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Clinical research on a novel oral therapy for Stargardt disease suggests uses a deuterated form of vitamin A. 

A recent update on phase 2 clinical research of a novel treatment for patients of Stargardt disease has reported a positive primary end-point slowing the growth rate of atrophic lesions.  The treatment for the investigational drug (“ALK-001” – C20-D3-retinyl acetate) is a chemically-modified vitamin A designed to prevent the formation of toxic vitamin A dimers in the eye. The phase 2 study uses a randomised, double-masked, placebo-controlled trial assessing long term safety, tolerability, pharmacokinetics and the effects of ALK-001 on the progression of Stargardt Disease patients between the ages of 8 and 70 years old. Stargardt disease is a rare genetic is caused by a defective ABCA4 gene, which affects the processing of vitamin A and leads to the formation of toxic vitamin A aggregates in the eye.  ALK-001 (also known as gildeuretinol) was designed as a specifically deuterated form of vitamin A that greatly reduces vitamin A dimerization, with the potential to slow or halt the progression.

Stargardt disease (STGD1) is an inherited disorder that can cause vision loss in children and young adults with an estimated 30,000 people affected in the U.S. and more than 150,000 worldwide. The disorder is caused by mutations in the photoreceptor-specific ABCA4 gene which encodes the adenosine triphosphate-binding cassette, subfamily A, member 4. The gene encodes a transporter protein within retinal photoreceptor cells facilitating the active transport of potentially toxic retinoid compounds removing toxic by-products from the visual cycle. A number of pathogenic variants within certain introns of the ABCA4 gene may result aberrant splicing of the gene – including pseudogenes – essentially non-functional segments of DNA.  Loss of the protein results in the accelerated dimerization of vitamin A, forming toxic by-products that irreversibly damage the retina, resulting in progressive vision loss.  In the recent study, the researchers evaluated a primary end-point for safety and tolerability over 24 months of daily dosing of ALK-001, and assessed by incidence and/or clinically significant changes of a combination of ocular and non-ocular adverse events  and; secondary effects of ALK-001 on changes in atrophic lesion size, best corrected visual acuity (BCVA), and ocular assessments.

According to preliminary data from the clinical trial, gildeuretinol has slowed 21% of the growth rate of atrophic retinal lesions during the two-year study (square root transformation analysis) or 28%, using untransformed atrophic areas. The growth rates of atrophic retinal lesions were 0.19 mm/year (0.90 mm2/year untransformed area) with gildeuretinol and 0.24 mm/year (1.25 mm2/year) in the untreated arm, mean difference 0.05 mm2/year (0.35 mm2/year) (95% confidence interval, 0.03 to 0.07, p<0.001, R² = 0.9996). In addition, a post-hoc comparison, gildeuretinol-treated patients had an 80% slower rate of retinal sensitivity loss compared to the 330 eyes ProgStar natural history (0.4 dB/year loss in gildeuretinol vs. 2.2 dB/year in ProgStar). In total, over 150 patients have been treated with gildeuretinol for over a year in several studies. Commenting on the summary results, Dr. Catherine Kay, M.D., of Vitreo Retinal Associates Florida, and a principal investigator,  stated that, “it is extremely satisfying and humbling to have the opportunity to provide positive data at the Academy regarding the TEASE-1 trial [TEASE – Tolerability and Effects of ALK-001 on Stargardt Disease]. I think gildeuretinol has the capacity to benefit patients with Stargardt disease in a clinically-meaningful way. I am hopeful gildeuretinol will be our first FDA-approved therapy for Stargardt disease, one of the most common inherited retinal diseases.”