Aims: Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD).Methods: This study included Part A:... Show moreAims: Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD).Methods: This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7.5 mg (n = 6) or 15 mg (n = 6); and Part C: FSHD subjects received open-label losmapimod 15 mg (n = 5) twice daily for 14 days. Biopsies were performed in FSHD subjects at baseline and Day 14 in magnetic resonance imaging-normal appearing (Part B) and affected muscle identified by abnormal short-tau inversion recovery sequence + (Part C). PK and TE, based on pHSP27:total HSP27, were assessed in muscle and sorbitol-stimulated blood.Results: PK profiles were similar between healthy volunteers and FSHD subjects, with mean C-max and AUC(0-12) for 15 mg in FSHD subjects (Part B) of 85.0 +/- 16.7 ng*h/mL and 410 +/- 50.3 ng*h/mL, respectively. Part B and Part C PK results were similar, and 7.5 mg results were approximately dose proportional to 15 mg results. Dose-dependent concentrations in muscle (42.1 +/- 10.5 ng/g [7.5 mg] to 97.2 +/- 22.4 ng/g [15 mg]) were observed, with plasma-to-muscle ratio from similar to 0.67 to similar to 1 at estimated t(max) of 3.5 hours postdose. TE was observed in blood and muscle. Adverse events (AEs) were mild and self-limited.Conclusion: Losmapimod was well tolerated, with no serious AEs. Dose-dependent PK and TE were observed. This study supports advancing losmapimod into Phase 2 trials in FSHD. Show less
