Abstract
Purpose :
We hypothesized that four weeks of daily oral gildeuretinol acetate would effectively replace plasma vitamin A (retinol) with gildeuretinol. Gildeuretinol (formally ALK-001 and C20D3-Vitamin A) is an investigational therapeutic for Stargardt disease, engineered to replace vitamin A. Gildeuretinol inhibits the pathological dimerization of vitamin A, which is thought to cause Stargardt Disease.
Methods :
In a Phase 1 safety and pharmacokinetic study, we investigated gildeuretinol acetate at six daily dose levels (2, 3.5, 5, 7, 10, and 14 mg) for 28 days. Healthy adults aged 21 to 70, at least 6 subjects per dose level, were given a 30-capsule bottle of gildeuretinol acetate for home administration. Plasma concentrations of retinol and gildeuretinol were assessed at baseline, 2 weeks, and 4 weeks. Each visit included adverse event assessments, 12-lead electrocardiograms (ECG), vital signs monitoring, physical examinations, and corrected visual acuity assessments, blood biochemistry and hematology. The primary outcome measure was the percentage of gildeuretinol over total vitamin A (combining retinol + gildeuretinol).
Results :
The trial took place at one center in the United States and enrolled thirty-seven subjects, 43% female. At baseline, average plasma retinol for all cohorts ranged between 419 to 576 ng/mL, falling within normal limits. Plasma gildeuretinol demonstrated a dose- and time-dependent increase, alongside a concurrent decrease in plasma retinol. After four weeks, the highest dosed cohort (14 mg/day) experienced a substantial conversion of an average of 79% of plasma retinol into gildeuretinol. The conversion percentage was dose-dependent across all cohorts (Figure 1). Despite the increase in plasma gildeuretinol, the combined levels of plasma gildeuretinol and retinol remained consistent with initial retinol levels, suggesting that all participants maintained gildeuretinol levels under hemostatic control. All doses were well-tolerated. No subject discontinued treatment. There was no serious adverse events or adverse events. No subject had clinically-significant abnormal hematology, biochemistry, ECG, findings by physical exam, vital signs, or a decrease in visual acuity.
Conclusions :
Daily oral gildeuretinol acetate 14 mg rapidly replaced plasma vitamin A with gildeuretinol without dietary modification.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.