Long-term safety and efficacy of sepofarsen in a Ph1b/2 INSIGHT extension trial in CEP290-associated Leber congenital amaurosis (LCA10)

ABSTRACT

Purpose: Autosomal recessive CEP290-LCA (LCA10) is a severe inherited retinal disease resulting in early vision loss and currently has no treatment. Sepofarsen is an RNA antisense oligonucleotide targeting the most common c.2991+1655A>G disease-causing variant in the CEP290 gene. Long-term safety and efficacy of sepofarsen in the first eye treated (FE) and safety and efficacy in the second eye treated (SE) in this extension trial (Insight;NCT03913130) were evaluated. Methods: Subjects who completed the Ph1b/2 sepofarsen trial could enroll in the extension trial for continued dosing in the FE and initiation in the SE with the 160/80μg loading/maintenance dose. Frequency and severity of adverse events, and change in best-corrected visual acuity (BCVA) and full-field stimulus testing (FST) threshold were assessed. Baseline was defined as the value measured within the same month of-or last measurement prior to-the first dosing for each eye. Due to covid-19, some participants have missed scheduled injections. As such data up to-or available measurement prior to-6 months after the last dosing have been included in the analysis for each eye. Results: At data cut-off in mid-October 2021, 9 subjects (of 11 from the Ph1b/2 trial) aged 15-45 years were followed up to 46 months, 5 of them received at least one intravitreal injection of sepofarsen in the SE. Three subjects developed cataracts in the FE and 2 in the SE, of which 2 recovered following cataract surgery. Time to onset since initial dose was 13 months or later. Between 35-46 months after the 1 injection, long term BCVA improvement was reported in 4/6 FE ranging from-0.20 to-0.54 logMAR and 5/5 FE improved in either blue FST, red FST or both ranging from-0.21 to-2.06 log cd/m2. The SE showed a similar trend as the FE in BCVA (3/5 SE showed a change ranging from-0.06 to-2.50 logMAR) and in blue and red FST (4/4 SE showed improvement ranging from-0.27 to-4.57 log cd/m2). st Conclusions: The longer-term sepofarsen safety profile is consistent with that observed in the Ph1b/2. Meaningful BCVA and FST improvements observed in the Ph1b/2 continued up to 46 months. The responses in the SE were similar to the responses seen in the FE in both visual acuity and retinal sensitivity improvements. A Phase 2/3 (ILLUMINATE;NCT03913143), multiple dose, double-masked, randomized, sham-controlled trial is ongoing.