Subfoveal gene augmentation therapy for choroideremia: One-year results from a Phase I/II trial of AAV2-hCHM

Abstract

Purpose : Clinical trials of gene augmentation therapy for choroideremia have primarily enrolled individuals with advanced visual field loss. The purpose of this expansion cohort in a fully enrolled, ongoing phase I/II clinical trial was to assess the safety and efficacy of unilateral subfoveal AAV2-hCHM in individuals with better-preserved visual fields.

Methods : Five individuals with pathogenic CHM variants who were between 20 and 32 years of age at treatment received a subfoveal injection of AAV2-hCHM in the worse-seeing eye with a dose of up to 1x10¹¹ viral genomes. Safety and efficacy endpoints were assessed with functional and structural assessments including visual acuity, microperimetry, kinetic and static perimetry, autofluorescence, and optical coherence tomography.

Results : Treatment was well-tolerated without inflammation or persistent subretinal fluid. There were no drug-related AEs or SAEs. Surgery was uneventful except for in one patient in whom a macular hole developed intraoperatively resulting in a SAE due to persistent vision loss. Among the other 4 participants, the mean baseline visual acuity was 84.4 ETDRS letters in the treated eye (range 80.5 to 87) and 88 letters in the control eye (range 85.5 to 90). At Year 1, the mean change was -0.6 letters in the treated eye (range -6.5 to +2.0) and -0.5 letters in the control eye (range -1.5 to +2.5). Decreases of a similar magnitude were present between treated and untreated fellow eyes on microperimetry (mean macular sensitivity change: treated eyes -1.0 dB, untreated -2.8 dB; mean foveal sensitivity change: treated eyes -2.9 dB, untreated -2.8 dB). Retinal imaging was stable in these four individuals. Octopus kinetic perimetry for the cohort demonstrated enlarged visual fields in some participants of uncertain significance relative to baseline mean V4e areas of 10,487 mm² in the control eyes and 9,457 mm² in the treated eyes. In the patient with the macular hole, visual acuity decreased from 84 ETDRS letters at baseline to 55 letters at Year 1. Other measures of visual function were also affected. There were no additional significant surgical or drug-related complications.

Conclusions : AAV2-hCHM was well-tolerated over a one year interval. Longer-term evaluation of the advancing edge of degeneration is needed to determine whether treatment changes the progression rate in these patients with preserved foveal function.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.