In aspects, treatment efficacy of a Tn3 scaffold on sCD40L can be assessed over time using a suitable immunoassay. In aspects, effects of a Tn3 scaffold are assessed over time using a qualified immunoassay. In aspects, effects of a Tn3 scaffold with and without a TNFi are assessed over time using a qualified immunoassay. In aspects, total sCD40L is a measure of target engagement. Suitable immunoassays may comprise flow cytometry, histology, immunohistochemistry, blood analysis, microscopy, PCR, ELISA, and combinations thereof.
In aspects, a Tn3 scaffold may achieve at least about 10%, 15%, 20%, 25%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or up to 100% reduction in sCD40L levels as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold. Reduction or elimination of sCD40L may persist for extended periods of time. In aspects, sCD40L depletion may persist for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 15 days, at least 20 days, at least 25 days, or at least 30 days. In another embodiment, sCD40L depletion may persist for at least 1 week, at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 5 weeks, at least 6 weeks, at least 7 weeks, at least 8 weeks, at least 9 weeks, or at least 10 weeks. In aspects, sCD40L depletion may persist for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months or at least 12 months. In aspects, sCD40L depletion may be improved when a Tn3 scaffold is combined with a TNFi.
In aspects, an assessment comprises determining composite disease score. Composite disease scores are selected from the group consisting of, but not limited to: DAS28-CRP, CDAI, SDAI, 28-Joint Count (TJC and SJC), MDGA, PGA, CRP, and combinations thereof. In aspects, a change from baseline may be determined in any of the aforementioned disease scores. In aspects, a disease score may be reduced post administration of a composition provided herein. In aspects, a disease may be treated post administration of a composition provided herein. In aspects, a disease may be reduced post administration of a composition provided herein. In aspects, a disease may go into remission post administration of a composition provided herein. In aspects, a disease may be eliminated post administration of a composition provided herein. In aspects, low disease activity comprises a DAS28-CRP≤3.2 and an improvement of DAS28-CRP score>0.6 from baseline, and/or a proportion of subjects with remission defined as CDAI≤2.8 or SDAI≤3.3.
In aspects, a pharmacodynamic assessment to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, a pharmacodynamic assessment to a Tn3 scaffold can be assessed on about Day 1, Day 15±1, Day 29±3, Day 57±3, Day 85±3, Day 113±5, Day 1415, Day 169±5, Day 197±7, Day 225±7, Day 253±7, Day 281±7, and Day 309±7 post treatment initiation.
In aspects, an assessment comprises DAS28-CRP. DAS28-CRP is a composite score that includes an assessment of 28 specified joints for tenderness and swelling (TJC and SJC), the PGA, and CRP levels (mg/L) (Table 5). Calculation of a DAS28-CRP score may be as follows: DAS28-CRP=0.56×(TJC28)+0.28×(SJC28)+0.014×PGA+0.36×ln(CRP+1)+0.96 (Formula 1), where TJC28 is a TJC using 28 joints, SJC28 is a SJC using 28 joints, and PGA is a patient global assessment on a scale 0-100 mm. The range of a DAS28-CRP score is 0.96-9.31.
In aspects, remission by DAS28-CRP score may be DAS28-CRP≤2.6 (Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis Care Res. 2012; 64(5):640-7). Low disease activity may be defined as DAS28 CRP≤3.2, and an improvement of DAS28 CRP score>0.6 may define a responder (Wells G, Becker J C, Teng J, Dougados M, Schiff M, Smolen J, et al. Validation of the 28-joint Disease Activity Score (DAS28) and European League Against Rheumatism response criteria based on C-reactive protein (CRP) against disease progression in subjects with rheumatoid arthritis, and comparison with the DAS28 based on erythrocyte sedimentation rate. Ann Rheum Dis. 2009; 68(6):954-60). In aspects, a change from baseline is determined
In aspects, a DAS28-CRP assessment to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, a DAS28-CRP assessment to a Tn3 scaffold can be assessed on about Day 1, Day 15±1, Day 29±3, Day 57±3, Day 85±3, Day 113±5, Day 1415, Day 169±5, Day 197±7, Day 225±7, Day 253±7, Day 281±7, and Day 309±7 post treatment initiation.
In aspects, an assessment comprises CDAI. CDAI may be a clinical composite score that includes but is not limited to: 28-joint count, MDGA, PGA, and combinations thereof. Remission comprises an CDAI≤about 2.8. In aspects, remission comprises an CDAI of about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4. In aspects, remission comprises a CDAI of at most or at least about 3.3. In aspects, remission comprises a CDAI from about: 1-2.8, 1.5-3, 2-3, 2-2.8, 1.8-2.8, or 2.2-3. In aspects, a change from baseline is determined.
In aspects, CDAI assessment to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, CDAI assessment to a Tn3 scaffold can be assessed on about Day 1, Day 15 1, Day 29 3, Day 57 3, Day 85 3, Day 113 5, Day 141 f 5, Day 169±5, Day 253±7, and Day 309±7 post treatment initiation.
In aspects, an assessment comprises SDAI. SDAI may be a composite score that includes, but is not limited to: DAS28-CRP, 28-joint count, PGA, and CRP, and combinations thereof. In aspects, remission comprises an SDAI of about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, or 4. In aspects, remission comprises SDAI≤about 3.3. In aspects, remission comprises an SDAI of at most or at least about 3.3. In aspects, remission comprises an SDAI from about: 2-3.3, 3-3.3, 3-3.4, 3.1-3.4, 3.1-3.3, 3-4, 3.1-3.4, or 3.2-3.4. Change may also be measured versus baseline.
In aspects, SDAI assessment to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, SDAI assessment to a Tn3 scaffold can be assessed on about Day 1, Day 15 1, Day 29 3, Day 57±3, Day 85±3, Day 113±5, Day 141 f 5, Day 169±5, Day 253±7, and Day 309±7 post treatment initiation. 28-Joint Count
In aspects, an assessment comprises 28-Joint Count (TJC and SJC). TJC and SJC assess 28 specified joints for tenderness and swelling. In aspects, 28 specified joints comprise, but are not limited to: the 8 proximal interphalangeal joints of the fingers, the 2 interphalangeal joints of the thumbs, the 10 metacarpophalangeal joints, and the wrists, elbows, shoulders, and knees. Change may be measured versus baseline.
In aspects, a TJC and SJC assessment to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, a TJC and SJC assessment to a Tn3 scaffold can be assessed on about Day 1, Day 15±1, Day 29±3, Day 57±3, Day 85±3, Day 113±5, Day 141±5, Day 169±5, Day 197±7, Day 225±7, Day 253±7, Day 281±7, and Day 309±7 post treatment initiation.
In aspects, an assessment comprises MDGA. In aspects, MDGA may comprise determining a subject's level of disease activity due to RA on a scale of 0 (no disease) activity to 100 (maximum disease activity) on a 100 mm visual analog scale (VAS) (Rohekar and Pope, 2009). In aspects, MDGA may be scored from about 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, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, and up to about 100.
In aspects, MDGA is from about 1-10, about 10-30, about 20-40, about 30-50, about 40-60, about 50-70, about 60-80, about 70-90, or about 80-100. In aspects, a change from baseline in MDGA is determined.
In aspects, a MDGA assessment to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, a MDGA assessment to a Tn3 scaffold can be assessed on about Day 1, Day 15±1, Day 29±3, Day 57±3, Day 85±3, Day 113±5, Day 141±5, Day 169±5, Day 197±7, Day 225±7, Day 253±7, Day 281±7, and Day 309±7 post treatment initiation.
In aspects, an assessment comprises PGA. PGA is a measure of a subject's general health (Rohekar G, Pope J. Test-retest reliability of patient global assessment and physician global assessment in rheumatoid arthritis. J Rheumatol. 2009; 36(10):2178-82). In aspects, a subject can be asked to rate their current quality of life by making a mark on a 100 mm VAS in response to these exemplary instructions: “Considering all the ways that your rheumatoid arthritis affects you, please rate how well you are doing on a scale of 0 (very well) to 100 (very poorly).” In aspects, PGA is from about 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, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or up to about 100. In aspects, GA is from at least about 1-10, about 10-30, about 20-40, about 30-50, about 40-60, about 50-70, about 60-80, about 70-90, or about 80-100. In aspects, a change from baseline in PGA is determined.
In aspects, a PGA assessment to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, a PGA assessment to a Tn3 scaffold can be assessed on about Day 1, Day 15±1, Day 29±3, Day 57±3, Day 85±3, Day 113±5, Day 141 f 5, Day 169±5, Day 197±7, Day 225±7, Day 253±7, Day 281±7, and Day 309±7 post treatment initiation.
In aspects, an assessment comprises a FACIT-Fatigue scale and/or a HAQ. A FACIT-Fatigue Scale is a 13-item subject-completed questionnaire used to assess the impact of fatigue. The FACIT-Fatigue scale recall period is about 7 days. Responses to a FACIT-Fatigue questionnaire range from 0 (Not at all) to 4 (Very much). In aspects, a FACIT-fatigue score is at least about 0, about 1, about 2, about 3, or about 4.
In aspects, a HAQ is a subject-completed questionnaire used to assess a subject's ability to perform activities of daily living and a subject's pain due to illness. The HAQ recall period is about 7 days. HAQ questions may be selected from the following exemplary groups: Dressing & Grooming, Arising, Eating, Walking, Hygiene, Reach, Grip, and Activities, or combinations thereof. Four response categories are available for each question, from 0 (Without any difficulty) through 4 (Unable to do).
Subjects are asked about their use of aids and devices and if they need help from another person to complete activities. A HAQ also includes a VAS pain score asking, “How much pain have you had because of your illness in the past week”, with a line for the subject to mark between 0 (No pain) and 100 (Severe pain). In aspects, a baseline level of any one of the aforementioned assays is reduced by at least about 1, about 2, about 3, or about 4 points post treatment with a composition provided herein. In aspects, a subject's score is reduced as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold.
In aspects, a FACIT-Fatigue scale and/or HAQ assessment to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, a FACIT-Fatigue scale and/or HAQ assessment to a Tn3 scaffold can be assessed on about Day 1, Day 1, Day 29 3, Day 57 3, Day 85 3, Day 113 5, Day 141 5, Day 169±, Day 197 7, Day 225±7, Day 253±7, Day 281±7, and Day 309±7 post treatment initiation.
In aspects, an assessment comprises a PROMIS-29 profile. A PROMIS-29 adult profile is a brief generic health measure comprising 29-items from the PROMIS domains of anxiety, depression, fatigue, pain (intensity and interference), physical function, sleep disturbance, satisfaction with participation in social roles (social participation), or combinations thereof. In aspects, a treated subject has an improved score on a PROMIS-29 as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold.
In aspects, a PROMIS-29 assessment to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, a PROMIS-29 assessment to a Tn3 scaffold can be assessed on about Day 1, Day 15±1, Day 29±3, Day 57±3, Day 85±3, Day 113±5, Day 141±5, Day 169±5, Day 197±7, Day 225±7, Day 253±7, Day 281±7, and Day 309±7 post treatment initiation.
In aspects, an assessment comprises a RAPID3 (routine assessment of patient index data 3). RAPID is a pooled index of the 3 patient-reported American College of Rheumatology RA Core Data Set measures: function, pain, and patient global estimate of status. Each of the 3 individual measures may be scored from at least about 0, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, to about 10, for a maximum total of 30. Disease severity may be classified based on the following RAPID3 scores: >12=high; 6.1-12=moderate; 3.1-6=low; <or =3=remission. In aspects, a RAPID3 scores is correlated with a disease activity score 28 (DAS28) and clinical disease activity index (CDAI), or a combination thereof. In aspects, a treated subject comprises an improved RAPID3 score as compared to an otherwise comparable method wherein the subject of the otherwise comparable method is not administered a Tn3 scaffold.
In aspects, a RAPID3 assessment to a Tn3 scaffold can be assessed on about 0 day, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 21 weeks, 22 weeks, 23 weeks, 24 weeks, 25 weeks, 26 weeks, 27 weeks, 28 weeks, 29 weeks, 30 weeks, 31 weeks, 32 weeks, 33 weeks, 34 weeks, 35 weeks, 36 weeks, 37 weeks, 38 weeks, 39 weeks, 40 weeks, 41 weeks, 42 weeks, 43 weeks, 44 weeks, 45 weeks, 46 weeks 47 weeks, or at least about 48 weeks post treatment initiation. In aspects, a RAPID3 assessment to a Tn3 scaffold can be assessed on about Day 1, Day 15±1, Day 29±3, Day 57±3, Day 85±3, Day 113±, Day 141±, Day 169±, Day 197±, Day 225±, Day 253±, Day 281±, and Day 309±7 post treatment initiation.
In aspects, provided is a pharmaceutical composition. A pharmaceutical composition can comprise a Tn3 scaffold and/or a TNFi. In aspects a pharmaceutical composition is part of a therapeutic regimen that comprises a Tn3 scaffold and one or more additional therapeutics provided herein. In aspects, the one or more additional therapeutics can comprise a TNFi.
Many drugs can be administered orally as liquids, capsules, tablets, or chewable tablets. Because the oral route is the most convenient and usually the safest and least expensive, it is the one most often used. However, it has limitations because of the way a drug typically moves through the digestive tract. For drugs administered orally, absorption may begin in the mouth and stomach. However, most drugs are usually absorbed from the small intestine. The drug passes through the intestinal wall and travels to the liver before being transported via the bloodstream to its target site. The intestinal wall and liver chemically alter (metabolize) many drugs, decreasing the amount of drug reaching the bloodstream. Consequently, these drugs are often given in smaller doses when injected intravenously to produce the same effect.
For a subcutaneous route, a needle is inserted into fatty tissue just beneath the skin. After a drug is injected, it then moves into small blood vessels (capillaries) and is carried away by the bloodstream. Alternatively, a drug reaches the bloodstream through the lymphatic vessels. The intramuscular route is preferred to the subcutaneous route when larger volumes of a drug product are needed. Because the muscles lie below the skin and fatty tissues, a longer needle is used. Drugs are usually injected into the muscle of the upper arm, thigh, or buttock. How quickly the drug is absorbed into the bloodstream depends, in part, on the blood supply to the muscle: The sparser the blood supply, the longer it takes for the drug to be absorbed. For the intravenous route, a needle is inserted directly into a vein. A solution containing the drug may be given in a single dose or by continuous infusion. For infusion, the solution is moved by gravity (from a collapsible plastic bag) or, more commonly, by an infusion pump through thin flexible tubing to a tube (catheter) inserted in a vein, usually in the forearm.
In aspects, a pharmaceutical composition provided herein is administered via infusion. An infusion can take place over a period of time. For example, an infusion can be an administration of a pharmaceutical over a period of about 5 minutes to about 10 hours. An infusion can take place over a period of about 5 min, 10 min, 20 min, 30 min, 40 min, 50 min, 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or up to about 10 hours.
In aspects, intravenous administration is used to deliver a precise dose quickly and in a well-controlled manner throughout the body. It is also used for irritating solutions, which would cause pain and damage tissues if given by subcutaneous or intramuscular injection. When given intravenously, a drug is delivered immediately to the bloodstream and tends to take effect more quickly than when given by any other route. Consequently, health care practitioners closely monitor people who receive an intravenous injection for signs that the drug is working or is causing undesired side effects. Also, the effect of a drug given by this route tends to last for a shorter time. Therefore, some drugs must be given by continuous infusion to keep their effect constant. In aspects, infusion reactions can occur and include headache, nausea, somnolence, dyspnea, fever, myalgia, rash, or other symptoms. Potential risks associated with administration of a Tn3 scaffold are infection, redness, swelling, pain, and induration at the administration site. Prior to each IV infusion subjects may receive prophylaxis with IV methylprednisolone, oral diphenhydramine, and oral acetaminophen, or equivalent(s) to reduce the risk or severity of potential reactions.
In aspects, a pharmaceutical is administered intrathecally. For the intrathecal route, a needle is inserted between two vertebrae in the lower spine and into the space around the spinal cord. The drug is then injected into the spinal canal. A small amount of local anesthetic is often used to numb the injection site. This route is used when a drug is needed to produce rapid or local effects on the brain, spinal cord, or the layers of tissue covering them (meninges)—for example, to treat infections of these structures.
Drugs administered by inhalation through the mouth can be atomized into smaller droplets than those administered by the nasal route, so that the drugs can pass through the windpipe (trachea) and into the lungs. How deeply into the lungs they go depends on the size of the droplets. Smaller droplets go deeper, which increases the amount of drug absorbed. Inside the lungs, they are absorbed into the bloodstream. Drugs applied to the skin are usually used for their local effects and thus are most commonly used to treat superficial skin disorders, such as psoriasis, eczema, skin infections (viral, bacterial, and fungal), itching, and dry skin. The drug is mixed with inactive substances. Depending on the consistency of the inactive substances, the formulation may be an ointment, cream, lotion, solution, powder, or gel.
In aspects, a treatment regime comprising a pharmaceutical composition may be dosed according to a body weight of a subject. In subjects who are determined obese (BMI>35) a practical weight may need to be utilized. BMI is calculated by BMI=weight (kg)/[height (m)]2. An ideal body weight may be calculated for men as 50 kg+2.3*(number of inches over 60 inches) or for women 45.5 kg+2.3 (number of inches over 60 inches). An adjusted body weight may be calculated for subjects who are more than 20% of their ideal body weight. An adjusted body weight may be the sum of an ideal body weight+(0.4×(Actual body weight—ideal body weight)). In aspects, body surface area may be utilized to calculate a dosage. A body surface area (BSA) may be calculated by: BSA (m2)=VHeight (cm)*Weight (kg)/3600.
In aspects, a pharmaceutical composition can be administered either alone or together with a pharmaceutically acceptable carrier or excipient, by any routes, and such administration can be carried out in both single and multiple dosages. More particularly, a pharmaceutical composition can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hand candies, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. Exemplary carriers and excipients can include dextrose, sodium chloride (NaCl), sucrose, lactose, cellulose, xylitol, sorbitol, maltitol, gelatin, PEG, PVP, histidine/histidine hydrochloride, trehalose dihydrate, polysorbate 80, and any combination thereof. In aspects, an excipient comprises: histidine/histidine hydrochloride, NaCl, trehalose dihydrate, and polysorbate 80.
Notwithstanding the appended claims, the following numbered embodiments also form part of the instant disclosure.
Example 1—A phase 2, randomized, double-blind, placebo-controlled, mechanistic insight and dosage optimization study of the efficacy and safety of Dazodalibep (VIB4920), in subjects with rheumatoid arthritis (RA) Study Design
A multicenter, randomized, double-blind, placebo-controlled, parallel-cohort study to evaluate the safety, efficacy, and PK of VIB4920, an exemplary Tn3 scaffold comprising an anti-CD40L-Tn3 fusion protein, in adults with active, moderate-to-severe adult-onset RA (DAS28 CRP>3.2;≥4 TJC and >4 SJC), and presence of serum RF and/or ACPA who have had an inadequate response to MTX, cDMARD, or an anti-TNFα agent; who are not currently receiving an anti-TNFα agent; and who have had no prior treatment with rituximab or B-cell depletive agents. The effect of VIB4920 on disease activity as assessed by a composite measure in subjects with adult-onset RA is evaluated and/or the tolerability and safety of VIB4920 in subjects with adult-onset RA.
The primary efficacy endpoint was change from baseline to dl 13 in DAS28-CRP. Secondary endpoints included proportions with clinical remission (CR) by DAS28-CRP<2.6) at dl 13, time to rescue medication, change from baseline to dl 13 in RF/ACPAs, treatment-emergent adverse events (AE), serious AE(SAE) and AE of special interest (AESI).
After a screening period of up to 28 days, approximately 75 subjects are randomized in a 1:1:1:1:1 ratio into 5 cohorts:
An exemplary study schematic is presented in
Subjects receive the background therapy that was established for them by their personal physician. Subjects are asked, but not required, to delay institution of any new treatment for RA for 12 weeks (Day 85), at which time rescue therapy may be instituted. Rescue therapy is any new or intensified immunosuppressive, conventional DMARD (cDMARD), or biologic DMARD (bDMARD) treatment for RA, including:
If a subject receives rescue therapy prior to the final dose of VIB4920, VIB4920 is discontinued.
Subjects administered rescue therapy do not need to be followed until Day 309 but can complete the study at or after Day 113. Subjects must also complete a 3-month safety follow-up period after the final dose of VIB4920 and must return for at least one visit after initiating rescue therapy to complete remaining assessments (Table 2).
Note: All actions include the required Day 113 visit, 3 months of follow-up, and one visit post-initiation of rescue therapy.
All subjects are followed at least through the primary (interim) analysis (Day 113), and those who have not instituted rescue therapy are followed through Day 309 to determine the duration of clinical response. The primary analysis is after all subjects have completed Day 113, and the final analysis is after all subjects have completed follow-up.
To be included in the study, each subject must satisfy all the following criteria:
a This is also considered to be a hormonal method.
b With appropriate post-vasectomy documentation of surgical success (absence of sperm in ejaculate).
c Sexual abstinence is considered to be a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of the study and if it is the preferred and usual lifestyle of the subject.
d Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action (minipill) is not accepted as a highly effective method.
Any of the following excludes a subject from participation in the study:
Subjects should be assessed for epidemiologic risk of COVID-19 (recent exposures, high-risk housing) and for health-related risk of COVID-19 severity based on current understanding of risk factors for severe disease when making a decision regarding the subject subject's risk of participation. Subjects who have active COVID-19 infection or disease or other significant infection, or, in the judgment of the investigator, who may be at unacceptable risk of COVID-19 or its complications should not be randomized.
Ensure that the subject has a documented negative SARS-CoV-2 test within two weeks prior to randomization. Subjects with a positive test for SARS-CoV-2 may be rescreened at least 2 weeks after a positive test if asymptomatic and at least 3 weeks after symptomatic COVID-19 illness.
Repeat of study laboratory tests is acceptable in the event that an initial screening safety laboratory result is outside of acceptable limits for the study. If the investigator considers the value to be a potential outlier not representative of the subject's true state of health, testing may be repeated once, using the central laboratory, at the investigator's discretion. Subjects may be rescreened once if, in the Investigator's judgment, the reason for ineligibility is likely to have resolved at the time of rescreening.
Subjects must, based on moderate-to-severe disease despite DMARD therapy, have failed a prior regimen. To avoid confounding interpretation of safety and efficacy data based on the use of prior biologics, especially B-cell depletive agents, subjects with prior use of these drugs, other than prior but not current use of TNFα inhibitors, are excluded. Subjects must have at least 4 tender and 4 swollen joints to permit assessment of joint response during the study.
A complete physical examination (with the exception of rectal and pelvic examinations) is conducted, including vital signs, height, and weight. DAS28-CRP assessments are performed at screening along with testing for RF and ACPA. Laboratory tests (serum chemistry, hematology, and urinalysis), coagulation parameters, chest X-ray (unless recent reading available [prior 6 months]), ECG, and serum human chorionic gonadotropin (β-hCG) pregnancy test for females are performed.
Screening tests comprise: Hepatitis B testing: HbsAg, anti-HBc; Hepatitis C antibody; HIV testing: HIV-1 antibody, HIV-2 antibody; TB testing (e.g., QuantiFERON®-TB Gold Test or other interferon-gamma release assay test) as per local standard of care guidelines.
An AE is any untoward medical occurrence associated with the use of an intervention in humans whether or not it is considered intervention-related.
A SAE is considered “serious” if it results in any of the following outcomes:
An assessment of the relationship of AEs and SAEs to the IP is determined. An event is considered “not related” to use of VIB4920 if any of the following tests are met:
Subject AE/SAE reports are considered “related” to use of the VIB4920 if the “not related” criteria are not met. “Related” implies that the event is considered to be “associated with the use of the drug” meaning that there is “a reasonable possibility” that the event may have been caused by the product (i.e., there are facts, evidence, or arguments to suggest possible causation).
The formulation of VIB4920 is shown in Table 4.
Treatment administration should, wherever possible, be at a consistent time of day for each dose. Vital signs are obtained prior to the start of each infusion, every 30 (±5) minutes during the infusion, and at the end of the infusion (±5 minutes). Vital signs also are checked every hour (±10 minutes) during the 4-hour observation period after Dose 1 and at the end (±10 minutes) of the one-hour observation period after doses 2, 3, and 4. If vital signs are abnormal, they should be rechecked.
Treatment is infused using an IV infusion pump. Infusion times are as per Table 5. For Doses 1 and 4, IP is either VIB4920 1500 mg, VIB4920 3000 mg, or placebo. For Doses 2 and 3, IP are either VIB4920 1500 mg or placebo. Table 6 shows the study treatment administration scheme.
aOr placebo matched to that dose of VIB4920.
bIf, after dosing of at least 4 subjects with Dose 1, >25% of the subjects dosed have a Grade 2 or higher infusion reaction, all subsequent doses that could include 3000 mg (i.e., Dose 4) is administered over 180 minutes(~8-17 mg/min) and Doses 2 and 3 is administered over 120 minutes (~13 mg/min).
cIf >25% of the subjects dosed have a Grade 2 or higher infusion reaction, Dose 3 is administered over 120 minutes and Dose 4 is administered over 180 minutes.
To evaluate the effect of VIB4920 on disease activity as assessed by a composite measure in subjects with adult-onset RA and to evaluate the safety and tolerability of VIB4920 in subjects with adult-onset RA, post-treatment, subjects are assessed for one or more of the following:
To evaluate the duration of clinical response to VIB4920 as assessed by time to institution of rescue therapy and to characterize the pharmacokinetics (PK) of VIB4920, evaluate the pharmacodynamic effect of VIB4920, evaluate the immunogenicity of VIB4920, evaluate the effect of VIB4920 on autoantibodies, and assess the effect of VIB4920 on clinical remission as assessed by a composite measure in subjects with adult-onset RA, subjects are assessed for one or more of the following:
To evaluate the effect of VIB4920 on markers of inflammation; immune cell populations and cytokines, RNA, DNA, and protein biomarkers; subject outcomes as recorded in subject-reported outcome (PRO) instruments; and on additional measures of efficacy, and to evaluate the duration of clinical response to VIB4920 in subjects who have had a clinical response subjects are assessed for one or more of the following:
Post-treatment, blood, urine and respiratory (swab or saliva) samples are collected for laboratory safety tests. A hematology panel includes a complete blood count, with white blood cell count (WBC) and differential (basophils, eosinophils, lymphocytes, monocytes, and neutrophils), hemoglobin, hematocrit, and platelet count. Serum chemistry will also be analyzed for:
Coagulation parameters will also be assessed: prothrombin time and PTT.
Urinalysis evaluates color, appearance, and specific gravity. Dipstick analysis includes pH, protein, glucose, blood, ketones, and bilirubin. Samples with abnormal dipstick will have microscopy performed. Microscopy includes WBC/HPF (high power field) and red blood cell count/HPF.
Testing for SARS-COV-2 is performed.
Vital signs, including systolic and diastolic blood pressure (mmHg), pulse rate (beats/min), respiratory rate (breaths/min), body temperature (° C.), and body weight (kg), are measured.
An electrocardiogram (ECG) is performed. ECG analysis includes ventricular heart rate and intervals (PR, QRS, QT, QTc).
a In females of childbearing potential; result must be negative prior to dosing.
b On study days when IP is not administered, only one plasma sample for PK is required to be collected at a consistent time across the different study days.
c Whole blood is collected on indicated days for processing to PBMCs.
d IP administration should, wherever possible, be at a consistent time of day for each dose. All procedures and blood sampling, except for postdose PK, must be performed before IP administration.
e Vital signs are obtained prior to the start of each IP infusion, every 30 (± 5) minutes during the infusion, and at the end of the infusion (+ 5 minutes). Vital signs also are checked every hour (± 10 minutes) during the 4-hour observation period after Dose 1 and at the end (+ 10 minutes) of the one-hour observation period after Doses 2, 3 and 4. If vital signs are abnormal, they should be repeated.
f Plasma samples for PK of VIB4920 are collected predose (within 30 minutes prior to start of infusion), and within 10 minutes of the end of infusion.
g After the Day 85 visit, the dose of background cDMARDs and corticosteroids may be adjusted or a new cDMARD may be added (except that MTX and leflunomide may not be used concurrently and rituximab may not be added without discontinuation of VIB4920) if it is clinically indicated to improve disease management.
78 subjects were randomized (1:1:1:1:1) in a placebo-controlled, parallel design. The anti-CD40L-Tn3 fusion protein (VIB4920) was VIB4920. The groups were placebo, VIB4920 3000 mg×1, VIB4920 1500 mg×2, VIB4920 3000 mg×2, and VIB4920 1500 mg×4, as described in the cohorts above and in
As described above, the study population included adults with active, moderate-to-severe adult-onset RA (DAS28-CRP>3.2; ≥4 tender and >4 swollen joints) and presence of serum rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPAs) with inadequate response to MTX, cDMARD, or TNFi agent and no prior treatment with rituximab or B cell depletive agents.
All subjects in this analysis completed Day 113 or discontinued prior to Day 113. All data up to the cut-off date are included in this analysis.
73 subjects (93.6%) completed treatment and 65 (83%) completed the study. At baseline, mean(SD) age was 56 (13) years, 80% female. Demographics and disease characteristics were similar across arms, except for RF+proportion and mean CRP (Table 9). The primary endpoint (DAS28-CRP change from baseline) was met (Table 9) at all doses at dl 13. Observed treatment effect was consistently maintained for cohort 3 through study end. Prolonged responses, beyond dl 13 were also observed for other doses most notably for cohort 1. RF levels decreased significantly vs placebo (PBO) starting d57 to d113 (p<0.0035) for all doses. There was a similar trend with ACPA levels that was significant with cohorts 1 and 4. DAS28-CRP CR rates were similar in all groups but fewer DAZO patients had high disease activity (DAS28-CRP>5.1) at dl 13. Time-to-rescue medication did not differ.
Patients with≥1AE were numerically higher with DAZO vs PBO (74% vs 63%); 3 patients had 4 SAEs in the DAZO group vs none in PBO: 1 nephrolithiasis (discontinued study), 1 COVID-19 infection and 1 patient was hospitalized for COVID and died from unknown cause 2 days after hospital discharge (232d after last dose), all were deemed unrelated to study drug. 11/62 (18%) vs 4/16 (25%) patients had >1AE deemed related to DAZO and PBO, respectively.
The subject status, baseline characteristics, and drug exposure for subjects in placebo, VIB4920 3000 mg×1, VIB4920 1500 mg×2, VIB4920 3000 mg×2, and VIB4920 1500 mg×4 groups are reported in Tables 9-11.
aDuration of exposure = last dose date + 28 − first dose date + 1
All 4 VIB4920 doses (VIB4920 3000 mg×1, VIB4920 1500 mg×2, VIB4920 3000 mg×2, and VIB4920 1500 mg×4) met statistical significance in the change from baseline DAS28-CRP at Day 113. No dose-response relationship was observed (
Data from other endpoints including CDAI (
Table 12 shows the change from Baseline DAS28-CRP to Day 113 and Table 13 shows DAS28-CRP Response Categories for subjects in placebo, VIB4920 3000 mg×1, VIB4920 1500 mg×2, VIB4920 3000 mg×2, and VIB4920 1500 mg×4 groups.
Clinical remission data is shown in
No subject received rescue medications prior to Day 113, and few subjects overall received rescue medications (
A statistically significant difference in reduction from baseline in RF (
A statistically significant reduction from baseline (˜30-40%) in CXCL13 was observed across all 4 VIB4920 doses (VIB4920 3000 mg×1, VIB4920 1500 mg×2, VIB4920 3000 mg×2, and VIB4920 1500 mg×4) compared to placebo through Day 29, but all but the 1500 mg 4 times group lost suppression by Day 57, with decline achieving statistical significance again observed on Day 85 in all but the single 3000 mg dose group (
An increase in total sCD40L was observed, indicating binding of VIB4920 to sCD40L and target engagement. Through Day 85, this increase in total sCD40L was not dose-dependent, but by Day 113, the single 3000 mg dosing cohort was substantially different from the other cohorts but still above baseline (
Table 14 shows baseline measure of disease activity score 28° C.-reactive protein. The DAS28-CRP is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity.
The total soluble cluster of differentiation 40 ligand (sCD40L) plasma concentration was evaluated over time. Total sCD40L (free sCD40L and sCD40L bound to VIB4920) was measured in plasma samples using a modified commercially available kit. Measurements were taken at Day 1 (Baseline), Days 15, 29, 57, 85,113,141, 169, 197, 225, 253, 281, and day 309. Results are shown in Table 15.
The percentage of subjects with positive anti-drug antibodies (ADA) was also evaluated according to the below metrics:
Measurements were taken at Day 1 (Baseline) to Day 309 Day 1 (Baseline) up to Day 309 (±7 days). Results are shown in Table 16.
Change from baseline to Day 113 in Anti-Citrullinated Protein Antibodies (ACPAs) was also evaluated. Excluding data after rescue. Adjusted geometric mean ratio to baseline (90% CI) results are from MMRM analysis on log(ratio to baseline) with treatment, visit, visit by treatment interaction, and log(baseline) included in the model. Ratios less than 1 indicate a decrease. Results are shown in Table 17.
Geometric Mean (90% Confidence Interval). Unit of measure: ratio
Change From Baseline to Day 113 in Rheumatoid Factor (RE) was also evaluated. Excluding data after rescue. Adjusted geometric mean ratio to baseline (90% CI) results are from MMRM analysis on log(ratio to baseline) with treatment, visit, visit by treatment interaction, and log(baseline) included in the model. Ratios less than 1 indicate a decrease. Results are shown in Table 18.
Geometric Mean (90% Confidence Interval). Unit of measure: ratio
The percentage of subjects with clinical remission at Day 113 was determined. Clinical remission is defined as DAS28-CRP≤2.6. The DAS28-CRP is a composite index used to assess rheumatoid arthritis disease activity, calculated based on the tender joint count (out of 28 evaluated joints), swollen joint count (out of 28 evaluated joints), Patient's Global Assessment of Disease Activity (0-100 mm), and high-sensitivity C-reactive protein (hsCRP; in mg/L). Scores on the DAS28-CRP range from 0 to approximately 10, where higher scores indicate more disease activity. Results are shown in Table 19.
Dazodalibep (VIB4920) reduced DAS28-CRP and RF significantly as compared to placebo at day 113 in all dose regimens tested. The study met its primary endpoint of change from baseline in DAS28-CRP at Day 113 in all four Dazodalibep dosing arms. This endpoint is a standardized measure that is used in RA clinical trials to measure disease activity. Dazodalibep was well tolerated. The Dazodalibep Phase 2 trial follows the Phase 1b, multiple ascending dose study in patients with active moderate-to-severe RA. In this trial, the last dose of Dazodalibep was given at Day 85 and follow-up data at Day 169 showed a prolonged and sustained benefit on disease activity. Of note was that the single 3000 mg administration was as effective as multiple administrations of Dazodalibep, thereby indicating the viability of less frequent dosing. Indeed, treatment effects were observed at day 113 and the prolonged duration of responses support less frequent dosing.
A phase 2, multi-site, prospective, randomized, placebo-controlled, three-arm [two arms double-blinded, one arm evaluator-blinded (subject is aware of his/her treatment status, but evaluator is not)] trial of VIB4920, an exemplary Tn3 scaffold, in 104 adults with seropositive RA in the United States is described. Subjects are eligible if they have moderate or high disease activity (Simplified Disease Activity Index [SDAI]>17) despite treatment with a TNFi (etanercept or adalimumab) for at least 12 weeks. The schedule of events for the study drug administration period is provided in Table 22.
Subjects are Randomized in a 2:1:1 Fashion into One of the Following Three Study Arms:
After week 12, all subjects randomized to VIB4920 or VIB4920 placebo will continue treatment with their background disease-modifying drugs, including their TNFi, and are followed through week 40. Subjects randomized to receive VIB4920 after stopping their TNFi will not restart their TNFi and are followed through week 40. In addition, subjects who achieve the primary endpoint at week 16 are followed through week 40 and undergo weekly home fingerstick blood sampling (“dense sampling”) and RAPID3 assessment, see
Three arms are included in this study to assess the efficacy of adding VIB4920 to background disease modifying RA therapy including TNFi and replacing TNFi with VIB4920, as well as the safety of this combination of biologic agents compared to either agent alone. Subjects are assessed for the primary endpoint, achievement of low disease activity (defined as SDAI≤11), at week 16. Subjects will then be followed until week 40 while they continue their other disease-modifying treatments to assess for sustained clinical response and safety. Subjects who achieve the primary endpoint at week 16 are eligible to undergo weekly blood sampling and RAPID3 evaluation at home. This weekly blood sampling is optional for eligible subjects and are obtained from week 16 through week 40 using a fingerstick method. This “dense sampling” approach is used to explore transcriptional signatures that may be associated with increases in disease activity, see schedule of events in Table 23. Subjects who do not achieve the primary endpoint or elect not to participate in the optional dense sampling collection are followed from week 16 to week 40 using the schedule of events provided in Table 24. All clinical assessments are performed by a blinded study assessor for the entire duration of the study, see
The primary endpoint is the proportion of subjects achieving low disease activity, as defined by a SDAI≤11 at week 16. In addition, subjects who take prohibited medications as treatment for RA prior to week 16 are considered to have failed the primary endpoint. The primary analysis of the primary endpoint is performed on the mITT sample utilizing subjects in the VIB4920 with TNFi and VIB4920 placebo with TNFi arms and is designed to test the following hypotheses:
Null hypothesis: The proportion achieving low disease activity at week 16 does not differ between the VIB4920 with TNFi and VIB4920 placebo with TNFi groups.
Alternate hypothesis: The proportion achieving a low disease activity at week 16 differs between the VIB4920 with TNFi and VIB4920 placebo with TNFi groups.
The proportion of mITT subjects achieving low disease activity at week 16 are estimated for the VIB4920 with TNFi and VIB4920 placebo with TNFi groups. Groups are compared using a two-sided Fisher's Exact test evaluated using a Type 1 error rate of α=0.10.
All secondary endpoints are assessed across all three study treatment arms.
Secondary efficacy endpoints: (A) Sustained remission. (1) Proportion of subjects who achieve sustained remission defined by SDAI≤3.3 at all available disease activity assessments between week 16 and week 40. (B) Low disease activity by DAS28-CRP. (2) Proportion of subjects achieving low disease activity defined by DAS28-CRP≤3.2 at week 16. (C) Remission. (3) Proportion of subjects achieving remission defined by SDAI≤3.3 at week 16. (4) Proportion of subjects achieving remission defined by DAS28-CRP≤2.6 at week 16. (D) ACR20/50/70 endpoints. (5) The proportion of subjects achieving an ACR20 response at week 16. (6) The proportion of subjects achieving an ACR50 response at week 16. (7) The proportion of subjects achieving an ACR 70 response at week 16. (8) The proportion of subjects achieving an ACR20 response at week 40. (9) The proportion of subjects achieving an ACR50 response at week 40. (10) The proportion of subjects achieving an ACR 70 response at week 40. (E) Time to low disease activity or remission. For subjects who fail to achieve low disease activity or remission prior to escalating their disease-modifying therapy or taking a prohibited medication for treatment of RA, low disease activity is assumed and remission is not achievable within 40 weeks. (11) Time to first occurrence of low disease activity as defined by SDAI≤11. (12) Time to first occurrence of low disease activity as defined by DAS28-CRP≤3.2. (13) Time to first occurrence of remission as defined by SDAI≤3.3. (14) Time to first occurrence of remission as defined by DAS28-CRP≤2.6. (F) Time to loss of low disease activity or remission. Subjects who escalate their disease-modifying therapy or take prohibited medications for treatment of their RA are considered to have lost the low disease activity or remission response. (15) Time to loss of low disease activity defined by SDAI>11 for the subset of subjects achieving low disease activity by the SDAI criteria at week 16. (16) Time to loss of low disease activity defined by DAS28-CRP>3.2 for the subset of subjects achieving low disease activity by the DAS28-CRP criteria at week 16. (17) Time to loss of remission defined by SDAI>3.3 for the subset of subjects achieving remission by the SDAI criteria at week 16. (18) Time to loss of remission defined by DAS28-CRP>2.6 for the subset of subjects achieving remission by the DAS28-CRP criteria at week 16. (E) Longitudinal trends. (19) Longitudinal trends in SDAI from week 0 to week 40. (20) Longitudinal trends in DAS28-CRP from week 0 to week 40. (H) HAQ-DI and PROMIS. (21) Change in the Health Assessment Questionnaire—Disability Index (HAQ-DI), see
The study recruits subjects with inclusion and exclusion criteria as in Table 20. The study recruits subjects with seropositive RA who have had an inadequate response to a TNFi. Subjects with persistent disease activity despite treatment with a TNFi (with or without methotrexate or other cDMARD) are at risk for progressive joint damage and are candidates fora change in disease-modifying therapy. Subjects with active disease that are receiving a TNFi are enrolled as it is hypothesized that combining TNF-ca inhibition with an agent that interferes with a dysregulated adaptive immune response, in this case a drug targeting the CD40L-CD40 pathway, will improve disease control and lead to a sustained clinical benefit. The study will enroll adults that are 70 years of age or younger to mitigate the impact of infections, which may be a risk for subjects receiving this untested combination of biologic agents. In addition, subjects with clinical or laboratory features associated with an increased risk for infection will not be eligible for this trial. Subjects will need to have moderate or high disease activity, as well as a sufficient number of tender and swollen joints that would warrant a change in treatment strategy.
Subjects will receive VIB4920 or VIB4920 placebo given intravenously at a dose of 1500 mg at weeks 0, 2, 4, 8, and 12. Subjects randomized to VIB4920 with TNFi or VIB4920 placebo with TNFi will continue their background disease-modifying therapy, including their TNFi. Subjects randomized to VIB4920 without TNFi will discontinue TNFi therapy while maintaining all other background disease-modifying RA therapy.
VIB4920 is administered at a dose of 1500 mg as an intravenous infusion at weeks 0, 2, 4, 8, and 12. To prepare the dose, VIB4920 is removed from refrigerated storage conditions and allowed to equilibrate in the carton for 15 minutes to 2 hours. The investigational product is diluted into 250 mL 0.9% saline for IV infusion. The diluted investigational product can be stored for a maximum of 24 hours at 2-8° C. or 4 hours at room temperature, including preparation time. The investigational product is prepared by an unblinded pharmacist and covered by an opaque bag before being given to blinded study personnel for administration.
VIB4920 placebo is administered as an intravenous infusion at weeks 0, 2, 4, 8, and 12. For the VIB4920 placebo, a bag of 250 mL 0.9% saline is stored in the same fashion as VIB4920 and covered by an opaque bag before being given to blinded study personnel for administration. Subjects are administered VIB4920 or VIB4920 placebo in a clinical trial facility and monitored for evidence of an infusion reaction. Appropriate drugs and medical equipment to treat acute hypotensive, broncho constrictive, or anaphylactic reactions are immediately available, and study personnel trained to recognize and treat these reactions are available. VIB4920 or VIB4920 placebo are administered over a minimum of 90 minutes. The infusion is slowed down or discontinued if there is evidence of an infusion reaction. Subjects are monitored for 2 hours after the first three doses of study treatment, and then for 1 hour after the subsequent doses of study treatment. Vital signs are monitored prior to the infusion and approximately every 30 minutes during treatment administration and the subsequent observation period. VIB4920 or VIB4920 placebo is not administered on the same days as the TNFi. If VIB4920 or VIB4920 placebo and TNFi are scheduled to be administered on the same day, then the TNFi should be administered the day before or day after VIB4920 or VIB4920 placebo administration and maintained on that treatment schedule.
Infusion or hypersensitivity reactions: Subjects are monitored for infusion or hypersensitivity reactions, and receive VIB4920 or VIB4920 placebo in a clinical trial facility with personnel, medications, and equipment available to treat these types of reactions. Anti-histamine (e.g., diphenhydramine or cetirizine) and/or acetaminophen can be administered per institutional guidelines prior to VIB4920 infusion to help prevent infusion reactions. Administration of glucocorticoids prior to VIB4920 infusion to help prevent infusion reactions is not permitted. Administration of study treatment is permanently discontinued if the subject develops a grade 3 or greater hypersensitivity, anaphylactic, or infusion reaction.
Infection: clinical assessments for signs of infection are performed at each study visit. Subjects are contacted by telephone at study weeks 6, 10, and 14 to assess for infection. Subjects are given instructions on potential signs of infection and instructed to contact the site investigator if they have signs or symptoms of an infection. VIB4920/VIB4920 placebo administration is discontinued if the subject is diagnosed with an active SARS-CoV-2 (COVID-19) infection, confirmed by PCR or alternative viral test according to CDC guidance, independent of symptoms or grade of infection. VIB4920/VIB4920 placebo is suspended if the subject develops a non-COVID-19 infection that is grade 2 or greater where systemic treatment (e.g., antibiotic, antifungal or antiviral) is indicated, or the investigator judges to be significant. If the infection resolves, VIB4920 or placebo may be restarted at the next scheduled dose at the investigator's discretion.
Thromboembolic events: Thromboembolic events are monitored by AE evaluations and physical examinations performed during the study. Study treatment is suspended if a subject is suspected to have a deep venous thrombosis or arterial thrombotic event. Study treatment is permanently discontinued for subjects who have a confirmed deep vein thrombosis or arterial thromboembolic event.
Liver chemistry abnormalities: Subjects are monitored for drug induced liver injury. If liver chemistries are found to be abnormal in a subject, they should be repeated in 1-2 weeks for confirmation. If liver chemistry abnormalities are confirmed, then the dosing of VIB4920 or VIB4920 placebo should be adjusted as shown in Table 21.
Subjects with persistent disease activity that may require a change in disease-modifying therapy
From week 12 to week 40, a subject may be considered for a change in disease modifying treatment regimen (e.g., change TNFi, increase dose of disease-modifying medication, switch to another disease-modifying drug, increase glucocorticoid use, or use a prohibited disease-modifying medication described herein) if either of the following occurs: (a) The subject has an SDAI>26 at week 12 or later, which is confirmed at a study visit (scheduled or unscheduled) in the next 2-4 weeks; (b) The subject has an SDAI>11 at week 16 or later, and his/her SDAI has decreased by less than 50% from baseline, and both are confirmed at a study visit (scheduled or unscheduled) in the next 2-4 weeks.
Subjects who fulfill any of these criteria above are treated at the discretion of the subject's rheumatologist/treating physician. Alternate monitoring includes assessment of grade 2 or higher adverse events that received medical attention, AESIs, and concomitant medications at weeks 2, 4, 8, 12, 16, 24, 32, and 40, as well as disease activity assessments at weeks 16 and 40, if those visits have not already occurred. More frequent assessments can occur, as clinically indicated.
Subjects randomized to the VIB4920 with TNFi or VIB4920 placebo with TNFi arms are to continue their prescribed TNFi (adalimumab or etanercept) and maintain the same dose (the dose at study entry) until week 40 unless the TNFi is changed for persistent or worsening disease activity. Subjects randomized to VIB4920 without TNFi are required to stop TNFi use at randomization (week 0).
For all subjects, changes in disease-modifying therapy may be considered after week 12 in the setting of persistent or worsening disease activity.
The following DMARDs are permitted at study entry. Their dose is maintained at the same dose for the duration of the study unless the dose is reduced or the medication is stopped due to toxicity.
Oral prednisone is permitted up to 10 mg oral daily (or equivalent dose of other oral glucocorticoid) at study entry. The prednisone dose cannot be tapered prior to the assessment of the primary endpoint at week 16. Prednisone can be tapered between weeks 16 to 30 if the subject is in remission (SDAI≤3.3). Prednisone can be tapered at the investigator's discretion and according to subject preferences, but it is recommended to be not faster than decreasing the daily dose by 2.5 mg every two weeks for subjects taking prednisone 5-10 mg/day, and not faster than 1 mg every 2 weeks for subjects taking prednisone 1-5 mg/day. One course of oral prednisone can be used to treat conditions other than RA, provided the dose does not exceed 40 mg daily and the duration is <2 weeks. This course of prednisone cannot occur within weeks 12-16 or weeks 36-40. One intra-articular or bursa injection of glucocorticoids is permitted after the assessment of the primary endpoint between weeks 16-32, provided the dose does not exceed 40 mg of triamcinolone (or equivalent dose of another injectable glucocorticoid).
Use of non-steroidal anti-inflammatory medications is permitted. While not prohibited, use of herbal remedies is discouraged and should be discussed with the site investigator. SARS-CoV-2 vaccines approved by the FDA or available under Emergency Use Authorization are considered to be permitted concomitant treatments. Subjects are instructed not to take any new medications or over-the-counter products without first consulting with the site investigator unless the medications are prescribed by a healthcare provider for another medical condition that develops or worsens during the study.
No prophylactic medications are required by this protocol. It is recommended that subjects be up-to-date with their recommended vaccinations at least 2 weeks prior to study entry, since VIB4920 may decrease responses to vaccinations. It is recommended that subjects do not receive non-live vaccines from the start of screening (Visit −1) to the end of study drug treatment (week 16). Completion of SARS-CoV-2 vaccination at least 2 weeks prior to study screening is recommended for all subjects willing and able to receive the vaccine.
The following medications and procedures are prohibited: Any investigational drug or treatment other than VIB4920, Live-attenuated vaccines, Concurrent use of methotrexate and leflunomide, Injection of corticosteroids into joints or bursae, except as permitted after the assessment of the primary endpoint and between weeks 16-32, Intravenous glucocorticoids, unless used to treat infusion reactions, Intramuscular injections of glucocorticoids, Oral prednisone at doses or duration greater than herein described, Addition of a new treatment or increase in dose of current disease modifying therapy to treat RA except as specified herein, Plasmapheresis or plasma exchange, any other medication that fulfills exclusion criteria described herein.
(1) Informed consent: Written informed consent is obtained before any study assessments or procedures are performed. (2) Eligibility criteria: Eligibility for study participation is assessed during the screening period. (3) Demographics: age, gender and ethnicity. (4) Medical history: A history is taken to determine if the subject has had any clinically significant diseases or medical procedures other than the disease under study. (5) Rheumatoid arthritis history, including date of diagnosis and previous treatments. (6) Comprehensive physical examination includes body systems: musculoskeletal, respiratory, cardiovascular, gastrointestinal, skin, neurologic and renal/urinary. (7) Limited physical examination focuses on the musculoskeletal exam and body systems relevant to the subject's clinical complaints and clinical status at the study visit. (8) Adverse events: Subjects are assessed for adverse events. All adverse events are graded, recorded on the case report forms (CRFs). (9) Concomitant medications: All concomitant medications and their indications are recorded. (10) Vital signs: Height and weight are obtained at screening (V-1); weight, temperature, blood pressure, respiration, and pulse are obtained at all visits. Temperature, blood pressure, respiration, and pulse are obtained prior to VIB4920/VIB4920 placebo infusion, and approximately every 30 minutes (±5 min) during study drug administration and for 2 hours after completion of the first 3 infusions, and for 1 hour after completion of the remaining infusions.
(1) Hematology: CBC with differential. (2) Chemistry: Creatinine, total bilirubin, AST, ALT, alkaline phosphatase, and albumin. (3) Inflammatory markers: Erythrocyte sedimentation rate, C-reactive protein. (4) HIV (RNA or antibody). (5) Hepatitis B (surface antigen, core antibody). (6) Hepatitis C (RNA or antibody). (7) Tuberculosis testing: QuantiFERON-TB Gold, QuantiFERON-TB Gold Plus, or T-SPOT.TB test. PPD skin test for participants with an indeterminate QuantiFERON-TB Gold, QuantiFERON-TB Gold Plus, or T-SPOT.TB test, if not performed within the past 3 months. AP and lateral chest radiograph for subjects with an indeterminate QuantiFERON-TB Gold, QuantiFERON-TB Gold Plus, or T-SPOT.TB test, if not performed within the past 3 months. (8) Anti-phospholipid antibodies (anti-cardiolipin IgG, IgM, and IgA; anti-beta2-glycoprotein I IgG, IgM, and IgA; lupus anticoagulant). (9) Rheumatoid factor (RF). (10) Anti-citrullinated peptide antibodies (ACPA). (11) Serum pregnancy (for women with childbearing potential). (12) STAT urine pregnancy (for women with childbearing potential). (13) PCR test for SARS-CoV-2 (or alternative viral test according to CDC guidance).
Adverse events are graded on a scale from 1 to 5 according to the following standards in the NCI-CTCAE manual: Grade 1=mild adverse event. Grade 2=moderate adverse event. Grade 3=severe adverse event. Grade 4=life-threatening adverse event or urgent intervention indicated. Grade 5=death.
For this study, liver chemistry abnormalities are graded using protocol specific criteria, and are defined relative to the upper limit of normal (ULN) as follows:
(1) Tender and swollen joint count: 44 joint count. (2) Subject global health assessment. (3) Health care provider global health assessment. (4) Visual analog pain scale. (5) Health Assessment Questionnaire—Disability Index (HAQ-DI, see
The following samples are collected for mechanistic assessments: Clinic collection: Plasma PK, anti-drug antibody, and sCD40L assays, Serum PK assays, Peripheral blood mononuclear cells (PBMCs), Serum, Whole blood DNA, Whole blood RNA, Whole blood RNA-microcontainer. Home collection after week 16 and through week 40 by subject: Whole blood RNA-microcontainer.
Serial blood specimens are collected to interrogate mechanisms of tolerance induction and maintenance. The objectives are to determine how the addition of VIB4920 to TNF-α inhibition affects the frequencies, phenotypes, and functional profiles of relevant T cell, B cell and myeloid cell populations in blood, and to quantify soluble mediators in serum and plasma associated with RA and the blockade of CD40:CD40L signaling. These studies explore immune signatures that correlate with clinical response outcomes.
Flow cytometry, mass cytometry, CITE-seq, single cell or bulk RNAseq, ATACseq, and DNA methylation sequencing are done at ITN laboratories to determine how the addition of VIB4920 to a TNFi affects the frequency, phenotype, gene expression, and functional status of specific immune cell populations in viably cryopreserved PBMC. In addition, functional status of various cell subsets may be examined by in vitro culture. To investigate oligoclonality of purified T cells and B cells, DNA and/or RNA encoding the T cell receptor and B cell receptor, respectively are sequenced. Profiles of circulating cells are compared between the baseline and various time points following treatment.
Additional comparisons may be made between treatment groups to evaluate the effect of treatment on specific cell phenotypes and profiles and to identify phenotypes and/or profiles that correlate with clinical outcomes. The following cellular parameters may be interrogated to determine the effects of VIB4920 or placebo in RA subjects that have responded inadequately to TNF-α inhibition:
Subject serum and plasma are collected and stored for longitudinal analyses using validated platforms to determine how addition of VIB4920 or VIB4920 placebo affects RA in subjects that have responded inadequately to TNFi therapy. Soluble factors that may be examined include: (1) Levels of antibodies or autoantibodies, such as rheumatoid factor and anti-cyclic citrullinated peptide antibody (ACPA). (2) Levels of sCD40L. (3) Levels of anti-drug antibodies targeting adalimumab, etanercept, and VIB4920. (3) Levels of VIB4920. (4) Levels of adalimumab or etanercept as applicable. (5) Levels of CXCL13, sICAM, and any other relevant soluble mediators (e.g., IL-21, IL-10, IL-2, IL-17A, IFNγ, etc.).
Levels of soluble immune parameters may be compared between the baseline and time points following treatment. Comparisons may be made between treatment groups to evaluate the effect of the therapeutic intervention on changes in circulating levels of soluble immune parameters. In addition, the relationship between baseline sICAM and CXCL13 levels and treatment response is determined. The impact of coadministration of TNFi and VIB4920 on the drug levels of VIB4920 and adalimumab or etanercept may be assessed using parameters such as AUC, Cmax, and t1/2 (half-life). Finally, levels of soluble immune parameters may also be evaluated for associations with frequency, phenotype, and/or functional profile of circulating cells, such as T cell, B cell and myeloid populations
RNA: Systemic treatment with biologic medications has been shown to modulate gene expression in autoimmune disease; therefore, whole blood can be used to evaluate changes in the transcriptional signatures of circulating immune cells related to the experimental intervention, namely VI1B4920. Whole blood is collected and may be used to evaluate gene expression profiles before, during, and after treatment. Gene expression of molecules found to be modulated by treatment in blood leukocytes may be investigated in whole blood using quantitative methods.
In the current study, whole blood is collected in clinic at week 16 and then weekly at home (“dense sampling collection”) from week 17 through week 40 by subjects who achieve the primary endpoint at week 16 (SDAI≤11). These samples are used to examine gene expression signatures of various cell types and their changes over time, as well as to explore whether the circulating fibroblast and activated B cell gene signatures detected shortly before a disease flare as assessed by RAPID3.
DNA: Specific CD40 alleles are associated with RA risk and B cells homozygous for the CD40 risk allele display increased surface expression of CD40 compared to their non-risk allele counterparts. Thus, genetic differences may, in part, determine response to CD40L blockade with V1B4920. DNA is collected from all consenting subjects, and ITN may perform genotyping or sequencing of relevant disease- or immune-associated genes, such as HLA Class I/II alleles, genes with reported associations to RA, or genes related to the CD40L-CD40 pathway to investigate correlations with disease activity and therapeutic response. Similarly, whole blood may be used to examine epigenetic status of relevant disease- or immune-associated genes and to investigate relationships between epigenetics and disease activity or therapeutic response.
1Unscheduled visit
2Treatment Modification or Study Discontinuation visit. If treatment modification or intent to discontinue the study is identified during an in-person visit, convert that visit to a Treatment Modification Visit or Study Discontinuation visit. . If treatment modification or intent to discontinue the study is identified between in-person visits, then schedule the Treatment Modification or Study Discontinuation Visit for the next scheduled in-person visit
3Vitals monitored as described herein
4Assessed by blinded evaluator
5For participants with indeterminate QuantiFERON-TB Gold, QuantiFERON-TB Gold Plus or T-SPOT.TB tests: 1) PPD skin test, if not performed within the past 3 months; 2) AP and lateral chest radiograph, if not performed within the past 3 months
6For women with childbearing potential
7Plasma and serum samples for PK collected pre-infusion and within 15 min +/− 5 min minutes post-infusion
8Unscheduled visit.
9Treatment Modification or Study Discontinuation visit. If treatment modification or intent to discontinue the study is identified during an in person visit, convert that visit to a Treatment Modification Visit or Study Discontinuation visit. If treatment modification or intent to discontinue the study is identified between in-person visits, then schedule the Treatment Modification or Study Discontinuation Visit for the next scheduled in-person visit.
10Unscheduled visit.
11Study Discontinuation visit. If intent to discontinue the study is identified during an in person visit, convert that visit to a Study Discontinuation visit. If intent to discontinue the study is identified between in-person visits, then schedule the Study Discontinuation Visit for the next scheduled in-person visit.
12Adverse event monitoring will assess grade 2 or higher adverse events that receive medical attention and AESIs.
All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.
The present application is a continuation of International Application No. PCT/US2022/077192, filed Sep. 28, 2022, which claims priority to U.S. Provisional Patent Application No. 63/337,274, filed May 2, 2022, U.S. Provisional Patent Application No. 63/322,379, filed Mar. 22, 2022, and U.S. Provisional Patent Application No. 63/249,552, filed Sep. 28, 2021, each of which is incorporated by reference herein in their entirety for all purposes.
| Number | Date | Country | |
|---|---|---|---|
| 63249552 | Sep 2021 | US | |
| 63322379 | Mar 2022 | US | |
| 63337274 | May 2022 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | PCT/US2022/077192 | Sep 2022 | WO |
| Child | 18615679 | US |
