Methods and formulations for treating vascular eye diseases

Inactive Publication Date: 2016-05-26
REGENERON PHARM INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015]According to another aspect of the present invention, methods are provided for reducing the dependence and treatment burden of frequent intravitreal injections in a subject with a vascular eye disease or disorder. The methods comprise sequentially administering an initial dose followed by one or more secondary doses of a therapeutically effective amount of a pharmaceutical composition comprising an Ang-2 inhibitor in combination with a VEGF antagonist to the subject in need thereof; wherein the administration of the pharmaceutical composition is reduced to once every 9 weeks as compared to a subject who has been administered the VEGF antagonist alone.
[0026]According to another aspect of the present invention, a stable liquid pharmaceutical formulation is provided, comprising: (i) a VEGF antagonist; (ii) an antibody or antigen-binding fragment thereof that specifically binds to Ang-2; (iii) a buffer; (iv) a non-ionic detergent; (v) a tonicity agent; and (vi) a stabilizer. In one embodiment, a stable ophthalmic formulation is provided, comprising: (i) a VEGF antagonist; (ii) an antibody or antigen-binding fragment thereof that specifically binds to Ang-2; (iii) a buffer; (iv) a non-ionic detergent; (v) a tonicity agent; and (vi) a stabilizer.

Problems solved by technology

However, in AMD, although ˜95% of patients maintained their vision, only approximately 30% of patients achieved an improvement of 15 or more letters in best corrected visual acuity (BCVA) at 1 year.

Method used

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  • Methods and formulations for treating vascular eye diseases
  • Methods and formulations for treating vascular eye diseases
  • Methods and formulations for treating vascular eye diseases

Examples

Experimental program
Comparison scheme
Effect test

example 1

Effects of Combined Inhibition of VEGF and Ang2 Using Aflibercept (VEGF Trap) and Anti-Ang2 Antibody on the Developing Retinal Angiogenesis in Mice

[0141]Introduction: VEGF is the key modulator of angiogenesis in normal and pathological angiogenesis. However, other growth factors are also involved in angiogenesis and are able to mediate blood vessel resistance to anti-VEGF therapies. Angiopoietin-2 (Ang2) was shown to be involved in blood vessel growth and regression in various circumstances in a context-dependent manner. In this study we tested the effects of VEGF blockade using aflibercept alone and in combination with Ang2 inhibition with an anti-Ang2 antibody on blood vessel growth and regression in a normal retinal vascular development (RVD) model.

[0142]Human anti-Ang-2 antibodies were generated as described in US Patent Application Publication No. US20110027286. The exemplary anti-Ang-2 antibody used in the present and following Examples is the human anti-Ang-2 antibody designa...

example 2

Effect of IVT Injection of Co-Formulated mAb1 and Aflibercept on DL-Alpha-Aminoadipic Acid (DL-Alpha-AAA)-Induced Retinal Neovascularization (RNV) in Rabbit Eyes

[0148]The glial toxin DL-alpha-AAA targets retinal Muller cells and astrocytes and leads to neovascularization and chronic vascular leak lasting at least 12 months (Kato et al 1993; Neuroscience 57: 473). The purpose of this study was to evaluate the effects of IVT injection of co-formulated Anti-Ang2 and aflibercept on RNV induced by DL-alpha-AAA.

[0149]Methods: Male New Zealand White Rabbits (>2 kg body weight) were treated with a single intravitreal injection of DL-alpha-AAA to induce RNV. The leak was monitored and quantitated non-invasively using fluorescein angiography (FA). Pathological vasculature and a relatively invariable leakage area were established over 13 weeks post injection. Upon disease establishment, the subjects were split into three groups for treatment, as shown below:

[0150]Group I: 125 μg / 50 μl of aflib...

example 3

Systemic Administration of mAb1 Alone or Co-Treatment with VEGF Trap-Eye IVT on DL-AAA Induced Retinal Neo-Vascular Leak in Rabbit Eyes

[0155]The purpose of this study was to evaluate the effects of co-treatment of Anti-Ang2 antibody and aflibercept on RNV induced by DL-alpha-AAA, wherein the intravitreal administration of aflibercept was followed by systemic administrations of mAb1. The rationale of this study was to try and maintain the suppression of leakage over longer periods of time with an initial IVT injection of aflibercept and follow up with systemic injections once in two weeks (q2w) of anti-Ang 2 antibody.

[0156]As disclosed in Example 2, retinal neovascularization was induced in male New Zealand rabbits with a single intravitreal injection of DL-alpha-AAA. Stable retinal neovascularization and vascular leak was established 10 weeks post induction. After ten weeks of disease establishment, the subjects were split into four groups with balanced leakage severity and treatmen...

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Abstract

The present invention provides methods for treating, preventing or reducing the severity of an eye disease. The methods of the present invention comprise administering to a subject in need thereof a therapeutic composition comprising an angiopoietin-2 (Ang-2) inhibitor such as an anti-Ang-2 antibody in combination with a vascular endothelial growth factor (VEGF) antagonist (e.g., aflibercept).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit under 35 U.S.C. §119(e) of US provisional application Nos. 62 / 084,003, filed on Nov. 25, 2014; and 62 / 147,232, filed on Apr. 14, 2015, the disclosures of each herein incorporated by reference in their entireties.FIELD OF THE INVENTION[0002]The present invention relates to methods of treating or ameliorating at least one symptom or indication of a vascular eye disease comprising administering a pharmaceutical formulation comprising an angiopoietin-2 (Ang-2) inhibitor and a vascular endothelial growth factor (VEGF) antagonist to a subject in need thereof.BACKGROUND[0003]Vascular eye diseases are the leading cause of vision loss in today's aging population. These diseases are characterized by abnormal ‘leaky’ blood vessels growing into the retina. Two of the largest contributors to this patient population are diabetic retinopathy and exudative age-related macular degeneration.[0004]Diabetic retinopathy (DR...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K39/395
CPCA61K39/3955A61K38/179A61K39/39591C07K16/22A61K2039/505A61K2039/54C07K2319/30A61P27/02A61P9/10A61P3/10A61K2300/00A61K9/0048A61K47/02A61K47/26C07K14/71C07K16/46C07K2317/21C07K2317/565C07K2317/76C07K2319/32
Inventor VITTI, ROBERT L.ERICKSON, KRISTINE A.CHU, KAREN W.WIEGAND, STANLEY J.CAO, JINGTAILOBOV, IVAN B.WADHWA, SAURABHGRAHAM, KENNETH S.DIX, DANIEL
Owner REGENERON PHARM INC
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