PMID- 27865764 OWN - NLM STAT- MEDLINE DCOM- 20170214 LR - 20220408 IS - 2352-3964 (Electronic) IS - 2352-3964 (Linking) VI - 14 DP - 2016 Dec TI - Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration. PG - 168-175 LID - S2352-3964(16)30520-5 [pii] LID - 10.1016/j.ebiom.2016.11.016 [doi] AB - 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 (1x10(11)vg). 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. CI - Copyright (c) 2016 The Authors. Published by Elsevier B.V. All rights reserved. FAU - Constable, Ian J AU - Constable IJ AD - Lions Eye Institute, Nedlands, WA, Australia; Sir Charles Gairdner Hospital, Nedlands, WA, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia. FAU - Pierce, Cora M AU - Pierce CM AD - Lions Eye Institute, Nedlands, WA, Australia. FAU - Lai, Chooi-May AU - Lai CM AD - Lions Eye Institute, Nedlands, WA, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia. FAU - Magno, Aaron L AU - Magno AL AD - Lions Eye Institute, Nedlands, WA, Australia. FAU - Degli-Esposti, Mariapia A AU - Degli-Esposti MA AD - Lions Eye Institute, Nedlands, WA, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia. FAU - French, Martyn A AU - French MA AD - School of Pathology and Laboratory Medicine, The University of Western Australia, Crawley, WA, Australia; Department of Clinical Immunology, The University of Western Australia, Crawley, WA, Australia. FAU - McAllister, Ian L AU - McAllister IL AD - Lions Eye Institute, Nedlands, WA, Australia; Sir Charles Gairdner Hospital, Nedlands, WA, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia. FAU - Butler, Steve AU - Butler S AD - Avalanche Biotechnologies, Inc., Menlo Park, CA, USA. FAU - Barone, Samuel B AU - Barone SB AD - Avalanche Biotechnologies, Inc., Menlo Park, CA, USA. FAU - Schwartz, Steven D AU - Schwartz SD AD - University of California Los Angeles, CA, USA. FAU - Blumenkranz, Mark S AU - Blumenkranz MS AD - Byers Eye Institute, Stanford Department of Ophthalmology, Palo Alto, CA, USA. FAU - Rakoczy, Elizabeth P AU - Rakoczy EP AD - Lions Eye Institute, Nedlands, WA, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia. Electronic address: Elizabeth.rakoczy@uwa.edu.au. LA - eng SI - ClinicalTrials.gov/NCT01494805 PT - Clinical Trial, Phase II PT - Journal Article DEP - 20161110 PL - Netherlands TA - EBioMedicine JT - EBioMedicine JID - 101647039 RN - EC 2.7.10.1 (FLT1 protein, human) RN - EC 2.7.10.1 (Vascular Endothelial Growth Factor Receptor-1) RN - ZL1R02VT79 (Ranibizumab) SB - IM MH - Aged MH - Aged, 80 and over MH - Case-Control Studies MH - Combined Modality Therapy MH - Dependovirus/*genetics/immunology MH - Female MH - *Genetic Therapy/adverse effects/methods MH - Genetic Vectors/*administration & dosage/*genetics/immunology MH - Humans MH - Male MH - Ranibizumab/administration & dosage/therapeutic use MH - Retina/metabolism/pathology MH - Tissue Distribution MH - Tomography, Optical Coherence MH - Treatment Outcome MH - Vascular Endothelial Growth Factor Receptor-1/*genetics MH - Wet Macular Degeneration/diagnosis/drug therapy/*genetics/*therapy PMC - PMC5161436 OTO - NOTNLM OT - AAV.sFLT-1 OT - Clinical trial OT - Gene therapy OT - Wet age related macular degeneration EDAT- 2016/11/21 06:00 MHDA- 2017/02/15 06:00 PMCR- 2016/11/10 CRDT- 2016/11/21 06:00 PHST- 2016/11/08 00:00 [received] PHST- 2016/11/09 00:00 [accepted] PHST- 2016/11/21 06:00 [pubmed] PHST- 2017/02/15 06:00 [medline] PHST- 2016/11/21 06:00 [entrez] PHST- 2016/11/10 00:00 [pmc-release] AID - S2352-3964(16)30520-5 [pii] AID - 10.1016/j.ebiom.2016.11.016 [doi] PST - ppublish SO - EBioMedicine. 2016 Dec;14:168-175. doi: 10.1016/j.ebiom.2016.11.016. Epub 2016 Nov 10.