Abstract
Purpose :
In Stargardt disease (STGD), a rare, inherited retinal degeneration, toxic bis-retinoids accumulate in the RPE. Emixustat hydrochloride is an oral visual cycle modulator that limits the availability of 11-cis-retinal, a precursor of toxic bis-retinoids, by inhibiting RPE65. This clinical trial characterized the pharmacodynamics, safety, and tolerability of emixustat in subjects with macular atrophy (MA) secondary to STGD.
Methods :
Subjects with MA secondary to STGD were randomized 1:1:1 to 1 month daily emixustat 2.5 mg, 5 mg, or 10 mg. Visits included screening, baseline, end-of-treatment, and study exit (1 month after end-of-treatment). The primary endpoint was the % suppression of rod b-wave recovery rate on electroretinography (ERG) after photobleaching at the end of the 1-month treatment period (compared to baseline), a marker for RPE65 inhibition. Secondary outcomes included incidence, severity, seriousness of, and discontinuations due to treatment-emergent adverse events (TEAEs).
Results :
Of the 23 subjects randomized to daily emixustat treatment (7 to 2.5 mg, 9 to 5 mg, 7 to 10 mg), all but 1 (from the 5 mg group) completed the study. Subjects treated with 10 mg showed near-complete suppression of the rod b-wave recovery rate post-photobleaching (mean=91.9%, median=96.7%), whereas those treated with 5 mg showed moderate suppression (mean=52.2%, median=68.0%). No effect was observed for the 2.5 mg group (mean=-3.3%, median=-12.2%). No effect was seen on cone ERG in any group. Most subjects (21/23) experienced at least 1 TEAE (total of 49), the most common being delayed dark adaptation (11/23), erythropsia (5/23), blurred vision (4/23), and photophobia and visual impairment (3/23). No serious TEAEs occurred. Subjects in the 5 mg group experienced more TEAEs (21) than those in the 10 mg (16 TEAEs) or 2.5 mg (12 TEAEs) groups.
Conclusions :
At 10 mg daily, emixustat provided robust suppression of rod b-wave recovery after photobleach in subjects with MA secondary to STGD. The TEAEs experienced are consistent with those experienced by patients with other retinal conditions treated with emixustat, and with RPE65 inhibition. These results informed dose selection for an ongoing, 24-month, Phase 3 trial of daily emixustat 10 mg vs placebo for the treatment of MA secondary to STGD (SeaSTAR Study, NCT03772665).
This is a 2020 ARVO Annual Meeting abstract.