Stealth BioTherapeutics Inc.: elamipretide

We extensively evaluated whether the evidence for the endpoints that directly assessed clinical benefit (i.e., how patients feel, function, or survive) in your studies could establish the effectiveness of elamipretide for traditional approval.

For the reasons described below, we are unable to conclude that these approaches establish the effectiveness of elamipretide for traditional or accelerated approval, even when applying regulatory flexibility for this rare, serious disease.

However, one of the endpoints in SPIBA-201, Part 2 - muscle strength of the knee extensors assessed using handheld dynamometry - could be reasonable as an intermediate clinical endpoint for accelerated approval.

The effectiveness of elamipretide has not been established for traditional approval for the following reasons:

SPIBA-201, Part 1, the only randomized, placebo-controlled, study of elamipretide in patients with BTHS, did not show superiority of elamipretide to placebo on the primary endpoint family of distance walked on 6-minute walk test (6MWT) (p=0.97) and total fatigue score (TFS) on the Barth syndrome symptom assessment (p=0.89) at the end of the 12-week treatment period.

We were unable to conclude that there is evidence of a meaningful treatment effect with elamipretide based on these findings.

This concern identified for these endpoints for the elamipretide-treated subjects in SPIBA-201, Part 2 could not be overcome by comparing these subjects to an external control of patients who knew they were not receiving elamipretide and, therefore, would have no expectation that they would improve.

In your cover letter with your NDA resubmission, you proposed that if the findings on the clinical endpoints were not sufficient for traditional approval that FDA consider accelerated approval based on surrogate endpoints of LVSV, MLCL:CL ratio, and/or acylcarnitines, and/or an intermediate clinical endpoint such as BMWT.

FDA has consistently used 6MWT as an endpoint for full approval (it is a direct measure of clinical benefit), not as an intermediate clinical endpoint for accelerated approval.

While your proposed endpoints of LVSV, MLCL:CL ratio, and/or acylcarnitines are not effort dependent or impacted by knowledge of treatment assignment, we identified the following major limitations, precluding their use for accelerated approval for elamipretide.

FDA is considering the endpoint on muscle strength of the knee extensors assessed using handheld dynamometry in SPIBA-201, Part 2, as a potential intermediate clinical endpoint for accelerated approval of elamipretide, if it is reasonably likely to predict a clinical benefit in BTHS.

This endpoint could not be considered for traditional approval because it assessed only a single muscle group and was not accompanied by clinical benefit (e.g., an improvement in how patients function).

We encourage you to request an End-of-Review meeting to discuss this potential approach.

In the briefing document for this meeting, provide FDA with information on what clinical benefit this endpoint would be reasonably likely to predict and include your proposed design of a confirmatory postmarketing clinical trial that would be able to verify whether elamipretide has this predicted clinical benefit.

The facility should provide satisfactory responses to these deficiencies to the FDA office indicated on the FDA 483 prior to submission of your complete response.

PAI and the CGMP surveillance inspections will be needed prior to an approval of the application.

We reserve further comment on the proposed labeling until the application is otherwise adequate.

Section 505(0)(3) of the FDCA authorizes FDA to require holders of approved drug and biological product applications to conduct postmarketing studies and clinical trials for certain purposes, if FDA makes certain findings required by the statute.

FDA has determined that if NDA 215244 is approved, an analysis of spontaneous postmarketing adverse events reported under subsection 505(k)(1) of the FDCA will not be sufficient to assess these serious risks of carcinogenicity and drug-drug interactions.

215244 is approved, you will be required to conduct the following postmarketing studies:

Any additional specific details of these required postmarketing studies, including a timetable and annual reporting requirements, will be described more fully in the approval letter for this application, if it is approved.

If you complete these studies prior to re-submitting your application, include the final report and relevant data sets in your complete response submission to facilitate review of the information.