Abstract
Purpose :
Childhood-onset Stargardt Disease (STGD1) is characterized by accumulation of bisretinoids which cause progressive retinal atrophy leading to rapid visual loss. Because bisretinoid toxins are derived from circulating retinol, reduction of retinol delivery to the eye, via antagonism of serum retinol binding protein 4 (RPB4), has been explored as a means to slow disease progression in STGD1. Tinlarebant, an orally administered, potent and specific non-retinoid antagonist of RPB4, has been developed to determine whether reduction of circulating RPB4-retinol is a safe and effective treatment approach for STGD1.
Methods :
The Phase 1b/2 study is a multicenter, single arm, open-label study followed by a 2-year extension to evaluate safety and tolerability and efficacy of Tinlarebant. Eleven subjects aged 12-18 years received oral Tinlarebant (5 mg) daily for a 28-day treatment period. Treatment emergent adverse events (TEAEs), PK/PD, and visual function outcomes were evaluated.
Results :
A total of 28 TEAEs were reported and were mild in severity. Seven TEAEs reported by 6 subjects (54.5%) were non-ophthalmic and considered to be non-drug-related; 21 TEAEs reported by 10 subjects (90.9%) were ophthalmic. Delayed dark adaptation (DDA) and xanthopsia (both mild and reversible), reported by 7 subjects (63.6%), were attributed to drug. DDA and xanthopsia were noticed principally on waking and resolved within 10 minutes. All subjects tolerated these AEs. Tinlarebant plasma concentration and RBP4 suppression appeared to be correlated. RBP4 levels declined rapidly within 4 hours of treatment on Day 1. Mean RBP4 level reached 20% of mean baseline on Day 8 of treatment. Suppression was maintained throughout the study. Mean RBP4 level returned to 92.3% of baseline values following 14 days of drug cessation. Visual acuity (VA) was available for all time points in 8 subjects, 7 improved with 3 subjects experiencing a 5-, 10-, and 24-letter improvement, in at least one eye. Where quantitative autofluorescence (qAF) was available qAF was correlated with VA improvements.
Conclusions :
Tinlarebant has an acceptable safety profile in adolescent STGD1 subjects. There was a trend for VA improvement. The observed AEs were anticipated based on mode of action. STGD1 subjects from the Phase 1b study are now participating in the 2-year Phase 2 extension study.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.