Safety and Effects of Gildeuretinol Acetate on Retinal Atrophic Lesions in Stargardt Disease

Abstract

Importance Stargardt disease (STGD) is the most common macular dystrophy, resulting in profound loss of vision. There is no approved treatment. Objective To evaluate the safety and effects of oral gildeuretinol acetate on the growth of retinal atrophic lesions in individuals with STGD. Design, Setting, and Participants TEASE-1 was a 2-year, multicenter, double-masked, placebo-controlled randomized clinical trial incorporating a crossover group and additional natural history (NH) cases selected prior to drafting the statistical analysis plan. The trial was conducted at 7 outpatient clinics in the US. Participants were aged 12 years or older, clinically diagnosed with STGD, with well-demarcated area(s) of significantly reduced autofluorescence, and supported with at least 1 ABCA4 disease-causing or likely disease-causing variant. The study was conducted between August 2015 and October 2019; data were analyzed between July and December 2020. Interventions Participants were randomized 1.5:1.5:1:1 to daily oral gildeuretinol acetate, 14 mg; gildeuretinol acetate, 24 mg; or placebo for 24 months; or placebo for 12 months followed by gildeuretinol for 12 months. Main Outcomes and Measures The primary efficacy end point was the growth rate of well-delineated and homogeneous areas of retinal atrophic lesions over 24 months of treatment on fundus autofluorescence imaging. Safety end points included treatment-emergent adverse events (AEs), serious AEs, and clinical laboratory assessments. Results A total of 50 participants were randomized, and 54 NH cases included. The mean (range) age of randomized participants was 44.3 (18-60) years. Overall, 58 of 104 participants or cases (55.8%) were female. The growth rate of retinal atrophic lesions was 0.182 mm/y with gildeuretinol and 0.232 mm/y in the untreated group (placebo and NH), representing a mean difference of −0.050 mm/y (95% CI, −0.072 to −0.027; P < .001) and a 21.6% relative reduction. In a prespecified sensitivity analysis restricted to randomized participants, the growth rate was 0.206 mm/y with gildeuretinol and 0.242 mm/y with placebo, representing a mean difference of −0.036 mm/y (95% CI, −0.062 to −0.009; P = .008) and a 14.9% relative reduction. The majority of AEs were mild or moderate and equally distributed between groups. No treatment-related serious AEs, clinically significant liver function abnormalities, or participant-reported night blindness or dark adaption difficulties occurred. Conclusions and Relevance In the TEASE-1 randomized clinical trial, the primary efficacy end point of retinal atrophic lesion growth from 6 to 24 months was 0.05 mm/y greater on average in the untreated group (placebo and NH) than the gildeuretinol acetate group. Further research is needed to determine the clinical relevance of this end point. Trial Registration ClinicalTrials.gov Identifier: NCT02402660