Topline Efficacy and Safety Results from REACH: Phase 3 Placebo-Controlled Trial of Losmapimod for Facioscapulohumeral Muscular Dystrophy (FSHD)

Topic:

Clinical Trials

Poster Number: O196

Author(s):

Jeffrey Statland, MD, University of Kansas Medical Center, Angela Rosenbohm, MD, Universitätsklinikum Ulm, Germany, Adolfo Lopez de Munain Arregui, MD, Hospital Universitario de Donostia, Spain, Sabrina Sacconi, MD, Peripheral Nervous System and Muscle Department, University Côte d’Azur, Doris Leung, MD, PhD, Kennedy Krieger Institute, Lawrence Hayward, MD, PhD, UMass Memorial Health, USA, Umesh Badrising, MD, Leids Universitair Medisch Centrum, Netherlands, John Vissing, MD, University of Copenhagen, Nicol Voermans, MD PhD, Radboud University Medical Center, Nuria Muelas, MD, Hospital Universitari i Politecnic La Fe de Valencia, Spain, Benedikt Schoser, MD, LMU Klinikum der Universität München, Germany, Leo Wang, MD, PhD, University of Washington, Enrico Bugiardini, PhD, University College London Hospitals (UCLH), United Kingdom, Hanns Lochmuller, MD, Children’s Hospital of Eastern Ontario Research Institute, Erin O'Ferrall, MD, Montreal Neurological Institute and Hospital, Canada, Henning Andersen, MD, PhD, Aarhus Universitetshospital, Denmark, Johanna Hamel, MD, The university of Rochester, Namita Goyal, MD, University of California Irvine, USA, SH Subramony, MD, University of Florida, Perry Shieh, MD, UCLA, Miriam Freimer, MD, Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA, Elie Naddaf, MD, Mayo Clinic, USA, Thomas Ragole, MD, University of Colorado Hospital, USA, Lawrence Korngut, MD, Heritage Medical Research Clinic, USA, Teresinha Evangelista, MD, Institute of Myology, Cornelia Kornblum, MD, Universitätsklinikum Bonn, Germany, Lorenzo Maggi, MD, Fondazione IRCCS Istituto Neurologico Carlo Besta, Valeria Sansone, MD, PhD, Fondazione Serena Onlus - Centro Clinico NEMO, Italy, Giorgio Tasca, MD, PhD, Newcastle University, John Jiang, PhD, Fulcrum Therapeutics, Cambridge, MA, USA, Marie-Helene Jouvin, MD, Fulcrum Therapeutics, Cambridge, MA, USA

Background: Facioscapulohumeral muscular dystrophy (FSHD) is caused by gain of function of the DUX4 gene in skeletal muscle, resulting in progressive weakness and disability. Losmapimod is a selective inhibitor of p38α/β MAPK that reduced aberrant expression of DUX4 in patient derived cell lines. A phase 2 study showed benefits on muscle function.

Objective: REACH is a Phase 3 double-blind, placebo-controlled trial to assess efficacy and safety of losmapimod for the treatment of FSHD.

Methods: Participants, 18–65 years old, with genetically confirmed FSHD and Ricci score 2–4, were randomized 1:1 to receive losmapimod 15 mg or placebo orally, twice daily for 48 weeks. The primary efficacy endpoint was change in total relative surface area (RSA) Q1–Q5 with 500 g wrist weight on reachable workspace. Secondary efficacy endpoints included change in shoulder abductor strength by hand-held dynamometry, muscle fat infiltration (MFI) in B muscles and response to the NeuroQoL-UE questionnaire. Responses to the Patient Global Impression of Change (PGIC) at week 48 were collected.

Results: Two-hundred-sixty people (242 FSHD1, 18 FSHD2) were enrolled; mean age was 43.9 (SD 12.2) years; 56% male; 89% white. The mean baseline total RSA was 0.519 (SD 0.166), and the mean baseline Ricci score was 3.19 (SD 0.59). No benefit was seen in participants treated versus placebo for RWS, MFI, dynamometry, the NeuroQoL or PGIC patient-reported outcomes.

The overall rate of AEs was similar in the two treatment cohorts. In the losmapimod cohort there were no treatment-related SAEs, discontinuations due to AEs, or deaths.

Conclusions: This phase 3 study did not replicate the clinical benefits observed in the phase 2 study, providing level one evidence of no benefit of losmapimod compared to placebo in changes in RWS, dynamometry, MFI, or patient reported impact. Secondary and post hoc analysis, including subgroup analyses, are ongoing.