Results of the Dose-Escalation Portion of a Phase 2 Study of ACE-083, a Local Muscle Therapeutic, in Patients with Charcot-Marie-Tooth (CMT) Disease (S58.006)

Objective: To evaluate the effects of ACE-083 injected into the tibialis anterior (TA) muscle of patients with CMT1 or CMTX and mild-moderate ankle dorsiflexion weakness.

Background: ACE-083 is a locally-acting protein therapeutic consisting of a modified form of human follistatin that binds myostatin plus other negative regulators of muscle. ACE-083 has been shown to increase muscle mass and force in neuromuscular disease mouse models and to increase muscle mass in healthy volunteers and patients with facioscapulohumeral dystrophy (FSHD).

Design/Methods: This ongoing, multicenter study evaluates safety and tolerability (Part 1); pharmacokinetics, pharmacodynamics, and efficacy (Part 2), of ACE-083 administered bilaterally into the TA every 3 weeks. Part 1 is 3-month, open-label with 3 dose cohorts (150, 200, 240 mg/muscle, n=6 each); Part 2 is 6-month, placebo-controlled, followed by 6-month open-label (n=40 planned).

Results: As of 24 Aug 2018, preliminary Part 1 data are: median (range) age 48 yrs (18–62); 11 patients with CMT1A, 4 with CMT1B, and 3 with CMTX1; median (range) baseline fat fraction (FF) 30% (9–45). No serious AEs were reported and related AEs were primarily injection-site related. Changes in MRI parameters across the 3 cohorts are provided at Day 106 (3 weeks after last dose, average left and right sides). Mean percent increase in total muscle volume was 12.6 to 14.2% and contractile muscle volume increased 15.8 to 19.6%. Mean absolute decrease in FF% was −1.7 to −3.5%.

Conclusions: Local muscle injections of ACE-083 were well tolerated in patients with CMT and resulted in increases in muscle volume and decreases in fat fraction. The ongoing, placebo-controlled Part 2 of the study will evaluate effects on function and quality of life.

Disclosure: Dr. Thomas has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acorda Therapeutics, Biogen, Genzyme, Novartis and Teva Neuroscience. Dr. Thomas has received research support from Biogen and Teva Neuroscience. Dr. Shy has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron. Dr. Herrmann has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Guidepoint Global, GLG. Dr. Herrmann has received royalty, license fees, or contractual rights payments from University of Rochester. Dr. Herrmann has received research support from Acceleron Pharma, Flex Pharma. Dr. Statland has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma, Inc., Expansion Therapeutics, , Fulcrum Therapeutics, Genea Biocells, and Strongbridge Biopharma. Dr. Statland has received research support from FSH Society, Muscular Dystrophy Association, and the National Institutes of Health. Dr. Walk has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma. Dr. Walk has received personal compensation in an editorial capacity for Pain Medicine. Dr. Walk has received research support from Acceleron Pharma and PharNEXT. Dr. Quinn has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma. Dr. Johnson has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron. Dr. Johnson has received personal compensation in an editorial capacity for Continuum. Dr. Johnson has received research support from Acceleron. Dr. Subramony has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma. Dr. Subramony has received research support from Acceleron, Reata, Takeda, Horizon, and Biohaven. Dr. Karam has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Akcea, Alexion, Alnyalm, Biogen, CSL Behring, Cytokinetics, Genzyme, Guidepoint, GLG. Dr. Karam has received research support from Genzyme. Dr. Mozaffar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Amicus, Alexion, CSL and Genzyme. Dr. Mozaffar has received research support from Alexion, Amicus, aTyr, Genzyme, Grifols, Idera, Ionis Pharmaceuticals, and Ultragenyx. Dr. Glasser has nothing to disclose. Dr. Miller has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma. Dr. Leneus has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma. Dr. Zeldin has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma, Ablynx. Dr. Attie has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Versartis, Acceleron Pharma.