Objective: Investigate safety, tolerability, pharmacokinetics (PK), and target engagement (TE) of losmapimod in healthy volunteers (HV) and FSHD1 patients.
Background: FSHD is caused by the aberrant expression of the homeobox transcription factor DUX4 in skeletal muscle. DUX4 activates a transcriptional program resulting in muscle loss and disability. Losmapimod is a selective small molecule inhibitor of p38α/β being developed to reduce DUX4 expression, the root cause of FSHD.
Design/Methods: This was a three-part study. Part A: 10 HV randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n=8) or placebo (both dosing periods; n=2). Part B: Parallel-group study of losmapimod15 FSHD1 patients randomized to placebo (n=3), losmapimod 7.5 mg (n=6) or 15 mg (n=6) twice daily for 14 days. Part C: Open-label losmapimod 15 mg (n=5) twice daily for 14 days. Muscle biopsies were performed at baseline and during treatment, targeting MRI normal appearing (Part B) and STIR + (Part C) muscle tissue. PK and TE, measured by phosphorylated and total HSP27, were assessed in blood and muscle.
Results: Preliminary blinded analysis showed that adverse events (AE) were mild and self-limited. PK profiles were similar between HV and FSHD patients: mean Cmax in blood of 36.6 (HV) and 40.9 ng/mL (FSHD1) for 7.5 mg, and 74.6 ng/mL (HV) and 85.0 ng/mL (FSHD1) for 15 mg. Dose-dependent concentrations in muscle (42.1 and 63.6 ng/g) were observed, with a plasma to muscle ratio of approximately 1:1. Dose-dependent TE was observed in blood with robust and sustained target engagement at 15 mg.
Conclusions: Losmapimod was well tolerated with no SAEs reported and achieved dose-dependent exposure in plasma and muscle at concentrations predicted by pre-clinical models demonstrating efficacy by reducing DUX4 activity. These results support advancing the 15 mg dose into Phase 2. Final data will be presented.