Stealth, Barth Community Await FDA Verdict With ‘Everything at Stake’

As the clock winds down on the FDA’s deadline to review Stealth BioTherapeutics’ application for Barth syndrome therapy elamipretide, a tiny but “indefatigable” patient community holds its collective breath.

“We have everything at stake in this,” Kate McCurdy, board chair at the Barth Syndrome Foundation who lost a son to the ultra-rare disease, told BioSpace. “It’s not just hearsay or sort of wishful thinking that we see the benefits of this drug. We can see it.”

Barth patients and their families aren’t the only ones with a lot on the line, McCurdy continued. “If this drug is not approved, then I believe it’s fair to say . . . that Stealth will go out of business, and so this drug will not be available to anyone, and that would be unconscionable.”

Claire Davies, shareholder at the law firm Polsinelli and a former FDA lawyer, agreed that elamipretide’s future is hanging in the balance. “It’s difficult to see what the path forward is if they don’t get this accelerated approval,” she told BioSpace.

It’s been a long road for Stealth—and for the Barth Syndrome Foundation—which approached the biotech with an apparent match in 2014. Stealth was giving a presentation about elamipretide at a conference, and the Foundation had an idea.

“We said, ‘You’ve probably never heard of our little, tiny disease, but our primary defect is in exactly what the mechanistic pathway says is the target of your drug, so we think you should study it in our disease, because if it works for us, it may work for other people with tangential problems in this area,’” McCurdy recalls.

Stealth agreed, and after years of R&D and discussion with the FDA, the company submitted elamipretide for traditional approval in January 2024. But in May, after a 16.5-month review—and despite the support of an advisory committee—the FDA rejected the drug, forcing the biotech to let go of 30% of its staff in order to support an NDA resubmission “and avoid interrupting patients’ access to elamipretide” through Stealth’s expanded access program.

Stealth filed that resubmission on Aug. 15—this time for accelerated approval, as the FDA had recommended—with a minor safety update and confirmation that certain manufacturing deficiencies had been resolved. The company announced acceptance of the resubmitted NDA less than a week later, with a target review date of Sept. 26, well ahead of a typical six-month deadline.

According to Davies, the expedited application, along with Stealth’s description of the resubmission with specific FDA guidance to submit for accelerated approval, indicates that the FDA “is inclined to grant accelerated approval.”

Speaking to BioSpace two weeks ahead of the FDA’s target action date, McCurdy said she was feeling “cautiously optimistic.”

Earlier this month, the FDA unveiled the Rare Disease Evidence Principles, its new framework meant to streamline the approval of therapies for ultra-rare diseases—generally those affecting less than 1,000 Americans. The document follows months of commentary by FDA leaders, including Commissioner Marty Makary and Centers for Biologics Evaluation and Research Director Vinay Prasad, toward this end.

Barth syndrome is the very epitome of an ultra-rare disease, currently afflicting just 150 people in the U.S. A genetic mitochondrial disorder characterized by cardiac abnormalities leading to muscle weakness, debilitating fatigue and heart failure, it claims around 85% of its victims by the age of five, according to Stealth. There are currently no approved treatments.

Elamipretide targets the mitochondria, generating around 90% of the energy we need to maintain healthy organ function. “Elamipretide works by interacting with a key mitochondrial phospholipid to improve mitochondrial structure and function in dysfunctional mitochondria,” she explained.

But elamipretide has a checkered clinical development history. In the first part of Stealth’s Phase II TAZPOWER trial, the candidate failed to meet the primary endpoints of change from baseline to week 12 in how far a patient can walk in six minutes. In its resubmission, Stealth proposed accelerated approval on the basis of an intermediate endpoint, knee extensor muscle strength, which improved by around 45% in the Phase II TAZPOWER open-label study and was correlated with improvements in the six-minute walk test.

Prior to an FDA advisory committee meeting held in October 2024, the FDA published a briefing document in which staffers wrote that neither TAZPOWER study qualified as an “adequate and well-controlled” trial that could sufficiently establish elamipretide’s effectiveness.

The FDA reviewers raised concerns such as “performance bias” that they said could have affected the results of an effort-based endpoint such as the walk test based on the patients’ knowledge of their treatment assignment.

Despite the FDA’s reservations, the adcomm voted 10-6 in favor of elamipretide—though the experts struggled with the decision. “This was just impossible,” Gerard Berry, a professor of Pediatrics at Harvard Medical School who voted yes, said during the meeting. “As a pediatrician and metabolic specialist who’s cared for these patients, to deprive somebody of being able to get the medicine that might help is just untenable for me.”

In fact, a petition signed by 82 Barth syndrome experts calling for elamipretide’s approval and submitted to Makary on Aug. 8 included an addendum letter from one adcomm member who voted against the drug but has now changed their mind. McCurdy, who has reviewed the petition, described his position: “I now have seen this drug work, and I have put my patient on it.”

McCurdy, too, has borne witness to improvements she attributes to elamipretide. “We can see kids walk upstairs when they could never do that before,” she said. “We’ve seen them be able to go to school for a full day when they could never do that before.”

And these are the older children. As of April 30, 35 patients worldwide had received elamipretide under expanded or emergency access, including critically ill infants and toddlers. “Quite a number of babies who’ve been born in just dire straits, put on . . . ECMO, Berlin heart, every machine, in their first say, week of life, or month of life, are now at home as normal toddlers running around,” McCurdy said. “This drug is lifesaving in the younger ages, life-enhancing big time as one gets older.”

Securing an approval for younger children could be a particular challenge, however, as Stealth’s Phase II TAZPOWER trial only studied elamipretide in patients 12 years and older. In its complete rejection letter (CRL), recently made public by the FDA and reviewed by BioSpace, the regulator wrote, “It will not be possible to extrapolate efficacy findings from the more stable subjects 12 years and older evaluated in your existing studies to those who present with life-threatening heart failure soon after birth.”

If indeed an approval for this younger cohort is not granted, McCurdy implored the FDA to “please, please include in the label itself references to the peer reviewed multiple case studies in the younger kids,” as this will help to enable off-label coverage for these patients.

In the final paragraph of the petition, according to McCurdy, the 82 Barth syndrome experts write, “We are asking FDA leadership to take this opportunity to re-align review with current FDA statements on ultra-rare indications and immediately reverse course on this decision.”