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.