FDA Rejects Elamipretide Despite Review Support

Highlights

• The FDA issued a Complete Response Letter (CRL) rejecting Stealth Biotherapeutics' drug elamipretide after a 16.5-month priority review.
• A split advisory committee vote (10-6) in favor of approval raised expectations that were ultimately unmet.
• The FDA offered a resubmission pathway under accelerated approval, accepting muscle strength as a valid endpoint.
• Stealth is cutting 30% of its staff to preserve resources for a resubmission.
• The biotech plans to hold a Type A meeting with the FDA in late June and anticipates a two to six-month review period post-resubmission.
• The Barth syndrome patient community and advocacy groups are calling for swift regulatory action due to the lack of alternative therapies.

Unexpected Setback After Prolonged Review

Stealth Biotherapeutics has encountered another significant hurdle in its effort to secure FDA approval for elamipretide, an investigational treatment for the ultra-rare genetic condition Barth syndrome. Despite extensive interactions with the regulatory agency and a split advisory committee vote favoring approval, the FDA issued a Complete Response Letter (CRL) on May 29, rejecting the application after more than 16 months under priority review.

In an interview with Fierce Biotech, CEO Reenie McCarthy expressed confusion and disappointment over the decision. "It’s yet another delay after an already missed PDUFA date and an already extended PDUFA date and a really long priority review,” McCarthy stated. "That's a head scratcher for me—it doesn't seem like the most efficient approach."

Advisory Committee and FDA Signals Raised Hopes

Back in October 2024, an FDA advisory committee voted 10-6 in favor of approval. McCarthy pointed to this positive outcome as a key indicator that the company was on track for approval. "It's a shock, because obviously there was a positive adcomm vote, and most of the time—like 97% of the time—the FDA follows positive outcome votes,” she said.

Following the vote, Stealth submitted additional data as requested by the agency. However, the FDA later classified these submissions as a major amendment, pushing the decision timeline further into April. Despite the extended review, McCarthy believed approval was imminent due to active correspondence from the FDA, including labeling feedback and packaging font size discussions.

FDA Offers Path to Accelerated Approval

The CRL did include a potential pathway forward. The FDA acknowledged knee extensor muscle strength as an acceptable intermediate clinical endpoint for accelerated approval, which Stealth had previously advocated for. "There's a paragraph in the CRL literally captioned ‘a(chǎn) path forward,’ that lays out a pretty clear-cut resubmission pathway, as far as we can read it,” said McCarthy.

The FDA is requesting a safety update based on recent data, but McCarthy believes this will not materially impact the drug’s safety profile. Still, she voiced frustration over the inconsistency in the agency’s actions. "It seems like accelerated approval on the basis of muscle strength, data that we already submitted, should have just meant an approval instead of a CRL,” she remarked.

Resource Strain and Workforce Reduction

The extended regulatory process has placed a heavy burden on Stealth’s limited resources. In response to the continued delay, the company has reduced its workforce by 30% to conserve cash for the resubmission process. "This has been really hard, and the reduction in force that we've done is really intended to prioritize this program,” McCarthy explained.

Stealth had originally anticipated a decision by January and organized its operations accordingly. "If this was going to be the decision and they gave it to us even in January, on the original PDUFA date, we could have been resubmitted by now, right?” she questioned. The prolonged process has also delayed other programs and consumed resources in pre-commercialization activities.

History of Regulatory Challenges

Stealth has faced multiple setbacks in its journey with elamipretide. The FDA rejected its original new drug application (NDA) in 2021, citing a lack of a single adequate and well-controlled trial. Despite skepticism from the agency about previous trial data, Stealth proceeded with a resubmission in 2022. This included data from a phase 2 study, a follow-up crossover study, and a phase 3 trial focused on walking distance outcomes.

"From 2019 through 2021, we were moved through four FDA review divisions,” McCarthy said. "They changed their mind on that, and we ended up with a refusal-to-file that year." The biotech has remained committed to the Barth syndrome community, despite challenges associated with the ultrarare nature of the disease, which affects only about 130 people in the U.S.

Next Steps and Industry Implications

Stealth plans to request a Type A meeting with the FDA in late June to discuss the resubmission path. McCarthy estimates the revised submission could be processed in two to six months if the agency’s guidance holds.

When asked about a potential appeal, McCarthy emphasized the priority remains on delivering the drug to patients. "We are kind of hanging on by our fingernails here to try to bring this drug to the patient community,” she said. An appeal cannot proceed concurrently with a resubmission, making the latter the most viable option.

Community Urges Swift Action

Barth syndrome, a life-threatening X-linked genetic disorder, primarily affects the heart and muscles. Mortality rates are particularly high in the early years of life. The Barth Syndrome Foundation has joined the call for decisive FDA action. "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,” said Emily Milligan, the foundation’s executive director.

McCarthy echoed this sentiment, urging the FDA not to leave the patient community behind. "The medical community and the patient community both have been urging the FDA to act here and act quickly,” she stated.