A US Food and Drug Administration (FDA) advisory committee (AdCom) has voted in support of Stealth BioTherapeutics’ first-line Barth syndrome drug, despite a trial studying the drug not meeting its primary endpoint. 

The Cardiovascular and Renal Drugs Advisory Committee voted 10-6 supporting Stealth’s elamipretide for the treatment of Barth syndrome, an ultra-rare genetic disorder caused by mutations in the TAZ gene, which primarily affects males. 

The life-threatening disease – which causes symptoms like cardiomyopathy and growth delays – has no cure, and no other therapies in late-stage clinical development, according to the Barth syndrome Foundation. The FDA is expected to decide whether to approve the new drug application in January 2025. 

During the committee meeting, the panel discussed findings from the SPIBA-201 clinical trial (NCT03098797). The trial, which assessed the impact of elamipretide in 12 male patients over 12 weeks of daily treatment, failed to meet the primary endpoint of improving walking distance. 

Patients treated with elamipretide walked an average of 443.1 metres compared to 443.9 for patients on placebo. While there was a slight increase in walking distance from baseline – 43 metres for the elamipretide group compared to 31 metres for placebo – the difference was not statistically significant. The FDA reviewers told the committee that Stealth’s drug did not meet statistical significance in the primary or secondary endpoints. 

However, the AdCom heard from patients, doctors, and parents of children with Barth syndrome, saying that the drug had helped patients gain weight, strength, and stamina, advocating for elamipretide’s approval. Jacob Wilson, a 24-year-old male with Barth syndrome told the panel the medicine “made him feel like a new person”. 

Elamipretide has previously faced rejection from the FDA. In August 2021, Stealth filed a new drug application (NDA) for the candidate, however the FDA responded in October of the same year with a refuse-to-file letter, stating that the NDA "did not contain an adequate and well-controlled trial that provides evidence of effectiveness". Stealth did not conduct another Phase III study, despite advice from the FDA to do so.  Its initial application was linked to the SPIBA-001 study (NCT04689360), a Phase III trial that included both treated patients from SPIBA-201 and new, untreated patients. Despite the trial meeting its primary endpoint, the FDA raised concerns about how the data were analysed. Results were compared to an open-label extension from the Phase II/III SPIBA-201 crossover study and historical control data from 19 subjects monitored between 2012 and 2019 at the Johns Hopkins Kennedy-Krieger Institute. This approach was criticised by the FDA. 

The panel raised concerns about two potential biases in the SPIBA-001 trial design. Selection bias could result from differences in the natural history control subsample, while a confounding bias may arise due to the lack of randomisation. The panel also argued that the propensity score method used in the Phase III trial failed to adequately correct for these biases.  

Despite this, the committee ultimately decided to vote in favour of the mitochondrial-targeting peptide drug. The committee also acknowledged “the devastating impact of Barth’s” and “the significant unmet medical need” in a document released in advance of the AdCom meeting. 

This unmet need was reiterated by Emily Milligan, executive director of the Barth syndrome Foundation: “We strongly urge the FDA to move swiftly toward approving elamipretide for use in Barth syndrome, bringing patients closer to having sustained access to this critical therapy. Our plight is not just about Barth syndrome—it sets an important precedent for how we address the unmet needs of patients and families affected by many rare diseases.” 

Attention will now turn to the 29 January decision date, as in the briefing document before the AdCom, the FDA said it does not believe that the available evidence establishes the effectiveness of elamipretide for Barth syndrome. While the FDA takes AdCom recommendations into consideration, it are not required to follow them.