FDA clears the first drug for Barth syndrome, four months after rejecting it

The FDA approved Forzinity (elamipretide) injection on 19 September, for use in improving muscle strength in adult and paediatric patients with Barth syndrome weighing at least 30 kg [s1]. It is the first drug approved for the disease.

The approval was granted under accelerated approval, pursuant to section 506(c) of the Federal Food, Drug, and Cosmetic Act and 21 CFR 314.510 [s1]. That is the pathway reserved for products whose benefit is demonstrated on a surrogate or intermediate endpoint reasonably likely to predict clinical benefit, and it carries an obligation to confirm the benefit afterwards.

The regulatory history is unusually visible

Approval letters are dry documents, but this one contains the whole arc. The application was dated and received 29 January 2024 [s1]. On 15 May 2025, FDA issued an action letter — the agency's term for a decision that is not an approval [s1]. Stealth BioTherapeutics submitted an amendment on 15 August 2025 that constituted a complete response to that letter [s1]. The approval followed 35 days later [s1].

A rejection in May and an approval in September for the same product means the intervening submission changed the agency's assessment of the same underlying evidence, or added to it. The letter does not say which.

What Barth syndrome is, and why a surrogate endpoint was needed

Barth syndrome is an exceedingly rare and potentially fatal X-linked mitochondrial disease arising from pathogenic variants in TAFAZZIN, which cause defects in mature cardiolipin synthesis and in its integration into the inner mitochondrial membrane [s2]. Clinical features that may be severe include cardiomyopathy, cyclic neutropenia, skeletal myopathy and growth delay [s2]. Elamipretide has been shown to stabilise cardiolipin and improve mitochondrial bioenergetics in pre-clinical and clinical studies in older individuals with Barth syndrome [s2] — a review published in Molecular Genetics and Metabolism in August 2025, written before the approval, noted that no FDA-approved therapies existed at that point [s2].

The patient population is small enough that a conventional outcome trial — one powered on hospitalisation or survival — is not feasible on any practical timescale. That is the situation accelerated approval exists for, and it is also why the indication is written in terms of muscle strength rather than cardiac outcomes [s1].

The obligations attached

Three features of the letter deserve attention because they define what has and has not been established.

First, the confirmatory trial timetable. Stealth submitted a schedule on 17 September 2025 under which the final protocol was complete in September 2025, study initiation — first subject, first visit screened — falls in March 2026, full enrolment in March 2028, study completion in September 2029, and the final report in March 2030 [s1]. The drug will therefore be on the US market for roughly four and a half years before the trial required to confirm its benefit completes.

Second, the reporting cadence. Stealth must submit status reports 180 days after approval and approximately every 180 days thereafter — two per year for each open trial required under section 506(c) — until the final report [s1]. These are the documents that will reveal, in public, whether the confirmatory trial is enrolling on schedule.

Third, the product received a rare paediatric disease priority review voucher [s1]. The voucher is transferable, including by sale, with no limit on the number of transfers, and FDA may revoke it if the product is not marketed in the US within one year of approval [s1]. Stealth must also report, no later than five years after approval, on the estimated US patient population, estimated demand, and actual amount of product distributed for each of the first four post-approval years [s1].

Because the product has orphan drug designation, the sponsor is exempt from the paediatric assessment requirement that the Pediatric Research Equity Act would otherwise impose [s1].

What this does and does not establish

Accelerated approval is a statement about a surrogate endpoint, not a verdict on clinical benefit. The indication FDA granted is narrow and specific — improving muscle strength, in patients weighing at least 30 kg [s1] — and does not claim an effect on the cardiomyopathy that drives most of the disease's mortality.

The weight floor is itself a limit worth noting. The indication covers patients weighing at least 30 kg [s1], which excludes infants and young children — and cardiomyopathy is among the severe clinical features of the disease [s2]. What the approval offers those patients is nothing.

The withdrawal mechanism is real but slow. If the confirmatory trial fails, or is not conducted with due diligence, the accelerated approval regulations provide for withdrawal — but the timetable in this letter puts that decision point in 2030 at the earliest [s1].

For families, the approval means a treatment exists where none did. For the evidence base, it means the central question is now scheduled to be answered rather than answered.

What to watch: whether the confirmatory trial initiates on time in March 2026, and what the first 180-day status report says.

This article is informational and is not medical advice.

Sources

• [s1] US Food and Drug Administration, NDA 215244 approval letter, Forzinity (elamipretide) injection, 19 September 2025. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2025/215244Orig1s000ltr.pdf
• [s2] "Elamipretide in the Management of Barth Syndrome: Current Evidence and a Case Report," Molecular Genetics and Metabolism, 11 August 2025. https://doi.org/10.1016/j.ymgme.2025.109220