Alkeus Pharmaceuticals' gildeuretinol (ALK-001), an investigational oral therapy, has been granted Rare Pediatric Disease and Fast Track designations by the FDA for the treatment of Stargardt disease. These designations aim to expedite the development and review of the drug, which has already received Breakthrough Therapy and Orphan Drug designations. Stargardt disease, a progressive inherited retinal disease, leads to severe vision loss in both children and adults, and currently, there are no approved treatments available.
Mechanism of Action
Gildeuretinol acetate (ALK-001) is designed to reduce the dimerization of vitamin A without affecting the visual cycle. Preclinical studies have shown that gildeuretinol can decrease vitamin A dimerization to normal rates, preventing retinal degeneration and vision loss in animal models of Stargardt disease.
Clinical Trial Data
Recent data from Alkeus’ TEASE (Tolerability and Effects of ALK-001 on Stargardt disease) program were presented at the 2024 American Academy of Ophthalmology (AAO) Annual Meeting. The TEASE program consists of four independent clinical studies of oral gildeuretinol (ALK-001) in Stargardt disease, denoted as TEASE-1, TEASE-2, TEASE-3 and TEASE-4.
In the TEASE-1 study, a 24-month, placebo-controlled, double-masked, randomized trial, gildeuretinol slowed the growth rate of atrophic retinal lesion area (square root) by 21.6% compared to untreated patients (p<0.001). A sensitivity analysis using non-transformed values showed a 29.5% reduction in lesion growth. Specifically, the growth rates of atrophic retinal lesions were 0.18 mm/year (0.87 mm²/year untransformed area) in the gildeuretinol-treated group, compared to 0.23 mm/year (1.23 mm²/year) in the untreated group, with a mean difference of 0.05 mm/year (95% CI: 0.03 to 0.07, p<0.001). Using non-transformed analysis, the difference was 0.36 mm²/year (95% CI: 0.23 to 0.50, p<0.001).
Interim data from the TEASE-3 study indicated that early-stage Stargardt disease patients treated with gildeuretinol showed no disease progression and remained asymptomatic while on therapy for between two and six years. In these early-stage patients, gildeuretinol treatment was associated with relatively stable visual acuity.
Implications of FDA Designations
The Rare Pediatric Disease designation allows Alkeus to potentially receive a priority review voucher (PRV) upon approval, which can be used to expedite the development of another clinical program. The Fast Track designation expedites the review of drugs intended to treat serious conditions with clinical data demonstrating the potential to address an unmet medical need.
Stargardt Disease: An Unmet Need
Stargardt disease affects an estimated 30,000 to 87,000 people in the U.S. The disease is characterized by a defect in the ABCA4 protein, leading to accelerated dimerization of vitamin A and the formation of toxic by-products that damage the retina, resulting in progressive vision loss. Currently, there are no approved treatments for Stargardt disease, highlighting the urgent need for effective therapies.
Safety and Tolerability
In both TEASE-1 and TEASE-3, gildeuretinol demonstrated a favorable safety and tolerability profile. There were no adverse events related to hyper- or hypo-vitaminosis A, such as xerophthalmia, chromatopsia, dark adaptation delays, or night blindness.
Ongoing Studies
The TEASE-2 trial is an ongoing, fully enrolled, randomized, double-masked, placebo-controlled trial in 80 patients with moderate Stargardt disease, with topline data expected in 2025. TEASE-4 is an open-label extension study.
