Primary objective is to evaluate the efficacy of losmapimod in inhibiting aberrant expression of DUX4, the root cause of FSHD. Secondary objectives are to evaluate safety, tolerability, pharmacokinetic (PK), and target engagement (TE) in blood and muscle.

FSHD is caused by aberrant expression of the transcription factor DUX4 in skeletal muscle. DUX4 activates a downstream transcriptional program resulting in skeletal muscle loss and disability. Losmapimod is a small molecule inhibitor of p38α/β. Pre-clinical studies demonstrated treatment with losmapimod resulted in dose-dependent reduction of DUX4 protein, DUX4 transcriptional program and skeletal muscle cell death in FSHD myotubes across all genotypes tested. Losmapimod has been studied across other adult indications resulting in over 3,500 human exposures with adequate safety and tolerability. 

Approximately 66 subjects age 18 to 65 with genetically confirmed FSHD1, clinical severity score of 2 to 4 (Ricci 0-5) and MRI identified muscle(s) for needle biopsy are being randomized 1:1 to receive 15 mg losmapimod (n=33) or placebo (n=33) PO BID for 24 weeks.  Subjects participate for approximately 29 weeks, including a 4-week screening period and 7-day safety follow-up period.  All participants undergo muscle biopsies pre-treatment and at Week 16 to measure treatment effects on DUX4 activity. PK and TE are measured in blood and muscle. Musculoskeletal MRIs will be performed at screening, Week 12, and Week 24 for assessment of change in musculoskeletal parameters. Clinical outcome assessments include reachable workspace (RWS), FSHD-timed up and go (FSHD-TUG), dynamometry, and motor function measure domain 1 (MFM). Patient reported outcomes are being assessed with FSHD-Health Index (FSHD-HI) and patient global impression of change (PGIC).