Complete Response Letter NDA 505b1 219195 (Nov 27, 2024)

Summary

The FDA has identified significant deficiencies in NDA 219195 for govorestat, concluding that the currently available evidence does not support the drug's effectiveness for treating CG, nor does it validate plasma galactitol as a reasonably likely surrogate endpoint for accelerated approval. The agency requires substantial evidence of effectiveness, including new adequate and well-controlled clinical trials, and comprehensive data to support galactitol's role as a surrogate endpoint.

Key points

• Provide substantial evidence of effectiveness for govorestat for the treatment of CG.
• Conduct at least one new adequate and well-controlled trial demonstrating an effect of govorestat on clinically meaningful endpoint(s) in subjects with CG.
• If demonstrating effectiveness with one trial plus confirmatory evidence, consider conducting a well-designed and adequately powered nonclinical efficacy study in an animal model of CG demonstrating a robust effect of govorestat treatment at human-relevant exposures, assessed using validated assays, on clinically relevant neurobehavioral outcomes, histopathology, and metabolic markers of CG.
• Consider evaluation of a clinically relevant functional endpoint(s) in studies.
• Provide strong mechanistic evidence for the role of galactitol as the major mediator in the pathogenesis of the neurobehavioral symptoms of CG for accelerated approval consideration.
• Adequately and comprehensively address evidence from published literature regarding plausible alternative toxic metabolites/pathophysiologic mechanisms of disease.
• Determine and provide evidence to support a galactitol reduction response threshold that would be reasonably likely to predict clinical benefit.
• For accelerated approval, provide substantial evidence of effectiveness of govorestat on the reasonably likely surrogate endpoint (RLSE) based on adequate and well-controlled clinical investigation(s) and confirmatory evidence, if a single trial is primary evidence.

Cited reasons

• Lack of Substantial Evidence of Effectiveness from Clinical Trial
• Inadequate Confirmatory Evidence and Issues with Reasonably Likely Surrogate Endpoint (RLSE)
• Proprietary Name Resubmission Required
• Safety Update Required
• The application lacks substantial evidence of effectiveness for govorestat for the treatment of CG, primarily due to the failure of the pivotal clinical trial to meet statistical significance and significant data quality issues. Additionally, the evidence provided is insufficient to support plasma galactitol as a reasonably likely surrogate endpoint for accelerated approval, with nonclinical studies exhibiting technical limitations and design flaws. Procedural requirements for proprietary name resubmission and a safety update are also noted.

Recommended actions

• Provide substantial evidence of effectiveness for govorestat for the treatment of CG.
• Conduct at least one new adequate and well-controlled trial demonstrating an effect of govorestat on clinically meaningful endpoint(s) in subjects with CG.
• If demonstrating effectiveness with one trial plus confirmatory evidence, consider conducting a well-designed and adequately powered nonclinical efficacy study in an animal model of CG demonstrating a robust effect of govorestat treatment at human-relevant exposures, assessed using validated assays, on clinically relevant neurobehavioral outcomes, histopathology, and metabolic markers of CG.
• Consider evaluation of a clinically relevant functional endpoint(s) in studies.
• Provide strong mechanistic evidence for the role of galactitol as the major mediator in the pathogenesis of the neurobehavioral symptoms of CG for accelerated approval consideration.
• Adequately and comprehensively address evidence from published literature regarding plausible alternative toxic metabolites/pathophysiologic mechanisms of disease.
• Determine and provide evidence to support a galactitol reduction response threshold that would be reasonably likely to predict clinical benefit.
• For accelerated approval, provide substantial evidence of effectiveness of govorestat on the reasonably likely surrogate endpoint (RLSE) based on adequate and well-controlled clinical investigation(s) and confirmatory evidence, if a single trial is primary evidence.

Deficiency summary

The application lacks substantial evidence of effectiveness for govorestat for the treatment of CG, primarily due to the failure of the pivotal clinical trial to meet statistical significance and significant data quality issues. Additionally, the evidence provided is insufficient to support plasma galactitol as a reasonably likely surrogate endpoint for accelerated approval, with nonclinical studies exhibiting technical limitations and design flaws. Procedural requirements for proprietary name resubmission and a safety update are also noted.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

NDA

Impact

Impact score

0.75

Estimated delay

365 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary theme is the lack of robust evidence for both direct clinical efficacy and the validity of a proposed surrogate endpoint (plasma galactitol) for accelerated approval, necessitating new clinical and nonclinical studies. This indicates a fundamental issue with the efficacy data package.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 25%