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

PURPOSE: Evaluate long-term efficacy and safety of elamipretide during the open-label extension (OLE) of the TAZPOWER trial in individuals with Barth syndrome (BTHS). METHODS: TAZPOWER was a 28-week randomized, double-blind, and placebo-controlled trial followed by a 168-week OLE. Patients entering the OLE continued elamipretide 40 mg subcutaneous daily. OLE primary endpoints were safety and tolerability; secondary endpoints included change from baseline in the 6-minute walk test (6MWT) and BarTH Syndrome Symptom Assessment (BTHS-SA) Total Fatigue score. Muscle strength, physician- and patient-assessed outcomes, echocardiographic parameters, and biomarkers, including cardiolipin (CL) and monolysocardiolipin (MLCL), were assessed. RESULTS: Ten patients entered the OLE; 8 reached the week 168 visit. Elamipretide was well tolerated, with injection-site reactions being the most common adverse events. Significant improvements from OLE baseline on 6MWT occurred at all OLE time points (cumulative 96.1 m of improvement [week 168, P = .003]). Mean BTHS-SA Total Fatigue scores were below baseline (improved) at all OLE time points. Three-dimensional (3D) left ventricular stroke, end-diastolic, and end-systolic volumes improved, showing significant trends for improvement from baseline to week 168. MLCL/CL values showed improvement, correlating to important clinical outcomes. CONCLUSION: Elamipretide was associated with sustained long-term tolerability and efficacy, with improvements in functional assessments and cardiac function in BTHS.

Natural history comparison study to assess the efficacy of elamipretide in patients with Barth syndrome.

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.

Quality of life in Barth syndrome.

Introduction: Barth syndrome (BTHS) is a rare X-linked disorder characterized by cardiomyopathy, neutropenia, growth abnormalities, and skeletal myopathy. There have been few studies investigating health-related quality of life (HRQoL) in this population. This study investigated the impact of BTHS on HRQoL and select physiologic measures in affected boys and men. Methods: In this study, we characterize HRQoL in boys and men with BTHS through cross-sectional analysis of a variety of outcome measures including the Pediatric Quality of Life Inventory (PedsQLTM) Version 4.0 Generic Core Scales, PedsQLTM Multidimensional Fatigue Scale, Barth Syndrome Symptom Assessment, the PROMISTM Fatigue Short Form, the EuroQol Group EQ-5DTM, the Patient Global Impression of Symptoms (PGIS), and the Caregiver Global Impression of Symptoms (CaGIS). For a specific subset of participants, physiologic data were available in addition to HRQoL data. Results: For the PedsQLTM questionnaires, 18 unique child and parent reports were analyzed for children aged 5-18 years, and nine unique parent reports were analyzed for children aged 2-4 years. For the other HRQoL outcome measures and physiologic measurements, the data from 12 subjects (age range 12-35 years) were analyzed. Based on parent and child reports, HRQoL is significantly impaired in boys and men with BTHS, especially in school functioning and physical functioning. Parent and child reports of more severe fatigue are significantly correlated with more impaired HRQoL. When exploring the potential relationship between physiology and HRQoL, the CaGIS as a whole for pediatric subjects and individual questionnaire items from the PGIS and CaGIS for pediatric subjects assessing tiredness, muscle weakness, and muscle pain showed the strongest correlations. Conclusion: This study provides a unique characterization of the HRQoL in boys and men with BTHS using a variety of outcome measures, and it highlights the negative impact of fatigue and muscle weakness on HRQoL in BTHS. Trial registry name: A Trial to Evaluate Safety, Tolerability and Efficacy of Elamipretide in Subjects with Barth Syndrome (TAZPOWER). https://clinicaltrials.gov/ct2/show/NCT03098797.Registration Number: NCT03098797.

Quality of Life in Barth Syndrome Barth syndrome is a rare disorder characterized by heart issues, muscle weakness, tiredness, exercise intolerance, and growth delays. The study was done to determine the effect of Barth syndrome on health-related quality of life of the boys and men affected. We analyzed health-related quality of life questionnaires completed by subjects and/or their parents from the following: • Interdisciplinary Barth Syndrome Clinic at Kennedy Krieger Institute. There were 24 subjects in total from this clinic. • Baseline data from a clinical drug trial for Barth Syndrome that included both health-related quality of life data and physical function data. There were data from 12 subjects in total from the trial. We discovered that health-related quality of life is significantly impaired in boys and men with Barth syndrome, especially in school and physical function. Parent and child reports of more severe tiredness are significantly linked with impaired health-related quality of life. There are strong relationships between some health-related quality of life reports and physical function measurements. Tiredness and muscle weakness negatively impact health-related quality of life. We are hopeful that the results of this study will be used in the treatment of boys and men with Barth syndrome to result in improved health-related quality of life.

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.

PURPOSE: To evaluate effectiveness of elamipretide in Barth syndrome (BTHS), a genetic condition of defects in TAZ, which causes abnormal cardiolipin on the inner mitochondrial membrane. METHODS: We performed a randomized, double-blind, placebo-controlled crossover trial followed by an open-label extension in BTHS to test the effect of elamipretide, a mitochondrial tetrapeptide that interacts with cardiolipin. In part 1, 12 subjects were randomized to 40 mg per day of elamipretide or placebo for 12 weeks, followed by a 4-week washout and then 12 weeks on the opposite arm. Ten subjects continued on the open-label extension (part 2) of 40 mg per day of elamipretide, with eight subjects reaching 36 weeks. Primary endpoints were improvement on the 6-minute walk test (6MWT) and improvement on a BTHS Symptom Assessment (BTHS-SA) scale. RESULTS: In part 1 neither primary endpoint was met. At 36 weeks in part 2, there were significant improvements in 6MWT (+95.9 m, p = 0.024) and BTHS-SA (-2.1 points, p = 0.031). There were also significant improvements in secondary endpoints including knee extensor strength, patient global impression of symptoms, and some cardiac parameters. CONCLUSION: In this interventional clinical trial in BTHS, daily administration of elamipretide led to improvement in BTHS symptoms.