Three-Year Safety Results of SAR422459 (EIAV-ABCA4) Gene Therapy in Patients With ABCA4-Associated Stargardt Disease: An Open-Label Dose-Escalation Phase I/IIa Clinical Trial, Cohorts 1-5

Purpose: To report on the safety of the first 5 cohorts of a gene therapy trial using recombinant equine infectious anemia virus expressing ABCA4 (EIAV-ABCA4) in adults with Stargardt dystrophy due to mutations in ABCA4.

Design: Nonrandomized multicenter phase I/IIa clinical trial.

Methods: Patients received a subretinal injection of EIAVABCA4 in the worse-seeing eye at 3 dose levels and were followed for 3 years after treatment.

Main outcome measures: The primary end point was ocular and systemic adverse events. The secondary end points were best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, multifocal ERG, color fundus photography, short-wavelength fundus autofluorescence, and spectral domain optical coherence tomography.

Results: The subretinal injections were well tolerated by all 22 patients across 3 dose levels. There was 1 case of a treatment-related ophthalmic serious adverse event in the form of chronic ocular hypertension. The most common adverse events were associated with the surgical procedure. In 1 patient treated with the highest dose, there was a significant decline in the number of macular flecks as compared with the untreated eye. However, in 6 patients, hypoautofluorescent changes were worse in the treated eye than in the untreated eye. Of these, 1 patient had retinal pigment epithelium atrophy that was characteristic of tissue damage likely associated with bleb induction. No patients had any clinically significant changes in best-corrected visual acuity, static perimetry, kinetic perimetry, total field hill of vision, full field electroretinogram, or multifocal ERG attributable to the treatment.

Conclusions: Subretinal treatment with EIAV-ABCA4 was well tolerated with only 1 case of ocular hypertension. No clinically significant changes in visual function tests were found to be attributable to the treatment. However, 27% of treated eyes showed exacerbation of retinal pigment epithelium atrophy on fundus autofluorescence. There was a significant reduction in macular flecks in 1 treated eye from the highest dose cohort. Additional follow-up and continued investigation in more patients will be required to fully characterize the safety and efficacy of EIAV-ABCA4.