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


Clinical Trials

Poster Number: 90


Joost Kools, MD, Radboud University Medical Centre (Radboudumc), Nijmegen, NL, Nicol Voermans, MD, Radboud University Medical Centre (Radboudumc), Nijmegen, NL, Karlien Mul, MD, Radboud University, Lucienne Ronco, PhD, Fulcrum Therapeutics, Inc., John Jiang, PhD, Fulcrum Therapeutics, Inc., Jennifer Shoskes, PharmD, Fulcrum Therapeutics, Inc., Kelly Marshall, Fulcrum Therapeutics, Inc., Diego Cadavid, MD, Fulcrum Therapeutics, Inc., Michelle L Mellion, MD, Fulcrum Therapeutics, Inc., Baziel van Engelen, MD, PhD, Radboud University Medical Centre (Radboudumc), Nijmegen, NL

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

Background: FSHD is caused by aberrant expression of DUX4. Losmapimod is an orally active, selective, small molecule inhibitor of p38?/?. Preclinical studies demonstrated that losmapimod reduces DUX4 in differentiating FSHD myotubes across multiple genotypes.

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.