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Published on: January 7, 2019
Randomized Phase 2 Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
Florian P Thomas1, Thomas H Brannagan2, Russell J Butterfield2
1From Hackensack University Medical Center (F.P.T.), Hackensack Meridian School of Medicine, Nutley, NJ; Columbia University Medical Center (T.H.B.), New York, NY; University of Utah (R.J.B.), Salt Lake City; Carolinas Healthcare System Neurosciences Institute (U.D.), Charlotte, NC; University of California Irvine (A.A.H.); University of Rochester Medical Center (D.N.H., K.J.E.), NY; Virginia Commonwealth University (N.E.J.), Richmond; Oregon Health & Science University (C.K.), Portland; Washington University School of Medicine (A.P.), St. Louis, MO; University of Pennsylvania (C.Q.), Philadelphia; University of Iowa (M.E.S.), Iowa City; University of Kansas Medical Center (J.M.S.), Kansas City; University of Florida (S.H.S.), Gainesville; University of Minnesota (D.W.), Minneapolis; Cadent Medical Communications, LLC, a Syneos Health group company (K.S.-F.), New York, NY; Acceleron Pharma (B.M., A.L., M.F., M.v.d.R., K.M.A.), Cambridge, MA. thomasfp@slu.edu.
Background And Objectives:
The goal of this work was to determine whether locally acting ACE-083 is safe and 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 the 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 into 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-m 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 adverse events, TEAEs of grade 3 or greater, 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 (least-squares 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.
Discussion:
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.
Trial Registration Information:
Clinical Trials Registration: NCT03124459.
Classification Of Evidence:
This study provides Class II evidence that intramuscular ACE-083 is safe and well tolerated and increases total muscle volume after 6 months of treatment in adults with CMT1 or CMTX.
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