18 Month Analysis of Macular Structure using Optical Coherence Tomography (OCT) from a Phase 1/2 Clinical Study of Subretinal Gene Therapy Drug AGTC-501 for X-Linked Retinitis Pigmentosa

Abstract

Purpose : X-linked retinitis pigmentosa (XLRP) is caused by mutations in the retinitis pigmentosa GTPase regulator gene, RPGR, which leads to progressive night blindness, loss of peripheral vision, and eventually central vision loss. This is a follow-up report of macular structure analysis from an ongoing, phase 1/2, open label, dose escalation clinical trial using a recombinant adeno-associated viral (rAAV) vector to deliver a functioning gene copy of RPGR via subretinal injection.

Methods : Male participants (n=29), age ≥6, were assigned to five dose groups and received subretinal injection of AGTC-501 (rAAV2tYF-GRK1-RPGR) into the central or peripheral region of the study eye. Primary outcome was safety. Among the 21 centrally dosed patients analyzed in this study, the secondary outcome was macular structure (OCT) and function (MAIA microperimetry and best-corrected visual acuity (BCVA) as assessed by ETDRS). Up to 18 months post-treatment data were analyzed.

Results : Subretinal administration of AGTC-501 was well-tolerated across a wide dose range. The majority of adverse events were mild-moderate in severity, consistent with the subretinal injection and vitrectomy procedures, and/or concomitant prophylactic steroid regimen used to mitigate inflammation. Of the 21 patients who received a subretinal injection within the macula of the study eye, 13 had visible foveal ellipsoid zone (EZ) on OCT at baseline. Post-injection, the macular EZ recovered by 3-6 months in 9 eyes (69%). Of these eyes, six (67%) subsequently showed improvement of EZ line area and reflectivity compared to baseline by month 12, which was sustained to month 18. Treated eyes with EZ improvement had improved macular function on MAIA (p =0.003) and stable foveolar thickness on OCT (p =0.0003) compared to eyes without EZ improvement.

Conclusions : Consistent safety and efficacy signals in the study eyes that underwent subretinal administration of AGTC-501 were observed up through month 18. Of the study eyes with visible EZ at baseline, most showed recovery of foveal EZ after macular injection, and nearly half had improved EZ appearance which correlated with improvement in macular sensitivity. Follow-up is ongoing through 5 years to assess long-term safety and durability of response.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.