An oral form of modified vitamin A slowed the expansion of retinal atrophic lesions in patients with Stargardt disease (STGD), according to results from the phase II TEASE-1 randomized clinical trial published in JAMA Ophthalmology. The findings offer encouraging evidence for a potential disease-modifying therapy in a condition for which no treatment is currently approved.
STGD, most commonly associated with pathogenic variants in ABCA4, is characterized by progressive loss of photoreceptors, retinal pigment epithelium, and choriocapillaris. Disease pathogenesis is thought to involve abnormal dimerization of vitamin A and accumulation of toxic bisretinoids in the retina. Gildeuretinol acetate – also known as ALK-001 – is a deuterated form of vitamin A designed to inhibit this dimerization while preserving vitamin A's other biological functions.
TEASE-1 was a 24-month, multicenter, double-masked, placebo-controlled trial conducted at seven US sites. Fifty participants aged 18–60 years were randomized to receive oral gildeuretinol acetate at 14 mg or 24 mg daily, placebo, or placebo for one year followed by gildeuretinol for the second year. An additional 54 eligible natural history cases were incorporated into the primary analysis to augment the untreated control group.
The primary endpoint was the rate of growth of well-delineated retinal atrophic lesions measured using fundus autofluorescence imaging. Among participants with evaluable data, lesion growth was 0.182 mm/year with gildeuretinol versus 0.232 mm/year in the combined untreated group, corresponding to a difference of −0.050 mm/year and a 21.6% relative reduction in lesion growth.
Importantly, a prespecified sensitivity analysis restricted to randomized participants also favored treatment. Lesion growth was 0.206 mm/year with gildeuretinol compared with 0.242 mm/year with placebo – a 14.9% relative reduction. A second analysis using untransformed lesion area suggested a 29.5% relative reduction. Treatment effects were consistent across prespecified subgroups, including baseline visual acuity, lesion characteristics, genotype, and sex.
However, the anatomical benefit did not translate into a detectable visual acuity advantage during the two-year study. Mean best-corrected visual acuity changed by −1.6 letters with gildeuretinol and −1.1 letters with placebo at 24 months, with no significant differences observed between groups. The investigators noted that visual acuity loss in STGD can be slow and variable, complicating its use as a clinical trial endpoint.
Safety findings for gildeuretinol acetate were generally reassuring. Most treatment-emergent adverse events were mild or moderate, and none of the three serious adverse events was considered treatment related. One participant developed transient papilledema and increased intracranial pressure while receiving the 24-mg dose; the event resolved after temporary treatment interruption and acetazolamide, and did not recur after therapy resumed.
The study authors cautioned that TEASE-1’s sample size was small and relied partly on nonrandomized natural history controls. They also emphasized that the clinical significance of the observed reduction in atrophy growth remains uncertain. Longer-term studies, including intervention at earlier disease stages, will be needed to establish whether slowing retinal atrophy ultimately preserves meaningful visual function.
