FDA CRL - Applied Therapeutics, Inc.

The FDA issued a Complete Response Letter (CRL) to Applied Therapeutics, Inc. for its New Drug Application (NDA 219195) for govorestat, a treatment for classic galactosemia (CG). The agency concluded that the application could not be approved due to a lack of substantial evidence of effectiveness. Key issues stemmed from Trial AT-007-1002, where major systemic data quality problems were identified, including improperly implemented Clinical Outcome Assessments (COAs), unresolved efficacy data discrepancies, and inadequate data management, compromising the reliability of primary outcome data. Moreover, the trial failed to meet prespecified statistical significance for its primary efficacy endpoints under various protocol versions, indicating no convincing treatment effect. The FDA also determined that plasma galactitol, a proposed biomarker, was inadequate as confirmatory evidence or as a reasonably likely surrogate endpoint for accelerated approval. This was due to limited evidence supporting galactitol as the major pathogenic driver of CG, technical flaws in nonclinical studies, and weak, inconsistent correlations between galactitol levels and clinical outcomes. To address these deficiencies, Applied Therapeutics must conduct at least one new, adequate, and well-controlled clinical trial demonstrating a clinically meaningful effect of govorestat. If pursuing the single trial plus confirmatory evidence pathway, a robust nonclinical efficacy study is recommended. For accelerated approval, the company needs to provide strong mechanistic evidence for galactitol's primary role in CG pathogenesis, address alternative mechanisms, and define a galactitol reduction threshold predictive of clinical benefit.