Gene Therapy in Neovascular Age-related Macular Degeneration: Three-Year Follow-up of a Phase 1 Randomized Dose Escalation Trial

Am J Ophthalmol. 2017 May;177:150-158. doi: 10.1016/j.ajo.2017.02.018. Epub 2017 Feb 27.

Abstract

Purpose: To assess the safety of rAAV.sFlt-1 subretinal injection in neovascular age-related macular degeneration (wet AMD) over 36 months.

Design: Phase 1 dose escalation trial.

Methods: Eight subjects with advanced, treatment-experienced wet AMD were randomly assigned (3:1) to treatment and non-gene therapy control groups. Eligible subjects were ≥65 years, had wet AMD, and had best-corrected visual acuity (BCVA) 10/200 to 20/80 in the study eye and 20/200 or better in the other eye. Three of the treatment group subjects received low-dose (1 × 1010 vector genomes) and 3 high-dose (1 × 1011 vector genomes) rAAV.sFLT-1 via subretinal injection. Study monitoring was monthly to the primary endpoint at month 12 and then protocol-driven follow-up study visits were conducted at months 18 and 36. All subjects received intravitreal ranibizumab at baseline and at week 4, and retreatment injections at subsequent visits based on prespecified criteria for active wet AMD. The primary endpoint was ocular and systemic safety, but exploratory data including BCVA, retinal center point thickness, and the number of ranibizumab retreatments at and between study visits were also analyzed.

Results: Six of the 8 subjects completed the 36-month study. Subretinal injection with pars plana vitrectomy was well tolerated in this cohort. No ocular or systemic safety signals were observed during the long-term follow-up period. Exploratory data analysis suggests stability of wet AMD over the 36-month period.

Conclusions: Subretinal delivery of rAAV.sFLT-1 was well tolerated and demonstrated a favourable safety profile through month 36. Thus, rAAV.sFLT-1 could be safely considered for future evaluation in the treatment of wet AMD.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Aged, 80 and over
  • Choroidal Neovascularization / complications
  • Choroidal Neovascularization / therapy*
  • Dose-Response Relationship, Drug
  • Female
  • Follow-Up Studies
  • Genetic Therapy / methods*
  • Humans
  • Injections
  • Interleukin-1 Receptor-Like 1 Protein / administration & dosage*
  • Male
  • Receptors, Interleukin-1
  • Retina
  • Time Factors
  • Tomography, Optical Coherence
  • Treatment Outcome
  • Visual Acuity*
  • Vitrectomy
  • Wet Macular Degeneration / physiopathology
  • Wet Macular Degeneration / therapy*

Substances

  • IL1RL1 protein, human
  • Interleukin-1 Receptor-Like 1 Protein
  • Receptors, Interleukin-1