title: Phase 2a Randomized Clinical Trial: Safety and Post Hoc Analysis of Subretinal rAAV.sFLT-1 for Wet Age-related Macular Degeneration.
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.
  
  
  RESULTS
  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.
  
  
  BACKGROUND
  National Health and Medical Research Council of Australia (AP1010405), Lions Eye Institute, Perth Australia, Avalanche Biotechnologies, Menlo Pk, CA, USA.
authors.affiliation: 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.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Constable
authors.affiliation: Lions Eye Institute, Nedlands, WA, Australia.
authors.forename: Cora M
authors.initials: CM
authors.lastname: Pierce
authors.affiliation: Lions Eye Institute, Nedlands, WA, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Chooi-May
authors.initials: CM
authors.lastname: Lai
authors.affiliation: Lions Eye Institute, Nedlands, WA, Australia.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Magno
authors.affiliation: Lions Eye Institute, Nedlands, WA, Australia; Centre for Ophthalmology and Visual Science, The University of Western Australia, Crawley, WA, Australia.
authors.forename: Mariapia A
authors.initials: MA
authors.lastname: Degli-Esposti
authors.affiliation: 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.
authors.forename: Martyn A
authors.initials: MA
authors.lastname: French
authors.affiliation: 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.
authors.forename: Ian L
authors.initials: IL
authors.lastname: McAllister
authors.affiliation: Avalanche Biotechnologies, Inc., Menlo Park, CA, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Butler
authors.affiliation: Avalanche Biotechnologies, Inc., Menlo Park, CA, USA.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Barone
authors.affiliation: University of California Los Angeles, CA, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Schwartz
authors.affiliation: Byers Eye Institute, Stanford Department of Ophthalmology, Palo Alto, CA, USA.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Blumenkranz
authors.affiliation: 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.
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Rakoczy
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D000229:Dependovirus / Q000235:genetics* / Q000276:immunology; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008297:Male; D000069579:Ranibizumab / Q000008:administration & dosage / Q000627:therapeutic use; D012160:Retina / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics*; D057135:Wet Macular Degeneration / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000628:therapy*
chemical_list: C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D000069579:Ranibizumab
keywords: AAV.sFLT-1; Clinical trial; Gene therapy; Wet age related macular degeneration