Barth Syndrome Has Its First Approved Therapy —⁠ For Now Only in the U.S.

A Mitochondrial Disorder With Fatal Consequences

Barth syndrome (BTHS) is a rare X-linked genetic disorder caused by mutations in the TAFAZZIN gene, which is responsible for cardiolipin metabolism —⁠ a key phospholipid of the inner mitochondrial membrane. Disruption of this process leads to accumulation of monolysocardiolipin and a deficiency of mature cardiolipin, resulting in structural and functional mitochondrial impairment.

The disease usually manifests in early childhood. Typical symptoms include dilated cardiomyopathy, muscle weakness, fatigue, growth delay, and intermittent neutropenia. Although modern cardiology and supportive care have improved survival, no causal therapy existed until now.

Targeted Restoration

Elamipretide is a mitochondria-targeted peptide that selectively binds cardiolipin and stabilizes it within the inner mitochondrial membrane. This supports mitochondrial integrity, improves adenosine triphosphate (ATP) production, and reduces the generation of reactive oxygen species. The result is improved cellular energy balance.

The drug is approved for patients weighing at least 30 kg and is administered as a once-daily subcutaneous injection. It is not yet registered in Europe.

The TAZPOWER Study

The clinical development of elamipretide was based on the TAZPOWER study, conducted in two phases. The first was a 28-week, randomized, double-blind, placebo-controlled study involving 12 males with genetically confirmed Barth syndrome. Primary endpoints included the 6-minute walk test (6MWT) and the BTHS Symptom Assessment Total Fatigue Score.

The primary analysis did not show a statistically significant difference between elamipretide and placebo, leading the FDA to view the evidence as insufficient. However, patients continued into a 168-week open-label extension (OLE), which brought a notable turnaround.

Eight out of ten participants who remained in the study completed the extension. Long-term treatment with elamipretide resulted in a significant improvement in 6MWT distance (+96 m from baseline), improved muscle strength, and decreased fatigue scores. Echocardiography showed increased left ventricular volume and an improved monolysocardiolipin-to-cardiolipin ratio, correlating with clinical benefit.

The drug was generally well tolerated; the most common adverse effects were local injection-site reactions.

FDA Accelerated Approval

Based on these data, the FDA granted elamipretide accelerated approval on September 19, 2025. This pathway allows drugs for severe and life-threatening conditions to be approved based on surrogate endpoints reasonably likely to predict clinical benefit. For elamipretide, this surrogate endpoint was improvement in knee extensor muscle strength. The approval covers patients with Barth syndrome weighing at least 30 kg.

The FDA emphasized that evidence of efficacy remains limited due to the small patient population, open-label design, and reliance on effort-based endpoints. Stealth BioTherapeutics is therefore required to conduct confirmatory trials to verify whether improvements in strength and performance translate into meaningful gains in quality of life and cardiac function.

Significance and Future Perspectives

Elamipretide is the first mitochondria-targeted therapy ever approved by the FDA. It represents a major shift in how disorders of cellular energy metabolism may be treated. For patients with Barth syndrome, it is the first therapy that addresses the primary pathophysiological mechanism rather than secondary complications. It also paves the way for future mitochondrial therapies.

The mechanism of cardiolipin stabilization may have potential beyond Barth syndrome, including in more common conditions associated with mitochondrial dysfunction such as heart failure, muscular dystrophies, and neurodegenerative diseases. Challenges ahead include drug availability, cost, and extending the indication to younger children weighing less than 30 kg.

Editorial Team, Medscope.pro

Sources:
1. William R. T., Ryan M., Abbruscato A. et al. Long-term efficacy and safety of elamipretide in patients with Barth syndrome: 168-week open-label extension results of TAZPOWER. Genet Med 2024; 26 (7): 101138, doi: 10.1016/j.gim.2024.101138.
2. Leslie M. First approved drug for mitochondrial disease raises hopes for more. Science 2025; 390 (6769): 114–115, doi:10.1126/science.aec9018.
3. FDA grants accelerated approval of Forzinity (elamipretide HCl) for Barth syndrome. FDA 2025 Sep 19. Available at: www.fda.gov/news-events/press-announcements/fda-grants-accelerated-approval-first-treatment-barth-syndrome
4. Stealth BioTherapeutics announces FDA accelerated approval of FORZINITY™ (elamipretide) injection, the first therapy for progressive and life-limiting ultra-rare genetic disease Barth syndrome. Stealth BioTherapeutics 2025 Sep 19. Available at: www.stealthbt.com/...