Fulcrum Therapeutics, a Massachusetts-based biotechnology company, identified p38α/β MAPK inhibitors as potent suppressors of DUX4 expression, the de-suppression of which is theorized to cause FSHD. Among p38α/β MAPK inhibitors, Fulcrum chose losmapimod as its preferred developmental candidate due to its "substantial and attractive preclinical and clinical data" from previous GlaxoSmithKlineclinical trials. As Fulcrum discovered the potential utility of p38 MAPK inhibition in treating FSHD, a Saint Louis Universityresearch group independently arrived at the same conclusion. The SLU research group found that p38α and p38β isoforms independently contribute to DUX4 expression, which indicates potential gain in exploring isoform specific inhibition to balance therapeutic effects with side effects. A theoretical limitation of losmapimod is that p38 kinase inhibition could impair myogenesis, the opposite effect of what is desired. Facio Therapies, a Dutch pharmaceutical company with their own drug candidate for FSHD, announced that they had eliminated p38 kinase inhibitors as a developmental candidate because p38 kinase inhibitors resulted in impaired myotube formation on their drug development platform. Indeed, others have found that p38α abrogation impairs myotube formation. However, Fulcrum found that p38 kinase inhibition did not impair myotube fusion at levels sufficient for DUX4 reduction.
Fulcrum development timeline
April 2019: Fulcrum acquired from GSK the global rights to losmapimod.
October 2019: Fulcrum announced preliminary results of their phase 1 clinical trial of losmapimod. Oral dosing of losmapimod demonstrated sustained muscle tissue drug concentrations that in preclinical in vitro studies had shown effective in reducing DUX4 levels.
As of November 2019: Fulcrum is conducting two clinical trials of losmapimod for treatment of FSHD. One trial, ReDUX4, is evaluating drug efficacy in a randomized controlled phase IIb clinical trial with an estimated study completion date of August 2020. The second is a phase II open-label clinical trial in the Netherlands, with an estimated study completion date of January 2021.
January 2020: Fulcrum announced receiving orphan drug status for losmapimod.
June 2020, Fulcrum announced applying to the FDA to initiate a phase III clinical trial for losmapimod in treatment of COVID-19. Recent evidence indicates that p38 MAPK inhibition could be therapeutic, possibly by attenuating the exaggerated inflammatory response following SARS-CoV-2 infection.
Historical Investigations
Losmapimod was discovered and unsuccessfully developed by GSK for treating multiple medical conditions. Despite failing to prove efficacy, GSK clinical trials showed that losmapimod is generally well tolerated across more than 3,500 subjects. GSK investigated losmapimod as a therapeutic for patients post-myocardial infarction. Despite phase II clinical trials the phase IIIA clinical trial failed to show significantly improved clinical outcomes. In October 2015 GSK announced cancelling the planned phase IIIB trial, but would "evaluate all options for future development." GSK investigated losmapimod as a therapeutic for COPD, but multiple phase II clinical trials failed to show that losmapimod improves exercise tolerance, lung function, arterial inflammation, endothelial function, or rate of COPD exacerbations in subjects with COPD. GSK terminated development of losmapimod for COPD in 2016. GSK investigated losmapimod as a therapeutic for major depressive disorder on the basis of depression being correlated with elevated pro-inflammatory cytokines. Phase II clinical trials failed to show a significant improvement in depression symptoms and biomarkers.
