RARE Daily

Applied Therapeutics Reports Positive Results from Interim Analysis of Govorestat to Treat SORD

February 15, 2024

Rare Daily Staff

Applied Therapeutics reported interim results from its phase 3 INSPIRE trial of its experimental therapy govorestat to treat the rare neuropathy SORD deficiency met the primary endpoints and several key secondary endpoints.

Sorbitol dehydrogenase (SORD) deficiency is a rare, progressive, debilitating hereditary neuropathy that affects peripheral nerves and motor neurons. The disease is caused by a lack of the enzyme sorbitol dehydrogenase, responsible for the metabolism of sorbitol, which causes sorbitol to accumulate at high levels and become toxic to the body. Intracellular sorbitol accumulation results in significant disability, loss of sensory function, neuromuscular dysfunction, and decreased mobility.

Govorestat is a central nervous system penetrant aldose reductase inhibitor in development for the treatment of several rare neurological diseases, including galactosemia, SORD deficiency, and PMM2-CDG. The European Medicines Agency granted Govorestat Orphan Medicinal Product designation for both galactosemia and SORD deficiency. Govorestat has also received Orphan Drug designation from the U.S. Food and Drug Administration for the treatment of galactosemia, PMM2-CDG, and SORD deficiency, Pediatric Rare Disease designation for galactosemia and PMM2-CDG; and Fast Track designation for galactosemia.

The INSPIRE trial is a phase 3 double-blind placebo-controlled registrational study evaluating the effect of once-daily, oral govorestat in 56 patients aged 16-55 with SORD deficiency in the United States and Europe.

The objective of this pre-specified, 12-month interim analysis was to evaluate early indicators of govorestat treatment effect in order to inform future regulatory discussions and support a potential New Drug Application submission, due to the urgent need for treatment and absence of any other options for patients with SORD deficiency. The 12-month interim analysis was comprised of a clinical efficacy primary endpoint based on correlation of sorbitol with composite clinical outcome measures, and a pharmacodynamic (PD) biomarker primary endpoint based on sorbitol reduction.

The study demonstrated statistically significant correlation between sorbitol level and the prespecified CMT-FOM composite clinical endpoint (10-meter walk-run test, 4 stair climb, sit to stand test, 6-minute walk test and dorsiflexion).

Govorestat treatment provided sustained reduction in sorbitol level in patients with SORD deficiency over 12 months of treatment, which was statistically significant compared to placebo.

Treatment also resulted in a highly statistically significant effect on the CMT Health Index (CMT-HI), an important patient-reported outcome measure of disease severity and well-being, which was a secondary endpoint in the study. Aspects of the CMT-HI that demonstrated a treatment effect included lower limb function, mobility, fatigue, pain, sensory function, and upper limb function.

Govorestat was safe and well tolerated, with similar incidence of adverse events between active and placebo-treated groups.

The company said it believes the results from the 12-month interim analysis confirm the role of sorbitol as a key driver of disease severity and progression over time. Clinical outcomes of the ongoing INSPIRE trial are expected to be assessed again at 24 months, where the 10-meter walk run test serves as the primary clinical efficacy endpoint. The company plans to discuss a potential submission approval with the FDA based on the clinical data to date.

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