Alkeus Pharmaceuticals Inc. has announced positive interim results from its TEASE-3 study, revealing that gildeuretinol (ALK-001) halted the progression of early-stage Stargardt disease for up to six years in certain patients. This groundbreaking outcome offers hope for individuals with this inherited genetic mutation that typically leads to progressive vision loss and blindness. The study's findings highlight the potential of early intervention in managing Stargardt disease.
TEASE-3 Study Details
The TEASE-3 study is an open-label trial focusing on patients with early signs of Stargardt disease detectable through retinal imaging but who have not yet experienced symptoms of vision loss. Participants underwent fundus autofluorescence imaging and other assessments to evaluate the drug's impact on disease progression. The primary endpoint measured progression after the first two years of treatment. Notably, three teenagers enrolled in the study have remained symptom- and progression-free during treatment, with one patient followed for two years and two patients for six years.
Gildeuretinol Mechanism of Action
Gildeuretinol is described as a specialized form of deuterated vitamin A designed to reduce the dimerization of vitamin A without disturbing vision. Stargardt disease results from mutations in the ABCA4 gene, leading to the accumulation of toxic byproducts and subsequent retinal damage. By modifying vitamin A, gildeuretinol aims to mitigate this accumulation and prevent further cell death.
Comparison with Other TEASE Trials
In the TEASE-1 trial, gildeuretinol was tested in 50 patients with more advanced Stargardt disease. While the drug slowed disease progression, it did not halt it as observed in the TEASE-3 study of early-stage disease. According to Michael B. Gorin, MD, PhD, this difference underscores the importance of early intervention. "This is what makes the results with early disease so dramatic," Gorin stated, emphasizing the need to consider therapies at different stages of the condition. Gildeuretinol met its prespecified primary efficacy end-point with a 21% reduction in the growth rate of retinal atrophic lesions (P < .001; square root units, 28% effect for untransformed areas) against untreated patients.
Ongoing Research: TEASE-2 Trial
The TEASE-2 trial, a fully enrolled, randomized, triple-masked, placebo-controlled study involving 80 Stargardt disease patients, is ongoing. Top-line data from this trial are expected in 2025.
Addressing Ethical Considerations
The TEASE-3 study design involved ethical considerations, as it included asymptomatic children who were genetically predisposed to Stargardt disease. Investigators addressed concerns about testing asymptomatic children and the potential for survivor guilt by offering treatment to younger siblings with the same mutations as their affected older siblings. This approach allowed for age-matched comparisons within the same family, controlling for genetic and environmental factors.
Stargardt Disease and Vision Loss
Stargardt disease is primarily caused by mutations in the ABCA4 gene, which encodes a protein responsible for moving vitamin A within cells for reprocessing. When this protein malfunctions, vitamin A accumulates and forms toxic products, leading to cell death and vision loss. Current therapeutic approaches target various aspects of this process, including reducing vitamin A uptake, modifying vitamin A to prevent toxic byproduct formation, removing lipofuscin from cells, and blocking complement activation. Gene therapy and stem cell-based approaches are also being explored.
