Method for treating or preventing idiopathic polypoidal choroidal vasculopathy (IPCV)

Abstract

A method for treating or preventing idiopathic polypoidal choroidal vasculopathy is provided comprising intravitreal injections of Zimura™ (or another anti-C5 agent) and Eylea® (or another VEGF antagonist).

Claims

1. A method for treating idiopathic polypoidal choroidal vasculopathy (IPCV), comprising administering to a subject in need thereof: (a) an anti-C5 agent and (b) a VEGF antagonist, wherein (a) and (b) are administered in an amount that is effective for treating IPCV, wherein the administering occurs for a first administration period induction phase followed by a second administration period maintenance phase wherein only the anti-C5 agent is administered monthly throughout the maintenance phase, and wherein the anti-C5 agent is a pegylated aptamer (avacincaptad pegol) with the following nucleotide sequence: fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmG mAmGfUfUfUAfCf CfUmGfCmG-3T (SEQ ID NO: 1), or a pharmaceutically acceptable salt thereof, 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 an inverted deoxythymidine.

2. The method of claim 1 wherein the administering occurs once every month, ± about seven days, for a first administration period of at least three consecutive months, said first administration period comprises administration of (a) and (b) on the same day followed by administration of a subsequent dose of (a) after about 14 days.

3. The method of claim 2 wherein (a) and (b) are administered for a second administration period after completion of said first administration period, wherein (a) is administered at least once every month during said second administration period and (b) is administered once every other month together with administration of (a) during said second administration period.

4. The method of claim 3 wherein an additional dose of (a) is administered during said second administration period during months when (a) and (b) are both administered.

5. The method of claim 4 wherein said additional dose of (a) is administered about 48 hours before administering (a) and (b) on the same day.

6. The method of claim 3 wherein (a) and (b) are administered on the same day during the second administration period.

7. The method of claim 3 wherein avacincaptad pegol is administered intravitreally in an amount of 4.0 mg/eye once every month when (b) is not administered.

8. The method of claim 3 wherein the avacincaptad pegol or pharmaceutically acceptable salt thereof is administered intravitreally and in an amount of about 2.0 mg/eye.

9. The method of claim 8 wherein the VEGF antagonist is ranibizumab, bevacizumab, pegaptanib sodium, tivozanib, ESBA1008 or aflibercept.

10. The method of claim 9 wherein the VEGF antagonist is administered intravitreally.

11. The method of claim 10 wherein the VEGF antagonist is aflibercept and is administered in an amount of about 2 mg/eye, bevacizumab and is administered in an amount of about 1.25 mg/eye, or ranibizumab and is administered in an amount of about 0.5 mg/eye.

12. The method of claim 11 wherein the VEGF antagonist is aflibercept and is administered in an amount of about 2 mg/eye.

13. The method of claim 12 wherein avacincaptad pegol is administered intravitreally in an amount of 4.0 mg/eye once every month when (b) is not administered.

14. The method of claim 12 wherein avacincaptad pegol is administered after aflibercept during said first administration period.

15. The method of claim 14 wherein an additional dose of avacincaptad pegol is administered during said second administration period on months when avacincaptad pegol and aflibercept are both administered.

16. The method of claim 1 wherein (a) is administered after (b) during said first administration period.

17. The method of claim 1 wherein the avacincaptad pegol or pharmaceutically acceptable salt thereof is administered intravitreally and in an amount of about 2.0 mg/eye.

18. A method for treating idiopathic polypoidal choroidal vasculopathy (IPCV), comprising administering to a subject in need thereof: (a) an anti-C5 agent and (b) a VEGF antagonist, wherein (a) and (b) are administered in an amount that is effective for treating IPCV, and wherein the administering occurs for a first administration period induction phase followed by a second administration period maintenance phase wherein only the anti-C5 agent is administered monthly throughout the maintenance phase, wherein the anti-C5 agent is selected from the group consisting of eculizumab, LFG-316, and A217.

Description

DETAILED DESCRIPTION OF THE INVENTION

Definitions

(1) 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) (see FIGS. 2(A) and (B)) that arise by, e.g., alternative splicing of the VEGF-A/VPF gene including VEGF121, VEGF165 and VEGF189. 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 VEGFR-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.

(2) The term “effective amount,” when used in connection with an ophthalmological disease of IPCV, refers to an amount of the compositions of the invention comprising Zimura™ (or another anti-C5 agent) and Eylea® (or another VEGF antagonist) that is useful to treat or prevent IPCV. 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.

(3) Unless indicated otherwise, all percentages and ratios are calculated by weight based on the total weight of the composition.

(4) Zimura™ 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 Zimura™ 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 pyrimidines 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 Zimura™ (1 μM=13 μg/mL) are based on the mass of the aptamer, exclusive of the PEG mass.

(5) Eylea® (aflibercept) is a recombinant fusion protein consisting of portions of human VEGF receptors 1 and 2 extracellular domains fused to the Fc portion of human IgG1 formulated as an iso-osmotic solution for intravitreal administration. Aflibercept is a dimeric glycoprotein with a protein molecular weight of 97 kilodaltons (kDa) and contains glycosylation, consisting of an additional 15% of the total molecular mass, resulting in a total molecular weight of 115 kDa. Aflibercept is produced in recombinant Chinese Hamster Ovary (CHO) cells.

(6) VEGF Antagonists

(7) In one embodiment, the VEGF antagonist is the antibody ranibizumab or a pharmaceutically acceptable salt thereof (see U.S. Pat. No. 7,060,269 (FIG. 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.

(8) In another embodiment, the VEGF antagonist is the antibody bevacizumab or a pharmaceutically acceptable salt thereof (see U.S. Pat. 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.

(9) 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.

(10) In one embodiment, the VEGF antagonist is tivozanib or a pharmaceutically acceptable salt thereof (U.S. Pat. No. 6,821,987, which is hereby incorporated by reference in its entirety).

(11) In one embodiment, the VEGF antagonist is pegaptanib or a pharmaceutically acceptable salt thereof (U.S. Pat. No. 6,051,698 (FIG. 1), which is hereby incorporated by reference in its entirety). A composition comprising pegaptanib is commercially available under the trademark Macugen.

(12) 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.

(13) Anti-C5 Agent

(14) In one embodiment, the anti-C5 agent is Zimura™ (avacincaptad pegol), also known as ARC1905. ARC1905 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 pyrimidines 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 ARC1905 (1 μM=13 μg/mL) are based on the mass of the aptamer, exclusive of the PEG mass.

(15) ARC1905 has the Structure Set Forth Below:

(16) ##STR00001##
or a pharmaceutically acceptable salt thereof, where Aptamer fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCf 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. (U.S. Pat. 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.

(17) ARC1905 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. ARC1905 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 μL) providing a 2 mg/eye dose.

(18) In other embodiments, the anti-C5 agent is Soliris® (eculizumab, U.S. Pat. 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, Calif.).

(19) Methods For Treating Or Preventing IPCV

(20) The present invention provides new and improved methods and compositions for treating and preventing IPCV.

(21) In one embodiment, Zimura™ (or another anti-C5 agent) is administered in combination with Eylea® (or another VEGF antagonist such as ranibizumab, bevacizumab, pegaptanib sodium, tivozanib, abicipar pegol or ESBA1008). The invention provides treatment regimens, including treatment and dosing regimens, related to the coadministration of Zimura™ (or another anti-C5 agent) and Eylea® (or another VEGF antagonist).

(22) Zimura™ 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 have been added for pH adjustment. Zimura™ 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 red aluminum crimp seals. The product is preservative-free and intended for intravitreal injection only. The product should not be used if cloudy or if particles are present.

(23) Zimura™ will be supplied in single use vials for intravitreal injection.

(24) Injection volume for each administration of Zimura™ will be 0.1 mL (100 μL) providing a 2 mg/eye dose.

(25) In some embodiments, Zimura™ (or another anti-CF agent) and Eylea® (or another VEGF antagonist) are administered within 24 hours of each other. In some embodiments, Zimura™ and Eylea® are administered on the same day. In some embodiments, Zimura™ and Eylea® are administered concurrently or sequentially. In some embodiments, Zimura™ 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 Eylea®. In some embodiments, Eylea® is administered prior to administration of Zimura™. In other embodiments, Zimura™ is administered prior to administration of Eylea®. In some embodiments, Zimura™ 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 after administration of Eylea®. In some embodiments, Zimura™ and Eylea® are present in the same pharmaceutical composition and administered as a co-formulation.

(26) In one aspect, a method for treating or preventing IPCV is provided, comprising administering to a subject in need thereof (a) a therapeutically effective amount of Zimura™, wherein Zimura™ is a pegylated or unpegylated aptamer and (b) Eylea®, wherein (a) and (b) are administered in an amount that is effective for treating or preventing IPCV, and wherein the administration comprises administering Eylea® followed by administration of about 2.0 mg of Zimura™ approximately 48 hours after administration of Eylea®.

(27) In another aspect, a method for treating or preventing IPCV in treatment experienced subjects is provided. Treatment experienced is defined as 3 sequential Eylea® injections (or other antiVEGF agent) within the previous four (4) months with <1 line of visual improvement on the Snellen chart (not ETDRS chart) since the start of Eylea® treatment.

(28) In another aspect of the invention, a method for treating or preventing IPCV is provided, comprising administering to a subject in need thereof (a) a therapeutically effective amount of Zimura™, wherein Zimura™ is a pegylated or unpegylated aptamer that binds to C5 complement and (b) Eylea®, wherein (a) and (b) are administered in an amount that is effective for treating or preventing IPCV, and wherein the administration comprises: an induction phase administration period where Zimura™ and Eylea® are administered on Day 1, Month 1, and Month 2 in the following sequence, ±about seven days, wherein throughout said induction phase administration period a first dose of Eylea® is administered followed by an administration of Zimura™ on the same day and a second dose of Zimura™ is administered about 14 days later; and a maintenance phase administration period which occurs after the induction phase administration period wherein on Months 3, 5 and 7, Zimura™ is administered once monthly, and once every month on Months 4, 6, and 8, ±about seven days, wherein a single dose of Eylea® is administered followed by a single dose of Zimura™ on the same day. In another embodiment, an additional dose of Zimura™ is administered at months 4, 6, and 8 prior to the administration of Eylea and Zimura on the same day.

Example 1

(29) Drug Supply

(30) Zimura™

(31) Active Ingredient: Zimura™ 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
Dose and Administration

(32) Zimura™ is supplied in a single-use glass vial as noted above.

(33) Zimura™ and Eylea® will be injected without dilution.

(34) Zimura™ is supplied in a single-use glass vial. To prepare for injection of Zimura™, use a 19 gauge filter needle (supplied) and a new 1-mL sterile syringe to withdraw about 0.2 mL of Zimura™ from the glass vial using aseptic technique. Remove the filter needle and replace it with the sterile 30-gauge injection needle (supplied). Expel any air bubbles and adjust the injection volume to 0.1 mL (100 μL).

(35) Eylea® is a sterile, clear, and colorless pale yellow solution. Eylea® is supplied as a preservative-free, sterile, aqueous solution in a single-use, glass vial designed to deliver 0.05 mL (50 microliters) of Eylea® 2 mg (40 mg/mL in 10 mM sodium phosphate, 40 mM sodium chloride, 0.03% polysorbate 20, and 5% sucrose, pH 6.2). Eylea® will be administered in a total injection volume of 0.05 mL (50 μL). Intravitreal injections are administered according to the following regimens:

(36) Induction Phase: Zimura™ and Eylea® are administered on Day 1, Month 1, and Month 2, 14 days apart:

(37) Day 1: Eylea® 2 mg/eye followed by Zimura™ 2 mg/eye on the same day

(38) Day 14: Zimura™ 2 mg/eye

(39) Maintenance Phase:

(40) Zimura™ 2 mg/eye is administered on Months 3, 5, and 7

(41) Eylea® 2 mg/eye is administered followed by Zimura™ 2 mg/eye on the same day on Months 4, 6, and 8

Example 2

(42) Zimura™ and Eylea® are supplied as noted in Example 1. They are administered according to the following regimen:

(43) Induction Phase: Zimura™ and Eylea® are administered on Day 1, Month 1, and Month 2, 14 days apart:

(44) Day 1: Eylea® 2 mg/eye followed by Zimura™ 2 mg/eye on the same day

(45) Day 14: Zimura™ 2 mg/eye

(46) Maintenance Phase:

(47) Zimura™ 4 mg/eye (administered as two injections of Zimura™ 2 mg/eye) is administered on Months 3, 5, and 7

(48) Zimura™ 2 mg/eye is administered, followed by, 2 days later, an administration of Eylea® 2 mg/eye followed by Zimura™ 2 mg/eye on the same day, on Months 4, 6, and 8.

Example 3

(49) 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

(50) 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.