Patent Application
20230302085
The sequence listing of the present application is submitted electronically as an ASCII formatted sequence listing with a file name “10861WO01-Sequence”, creation date of May 16, 2022, and a size of 6,006 bytes. This sequence listing submitted is part of the specification and is herein incorporated by reference in its entirety.
The field of the present invention relates to methods for treating or preventing angiogenic eye disorders by administering a VEGF antagonist.
Neovascular (wet) AMD (nAMD) is a major health issue in aging populations globally. Vision loss in nAMD results from the abnormal growth and leakage of blood vessels in the macula. In elderly patients affected by nAMD, vision loss frequently has an even greater impact, as it substantially reduces the visual compensation of functional impairment by other age-related comorbidities, such as arthritis and osteoporosis.
Intravitreally (IVT) administered anti-vascular endothelial growth factor (VEGF) therapies like EYLEA® inhibit neovascular vessel growth and leakage in the retina, and they are currently the standard-of-care for patients with nAMD. They not only maintain visual function but also provide clinically meaningful visual gains. Treatment of nAMD is chronic and life-long in most patients to suppress retinal edema and recurrences of choroidal neovascularization (CNV). Although the currently approved IVT anti-VEGF therapies are efficacious and well-tolerated, the need for IVT injections every 4 to 8 weeks, specifically in the initial phase and during maintenance of treatment, represents a significant burden to physicians, patients, and caregivers. While the procedure is straightforward and relatively easy to perform, capacity issues for ensuring an appropriate injection frequency in order to achieve patient outcomes similar to those seen in the pivotal studies represent an increasing challenge to individual practices and the healthcare system, overall. Moreover, high frequency dosing leads to increased burdens on patients, e.g., to find transportation and miss work. A secondary effect of this burden is a lower probability of non-compliance with the prescribed treatment regimen.
While the efficacy and safety of currently approved VEGF antagonist therapies have been established for the treatment of nAMD, there remains an unmet medical need for the development of therapies with the potential to reduce treatment burden while providing at least similar or even improved visual outcomes over currently available standard-of-care.
EYLEA (2 mg dose, administered at a concentration of 40 mg/mL, also called intravitreal aflibercept injection [IAI]) is currently approved in the United States (US) for the treatment of nAMD, and is also approved for the treatment of macular edema following retinal vein occlusion (RVO), diabetic macular edema (DME), and diabetic retinopathy (DR).
The present invention provides a method for treating or preventing an angiogenic eye disorder (e.g., neovascular age-related macular edema (nAMD), diabetic macular edema (DME), diabetic retinopathy (DR), macular edema (ME) secondary to retinal vein occlusion (RVO) (ME-RVO), in a subject in need thereof, comprising administering to an eye of the subject (e.g., by intravitreal injection), e.g., in about 70 μl, a single initial dose of about 8 mg or more of a VEGF antagonist (e.g., aflibercept) to an eye of the subject, followed by one or more secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF antagonist; wherein each secondary dose is administered about 2 to 4 or 3 to 5 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 4, 8 or 12 weeks after the immediately preceding dose.
In an embodiment of the invention, wherein, e.g., while receiving such a regimen: (i) with respect to visual acuity or best corrected visual acuity (BCVA), the subject achieves: no loss in visual acuity or BCVA; a gain in visual acuity or BCVA; no loss of visual acuity or BCVA by about week 4, 8, 9, 12, 16, 20, 24, 28, 32, 36, 40 or 44, following the initial dose wherein visual acuity or BCVA is according to ETDRS or the Snellen equivalent; no loss of visual acuity or BCVA of about 5 or more, about 10 or more, or about 15 or more letters by about week 4, 8, 9, 12, 16, 20, 24, 28, 32, 36, 40 or 44, following the initial dose wherein visual acuity or BCVA is according to ETDRS or the Snellen equivalent; a gain in visual acuity or BCVA, of about 5 or more, about 10 or more or about 15 or more letters, by about week 4, 8, 9, 12, 16, 20, 24, 28, 32, 36, 40 or 44 following the initial dose, wherein visual acuity or BCVA is according to ETDRS or the Snellen equivalent; and/or a gain in visual acuity or BCVA of about 6 or 7 or 8 letters by about week 8 and maintaining a gain of about 6 or 7 or 8 letters until at least about week 44 wherein visual acuity or BCVA is according to ETDRS or the Snellen equivalent; (ii) with respect to central retinal thickness (CRT), the subject achieves: a decrease in central retinal thickness; a decrease in central retinal thickness by at least about 123, 125, 131, 142, 147, 149, 150, 151, 156, 157, 158, 159, 161, 162, 166, 167, 168, 172, 173, 175, 177, 178 or 183 micrometers (μm) by about week 4, 8, 9, 12, 16, 20, 24, 28, 32, 36, 40 or 44 following the initial dose; a decrease in central retinal thickness of about 47 micrometers from about week 12 to about week 20 following the initial dose; a decrease in central retinal thickness of about 17 micrometers from about week 24 to about week 32 following the initial dose; a decrease in central retinal thickness of about 18 micrometers from about week 36 to about week 44 following the initial dose; a decrease in central retinal thickness of about 123, 131 161 micrometers by about week 4, 8, 12, 16 or 20 following the initial dose and maintaining the decrease until at least about week 44 following the initial dose; and/or a reduction in CRT of about 159, 160, 161 or 162 micrometers by about week 4 or 8 or 12 and maintaining a reduction of about 159, 160, 161 or 162 micrometers until at least about week 44; (iii) with respect to retinal fluid, the subject achieves: a dry retina having no intraretinal fluid and no subretinal fluid; or no intraretinal fluid; or no subretinal fluid; in the center subfield or macula as measured by spectral domain optical coherence tomography; a dry retina having no intraretinal fluid and no subretinal fluid; or no intraretinal fluid; or no subretinal fluid; in the center subfield as measured by spectral domain optical coherence tomography by about week 4, 8, 9, 12, 16, 20, 24, 28, 32, 36, 40 or 44, following the initial dose; no SRF and IRF in the macula as measured by SD-OCT by week 16 or week 44 following the initial dose; no sub-retinal pigment epithelium (RPE) fluid until at least about week 44 following the initial dose as measured by spectral domain optical coherence tomography; and/or maintenance of a dry retina once achieved until at least about week 44 following the initial dose as measured by spectral domain optical coherence tomography; and/or (iv) the subject achieves: a reduction in total choroidal neovascularization (CNV) lesion size by at least about 3.2 or 3.3 μm by about week 4, 8, 9, 12, 16, 20, 24, 28, 32, 36, 40 or 44 following the initial dose; no significant increase in intraocular pressure from baseline by about week 4, 8, 9, 12, 16, 20, 24, 28, 32, 36, 40 or 44 or later following the initial dose; and/or no significant increase in systolic (S) and/or diastolic (D) blood pressure from baseline by about week 4, 8, 9, 12, 16, 20, 24, 28, 32, 36, 40 or 44 or later following the initial dose. The scope of the present invention also encompasses methods for achieving any of such achievements in a subject in need thereof who is suffering from an angiogenic eye disorder, by administering the dosing regimen set forth above. For example, in an embodiment of the invention, the method for treating or preventing an angiogenic eye disorder (e.g., neovascular age-related macular edema, diabetic retinopathy, diabetic macular edema or macular edema following retinal vein occlusion (RVO)) includes administering a single initial dose of VEGF antagonist (e.g., aflibercept), followed by one or more secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF antagonist; wherein each secondary dose is administered about 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 4, 8 or 12 weeks after the immediately preceding dose. In an embodiment of the invention, relative to a subject receiving such a dosing regimen, except that only 2 mg of VEGF antagonist is administered, the subject receiving 8 mg of VEGF antagonist exhibits a greater decrease in central retinal thickness after 4, 8, 12, 16 or more weeks; a greater improvement in best corrected visual acuity after 4, 8, 12, 16 or more weeks; and/or a greater likelihood of having a dry retina (e.g., lacks intraretinal fluid and/or subretinal fluid) after 4, 8, 12, 16 or more weeks. In an embodiment of the invention, 2-4 weeks is 2, 3 or 4 weeks. The present invention further provides a method for improving best corrected visual acuity, decreasing central retinal thickness and/or achieving a dry retina, in the eye of a subject (e.g., suffering from neovascular age-related macular edema, diabetic retinopathy, diabetic macular edema or macular edema following retinal vein occlusion (RVO)) in need thereof, comprising administering to the eye of the subject, a single initial dose of about 8 mg or more of a VEGF antagonist (e.g., aflibercept) to an eye of the subject, followed by one or more secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF antagonist; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 4, 8 or 12 weeks after the immediately preceding dose. Also provided by the present invention is a method for promoting retinal drying, in the eye of a subject suffering from an angiogenic eye disorder (e.g., neovascular age-related macular edema, diabetic retinopathy, diabetic macular edema or macular edema following retinal vein occlusion (RVO)), comprising administering to the eye of the subject, a single initial dose of about 8 mg or more of a VEGF antagonist, followed by one or more secondary doses of about 8 mg or more of the VEGF antagonist, followed by one or more tertiary doses of about 8 mg or more of the VEGF antagonist; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 4, 8 or 12 weeks after the immediately preceding dose; for example, wherein retinal drying is characterized by no intraretinal fluid (IRF) and/or no subretinal fluid (SRF) in the eye of the subject, e.g., after the subject has received the three monthly doses of the VEGF antagonist. In an embodiment of the invention, the VEGF antagonist is:
(i) a VEGF receptor fusion protein, for example, comprising two polypeptides that comprise
(1) a VEGFRI component comprising amino acids 27 to 129 of SEQ ID NO: 2; (2) a VEGFR2 component comprising amino acids 130-231 of SEQ ID NO: 2; and (3) a multimerization component comprising amino acids 232-457 of SEQ ID NO: 2;
(ii) a VEGF receptor fusion protein comprising two polypeptides that comprise immunoglobin-like (Ig) domain 2 of a VEGFRI and Ig domain 3 of VEGFR2, and a multimerizing component;
(iii) a VEGF receptor fusion protein comprising two polypeptides that comprise an immunoglobin-like (Ig) domain 2 of VEGFRI, an Ig domain 3 of VEGFR2, an Ig domain 4 of said VEGFR2; and a multimerizing component;
(iv) a VEGF receptor fusion protein comprising two VEGFR1R2-FcAC1(a) polypeptides encoded by the nucleic acid sequence of SEQ ID NO: 1; or
(v) selected from the group consisting of: aflibercept, conbercept, bevacizumab, ranibizumab, pegaptanib, brolucizumab, an anti-VEGF DARPin, abicipar pegol, faricimab, an anti-VEGF antibody or antigen-binding fragment thereof or biopolymer conjugate thereof (e.g., KSI-301), bevacizumab, ranibizumab and a bispecific anti-VEGF/ANG2 antibody.
In an embodiment of the invention, the VEGF antagonist is administered to the eye of the subject in a pharmaceutical formulation, for example, which is selected from the group consisting of A-KKKK as so designated herein. In an embodiment of the invention, the VEGF antagonist is administered to the eye from a syringe, e.g., a pre-filled syringe, (e.g., which is glass, plastic and/or sterile). In an embodiment of the invention, the syringe is characterized by the ornamental design as set forth in International Design Registration No. DM/212 509; which is herein incorporated by reference.
In an embodiment of the invention, a dosage of about 8 mg or more is a dose of about 9, 9.3, 9.33, 9.7, 9.8, 9.9, 9.7-9.9 mg or more and such a dosage amount may vary within a given range, e.g., ±about 0.5, or ±about 0.51 mg. The volume in which a dose is delivered can be, for example, about 70, 81, 82, 81.7, 85, 86, 87, 85-87 microliters and the volume may vary within a given range, e.g., ±about 4, 4.45, 4.5, or 5 microliters. Doses may be delivered with a dose delivery device (DDD) which is a syringe.
Highly precise doses of VEGF antagonist (e.g., aflibercept) may be delivered, for example, in a volume that is device-determined. In an embodiment of the invention, a dose is delivered with a syringe by a method that includes the steps: (a) withdrawing a plunger rod of the syringe to fill the syringe with the formulation; (b) priming the syringe, thereby removing air from the syringe and, thus avoiding injection of air into the eye, by advancing the plunger rod by a predetermined distance into the syringe body until advancement of the plunger rod is resisted by a stop; (c) rotating the plunger rod about a longitudinal axis; and (d) actuating the plunger rod to dispense a predetermined (device-determined) volume (e.g., about 70, 81, 82, 81.7, 85, 86, 87, 85-87 microliters, ±about 4, 4.45, 4.5, or 5 microliters) of the formulation.
Increasing the molar fraction of VEGF antagonist therapeutic protein in the dosing formulation is a potential way to bring further benefits to patients with chorioretinal vascular diseases, including nAMD. A higher dose of aflibercept administered IVT has the potential to prolong the drug's therapeutic effects and for improvement in pharmacodynamics such as better drying. The resulting extension of treatment intervals early after the initiation of treatment to every 12 weeks would reduce the number of injections in the first treatment year. A potential decrease in injection-related treatment burden and safety events with fewer injections could be a significant contribution to patient care and healthcare services. The present invention provides, in part, a safe and effective method for treating angiogenic eye disorders with an 8 mg dose of aflibercept in a regimen calling for monthly loading doses before quarterly maintenance doses. First, patients receiving an 8 mg dose, which is four times the dose approved for Eylea, (2 mg), were not observed in the CANDELA clinical trial (discussed herein) to develop any more hypertension treatment-emergent adverse events than patients receiving 2 mg (
The anatomical and visual improvements for the HD patients that was observed was also comparable to those of subjects in the VIEW1 and VIEW2 trials (VIEW1/2) that received a 2 mg dose every 8 weeks (following three monthly loading doses (2q8)). See e.g., Heier et al., Intravitreal Aflibercept (VEGF Trap-Eye) in Wet Age-related Macular Degeneration, Ophthalmology 2012;119:2537-2548. The VI EW1/2 2q8 subjects achieved 8.1 letters of BCVA mean improvement at 44 weeks following the initial dose (Heier et al. (2012),
“Isolated” VEGF antagonists and VEGF receptor fusion proteins (e.g., aflibercept), polypeptides, polynucleotides and vectors, are at least partially free of other biological molecules from the cells or cell culture from which they are produced. Such biological molecules include nucleic acids, proteins, other VEGF antagonists and VEGF receptor fusion proteins, lipids, carbohydrates, or other material such as cellular debris and growth medium. An isolated VEGF antagonist or VEGF receptor fusion protein may further be at least partially free of expression system components such as biological molecules from a host cell or of the growth medium thereof. Generally, the term “isolated” is not intended to refer to a complete absence of such biological molecules (e.g., minor or insignificant amounts of impurity may remain) or to an absence of water, buffers, or salts or to components of a pharmaceutical formulation that includes the VEGF antagonists or VEGF receptor fusion proteins.
A “subject” or “patient” is a mammal, for example a human, mouse, rabbit, monkey or non-human primate. A subject or patient may be said to be “suffering from” an angiogenic eye disorder such as nAMD, DR or DME. Such a subject has the disorder in one or both eyes. In an embodiment of the invention, a subject or patient has one or more of the following characteristics (at or before the start of treatment):
1. ≥50 years of age
2. Subfoveal CNV secondary to nAMD, e.g., including juxtafoveal lesions that affect the fovea in an eye.
3. Best Corrected Visual Acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 78 to 24 (Snellen equivalent of 20/32 to 20/320) in an eye; or about 58±10, 58±14 or 58±12 ETDRS letters (or Snellen equivalent).
4. A central retinal thickness in an eye greater than normal, e.g., greater than approximately 130, 140, 150, 160, 170 or 180 micrometers, e.g., as determined manually or by optical coherence tomography (OCT) mapping software, for example with a central retinal thickness of about 300, 400, 500 or 600 micrometers or more; or about 488.1±204.9, 516.2±175.64 or 502.1±190.6 micrometers.
5. Intraocular pressure of about 14.8±3.4 or 14.9±3.4 mmHg.
6. nAMD lesion size of about 7.9±6.21, 7.7±6.84 or 7.8±6.50 mm2.
7. Choroidal neovascularization lesion size of about 7.9±6.20, 7.5±6.86 or 7.7±6.51 mm2.
8. As per fluorescein angiography (FA), has occult choroidal neovascularization, minimally classic choroidal neovascularization or predominantly classic choroidal neovascularization. and/or, has or lacks any one or more of the following characteristics:
1. CNV (choroidal neovascularization) due to any cause other than nAMD in either eye.
2. Subretinal hemorrhage in an eye that is 50% of the total lesion area.
3. Intraocular pressure 25 mm Hg in an eye.
4. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in an eye.
5. Any intraocular inflammation and/or ocular infection in an eye.
6. Any history of macular hole of stage 2 and above in an eye.
7. Iris neovascularization, vitreous hemorrhage, or tractional retinal detachment visible in an eye.
8. Uncontrolled blood-pressure (BP) (defined as systolic >140 mm Hg or diastolic >90 mm Hg).
9. Variation by more than 10% in the 3 pre-randomization BP measurements.
10. History of cerebrovascular accident/ transient ischemic attack or myocardial infarction/acute coronary syndrome.
11. Renal failure, dialysis, or history of renal transplant.
12. Known sensitivity to aflibercept.
13. Any other intraocular surgery within 12 weeks (84 days).
The present invention includes methods for using a VEGF antagonist for treating or preventing angiogenic eye disorders. VEGF antagonists include molecules which interfere with the interaction between VEGF and a natural VEGF receptor, e.g., molecules which bind to VEGF or a VEGF receptor and prevent or otherwise hinder the interaction between VEGF and a VEGF receptor. Specific, exemplary VEGF antagonists include anti-VEGF antibodies, anti-VEGF receptor antibodies, and VEGF receptor fusion proteins.
For purposes herein, a “VEGF receptor fusion protein” refers to a molecule that comprises one or more VEGF receptors or domains thereof, fused to another polypeptide, which interferes with the interaction between VEGF and a natural VEGF receptor, e.g., wherein two of such fusion polypeptides are associated thereby forming a homodimer or other multimer. Such VEGF receptor fusion proteins may be referred to as a “VEGF-Trap” or “VEGF Trap”. VEGF receptor fusion proteins within the context of the present disclosure that fall within this definition include chimeric polypeptides which comprise two or more immunoglobulin (Ig)-like domains of a VEGF receptor such as VEGFRI (also known as Flt1) and/or VEGFR2 (also known as Flk1 or KDR), and may also contain a multimerizing domain (for example, an Fc domain).
An exemplary VEGF receptor fusion protein is a molecule referred to as VEGF1R2-FcΔC1(a) which is encoded by the nucleic acid sequence of SEQ ID NO:1 or nucleotides 79-1374 or 79-1371 thereof.
VEGF1R2-FcΔC1(a) comprises three components:
(1) a VEGFRI component comprising amino acids 27 to 129 of SEQ ID NO:2;
(2) a VEGFR2 component comprising amino acids 130 to 231 of SEQ ID NO:2; and
(3) a multimerization component (“FcΔC1(a)”) comprising amino acids 232 to 457 of SEQ ID NO:2 (the C-terminal amino acids of SEQ ID NO:2, i.e., K458, may or may not be included in the VEGF receptor fusion proteins, see U.S. Pat. No. 7,396,664 or 7,354,579, incorporated herein for all purposes). Note that amino acids 1 to 26 of SEQ ID NO:2 are the signal sequence.
If the multimerizing component (MC) of a VEGF receptor fusion protein is derived from an IgG (e.g., IgG1) Fc domain, then the MC has no fewer amino acids than are in amino acids 232 to 457 of SEQ ID NO:2. Thus, the IgG of the MC cannot be truncated to be shorter than 226 amino acids.
In an embodiment of the invention, the VEGF receptor fusion protein comprises amino acids 27-458 or 27-457 of SEQ ID NO: 2.
MVSYWDTGVLLCALLSCLLLTGSSSGSDTGRPFVEMYSEIPEIIHMTEGR
In an embodiment of the invention, aflibercept is N-glycosylated at any one or more of Asparagines 62, 94, 149, 222 and 308.
In an embodiment of the invention, the VEGF receptor fusion protein comprises
(1) an immunoglobin-like (Ig) domain 2 of a first VEGF receptor (e.g., VEGFRI), and
(2) an Ig domain 3 of a second VEGF receptor (e.g., VEGFR2),
(3) and, optionally, further including an Ig domain 4 of the second VEGF receptor (e.g., VEGFR2) and
(4) a multimerizing component (e.g., Fc domain of IgG including the hinge, CH2 and CH3 domains).
For example, in an embodiment of the invention, the VEGF receptor fusion protein has the following arrangement of said domains:
Note that the present disclosure also includes, within its scope, high concentration formulations including, instead of a VEGF receptor fusion protein, a VEGF binding molecule or anti-VEGF antibody or antigen-binding fragments thereof or biopolymer conjugate thereof (e.g., KSI-301) and uses thereof as discussed, e.g.,
In order to minimize the repetitiveness of the embodiments discussed herein, it is contemplated that the scope of the present invention includes embodiments wherein any of the formulations discussed herein include, in place of a VEGF receptor fusion protein, an anti-VEGF antibody or antibody fragment or other VEGF binding molecule as discussed herein (e.g., substituted with an anti-VEGF DARPin) at any of the concentrations discussed herein. For example, the present invention includes a formulation having 35 or 80 mg/ml ranibizumab, a buffer, a thermal stabilizer, a viscosity reducing agent and a surfactant.
DARPins are Designed Ankyrin Repeat Proteins. DARPins generally contain three to four tightly packed repeats of approximately 33 amino acid residues, with each repeat containing a p-turn and two anti-parallel a-helices. This rigid framework provides protein stability whilst enabling the presentation of variable regions, normally comprising six amino acid residues per repeat, for target recognition.
An “anti-VEGF” antibody or antigen-binding fragment of an antibody refers to an antibody or fragment that specifically binds to VEGF.
Illustrative VEGF receptor fusion proteins include aflibercept (EYLEA®, Regeneron Pharmaceuticals, Inc.) or conbercept (sold commercially by Chengdu Kanghong Biotechnology Co., Ltd.). See International patent application publication no. WO2005/121176 or WO2007/112675. The terms “aflibercept” and “conbercept” include biosimilar versions thereof. A biosimilar version of a reference product (e.g., aflibercept) generally refers to a product comprising the identical amino acid sequence but includes products which are biosimilar under the U.S. Biologics Price Competition and Innovation Act.
The present invention includes methods in which the VEGF antagonist (e.g., aflibercept) that is administered to the patient's eye is contained within a pharmaceutical formulation. The pharmaceutical formulation includes a VEGF antagonist along with a pharmaceutically acceptable carrier. Other agents may be incorporated into the pharmaceutical formulation to provide improved transfer, delivery, tolerance, and the like. The term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly, in humans. The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the VEGF antagonist is administered. A multitude of appropriate formulations can be found in the formulary known to all pharmaceutical chemists: Remington's Pharmaceutical Sciences (15th ed, Mack Publishing Company, Easton, Pa., 1975), e.g., Chapter 87 by Blaug, Seymour, therein.
Pharmaceutical formulations for use in a method of the present invention can be “high concentration”. High concentration pharmaceutical formulations of the present invention include VEGF antagonist, e.g., VEGF receptor fusion protein (e.g., aflibercept), at a concentration of greater than 40 mg/ml, at least 41 mg/ml, of at least 80 mg/ml, of at least 100 mg/ml, of at least 125 mg/ml, of at least 140 mg/ml, of at least 150 mg/ml, of at least 175 mg/ml, of at least 200 mg/ml, of at least 225 mg/ml, of at least 250 mg/ml, or of at least 275 mg/ml. “High concentration” can refer to formulations that include a concentration of VEGF antagonist of from about 140 mg/ml to about 160 mg/ml, at least about 140 mg/ml but less than 160 mg/ml, from about 41 mg/ml to about 275 mg/ml, from about 70 mg/ml to about 75 mg/ml or from about 80 mg/ml to about 250 mg/ml. In some aspects, the VEGF antagonist concentration in the formulation is about any of the following concentrations: 41 mg/ml; 42 mg/ml; 43 mg/ml; 44 mg/ml; 45 mg/ml; 46 mg/ml; 47 mg/ml; 48 mg/ml; 49 mg/ml; 50mg/ml; 51 mg/ml; 52 mg/ml; 53 mg/ml; 54 mg/ml; 55 mg/ml; 56 mg/ml; 57 mg/ml; 58 mg/ml; 59 mg/ml; 60 mg/ml; 61 mg/ml; 62 mg/ml; 63 mg/ml; 64 mg/ml; 65 mg/ml; 66 mg/ml; 67 mg/ml; 68 mg/ml; 69 mg/ml; 70 mg/ml; 71 mg/ml; 72 mg/ml; 73 mg/ml; 74 mg/ml; 75 mg/ml; 76 mg/ml; 77 mg/ml; 78 mg/ml; 79 mg/ml; 80 mg/ml; 81 mg/ml; 82mg/ml; 83 mg/ml; 84 mg/ml; 85 mg/ml; 86 mg/ml; 87mg/ml; 88 mg/ml; 89 mg/ml; 90 mg/ml; 91 mg/ml; 92 mg/ml; 93 mg/ml; 94 mg/ml; 95mg/ml; 96 mg/ml; 97 mg/ml; 98 mg/ml; 99 mg/ml; 100 mg/ml; 101 mg/ml; 102 mg/ml; 103 mg/ml; 104 mg/ml; 105 mg/ml; 106mg/ml; 107 mg/ml; 108 mg/ml; 109 mg/ml; 110 mg/ml; 111 mg/ml; 112 mg/ml; 113 mg/ml; 113.3 mg/ml; 114 mg/ml; 114.1 mg/ml; 114.2 mg/ml; 114.3 mg/ml; 114.4 mg/ml; 114.5 mg/ml; 114.6 mg/ml, 114.7 mg/ml, 114.8 mg/ml; 114.9 mg/ml; 115 mg/ml; 116 mg/ml; 117 mg/ml; 118 mg/ml; 119 mg/ml; 120 mg/ml; 121 mg/ml; 122 mg/ml; 123 mg/ml; 124 mg/ml; 125 mg/ml; 126 mg/ml; 127mg/ml; 128 mg/ml; 129 mg/ml; 130 mg/ml; 131 mg/ml; 132 mg/ml; 133 mg/ml; 133.3 mg/ml; 133.4 mg/ml, 134 mg/ml; 135 mg/ml; 136 mg/ml; 137 mg/ml; 138 mg/ml; 139 mg/ml; 140 mg/ml; 141 mg/ml; 142 mg/ml; 143 mg/ml; 144 mg/ml; 145 mg/ml; 146 mg/ml; 147 mg/ml; 148 mg/ml; 149 mg/ml; 150 mg/ml; 151 mg/ml; 152 mg/ml; 153 mg/ml; 154mg/ml; 155 mg/ml; 156 mg/ml; 157mg/ml; 158 mg/ml; 159 mg/ml; 160 mg/ml; 161 mg/ml; 162 mg/ml; 163 mg/ml; 164 mg/ml; 165 mg/ml; 166 mg/ml; 167 mg/ml; 168 mg/ml; 169 mg/ml; 170 mg/ml; 171 mg/ml; 172 mg/ml; 173 mg/ml; 174 mg/ml; 175 mg/ml; 176 mg/ml; 177 mg/ml; 178 mg/ml; 179 mg/ml; 180 mg/ml; 181 mg/ml; 182 mg/ml; 183 mg/ml; 184 mg/ml; 185 mg/ml; 186 mg/ml; 187 mg/ml; 188 mg/ml; 189 mg/ml; 190 mg/ml; 191 mg/ml; 192 mg/ml; 193 mg/ml; 194 mg/ml; 195 mg/ml; 196 mg/ml; 197 mg/ml; 198 mg/ml; 199 mg/ml; 200 mg/ml; 201 mg/ml; 202 mg/ml; 203 mg/ml; 204 mg/ml; 205 mg/ml; 206 mg/ml; 207 mg/ml; 208 mg/ml; 209 mg/ml; 210 mg/ml; 211 mg/ml; 212 mg/ml; 213 mg/ml; 214 mg/ml; 215 mg/ml; 216 mg/ml; 217 mg/ml; 218 mg/ml; 219 mg/ml; 220 mg/ml; 221 mg/ml; 222 mg/ml; 223 mg/ml; 224 mg/ml; 225 mg/ml; 226 mg/ml; 227 mg/ml; 228 mg/ml; 229 mg/ml; 230 mg/ml; 231 mg/ml; 232 mg/ml; 233 mg/ml; 234 mg/ml; 235 mg/ml; 236 mg/ml; 237mg/ml; 238 mg/ml; 239 mg/ml; 240 mg/ml; 241 mg/ml; 242 mg/ml; 243 mg/ml; 244 mg/ml; 245 mg/ml; 246 mg/ml; 247 mg/ml; 248 mg/ml; 249 mg/ml; 250 mg/ml; 251 mg/ml; 252 mg/ml; 253 mg/ml; 254 mg/ml; 255 mg/ml; 256 mg/ml; 257 mg/ml; 258 mg/ml; 259 mg/ml; 260 mg/ml; 261 mg/ml; 262 mg/ml; 263 mg/ml; 264 mg/ml; 265 mg/ml; 266 mg/ml; 267 mg/ml; 268 mg/ml; 269 mg/ml; 270 mg/ml; 271 mg/ml; 272 mg/ml; 273 mg/ml; 274 mg/ml; or 275 mg/ml. Other VEGF antagonist concentrations are contemplated herein, as long as the concentration functions in accordance with embodiments herein.
In an embodiment of the invention, a pharmaceutical formulation for use in a method of the present invention is of such a concentration as to contain about 4, 6, 8, 10, 12, 14, 16, 18 or 20 mg VEGF receptor fusion protein (e.g., aflibercept), or the amount of such protein in any of the acceptable doses thereof which are discussed herein, in about 100 μl or less, about 75 μl or less or about 70 μl or less, e.g., about 50 μI, 51 μI, 52 μI, 53 μI, 54 μl; 55 μl; 56 μl; 57 μl; 58 μl; 59 μl; 60 μl; 61 μl; 62 μl; 63 μl; 64 μl; 65 μl; 66 μl; 67 μl; 68 μl; 69 μl; 70 μl; 71 μl; 72 μl; 73 μl; 74 μl; 75 μl; 76 μl; 77 μl; 78 μl; 79 μl; 80 μl; 81 μl; 82 μl; 83 μl; 84 μl; 85 μl; 86 μl; 87 μl; 88 μl; 89 μl; 90 μl; 91 μl; 92 μl; 93 μl; 94 μl; 95 μl; 96 μl; 97 μl; 98 μl; 99 μl, or 100 μl.
The present invention includes methods of using (as discussed herein) any of the formulations set forth under “Illustrative Formulations” herein, but wherein the concentration of the VEGF receptor fusion protein (e.g., aflibercept) is substituted with a concentration which is set forth in this section (“VEGF Receptor Fusion Proteins and Other VEGF inhibitors”).
Buffers for use in pharmaceutical formulations herein that may be used in a method of the present invention refer to solutions that resist pH change by use of acid-base conjugates. Buffers are capable of maintaining pH in the range of from about 5.0 to about 6.8, and more typically, from about 5.8 to about 6.5, and most typically, from about 6.0 to about 6.5. In some cases, the pH of the formulation of the present invention is about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, or about 6.8. Example buffers for inclusion in formulations herein include histidine-based buffers, for example, histidine, histidine hydrochloride, and histidine acetate. Buffers for inclusion in formulations herein can alternatively be phosphate-based buffers, for example, sodium phosphate, acetate-based buffers, for example, sodium acetate or acetic acid, or can be citrate-based, for example, sodium citrate or citric acid. It is also recognized that buffers can be a mix of the above, as long as the buffer functions to buffer the formulations in the above-described pH ranges. In some cases, the buffer is from about 5 mM to about 25 mM, or more typically, about 5 mM to about 15 mM. Buffers can be about 5 mM, about 6 mM, about 7 mM, about 8 mM, about 9 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, or about 25 mM.
In an embodiment of the invention, a histidine-based buffer is prepared using histidine and histidine monohydrochloride.
Surfactant for use herein refers to ingredients that protect the higher concentration of VEGF antagonist, e.g., VEGF receptor fusion protein (e.g., aflibercept), from various surface and interfacial induced stresses. As such, surfactants can be used to limit or minimize VEGF receptor fusion protein aggregation and promote protein solubility. Suitable surfactants herein have been shown to be non-ionic, and can include surfactants that have a polyoxyethylene moiety. Illustrative surfactants in this category include: polysorbate 20, polysorbate 80, poloxamer 188, polyethylene glycol 3350, and mixtures thereof. Surfactants in the formulations can be present at from about 0.02% to about 0.1% weight per volume (w/v), and more typically, about 0.02% to about 0.04% (w/v). In some cases, the surfactant is about 0.02% (w/v), about 0.03% (w/v), about 0.04% (w/v), about 0.05% (w/v), about 0.06% (w/v), about 0.07% (w/v), about 0.08% (w/v), about 0.09% (w/v), or about 0.1% (w/v).
Thermal stabilizers for use in pharmaceutical formulations that may be used in methods set forth herein refers to ingredients that provide thermal stability against thermal denaturation of the VEGF antagonist, e.g., VEGF receptor fusion protein (e.g., aflibercept), as well as protect against loss of VEGF receptor fusion protein potency or activity. Suitable thermal stabilizers include sugars, and can be sucrose, trehalose, sorbitol or mannitol, or can be amino acids, for example L-proline, L-arginine (e.g., L-arginine monohydrochloride), or taurine. Additionally, thermal stabilizers may also include substituted acrylamides or propane sulfonic acid, or may be compounds like glycerol.
In some cases, the pharmaceutical formulations for use in a method herein include both a sugar and taurine, a sugar and an amino acid, a sugar and propane sulfonic acid, a sugar and taurine, glycerol and taurine, glycerol and propane sulfonic acid, an amino acid and taurine, or an amino acid and propane sulfonic acid. In addition, formulations can include a sugar, taurine and propane sulfonic acid, glycerol, taurine and propane sulfonic acid, as well as L-proline, taurine and propane sulfonic acid.
Embodiments herein may have thermal stabilizers present alone, each independently present at a concentration of, or present in combination at a total concentration of, from about 2% (w/v) to about 10% (w/v) or 4% (w/v) to about 10% (w/v), or about 4% (w/v) to about 9% (w/v), or about 5% (w/v) to about 8% (w/v). Thermal stabilizers in the formulation can be at a concentration of about 2% (w/v), about 2.5% (w/v), about 3% (w/v), about 4% (w/v), about 5% (w/v), about 6% (w/v), about 7% (w/v), about 8% (w/v), about 9% (w/v), about 10% (w/v) or about 20% (w/v).
With respect to taurine and propane sulfonic acid, in an embodiment of the invention, these thermal stabilizers can be present in the formulations at about from 25 mM to about 100 mM, and more typically from about 50 mM to about 75 mM (as compared to the other thermal stabilizers).
Viscosity reducing agents typically are used to reduce or prevent protein aggregation. Viscosity reducing agents for inclusion herein include: sodium chloride, magnesium chloride, D- or L-arginine (e.g., L-arginine monohydrochloride), lysine, or mixtures thereof. When present herein, viscosity reducing agents can be present at from about 10 mM to about 100 mM, and more typically from about 30 mM to about 75 mM, and even more typically from about 40 mM to about 70 mM. In some cases, the viscosity reducing agent is present at about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM or about 100 mM.
Pharmaceutical formulations for use in a method as set forth herein can also have a pharmaceutically acceptable viscosity for ocular administration, for example, intravitreal injection. Viscosity generally refers to the measure of resistance of a fluid which is being deformed by either shear stress or tensile stress (typically measured by techniques known in the art, viscometer or rheometer, for example). Typical viscosities of formulations for use in a method set forth herein are from about 5.0 cP (centipoise) to about 15 cP, from about 11 cP to about 14 cP, from about 12 cP to about 15 cP or from about 11 cP to about 12 cP. As such, formulation viscosity herein can be about 5.0 cP, about 6.0, about 7.1 cP, about 7.2 cP, about 7.3 cP, about 7.4 cP, about 7.5 cP, about 7.6 cP, about 10 cP, about 10.5 cP, about 11.0 cP, about 11.5 cP, about 12.0 cP, about 12.5 cP, about 13.0 cP, about 13.5 cP, about 14.0 cP, about 14.5 cP, or about 15.0 cP (e.g., when measured at 20° C.).
Various embodiments herein do not require inclusion of an inorganic salt, or other viscosity reducing agent, to maintain these highly useful viscosities. Typically, high concentration protein solutions require viscosity reducing agents to avoid protein aggregation and higher viscosity, making the formulations difficult for intravitreal injection and reducing the potency of the VEGF receptor fusion protein. As such, embodiments herein include methods of using formulations that have had substantially no, or no added, sodium chloride (NaCl), magnesium chloride (MgCl2), D- or L-arginine hydrochloride, lysine or other viscosity reducing agent.
Osmolality is a critical attribute for injectable pharmaceutical formulations for use in a method of the present invention. It is desirable to have products match physiological osmotic conditions. Furthermore, osmolality provides confirmation of soluble content in solution. In an embodiment of the invention, the osmolality of a formulation for use in a method of the present invention is less than or equal to about 506 mmol/Kg or from about 250 to about 506 mmol/Kg., e.g., about 250, 260, 270, 280, 290, 299, 300, 310, 314, 315, 316, 324, 343, 346, 349, 369, 384, 403, 426, 430 or 506 mmol/Kg. In an embodiment of the invention, the osmolality is lower than about 250 mmol/Kg.
Illustrative pharmaceutical formulations for use in the methods of the present invention include the following:
Formulation A: 80 mg/ml aflibercept, 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation B: 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation C: 80 mg/ml aflibercept, 10 mM citrate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation D: 80 mg/ml aflibercept, 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.
Formulation E: 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation F: 80 mg/ml aflibercept, 10 mM citrate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation G: 80 mg/ml aflibercept, 10 mM histidine-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation H: 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation I: 80 mg/ml aflibercept, 10 mM citrate-based buffer, 8% (w/v) sucrose, and 0.0 3% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation J: 80 mg/ml aflibercept, 10 mM histidine-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation K: 80 mg/ml aflibercept, 10 mM phosphate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation L: 80 mg/ml aflibercept, 10 mM citrate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation M: 150 mg/ml aflibercept, 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation N: 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation 0: 150 mg/ml aflibercept, 10 mM citrate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation P: 150 mg/ml aflibercept, 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.
Formulation Q: 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation R: 150 mg/ml aflibercept, 10 mM citrate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation S: 150 mg/ml aflibercept, 10 mM histidine-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation T: 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2 (e.g., 6.2), and, optionally, specifically excluding a viscosity reducing agent.
Formulation U: 150 mg/ml aflibercept, 10 mM citrate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation V: 150 mg/ml aflibercept, 10 mM histidine-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically
Formulation W: 150 mg/ml aflibercept, 10 mM phosphate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation X: 150 mg/ml aflibercept, 10 mM citrate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation Y: 80 mg/ml conbercept, 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation Z: 80 mg/ml conbercept, 10 mM phosphate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation AA: 80 mg/ml conbercept, 10 mM citrate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation BB: 80 mg/ml conbercept, 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.
Formulation CC: 80 mg/ml conbercept, 10 mM phosphate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation DD: 80 mg/ml conbercept, 10 mM citrate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation EE: 80 mg/ml conbercept, 10 mM histidine-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation FF: 80 mg/ml conbercept, 10 mM phosphate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation GG: 80 mg/ml conbercept, 10 mM citrate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation HH: 80 mg/ml conbercept, 10 mM histidine-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation II: 80 mg/ml conbercept, 10 mM phosphate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically
Formulation JJ: 80 mg/ml conbercept, 10 mM citrate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation KK: 150 mg/ml conbercept, 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation LL: 150 mg/ml conbercept, 10 mM phosphate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation MM: 150 mg/ml conbercept, 10 mM citrate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation NN: 150 mg/ml conbercept, 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 6.2.
Formulation 00: 150 mg/ml conbercept, 10 mM phosphate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation PP: 150 mg/ml conbercept, 10 mM citrate-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 80, and 40 mM sodium chloride, with a pH of 5.8 to 6.2.
Formulation QQ: 150 mg/ml conbercept, 10 mM histidine-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation RR: 150 mg/ml conbercept, 10 mM phosphate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation SS: 150 mg/ml conbercept, 10 mM citrate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 20, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation TT: 150 mg/ml conbercept, 10 mM histidine-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation UU: 150 mg/ml conbercept, 10 mM phosphate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically excluding a viscosity reducing agent.
Formulation VV: 150 mg/ml conbercept, 10 mM citrate-based buffer, 8% (w/v) sucrose, and 0.03% (w/v) polysorbate 80, with a pH of 5.8 to 6.2, and, optionally, specifically
Formulation WW: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 50 mM taurine, with a pH of 5.8.
Formulation XX: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 4% (w/v) proline, 0.03% (w/v) polysorbate 20, and 50 mM arginine hydrochloride, with a pH of 5.8.
Formulation YY: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 2.5% (w/v) sucrose, 2.0% (w/v) proline, 0.03% (w/v) polysorbate 20, and 50 mM taurine, with a pH of 5.8.
Formulation ZZ: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine-based buffer, 2.5% (w/v) sucrose, 2.0% (w/v) proline, 0.03% (w/v) polysorbate 20, and 50 mM arginine hydrochloride, with a pH of 5.8.
Formulation AAA: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 50 mM PSA, with a pH of 5.8.
Formulation BBB: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 2.5% (w/v) sucrose, 2.0% (w/v) proline, 0.03% (w/v) polysorbate 20, and 50 mM PSA, with a pH of 5.8.
Formulation CCC: 80, 100, 120 or 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 50 mM arginine hydrochloride, with a pH of 5.8.
Formulation DDD: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM histidine-based buffer, 4% (w/v) proline, 0.03% (w/v) polysorbate 20, and 50 mM PSA, with a pH of 5.8.
Formulation EEE: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5% (w/v) sucrose, and 0.03% (w/v) polysorbate 20 and, optionally, no thermal stabilizer, with a pH of 5.8.
Formulation FFF: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10mM sodium phosphate, 5% (w/v) sucrose and 0.03% polysorbate 20 with a pH of 6.2.
Formulation GGG: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium sulfate
Formulation HHH: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium thiocyanate
Formulation III: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose, 0.03% polysorbate 20; 40 mM sodium citrate
Formulation JJJ: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% Sucrose, 0.03% polysorbate 20; 50 mM glycine
Formulation KKK: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose, 0.03% polysorbate 20; 50 mM sodium chloride
Formulation LLL: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM lysine
Formulation MMM: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium aspartate
Formulation NNN: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium glutamate
Formulation OOO: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium citrate; 50 mM arginine hydrochloride
Formulation PPP: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM glycine; 50 mM arginine hydrochloride
Formulation QQQ: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium aspartate; 50 mM arginine hydrochloride
Formulation RRR: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM histidine, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 50 mM sodium glutamate; 50 mM arginine hydrochloride
Formulation SSS: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM His, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 10 mM L-arginine hydrochloride
Formulation TTT: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept); 20 mM His, pH 5.8; 5% sucrose; 0.03% polysorbate 20; 100 mM L-arginine hydrochloride
Formulation UUU: 30 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2
Formulation VVV: 30 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2
Formulation WWW: 60 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2
Formulation XXX: 60 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2
Formulation YYY: 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2
Formulation ZZZ: 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, pH 6.2
Formulation AAAA: 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10% sucrose, 10 mM phosphate, 0.03% polysorbate 20, 50 mM NaCl, pH 6.2
Formulation BBBB: 120 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20% sucrose, 10 mM phosphate, 0.03% polysorbate 20, 50 mM NaCl, pH 6.2
Formulation CCCC: 140 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 10 mM sodium phosphate, 5% sucrose, 40 mM sodium chloride, 0.03% PS20, pH 6.2
Formulation DDDD: 80 mg/ml VEGF receptor fusion protein (e.g., aflibercept), 20 mM histidine-based buffer, 5% (w/v) sucrose, 0.03% (w/v) polysorbate 20, and 50 mM L-arginine monohydrochloride, with a pH of 5.8.
Formulation EEEE: 120.0 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ±12 mg/ml), 20 mM histidine-based buffer (e.g., ±2 mM), 5% (w/v) sucrose (e.g., ±0.5%), 0.03% (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine monohydrochloride (e.g., ±5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).
Formulation FFFF: 113.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., 102-125 mg/ml), 20 mM histidine-based buffer (e.g., ±2 mM), 5% (w/v) sucrose (e.g., ±0.5%), 0.03% (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine monohydrochloride (e.g., ±5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).
Formulation GGGG: 114.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., 103-126 mg/ml), 10 mM histidine-based buffer (e.g., ±1 mM), 5% (w/v) sucrose (e.g., ±0.5%), 0.03% (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine (e.g., L-arginine monohydrochloride) (e.g., ±5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).
Formulation HHHH: 100.0 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ±10 mg/ml), 20 mM histidine-based buffer (e.g., ±2 mM), 5% (w/v) sucrose (e.g., ±0.5%), 0.03% (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine monohydrochloride (e.g., ±5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).
Formulation IIII: 133.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ±13 mg/ml), 20 mM histidine-based buffer (e.g., ±2 mM), 5% (w/v) sucrose (e.g., ±0.5%), 0.03% (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine monohydrochloride (e.g., ±5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).
Formulation JJJJ: 150 mg/ml aflibercept (e.g., aflibercept) (e.g., ±15 mg/ml), 10 mM sodium phosphate, 8% (w/v) sucrose (e.g., ±0.8%), 0.03% (w/v) polysorbate 20 (e.g., 0.02-0.04%) and 50 mM L-arginine hydrochloride, pH 6.2 (e.g., 6.0-6.4 or 5.9-6.5).
Formulation KKKK: 114.3 mg/ml VEGF receptor fusion protein (e.g., aflibercept) (e.g., ±14 mg/ml), 20 mM histidine-based buffer (e.g., ±2 mM), 5% (w/v) sucrose (e.g., ±0.5%), 0.03% (w/v) polysorbate 20 (e.g., 0.02-0.04%), and 50 mM L-arginine monohydrochloride (e.g., ±5 mM), with a pH of 5.8 (e.g., 5.6-6.0 or 5.5-6.1).
In an embodiment of the invention the formulation that can be administered, e.g., intravitreally, to a subject is an aqueous pharmaceutical formulation comprising: at least about 100 mg/ml of a VEGF receptor fusion protein comprising two polypeptides that each comprises an immunoglobin-like (Ig) domain 2 of VEGFRI, an Ig domain 3 of VEGFR2, and a multimerizing component (e.g., aflibercept);
about L-arginine (e.g., at a concentration of about 10-100 mM);
sucrose;
a histidine-based buffer; and
a surfactant;
wherein the formulation has a pH of about 5.0 to about 6.8; wherein the VEGF receptor fusion protein has less than about 3.5% high molecular weight species immediately after manufacture and purification and/or less than or equal to about 6% high molecular weight species after storage for about 24 months at about 2-8° C.
See International Patent Application Publication No. WO2019/217927 and US Pat. No. 11,103,552.
The present invention provides methods for treating angiogenic eye disorders by sequentially administering initial loading doses of greater than or equal to (>) about 8 mg (e.g., about every 2-4 or 3-5 weeks) of VEGF antagonist (e.g., aflibercept) followed by additional doses of >about 8 mg every 12 weeks of VEGF antagonist (e.g., aflibercept). For example, in an embodiment of the invention, the methods of the present invention include treating or preventing angiogenic eye disorders, such as diabetic retinopathy, diabetic macular edema or neovascular AMD, by administering, sequentially, one or more (e.g., 3, 4 or 5) doses (e.g., >about 8 mg) about every month (or about every 28 days, 28 ±5 days or about every 4 weeks), followed by one or more doses (e.g., >about 8 mg) about every 12 weeks. For example, in an embodiment of the invention, about 8 mg is 7.2 mg, 8.8 mg or 7.2-8.8 mg or 8 mg±about 10%.
The terms “initial dose,” “secondary doses,” and “tertiary doses,” refer to the temporal sequence of administration of the VEGF antagonist (e.g., aflibercept). Thus, the “initial dose” is the dose which is administered at the beginning of the treatment regimen (also referred to as the “baseline dose”); the “secondary doses” are the doses which are administered after the initial dose; and the “tertiary doses” are the doses which are administered after the secondary doses. The initial dose occurs on day 1 for the purposes of counting or numbering days thereafter (see e.g., Tables 1-1 and 1-2 herein). The initial, secondary, and tertiary doses may all contain the same amount of VEGF antagonist, but will generally differ from one another in terms of frequency of administration. In certain embodiments, however, the amount of VEGF antagonist contained in the initial, secondary and/or tertiary doses will vary from one another (e.g., adjusted up or down as appropriate) during the course of treatment. Thus, a dosing regimen of the present invention may be expressed as follows:
a single initial dose (e.g., >about 8 mg) of a VEGF antagonist (e.g., aflibercept), followed by one or more (e.g., 2, or 3 or 4) secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF antagonist;
wherein each secondary dose is administered 2 to 4 weeks after the immediately preceding dose; and
wherein each tertiary dose is administered about 12 weeks after the immediately preceding dose. The initial and secondary doses administered before the tertiary doses may be referred to, generally, as “loading” doses. The tertiary doses may be referred to as “maintenance” doses.
The present invention includes methods wherein one or more additional, non-scheduled, pro re nata (PRN) doses, in addition to any of the scheduled initial, secondary and/or tertiary doses of VEGF antagonist (e.g., aflibercept) are administered to a subject. Such PRN doses are typically administered at the discretion of the treating physician depending on the particular needs of the subject.
In an embodiment of the invention,
Dosing every “month” refers to dosing about every 28 days, about every 4 weeks, or about every 28±5 days and may encompass up to every 5 weeks. Dosing every “4 weeks” refers to dosing about every 28 days, about every month or about every 28±5 days, and may encompass up to every 5 weeks.
Dosing every “2-4 weeks” refers to dosing about every 2 weeks, 3 weeks or 4 weeks. Dosing every “8 weeks” refers to dosing about every 2 months, about every 56 days, 56±5 days.
Dosing every “12 weeks” refers to dosing about every 3 months, about every quarter year, about every 84, 90 days, 84±5 days, or 90±5 days.
A dose of greater than or equal to about 8 mg or >about 8 mg VEGF antagonist (e.g., aflibercept) includes 7.2 mg; 7.2-8.8 mg; 8.0 mg; 8.01 mg; 8.1 mg; 8.2 mg; 8.3 mg; 8.4 mg; 8.5 mg; 8.6 mg; 8.7 mg; 8.8 mg; 8.9 mg; 9 mg; 9.1 mg; 9.2 mg; 9.3 mg; 9.4 mg; 9.5 mg; 9.6 mg; 9.7 mg; 9.8 mg; 9.9 mg, 10.0 mg, 10.1 mg; 10.2 mg; 10.3 mg; 10.4 mg; 10.5 mg; 10.6 mg; 10.7 mg; 10.8 mg; 10.9 mg; 11 mg; 11.1 mg; 11.2 mg; 11.3 mg; 11.4 mg; 11.5 mg; 11.6 mg; 11.7 mg; 11.8 mg; 11.9 mg; 12 mg; 12.1 mg; 12.2 mg; 12.3 mg; 12.4 mg; 12.5 mg; 12.6 mg; 12.7 mg; 12.8 mg; 12.9 mg; 13 mg; 13.1 mg; 13.2 mg; 13.3 mg; 13.4 mg; 13.5 mg; 13.6 mg; 13.7 mg; 13.8 mg; 13.9 mg; 14 mg; 14.1 mg; 14.2 mg; 14.3 mg; 14.4 mg; 14.5 mg; 14.6 mg; 14.7 mg; 14.8 mg; 14.9 mg; 15 mg; 15.1 mg; 15.2 mg; 15.3 mg; 15.4 mg; 15.5 mg; 15.6 mg; 15.7 mg; 15.8 mg; 15.9 mg; 16 mg; 16.1 mg; 16.2 mg; 16.3 mg; 16.4 mg; 16.5 mg; 16.6 mg; 16.7 mg; 16.8 mg; 16.9 mg; 17 mg; 17.1 mg; 17.2 mg; 17.3 mg; 17.4 mg; 17.5 mg; 17.6 mg; 17.7 mg; 17.8 mg; 17.9 mg; 18 mg; 18.1 mg; 18.2 mg; 18.3 mg; 18.4 mg; 18.5 mg; 18.6 mg; 18.7 mg; 18.8 mg; 18.9 mg; 19 mg; 19.1 mg; 19.2 mg; 19.3 mg; 19.4 mg; 19.5 mg; 19.6 mg; 19.7 mg; 19.8 mg; 19.9 mg; or 20 mg (±about 10%,±about 0.5, or±about 0.51 mg of any of the foregoing). In an embodiment of the invention, a dosage of >8 mg VEGF antagonist is administered in a dose having a volume of about 100 μl or less, about 75 μl or less or about 70 μl or less, e.g., about 50 μl, 51 μl, 52 μl, 53 μl, 54 μl, 55 μl, 56 μl, 57 μl; 58 μl; 59 μl; 60 μl; 61 μl; 62 μl; 63 μl; 64 μl; 65 μl; 66 μl; 67 μl; 68 μl; 69 μl; 70 μl; 71 μl; 72 μl; 73 μl; 74 μl; 75 μl; 76 μl; 77 μl; 78 μl; 79 μl; 80 μl; 81 μl; 82 μl; 83 μl; 84 μl; 85 μl; 85-87 μl; 86 μl; 87 μl; 88 μl; 89 μl; 90 μl; 91 μl; 92 μl; 93 μl; 94 μl; 95 μl; 96 μl; 97 μl; 98 μl; 99 μl; or 100 μl (±about 4, 4.45, 4.5, or 5 microliters).
Any dosing frequency specified herein may, in an embodiment of the invention, be expressed as the specific frequency “±5 days” (e.g., where “4 weeks” is stated, the present invention also includes embodiments such as 4 weeks±5 days).
“Sequentially administering” means that each dose of VEGF antagonist (e.g., aflibercept) is administered to the eye of a patient at a different point in time, e.g., on different days separated by a predetermined interval (e.g., hours, days, weeks or months). The present invention includes methods which comprise sequentially administering, to the eye of a patient, a single initial dose of a VEGF antagonist, followed by one or more secondary doses of the VEGF antagonist, followed by one or more tertiary doses of the VEGF antagonist.
An effective or therapeutically effective dose of VEGF antagonist, e.g., aflibercept, for treating or preventing an angiogenic eye disorder refers to the amount of VEGF antagonist sufficient to alleviate one or more signs and/or symptoms of the disease or condition in the treated subject, whether by inducing the regression or elimination of such signs and/or symptoms or by inhibiting the progression of such signs and/or symptoms. In an embodiment of the invention, an effective or therapeutically effective dose of VEGF antagonist is >about 8 mg every month followed by once every 12 weeks.
An “angiogenic eye disorder” means any disease of the eye which is caused by or associated with the growth or proliferation of blood vessels or by blood vessel leakage. Non-limiting examples of angiogenic eye disorders that are treatable or preventable using the methods of the present invention include:
In an embodiment of the invention, a subject receiving a treatment for an angiogenic eye disorder as set forth herein (e.g., three monthly doses of about 8 mg aflibercept followed by doses of about 8 mg aflibercept every 12 weeks) achieves one or more of the following:
and/or
The center subfield of the retina is a 1 mm diameter area around the macula. The macula itself is about 6 mm in diameter.
The present invention also includes methods for achieving any one or more of the foregoing in a subject (e.g., increase in VA or BCVA, or decrease in CRT) suffering from an angiogenic eye disorder, e.g., nAMD, DR or DME, comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF antagonist (e.g., aflibercept), followed by one or more (e.g., 3, 4 or 5) secondary doses of about 8 mg or more of the VEGF antagonist, followed by one or more tertiary doses of about 8 mg or more of the VEGF antagonist; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks after the immediately preceding dose.
The present invention includes methods for treating or an angiogenic eye disorder (e.g., nAMD, DR, DME or ME-RVO), in a subject in need thereof, comprising administering to an eye of the subject, a single initial dose of about 8 mg or more of a VEGF antagonist (e.g., aflibercept), followed by one or more secondary doses of about 8 mg or more of the VEGF antagonist, followed by one or more tertiary doses of about 8 mg or more of the VEGF antagonist; wherein each secondary dose is administered about 2 to 4 weeks after the immediately preceding dose; and wherein each tertiary dose is administered about 12 weeks after the immediately preceding dose;
wherein the subject achieves a change in central retinal thickness, from baseline at the initiation of treatment, as depicted in
wherein the subject achieves a change in central retinal thickness, during the time period as set forth in the inset box of
wherein the subject achieves a change in BCVA, from baseline at the initiation of treatment, as depicted in
wherein the subject does not experience any one or more of the ocular TEAEs set forth in
Best corrected visual acuity (BCVA) can be measured in various methods known in the art. First, determining the proper level of lens refraction needed to best correct the visual acuity (VA) of a subject is determined before testing best corrected visual acuity (BCVA) with a visual acuity chart.
Two separate VA charts used for testing the right and left eye (e.g., Sloan Letter ETDRS Chart 1 and Sloan Letter ETDRS Chart 2, respectively), and a third refraction chart is used for testing appropriate refraction (e.g., Sloan Letter ETDRS Chart R). The features of the Sloan charts are high-contrast Sloan letters of equal difficulty, 5 letters in each of 14 rows, and a geometric progression of letter size (and, thus, an arithmetic progression of the logarithm of minimum angle of resolution [LogMAR]) from row to row. The charts have different letter sequences.
There are three basic components to determining refraction according to ETDRS protocol-determining spherical power, determining cylindrical axis and determining cylindrical power using methods known by practitioners in the art. For assessing refraction, if the subject wears contact lenses and has glasses, he or she should be told not to wear the contact lenses on the day of the examination or remove them 30-60 minutes before refraction is done. A trial frame is placed and adjusted on the subject's face so that lens cells placed in the frame are parallel to the anterior plane of the orbits and centered in front of the pupils. (It is permissible to use a phoroptor for subjective refraction. However, for testing visual acuity, the lenses from the final phoroptor refraction must be placed in a frame, and the final sphere must be rechecked).
BCVA can be measured first in one eye with a visual acuity chart, and then in the other eye with another visual acuity chart (e.g., Charts 1 and 2 as discussed herein), wherein each chart remains hidden from view until the eye in question is ready for testing. The distance from the subject's eyes to the visual acuity chart is typically 4 meters (13 feet and 1.5 inches, or 157.5 inches). The subject should be asked to read slowly (e.g., ata rate not faster than about one letter per second). Eyes reading 19 or fewer letters correctly at 4 meters can be tested at 1 meter.
Two commonly used tools for testing visual acuity (VA) or BCVA include the Snellen and the Early Treatment Diabetic Retinopathy Study (ETDRS) VA charts (Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1, Arch Ophthalmol. 1985 Dec;103(12):1796-806; Chen et al., Comparison of visual acuity estimates using three different letter charts under two ambient room illuminations. 2012; 60(2):101-104, Bailey & Lovie, New design principles for visual acuity letter charts, 1976; 53(11):740-745; Shamir et al., Comparison of Snellen and Early Treatment Diabetic Retinopathy Study charts using a computer simulation, Int. J. Opthamology 9(1): 119-123 (2016); Kaiser, Prospective Evaluation of Visual Acuity Assessment: A Comparison of Snellen Versus ETDRS Charts in Clinical Practice (An AOS Thesis), Trans Am Ophthalmol Soc 2009; 107:311-324). A version of the Bailey-Lovie chart (Bailey & Lovie, New design principles for visual acuity letter charts. Am J Optometry Physiol Opt 1976; 53:740-745) was modified in 1982 based on the recommendations of the Committee on Vision of the National Academy of Sciences, National Research Council, and Working Group 39, and by Dr. Rick Ferris for use in the Early Treatment Diabetic Retinopathy Study (ETDRS). The “ETDRS chart” and the protocol to test vision with the chart is commonly used in clinical trials. The ETDRS chart is typically tested from a shorter distance (13 feet (or 4 meters) rather than 20 feet) than Snellen, but does not allow the use of mirrors to simulate the correct distance, has the same amount of letters in every row (five letters each), and has an equal spacing of both the letters and the rows on a logarithmic scale. The Snellen Chart uses a geometric scale to measure visual acuity, with normal vision at a distance being set at 20/20. In an embodiment of the invention, VA or BCVA can be expressed in terms of ETDRS or Snellen. ETDRS VA values can be converted to a corresponding Snellen equivalent using methods known in the art. In an embodiment of the invention, VA or BCVA is measured with an ETDRS chart or with a Snellen chart.
The present invention provides methods as set forth herein wherein a VEGF antagonist (e.g., aflibercept) is delivered with a high amount of precision, e.g., with a drug delivery device (DDD) (e.g., with a 0.5 mL volume), whether pre-filled or capable of being filled from a vial, and delivering a volume of between 70 and 100 microliter with an average volume of about 81 or 82 or 81-82 microliters, e.g., with a standard deviation of about 4 or 5 or 4-5 microliters (e.g., about 4.5 or 4.46 microliters) or less. In an embodiment of the invention, the DDD is a syringe, e.g., with a 30 gauge, ½ inch needle.
One means for ensuring precision of a dose to be delivered with a device, such as a syringe, is by employing a syringe wherein the dose volume is device-determined. If the dose volume is device-determined, the device is designed only to deliver a single volume (e.g., 87 microliters) or a single volume with a limited amount of acceptable error (±4-5 microliters). Thus, if used properly, the user cannot deliver the wrong dose (e.g., cannot deliver more than the intended volume from the device).
The present invention includes embodiments wherein, a precise dosage of about 8 mg or more is a dose of about 9, 9.3, 9.33, 9.7, 9.8, 9.9, 9.7-9.9 mg or more±about 0.5, or ±about 0.51 mg is delivered to a subject's eye. The volume in which a dose is delivered can be, for example, about 70, 81, 82, 81.7, 85, 86, 87, 85-87 microliters±about 4, 4.45, 4.5, or 5 microliters. Doses may be delivered with a dose delivery device (DDD) which is a syringe.
Highly precise doses of VEGF antagonist (e.g., aflibercept) may be delivered, for example, in a volume that is device-determined (wherein the device is a syringe), by a method that includes the steps: (a) priming the syringe (e.g., a pre-filled syringe), thereby removing air from the syringe and, thus avoiding injection of air into the eye, by advancing the plunger rod by a predetermined distance into the syringe body until advancement of the plunger rod is resisted by a stop; (b) rotating the plunger rod about a longitudinal axis; and (c) actuating the plunger rod to dispense a predetermined (device-determined) volume (e.g., about 70, 81, 82, 81.7, 85, 86, 87, 85-87 microliters, ±about 4, 4.45, 4.5, or 5 microliters) of the formulation.
In an embodiment of the invention, the drug delivery device (DDD), comprises:
In an embodiment of the invention, the drug delivery device (DDD), comprises:
In an embodiment of the invention, the drug delivery device, includes:
In an embodiment of the invention, the drug delivery device, comprises:
Substances from such a DDD (e.g., a formulation including aflibercept as described herein), having a plunger rod and a barrel, may be dispensed as follows:
In an embodiment of the invention, the drug delivery device, includes:
See International patent application publication no. WO2019/118588.
In an embodiment of the invention, the drug delivery device (DDD), includes:
In an embodiment of the invention, the drug delivery device (DDD), includes:
In an embodiment of the invention, a drug delivery device, includes:
In an embodiment of the invention, a drug delivery device includes:
In an embodiment of the invention, a drug delivery device, includes:
In an embodiment of the invention, the drug delivery device, includes:
In an embodiment of the invention, a drug delivery device, includes:
A substance may be dispensed using such a DDD having a plunger rod and a body, may be done by a method including:
(a) advancing the plunger rod by a predetermined distance into the body until advancement of the plunger rod is resisted by a stop;
(b) rotating the plunger rod about a longitudinal axis; and
(c) actuating the plunger rod to dispense a predetermined volume of the substance,
wherein none of steps (a), (b), and (c) are reversible. In an embodiment of the invention, the DDD further includes a flange piece having a collar, and advancing the plunger rod and actuating the plunger rod comprise pressing an actuation portion of the plunger rod into the collar of the flange piece; for example, wherein the plunger rod comprises a protrusion, and wherein the collar of the flange piece abuts against the protrusion to resist advancement of the plunger rod. For example, in an embodiment of the invention, wherein rotating the plunger rod comprises twisting an actuation portion of the plunger rod relative to the flange piece, until a protrusion on the plunger rod becomes longitudinally aligned with a cavity in the collar of the flange piece, which may further include advancing the protrusion into the cavity until the protrusion abuts a distal side of the cavity, wherein the predetermined volume of the substance is dispensed when the protrusion abuts the distal side of the cavity.
See International patent application publication no. W02020/247686.
This phase 2, multi-center, randomized, single-masked study in patients with nAMD investigated the efficacy, safety, and tolerability of HD (8 mg doses) versus IAI (2mg doses). The Study dosing regimen is summarized in
The following are the portions of the protocol by which the CANDELA human clinical trial was conducted.
The study also includes a pharmacokinetic (PK) sub-study, with dense blood sampling (dense PK sub-study) for systemic drug concentrations and PK assessments for approximately 15 patients from each group from selected sites. Additional patients (up to approximately 50% more in each treatment group) may be enrolled in the dense PK sub-study to ensure adequate data is are captured.
The dosing schedule for the IAI and HD groups are set forth below in Table 1-1.
Additional visits for Dense PK Substudy:
Week 16: Additional treatment allowed after discussion with sponsor
See also Table 1-2 herein. As discussed in this Example, IAI dosing regimens call for 2 mg doses given as defined in Table 1-1; and HD dosing regimens call for 8 mg doses given as defined in Table 1-1.
The co-primary endpoints are:
There are no secondary endpoints in this study.
The exploratory endpoints are:
The efficacy variable relevant to the primary efficacy endpoint is the assessment of retinal fluid. The efficacy variables relevant to the exploratory endpoints are:
The safety variable relevant to the primary safety endpoint is the proportion of patients with TEAEs and SAEs.
The safety variables relevant to the exploratory endpoints are:
The PK variables are the concentrations of free and bound aflibercept in plasma at each time point using both sparse sampling and dense sampling.
The study will enroll approximately 100 patients to be randomized in a 1:1 ratio.
The study population consists of treatment-naïve patients with nAMD.
A patient must meet the following criteria at both the screening and/or the randomization visits to be eligible for inclusion in the study:
1. Men or women 50 years of age with active subfoveal CNV secondary to nAMD, including juxtafoveal lesions that affect the fovea in the study eye as assessed by an independent reading center.
2. Best Corrected Visual Acuity (BCVA) Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 78 to 24 (Snellen equivalent of 20/32 to 20/320) in the study eye.
3. Willing and able to comply with clinic visits and study-related procedures.
4. Provide informed consent signed by study patient or legally acceptable representative.
A patient who meets any of the following criteria at either the screening or randomization visits will be excluded from the study:
1. Evidence of CNV due to any cause other than nAMD in either eye.
2. Subretinal hemorrhage in the study eye that is ≥50% of the total lesion area.
3. Evidence of DME or diabetic retinopathy (defined as more than 1 microaneurysm) in either eye in diabetic patients.
4. Prior use of IVT anti-VEGF agents (aflibercept, ranibizumab, bevacizumab, brolucizumab, pegaptanib sodium) in the study eye.
5. Prior IVT investigational agents in either eye (e.g., anti-ang-2/anti-VEGF bispecific monoclonal antibodies, gene therapy).
6. Previous use of intraocular or periocular corticosteroids within 120 days of screening or
treatment with an IVT steroid implant at any time in the study eye.
7. Treatment with ocriplasmin in the study eye at any time.
8. Yttrium-aluminium-garnet capsulotomy in the study eye within 14 days of the screening Visits.
9. History of vitreoretinal surgery (including scleral buckling) in the study eye.
10. Intraocular pressure 25 mm Hg in the study eye.
11. Evidence of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye.
12. Any intraocular inflammation/infection in either eye within 90 days of the screening visit.
13. Any history of macular hole of stage 2 and above in the study eye.
14. Current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment visible at the screening assessments in the study eye.
15. Only 1 functional eye, even if that eye was otherwise eligible for the study (e.g., BCVA of counting fingers or less in the eye with worse vision).
16. Ocular conditions with poorer prognosis in the fellow eye.
17. Inability to obtain fundus photographs, fluorescein angiography (FA), or OCT (e.g., due to media opacity, allergy to fluorescein dye or lack of venous access) in the study eye.
18. Any prior systemic anti-VEGF administration.
19. Uncontrolled diabetes mellitus in the opinion of the investigator.
20. Uncontrolled BP (defined as systolic >140 mm Hg or diastolic >90 mm Hg). Patients may be treated with up to 3 agents known to have anti-hypertensive effects for arterial hypertension to achieve adequate BP control. This limit applies to drugs that could be used to treat hypertension even if their primary indication in the patient was not for BP control. Any recent changes in medications known to affect BP need to be stable for 90 days prior to the screening visit.
21. Variation by more than 10% in the 3 pre-randomization BP measures recorded at the screening 1, screening 2, and randomization visits.
22. History of cerebrovascular accident/ transient ischemic attack or myocardial infarction/acute coronary syndrome within 180 days of screening visit.
23. Renal failure, dialysis, or history of renal transplant.
24. Known sensitivity to any of the compounds of the study formulation.
25. Members of the clinical site study team and/or his/her immediate family, unless prior approval granted by the sponsor.
26. Pregnant or breastfeeding women
27. Women of childbearing potential* who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment, during the study, and for at least 90 days after the last dose. Highly effective contraceptive measures include:
a. stable use of combined (estrogen and progestogen containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles prior to screening.
b. intrauterine device (IUD); intrauterine hormone-releasing system (IUS)
c. bilateral tubal ligation
d. vasectomized partner
e. and or sexual abstinencet,
Additional Exclusion Criteria for the Dense PK Sub-study
1. Prior IAI in the fellow eye
2. Patients on more than 2 anti-hypertensive medications
3. Patients with known cardiac arrhythmia
4. Patients who, in the opinion of the investigator, are unlikely to have stable BP over the course of the study (e.g., due to known non-compliance with medication)
Investigational and Reference Treatments
The HD will be provided as a liquid formulation in a vial. The target concentration of aflibercept is 114.3 mg/mL. The dose will be delivered in an injection volume of 70 microliters. The IAI will be provided as a liquid formulation in a vial. The target concentration of aflibercept is 40 mg/mL. The dose will be delivered in an injection volume of 50 microliters.
Deviation from the treatment schedule defined in the protocol is discouraged. Efforts should be made to ensure adherence to the protocol-specified dosing intervals. If, however, in the investigator's judgement, a patient cannot adhere to the protocol-specified dosing interval due to persistent or worsening disease and requires an interim injection, the patient may receive additional treatment at week 16. The investigator must make reasonable efforts to consult with the study director or sponsor designee prior to additional treatment being allowed.
Patients will receive their randomized dose of aflibercept if it is determined that additional treatment will be administered. Patients who receive additional treatment will continue to receive their randomized treatment at future visits and will remain masked to treatment assignment. Data from patients receiving additional treatment will be censored from the time additional treatment is administered.
Dose modification for an individual patient is not allowed.
Any treatment administered from the time of informed consent to the final study visit will be considered concomitant medication. This includes medications that were started before the study and are ongoing during the study.
If a pretreatment concomitant medication is administered in the study eye before injection (e.g., antibiotic or anesthetic), it must be administered for fellow eye treatment as well.
Patients are not allowed to receive any standard or investigational treatment for nAMD in the study eye other than their assigned study treatment with HD or IAI, as specified in the protocol. This includes medications administered locally (e.g., IVT, topical, juxtascleral, or periorbital routes), as well as those administered systemically, with the intent of treating nAMD in the study eye or fellow eye.
If the fellow eye has nAMD, or any other approved indication, IAI (2 mg) will be allowed and supplied through the IWRS (Interactive web response system). Patients are not allowed to receive any other anti-VEGF agent in the fellow eye. Patients enrolled in the dense PK sub-study cannot receive IAI (2 mg) in the fellow eye before week 12.
Non-ocular (systemic) standard or investigational treatments for nAMD of the study or fellow eye are not permitted. Systemic anti-angiogenic agents and anti-Ang2 inhibitors are not permitted during the study.
Any other medications that are considered necessary for the patient's welfare, and that are not expected to interfere with the evaluation of the study drug, are allowed.
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:
X
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:
indicates data missing or illegible when filed
Footnotes:
1. For patients in the dense PK sub-study, the visit window is ±0 days.
2. For patients in the dense PK sub-study, the visit window is ±2 days.
3. Signed only by patients participating in the dense PK sub-study and in addition to the study ICF.
4. The optional genomic and FBR sub-study ICF (informed consent form) should be presented to patients at the screening visit and may be signed at any subsequent visit at which the patient chooses to participate after screening. The genomic DNA sample should be collected on day 1/baseline (pre-dose) or at any study visit from patients who have signed the sub-study ICF.
5. Refer to pharmacy manual for study drug injection guidelines. Following study drug injection, patients will be observed for approximately 30 minutes.
6. Patients will be dosed as needed per criteria herein.
7. Patients enrolled at sites participating in the optional visual function sub-study may undergo additional visual function tests. See study procedure manual for details.
8. Intraocular pressure will be measured bilaterally at all study visits. On days when study drug is administered, IOP should also be measured approximately 30 minutes after administration of study drug, in the study eye only. Intraocular pressure will be measured using Goldman applanation tonometry or Tono-penTM and the same method of measurement must be used in each patient throughout the study.
9. Indirect ophthalmoscopy should be performed bilaterally at all visits. On days when study drug is administered, it should also be performed immediately after administration of study drug (study eye only).
10. The same SD-OCT/FA/FP imaging system used at screening and day 1 must be used at all subsequent visits in each patient. Images will be taken in both eyes before dosing at each required visit.
11. Vital signs (temperature, BP, heart rate) should be measured pre-injection, per the procedure outlined in the study procedure manual. Blood pressure assessments will be taken using automated office blood pressure (AOBP) with the Omron Model HEM 907XL (or comparable). Measures will be taken in triplicate and a mean measure as displayed by the device will be recorded in the EDC. Detailed instructions can be found in the study procedure manual.
12. Timing of BP assessment at all visits must be within 2 hours of planned time of dosing on day 1 for patients in the dense PK sub-study. For all other patients, this window should be adhered to as closely as possible.
13. For patients participating in the dense PK sub-study, HR and BP also will be collected according to the schedule in Table 1-2.
14. Only BP and heart rate will be measured at these visits. No temperature measures are required.
15. All samples collected for laboratory assessments should be obtained prior to administration of fluorescein and prior to administration of study drug.
16. For women of childbearing potential, a negative serum pregnancy test at screening is required for eligibility. A negative urine pregnancy test is required before treatment is administered at subsequent visits.
17. For patients participating in the dense PK sub-study, urinalysis/UPCR will also be collected according to the schedule in Table 1-2.
18. Week 4 collection of urinalysis/UPCR only for patients in the dense PK sub-study.
19. Dense PK sampling will be performed in approximately 30 patients (15 in each group) drawn according to the schedule in Table 1-2. On dosing days, BP (blood pressure) and PK samples must be collected prior to study drug administration. Additional patients (up to approximately 50% more in each treatment group) may be enrolled in the dense PK sub-study to ensure adequate data is are captured.
20. Sparse PK sampling will be performed in all patients not enrolled in the dense PK sub-study according to the schedule defined in Table 1-2. On dosing days, PK samples should be collected prior to study drug administration.
21. Exploratory research serum sample should be drawn prior to the administration of study drug at baseline (visit 3, day 1) and week 44.
1Timing of all BP assessments must be within ±2 hours of the time of dosing on day 1. This may be done at the clinical study site or by the site personnel or another healthcare professional at a remote location (e.g., the patient's home or other appropriate location). Regardless of where BP measurements are taken, the procedures described herein must be followed.
2Blood pressure assessments will be taken using automated office blood pressure (AOBP) with the Omron Model HEM 907XL (or comparable). Measures will be taken in triplicate and a mean measure as displayed by the device will be recorded in the EDC. Detailed instructions can be found in the study procedure manual.
3Intraocular pressure will be measured at approximately 4 hours post-dose only if the IOP measurement from approximately 30 minutes to 60 minutes post-dose remains clinically significantly higher than the pre-injection reading.
4Intraocular pressure will be measured at approximately 8 hours post-dose only if the IOP measurements from approximately 30 minutes to 60 minutes and approximately 4 hours post-dose remain clinically significantly higher than the pre-injection reading.
5PK draw for all assessment days are to be performed within ±2 hours of the time of dosing on day 1.
6This may be done at the clinical study site or by the site personnel or another healthcare professional at a remote location (e.g., the patient's home or other appropriate location).
Intraocular Pressure. Intraocular pressure will be measured in both eyes at every visit using Goldmann applanation tonometry or Tono penTM, as specified in Table 1-2. The same method of IOP measurement must be used throughout the study for each individual patient. On dosing visits, IOP will also be measured approximately 30 minutes post-dose (study eye).
For patients in the dense PK sub-study, IOP will also be measured 4 hours post-dose if the reading from approximately 30 minutes to 60 minutes post-dose remains clinically significantly higher than the pre-dose reading, and again at approximately 8 hours post-dose if the reading from approximately 4 hours post-dose remains clinically significantly higher than the pre-dose reading.
Slit Lamp Examination. Patients' anterior eye structure and ocular adnexa will be examined bilaterally pre-dose at each study visit using a slit lamp (see study procedure manual) by the investigator, as specified herein
Indirect Ophthalmoscopy. Patients' posterior pole and peripheral retina will be examined by indirect ophthalmoscopy at each study visit pre-dose (bilateral) and post-dose (study eye) by the investigator, as specified herein. Post-dose evaluation must be performed immediately after injection.
Fundus Photography/Fluorescein Angiography. The anatomical state of the retinal vasculature will be evaluated by FP and FA as specified herein. Fundus photography and FA will be captured and transmitted to an independent reading center for both eyes. For FA, the study eye will be the transit eye.
Fundus and angiographic images will be sent to an independent reading center where images will be read by masked readers. All FPs and FAs will be archived at the site as part of the source documentation. Photographers must be certified by the reading center to ensure consistency and quality in image acquisition. A detailed protocol for image acquisition and transmission can be found in the study procedure manual. Imaging technicians should remain masked to treatment assignment.
Spectral Domain Optical Coherence Tomography. Retinal characteristics will be evaluated at every visit using SD-OCT. Images will be captured and transmitted for both eyes. Images will be sent to an independent reading center where they will be read by masked readers. All OCTs will be electronically archived at the study site as part of the source documentation. Optical coherence tomography technicians must be certified by the reading center to ensure consistency and quality in image acquisition. A detailed protocol for acceptable OCT machines and OCT image acquisition/transmission can be found in the study procedure manual. Imaging technicians should remain masked to treatment assignment.
Best Corrected Visual Acuity. Visual function of the study eye and the fellow eye will be assessed using the ETDRS protocol (Early Treatment Diabetic Retinopathy Study Research Group, 1985) at 4 meters at each study visit, as specified in Table 1-2. Visual acuity examiners must be certified to ensure consistent measurement of BCVA, and must remain masked to treatment assignment, treatment schedule and study eye. Best corrected visual acuity should be done before any other ocular procedures are performed. Patients enrolled at sites participating in the optional visual function sub-study may undergo additional visual function tests.
Adverse Event. An AE is any untoward medical occurrence in a patient administered a study drug which may or may not have a causal relationship with the study drug. Therefore, an AE is any unfavorable an unintended sign (including abnormal laboratory finding), symptom, or disease which is temporally associated with the use of a study drug, whether or not considered related to the study drug (ICH E2A Guideline. Clinical Safety Data Management: Definitions and Standards for Expedited Reporting, October 1994).
Serious Adverse Event. An SAE is any untoward medical occurrence that at any dose:
Ocular important medical event. An ocular important medical event may include the following:
Severity. The severity of AEs will be graded according to the following scale:
Causality. The investigator must provide causality assessment as whether or not there is a reasonable possibility that the drug caused the adverse event, based on evidence or facts, his/her clinical judgment, and the following definitions. The causality assessment must be made based on the available information and can be updated as new information becomes available.
The following factors should be considered when assessing causality:
Causality to the Study Drug.
Causality to the Injection Procedure. The relationship of AEs to the injection procedure is assessed by the investigator, and is a clinical decision based on all available information. The following question is addressed: Is there a reasonable possibility that the AE may have been caused by the injection procedure?
The possible answers are:
The concentrations of free and bound aflibercept over time will be summarized by descriptive statistics for each treatment group. No formal statistical hypothesis testing will be performed.
The PK parameters to be determined after the first dose for free and bound aflibercept may include, but are not limited to:
After repeat dosing in the dense PK sub-study, PK parameters to be determined may include, but are not limited to, Ctrough, time to reach steady-state, and accumulation ratio. The concentrations of free and bound aflibercept over time and selected PK parameters will be summarized by descriptive statistics by treatment group. This descriptive statistical assessment will include the geometric means and ratios of the geometric means for selected PK parameters, as deemed appropriate. No formal statistical hypothesis testing will be performed.
Results at week 16 (n=55)-values as reported at the time for patients reaching week 16.
The baseline demographics, eye characteristics, and blood pressure of “All patients” at this point in this trial are set forth in
After 16 weeks of study duration, patients receiving the 8 mg doses of aflibercept (HD dosing regimen) maintained (on average) greater vision improvements and anatomical improvements than that of patients receiving the 2 mg dose (IAI dosing regimen) (relative to baseline).
Patients (Completers) receiving the HD dosing regimen maintained a greater mean change in best corrected visual acuity (7.4) than the IAI patients (5.2) at week 16 (
Anatomical improvements were also remarkable at week 16. The central retinal thickness (CRT) of patients receiving the HD dosing regimen remained below that of patients (Completers) receiving the IAI dosing regimen-a mean change of −142 micrometers in HD patients vs −133 micrometers in IAI patients at week 16 (
Measures of retinal dryness were also strikingly better in patients receiving the HD dosing regimen. Overall, more patients (Completers) receiving the HD regimen had complete resolution of intraretinal/subretinal fluid at week 16. The proportion of HD patients with dry retinas at week 16 was 44% whereas the proportion of IAI patients with dry retinas was just 9% (
The HD and IAI dosing regimens were generally well tolerated. The ocular treatment-emergent adverse events (TEAEs) (
Results—Additional Patients Reaching Week 16 (n=106)—Values as Reported at the Time for a Larger Set of Patients Reaching Week 16
At week 16, a higher proportion of these patients in the HD aflibercept 8 mg group had no retinal or subretinal fluid (50.9%, n=27/53) in the center (1 mm) subfield on optical coherence tomography compared to patients treated with IAI EYLEA 2 mg (34.0%, n=18/53) (p=0.08). During the initial 16 weeks of the trial, treatment emergent adverse events (TEAEs) in the study eye occurred in 17.0% (9 of 53) of aflibercept 8 mg patients and 22.6% (12 of 53) of EYLEA 2 mg patients. AEs that occurred more frequently in the aflibercept 8 mg group were conjunctival hemorrhage (5.7% aflibercept 8 mg, 3.8% EYLEA 2 mg) and vitreous detachment (3.8% aflibercept 8 mg, 1.9% EYLEA 2 mg). Serious ocular AEs (SAEs) occurred in two patients overall, one in the aflibercept 8 mg group (retinal tear) and one in the EYLEA 2 mg group (visual acuity reduced). No intraocular inflammation, occlusive vasculitis, arterial thromboembolic events (adjudicated according to the Anti-Platelet Trialists' Collaboration definitions) or death in either patient group were identified through week 16.
The disposition and exposure, baseline demographics, baseline characteristics, and baseline blood pressure and medical history of patients in this analysis are set forth in
The proportion of HD patients achieving a dry retina (no IRF and no SRF in the central subfield on SD-OCT (spectral domain optical coherence tomography)) was 51% whereas the proportion of IAI patients was 34% (
The proportion of HD patients receiving additional treatment at week 16 (19%) was smaller than that of IAI patients (27%). Also, the occurrence of ocular TEAEs through week 16 was 17% among HD patients and 22.6% among IAI patients (
Results—Patients Reaching Week 44 (n=100)—Values as Reported at the Time for Patients Reaching Week 44
The study ended at week 44 with 100 patients. With an identical dosing regimen and slightly fewer rescue and/or PRN doses, a higher proportion of eyes receiving 8 mg aflibercept (HD) were dry in the center subfield relative to the eyes receiving 2 mg aflibercept (IAI). In addition, a change from baseline in central subfield thickness (CST) suggested better anatomic outcomes in the 8 mg HD group relative to the 2 mg IAI group. Changes in visual acuity from baseline favored the 8 mg dosing regimen (HD) over the 2 mg regimen (IAI) (+7.9 letters vs. +5.1 letters).
No new safety signals were seen and the safety profile for the HD group was comparable to that of IAI. There was one case of mild iritis in the HD group that resolved with topical therapy. Changes from baseline blood pressure and intraocular pressure were similar between the groups.
Out of the 106 patients that started in the study, 100 reached the 44-week point-49 in the IAI group and 51 in the HD group (
Patients in the HD group achieved numerically superior anatomical improvements in the eye. Retinal drying (lack of fluid in the center subfield-no intraretinal fluid (I RF) and no subretinal fluid (SRF)) at weeks 16 to 44 was higher in the HD group relative to that of the IAI group (
Patients in the HD group also achieved greater gains in vision. By week 44, the mean change, from baseline, in best corrected visual acuity (BCVA) was 7.9 in the HD group and 5.1 in the IAI group (
Ocular TEAEs and ocular serious TEAEs, intraocular inflammation TEAEs, intraocular pressure events, non-ocular TEAEs and non-ocular serious TEAEs were comparable between treatment groups (
This Example documents the procedure and execution results of deliverable volume characterization testing conducted to compare different presentations of a formulation including aflibercept (REGN3) at a concentration of 114.3 mg/ml.
The following devices will be compared:
Testing was conducted separately for each presentation. All samples were filled with 114.3 mg/mL aflibercept formulated drug substance.
REGN3-PFS-0.5 mL testing:
1 mL BD Luer Lok Syringe testing:
Deliverable volume was calculated by collecting the dose delivered through manual injection after the syringe was manually primed and weighing the collected dose on a balance. The collected mass was then divided by the density of the FDS (1.059 g/ml) to calculate the volume delivered.
V=(mdose/p)*1000,
where V is the delivered volume (μL), mdose dose is the dose mass (g), and ρ is the solution density (g/mL). Preconditioning of samples at 5° C. was conducted for the testing in order to maintain drug product integrity.
REGN3-PFS-0.5 mL:
1 mL BD (Becton Dickinson) Luer Lok syringe:
The testing of REGN3-PFS-0.5mL demonstrated that 59 out of 60 samples were able to administer a volume with high precision with 1 sample delivering volume of 64.684 microliters. See the histogram of delivered doses of REGN3-PFS-0.5mL in
Three hundred six (306) samples delivered with the 1 mL BD (Becton Dickinson) Luer Lok syringe were utilized for data analysis. Samples 21, 74, 117 and 125 were removed from analysis due to operator error in dose preparation prior to collection. Testing showed that 252 out of 306 samples were 70 microliters -100 microliters. See the histogram of delivered doses in
The deliverable volume data of both devices showed the difference in variability and accuracy. The 1 mL BD (Becton Dickinson) Luer Lok syringe has a lower average delivered volume at 74.7 microliters than the 0.5 mL PFS with 81.6 microliters. However, it has a larger spread of volumes delivered with a range of 53.5 microliters compared to 24.8 microliters for the 0.5 mL PFS. The increased variability depicted in the 1 mL BD (Becton Dickinson) Luer Lok syringe may be attributed to user variability in setting the dose to 70 microliters as well as the variability in graduation printing on the syringe. Individual delivered volumes for each device are set forth in
Both devices were able to provide a dose within a 70 microliters -100 microliters range; however, the REGN3-PFS-0.5 mL was able to deliver more consistent doses within a limited deliverable volume range with increased precision.
This application claims the benefit of U.S. Provisional Patent Application No. 63/189,541, filed May 17, 2021; U.S. Provisional Patent Application No. 63/235,398, filed Aug. 20, 2021; U.S. Provisional Patent Application No. 63/297,420, filed Jan. 7, 2022; and U.S. Provisional Patent Application No. 63/306,315, filed Feb. 3, 2022; each of which is herein incorporated by reference for all purposes.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/029462 | 5/16/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63189541 | May 2021 | US | |
| 63235398 | Aug 2021 | US | |
| 63297420 | Jan 2022 | US | |
| 63306315 | Feb 2022 | US |
