FDA Questions Stealth's Ultra-Rare Disease Drug Before Adcomm

Stealth BioTherapeutics is facing scrutiny from the FDA regarding its drug, elamipretide, intended to treat Barth syndrome—a rare and fatal mitochondrial disorder affecting approximately 130 individuals in the United States. According to briefing documents released by the FDA, the data submitted by Stealth BioTherapeutics appears insufficient for either standard or accelerated approval.

Elamipretide was previously rejected by the FDA in 2021. The drug is now up for discussion and a vote by an advisory committee. The FDA has emphasized that the only data provided by Stealth BioTherapeutics comes from a Phase 2 trial, which the agency had earlier indicated should not be considered adequate or well-controlled.

In the briefing documents ahead of the advisory committee meeting, the FDA highlighted that the placebo-controlled Phase 2 trial did not meet its primary objectives. Specifically, it failed to show a significant effect of elamipretide on the distance walked in a six-minute walk test, as well as on the total fatigue score measured by the Barth Syndrome Symptom Assessment. This assessment relies on patient-reported outcomes to gauge symptom severity.

Furthermore, the FDA argued that the accelerated approval pathway is inappropriate for elamipretide. The regulators examined whether there was compelling evidence showing an effect on echocardiographic parameters or cardiolipin findings, which could potentially serve as surrogate endpoints for accelerated approval. However, due to significant data limitations, the FDA concluded that the available data were not adequate to support this use.

The history between Stealth BioTherapeutics and the FDA regarding elamipretide dates back nearly a decade to the initial IND submission. According to the briefing documents, the FDA had told the company as early as 2021 that a Phase 3 trial was necessary and that the current data were insufficient. When Stealth BioTherapeutics initially applied for approval in 2021, they received a refuse-to-file letter from the FDA, which pointed out the lack of trial data establishing the drug's effectiveness.

Despite several correspondences and meetings, the FDA continued to recommend a new Phase 3 trial. Nevertheless, Stealth BioTherapeutics decided to resubmit their New Drug Application (NDA) without conducting a new trial. The FDA noted that although it cannot stop a company from submitting or resubmitting an NDA, the applicant is expected to fully address previous concerns in any resubmission.

Stealth BioTherapeutics maintains that elamipretide is effective. In their own briefing documents, the Massachusetts-based company argues that many patients with Barth syndrome are willing to take some risk with a new treatment. The company underscores that the conclusion regarding the benefit of elamipretide is supported by a risk-benefit analysis, considering the drug's well-characterized and generally benign safety profile. Additionally, they point out that patients are willing to accept some level of uncertainty concerning the drug's benefit.

This upcoming advisory committee meeting will be crucial for Stealth BioTherapeutics as it seeks regulatory approval for elamipretide. The outcome will determine whether the drug can move forward in its quest to become an approved treatment for Barth syndrome, despite the existing hurdles and the FDA's reservations.