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Elamipretide in patients with Barth syndrome: A randomized, double-blind, placebo-controlled clinical trial followed by 36-week open-label extension

BACKGROUND: Barth Syndrome (BTHS) is an X-linked disease caused by defects in TAZ, the tafazzin encoding gene, responsible for the final remodeling step to mature cardiolipin, critical for mitochondrial function. The inability to produce mature cardiolipin leads to clinical manifestations of cardiac and skeletal myopathy, neutropenia, and growth abnormalities. Elamipretide (ELAM) localizes to the inner mitochondrial membrane, where it is believed to associate with cardiolipin, improving membrane stability and ATP production. TAZPOWER is a clinical trial to evaluate ELAM in patients with BTHS.

METHODS: Twelve BTHS patients, ages 12-35 years (mean age 19.5 years) were randomized (1:1) to 40 mg of subcutaneous (SQ) ELAM once daily for 12 weeks followed by placebo for 12 weeks, or vice versa, in a blinded crossover trial design, followed by an open-label extension (OLE). Primary endpoints included change in 6-Minute Walk Test (6MWT) and Barth Syndrome Symptom Assessment Total Fatigue Score. Select secondary outcome variables included subject self-reported assessments and 3D echocardiographic parameters. Safety endpoints included cardiac monitoring and adverse events (AE).

RESULTS: At baseline, subjects showed reduced 3D LV end-diastolic volumes (EDV) (mean Z-score -2.0, SD 1.36) with normal ejection fraction (mean 60.6%, SD 4.0). In the blinded portion, primary endpoints were not statistically significant. After the 36-week OLE, the eight remaining subjects demonstrated consistent improvements in 6MWT (95.9 m, p=0.02) and Total Fatigue Score (-2.1, p=0.03). Baseline to 36-week cardiac findings included a trend toward increased LVEDV (mean change in Z-score +0.81, SD 1.23) and stroke volume. Ninety-one treatment emergent and one serious adverse events (AEs) were reported, the latter deemed unrelated to ELAM. Injection site reactions, the most commonly reported AE, occurred in all subjects.

CONCLUSION: TAZPOWER is the first clinical trial to evaluate the tolerability and efficacy of a potential therapeutic agent in patients with BTHS. At 36-week OLE, ELAM therapy was well tolerated and associated with improvements in the 6MWT, Total Fatigue Score and subject-reported assessments with a trend toward increased LVEDV and stroke volume.

William Reid Thompson1, Ryan Manuel2, Anthony Aiudi3, John J. Jones3, Jim Carr3, Brittany Hornby4, Hilary J. Vernon2

  1. Department of Pediatric Cardiology, Taussig Heart Center, Johns Hopkins University School of Medicine, Baltimore, MD
  2. Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore MD
  3. Stealth BioTherapeutics, Inc Newton MA;
  4. Department of Physical Therapy, Kennedy Krieger, Baltimore MD

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