Phase 1 Clinical Trial of Losmapimod in Facioscapulohumeral Muscular Dystrophy (FSHD): Safety, Tolerability and Target Engagement

Clinical Trials
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Michelle Mellion, MD, Lucienne Ronco, PhD, Drew Thompson, Michelle Hage, Sander Brooks, Emilie van Brummelen, Lisa Pagan, Umesh Badrising, Shane Raines, PhD, William Tracewell, Baziel van Engelen, MD, Geert Jan Groeneveld, Diego Cadavid, MD
1. Fulcrum Therapeutics, 2. Fulcrum Therapeutics, 3. Fulcrum Therapeutics, 4. Fulcrum Therapeutics, 5. CHDR, 12. Centre for Human Drug Research CHDR-Leiden, 13. Fulcrum Therapeutics

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.