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

Abstract

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.

Keywords: 6-minute walk test; Barth syndrome; cardiolipin; elamipretide.

Fig. 1. Study participant flowsheet for SPIBA 201 to test the efficacy and safety of single daily subcutaneous (SC) doses of 40 mg elamipretide (vs. placebo) in subjects with Barth syndrome.

Subjects were randomized (1:1) to one of two sequence groups: 12 weeks of single daily SC doses of 40 mg elamipretide in treatment period 1 followed by 12 weeks of treatment with placebo in treatment period 2 (separated by 4-week washout period), or vice versa. The crossover design was selected because of the additional anticipated power of subjects serving as their own control, given the anticipated scarcity of subjects available to participate in this study due to the ultrarare nature of Barth syndrome.

Fig. 2. Outcome measures at week 36, part 2 in 8 patients.

Statistical significance was achieved in improved measures for 6-minute walk test (m), the Barth Syndrome Symptom Assessment (BTHS-SA) total fatigue scale (mean score), Patient Global Impression (PGI) of symptoms (mean score), muscle strength measured by handheld dynamometry (HHD) (newtons), and the EQ-5D questionnaire Fig. 2. Favorable treatment effects were also seen in other measures (Promis Fatigue [mean score], Clinician Global Impression [CGI] of Barth syndrome symptoms [mean score], and SWAY balance), though not achieving statistical significance. Treatment effect was rescaled to a T-score and standard error unit of 1. *p values represent a t-test for matched pairs, comparing mean at baseline to mean at week 36 in part 2.

Fig. 3. 6-minute walk test and hand held dynamometry results per participant from baseline to open label extension, week 36.

(a) Change in 6-minute walk test (6MWT) results per participant from baseline to open label extension (OLE) week 36. The mean distance walked on the 6MWT increased from baseline across ten subjects at week 12, part 2, with a mean improvement of 60.5 m (16% increase, paired t-test: p = 0.02). At week 36, part 2 across eight subjects the mean improvement from baseline was 95.9 m (25% improvement, paired t-test: p = 0.02). (b) Change in handheld dynamometry (HHD) results per participant from baseline to open label extension (OLE) week 36. At week 12, part 2 there was a mean improvement from baseline HHD of 37.9 newtons (a 30% improvement, paired t-test: p = 0.003) across the ten subjects. At week 36, part 2 there was a mean improvement of +56.0 newtons (a 42% improvement, paired t-test: p = 0.001) across the eight participants who reached the 36 week study visit.