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

Abstract

BackgroundWe 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).MethodsAll 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 × 1011 vg). All patients were assessed every 4 weeks to the week 52 primary endpoint.FindingsOcular 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.FundingNational Health and Medical Research Council of Australia (AP1010405), Lions Eye Institute, Perth Australia, Avalanche Biotechnologies, Menlo Pk, CA, USA.

Gene therapy and the adeno‐associated virus in the treatment of genetic and acquired ophthalmic diseases in humans: Trials, future directions and safety considerations

“…When compared to the two control patients who were treated with ranibizumab, one patient required five rescue injections while the other patient was not able to be evaluated because of a vitreomacular traction . The results of the phase II clinical trial served to confirm the results from the phase I trial; however, no significant new results were shown …”

“…108 The results of the phase II clinical trial served to confirm the results from the phase I trial; however, no significant new results were shown. 109 VEGF is also being targeted in a currently recruiting phase I clinical trial, sponsored by Regenxbio. They are evaluating the safety and tolerability of RGX-314, an AAV8 vector that encodes a soluble anti-VEGF protein (NCT03066258).…”

Combining Engineered Nucleases with Adeno-associated Viral Vectors for Therapeutic Gene Editing

“…AAV has numerous natural serotypes with somewhat different viral capsid sequences and tissue tropisms, indicating that differences in the viral capsid proteins can lead to differences in infectivity. As a non-integrating virus with a strong safety record, AAV has strong promise as a clinical gene delivery vehicle, and as mentioned above there are numerous examples of strong proof of concept in clinical trials as well as a regulatory approval in the European Union [1–9]. …”

“…The last of these is the basis for a clinically approved gene therapy product in the European Union, and it is anticipated that a gene therapy for LCA2 may be approved in the US in 2017. In addition, early-stage clinical trials have demonstrated some positive signs in harnessing AAV to treat more complex disorders, such as overexpressing SERC2A in heart failure patients [8] and expressing the VEGF inhibitor sFLT-1 in patients with age-related macular degeneration [9]. …”

Surgical Removal of Internal Limiting Membrane and Layering of AAV Vector on the Retina Under Air Enhances Gene Transfection in a Nonhuman Primate

“…Previous studies report the use of soluble FMS-like tyrosine kinase-1 (sFLT-1), a naturally occurring VEGF inhibitor, coupled with an AAV delivery vector for sustained VEGF inhibition in the retina, hence negating the need for frequent anti-VEGF injections. [17][18][19] In AAV gene therapy, the effective expression of the transgene is contingent on the integration of the genetic material into the host genome of terminally differentiated and nondividing cells. In the context of AAV-mediated gene therapy for retinal diseases, this has previously been achieved via a subretinal injection to ensure close proximity of the vector with the cells that require transfection.…”