Applied Therapeutics, Inc.: govorestat

You submitted data from an 18-month, randomized, double-blind, placebo-controlled trial (Trial AT-007-1002) with confirmatory evidence of the drug effect on plasma galactitol from nonclinical studies and clinical studies to establish substantial evidence of effectiveness of govorestat for the treatment of classic galactosemia (CG) in adults and pediatric patients 2 years of age and older.

Based on our review of the data, we are unable to conclude there is substantial evidence of effectiveness.

As such, the Agency could not rely on these data to determine govorestat's efficacy.

17/SAP 3.0, the version the Agency considered prespecified for the purpose of hypothesis testing.

The discussion under the Confirmatory Evidence section above describing the limitations of the evidence to support the role of galactitol in the pathogenesis of the CG applies to the consideration of galactitol as a reasonably likely surrogate endpoint (RLSE) for the purpose of accelerated approval.

In summary, the Agency concludes the currently available evidence does not support plasma galactitol as a reasonably likely surrogate endpoint for CG.

Provide substantial evidence of effectiveness for govorestat for the treatment of CG.

Given the significant data quality issues with the efficacy endpoints in Trial AT-007-1002 and efficacy results outlined above, conduct at least one new adequate and wellcontrolled trial demonstrating an effect of govorestat on clinically meaningful endpoint(s) in subjects with CG.

Depending on the robustness of the results and the demonstrated relevance to the effects observed in animals to those observed in your clinical trial, the nonclinical study data could be considered confirmatory evidence, along with all other potential sources of confirmatory evidence.

For accelerated approval, you will need to provide substantial evidence of effectiveness of govorestat on the RLSE based on adequate and well controlled clinical investigation(s) and confirmatory evidence, if one single adequate and well controlled trial is being considered as primary evidence.

1. The submitted study using rat blood is insufficient to support the proposed claim in the Prescribing Information of the effect of govorestat on serum creatinine using the colorimetric assay.