Losmapimod Demonstrates Significant Slowing of Facioscapulohumeral Muscular Dystrophy Over Long-Term Period

Leo H. Wang, MD, PhD

New long-term findings from the phase 2b ReDUX4 trial (NCT04003974) showed that treatment with losmapimod (Fulcrum Therapeutics) slowed disease progression and demonstrated maintenance of effect through a 96-week period in patients with facioscapulohumeral muscular dystrophy (FSHD), expanding on the previously reported 48-week results.¹

Led by Leo H. Wang, MD, PhD, associate professor of neurology, University of Washington Medical Center, the study featured 80 adults, aged 18 to 65 years with genetically confirmed FSHD1 who were randomly assigned 1:1 to 15 mg losmapimod or placebo. Of these, 76 (99%) entered the open-label extension (OLE) after 48 weeks, and 74 (97%) were enrolled at week 96. All patients received study drug in the OLE, and had durability of treatment response assessed through upper extremity function with Reachable Workspace (RWS).

Presented at the 2023 Muscular Dystrophy Association (MDA) Clinical and Scientific Conference, held March 19-22, in Dallas, Texas, the durability of treatment response in RWS was observed at 96 weeks in those on continuous losmapimod throughout the study. Patients on placebo who converted to study drug at week 48 also demonstrated trends of slowing or stopping disease progression. Of note, those who converted to losmapimod during the OLE had been exposed for an average of 47 to 72 weeks, depending on when they entered the OLE due to implementation of a COVID-19 protocol amendment.

Relative to RWS, similar trends were observed in change in Total Relative Surface Area (RSA) without weight. Annualized total RSA in the dominant arm with weights demonstrated stability in the continuous losmapimod group during the 2nd year of dosing compared with the first (0.18%/yr vs –0.77%/yr, respectively) and improvement in those who crossed over (4.07% vs –9.96%). From weeks 48 to 96, the mean change in dominant RSA was 0.00 (SE, 0.01) for continuous losmapimod and 0.00 (SE, 0.01) for those on placebo who crossed over.

READ MORE: Post-Hoc Analysis of ADAPT Reveals Several Subgroup Responders to Efgartigimod

In terms of safety, no additional safety signals were observed up to 96 weeks of losmapimod 15 BID dosing. No drug-related serious adverse events (AEs) or treatment-emergent AEs leading to discontinuation or death were observed, and most AEs were mild in severity. The most common treatment-emergent AEs across groups were fall (22.4%), headache (14.5%), arthralgia (7.9%), back pain (7.9%), pain in extremities (6.6%), nasopharyngitis (6.6%), and pyrexia (6.6%).

The 48-week results of ReDUX4 were presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, with losmapimod showing statistically significant slowing of muscle function deterioration despite not changes in DUX4, the biomarker related to the cause of the disease. After 48 weeks of treatment, patients on the study drug demonstrated significant differences whole-body MSK-MRI muscle fat infiltration (MFI) (0.03% vs 0.52%; difference, –0.49; 95% CI, –0.86 to –0.12; P = .01) relative to those on placebo. Losmapimod, an investigational agent that selectively inhibits enzymes p38a/ß mitogen-activated protein kinases (MAPKs), which are modulators of DUX4 expression and mediators of inflammation, is also currently being evaluated in a phase 3 study, announced in March 2022.

Reduction in DUX4-driven gene expression, the primary end point, showed no differences between losmapimod (26.16) and placebo (25.68; difference, 0.43; 95% CI, –1.04 to 1.89; P = .56) on log2 scale. DUX4, a key biomarker of FSHD, activates a downstream transcriptional program that causes myofiber death, with maladaptive tissue remodeling characterized by replacement of muscle with fat ultimately resulting in progressive motor disability.

The phase 3 trial, REACH, is currently ongoing and is expected to enroll approximately 230 adults with FSHD. Investigators will randomize patients 1:1 to either losmapimod 15-mg tablet administered orally or placebo, for 48 weeks. Change from baseline RWS will represent the primary end point, along with other secondary end points such as MFI, Patients’ Global Impression of Change PGIC, and Quality of Life in Neurological Disorders of the upper extremity (Neuro-QoL-UE). Notably, the study will also include patient-centered assessments of healthcare utilization.

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REFERENCES
1. Wang L, Han J, Shoskes J, Jiang J, Tawi R. Results from 96 weeks open-label extension of a phase 2 trial of losmapimod in subjects with FSHD: ReDUX4. Presented at: MDA 2023; March 19-22; Dallas, TX. Abstract 120.
2. Tawil R, Statland J, Wang L, et al. A phase 2, randomized, double-blind, placebo-controlled, 48-week study of the efficacy and safety of losmapimod in subjects with FSHD:ReDUX4. Presented at: 2022 AAN Annual Meeting; April 2-7; Seattle, Washington. Abstract 2824
3. Fulcrum Therapeutics announces REACH, a phase 3 clinical trial of losmapimod in facioscapulohumeral muscular dystrophy (FSHD). News release. Fulcrum Therapeutics. March 3, 2022. Accessed March 22, 2023. https://www.biospace.com/article/releases/fulcrum-therapeutics-announces-reach-a-phase-3-clinical-trial-of-losmapimod-in-facioscapulohumeral-muscular-dystrophy-fshd-/