Background: ACE-083 is a locally acting muscle therapeutic based on follistatin that binds myostatin and other muscle regulators. ACE-083 has been shown to increase muscle mass of injected muscles in animal models, healthy subjects, and patients with FSHD or Charcot-Marie-Tooth (CMT) disease.
Objectives/Methods: The primary objectives were to determine if ACE-083 could safely increase total muscle volume (TMV) of the tibialis anterior (TA) or biceps brachii (BB) in patients with FSHD1 or 2. Part 1 was dose-ranging (N=37, previously reported); Part 2 was double-blind, placebo-controlled for 6 months followed by a 6-month open-label period. Patients were treated with ACE-083 240 mg/muscle or placebo (1:1) injected into the TA or BB bilaterally q3 weeks. Secondary endpoints included fat fraction (FF), strength, timed function tests, and quality of life (FSHD-Health Index, HI).
Results: We enrolled 58 patients (safety set) in Part 2 and 55 were evaluable for efficacy/PD endpoints. Median (range) baseline age (yr) was 46.0 (18-70) in TA cohorts, 46.0 (21-80) in BB cohorts. We saw mean (SEM) increases in TMV of 13.8% (2.9) for ACE-083 vs 4.3% (2.7) for placebo (p=0.01) in TA, and increases of 19.1% (2.8) for ACE-083 vs 2.7% (2.8) (p<0.0001) for placebo in BB. There were no statistically significant differences between ACE-083 and placebo groups for % change in 6-minute walk distance, 10m walk/run, 4-stair climb (TA) or Performance of Upper Limb (BB), nor for raw change in FSHD-HI scores. ACE-083 was generally well-tolerated; common adverse events included injection site reactions and myalgia.
Conclusions: Although ACE-083 demonstrated significant increases in mean TMV, there were no statistically significant improvements in other clinical outcome measures (COMs). Learning and placebo effects identified in some COMs support consideration of a run-in period and emphasize the importance of an appropriate comparator arm in neuromuscular studies.