Safety and Efficacy of EDIT-101 for Treatment of CEP290-associated Retinal Degeneration

Abstract

Purpose : Currently there is no treatment for severe early onset inherited retinal degeneration (IRD) caused by mutations in the CEP290 gene (CEP290-associated IRD). EDIT-101 is a novel CRISPR/Cas9 gene-editing therapy designed to treat CEP290-associated IRD caused by the c.2991+1655A>G IVS26 mutation. The BRILLIANCE trial (NCT03872479) aims to evaluate the safety and efficacy of EDIT-101.

Methods : BRILLIANCE is a phase 1/2, open-label, single ascending dose trial performed at five U.S. sites in persons ≥ 3 years of age with CEP290-associated IRD caused by a homozygous or compound heterozygous IVS26 mutation. Four cohorts of participants were recruited (Adult Low-dose [6x10¹¹ vg/mL], Adult Mid-dose [1x10¹² vg/mL], Adult High-dose [3x10¹² vg/mL], and Pediatric Mid-dose [1x10¹² vg/mL]) and received a single subretinal injection of EDIT-101 in the worse-seeing eye. Safety outcomes include frequency of adverse events (AEs) related to EDIT-101 or the injection procedure and incidence of dose-limiting toxicities (DLTs). Clinically meaningful functional efficacy outcomes included a change from baseline ≥ 0.3 logMAR in best-corrected visual acuity (BCVA), ≥ 0.6 log cd/m² in full-field stimulus testing (FST) sensitivity, and ≥ 3 points in visual function navigation (VFN) mobility score (determined from prior natural history study at p < 0.5 [NCT03396042]). Vision-related quality of life (QoL) score was included as a patient-reported outcome. A change in QoL score of ≥ 4 was considered clinically meaningful.

Results : Fourteen participants were treated. Two participants were homozygous for the IVS26 mutation. Median (range) age was 36 (9–63) years. Mean (SD) baseline BCVA in the treated eye was 2.4 (1.3) logMAR. EDIT-101 was well tolerated with no serious AEs related to the treatment or injection procedure. No DLTs were defined. Efficacy data demonstrated biologic activity for each endpoint: 4/14 participants improved in BCVA, 5/14 in FST, and 4/14 in VFN. Overall, 8/14 participants reported improved QoL, of whom six showed congruent improvement in either BCVA, FST, or VFN. Notably, 3/5 participants who improved on at least two functional endpoints recorded up to 1.3 logMAR improvement in BCVA.

Conclusions : Subretinal delivery of EDIT-101 has a favorable safety profile. Efficacy data demonstrate biologic activity and provide proof of concept for in-vivo CRISPR/Cas9 gene-editing in IRDs.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.