The investigational oral treatment losmapimod is able to suppress the toxic activity of the DUX4 gene, the root cause of muscle degeneration in facioscapulohumeral muscular dystrophy (FSHD), new research in patient-derived cells and in a mouse model suggests.
This supports a way forward in developing the first treatment for FSHD. Based on the promising results, losmapimod has recently advanced to a Phase 2b clinical trial (NCT04003974) to assess its safety and efficacy in adults with this type of muscular dystrophy.
The Fulcrum Therapeutics-sponsored trial, called ReDUX4, is recruiting participants ages 18-65 at clinical sites in the United States, with other locations in Canada and the European Union yet to open. The study will assess the treatment’s effectiveness and safety in an expected 66 participants over 24 weeks. More information is available here. Top-line results are expected in the second half of 2020.
The research findings were detailed in “Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy,” a study published in the Journal of Pharmacology and Experimental Therapeutics.
Normally, DUX4 is turned off in skeletal muscles. But in patients with FSHD, the gene is abnormally reactivated due to the mutations. This leads to production of the double homeobox 4 (DUX4) protein, thought to adversely impact the activity of other genes in muscle cells. This results in cell death and muscle degeneration that ultimately affects all muscles used for voluntary movement.
Scientists have been working on ways of preventing activation of the gene to halt or reverse the disease.
A team led by Francis M. Sverdrup, PhD, professor at Saint Louis University, has been testing small-molecule inhibitors of DUX4 and found that targeting one set of enzymes called p38 mitogen-activated protein kinases (MAPK) could work. These enzymes are typically involved in the cellular response to inflammatory stimuli.
Results revealed that losmapimod, a p38 MAPK blocker, suppressed the generation of RNA from DUX4 (its expression) in patient-derived muscle cells and animal models.
In mice transplanted with muscle-forming cells from a FSHD patient, losmapimod led to dose-dependent inactivation of DUX4 and its target genes.
Importantly, 14-day treatment with the experimental therapy blocked DUX4 without affecting muscle regeneration, specifically the ability of muscle progenitor cells (myoblasts) to proliferate and mature.
This is a “desirable characteristic of a drug intended for degenerative muscular dystrophy,” the researchers said.
“We have been working to find a safe drug that would ‘turn off’ the toxic gene that causes FSHD,” Sverdrup said in a press release.
“Now we have demonstrated that we can do this in an animal model with a drug that can be taken in pill form,” he said.
Sverdrup, who was motivated to find a treatment for FSHD after his own daughter was diagnosed with the disease, said he was encouraged by these findings.
Losmapimod inhibits p38 alpha and p38 beta, two p38 isoforms, or variants, important for the activity of DUX4. In vitro, or in the lab experiments revealed that individual suppression of either isoform equally inhibited gene activity.
“These studies uncover the exciting possibility of a disease-modifying treatment for FSHD by targeting the root cause of disease through p38 MAPK inhibition,” the team added.
Further lines of research could explore selective blockers of p38 beta, which appears to be dispensable for muscle differentiation. This could provide a better balance between efficacy and safety, the investigators said.