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.
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.
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.
In this interventional clinical trial in BTHS, daily administration of elamipretide led to improvement in BTHS symptoms.
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. 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). 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. 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.
The growing number of actors involved in China's international activities has led to fractured authority in foreign policy decision-making. Actors vie for the attention of senior officials to promote ...their interests on any specific issue. As a result, decision making is often a slow process; there are multiple channels of information, and actors appeal to public opinion to support their claims. Since 2012, Xi Jinping has taken charge of all foreign policy related decision-making bodies in what appears to be an attempt to improve coordination of interest groups. A slight shift to a more personified foreign policy than during the Hu or Jiang eras has also taken place. In this paper, we describe how foreign policy decisions should be made in China according to formal rules; next, we take into account the reality of how the Chinese political system deals with China's evolving international role. We conclude by assessing the risks of fragmentation, on the one hand, and Xi's efforts to recentralise foreign policy, on the other hand.
China's Belt and Road Initiative (BRI) remains a topic of great interest. But there is little knowledge about China's internal voices. Dissent remains rare, yet there has been considerable pushback ...on BRI policy and decision making. This is because there is an array of structural problems with the BRI's design. BRI is entirely an economic program, run by various parts of the economic bureaucracy. But it does not give bureaucrats sufficient mandate to pursue their interests within China's internal politics. So the BRI is attractive for central SOEs and dealmakers but unattractive to local leaders who are held accountable for whatever goes wrong in their respective areas. Although overt criticism is rare, failure to carry out orders is common. China's leaders have responded to critiques of the BRI, radically changing its official focus and policy. It has moved from a geoeconomic export policy to part of China's toolkit in the current US trade war. But there is no indication that the structural problems will be addressed, thus limiting the BRI's ability to achieve its goals, and as such, pushback will continue.
Barth Syndrome (BTHS) is an X-linked disease caused by defects in TAZ, the tafazzin encoding gene that creates mature cardiolipin. Clinical manifestations of cardiac/skeletal myopathy, neutropenia, ...and growth abnormalities result from immature cardiolipin. Elamipretide (ELAM) localizes to the inner mitochondrial membrane and associates with cardiolipin to improve mitochondrial membrane stability/ATP production.
TAZPOWER evaluated the efficacy/tolerability of ELAM in BTHS.
Randomization: 1:1 to SQ ELAM 40mg once daily for 12wks, then placebo for 12wks, after a 4-wk washout period, or vice versa, in a blinded, crossover design (Part 1); Part 1 patients enrolled in an open-label extension (OLE; Part 2). FDA guidance supports using natural history controls (NHCs) providing external control grps with matched propensity scores for drug development in interventional, rare-disease studies. ELAM's effect on BTHS symptoms and cardiomyopathy at OLE wk 36 were compared to NHC patients. We used 4 domains of primary (6 minute walk test 6MWT) and secondary (muscle strength by HHD, 5XSST Five Times Sit to Stand, SWAY balance) functional outcomes. A correlation between functional assessments and heart function may exist; the relationship of stroke volume improvement to stroke volume was also evaluated.
At OLE wk-36 baseline, ELAM-treated (N = 8) and NHC BTHS patients (N = 19) with similar between-grp prognostic covariates (age, 6MWT), performed poorly on functional assessments, and had pathologic exercise symptoms of heart failure with normal ejection fractions. At baseline, subjects showed markedly reduced indexed LV end-systolic and end-diastolic volumes resulting in markedly reduced stroke volumes. At OLE wk 36, ELAM-treated patients showed significantly greater mean improvements from baseline vs. NHC patients in 6MWT, muscle strength by HHD, 5xSST, and MDRI . Between-group difference in sway balance was not significant. Improvements in stroke volume appear to coincide with observed improvements in functional domain outcomes. Long-term ELAM-treated subjects showed significant increases in LVEDV, LVESV and avg indexed stroke volume . Treatment-emergent (91) and serious AEs (1, unrelated to ELAM) were reported, with injection site reactions being the most commonly reported AE.
In TAZPOWER OLE, ELAM was well tolerated and associated with large and statistically significant improvements vs. NHC in functional assessments after 36wks. LVEDV and stroke volume increases (major determinants of peak exercise capacity in hypertrophic cardiomyopathy) were also observed. Results demonstrate that BTHS patients on long-term ELAM therapy experience improvement in multiple disease-related symptoms, including cardiac function.
Evaluate long-term efficacy and safety of elamipretide during the open-label extension (OLE) of the TAZPOWER trial in individuals with Barth syndrome (BTHS).
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.
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.
Elamipretide was associated with sustained long-term tolerability and efficacy, with improvements in functional assessments and cardiac function in BTHS.
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