Abstract Details

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

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S6 - Neuromuscular and Clinical Neurophysiology (EMG): Genetic Muscle Disorders (1:24 PM-1:36 PM)

Poster/Presentation
Number 003

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 C_max in blood of 36.6 (HV) and 40.9 ng/mL (FSHD) 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 to provide efficacy by reducing DUX4 activity. These results support advancing the 15 mg dose into Phase 2. Final data will be presented.

Authors/Disclosures
Michelle L. Mellion, MD PRESENTER	Dr. Mellion has received personal compensation for serving as an employee of PepGen. Dr. Mellion has stock in PepGen.
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Umesh A. Badrising, MD, PhD (Leiden University Medical Centre)	The institution of Dr. Badrising has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Abcuro. The institution of Dr. Badrising has received research support from Fulcrum. The institution of Dr. Badrising has received research support from Prinses Beatrix Spierfonds. The institution of Dr. Badrising has received research support from AFM. Dr. Badrising has received personal compensation in the range of $500-$4,999 for serving as a guideline development group member with Federation for Medical Specialists.
Shane Raines	Shane Raines has received personal compensation for serving as an employee of Praxis Precision Medicines. Shane Raines has received personal compensation for serving as an employee of 2b Analytics.
	No disclosure on file
Baziel G. van Engelen, MD, PhD, MA (Radboud University Nijmegen Medical Centre)	The institution of Dr. van Engelen has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fulcrum . The institution of Dr. van Engelen has received research support from Stichting Spieren voor Spieren. The institution of Dr. van Engelen has received research support from Prinses Beatrix Fonds. The institution of Dr. van Engelen has received research support from Dutch FSHD society. Dr. van Engelen has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
Diego Cadavid, MD, FAAN (Verge Genomics)	Dr. Cadavid has received personal compensation for serving as an employee of Verge Genomics. Dr. Cadavid has received personal compensation for serving as an employee of X4 Pharmaceuticals. Dr. Cadavid has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Pheno Therapeutics. Dr. Cadavid has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk. Dr. Cadavid has stock in Verge Genomics.

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