Fulcrum's losmapimod fails interim analysis in muscle wasting trial 

Fulcrum Therapeutics’ losmapimod has performed no better than placebo in an interim analysis of data from a phase 2 clinical trial in patients with facioscapulohumeral muscular dystrophy (FSHD). Despite the setback, Fulcrum hailed the data as “very encouraging,” zeroing in on results from a pre-specified sensitivity analysis to make its case for an upbeat reading of the interim analysis.

Losmapimod is a p38α/β mitogen activated protein kinase inhibitor that Fulcrum picked up from GlaxoSmithKline last year. GSK developed the drug in cardiovascular disease, without success, but Fulcrum’s analysis of the pathogenesis of progressive muscle wasting disorder FSHD led it to spy a different application for the molecule. Fulcrum committed to pay up to $37.5 million in clinical and regulatory milestones for the asset in the belief it may block expression of DUX4.

The phase 2 trial is the first big clinical test of that hypothesis. So far, losmapimod is coming up short. After 16 weeks, subjects who received losmapimod twice daily experienced a 3.7-fold rise in DUX4 expression as measured in skeletal muscle biopsies, compared to a 2.8-fold increase in the placebo arm. Numerically, placebo performed better than losmapimod.

That headline finding of the interim analysis of the primary endpoint data sent shares in Fulcrum down 29% at points in premarket trading. Fulcrum CEO Robert Gould took a different view than investors, pointing to the results in a subgroup of eight subjects with the highest baseline levels of DUX4 expression to make his case.

In that subgroup analysis, the three patients on losmapimod experienced a 38-fold decrease in DUX4 expression, compared to a 5.4-fold decline in the five subjects on placebo. Fulcrum said the results indicate “muscle biopsies within the higher levels of DUX4-driven gene expression may be needed to observe a reduction from baseline.”

Fulcrum will need more data to validate that hypothesis. Work to gather the data is underway. The phase 2 enrolled 80 subjects and was due to evaluate DUX4 activity in all of them at 16 weeks. That plan changed when COVID-19 prevented researchers from taking muscle biopsies, leading Fulcrum to extend the study and take samples from some people at 36 weeks. In changing the protocol, Fulcrum chose to use biopsies already taken at 16 weeks for an interim analysis.

Topline primary endpoint results from the other subjects are due in the first quarter of next year. Fulcrum plans to follow up with a fuller dataset featuring secondary and exploratory endpoint results in the second quarter.

Those other endpoints may provide a clearer picture of whether losmapimod is improving the lives of FSHD patients, rather than just acting on a biomarker. The full list of outcomes evaluated in the phase 2 include muscle strength, motor function and quality of life.