Phase 2 Data Show ACE-083 Was Safe, Improved Muscle Function in Charcot-Marie-Tooth Disease Type 1


Despite good tolerability with few drug-related treatment emergent AEs and increased muscle volume, the failure to provide clinically relevant improvements in muscle function led to the discontinuation of ACE-083 for CMT in 2020.

Florian P. Thomas, MD

Florian P. Thomas, MD

Results from a 2-part phase 2 trial (NCT03124459) showed that treatment with intramuscular ACE-083 (Acceleron) resulted in statistically significant muscle volume increases in patients with Charcot-Marie-Tooth disease (CMT) type 1; however, this increase was largely driven by increases in the contractile muscle fraction and therefore did not indicate a statistically significant improvement in motor function tests or disease-related quality of life measures.1

The findings were published in Neurology, more than 2 years after Acceleron announced the discontinuation of ACE-083.2 Although treatment with the investigational agent resulted in a significantly greater change in total muscle volume (TMV), the study’s primary end point (least square [LS] mean difference, 13.5%; P = .0096), the company cited its lack of statistically significant improvements on any of the functional or quality of life secondary end points when compared with placebo as the reason for discontinuing.

Led by Florian P. Thomas, MD, chair, Department of Neurology, Hackensack University Medical Center, the phase 2 study was designed to evaluate ACE-083 in patients with CMT with muscle weakness in the tibialis anterior (TA), a muscle in the lower leg involved in ankle dorsiflexion. Part 1 was an open-label, dose-escalation study, with the study drug administered via injection into the TA muscle once every 3 weeks in 18 patients over a 3-month treatment period.

In Part 1, ACE-083 was generally well tolerated, with all participants experiencing at least 1 treatment-emergent adverse event (AE) and no serious AEs reported as well. Part 2 was a randomized, double-blind, placebo-controlled study using the optimal dose level selected in Part 1. In addition to TMV, other pharmacodynamic end points included contractile muscle volume (CMV), and fat fraction, analyzed at day 190 of treatment.1

Over that period, treatment with ACE-083 resulted in statistically significant differences from placebo in percent change in CMV (LS mean difference, 23.3%; 95% CI, 7.2-39.4]; P = .02), but not in absolutely change in fat fraction (LS mean, –3.1%; 95% CI, –6.8 to 0.6; P = .16). The study also included a 6-month open-label period following Part 2, which also showed similar percent increases in TMV and CMV in those treated with ACE-083 who were originally on placebo.

Compared with the placebo group, those on the study drug showed significantly greater changes in ankle dorsiflexion MMT decimal score (LS mean, 0.3; 90% CI, 0.1-0.5; P = .03). The increase from baseline in LS mean ankle dorsiflexion strength by handheld dynamometer in the ACE-083 group vs placebo at day 190 was not statistically significant (LS mean, 35.4; 90% CI, –3.2 to 74.0; P = .13), nor apparent at other time points.

Secondary end points such as 6-minute walk test (6MWT) and 10-meter walk/run (10mW/R) were not substantially different between treatment groups during the double-blind period and no improvement was observed in the placebo group upon switching to ACE-083 in the open-label extension. Notably, 6MWT distance and time to complete 10mW/R improved similarly in both the active and placebo groups, particularly over the first few measurements and at the start of the open-label phase, suggesting a placebo and/or learning effect.

CMT-Health Index total score, a patient-reported outcome, did not statistically differ (P = .63) between the treatment groups. For physician-reported outcomes at day 190, median percentage changes from baseline were small in CMT Examination Score version 2 score for placebo (–1.0) and the ACE-083 (3.8) treatment groups. Additionally, treatment with ACE-083 showed no statistically significant decrease in the risk of first fall (hazard ratio [HR], 1.04; 90% CI, 0.50-2.18; P = .93) or risk of recurrent fall (HR, 1.41; 90% CI, 0.72-2.74; P = .40).

1. Thomas FP, Brannagan TH, Butterfield RJ, et al. Randomized phase 2 study of ACE-083 in patients with Charcot-Marie-Tooth disease. Neurology. Published online May 11, 2022. doi:10.1212/WNL.0000000000200325
2. Acceleron announces topline results from the phase 2 trial of ACE-083 in patients with Charcot-Marie-Tooth disease. News release. March 9, 2020. Accessed May 17, 2022.
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