Pestronk, Alan

Background: Losmapimod is an orally administered small molecule and selective p38α/β mitogen-activated protein kinase (MAPK) inhibitor able to reduce aberrant expression of DUX4 in vitro and thereby potentially slowing disease progression in patients with facioscapulohumeral muscular dystrophy (FSHD). Objective: This global, randomized, placebo-controlled, double-blind phase 3 study in patients with FSHD1 and FSHD2 examined the efficacy and safety of losmapimod over a 48-week treatment period compared to placebo (NCT05397470, EUDRACT 2022-000389-16). Methods: The primary endpoint was change in quantification of reachable workspace (RWS) expressed as relative surface area (RSA). Other endpoints included measures of muscle composition (fat content and lean muscle) using magnetic resonance imaging (MRI), muscle strength using quantitative dynamometry, and quality of life measures. Results: 130 participants received losmapimod and 130 participants received placebo, with 252 participants completing the 48-week treatment period. There were no statistically significant differences between groups in change in RSA and all secondary efficacy endpoints from baseline to Week 48. Losmapimod treatment was well-tolerated, and most adverse events were mild. Conclusions: Losmapimod was generally well tolerated with a favorable safety profile at a dose of 15 mg twice daily. Although none of the efficacy endpoints were met, study design and data from the study may inform future studies of FSHD therapies.