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Clinical Trial
. 2022 Jul;66(1):50-62.
doi: 10.1002/mus.27558. Epub 2022 May 9.

Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy

Jeffrey M Statland  1 , Craig Campbell  2 , Urvi Desai  3 , Chafic Karam  4 , Jordi Díaz-Manera  5   6   7 , Jeffrey T Guptill  8 , Lawrence Korngut  9 , Angela Genge  10 , Rabi N Tawil  11 , Lauren Elman  12 , Nanette C Joyce  13 , Kathryn R Wagner  14 , Georgios Manousakis  15 , Anthony A Amato  16 , Russell J Butterfield  17 , Perry B Shieh  18 , Matthew Wicklund  19 , Josep Gamez  20 , Cynthia Bodkin  21 , Alan Pestronk  22 , Conrad C Weihl  22 , Juan J Vilchez-Padilla  23   6 , Nicholas E Johnson  24 , Katherine D Mathews  25 , Barry Miller  26 , Ashley Leneus  26 , Marcie Fowler  26 , Marc van de Rijn  26 , Kenneth M Attie  26
Affiliations
Clinical Trial

Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy

Jeffrey M Statland et al. Muscle Nerve. 2022 Jul.

Abstract

Introduction/aims: Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD.

Methods: Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated.

Results: Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions.

Discussion: Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.

Keywords: FSHD; controlled trial; facioscapulohumeral muscular dystrophy; randomized.

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Conflict of interest statement

J.M. Statland received grant support from the NIH, MDA, FSHD Society, and the Friends of FSH Research; he is a consultant or has served on advisory boards for Dyne, Fulcrum, Acceleron, Avidity, Strongbridge, Sarepta, and Genzyme. U. Desai has served on advisory boards for Alexion, CSL Behring, Argenx, Akcea, and Stealth Biotherapeutics and has served on the speaker's bureau for Alexion. 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. J. Díaz‐Manera has served as a consultant or on advisory boards for Sanofi‐Genzyme, Amicus, Audentes, Sarepta, and Spark. He has also received industry grant support from Sanofi Genzyme and Boehringer Ingelheim. J.T. Guptill has served as a consultant or on advisory boards for Immunovant, Alexion, Momenta, Ra Pharma, Grifols, Argenx, Jacobus, Becton Dickinson, Cabaletta, Regeneron, and Piedmont Pharmaceuticals and receives industry grant support from UCB for a fellowship training grant. A. Genge serves as a consultant for Mitsubishi Tanabe Pharma America, Sanofi Genzyme, AL‐S Pharma, AB Sciences, Biogen, Novartis, CSL Behring, Anavex, AveXis, Alexion, Wave Life Sciences, Revalesio, Roche, Cytokinetics, Orion, Akcea, Clene, Bayshore, and QurAlis. She participates as CRU Medical Director, PI, or sub‐PI on trials sponsored by AB Sciences, AL‐S Pharma, Acceleron, Amicus, Alnylam, Bioblast, Biogen, BMS, Boston Biomedical Cytokinetics, Sanofi Genzyme, Grifols, Ionis, Eli Lilly, Mallinckrodt, MedImmune, Novartis, Orion, Orphazyme, Pfizer, Ra Pharmaceuticals, Roche, Teva, and UCB. R.N. Tawil serves as an advisory board member or consultant for Acceleron Pharma, Fulcrum Therapeutics, MT Pharma, and Arrowhead Pharma. L. Elman has served on advisory boards for Roche/Genentech and Biogen and received royalties from UpToDate (Wolters Kluwer). K.R. Wagner has served on advisory boards or consulted for AskBio, Dyne, Arrowhead Pharma, Catabasis, Santhera, and Vita. G. Manousakis has served on advisory boards for Stealth Biotherapeutics and Argenx. A.A. Amato is an associate editor for Neurology and has served as a medical consultant or on advisory boards for Sarepta, Alexion, and Serono; he received royalties from UpToDate (Wolters Kluwer) and Harrison's Principles of Internal Medicine, Neuromuscular Disorders, 2nd ed. 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. M. Wicklund has received research funding from the NIH, MDA, Acceleron, Alexion, Baxalta, ML Bio, Orphazyme, and Sarepta Therapeutics and has served on advisory boards or in consultation for Affinia, Amicus, ML Bio, Sanofi, and Sarepta. J. Gamez has received grant funding from Fondo de Investigación Sanitaria (FIS‐FEDER) (grants PI16/01673 and PI19/00593). N.E. Johnson has received grant funding from the NINDS (4K23NS091511; R01NS104010), CDC (DD19‐002), and the FDA (7R01FD006071‐02); he receives royalties from the Congenital and Childhood Onset Myotonic Dystrophy Health Index and the Charcot‐Marie‐Tooth Health Index; 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. 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. The remaining authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Study design (Parts 1 and 2). Abbreviations: BB, biceps brachii; TA, tibialis anterior.
FIGURE 2
FIGURE 2
CONSORT flow diagram (Part 2). *All randomized participants. †All randomized participants who received at least one dose of study drug (includes placebo). ‡All participants randomized who received at least one dose of the study drug (including placebo) with no major protocol violations.
FIGURE 3
FIGURE 3
Mean ± SEM change from baseline in TMV and functional endpoints. A, TMV in the biceps brachii group. B, TMV in the tibialis anterior group. C, PUL midlevel domain score in the biceps brachii group. D, 6MWD in the tibialis anterior group. E, 10 mW/R in the tibialis anterior group (Part 2, per protocol set). Abbreviations: 6MWD, 6‐minute walk distance; 10 mW/R, 10‐meter walk/run; BSL, baseline; PUL, performance of the upper limb; SEM, standard error of the mean; TMV, total muscle volume.
FIGURE 4
FIGURE 4
Mean ± SEM change from baseline in the patient‐reported FSHD Health Index. A, Total score in the biceps brachii group. B, Arm/shoulder subscale score in the biceps brachii group. C, Total score in the tibialis anterior group. D, Mobility/ambulation subscale score in the tibialis anterior group (Part 2, per protocol set). Abbreviations: BSL, baseline; FSHD, facioscapulohumeral muscular dystrophy; FSHD‐HI, FSHD Health Index; SEM, standard error of the mean.
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