Facioscapulohumeral muscular dystrophy (FSHD) is the second-most prevalent muscular dystrophy in the world, with onset typically occurring during adolescence. This genetic condition currently has no disease-modifying treatment, with supportive care being the main part of treatment. Christopher Morabito, MD, Fulcrum Therapeutics, Cambridge, MA, explains the symptoms of FSHD, along with the underlying biological and genetic mechanisms. Abberant expression of the DUX4 gene is thought to play a key role in the muscular dystrophy. P38 MAP kinase (MAPK) is upstream of DUX4, and Dr Morabito explains the rationale behind investigating the p38 MAPK inhibitor losmapimod as a possible treatment for FSHD. A recent Phase II trial of losmapimod over a period of 48 weeks had a primary endpoint of changes in DUX4-driven gene expression, among other endpoints which included assessments of muscle fat infiltration using whole body MRI, upper body mobility, and patient-reported outcomes (PROs). There was found to be no change in DUX4-driven gene expression in the placebo or experimental arm, but there were significant differences in functional outcomes (such as muscle fat infiltration, upper body mobility, and PROs). However, Dr Morabito hypothesises that the unexpectedly large variability in DUX4-driven gene expression among the 80 enrolled patients at baseline, could have had a large impact on the statistical analysis. Dr Morabito also discusses the next steps for the investigation of losmapimod for FSHD, including the Phase III REACH trial (NCT05397470) which is currently recruiting. This interview took place at the American Academy of Neurology 2022 Congress in Seattle, WA.
Dr Morabito is a full time employee of Fulcrum Therapeutics.