Randomized Phase 2 Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease

Florian P. Thomas, Thomas H. Brannagan, Russell J. Butterfield, Urvi Desai, Ali A. Habib, David N. Herrmann, Katy J. Eichinger, Nicholas E. Johnson, Chafic Karam, Alan Pestronk, Colin Quinn, Michael E. Shy, Jeffrey M. Statland, Sub H. Subramony, David Walk, Katherine Stevens-Favorite, Barry Miller, Ashley Leneus, Marcie Fowler, Marc Van De RijnKenneth M. Attie

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9 Scopus citations


OBJECTIVE: To determine whether locally acting ACE-083 is safe, well tolerated, and increases muscle volume, motor function, and quality of life (QoL) in adults with Charcot-Marie-Tooth disease (CMT) type 1.

METHODS: This phase 2 study enrolled adults with CMT1 or CMTX (N=63). Part 1 was open-label and evaluated safety and tolerability of different dose levels of ACE-083 for use in Part 2. Part 2 was a randomized, placebo-controlled, 6-month study of 240 mg/muscle ACE-083 injected bilaterally in the tibialis anterior muscle, followed by a 6-month, open-label extension in which all patients received ACE-083. Pharmacodynamic endpoints included total muscle volume (TMV; primary endpoint), contractile muscle volume (CMV), and fat fraction. Additional secondary endpoints included 6-minute walk test, 10-meter walk/run, muscle strength, and QoL. Safety was assessed with treatment-emergent adverse events (TEAEs) and clinical laboratory tests.

RESULTS: In Part 1 (n=18), ACE-083 was generally safe and well tolerated at all dose levels, with no serious AEs, TEAEs ≥Grade 3, or death reported. In Part 2 (n=45 enrolled, n=44 treated), there was significantly greater change in TMV with ACE-083 compared with placebo (LS mean difference: 13.5%; p = 0.0096). There was significant difference between ACE-083 and placebo for CMV and change in ankle dorsiflexion strength. Fat fraction and all other functional outcomes were not significantly improved by ACE-083. Moderate-to-mild injection-site reactions were the most common TEAEs.

CONCLUSIONS: Despite significantly increased TMV and CMV, patients with CMT receiving ACE-083 in tibialis anterior muscles did not demonstrate greater functional improvement compared with those receiving placebo.

CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that intramuscular ACE-083 is safe, well tolerated, and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.

Original languageEnglish (US)
Pages (from-to)E2356-E2367
Issue number23
StatePublished - Jun 7 2022

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© American Academy of Neurology.

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