Axe falls on Stealth Bio staff after FDA rejects lead drug

Stealth BioTherapeutics' filing for rare disease drug elamipretide has been turned down by the FDA, although the company says the US regulator has given it a "path forward" for the programme.

Elamipretide is being developed for Barth syndrome, an inherited mitochondrial disorder that causes an enlarged and weakened heart, skeletal muscle problems and infections and affects around 150 people in the US.

The drug has had a troubled time at the FDA, which refused to accept Stealth's initial filing for the drug in 2019, saying it needed more robust clinical data, and has now turned down the biotech's second application filed in early 2024 after a lengthy delay – and against the advice of its own expert advisors.

Faced with another delay, the Needham, Massachusetts company has said it will have to slash around a third of its staff to conserve its cash reserves as it works towards another potential resubmission.

Stealth's latest application included data from a phase 2 clinical trial that showed a 45% improvement in knee extensor muscle strength that correlated with improvements on six-minute walking tests (6MWT), a well-established clinical endpoint.

The FDA has now agreed to consider knee extensor muscle strength as a potential intermediate clinical endpoint to support accelerated approval – a route formerly rejected by the agency – but the programme looks set for another lengthy delay.

Stealth refrained from criticising the FDA's decision on its application, which comes after the agency missed its own extended deadline for the review and its Cardiovascular and Renal Drugs Advisory Committee voted by 10 to six that elamipretide was effective for treating Barth syndrome at a meeting last year.

The company did, however, point out that the FDA has taken 16.5 months to review an application with a priority review and has now been considering the drug for more than five years.

"We recognise that the FDA's recommendation for an accelerated approval for elamipretide in Barth syndrome offers a path forward for this incurable paediatric disease that affects an incredibly small number of individuals worldwide," said Stealth chief executive Reenie McCarthy, who admitted she is puzzled by the regulator's stance.

"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 randomised controlled trials are unfeasible," added McCarthy.

She also expressed concern about an FDA proposal that elamipretide's label should exclude newborns, pointing out that most infants with Barth syndrome die in the first 12 months of life.

"We hope the FDA will also prioritise ensuring rapid access for neonates affected by the disease, subject to appropriate post-marketing safety monitoring," said McCarthy.

The company has indicated it is experiencing a "sharp increase" in emergency access requests for elamipretide from physicians around the world caring for critically ill patients.

It hopes to meet with the FDA in the coming weeks to discuss a post-marketing study that could clear the way for accelerated approval.

Elamipretide is also in phase 3 trials involving patients with dry age-related macular degeneration (AMD) and primary mitochondrial myopathy.