Approval Letter Other (Nov 13, 2025)

Summary

The FDA issued a 'not approvable' letter for Kyowa Pharmaceutical, Inc.'s New Drug Application (NDA 22-075) for istradefylline tablets (20mg, 40mg) due to inadequate information. The deficiencies cited include insufficient clinical evidence of meaningful benefit beyond a modest effect on 'OFF time' in Parkinson's Disease, required Phase 4 clinical pharmacology commitments, and incomplete nonclinical data regarding brain mineralization.

Key points

• Demonstrate, in an adequately designed and conducted controlled trial, that patients with advanced Parkinson's Disease (PD), who had been explicitly maximally and optimally treated with all appropriate available treatments, had a decrease in OFF time on istradefylline compared to placebo.
• Conduct a drug interaction study to investigate the inhibition potential of istradefylline on Pgp.
• Conduct in vitro studies to explore the induction potential of istradefylline on CYP1A2, and if potential exists, an in vivo study may be necessary.
• Provide an overall summary of the methodology used and the results of the original and re-examination of brain samples, and expert opinions regarding the nature of the mineralization and its possible relationship or lack of relationship to the drug.
• If an expanded histopathology of brain was not conducted for dog as was done in the rat and mouse, it should be conducted and the results submitted for review.
• Within 10 days after the date of this letter, amend the application, notify intent to file an amendment, or follow one of the other options under 21 CFR 314.120.
• Any amendment should respond to all listed deficiencies; a partial reply will not be processed as a major amendment and the review clock will not be reactivated until all deficiencies have been addressed.
• While effectiveness in decreasing OFF time is acknowledged, there is a uniform failure to find significant results on any secondary outcomes (e.g., UPDRS, ON time) or global measures (e.g., CGI, SF-36). This raises concerns about the strength of the finding and the overall clinical utility, suggesting no clear patient population for whom the drug would be a suitable choice. The agency believes the effect on OFF time is either inconsistent, clinically trivial, or offset by distressing side effects.

Cited reasons

• Lack of Demonstrable Clinical Utility and Meaningful Benefit
• Inadequate Summary and Analysis of Brain Mineralization Findings
• The application is not approvable due to a lack of demonstrable clinical utility beyond a single endpoint (OFF time) and unresolved nonclinical safety concerns regarding brain mineralization. The agency found no clear patient population for whom the drug would be a suitable choice, and the nonclinical data submission was poorly organized and incomplete.

Recommended actions

• Demonstrate, in an adequately designed and conducted controlled trial, that patients with advanced Parkinson's Disease (PD), who had been explicitly maximally and optimally treated with all appropriate available treatments, had a decrease in OFF time on istradefylline compared to placebo.
• Conduct a drug interaction study to investigate the inhibition potential of istradefylline on Pgp.
• Conduct in vitro studies to explore the induction potential of istradefylline on CYP1A2, and if potential exists, an in vivo study may be necessary.
• Provide an overall summary of the methodology used and the results of the original and re-examination of brain samples, and expert opinions regarding the nature of the mineralization and its possible relationship or lack of relationship to the drug.
• If an expanded histopathology of brain was not conducted for dog as was done in the rat and mouse, it should be conducted and the results submitted for review.
• Within 10 days after the date of this letter, amend the application, notify intent to file an amendment, or follow one of the other options under 21 CFR 314.120.
• Any amendment should respond to all listed deficiencies; a partial reply will not be processed as a major amendment and the review clock will not be reactivated until all deficiencies have been addressed.

Deficiency summary

The application is not approvable due to a lack of demonstrable clinical utility beyond a single endpoint (OFF time) and unresolved nonclinical safety concerns regarding brain mineralization. The agency found no clear patient population for whom the drug would be a suitable choice, and the nonclinical data submission was poorly organized and incomplete.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

NDA 505(b)

Impact

Impact score

0.95

Estimated delay

730 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The application failed to demonstrate sufficient clinical benefit and utility for a defined patient population, coupled with significant nonclinical data gaps and organizational issues, leading to a 'not approvable' decision.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%