Govorestat Hits Roadblock: FDA Denies Approval for Applied Therapeutics’ Rare Disease Drug

The US Food and Drug Administration (FDA) has rejected the New Drug Application (NDA) for govorestat (AT-007), an investigational treatment for classic galactosemia, citing deficiencies in its clinical application. This decision, communicated through a Complete Response Letter, means the drug cannot currently proceed to market. Applied Therapeutics, the developer, plans to meet with the FDA to address the issues and explore options for resubmission.

Govorestat is a central nervous system (CNS)-penetrant aldose reductase inhibitor designed to target a critical problem in classic galactosemia — a rare genetic condition that prevents proper metabolism of the sugar galactose. In this disorder, galactose accumulates as galactitol, a toxic substance that builds up in blood, tissues and organs — including the brain — leading to neurological complications, including cognitive and motor impairments.

The lack of existing treatments amplifies the unmet need for a viable therapy. Govorestat is the first therapy evaluated specifically for this ultra-rare condition.

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According to another study evaluating the disease burden and the health-related quality of life (HRQoL) in affected populations, patients with classic galactosemia face severe cognitive impairments, anxiety and fatigue.

Clinical trials for AT-007 showed promise. In the ACTION-Galactosemia Kids Phase III study, pediatric patients aged two to 17 demonstrated significant benefits in cognitive function, behavior, motor skills and daily living activities. The drug also reduced galactitol levels in both children and adults. Over three years, data from 185 participants underscored its potential efficacy and safety.

Despite these results, the FDA found the application lacking. Applied Therapeutics’ CEO, Shoshana Shendelman, emphasized the drug’s demonstrated ability to halt progressive clinical decline. Shendelman acknowledged the setback but reinforced plans to address the FDA’s concerns swiftly.

The Galactosemia Foundation, a non-profit advocating for individuals with galactosemia and their families, expressed disappointment in the FDA’s rejection. Highlighting the improvements seen in patients treated with govorestat, the foundation stressed the urgent need for treatment and urged the FDA to reconsider its decision.

Applied Therapeutics is also developing govorestat for other rare conditions, including sorbitol dehydrogenase deficiency, with plans to submit another application in early 2025. The FDA’s rejection speaks to the complexities of regulatory pathways for ultra-rare diseases. However, Applied Therapeutics will remain focused on refining its case for govorestat in classic galactosemia.