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Ahead of an FDA advisory committee meeting on Thursday, agency reviewers cast doubt on the efficacy of elamipretide for Barth syndrome, an ultra-rare disease that has no approved treatments.

In its new drug application, Stealth BioTherapeutics described elamipretide as a first-in-class mitochondrial protective agent that theoretically improves the function of cardiolipin-deficient mitochondria in patients with Barth syndrome, a cardioskeletal disease caused by TAFAZZIN gene mutations.

During Thursday's meeting, members of the will be asked to discuss the quality of the evidence provided by the sponsor and will vote on whether daily elamipretide injections are effective for Barth syndrome.

In released ahead of the meeting, FDA reviewers noted the years of back-and-forth with the applicant. Agency officials from various divisions have long maintained that the available data do not prove elamipretide's efficacy, and that a definitive trial would be needed; despite the advice, Stealth BioTherapeutics submitted a new drug application in 2021 and was shot down with a Refusal-to-File letter for not having a single "adequate and well-controlled" trial that establishes effectiveness.

Undeterred, at the beginning of this year, the company resubmitted the application in the hopes that reviewers will be swayed by a data package that includes:

• The randomized that found no improvement in 6-minute walk distance (6MWD) and fatigue scores with elamipretide versus placebo
• The uncontrolled, open-label that showed that elamipretide was associated with improvements in 6MWD, fatigue scores, and echocardiographic parameters
• The externally controlled that supported improvements in 6MWD and left ventricular stroke volume (LVSV) with elamipretide compared with retrospective natural history data

In the briefing document, FDA reviewers said the agency "does not believe that the available evidence establishes the effectiveness of elamipretide" for Barth syndrome.

The company's argument is that elamipretide's observed increase in LVSV and changes in cardiolipin ratio reflect a real treatment effect in patients with Barth syndrome, which is characterized by cardiomyopathy, hypotonia, growth delay, neutropenia, and 3-methylglutaconic aciduria.

The disease affects approximately 130 to 150 individuals in the U.S. -- predominantly boys starting in infancy. Mortality is highest in the first 4 years of life, commonly due to cardiomyopathy.

"Infancy and early childhood are particularly high-risk periods for cardiac transplantation and death, but those who survive experience improvements and stabilization of their cardiac function in the middle childhood years. However, as patients age, they may experience deterioration in their cardiac function, necessitating advanced cardiac therapies such as heart transplantation," FDA reviewers wrote in the briefing documents.

Stealth BioTherapeutics announced that it is also trying to develop elamipretide for .

While the FDA is not required to follow the advice of its advisory committees, it typically does. The agency is expected to make its decision on elamipretide by January 2025.

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