WO2019040397A1

WO2019040397A1 - A method for treating or preventing neovascular age-related macular degeneration

Info

Publication number: WO2019040397A1
Application number: PCT/US2018/047169
Authority: WO
Inventors: Kourous REZAEI
Original assignee: Ophthotech Corp
Current assignee: Iveric Bio Inc
Priority date: 2017-08-21
Filing date: 2018-08-21
Publication date: 2019-02-28
Anticipated expiration: 2020-02-21

Abstract

A method for treating or preventing neovascular age-related macular degeneration is provided comprising intravitreal injections of an anti-C5 agent and VEGF antagonist.

Description

A METHOD FOR TREATING OR PREVENTING NEOVASCULAR AGE-RELATED MACULAR DEGENERATION

Sequence Listing

[0001] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on August 7, 2017, is named A112-36_SL.txt and is 1,946 bytes in size.

Field of the Invention

[0002] This invention relates to methods and compositions useful for the treatment or prevention of an ophthalmological disease or disorder, namely neovascular age-related macular degeneration, comprising administration of an effective amount of an anti-C5 agent in combination with a VEGF antagonist.

Background of the Invention

[0003] Age-related macular degeneration (AMD) is a disease

characterized by progressive degenerative abnormalities in the macula of the eye, a small area in the central portion of the retina. It is characteristically a disease of individuals > 50 years of age and is the leading cause of visual loss in developed countries. In the United States, it is estimated that approximately 6% of individuals 65 - 74 years of age and 20% of those older than 75 years of age are affected with AMD (Busbee et al., 2013; Leibowitz et al., 1980). Because of the increasing life expectancy in developed and developing countries, the elderly sector of the general population is expected to rise at a greater rate in the coming decades. While 1 of 8 Americans was considered to be elderly in 1994, it is expected that 1 of 5 will fall into this category in 2030. Using U.S. Census Bureau projections, the number of Americans over 65 years of age will more than double to 80 million by the middle of this century (Day, 1993). In the absence of adequate prevention or treatment measures, the number of cases of AMD with visual loss is expected to grow accordingly.

[0004] Age-related macular degeneration is classified into one of two general subgroups: the non-neovascular (non-exudative or dry) form of the disease and the neovascular (exudative or wet) form of the disease (NVAMD). The non-neovascular form of AMD is more prevalent, accounting for

approximately 90% of all AMD cases, and is often characterized by a slow degeneration of the macula resulting in atrophy of the central retina with gradual vision loss over a period of years. By contrast, NVAMD, although less prevalent, commonly causes sudden, often substantial, loss of central vision and is responsible for most cases of severe loss of visual acuity in this disease (Vingerling, 1995). This type of AMD results when abnormal blood vessels (neovascularization) proliferate under and/or within the retina. These blood vessels leak blood and fluid into and under the retina, which results in rapid vision loss. The end stage of the disease features scarring with irreversible destruction of the central retina.

[0005] The current FDA approved pharmacologic therapies for NVAMD target and inhibit Vascular Endothelial Growth Factor (VEGF). VEGF is an endothelial cell survival factor and a mitogen. Endothelial cells are a key component of neovascular tissue. All approved anti-VEGF agents for NVAMD are administered by the intravitreal route of administration. These include Lucentis^® (ranibizumab) and Eylea^® (aflibercept) (Brown et al., 2006; Heier et al, 2012; osenfeld et al, 2006).

[0006] In addition, although not labeled by the FDA for the treatment of NVAMD, the anti-VEGF agent Avastin^® (bevacizumab) is currently used to treat -50% of the eyes with NVAMD in the United States. (Parikh, et al, 2017) A multicenter, prospective, randomized trial, funded by the US National Eye Institute, "The Comparison of Age-Related Macular Degeneration Treatments Trials" (CATT) demonstrated that monthly dosing with Avastin^® 1.25 mg (0.05 mL) was non-inferior to monthly dosing of Lucentis^® for eyes with NVAMD (Martin et al, 2012).

[0007] Avastin^®, Lucentis^®, and Eylea^®, on average, all improve the visual outcome in eyes with NVAMD. The primary functional impact of these anti- VEGF agents is to decrease intraretinal and subretinal fluid associated with abnormal blood vessels. Despite maximal therapy with intravitreal monotherapy anti-VEGF agents, the majority of patients do not achieve significant visual gain (> 15 letters of vision), and approximately 20% to 30% lose additional vision from baseline.

[0008] The etiology of AMD is not completely understood. In addition to advanced age, there are environmental and genetic risk factors for AMD including ocular pigmentation, dietary factors, a positive family history for AMD, high blood pressure, and smoking (Vingerling, 1995). Recent work suggests inflammation as a major contributor to the pathogenesis of the disease (Bok, 2005; Donoso et al, 2006).

[0009] The complement pathway is part of the innate immune system and is a complex system of serum proteins that interact in a cascade. This

complement cascade is activated via the classical (antibody-dependent), the alternative (antibody-independent) and the lectin pathways. Activation of the complement cascade has been implicated in drusen formation (Klein, 2004, Bora, 2005). Additionally, complement components may induce up-regulation of VEGF, a well-known mediator of choroidal neovascularization (CNV) (Nozaki et al., 2006). Preclinical laser-induced CNV models have also implicated complement activation.

[0010] Further, the choroid may serve as a nidus for the deposition of membrane attack complex (MAC) when compared to other tissues in the body (Chirco et al., 2015). MAC accumulation leads to mitochondrial damage and cellular dysfunction in RPE cells (Georgiannakis et al. 2015). In experimental models of CNV, (MAC) formation has been shown to be important (Johnson et al., 2000). MAC is also responsible for causing pores in the affected cells that eventually leads to cell death.

[0011] Inhibition of complement activation has led to a decrease in CNV formation in experimental mouse model (Rohrer et al., 2009; Jo et al., 2017). In a CD29 knockout model, mice that were deficient in MAC inhibition developed a larger CNV size when compared to wild type mice (Schnabolk G, et al., 2017). Evidence for the role of complement in AMD is further reinforced by genetic linkage and association studies, which suggest that approximately 50 to 75% of AMD cases have polymorphism in complement regulatory proteins compared to age-matched controls. Furthermore, polymorphism in genes coding for complement or complement regulatory proteins have demonstrated

increased risk in age-related macular degeneration (Edwards et al., 2005;

Hageman et al., 2005, Haines et al., 2005; Klein et al., 2005, Naranyan et al., 2007).

[0012] Avastin^®, Lucentis^®, and Eylea^®, on average, all improve the visual outcomes in eyes with NVAMD. Despite maximal therapy with intravitreal monotherapy anti-VEGF agents, a majority of patients do not achieve

significant visual gain (> 15 letters of vision), and approximately 20% to 30% lose additional vision from baseline. Further, an increase in dosage or regimen did not lead to additional efficacy and it appears that a "ceiling" of anti-VEGF effect may have been reached (Busbee et al., 2013).

[0013] In addition, approximately one fifth of the patients who had received anti-VEGF therapy developed geographic atrophy (GA) within 2 years of treatment (Grunwald et al., 2014). The authors concluded that anti-VEGF therapy may play a role in the development of atrophy. At 5 years the cumulative incidence had increased to 38%, concluding that the development of GA was common after 5 years of treatment (Gruwald et al., 2017).

[0014] A meta-analysis of 13 published studies proposed that patients who are homozygous for complement factor H (CFH) polymorphism Y402H experience a reduced response to anti-VEGF treatment (Chen et al., 2015). Further, a direct relationship between VEGF and CFH was recently

demonstrated where VEGF upregulated CFH expression and VEGF inhibition lead to a decrease in CFH expression in RPE cells (Keir et al., 2017). Mice that received anti-VEGF treatment, showed a significant decrease in VEGF and CFH. This led to a 200 fold increase in retinal C3 RNA and increased MAC expression, suggesting that VEGF inhibition may contribute to complement activation (Keir et al., 2017). Further, in patients with NVAMD, aqueous humor samples collected 48 hours after intravitreal injection of bevacizumab

demonstrated a decrease in VEGF levels but an increase in C3a, C4a, and C5a levels (Keir et al. 2017). [0015] Taken together, these findings may potentially indicate that although VEGF inhibition has potent anti-permeability characteristics, it may also contribute to complement activation by reducing CFH expression and therefore limit the full therapeutic potential of the anti-VEGF therapy in

NVAMD patients.

[0016] ARC 1905 (avacincaptad pegol sodium), a PEGylated RNA aptamer, is a potent and specific inhibitor of complement activation. It inhibits C5, a central component of the complement cascade, which plays multiple roles in innate immunity and inflammatory diseases. Inhibition of this key step in the complement cascade at the level of C5 prevents the formation of key terminal fragments (C5a and C5b-9) regardless of which pathway (alternate, classical or lectin) induced their generation. The C5a fragment is an important inflammatory activator inducing vascular permeability, recruitment and activation of phagocytes. C5b is involved in the formation of MAC: C5b-9, which initiates cell lysis. By inhibiting these C5-mediated inflammatory and MAC activities, therapeutic benefit may be achieved in NVAMD.

[0017] In a phase 1 ascending dose and parallel group clinical trial the safety, tolerability, and pharmacokinetic profile of multiple intravitreal injections of ARC1905 in combination with Lucentis^® 0.5 mg was evaluated in subjects with NVAMD (OPH 2000). [0018] ARC 1905 was well-tolerated and no particular safety concerns were identified. No significant evidence of intraocular inflammation, retinal vasculitis, or choroidal vasculopathy was evident. One patient was noted to develop a mild cataract, which was related to the drug by the investigator and visual acuity improved in this patient. No adverse events (AEs) were assessed to be related to Lucentis^® administration.

[0019] Visual acuity (VA) assessments were primarily safety assessments to detect any decrease in vision associated with the intravitreal injections. There were no safety issues identified through measurement of VA. Assessment of VA was focused on the treatment-naive (TN) patient subgroup of 43 patients who had received 6 injections at doses of 0.3 mg, 1 mg or 2 mg. There was a trend towards a mean increase in VA (number of ETDRS letters) from Baseline at all time points for patients in the 0.3, 1 and 2 mg dose groups in the TN subgroup who received 6 injections. At Week 24, there was an improvement in mean VA from Baseline of 13.6 ETDRS letters for the 0.3 mg dose group, 11.7 ETDRS letters for the 1 mg dose group and 15.3 ETDRS letters for the 2 mg dose group.

[0020] Fifty-one percent (51%) of patients in the TN subgroup (n=43 patients) gained >_15 ETDRS letters at Week 24. This included 6 patients (46%) in the 0.3 mg dose group, 7 patients (47%) in the 1 mg dose group, and 9 patients (60%) in the 2 mg dose group gaining >_15 ETDRS letters of VA. [0021] A separate phase 1 study was also performed in subjects diagnosed with geographic atrophy (GA). In this study, a total of 47 subjects were enrolled, in the 0.3 mg dose arm (n=24) and 1 mg dose arm (n=23). Subjects received treatment with 3 initial intravitreal injections of ARC1905 0.3 mg/eye or 1 mg/eye, administered at Day 0, Week 4 and Week 8 with a follow up visit at Week 16. Subjects received 2 subsequent injections at Week 24 and Week 36 followed by a final follow up visit at Week 48. Standard safety assessments were performed for ophthalmic variables that included VA, IOP, ophthalmic examination, fundus autofluorescence (FAF), Fluorescein Angiography (FA), and optical coherence tomography (SD-OCT) together with AEs, vital signs and laboratory variables.

[0022] Another study was performed to evaluate the safety and tolerability of ARC 1905 intravitreal injection in combination with VEGF therapy in subjects with idiopathic polypoidal choroidal vasculopathy (IPCV). Subjects included in the study were treatment experienced (prior treatment with anti-VEGF monotherapy of > 8 injections in the previous 12 months) of either gender aged 50 years or above with diagnosis of IPCV. Subjects received 3 monthly intravitreal injections of ARC1905 (1 mg/eye) in combination with intravitreal injection of anti-VEGF agent (Avastin^® 1.25 mg/eye or Lucentis^® 0.5 mg/eye or Eylea^® 2 mg/eye). [0023] Multiple investigations of currently available anti-VEGF agents (Lucentis®, Avastin® and Eylea®) suggest that they are essentially similar with respect to their safety and efficacy profiles (Brown et al., 2006; Martin et al., 2012; osenfeld et al., 2006; Schmidt-Erfurth et al., 2014). Furthermore, the "ceiling" of anti-VEGF mediated therapeutic benefit in NVAMD appears to have been reached as attempts at improving visual outcomes by altering the dose and regimen of anti-VEGF therapy have been unsuccessful (Busbee et al., 2013; Schmidt-Erfurth et al., 2014). Despite maximal therapy with intravitreal monotherapy anti-VEGF agents, the majority of patients do not achieve significant visual gain (> 15 ETDRS Letters) or achieve visual acuity of 20/40 or better. In addition, approximately 25% of the patients lose additional vision (Martin et al., 2012). Further, less than monthly regimen results in worse visual outcomes in the real world setting and over time patients in general lose vision with anti-VEGF monotherapy (Rakic et al. 2013, Rasmussen et al., 2013;

Rofagha et al, 2013). Approximately one fifth of patients who had received anti-VEGF therapy developed GA within 2 years of treatment (Grunwald et al., 2014). The authors concluded that anti-VEGF therapy may play a role in the development of atrophy. At 5 years, the cumulative incidence was 38%, concluding that the development of GA was common after 5 years of anti- VEGF treatment (Grunwald et al., 2017). [0024] Thus, despite advances in the field, the need remains for improved therapies to treat or prevent NVAMD.

Summary of the Invention

[0025] The present invention relates to methods and compositions useful for the treatment or prevention of an ophthalmological disease or disorder, particularly NVAMD.

[0026] The present invention provides methods for treating or preventing NVAMD, comprising administering to a subject in need thereof: (a) ARC1905 and (b) a VEGF antagonist, wherein ARC1905 and the VEGF antagonist are administered in an amount that is effective for treating or preventing NVAMD.

[0027] In addition, the present invention provides new and improved methods and compositions for treating and preventing NVAMD, including, e.g., combination therapies, and treatment and dosing regimens. In addition, the invention provides coformulations that comprise an anti-C5 agent and a VEGF antagonist. In certain embodiments, the coformulations are pharmaceutically acceptable compositions comprising an effective amount of an anti-C5 agent and VEGF antagonist, and a pharmaceutically acceptable carrier or vehicle. Detailed Description of the Invention

[0028] In certain aspects, the present invention provides new and improved methods and compositions for treating and preventing NVAMD, including new dosing regimens.

[0029] In particular embodiments, ARC 1905 or another pharmaceutically acceptable salt thereof is administered in combination with a VEGF antagonist. In one embodiment, ARC 1905 or another pharmaceutically acceptable salt thereof is administered in combination with ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, tivozanib, abicipar pegol or ESBA1008.

[0030] The invention provides treatment regimens, including treatment and dosing regimens, related to the coadministration of ARC 1905 (or another pharmaceutically acceptable salt thereof) and a VEGF antagonist.

Definitions

[0031] The term "VEGF" refers to a vascular endothelial growth factor that induces angiogenesis or an angiogenic process. As used herein, the term "VEGF" includes the various subtypes of VEGF (also known as vascular permeability factor (VPF) and VEGF-A) that arise by, e.g., alternative splicing of the VEGF-A/VPF gene including VEGF 121, VEGF 165 and VEGF 189. Further, as used herein, the term "VEGF" includes VEGF-related angiogenic factors such as PIGF (placenta growth factor), VEGF-B, VEGF-C, VEGF-D and VEGF-E, which act through a cognate VEFG receptor (i.e., VEGFR) to induce angiogenesis or an angiogenic process. The term "VEGF" includes any member of the class of growth factors that binds to a VEGF receptor such as VEGF -1 (Flt-1), VEGFR-2 (KDR/Flk-1), or VEGFR-3 (FLT-4). The term "VEGF" can be used to refer to a "VEGF" polypeptide or a "VEGF" encoding gene or nucleic acid.

[0032] The term "effective amount," when used in connection with an ophthalmological disease of NVAMD, refers to an amount of the compositions of the invention comprising ARC 1905 or another pharmaceutically acceptable salt thereof and a VEGF antagonist or a pharmaceutically acceptable salt thereof that is useful to treat or prevent NVAMD. The "effective amount" can vary depending upon the mode of administration, specific locus of the

ophthalmological disease, the age, body weight, and general health of the mammal.

[0033] Unless indicated otherwise, all percentages and ratios are

calculated by weight based on the total weight of the composition.

Methods For Treating Or Preventing NVAMD

[0034] In some embodiments, an anti-C5 agent and the VEGF antagonist are administered within 24 hours of each other. In some embodiments, an anti- C5 agent and the VEGF antagonist are administered on the same day. In some embodiments, an anti-C5 agent and the VEGF antagonist are administered concurrently or sequentially. In some embodiments, an anti-C5 agent is administered within about 1 min, about 2 min, about 5 min, about 10 min, about 15 min, about 20 min, about 25 min, about 30 min, about 40 min, about 50 min, about 60 min, about 90 min, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 24 hours or about 48 hours of administration of the VEGF antagonist. In some embodiments, the VEGF antagonist is

administered prior to administration of the anti-C5 agent. In other

embodiments, the anti-C5 agent is administered prior to administration of the VEGF antagonist. In some embodiments, an anti-C5 agent is administered at least about 1 min, about 2 min, about 5 min, about 10 min, about 15 min, about 20 min, about 25 min, about 30 min, about 40 min, about 50 min, about 60 min, about 90 min, about 2 hours, about 4 hours, about 6 hours, about 8 hours, about 12 hours, about 24 hours or about 48 hours before or after administration of the VEGF antagonist. In some embodiments, an anti-C5 agent and a VEGF antagonist are present in the same pharmaceutical composition and administered as a co-formulation.

[0035] In one aspect, a method for treating or preventing NVAMD is provided, comprising administering to a subject in need thereof (a) a

therapeutically effective amount of on an anti-C5 agent, wherein the anti-C5 agent is a pegylated or unpegylated aptamer that binds to C5 complement and has the sequence of SEQ ID NO: 1 or another pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in an amount that is effective for treating or preventing NVAMD, and wherein the administration comprises administering the VEGF antagonist followed by administration of about 4.0 mg of said anti-C5 agent approximately 48 hours after administration of the VEGF antagonist.

[0036] In another aspect of the invention, a method for treating or preventing NVAMD is provided, comprising administering to a subject in need thereof (a) a therapeutically effective amount on an anti-C5 agent, wherein the anti-C5 agent is a pegylated or unpegylated aptamer that binds to C5

complement and has the sequence of SEQ ID NO: 1 or another

pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in an amount that is effective for treating or preventing NVAMD, and wherein the administration comprises:

[0037] a first administration period which occurs once every month, ± about seven days, wherein throughout said first administration period a first dose of the anti-C5 agent is administered on the same day following

administration of the VEGF antagonist and a second dose of the anti-C5 agent is administered about 14 days after administration of the VEGF antagonist; and

[0038] a second administration period commencing after the first administration period and which occurs once every month, ± about seven days, wherein a single dose of the anti-C5 agent is administered on the same day following administration of the VEGF antagonist.

[0039] In another aspect of the invention, a method for treating or preventing NVAMD is provided, comprising administering to a subject in need thereof (a) a therapeutically effective amount on an anti-C5 agent, wherein the anti-C5 agent is a pegylated or unpegylated aptamer that binds to C5

complement and has the sequence of SEQ ID NO: 1 or another

[0040] a first administration period which occurs once every month, ± about seven days, wherein throughout said first administration period a first dose of the anti-C5 agent is administered on the same day following

[0041] a second administration period commencing after the first administration period and which occurs once every month, ± about seven days, wherein the anti-C5 agent is administered as a monotherapy and is followed about 48 hours later by administration of a combination of the VEGF antagonist followed by administration of the anti-C5 agent on the same day. According to another aspect of the invention, the first administration period is at least about 3 months.

VEGF Antagonists

[0042] In one embodiment, the VEGF antagonist is the antibody

ranibizumab or a pharmaceutically acceptable salt thereof (see US Patent No. 7,060,269 (Figure 1) for the heavy chain and light chain variable region sequences, which is hereby incorporated by reference in its entirety).

Ranibizumab is commercially available under the trademark Lucentis®.

[0043] In another embodiment, the VEGF antagonist is the antibody bevacizumab or a pharmaceutically acceptable salt thereof (see US Patent No. 6,054,29 for the heavy chain and light chain variable region sequences, which is hereby incorporated by reference in its entirety). Bevacizumab is commercially available under the trademark Avastin®.

[0044] In another embodiment, the VEGF antagonist is aflibercept or a pharmaceutically acceptable salt thereof (Do et al. (2009) Br J Ophthalmol. 93: 144-9, which is hereby incorporated by reference in its entirety). Aflibercept is commercially available under the trademark Eylea®.

[0045] In one embodiment, the VEGF antagonist is tivozanib or a pharmaceutically acceptable salt thereof (US Patent No. 6,821,987, which is hereby incorporated by reference in its entirety). [0046] In one embodiment, the VEGF antagonist is pegaptanib or a pharmaceutically acceptable salt thereof (US Patent No. 6,051,698 (Figure 1), which is hereby incorporated by reference in its entirety). A composition comprising pegaptanib is commercially available under the trademark

Macugen®.

[0047] In another embodiment, the VEGF antagonist is sorafenib or a pharmaceutically acceptable salt thereof (Kernt et al. (2008) Acta Ophthalmol. 86:456-8, which is hereby incorporated by reference in its entirety). A

composition comprising sorafenib is commercially available under the trademark Nexavar®.

Anti-C5 Agent

[0048] In one embodiment, the anti-C5 agent is ARC 1905. ARC 1905 is a PEGylated RNA aptamer consisting of a 13 kDa modified RNA aptamer that is conjugated at the 5' terminus to a -43 kDa branched polyethylene glycol (PEG) moiety. The aptamer portion of ARC1905 is 39 nucleotides in length and modified with a primary amine at the 5' terminus to provide a reactive site for subsequent site specific conjugation ("PEGylation"). The nucleotide

composition consists of 2' hydroxyl purines and modified 2' fluoro pyrimi dines and 2' methoxy purines. The modified nucleotides minimize endonuclease digestion and contribute to activity. The 3 ' terminus is capped with an

"inverted" 3 '-3' phosphodiester linkage to a deoxythymidine nucleotide (idT) to minimize 3' exonuclease degradation. PEGylation is employed because it confers delayed clearance in vivo without diminishing affinity or activity. All concentrations and doses for ARC 1905 (1 μΜ = 13 μg/mL) are based on the mass of the aptamer, exclusive of the PEG mass.

[0049] ARC1905 has the structure set forth below:

[0050] or a pharmaceutically acceptable salt thereof, where Aptamer = fCmGfCfCGfCm Gm GfUfCfUfCm AmGm GfCGfCfUm Gm Am GfUfCfUmGmA mGfUfUfUAfCf CfUmGfCmG-3T (SEQ ID NO: 1)

[0051] wherein fC and fU = 2'-fluoro nucleotides, and mG and mA = 2'- OMe nucleotides and all other nucleotides are 2'-OH and where 3T indicates and inverted deoxy thymidine. (US Patent No. 7,538,211 which is hereby incorporated by reference in its entirety). In some embodiments, each 20 kDa mPEG of the above structure has a molecular weight of about 20 kDa.

[0052] ARC 1905 drug product is formulated at a concentration of 20 mg/mL (oligonucleotide mass) in phosphate buffered saline at pH 6.8-7.8 as a sterile aqueous solution. Sodium hydroxide or hydrochloric acid may be added for pH adjustment. ARC 1905 drug product is presented in a USP Type I high recovery glass vial that contains a 0.5 mL v-shaped well sealed with fluorotec coated, halobutyl rubber stoppers and aluminum crimp seals. The product is supplied in single use vials and is preservative-free and intended for intravitreal injection only. The product should not be used if cloudy or if particles are present. Injection volume for each administration of ARC1905 is 0.1 mL (100 μΐ.) providing a 2 mg/eye dose.

[0053] In other embodiments, the anti-C5 agent is Soliris® (ecluzimab, US Patent No. 6,355,245 which is hereby incorporated by reference in its entirety) or LFG-316 (Novartis; US Patent Application No. 2010/0034809 which is hereby incorporated by reference in its entirety), or A217 (Quidel Corp., San Diego, CA).

Example 1

[0054] ARC 1905 is administered to treatment-naive patients (patients having any prior treatment for AMD or any intravitreal treatment for any indication in the study eye prior to baseline visit, except oral supplements of vitamins and minerals, are excluded) with active subfoveal NVAMD (as documented by fluorescein angiography) in combination with Lucentis

(ranibizumab) according to the following: Drug Supply ARC 1905 Active

Ingredient: ARC 1905 is formulated as

20 mg/mL solution for injection

Excipients: Sodium Chloride, USP

Sodium Phosphate Monobasic, Monohydrate, USP Sodium Phosphate Dibasic, Heptahydrate, USP

Nitrogen, NF

Sodium Hydroxide, NF (as needed)

Hydrochloric acid, NF (as needed)

Water for injection, USP

Lucentis^®

[0055] Lucentis^® is a recombinant humanized IgGl kappa isotype monoclonal antibody fragment designed for intraocular use. Lucentis^® has a molecular weight of approximately 48 kilodaltons and is produced by an E. coli expression system in a nutrient medium containing the antibiotic tetracycline. Tetracycline is not detectable in the final product.

Dose and Administration

[0056] ARC1905 and Lucentis^® are injected without dilution.

[0057] ARC1905 is supplied in a single-use glass vial as noted above.

[0058] Lucentis^® injection is a preservative-free colorless to pale yellow sterile solution, presented in a single-use glass vial or as a pre-filled syringe designed to deliver 0.05 mL of 10 mg/mL ranibizumab injection aqueous solution with 10 mM histidine HC1, 10% a, a-trehalose dihydrate, 0.01% polysorbate 20, pH 5.5. Where a vial is used, aseptic technique, all (0.2 mL) of the Lucentis^® injection vial contents are withdrawn through a 5-micron 19- gauge filter needle attached to a 1-cc tuberculin syringe. The filter needle should be discarded after withdrawal of the vial contents and should not be used for intravitreal injection. Where a vial is used the filter needle should be replaced with a sterile 30-gauge χ 1/2-inch needle for the intravitreal injection. The contents should be expelled until the plunger tip is aligned with the line that marks 0.05 mL on the syringe.

[0059] Intravitreal injections are administered according to the following regimens:

[0060] I. ARC1905 and Lucentis are administered monthly for a total of 6 times, in the following sequence, 2 days apart:

• Day 0: Lucentis^® 0.5 mg/eye

• Day 2: ARC1905 4 mg/eye (administered as two injections of ARC 1905 2 mg)

[0061] II. ARC 1905 and Lucentis are administered monthly for a total of 6 times, in the following sequence:

• Lucentis^® 0.5 mg/eye followed by ARC 1905 2 mg/eye on the same day [0062] III. Induction Phase: ARC 1905 and Lucentis are administered monthly for a total of 3 times, in the following sequence, 14 days apart:

• Day 0: Lucentis^® 0.5 mg/eye followed by ARC1905 2 mg/eye on the same day

• Day 14: ARC1905 2 mg/eye (monotherapy)

[0063] Maintenance Phase: ARC1905 and Lucentis are administered monthly for a total of 3 times (Month 3 - Month 5), in the following sequence:

• Lucentis^® 0.5 mg/eye followed by ARC 1905 2 mg/eye on the same day

[0064] IV. Induction Phase: ARC 1905 and Lucentis are administered monthly for a total of 3 times (Day 1 - Month 2), in the following sequence, 14 days apart:

• Day 0: Lucentis^® 0.5 mg/eye followed by ARC1905 2 mg/eye on the same day

• Day 14: ARC1905 2 mg/eye (monotherapy)

[0065] Maintenance Phase: ARC1905 and Lucentis are administered monthly for a total of 3 times (Month 3 - Month 5), in the following sequence, 2 days apart:

• Day 0: ARC1905 2 mg/eye (monotherapy)

• Day 2: Lucentis^® 0.5 mg/eye followed by ARC1905 2 mg/eye on the same day [0066] All subjects will have a final follow-up visit at Month 6. Example 2

[0067] Visual acuity testing is performed at each visit using the procedure set forth in Example 2 of WO 2016/025313 ( herein incorporated in its entirety by reference).

Incorporation By Reference

[0068] All publications and patent applications disclosed in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method for treating or preventing neovascular age-related macular degeneration, comprising administering to a subject in need thereof (a) a therapeutically effective amount on an anti-C5 agent, wherein the anti-C5 agent is a pegylated or unpegylated aptamer that binds to C5 complement and has the sequence of SEQ ID NO: 1 or another pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in an amount that is effective for treating or preventing neovascular AMD, and wherein the administration comprises administering the VEGF antagonist and about 4.0 mg of said anti-C5 agent.

2. The method of claim 1 wherein the anti-C5 agents comprises the structure set forth below:

or a pharmaceutically acceptable salt thereof, where Aptamer = fCmGfCfCGfCm Gm GfUfCfUfCm AmGm GfCGfCfUm Gm Am GfUfC fUmGmAmGfUfUfUAfCf CfUmGfCmG-3T (SEQ ID NO: 1) wherein fC and fU = 2'-fluoro nucleotides, and mG and mA = 2'-OMe nucleotides and all other nucleotides are 2'-OH and where 3T indicates and inverted deoxy thymidine.

3. The method of claim 2 wherein the VEGF antagonist is selected from ranibizumab, bevacizumab, ESBA 1008 or aflibercept.

4. The method of claim 2, wherein the VEGF antagonist is bevacizumab and is administered intravitreally in an amount of about 1.25 mg/eye.

5. The method of claim 2, wherein the VEGF antagonist is aflibercept and is administered intravitreally in an amount of about 2 mg/eye.

6. The method of claim 2, wherein the VEGF antagonist is ranibizumab and is administered intravitreally in an amount of about 0.5 mg/eye.

7. The method of claim 2 wherein (a) and (b) are administered monthly.

8. The method of claim 2 wherein the anti-C5 agent is administered about 48 hours after administration of said VEGF antagonist.

9. A method for treating or preventing neovascular age-related macular degeneration, comprising administering to a subject in need thereof (a) a therapeutically effective amount on an anti-C5 agent, wherein the anti-C5 agent is a pegylated or unpegylated aptamer that binds to C5 complement and has the sequence of SEQ ID NO: 1 or another pharmaceutically acceptable salt thereof and (b) a VEGF antagonist, wherein (a) and (b) are administered in an amount that is effective for treating or preventing neovascular AMD, and wherein the administration comprises a first administration period which occurs once every month, ± about seven days, wherein said first administration period comprises administration of an initial dose of the anti-C5 agent administered on the same day with administration of the VEGF antagonist and a second dose of the anti-C5 agent administered about 14 days after the initial dose.

10. The method of claim 9 further comprising a second administration period after said first administration period is completed, wherein said second administration period occurs once every month, ± about seven days, and comprises administration of a combination dose of the anti-C5 agent on the same day with administration of the VEGF antagonist.

11. The method of claim 10 further comprising administration of a monotherapy dose of the anti-C5 agent about 48 hours prior to administration of said combination dose.

12. The method of claim 9 or 10 wherein the anti-C5 agents comprises the structure set forth below:

13. The method of claim 12 wherein the anti-C5 agent is administered as a 2 mg dose.

14. The method of claim 13, wherein the VEGF antagonist is bevacizumab and is administered intravitreally in an amount of about 1.25 mg/eye.

15. The method of claim 13, wherein the VEGF antagonist is aflibercept and is administered intravitreally in an amount of about 2 mg/eye.

16. The method of claim 13, wherein the VEGF antagonist is ranibizumab and is administered intravitreally in an amount of about 0.5 mg/eye.

17. The method of claim 13, wherein each of said first and second administration periods continue for at least 3 consecutive months.

18. The method of claim 12 wherein during said first administration period, the anti-C5 agent is administered after the VEGF antagonist.

19. The method of claim 10 wherein said combination dose comprises administration of the anti-C5 agent after administration of the VEGF antagonist.