A phase 2/3 randomized clinical trial followed by an open-label extension to evaluate the effectiveness of elamipretide in Barth syndrome, a genetic disorder of mitochondrial cardiolipin metabolism
Thompson WR, Hornby B, Manuel R, Bradley E, Laux J, Carr J, Vernon HJ
Genetics in Medicine (2021) · n=12
Across 12 subjects with genetically confirmed Barth syndrome, the randomized 12-week crossover period missed both primary endpoints, but the 36-week open-label extension produced a 95.9-metre improvement in six-minute walk distance and meaningful gains in patient-reported and strength endpoints — the foundational efficacy dataset behind the September 2025 FDA approval of Forzinity for Barth syndrome.
This 2021 Genetics in Medicine paper (TAZPOWER, also designated SPIBA-201) is the pivotal trial behind elamipretide's eventual September 2025 FDA approval as Forzinity for Barth syndrome — a rare X-linked disorder of mitochondrial cardiolipin remodeling that fits the SS-31 mechanism more precisely than any other indication the molecule has been tested in. The trial enrolled 12 subjects at Johns Hopkins. Part 1 was a randomized, double-blind, placebo-controlled crossover: 12 weeks of 40 mg/day subcutaneous elamipretide or placebo, a 4-week washout, then 12 weeks of the opposite arm. The primary endpoints were the six-minute walk test (6MWT) and the Barth Syndrome Symptom Assessment (BTHS-SA). Neither primary endpoint was met in Part 1. In Part 2 — the open-label extension at 40 mg/day for all participants — 10 subjects continued and 8 reached the 36-week endpoint. At 36 weeks the OLE produced statistically significant gains: 6MWT improved 95.9 metres (p = 0.024), BTHS-SA improved 2.1 points (p = 0.031), and knee extensor strength rose 56.0 newtons (a 42% improvement, p = 0.001). A subsequent 168-week long-term extension (Carr et al. 2024) extended the safety dataset and demonstrated durability of the functional gains. The FDA approved Forzinity for Barth syndrome in September 2025 — the first regulatory-grade SS-31 indication, after the larger MMPOWER-3 Phase 3 trial in primary mitochondrial myopathy had failed its prespecified primary endpoints.
This is a 12-subject trial in a rare disease, conducted at a single center (Johns Hopkins), with a sponsor-affiliated author (Stealth BioTherapeutics). The crossover-period primary-endpoint miss is the most important methodological fact and should not be glossed over by readers cherry-picking the OLE results — the 12-week placebo-controlled crossover did NOT separate elamipretide from placebo on either prespecified primary endpoint. The OLE 36-week gains are statistically significant within an 8-subject open-label cohort, which is the conventional way rare-disease drug-development trials demonstrate signal but is also the methodological structure most prone to placebo, regression-to-the-mean, and natural-history confounding. The FDA approval ultimately rested on the combination of mechanism specificity (SS-31 binds cardiolipin; Barth syndrome IS a cardiolipin-remodeling disorder), the OLE functional gains, the long-term safety record, and the absence of any alternative therapy in a rare ultra-orphan condition. None of these justify extrapolating the Barth-syndrome efficacy result to non-Barth populations. The generalization that gets made in some practitioner contexts — "FDA-approved peptide therefore broadly efficacious" — does not survive the data.
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