FDA Refuses to Approve Stealth’s Barth Syndrome Therapy, But Offers Path Forward

Rare Daily Staff

The U.S. Food and Drug Administration notified Stealth Biotherapeutics that it would not approve elamipretide, the company’s experimental therapy for the rare mitochondrial condition Barth syndrome, but did offer a path forward.

The decision comes after a more than 16-month wait since Stealth applied for approval to market elamipretide, five years of discussion with the agency, and a positive recommendation from a 2024 Cardiovascular and Renal Drugs Advisory that found elamipretide effective for the treatment of Barth syndrome.

The regulatory pathway for elamipretide has been complex and extended across four different FDA review divisions since data was first presented to the agency in 2019. The ultra-rare nature of Barth syndrome, the FDA’s reservations regarding the positive data from a phase 3 natural history control study assessing the functional endpoints utilized in the open-label extension, and the FDA’s prior refusal to consider an accelerated approval pathway all contributed to the challenges of the review.

The case is being watched to see how the agency under the new administration will approach ultra-rare diseases and what regulatory flexibility they may use. FDA Commissioner Marty Makary has expressed a willingness to craft a more flexible pathway for ultra-rare disease therapies, but has offered no specifics about such a pathway.

“It’s unconscionable that it now will take even longer for the FDA to rule on this drug for our very small population with no other specific therapies,” said Emily Milligan, executive director, Barth Syndrome Foundation. “This administration has sent strong signals it’s serious about defining a process that works for rare disease families. Now is the time to deliver. We need FDA leadership to take strong, decisive action and put an end to the hemming and hawing. This literally translates into life, death, and better lives for our children.”

In its application to the FDA, Stealth proposed the agency consider knee extensor muscle strength as a potential intermediate clinical endpoint to support accelerated approval. Stealth previously submitted data on this measure and the FDA has now agreed to this. The phase 2 data showed that knee extensor muscle strength improved by more than 45 percent and it was significantly correlated with improvements on the six-minute walk test, an FDA-recognized indicator of clinical benefit. The FDA has recommended that the company resubmit its application.

The company said it has implemented a 30 percent reduction in its personnel to conserve resources to fund a potential resubmission of its application and avoid interrupting patients’ access to elamipretide through the company’s expanded access program.

“We recognize that the FDA’s recommendation for an accelerated approval for elamipretide in Barth syndrome offers a path forward for this incurable pediatric disease that affects an incredibly small number of individuals worldwide,” said Reenie McCarthy, CEO. “Elamipretide, which targets the cardiolipin deficit central to Barth syndrome, is the only agent in clinical development to treat this ultra-rare disease for which the FDA has acknowledged that additional pre-approval randomized controlled trials are unfeasible. We hope the FDA will also prioritize ensuring rapid access for neonates affected by the disease subject to appropriate post-marketing safety monitoring.

Barth syndrome is an ultra-rare genetic mitochondrial disease leading to exercise intolerance, muscle weakness, debilitating fatigue, heart failure, recurrent infections, and delayed growth. The disease is associated with reduced life expectancy, with 85 percent of early deaths occurring by age five. Barth syndrome occurs primarily in males and is estimated to affect one in 1,000,000 males worldwide or around 150 individuals in the United States. There are no approved therapies for the treatment of Barth syndrome.

Elamipretide is a peptide that targets the inner mitochondrial membrane where it binds to cardiolipin, which plays an essential role in energy conversion within cells. It has received Orphan Drug, Fast Track, Priority Review, and Rare Pediatric designations from the FDA and Orphan Drug designation from the European Medicines Agency for the treatment of Barth syndrome.

The FDA did not raise concerns with the clinical safety data, requesting only that a resubmission include any additional safety data collected since NDA submission. The company will meet with the FDA next month to discuss the proposed post-marketing study, with which the Agency previously expressed alignment when originally proposed by the Company in 2022.

The FDA’s decision to now consider an accelerated approval offers hope for access to treatment for the U.S. Barth syndrome patient community, approximately 20 percent of whom already receive elamipretide under the company’s expanded access program. However, Stealth said the agency has expressed reluctance to extend the accelerated pathway to critically ill neonates, who comprise nearly two-thirds of the company’s expanded access program. Half of early deaths reported in this lethal pediatric disease occur by age one.