Abstract Details

Title An Open-Label Study of Losmapimod to Evaluate the Safety, Tolerability, and Biomarker and Clinical Outcome Assessment Changes in Subjects with FSHD1

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S23 - Therapeutics for Muscle Diseases (4:54 PM-5:06 PM)

Poster/Presentation
Number 008

Background FSHD is caused by aberrant expression of DUX4. Losmapimod is an orally active, selective, small molecule inhibitor of p38α/β. Preclinical studies demonstrated that losmapimod reduces DUX4 in differentiating FSHD myotubes across multiple genotypes

Objective Evaluate long-term safety and efficacy of losmapimod for the treatment of FSHD.

Design/Methods Subjects age 18 to 65 years with genetically confirmed FSHD1, clinical severity score of 2 to 4 (range 0-5) and MRI-eligible skeletal muscles for needle biopsy received 15 mg twice daily losmapimod for 52 weeks. Primary endpoint was safety. Efficacy was assessed by DUX4-driven gene expression in muscle biopsy. Quantitative WB-MSK-MRI assessed muscle health. Clinical assessments included RWS, TUG, FSHD-TUG, dynamometry, MFM, 6-MWT and PROs (PGIC, FSHD-HI, FSHD-RODS).

Results Fourteen subjects, mean age 45.7 (+/- 11.61) years, Ricci score 3.5 were enrolled. Losmapimod was well tolerated with no serious drug-related adverse events. Change from baseline in DUX4 driven gene expression was not observed. No or minimal changes were observed on quantitative MRI assessment of muscles that were not end-stage. RWS demonstrated improvements in RSA with and without weights bilaterally; range 0.03-0.04; with annualized rate of change (%) range 3.28 to 5.68. Evaluation of the RSA by domain, demonstrated either no progression from baseline or improvements, particularly in quadrants 1 and 3 (above shoulder), and 5 (posterior). Dynamometry assessment showed stability or improvements from baseline, in the bilateral strength of shoulder abductors, ankle dorsiflexors, and hand grip. On PGIC, over 80% of subjects reported improvement or no change after 56 weeks of treatment; no patients reported feeling much worse over 56 weeks. Minimal changes were observed in TUG, FSHD-TUG, MFM, and 6-MWT.

Conclusions

This study supports benefit of treatment with losmapimod on structural and FSHD relevant clinical endpoints that is recognized by subjects, and favorable safety and tolerability supporting continued development.

Authors/Disclosures
PRESENTER	No disclosure on file
Joost Kools, MD (Radboudumc)	The institution of Mr. Kools has received research support from Fulcrum Therapeutics.
	No disclosure on file
Karlien Mul	The institution of Karlien Mul has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avidity Biosciences.
	No disclosure on file
John Jiang	No disclosure on file
	No disclosure on file
Diego Cadavid, MD, FAAN (Verge Genomics)	Dr. Cadavid has received personal compensation for serving as an employee of X4 Pharma. Dr. Cadavid has received personal compensation for serving as an employee of Fulcrum Therapeutics. Dr. Cadavid has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arvinas. Dr. Cadavid has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abata Therapeutics. Dr. Cadavid has received stock or an ownership interest from X4 Pharma. Dr. Cadavid has received stock or an ownership interest from Fulcrum Therapeutics.
Michelle L. Mellion, MD	Dr. Mellion has received personal compensation for serving as an employee of PepGen. Dr. Mellion has stock in PepGen.
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 $10,000-$49,999 for serving as a Consultant for Facio. 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.