Results of a phase 1b/2 trial of intravitreal (IVT) sepofarsen (QR-110) antisense oligonucleotide in Leber congenital amaurosis 10 (LCA10) due to p.Cys998X mutation in the CEP290 gene

Abstract

Purpose : LCA10 is a severe, degenerative inherited retinal disease resulting in childhood blindness, which has no treatment. The most common causative mutation is p.Cys998X in the CEP290 gene. Safety, pharmacokinetics (PK), and efficacy of sepofarsen, an RNA antisense oligonucleotide, in subjects with LCA10 were evaluated.

Methods : In a 12-month, multicenter, open-label, multiple-dose escalation, phase 1b/2 study (NCT03140969), subjects (N=11) aged 8–44 years received sepofarsen at loading/maintenance dose of 160/80 µg (n=6) or 320/160 µg (n=5) via 1–4 IVT injections in the eye with worse best-corrected visual acuity (BCVA). Primary endpoint: frequency and severity of ocular adverse events (AEs) in the treated (TE) and untreated contralateral (CE) eyes. Secondary endpoints included serum PK, non-ocular AEs, and change in functional and anatomic ophthalmic findings.

Results : There were 8 cases of cataract; 6 needed surgery. In the 320/160 µg group, 2 cases of mild cystoid macular edema (successfully treated) and 2 cases of subclinical retinal thinning occurred. No events led to subject withdrawal. Serum levels of sepofarsen were below the level of quantification for all subjects. Pooled dose group data showed significant improvement in TE from baseline (BL) to M12 vs CE in mean BCVA (-0.55 [standard error of the mean 0.26] vs -0.12 [0.07] logMAR; p<0.05), red full-field stimulus threshold (FST; -0.91 [0.18] vs -0.16 [0.16] log cd/m²; p<0.01), and blue FST (-0.79 [0.23] vs 0.02 [0.11] log cd/m²; p<0.02). The 160/80 µg dose group showed significant improvement in TE at M12 vs BL in mean BCVA (-0.93 [0.43] logMAR vs BL; p<0.01), red FST (-0.66 [0.14] log cd/m² vs BL; p<0.01), and blue FST (-0.63 [0.31] log cd/m² vs BL; p<0.01; Table, Figure). For CE, changes in mean BCVA, red FST, and blue FST were not significant vs BL. A significant improvement in composite mobility course score was seen in TE (+4.0 [1.27] levels vs BL; p<0.01) and CE (+2.7 [1.11] levels vs BL; p<0.05). P-values are based on a mixed model repeated measurement analysis over all visits.

Conclusions : Although sepofarsen treatment is associated with cataract development, it is well tolerated and shows improvement in BCVA, FST, and mobility course. The 160/80 µg dose has a more favorable benefit:risk profile than 320/160 µg. The phase 2/3 trial is ongoing.

This is a 2020 ARVO Annual Meeting abstract.