Fulcrum repurposes failed GSK drug for rare disease

GSK’s failed cardiovascular drug losmapimod looks like it might get a new lease of life after being picked up by biotech Fulcrum Therapeutics, who want to repurpose the drug to treat the rare genetic disease facioscapulohumeral muscular dystrophy (FSHD). Fulcrum had identified inhibitors of p38/ mitogen activated protein kinase (MAPK) as powerful inhibitors of DUX4 expression. DUX4 is the gene that is the root cause of FSHD, a progressive muscle wasting disorder. This insight into the DUX4 regulatory pathway led the team to review existing p38/ MAPK inhibitors and identify losmapimod as a compound with the potential to address the root cause of FSHD by decreasing DUX4 expression. GSK initially trialled losmapimod as a cardiovascular disease treatment, before shelving the drug after late-stage failures. The drug was never tested in muscular dystrophies, but Fulcrum notes that the 24 trials it went through proved the drug to have a robust safety profile. Meanwhile, the company has conducted preclinical testing of losmapimod in patient-derived cell models and observed “precise and potent” downregulation of DUX4 expression and restoration of a healthy muscle phenotype without an effect on myogenesis.