ACE-083, a locally-acting TGF-beta superfamily ligand trap, increases muscle volume of targeted muscle: Preliminary results from a phase 1 dose escalation study in healthy volunteers

Background: ACE-083 is an investigational protein therapeutic that acts as a localized ligand trap for myostatin (GDF8) and other negative regulators of muscle growth in the TGF-β superfamily. In wild-type mice and the mdxmodel of Duchenne muscular dystrophy (DMD), local injection of ACE-083 into a target muscle led to dose-dependent increases in muscle mass and force with no systemic pharmacodynamic (PD) effects. Methods: This is a single-center double-blind, placebo-controlled, dose escalation study to evaluate the safety, tolerability, pharmacokinetics, and PD effects of ACE-083 in healthy, postmenopausal women. Five cohorts of 8 subjects each were randomized to ACE-083 (n=6) or placebo (n=2), administered as 2-4 EMG-guided injections into the right rectus femoris (RF) muscle: Cohorts 1-3 (50, 100, 200 mg) on Day 1, and Cohorts 4-5 (100, 200 mg) on Days 1 and 22. MRI to assess thigh muscle volume was performed at baseline, and 3 and 8 weeks after last dose. Fixed and hand-held knee extension strength measurements were evaluated during treatment and follow-up. Additional cohorts to evaluate injections into the tibialis anterior muscle and dorsiflexion are ongoing. Results: The difference in mean % change in RF muscle volume from baseline between the injected right RF and the uninjected left RF at 3 weeks after the last dose was +0.6% in the placebo group, compared to +1.2%, +2.8%, +4.2%, +6.2%, and +13.2% in ACE-083-treated subjects from cohorts 1-5, respectively. In Cohorts 2-5, RFmuscle volume remained increased, though attenuated, at 8 weeks after the last dose. Changes in knee extension strength did not correlate with muscle volume increases in these healthy subjects. All AEs were grade 1-2 and reversible. The most frequent related AEs (≥15%) included injection site pain, muscle twitching, myalgia, and injection site reaction, with similar incidences in activeand placebo-treated groups. Conclusions: Local administration of ACE-083 into the RF muscle was well-tolerated and associated with dose-dependent increases in RF muscle volume. These observed increases in muscle mass compare favorably with systemic agents in development and support further studies of ACE-083 in diseases with focal muscle involvement, such as facioscapulohumeral muscular dystrophy (FSHD).