Long-term efficacy and safety of elamipretide in patients with Barth syndrome: open label extension results of TAZPOWER through 168 weeks

Authors: William Reid Thompson (1), Ryan Manuel (2), Anthony Abbruscato (3), Jim Carr (3), Brittany Hornby (4), Hilary J. Vernon (2)

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

Introduction: Barth Syndrome (BTHS) is a rare, X-linked mitochondrial disorder characterized by cardiomyopathy, skeletal myopathy, neutropenia, growth abnormalities and shortened lifespan. BTHS is caused by defects in TAZ, the gene that encodes for tafazzin, an acyltransferase involved in the final remodeling step to mature cardiolipin, which plays a critical role in mitochondrial function. Elamipretide is a novel mitochondrial-targeting agent that readily penetrates and transiently localizes to the inner mitochondrial membrane where it associates with cardiolipin to improve membrane stability, enhance ATP synthesis, and reduce the production of pathogenic reactive oxygen species.

Objective: Evaluate the long-term efficacy/safety of elamipretide in BTHS patients.

Methods: TAZPOWER was a 28-week crossover trial of patients age ≥12 years with genetically confirmed BTHS receiving elamipretide 40mg SQ daily for 12weeks with a 4-week washout between treatments, followed by a 168-week open-label-extension (OLE). Primary outcomes: 6-minute walk test (6MWT) and Total Fatigue score on the BarTH Syndrome Symptom Assessment (BTHS-SA). Secondary outcomes included muscle strength by hand-held dynamometry (HHD; knee extensors of both legs, two attempts, two attempts), Five Times Sit to Stand (5XSST), and SWAY balance. Results: Of ten patients entering OLE, 8 reached Week 168 visit; 3 of whom completed Week 192 visit. Significant improvements on the 6MWT were seen at all timepoints throughout the OLE with cumulative 96.1 meters (wk168, p=0.003) and 122.7 meters (wk192, p=0.009) of improvement. Mean BTHS-SA Total Fatigue scores were decreased from baseline at the start of the OLE and maintained below baseline at all OLE-timepoints through wk192. An overall increase in the mean muscle strength by HHD from baseline was noted for all subjects over time. The mean changes from baseline were statistically significant at all OLE visits (p<0.05). Although there was an overall decrease in the mean 5XSST time observed for all subjects over time, no statistically significant changes were noted. An overall increase in the mean SWAY balance score was statistically significant (p<0.05) for all subjects over time (weeks 24, 48, 72 and 168). Previously reported baseline to 36-week cardiac findings showed a trend toward increased LVEDV (Z-score mean change +0.81, SD 1.23) and stroke volume. Additional cardiac-function data requires further analysis and will be available for congress presentation. The most common adverse event was injection site erythema. Two patients discontinued elamipretide because of an adverse event (urticaria [n=1], urticaria and drug eruption [n=1]).

Conclusion: Elamipretide was associated with sustained long-term efficacy, with improvements in functional assessments.