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

Ian J Constable, Cora M Pierce, Chooi-May Lai, Aaron L Magno, Mariapia A Degli-Esposti, Martyn A French, Ian L McAllister, Steve Butler, Samuel B Barone, Steven D Schwartz, Mark S Blumenkranz, Elizabeth P Rakoczy, Ian J Constable, Cora M Pierce, Chooi-May Lai, Aaron L Magno, Mariapia A Degli-Esposti, Martyn A French, Ian L McAllister, Steve Butler, Samuel B Barone, Steven D Schwartz, Mark S Blumenkranz, Elizabeth P Rakoczy

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 (1×1011vg). All patients were assessed every 4weeks 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.

Keywords: AAV.sFLT-1; Clinical trial; Gene therapy; Wet age related macular degeneration.

Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Trial profile for Phase 1 (Rakoczy et al., 2015) and Phase 2a clinical trials.
Fig. 2
Fig. 2
Graphs of median BCVA and CPT over time A: Median BCVA over 52 weeks. B: Median change in BCVA from baseline to week 52. C: Median change in BCVA from week 8 (activation of gene therapy) to week 52. D: Median CPT over 52 weeks. E: Median change in CPT from baseline to week 52. F: Median change in CPT from week 8 (activation of gene therapy) to week 52. BCVA = Best Corrected Visual Acuity; CPT = Center Point Thickness.
Fig. 3
Fig. 3
BCVA change category by treatment group. Patients categorized by change in BCVA at week 52. BCVA = Best Corrected Visual Acuity.
Fig. 4
Fig. 4
Ranibizumab retreatments by treatment group. Distribution of the number of ranibizumab retreatments in each treatment group, showing the median (thickest line), the 25th and 75th percentiles (box boundaries), and the range (whiskers).
Fig. 5
Fig. 5
BCVA vs number of ranibizumab retreatments at week 52. Linear regression of BCVA change on the number of ranibizumab retreatments showed a significant negative association (P = 0.01) for Phase 2a gene therapy patients. A subset of rAAV.sFLT-1 treated patients received 2 or fewer ranibizumab retreatments (solid box). A second subset of rAAV.sFLT-1 treated patients received > 2 ranibizumab retreatments (dashed box). BCVA = Best Corrected Visual Acuity.

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