FDA CRL - Stealth BioTherapeutics, Inc

The FDA issued a Complete Response Letter (CRL) to Stealth BioTherapeutics Inc. for its New Drug Application (NDA 215244) concerning elamipretide injection, a treatment for Barth syndrome. The agency determined it could not approve the application due to several significant deficiencies, despite acknowledging the high unmet medical need for this rare disease.

The main issues involve the lack of established effectiveness for elamipretide under both traditional and accelerated approval pathways. For traditional approval, the primary randomized, placebo-controlled study (SPIBA-201 Part 1) did not demonstrate superiority for key clinical endpoints such as the 6-minute walk test and total fatigue score. Subsequent open-label and externally controlled studies (SPIBA-201 Part 2 and SPIBA-001) were found to be inadequate, primarily due to concerns about bias from effort-dependent endpoints, subjects' knowledge of treatment assignment, and significant methodological limitations, including issues with data reliability and statistical analysis.

For accelerated approval, the FDA deemed the proposed surrogate endpoints, including left ventricular stroke volume (LVSV), the MLCL:CL ratio, and acylcarnitines, unsuitable due to major limitations. While the 6-minute walk test is a direct measure for full approval, its effectiveness was not established. However, the FDA noted that muscle strength of the knee extensors, measured by handheld dynamometry, could potentially serve as an intermediate clinical endpoint for accelerated approval, outlining a potential path forward for this specific approach.

Finally, deficiencies were identified at the drug product manufacturing facility that must be resolved prior to any approval. Stealth BioTherapeutics Inc. must address these efficacy data shortcomings and manufacturing facility issues to proceed with the application.