The FDA has declined to approve Applied Therapeutics' New Drug Application (NDA) for govorestat, a treatment for classic galactosemia, citing deficiencies in the clinical application. This decision casts uncertainty over the future of the drug, which was intended to be the first approved therapy for this rare genetic metabolic disorder.
Govorestat's Mechanism and Clinical Data
Govorestat is a central nervous system (CNS)-penetrant aldose reductase inhibitor (ARI) designed to reduce the levels of galactitol, a toxic metabolite that accumulates in individuals with galactosemia due to their inability to properly metabolize galactose. The accumulation of galactitol leads to neurological complications, including cognitive and motor skill deficits.
The NDA was supported by data from the Phase 3 ACTION-Galactosemia Kids trial, which evaluated govorestat against placebo in children aged 2 to 17 years. While the trial did not meet its primary endpoint, post-hoc analyses showed statistically significant benefits in behavior and activities of daily living (P = .0205), as well as improvements in tremor (P = .0428) and adaptive skills (P = .0265). The Phase 1/2 ACTION-Galactosemia study in adults also demonstrated significant reductions in plasma galactitol levels.
FDA's Concerns and Applied Therapeutics' Response
The FDA's Complete Response Letter (CRL) indicated that the NDA could not be approved in its current form due to unspecified deficiencies in the clinical application. In response, Applied Therapeutics is reviewing the FDA's feedback and intends to request a meeting to discuss the requirements for a potential resubmission of the NDA or appeal of the decision.
Shoshana Shendelman, PhD, Founder and CEO of Applied Therapeutics, expressed disappointment with the FDA's decision, stating, "We are disappointed by the FDA's decision today... As we move forward, we plan to work with the FDA to address the concerns in the CRL and determine an expeditious path to bring this much needed treatment to patients."
Impact on the Galactosemia Community
The Galactosemia Foundation has voiced its disappointment, urging the FDA to reconsider its decision. Nicole Casale, president of the Galactosemia Foundation, stated, "The galactosemia community is devastated by the FDA's decision to not approve the first and currently only potential treatment for this ultra-rare, life-altering disease... Individuals facing this devastating disease need a treatment now."
Future Plans for Govorestat
Applied Therapeutics is also developing govorestat for the treatment of Sorbitol Dehydrogenase (SORD) Deficiency, a rare and progressive neuromuscular disease. The company expects to submit an NDA for this indication in the first quarter of 2025, and the review and potential approval of govorestat for SORD is independent of the ongoing review for classic galactosemia.
Galactosemia: An Unmet Medical Need
Classic galactosemia is a rare genetic metabolic disease that affects approximately 3,300 patients in the U.S. and 4,400 in the EU. The condition results from an inability to metabolize galactose, leading to the accumulation of galactitol, which causes neurological complications, including deficiencies in cognition, behavior, and motor skills. Currently, the primary treatment for galactosemia is a galactose-restricted diet, but even with dietary restrictions, complications can arise, highlighting the urgent need for effective therapies.
