Stargardt Disease Phase 2 Clinical Trial: Design and Baseline Characteristics

Abstract

Purpose : Stargardt disease (STGD) is the most frequent inherited macular dystrophy. The disease results from defects in the ABCA4 gene, which accelerate the formation of retinaldehyde dimerization products (RDP) such as A2E, thought to be responsible for the pathology. No treatment exists. We present the design, baseline data, pharmacokinetics and initial safety for subjects enrolled in an ongoing clinical study to evaluate an oral treatment for STGD: the “TEASE” trial.

Methods : ALK-001, self-administered as a once-a-day pill, is a deuterated vitamin A, which slows the formation of RDP in the eye 4 to 5-fold without inhibiting the visual cycle. TEASE is a two-year Phase 2 double-masked placebo-controlled study enrolling up to 50 subjects confirmed to have STGD and a well-delineated area of atrophy (Fig 1). Patients with any visual acuity are eligible and subjects are randomized to receive ALK-001 (n=30) or placebo (n=20) during the first year. After one year of treatment, 50% of placebo subjects cross over to ALK-001 in a masked and randomized fashion. Outcome measures include atrophy lesion size, best-corrected visual acuity (BCVA), and reading speed among others.

Results : 44 of the 50 subjects (33 White; 23 Female) have been enrolled at 7 clinical sites. Median age was 46 years (range, 18-60) and disease duration 10 years (2-32). For subjects with 1 (n=10) or 2+ ABCA4 mutations, the median age of onset of symptoms was 43 or 30 years respectively. Median BCVA at baseline was 49 letters (8-91) or 20/100. Median reading speed was 97 wpm (2-199), a 59% reduction from normative speed; cross sectional analysis indicated that a decrease in BCVA of 3 lines of vision was associated with a decrease of about 22 wpm in reading speed. Atrophic lesions were bilateral in 75% of cases with a 5.1 mm² (0.25-31.6) median area.
As of November 2016, the longest treatment duration was 15 months. Over 90% of vitamin A was replaced by ALK-001 in plasma without increases in total vitamin A (deuterated + natural). The treatment is so far well-tolerated with no toxicity, nor report of systemic or ocular side effects.

Conclusions : ALK-001 has shown promise in the treatment of STGD by slowing RDP formation in Abca4 knockout mice. The TEASE Phase 2 study is close to full enrollment and the largest ongoing effort to slow or prevent the progression of STGD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.

 

Fig. 1 Fundus autofluorescence and fovea (red outline) of 2 age-matched subjects in TEASE