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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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

Bibliographical note

Funding Information:
The authors thank the patients and their families for their participation and contributions, as well as the following team members: subinvestigators: Amy Visser, Mazen Dimackie, Georgious Manousakis, Peter Creigh, Russell Butterfield, Lauren Elman, Eric Mittelmann, Robert Connors, Mamatha Pasnoor, Omar Jawdat, Nivedita Jerath, Ludwig Gutmann, Gene Han, Clement Yang, Jeffrey Shije, Mamatha Pasnoor, Omar Jawdat; clinical evaluators: Katy Eichinger, Deanna DiBella, Melissa McIntyre, Amelia Wilson, Lindsay Baker, Keegan Kitzgerald, Jeff Schilmgen, Denise Davis, Patrick Tierney, Kyle Cunningham, Lauren Draper, Chelsea Bacon, Melissa Currence, Laura Herbelin, Ludo De Wolf, Hope Anneliese Lane, Samantha Pierre, Raphael Kupferman, Molly Stark, Sandy Swanson, Lisa H. Yoon, Scott Holsten; clinical site coordinators: Bryant Gordon, Jeanette Overton, Sonya Aziz-Zaman, Kelsey Moulton, Amanda Cowsert, Nicole Kressin, Ayla McCalley, Natalya Burlakova, Christine Cavallo, Lee Ifhar, Janet Sowden, Beth Wood, Diana Dimitrova, Raisy Fayerman, Leidy J Gonzalez, Lee Ifhar, Lisa Ranzinge; independent safety review: Mario Saporta, MD, PhD; MedPace: Richard Scheyer, MD, Georgiana Salyers, Megan Kolthoff, Taylor Meece, Stephanie Porter, Gina Kavanaugh, Emily Birkmeyer, Katie Ard, Jacob Giltrow, Elizabeth Do, Sabrina Lesh, Courtney Pearce, Leslie Foertsch; and Acceleron: Leah Leahy, Jade Sun, Saba Qamar, Connie Slocum, Carrie Barron, Shuree Harrison, Thienhuu Nguyen, Suada Celikovic, Bronwyn Owens, Barbara Leibo, Joseph G. Reynolds. Medical writing and editorial assistance were provided by Cadent Medical Communications, LLC, a Syneos Health group company, and was supported by Acceleron Pharma.

Funding Information:
F.P. Thomas has provided consultation for Acceleron Pharma. T.H. Brannagan III declares no disclosures relevant to the manuscript. R.J. Butterfield is receiving funding via contracts for clinical trials from AveXis, PTC Therapeutics, Sarepta Therapeutics, Pfizer, Biogen, Capricorn, and Catabasis; he serves on Scientific Advisory boards for Sarepta Therapeutics, Biogen, AveXis, and Pfizer. U. Desai and A.A. Habib declare no disclosures relevant to the manuscript. D.N. Herrmann receives grant funding from NIH, CMT Association, and the Friedreich Ataxia Research Alliance. Dr. Herrmann also report grants and has undertaken consulting for Acceleron Pharma. Dr. Herrmann also has undertaken consulting for Neurogene, Sarepta, Regenacy (Scientific Advisory Board), Alnylam (Medical Advisory Board), Guidepoint Global, GLG, Narrow River Management, Slingshots, and Human First Therapeutics outside the submitted work. In addition, Dr. Herrmann reports that the University of Rochester has a copyright for the CMT-HI, of which he is a codeveloper. K.J. Eichinger declares no disclosures relevant to the manuscript. N.E. Johnson has received grant funding from the National Institute of Neurological Disorders and Stroke (4K23NS091511, R01NS104010), Centers for Disease Control and Prevention (DD19-002), and the Food and Drug Administration (7R01FD006071-02); he receives royalties from the Congenital and Childhood Onset Myotonic Dystrophy Health Index and the CMT-HI; receives research funds from Dyne, AveXis, CSL Behring, Vertex Pharmaceuticals, Fulcrum Therapeutics, ML Bio, Sarepta, and Acceleron Pharma; and has provided consultation for AveXis, AMO Pharma, Strongbridge BioPharma, Acceleron Pharma, Fulcrum Therapeutics, Dyne, Avidity, and Vertex Pharmaceuticals. C. Karam has undertaken consulting or educational activities for Akcea, Alexion, Alnylam, Argenx, Biogen, CSL Behring, Medscape, and Sanofi Genzyme, and has received research grants from Sanofi Genzyme and Akcea. A. Pestronk, C. Quinn, and M.E. Shy declare no disclosures relevant to the manuscript. J.M. Statland received grant support from the NIH, Muscular Dystrophy Association, FSHD Society, and Friends of FSH Research; he is a consultant or has served on advisory boards for Dyne, Fulcrum, Acceleron, Avidity, Strongbridge, Sarepta, and Genzyme. S.H. Subramony, D. Walk, and K. Stevens-Favorite declare no disclosures relevant to the manuscript. B. Miller, A. Leneus, M. Fowler, M. van de Rijn, and K. Attie were employed by Acceleron Pharma during the study and had stock ownership and/or options. Go to Neurology.org/N for full disclosures.

Publisher Copyright:
© American Academy of Neurology.

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