June 2017
Volume 58, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2017
Safety and post hoc analysis of subretinal rAAV.sFLT-1 for wet age-related macular degeneration following a phase 2a randomized clinical trial
Author Affiliations & Notes
  • Elizabeth P Rakoczy
    Centre for Ophthalmol & Visual Sciences, University of Western Australia, Perth, Western Australia, Australia
    Molecular Ophthalmology, Lions Eye Institute, Perth, Western Australia, Australia
  • Chooi-May Lai
    Centre for Ophthalmol & Visual Sciences, University of Western Australia, Perth, Western Australia, Australia
    Molecular Ophthalmology, Lions Eye Institute, Perth, Western Australia, Australia
  • Aaron Magno
    Molecular Ophthalmology, Lions Eye Institute, Perth, Western Australia, Australia
  • Martyn French
    School of Pathology, University of Western Australia, Perth, Western Australia, Australia
  • Steve Butler
    Adverum Biotechnologies, San Francisco, California, United States
  • Samuel Barone
    Adverum Biotechnologies, San Francisco, California, United States
  • Steven D Schwartz
    University of California, Los Angeles, Los Angeles, California, United States
  • Mark Blumenkranz
    Byers Eye Institute, Stanford University, Palo Alto, California, United States
  • Mariapia Degli-Esposti
    Centre for Ophthalmol & Visual Sciences, University of Western Australia, Perth, Western Australia, Australia
  • Ian Constable
    Centre for Ophthalmol & Visual Sciences, University of Western Australia, Perth, Western Australia, Australia
    Molecular Ophthalmology, Lions Eye Institute, Perth, Western Australia, Australia
  • Footnotes
    Commercial Relationships   Elizabeth Rakoczy, Avalanche Biotechnologies (C), Avalanche Bitechnologies (P); Chooi-May Lai, Avalanche Biotechnologies (E), Avalanche Bitechnologies (P); Aaron Magno, Avalanche Biotechnologies (E); Martyn French, None; Steve Butler, Avalanche Biotechnologies (E); Samuel Barone, Avalanche Biotechnologies (E); Steven Schwartz, Avalanche Biotechnologies (I); Mark Blumenkranz, Avalanche Biotechnologies (I); Mariapia Degli-Esposti, None; Ian Constable, Avalanche Biotechnologies (F), Avalanche Biotechnologies (P)
  • Footnotes
    Support  National Health and Medical Research Council of Australia, Avalanche Biotechnologies
Investigative Ophthalmology & Visual Science June 2017, Vol.58, 4476. doi:
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      Elizabeth P Rakoczy, Chooi-May Lai, Aaron Magno, Martyn French, Steve Butler, Samuel Barone, Steven D Schwartz, Mark Blumenkranz, Mariapia Degli-Esposti, Ian Constable; Safety and post hoc analysis of subretinal rAAV.sFLT-1 for wet age-related macular degeneration following a phase 2a randomized clinical trial. Invest. Ophthalmol. Vis. Sci. 2017;58(8):4476.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : To assess the safety and tolerability of rAAV.sFLT-1 in patients with wet age-related macular degeneration (wAMD).

Methods : Thirty-two patients (55 years or older) with wAMD and best corrected visual acuity worse (BCVA) than 20/40 secondary to wAMD due to active subfoveal choroidal neovascularization in their study eye were recruited. Patients were randomized in a 2:1 ratio (gene therapy:control). All patients received intravitreal ranibizumab at baseline (Day 0) and at day 28. Gene therapy patients received rAAV.sFLT-1, 1x1011 vg subretinally at Day 7. Both arms received intravitreal ranibizumab pro nata after day 28. Patients were assessed every 4 weeks to the 52-week primary endpoint using clinical laboratory testing, physical and ophthalmic examinations. Biodistribution and immune response to the vector was evaluated by a range of laboratory tests.

Results : Treatment group patients injected subretinally with rAAV.sFlt-1 tolerated the procedure well. All procedure-related ocular adverse events self-resolved. No systemic safety signals were observed and serious AEs were deemed not associated with rAAV.sFLT-1. There was no change in sFLT-1 levels and AAV2 capsid was not detected in the bodily fluids. rAAV.sFLT-1 DNA was detected transiently in the tears of 13 rAAV.sFLT-1-injected patients. There were no notable changes in T-cell response identified by ELISPOT analysis. The presence of AAV neutralizing antibodies at baseline was not associated with diminished efficacy. In the treatment group patients, best corrected visual acuity improved by a median of 1.0 (IQR: 1.0 to 9.0) Early Treatment Diabetic Retinopathy Study (ETDRS) letter from baseline compared to a median -5.0 (IQR: -17.5 to 1.0) ETDRS letter change in control patients. Twelve rAAV.sFLT-1-injected patients maintained or improved vision compared to 4 control patients. The median number of ranibizumab retreatments in rAAV.sFLT-1-injected and control group patients was 2.0 (IQR: 1.0 to 6.0) and 4.0 (IQR: 3.5 to 4.0), respectively.

Conclusions : These results suggest that ocular gene therapy combined with the option for intravitreal anti-VEGF protein rescue treatment appears safe and may be a viable approach to reducing the treatment burden of wAMD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

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