Efficacy and safety of sepofarsen, an intravitreal RNA antisense oligonucleotide, for the treatment of CEP290-associated Leber congenital amaurosis (LCA10): a randomized, double-masked, sham-controlled, Phase 3 study (ILLUMINATE)

Abstract

Purpose : LCA10 is a severe, degenerative inherited retinal disease resulting in childhood blindness, which has no treatment. Sepofarsen, an RNA antisense oligonucleotide designed for LCA10 due to the frequent c.2991+1655A>G variant in the CEP290 gene, produced clinically meaningful improvements in visual acuity in a Phase 1b/2 trial. The aim of the phase 3 trial (ILLUMINATE) was to assess the efficacy and safety of sepofarsen compared to sham in c.2991+1655A>G-LCA10 participants.

Methods : ILLUMINATE (NCT03913143) was a double-masked, randomized, sham-controlled study performed across 14 sites in Europe, North America and Latin America. Eligible participants were aged ≥ 8 years, carried at least one c.2991+1655A>G in the CEP290 gene and had best-corrected visual acuity (BCVA) ranging from 0.4 (20/50 Snellen equivalent) to 3.0 logMAR (Hand Motion). Participants were randomly assigned (1:1:1) to receive intravitreal injection of sepofarsen 160/80 µg (maintenance dose of 80 µg every 6 months, starting 3 months after the loading dose of 160 µg), 80/40 µg (same regimen but doses of 40µg and 80µg respectively), or sham. The primary endpoint was mean change from baseline in BCVA, in the treatment eye (worse seeing eye), compared with sham at Month 12. Secondary endpoints included full-field stimulus testing threshold (FST; red, blue, white), a mobility course composite score, and safety. Trial recruitment was completed in January 2021.

Results : Between March 29, 2019 and January 6, 2021, 52 participants were screened, of whom 36 were randomized (group allocation masked at the time of abstract submission). At baseline, the mean age was 29.0 (SD 14.5) years, including 12 (SD 33.3%) participants aged 8 to 18 and 24 (66.7%) participants aged >18 years. Sixteen (44.4%) of the participants were homozygous for the target variant whereas 20 (55.6%) were compound heterozygous. Mean baseline BCVA in the treatment eye was 1.25 logMAR (SD 0.66) and mean baseline BCVA in the fellow eye was 1.01 logMAR (SD 0.27).

Conclusions : Sepofarsen, an innovative RNA antisense oligonucleotide, is the most advanced program in development for the treatment of LCA10. Learning from recruitment suggested the commonality of the c.2991+1655A>G variant in LCA10. Updated results will be included as available.

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