Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy

Kathryn R Wagner; Hoda Z Abdel-Hamid; Jean K Mah; Craig Campbell; Michela Guglieri; Francesco Muntoni; Yasuhiro Takeshima; Craig M McDonald; Anna Kostera-Pruszczyk; Peter Karachunski; Russell J Butterfield; Eugenio Mercuri; Chiara Fiorillo; Enrico S Bertini; Cuixia Tian; Jeffery Statland; Alesia B Sadosky; Vivek S Purohit; Sarah P Sherlock; Jeffrey P Palmer; Michael Binks; Lawrence Charnas; Shannon Marraffino; Brenda L Wong

doi:10.1016/j.nmd.2020.05.002

Randomized phase 2 trial and open-label extension of domagrozumab in Duchenne muscular dystrophy

Neuromuscul Disord. 2020 Jun;30(6):492-502. doi: 10.1016/j.nmd.2020.05.002. Epub 2020 May 19.

Authors

Kathryn R Wagner¹, Hoda Z Abdel-Hamid², Jean K Mah³, Craig Campbell⁴, Michela Guglieri⁵, Francesco Muntoni⁶, Yasuhiro Takeshima⁷, Craig M McDonald⁸, Anna Kostera-Pruszczyk⁹, Peter Karachunski¹⁰, Russell J Butterfield¹¹, Eugenio Mercuri¹², Chiara Fiorillo¹³, Enrico S Bertini¹⁴, Cuixia Tian¹⁵, Jeffery Statland¹⁶, Alesia B Sadosky¹⁷, Vivek S Purohit¹⁸, Sarah P Sherlock¹⁸, Jeffrey P Palmer¹⁸, Michael Binks¹⁸, Lawrence Charnas¹⁸, Shannon Marraffino¹⁸, Brenda L Wong¹⁹

Affiliations

¹ Center for Genetic Muscle Disorders, Baltimore, Kennedy Krieger Institute, Departments of Neurology and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address: wagnerk@kennedykrieger.org.
² University of Pittsburgh, Pittsburgh, PA, USA.
³ Cumming School of Medicine, University of Calgary, Alberta Children's Hospital, Calgary, AB, Canada.
⁴ Department of Pediatrics, Clinical Neurological Sciences and Epidemiology, University of Western Ontario, Children's Hospital London Health Sciences Centre, London, ON, Canada.
⁵ The John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
⁶ NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, University College London, & Great Ormond Street Hospital Trust, London, UK.
⁷ Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
⁸ Lawson Health Research Institute: Children's Hospital, London, ON, Canada.
⁹ Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
¹⁰ University of Minnesota, Minneapolis, MN, USA.
¹¹ University of Utah School of Medicine, Salt Lake City, UT, USA.
¹² Paediatric Neurology, Catholic University, Rome, Italy; Centro Clinico Nemo, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
¹³ IRCCS Giannina Gaslini, Genova, Italy.
¹⁴ Bambino Gesu Children's Research Hospital IRCCS, Rome, Italy.
¹⁵ Cincinnati Children's Hospital Medical Center; College of Medicine University of Cincinnati, Cincinnati, OH, USA.
¹⁶ University of Kansas Medical Center, Kansas City, KS, USA.
¹⁷ Pfizer Inc, New York, NY, USA.
¹⁸ Pfizer Inc, Cambridge, MA, USA.
¹⁹ University of Massachusetts Medical School, Worcester, MA, USA.

PMID: 32522498
DOI: 10.1016/j.nmd.2020.05.002

Abstract

We report results from a phase 2, randomized, double-blind, 2-period trial (48 weeks each) of domagrozumab and its open-label extension in patients with Duchenne muscular dystrophy (DMD). Of 120 ambulatory boys (aged 6 to <16 years) with DMD, 80 were treated with multiple ascending doses (5, 20, and 40 mg/kg) of domagrozumab and 40 treated with placebo. The primary endpoints were safety and mean change in 4-stair climb (4SC) time at week 49. Secondary endpoints included other functional tests, pharmacokinetics, and pharmacodynamics. Mean (SD) age was 8.4 (1.7) and 9.3 (2.3) years in domagrozumab- and placebo-treated patients, respectively. Difference in mean (95% CI) change from baseline in 4SC at week 49 for domagrozumab vs placebo was 0.27 (-7.4 to 7.9) seconds (p = 0.94). There were no significant between-group differences in any secondary clinical endpoints. Most patients had ≥1 adverse event in the first 48 weeks; most were mild and not treatment-related. Median serum concentrations of domagrozumab increased with administered dose within each dose level. Non-significant increases in muscle volume were observed in domagrozumab- vs placebo-treated patients. Domagrozumab was generally safe and well tolerated in patients with DMD. Efficacy measures did not support a significant treatment effect. Clinicaltrials.gov identifiers: NCT02310763 and NCT02907619.

Keywords: 4-stair climb; Duchenne muscular dystrophy; domagrozumab; myostatin inhibitor.

Publication types

Clinical Trial, Phase II
Randomized Controlled Trial

MeSH terms

Adolescent
Antibodies, Monoclonal, Humanized / administration & dosage
Antibodies, Monoclonal, Humanized / adverse effects
Antibodies, Monoclonal, Humanized / blood
Antibodies, Monoclonal, Humanized / pharmacology*
Child
Exercise Test
Humans
Male
Muscular Dystrophy, Duchenne / drug therapy*
Myostatin / antagonists & inhibitors*
Outcome Assessment, Health Care*
Treatment Failure

Substances

Antibodies, Monoclonal, Humanized
Myostatin
domagrozumab

Associated data

ClinicalTrials.gov/NCT02310763
ClinicalTrials.gov/NCT02907619