Abstract Details

Title Results of a Phase 2 Double-Blind Placebo-Controlled Study of a Local Muscle Therapeutic, ACE-083, in Subjects with Charcot-Marie-Tooth (CMT) Disease

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S46 - Neuromuscular and Clinical Neurophysiology (EMG): Motor Neuron/Charcot Marie Tooth (5:18 PM-5:30 PM)

Poster/Presentation
Number 010

Background ACE-083 is a locally-acting protein therapeutic containing modified human follistatin, which binds myostatin plus other negative regulators of muscle. ACE-083 increased muscle mass and force in neuromuscular disease mouse models and increased muscle mass in healthy volunteers and in subjects with CMT or facioscapulohumeral dystrophy (FSHD). ACE-083 was well tolerated in the 3-month open-label dose-escalation portion of this study and demonstrated a mean percent increase from baseline to Day 106 of 12.6-14.2% in TA total muscle volume (TMV) and 15.8-19.6% in contractile muscle volume (CMV), with a mean absolute decrease in fat fraction (FF) of 1.7-3.5%.

Objective

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

Design/Methods This 2-part, multicenter study evaluates the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy of ACE-083 injected into the TA muscles of subjects with CMT1/X. Subjects in Part 2 were randomized 1:1 to ACE-083, 240 mg/muscle, or placebo bilaterally every 3 weeks for 6 months, followed by a 6-month open-label period. Imaging biomarkers include whole muscle MRI change or % change in TMV, CMV, and FF. Additional outcome measures include change or % change in strength (quantitative muscle testing), motor function tests, and quality of life (CMT-Health Index).

Results Baseline characteristics for all subjects in the placebo-controlled Part 2 (N=44) include median (range) age 47.5 years (18-71) and duration of symptoms 27.0 years (1-64). This included 31 subjects with CMT1A, 6 with CMT1B, and 7 with CMTX. Results from Part 2 will be presented.

Conclusions

Locally administered ACE-083 was well tolerated in subjects with CMT treated up to three months. Results from the 6-month placebo-controlled portion of the study will inform the effects of ACE-083 on muscle volume, fat fraction, functional endpoints, and patient-reported outcomes.

Authors/Disclosures
Florian P. Thomas, MD, PhD, MA, FAAN (Hackensack Meridian Health) PRESENTER	Dr. Thomas has received personal compensation for serving as an employee of Hackensack Meridian Health. Dr. Thomas has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Pharnext. Dr. Thomas has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Journal of Spinal Cord Medicine. Dr. Thomas has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Gravel & Shae. The institution of Dr. Thomas has received research support from University of Pennsylavania. Dr. Thomas has a non-compensated relationship as a Board Member, Metro New Jersey with National MS Society that is relevant to AAN interests or activities. Dr. Thomas has a non-compensated relationship as a Board Member with American Paraplegia Society that is relevant to AAN interests or activities.
Michael E. Shy, MD, FAAN (University of Iowa)	Dr. Shy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Applied Therapeutics. The institution of Dr. Shy has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for DTx Pharma. The institution of Dr. Shy has received research support from NIH. The institution of Dr. Shy has received research support from Muscular Dystrophy Association. The institution of Dr. Shy has received research support from Charcot Marie Tooth Association. The institution of Dr. Shy has received research support from Applied Therapeutics.
Colin Quinn, MD (University of Pennsylvania)	Dr. Quinn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx Pharmaceuticals. Dr. Quinn has received personal compensation in the range of $0-$499 for serving as a Consultant for Amicus. Dr. Quinn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta Therapeutics. Dr. Quinn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Quinn has received personal compensation in the range of $0-$499 for serving as a Consultant for Clene Nanomedicine. Dr. Quinn has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sanofi. Dr. Quinn has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Partners Health Care. Dr. Quinn has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Robins Kaplan.
Urvi G. Desai, MD, FAAN (Dept of Neurology, CMC)	Dr. Desai has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Takeda. Dr. Desai has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fulcrum. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Catalyst. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alexion. Dr. Desai has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Argenx.
David N. Herrmann, MD, FAAN (University of Rochester Medical Center)	Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Acceleron. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Guidepoint global. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GLG. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurogene. Dr. Herrmann has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta. Dr. Herrmann has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Regenacy. Dr. Herrmann has received intellectual property interests from a discovery or technology relating to health care.
Jeffrey Statland, MD (University of Kansas Medical Center)	Dr. Statland has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ML Bio. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Epic Bio. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Armatus . Dr. Statland has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Kate Therapeutics. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vita Therapeutics. Dr. Statland has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Dyne Therapeutics. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Avidity . Dr. Statland has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fulcrum Therapeutics. Dr. Statland has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Statland has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Vertex . The institution of Dr. Statland has received research support from NIH. The institution of Dr. Statland has received research support from FSHD Society. The institution of Dr. Statland has received research support from Friends of FSH Research. The institution of Dr. Statland has received research support from FSHD Canada. The institution of Dr. Statland has received research support from MDA.
S H. Subramony, MBBS, FAAN (University of Florida)	Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avidity. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dyne. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lupin. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Fallonmedica. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amicus. Dr. Subramony has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Fulcrum. The institution of Dr. Subramony has received research support from Reata. The institution of Dr. Subramony has received research support from Retrotope. The institution of Dr. Subramony has received research support from Acceleron. The institution of Dr. Subramony has received research support from Biohaven. The institution of Dr. Subramony has received research support from Pharnext. The institution of Dr. Subramony has received research support from Fulcrum. The institution of Dr. Subramony has received research support from National Ataxia Foundation. The institution of Dr. Subramony has received research support from Friedreich Ataxia Research Alliance. The institution of Dr. Subramony has received research support from Muscular Dystrophy Association. The institution of Dr. Subramony has received research support from Univ of Rochester, MDA. The institution of Dr. Subramony has received research support from Virginia Commonwealth Univ (FDA, Wyck Foundation)). The institution of Dr. Subramony has received research support from Children's Hospital, Philadelphia (FDA). The institution of Dr. Subramony has received research support from Houston Methodist (NIH). The institution of Dr. Subramony has received research support from NIHR01 AR076060-01A1 . The institution of Dr. Subramony has received research support from NIH2R42HD089804-04 . The institution of Dr. Subramony has received research support from NIH R01 AR056973 . The institution of Dr. Subramony has received research support from FSHD Society. The institution of Dr. Subramony has received research support from AAVANTI BIO. The institution of Dr. Subramony has received research support from COHAV FL State Dept of Health. The institution of Dr. Subramony has received research support from Avidity. The institution of Dr. Subramony has received research support from PTC. The institution of Dr. Subramony has received research support from Biohaven. The institution of Dr. Subramony has received research support from Fulcrum. The institution of Dr. Subramony has received research support from Vertex. The institution of Dr. Subramony has received research support from Arthrex.
Thomas Brannagan III, MD, FAAN (Columbia University)	Dr. Brannagan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pfizer. Dr. Brannagan has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alnylam. Dr. Brannagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Grifols. Dr. Brannagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for CSL. Dr. Brannagan has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alnylam. The institution of Dr. Brannagan has received research support from Alnylam. The institution of Dr. Brannagan has received research support from Acceleron. The institution of Dr. Brannagan has received research support from Ionis. The institution of Dr. Brannagan has received research support from Pharnext.
Ali A. Habib, MD (University of California, Irvine)	Dr. Habib has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alexion. Dr. Habib has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for argenx. Dr. Habib has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Immunovant. Dr. Habib has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for UCB. Dr. Habib has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pfizer. Dr. Habib has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech/Roche. Dr. Habib has received personal compensation in the range of $500-$4,999 for serving as a Consultant for NMD Pharma. Dr. Habib has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alpine Immune Sciences. Dr. Habib has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Arcellx. Dr. Habib has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Horizon/ Amgen. Dr. Habib has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Grifols. Dr. Habib has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NIH/NINDS. Dr. Habib has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Immunis Biomedical. Dr. Habib has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Hoffman-La Roche. Dr. Habib has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Alexion. Dr. Habib has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for argenx. Dr. Habib has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for UCB. The institution of Dr. Habib has received research support from Alexion. The institution of Dr. Habib has received research support from Horizon/Amgen. The institution of Dr. Habib has received research support from Immunovant. The institution of Dr. Habib has received research support from UCB. The institution of Dr. Habib has received research support from argenx. The institution of Dr. Habib has received research support from CabalettaBio. The institution of Dr. Habib has received research support from Genentech. The institution of Dr. Habib has received research support from Regeneron.
Chafic Y. Karam, MD (University of Pennsylvania)	Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Alnylam. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ionis. Dr. Karam has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Sanofi. Dr. Karam has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Argenx. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Karam has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neuroderm.
Alan Pestronk, MD, FAAN (Washington University in Saint Louis - Neurology)	The institution of Dr. Pestronk has received research support from Jain. The institution of Dr. Pestronk has received research support from Fulcrum. The institution of Dr. Pestronk has received research support from Argenyx. The institution of Dr. Pestronk has received research support from NeuroNext.
David Walk, MD, FAAN (Dept. of Neurology)	No disclosure on file
Russell Butterfield, MD, PhD, BS (University of Utah)	Dr. Butterfield has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sarepta. Dr. Butterfield has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. Dr. Butterfield has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Reata. The institution of Dr. Butterfield has received research support from NIH. The institution of Dr. Butterfield has received research support from Ionis. The institution of Dr. Butterfield has received research support from CDC.
Nicholas E. Johnson, MD, FAAN (Virginia Commonwealth University)	Dr. Johnson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta Therapuetics. Dr. Johnson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Dyne Therapeutics. Dr. Johnson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vertex Pharma. Dr. Johnson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avidity. Dr. Johnson has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Arthex. Dr. Johnson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Juvena. Dr. Johnson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Rgenta. Dr. Johnson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Angle Therapeutics. Dr. Johnson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AskBio. Dr. Johnson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Johnson has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Dr. Johnson has stock in Angle Therapeutics. Dr. Johnson has stock in Juvena Therapeutics. Dr. Johnson has stock in Myogene Therapies. The institution of Dr. Johnson has received research support from Novartis. The institution of Dr. Johnson has received research support from Takeda . The institution of Dr. Johnson has received research support from AMO Pharma. The institution of Dr. Johnson has received research support from Sarepta. The institution of Dr. Johnson has received research support from Dyne Therapeutics. The institution of Dr. Johnson has received research support from AskBio. The institution of Dr. Johnson has received research support from Pepgen. The institution of Dr. Johnson has received research support from ML Bio. The institution of Dr. Johnson has received research support from Vertex. The institution of Dr. Johnson has received research support from Arthex. The institution of Dr. Johnson has received research support from Avidity Biosciences. The institution of Dr. Johnson has received research support from Edgewise. Dr. Johnson has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
Barry Miller	No disclosure on file
	No disclosure on file
Marc J. Van De Rijn, MD (spaulding Rehabilitation Hospital)	No disclosure on file
Kenneth M. Attie, MD (Acceleron Pharma)	No disclosure on file

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