The long-term goal of this clinical research is to develop an oral treatment to prevent or slow the pro- gression of Stargardt disease (STGD), a leading, but rare form of juvenile blindness with a prevalence of 1 in 10,000 in the United States. There is no FDA-approved cure or preventative treatment for STGD. Vision loss in STGD is caused by mutations on the ABCA4 gene. These mutations lead to the accelerated formation of toxic vitamin A aggregates called ?vitamin A dimers?. The central hypothesis is that retarding the formation of these dimers will slow the development and/or progression of STGD. This study will investigate the effects of a mole- cule called ALK-001, which inhibits the dimerization of vitamin A, on the progression of STGD. In rodent models of STGD, administration of ALK-001 for over one year, led to significant, sustained slowing of vitamin A dimerization, and to preservation of visual function. In a 4-week long, multi-dose, phase 1a clinical study in healthy volunteers, and in an 8-week long phase 1b in patients with Stargardt disease, ALK- 001 reached ?bioactive levels?, was well-tolerated by all subjects, and showed no side effects or toxicity. For ALK-001 to become a FDA-approved therapeutic however, it must first be evaluated in Phase 2 then Phase 3 clinical trials. The specific objective of this application is to collect additional data regarding the safety and ef- fects of ALK-001 so that Phase 3, confirmatory trials can be designed and performed. This will be achieved by completing the following specific aim: Perform a 24-month, randomized, double-masked, placebo-controlled study with a cross-over arm, in 50 subjects with STGD, to evaluate the safety, tolerability and effects of ALK- 001 on the progression of STGD. This study will be performed at multiple clinical sites across the United States. Safety outcome measures include: adverse events (AE), serious adverse events (SAE), 12-lead elec- trocardiograms, vital signs, physical exam, ocular exam, blood tests (liver enzymes, blood chemistry, hematol- ogy, and lipid panels). Efficacy outcome measures include size of atrophic lesions by fundus autofluorescence (FAF), best-corrected visual acuity, microperimetry, optical coherence tomography (SD-OCT), visual function questionnaire, reading speed, and dark adaptation. Completion of the proposed work will generate clinical data to: (a) assess the safety and tolerability of 24 months of daily dosing of ALK-001 in STGD patients; (b) determine the quantity of ALK-001 and its metabo- lites in plasma, in response to daily dosing for up to 24 months; (c) obtain estimates of the effect size of ALK- 001 on the progression of STGD, as measured by changes in: areas of significantly decreased FAF, micrope- rimetry, visual acuity, reading speed, retinal thickness and/or volume by OCT; (d) explore dose-response de- pendencies using the above efficacy and safety parameters; and (e) gather data to better understand how STGD progresses. The above data will be used to power a Phase 3 safety and efficacy study to evaluate the extent to which inhibiting the dimerization of vitamin A in the retina prevents vision loss due to STGD, and to finalize the clinical development of a possible treatment for STGD. An oral drug to prevent or slow the worsen- ing of STGD would have tremendous impact on the quality of life of people with STGD.
/ PUBLIC HEALTH RELEVANCE The proposed research is relevant to overall public health because it seeks to evaluate the safety and efficacy of ALK-001, a potential treatment for Stargardt disease (STGD), a leading and currently untreatable cause of juvenile blindness in the United States.