Fulcrum Therapeutics Publishes Phase 2b Losmapimod Trial Results in FSHD in The Lancet Neurology

Fulcrum Therapeutics, Inc. has announced significant findings from its Phase 2b clinical trial of losmapimod for treating facioscapulohumeral muscular dystrophy (FSHD). These results have been published in The Lancet Neurology, emphasizing the potential of losmapimod in addressing this debilitating disease.

FSHD is a progressive and rare condition marked by fat infiltration in skeletal muscles, leading to muscular atrophy. This atrophy primarily affects the face, shoulder girdle, upper arms, abdomen, and lower limbs. The disease is driven by the abnormal expression of the DUX4 protein and results in increasing muscle weakness and functional impairments. Currently, there are no approved treatments that modify the disease’s progression.

Dr. Patrick Horn, Fulcrum’s Chief Medical Officer, highlighted the importance of these findings. He stated that these results have not only shaped the design and efficacy endpoints of the ongoing Phase 3 clinical trial but also validated losmapimod's therapeutic potential. He emphasized their commitment to the FSHD patient community and expressed optimism about advancing towards a potential New Drug Application (NDA) filing and commercial launch for losmapimod.

Although the primary endpoint, which involved evaluating changes in DUX4-driven gene expression in muscle biopsies, showed no significant difference between the treatment and placebo groups, other key outcomes were positive. Losmapimod demonstrated improvements in structural and functional results, such as reduced muscle fat infiltration and enhanced shoulder girdle function. Additionally, patients reported a global impression of change favoring losmapimod over placebo. The drug was well tolerated throughout the trial, with no serious adverse events leading to discontinuation.

In September 2023, Fulcrum achieved full enrollment for the Phase 3 clinical trial of losmapimod in FSHD patients across the United States, Canada, and Europe. This Phase 3 study remains on track, with topline data expected in the fourth quarter of 2024.

The ReDUX4 Phase 2b clinical trial, which enrolled 80 participants aged 18 to 65 with FSHD type 1, was pivotal. These participants were randomly assigned to receive either losmapimod or a placebo, administered orally at a dose of 15 mg twice daily for 48 weeks.

Losmapimod is a selective inhibitor of the p38α/β mitogen-activated protein kinase (MAPK). Fulcrum exclusively in-licensed losmapimod from GSK after identifying the role of p38α/β inhibitors in reducing DUX4 aberrant expression. Phase 2b trial results indicate that losmapimod could potentially slow disease progression and improve upper extremity function, making it a promising therapy for FSHD. While losmapimod had not been previously tested in muscular dystrophies, it has been evaluated in over 3,600 subjects across various other indications without any significant safety issues. The drug has received Fast Track designation and Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of FSHD.

FSHD affects an estimated 30,000 people in the United States. It progressively impairs patients' ability to perform daily activities due to loss of upper limb function, mobility, independence, and chronic pain, making it one of the most common forms of muscular dystrophy.

Fulcrum Therapeutics is dedicated to developing treatments for rare, genetically defined diseases with high unmet needs. Their leading programs include losmapimod for FSHD and pociredir for sickle cell disease (SCD) and other hemoglobinopathies. Using their proprietary FulcrumSeek™ platform, they aim to identify drug targets that modulate gene expression to treat the underlying causes of gene mis-expression.