Objective:

Evaluate the safety and tolerability of losmapimod in the treatment for FSHD.

Background:

FSHD is a relentless, variably progressive disease leading to accumulation of disability over decades. Fulcrum has assessed losmapimod, a small molecule p38 α/β MAPK inhibitor, in FSHD in one completed Phase 1 study (FIS-001-2018) and two ongoing Phase 2 studies in the open-label extension period (FIS-001-2019 and FIS 002-2019).

Design/Methods:

Subjects aged 18-65 years with genetically confirmed FSHD1, Clinical Severity Score 2-4, and MRI-eligible muscles for biopsy were exposed to losmapimod 7.5 or 15 mg BID PO for 14 days and up to 76 weeks. In study FIS 001-2018, 6 subjects were exposed to 7.5 mg and 11 subjects to 15 mg twice daily dosing for 14 consecutive days. In studies FIS-001-2019 and FIS-002-2019, 14 and 77 subjects respectively, received at least one dose of losmapimod 15 mg twice daily for up to 76 weeks.

Results:

A total of 108 subjects with FSHD1 have been exposed to losmapimod, with ~131 patient-years of exposure. Fifty-seven subjects were exposed to losmapimod for 12 to 18 months, and 30 were exposed for over 18 months. Most adverse events (AEs) observed during the studies were considered mild to moderate in severity. Most common AEs were alanine aminotransferase increase, headache, dizziness, dry skin, eczema and gastrointestinal disorders. The majority of AEs resolved with continued dosing. Dosing has been paused for 14 days in four subjects (3 in FIS 001-2019 and 1 in FIS-002-2019) subjects due to COVID-19 infection. No drug-related SAEs, deaths, discontinuations due to AEs, or clinically significant changes in vital signs, clinical laboratory results, or ECG parameters were reported.

Conclusions:

Losmapimod administered up to 15 mg BID in >100 subjects with FSHD1 for up to 76 weeks has been generally well-tolerated; the benefit-risk profile of losmapimod for the treatment of FSHD remains favorable.