The long-term goal of this clinical research is to develop an oral treatment to prevent or slow the progression 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 molecule 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 effects 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 up to 110 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 electrocardiograms, vital signs, physical exam, ocular exam, blood tests (liver enzymes, blood chemistry, hematology, 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 metabolites 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, microperimetry, visual acuity, reading speed, retinal thickness and/or volume by OCT; (d) compare the safety and effects of ALK-001 in patients of different age or varying phenotypes; (e) explore dose-response dependencies using the above efficacy and safety parameters; and (f) 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 worsening of STGD would have tremendous impact on the quality of life of people with STGD.

Public Health Relevance

/ 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.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1)
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Alkeus Pharmaceuticals, Inc.
United States
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