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FDA advisors indicated a possible path forward for elamipretide as a treatment for Barth syndrome despite the lack of definitive evidence.

On Thursday, the voted 10-6 that elamipretide is effective for the ultra-rare cardioskeletal disease caused by TAFAZZIN gene mutations. Elamipretide is proposed as a first-in-class mitochondrial protective agent that theoretically improves the function of cardiolipin-deficient mitochondria in patients with Barth syndrome.

"This was worse than our national election," said Eric Peterson, MD, MPH, a cardiologist at the University of Texas Southwestern Medical Center in Dallas, one of those voting "yes" after much deliberation. He called the empiric evidence for elamipretide "lacking," though he ultimately reasoned that he "was swayed by the preponderance of the evidence, albeit imperfect, that fell on the side of supporting the drug."

Committee members had spent most of the day discussing the rocky data package submitted by Stealth BioTherapeutics. The company has persisted in filing another new drug application to the FDA after years of pushback from the agency regarding its lack of a single "adequate and well-controlled" trial that establishes effectiveness for elamipretide.

Both the FDA and Stealth agree that the Barth syndrome population is too small to expect a large phase III randomized trial -- with an estimated 130 to 150 affected individuals in the entire U.S.

Data presented Thursday included positive-leaning and a alongside the negative , a phase II/III study that had shown no improvement in 6-minute walk distance (6MWD) and fatigue scores with elamipretide.

"I did overall feel the anecdotal evidence and trends snuck it over the line for me," said panelist Carole Tucker, PhD, a physical therapist at the University of Texas Medical Branch in Galveston, who also voted "yes." She acknowledged the difficulty generating robust evidence for such an ultra-rare disease.

Barth syndrome is characterized by cardiomyopathy, hypotonia, growth delay, neutropenia, and 3-methylglutaconic aciduria. Affecting predominantly boys, the disease starts in infancy and mortality is highest in the first 4 years of life, commonly due to cardiomyopathy. Those surviving to older age can still experience deterioration in their cardiac function to the point of requiring a heart transplant.

"I have huge concerns," said biostatistician Pamela Shaw, PhD, MS, of Kaiser Permanente Washington Health Research Institute in Seattle, who provided one of the "no" votes. "This is a very vulnerable population. I'd be afraid to approve a drug with the lack of systematic evidence that we currently have."

"I wish we had better mechanistic data, so either there needs to be existing data brought forward or new studies could be done that could add to the totality of the evidence," Shaw added. "If we approve [elamipretide], our ability to understand what's going on is going to go out the window because we won't be able to do any more systematic studies."

The FDA panel's acting consumer representative Devin Shuman, MS, a genetic counselor in Bellevue, Washington, said it was like being stuck between a "rock and a hard place" trying to interpret the limited data for such a rare disease. She ultimately voted yes.

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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