Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration

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Abstract

Background

We present the results of a Phase 2a randomized controlled trial investigating the safety, and secondary endpoints of subretinal rAAV.sFLT-1 gene therapy in patients with active wet age-related macular degeneration (wAMD).

Methods

All patients (n = 32), ( ClinicalTrials.gov; NCT01494805), received ranibizumab injections at baseline and week 4, and thereafter according to prespecified criteria. Patients in the gene therapy group (n = 21) received rAAV.sFLT-1 (1 × 10 ¹¹ vg). All patients were assessed every 4 weeks to the week 52 primary endpoint.

Findings

Ocular adverse events (AEs) in the rAAV.sFLT-1 group were mainly procedure related and self-resolved. All 11 phakic patients in the rAAV.sFLT-1 group showed progression of cataract following vitrectomy. No systemic safety signals were observed and none of the serious AEs were associated with rAAV.sFLT-1. AAV2 capsid was not detected and rAAV.sFLT-1 DNA was detected transiently in the tears of 13 patients. ELISPOT analysis did not identify any notable changes in T-cell response. In the rAAV.sFLT-1 group 12 patients had neutralizing antibodies (nAb) to AAV2. There was no change in sFLT-1 levels in bodily fluids. In the rAAV.sFLT-1 group, Best Corrected Visual Acuity (BCVA) improved by a median of 1.0 (IQR: − 3.0 to 9.0) Early Treatment Diabetic Retinopathy Study (ETDRS) letters from baseline compared to a median of − 5.0 (IQR: − 17.5 to 1.0) ETDRS letters change in the control group. Twelve (57%) patients in the rAAV.sFLT-1 group maintained or improved vision compared to 4 (36%) in the control group. The median number of ranibizumab retreatments was 2.0 (IQR: 1.0 to 6.0) for the gene therapy group compared to 4.0 (IQR: 3.5 to 4.0) for the control group.

Interpretation rAAV.sFLT-1 combined with the option for co-treatment appears to be a safe and promising approach to the treatment of wAMD.

Funding

National Health and Medical Research Council of Australia (AP1010405), Lions Eye Institute, Perth Australia, Avalanche Biotechnologies, Menlo Pk, CA, USA.

Highlights

•

Subretinal injection of rAAV.sFLT-1 was found to be safe in 21 patients with wet age-related macular degeneration.
•

Visual acuity was maintained in gene therapy treated patients over the 52 week period.
•

The gene therapy treated group of patients had a trend towards fewer ranibizumab retreatments than the control group.

Wet age-related macular degeneration (wAMD) is a common cause of vision loss in the elderly. We propose to use gene therapy to treat this disease. This study reinforces the findings from our Phase 1 study examining the safety of the delivery of rAAV.sFLT-1 by subretinal injection as a form of treatment of wAMD. The findings from this trial demonstrate that the surgical subretinal administration of rAAV.sFLT-1 has a favorable safety profile and that it can potentially be used in conjunction with current therapies to provide an improved outcome in the treatment of wAMD.

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Most cited references 22

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Ranibizumab and bevacizumab for neovascular age-related macular degeneration.

Daniel Martin, Maureen Maguire, Gui-shuang Ying … (2011)

Clinical trials have established the efficacy of ranibizumab for the treatment of neovascular age-related macular degeneration (AMD). In addition, bevacizumab is used off-label to treat AMD, despite the absence of similar supporting data. In a multicenter, single-blind, noninferiority trial, we randomly assigned 1208 patients with neovascular AMD to receive intravitreal injections of ranibizumab or bevacizumab on either a monthly schedule or as needed with monthly evaluation. The primary outcome was the mean change in visual acuity at 1 year, with a noninferiority limit of 5 letters on the eye chart. Bevacizumab administered monthly was equivalent to ranibizumab administered monthly, with 8.0 and 8.5 letters gained, respectively. Bevacizumab administered as needed was equivalent to ranibizumab as needed, with 5.9 and 6.8 letters gained, respectively. Ranibizumab as needed was equivalent to monthly ranibizumab, although the comparison between bevacizumab as needed and monthly bevacizumab was inconclusive. The mean decrease in central retinal thickness was greater in the ranibizumab-monthly group (196 μm) than in the other groups (152 to 168 μm, P=0.03 by analysis of variance). Rates of death, myocardial infarction, and stroke were similar for patients receiving either bevacizumab or ranibizumab (P>0.20). The proportion of patients with serious systemic adverse events (primarily hospitalizations) was higher with bevacizumab than with ranibizumab (24.1% vs. 19.0%; risk ratio, 1.29; 95% confidence interval, 1.01 to 1.66), with excess events broadly distributed in disease categories not identified in previous studies as areas of concern. At 1 year, bevacizumab and ranibizumab had equivalent effects on visual acuity when administered according to the same schedule. Ranibizumab given as needed with monthly evaluation had effects on vision that were equivalent to those of ranibizumab administered monthly. Differences in rates of serious adverse events require further study. (Funded by the National Eye Institute; ClinicalTrials.gov number, NCT00593450.).

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Causes and prevalence of visual impairment among adults in the United States.

Nathan Congdon, Benita J O'Colmain, Caroline C. W. Klaver … (2004)

To estimate the cause-specific prevalence and distribution of blindness and low vision in the United States by age, race/ethnicity, and gender, and to estimate the change in these prevalence figures over the next 20 years. Summary prevalence estimates of blindness (both according to the US definition of < or =6/60 [< or =20/200] best-corrected visual acuity in the better-seeing eye and the World Health Organization standard of < 6/120 [< 20/400]) and low vision (< 6/12 [< 20/40] best-corrected vision in the better-seeing eye) were prepared separately for black, Hispanic, and white persons in 5-year age intervals starting at 40 years. The estimated prevalences were based on recent population-based studies in the United States, Australia, and Europe. These estimates were applied to 2000 US Census data, and to projected US population figures for 2020, to estimate the number of Americans with visual impairment. Cause-specific prevalences of blindness and low vision were also estimated for the different racial/ethnic groups. Based on demographics from the 2000 US Census, an estimated 937 000 (0.78%) Americans older than 40 years were blind (US definition). An additional 2.4 million Americans (1.98%) had low vision. The leading cause of blindness among white persons was age-related macular degeneration (54.4% of the cases), while among black persons, cataract and glaucoma accounted for more than 60% of blindness. Cataract was the leading cause of low vision, responsible for approximately 50% of bilateral vision worse than 6/12 (20/40) among white, black, and Hispanic persons. The number of blind persons in the US is projected to increase by 70% to 1.6 million by 2020, with a similar rise projected for low vision. Blindness or low vision affects approximately 1 in 28 Americans older than 40 years. The specific causes of visual impairment, and especially blindness, vary greatly by race/ethnicity. The prevalence of visual disabilities will increase markedly during the next 20 years, owing largely to the aging of the US population.

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Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies.

Ursula Schmidt-Erfurth, Peter K Kaiser, Jean-François Korobelnik … (2014)

To determine efficacy and safety of intravitreal aflibercept in patients with neovascular age-related macular degeneration (AMD) during a second year of variable dosing after a first-year fixed-dosing period. Two randomized, double-masked, active-controlled, phase 3 trials. Two thousand four hundred fifty-seven patients with neovascular AMD. From baseline to week 52, patients received 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), 2 mg aflibercept every 4 weeks (2q4), 0.5 mg aflibercept every 4 weeks (0.5q4), or 2 mg aflibercept every 8 weeks (2q8) after 3 monthly injections. During weeks 52 through 96, patients received their original dosing assignment using an as-needed regimen with defined retreatment criteria and mandatory dosing at least every 12 weeks. Proportion of eyes at week 96 that maintained best-corrected visual acuity (BCVA; lost <15 letters from baseline); change from baseline in BCVA. Proportions of eyes maintaining BCVA across treatments were 94.4% to 96.1% at week 52 and 91.5% to 92.4% at week 96. Mean BCVA gains were 8.3 to 9.3 letters at week 52 and 6.6 to 7.9 letters at week 96. Proportions of eyes without retinal fluid decreased from week 52 (60.3% to 72.4%) to week 96 (44.6% to 54.4%), and more 2q4 eyes were without fluid at weeks 52 and 96 than Rq4 eyes (difference of 10.4% [95% confidence interval {CI}, 4.9-15.9] and 9.0% [95% CI, 3.0-15.1]). Patients received on average 16.5, 16.0, 16.2, and 11.2 injections over 96 weeks and 4.7, 4.1, 4.6, and 4.2 injections during weeks 52 through 96 in the Rq4, 2q4, 0.5q4, and 2q8 groups, respectively. The number of injections during weeks 52 through 96 was lower in the 2q4 and 2q8 groups versus the Rq4 group (differences of -0.64 [95% CI, -0.89 to -0.40] and -0.55 [95% CI, -0.79 to -0.30]; P < 0.0001, post hoc analysis). Incidences of Antiplatelet Trialists' Collaboration-defined arterial thromboembolic events were similar across groups (2.4% to 3.8%) from baseline to week 96. All aflibercept and ranibizumab groups were equally effective in improving BCVA and preventing BCVA loss at 96 weeks. The 2q8 aflibercept group was similar to ranibizumab in visual acuity outcomes during 96 weeks, but with an average of 5 fewer injections. Small losses at 96 weeks in the visual and anatomic gains seen at 52 weeks in all arms were in the range of losses commonly observed with variable dosing. Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Elizabeth P. Rakoczy

Journal

Journal ID (nlm-ta): EBioMedicine

Journal ID (iso-abbrev): EBioMedicine

Title: EBioMedicine

Publisher: Elsevier

ISSN (Electronic): 2352-3964

Publication date PMC-release: 10 November 2016

Publication date Collection: December 2016

Publication date (Electronic): 10 November 2016

Volume: 14

Pages: 168-175

Affiliations

[a ]Lions Eye Institute, Nedlands, WA, Australia

[b ]Sir Charles Gairdner Hospital, Nedlands, WA, Australia

[c ]Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia

[d ]School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, WA, Australia

[e ]Department of Clinical Immunology, The University of Western Australia, Crawley, WA, Australia

[f ]Avalanche Biotechnologies, Inc., Menlo Park, CA, USA

[g ]University of California Los Angeles, CA, USA

[h ]Byers Eye Institute, Stanford Department of Ophthalmology, Palo Alto, CA, USA

Author notes

[* ]Corresponding author at: Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia.Centre for Ophthalmology and Visual ScienceThe University of Western AustraliaCrawleyWAAustralia Elizabeth.rakoczy@ 123456uwa.edu.au

Article

Publisher ID: S2352-3964(16)30520-5

DOI: 10.1016/j.ebiom.2016.11.016

PMC ID: 5161436

PubMed ID: 27865764

SO-VID: 7046dded-a1e6-4d20-ba2a-88ace5096c75

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration

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Abstract

Background

Methods

Findings

Funding

Highlights

Related collections

Drug Repurposing

Most cited references 22

Ranibizumab and bevacizumab for neovascular age-related macular degeneration.

Causes and prevalence of visual impairment among adults in the United States.

Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies.

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