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Background: Natural history studies are increasingly recognized as having an important role in drug development for rare diseases. A phase 3, observational, retrospective, and non-interventional study was designed to establish a natural history control (NHC) cohort of patients with Barth syndrome (BTHS) to provide further analysis of the efficacy of elamipretide observed in an open-label extension (OLE) phase of the TAZPOWER trial, a clinical trial that tested the efficacy of 40 mg daily of elamipretide in patients with BTHS., Methods: This was a retrospective, non-interventional study. A propensity score model was used to compare elamipretide-treated patients and NHCs. The analysis included 8 patients from the TAZPOWER OLE and 19 untreated NHCs (including 12 with serial echocardiographic assessments)., Results: For the 6-min walk test (6MWT, primary endpoint), the least squares (LS) mean difference between groups was 79.7 m (P = 0.0004) at week 64 and 91.0 m (P = 0.0005) at week 76 in favor of elamipretide. Significant improvements in muscle strength (secondary endpoint), as assessed by handheld dynamometry (HHD) were also observed with elamipretide, with LS mean differences of 40.8 Newtons at 64 weeks (P = 0.0002) and 56.7 Newtons at 76 weeks (P = 0.0005). Patients continuously treated with elamipretide also experienced statistically significant improvements in other secondary endpoints (i.e., 5 times sit-to-stand [5XSST], multi-domain responder index [MDRI]). The functional improvements were robust to sensitivity analyses. Left ventricular stroke volume increased from baseline in patients with elamipretide but decreased in NHCs., Conclusions: Overall, the study established a NHC for use in assessing the efficacy of therapeutic interventions in patients with BTHS and the results suggest that elamipretide may improve natural history of BTHS at least in part by attenuating the natural decline in heart function and provide meaningful improvements in heart function and functional capacity in patients with BTHS compared to NHCs., Highlights: A matched Natural History Control (NHC) was used to evaluate elamipretide in BTHS Elamipretide may improve natural history of BTHS by attenuating natural decline in heart function Elamipretide was associated with meaningful clinical improvements in skeletal muscle and cardiovascular parameters that were not observed in NHCs The study established a NHC for use in assessing the efficacy of therapeutic interventions in BTHS., (© 2022. The Author(s).)

Background: Barth syndrome (BTHS) is an X-linked disorder caused by defects in TAZ with key clinical features including cardiomyopathy, neutropenia and skeletal myopathy. In order to gain a better understanding of the range of clinical features, identify targets for monitoring, and increase knowledge of natural history of the disease, we conducted muscle strength testing, functional exercise capacity testing, physical activity assessment, balance assessment and motion reaction time testing in 33 affected individuals and 14 controls. We analyzed data points to provide a cross-sectional quantitative spectrum of disease characteristics. We also compared these data points to the matched data points collected two years prior to provide insight into effects of BTHS over time., Results: In comparison to controls, pediatric subjects with BTHS present with significantly impaired balance and motion reaction time while adult subjects with BTHS present with significantly impaired motion reaction time. In comparison to controls, subjects with BTHS presented with decreased functional exercise capacity (assessed via 6 MWT), knee extensor strength (both assessed via handheld dynamometry and five times sit-to-stand (5 TSTS)), and self-reported physical activity. Comparison of functional exercise capacity, knee extensor strength and self-reported physical activity from identical cohorts in 2014 and 2016 BTHS showed that the deficits in 6 MWT do not change significantly over the 2 year time span., Conclusion: In this comprehensive assessment of musculoskeletal parameters in a cross-section of individuals with BTHS, we uncovered deficits in motion reaction time and balance, which were previously not known to be abnormal in in BTHS. We also confirmed results of our previous study showing that pediatric and adult subjects with BTHS have decreased functional exercise capacity, knee extensor strength, and physical activity in comparison to controls, r, verifying the importance of including these measures as part of the regular clinical assessment in individuals with BTHS, as well as introducing 5 TSTS as an additional testing parameter. Perhaps most importantly, we demonstrated that 6 MWT results do not significantly vary in pediatric and adult cohorts with BTHS over a 2-year period, supporting this as a reliable quantitative measure of therapeutic outcomes in clinical studies and for clinical monitoring.