Losmapimod for facioscapulohumeral muscular dystrophy

Losmapimod showed improvement on relevant clinical endpoints in the treatment of facioscapulohumeral muscular dystrophy (FSHD) in the ReDUX4 trial. Its favourable safety and tolerability results support continued development.

FSHD is caused by the misexpression of the double homeobox protein 4 (DUX4) transcription factor in skeletal muscle. This condition ultimately results in progressive motor disability. Currently, no treatment options are available for FSHD that prevent or slow muscle weakness and wasting. Losmapimod is an orally active, selective, small molecule inhibitor of p38α/β that reduced DUX4. It has been evaluated in over 3,500 subjects in clinical trials across 10 other indications, with no safety signals. The efficacy and safety results of losmapimod from the phase 2 ReDUX4 trial were presented by Prof. Al-Rabi N. Tawil (University of Rochester, NY, USA) [1]. Enrolled were 80 FSHD participants aged 18–65 years (mean age 46 years) who were randomised 1:1 to losmapimod (15 mg twice daily) or matching placebo.

Losmapimod exhibited expected pharmacokinetic and target engagement in blood and muscle. No difference was observed in DUX4-driven gene expression in muscle biopsy, which was the study's primary endpoint (26.16 for losmapimod vs 25.68 for placebo; difference 0.43; 95% CI -1.04–1.89; P=0.56). At week 48, losmapimod did demonstrate significantly better muscle health. Muscle fat infiltration (MFI) was 0.03% versus 0.52% (difference -0.49; 95% CI -0.86 to -0.12; P=0.01). Significant improvements were also measured in Reachable Workspace (RWS) with weights, Patients' Global Impression of Change (PGIC), and dynamometry. There was a non-significant slowing of progression in Timed Up and Go (TUG) completion, and no differences in FSHD-TUG, motor function measurement (MFM), or FSHD-Health Index.

Losmapimod was well tolerated with no serious drug-related adverse events (AEs). Treatment-emergent AEs occurred in 29 (73%) and 23 (58%) patients in the experimental and placebo group, respectively. In both groups, most treatment-emergent AEs were mild or moderate and deemed unrelated to study drug. A phase 3 trial is in preparation.

1. Tawil R, 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. S23.007, AAN 2022, 02–07 April, Seattle, USA.

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Posted on 2 June 2022