After showing several significant differences between placebo, the company has planned a phase 3 study that will assess the therapeutic in a cohort of 230 adults with FSHD.
Results from the phase 2b ReDUX4 trial (NCT04003974) showed statistically significant slowing of muscle function deterioration in patients with facioscapulohumeral muscular dystrophy (FSHD) with treatment of losmapimod (Fulcrum Therapeutics), despite no changes in DUX4, the biomarker related to the cause of the disease.1
After 48 weeks of treatment, patients on the study drug demonstrated significant differences whole-body MSK-MRI muscle fat infiltration (MFI) (0.03% vs 0.52%; difference, –0.49; 95% CI, –0.86 to –0.12; P = .01) relative to those on placebo. Losmapimod, an investigational agent that selectively inhibits enzymes p38a/ß mitogen-activated protein kinases (MAPKs), which are modulators of DUX4 expression and mediators of inflammation, is also currently being evaluated in a phase 3 study, announced in March 2022.2
Presented at the 2022 American Academy of Neurology (AAN) Annual Meeting, April 2-7, in Seattle Washington, the study included 80 individuals, aged 18-65 years with FSHD1 who were randomized 1:1 to either losmapimod 15-mg BID or placebo for 48 weeks. The cohort had a mean age of 45.7 years (±12.7), with an overall Ricci score of 3.2.
Reduction in DUX4-driven gene expression, the primary end point, showed no differences between losmapimod (26.16) and placebo (25.68; difference, 0.43; 95% CI, –1.04 to 1.89; P = .56) on log2 scale. DUX4, a key biomarker of FSHD, activates a downstream transcriptional program that causes myofiber death, with maladaptive tissue remodeling characterized by replacement of muscle with fat ultimately resulting in progressive motor disability.
At the end of the 48-week treatment period, those on active drug did however see significant improvements in Reachable Workspace with weights and dynamometry. Additionally, relative to placebo, these patients had significant improvements on Patients’ Global Impression of Change (PGIC) scale (difference, –0.58; Likert scale, P = .02).
Consistent with losmapimod’s safety and tolerability profiles outside of FSHD, there were no serious treatment-related adverse events observed in the phase 2b trial. Investigators observed a nonsignificant slowing of progression in Timed Up & Go (TUG) time (0.16 vs 0.74 seconds; difference, –0.58), and no differences in FSHD-TUG, Motor Function Measurement, or FSHD-HI.
There are currently no FDA-approved therapies for FSHD. When the company announced its phase 3 trial, REACH, Judith A. Dunn, PhD, president of research and development, said in a statement, "We learned from our phase 2b trial that RWS, MFI and patient-reported outcomes are reliable measures of disease progression and that we can observe meaningful differences in these endpoints compared to placebo after just 48 weeks of treatment with losmapimod. REACH is optimized to demonstrate similar statistically and clinically significant benefits and represents an important step in delivering a life-changing therapy to people with FSHD."2
REACH, a double-blind, multi-national, placebo-controlled trial is expected to enroll approximately 230 adults with FSHD. Investigators will randomize patients 1:1 to either losmapimod 15-mg tablet administered orally or placebo, for 48 weeks. Change from baseline RWS will represent the primary end point, along with other secondary end points such as MFI, PGIC, and Quality of Life in Neurological Disorders of the upper extremity (Neuro-QoL-UE). Notably, the study will also include patient-centered assessments of healthcare utilization.
"For people with FSHD, every day without a treatment is another day that they may lose strength, the ability to lift their arms, or walk unassisted. Losmapimod is the first and only investigational medicine in clinical development," Nicholas Johnson, MD, MSc, FAAN, associate professor, division chief of neuromuscular, and vice chair of research, department of neurology, Virginia Commonwealth University said following the announcement. "The data to date are very promising, showing meaningful clinical benefit and a well-established safety and tolerability profile. I look forward to further investigating losmapimod in the REACH trial."2
1. Tawil R, Statland J, Wang L, et al. A phase 2, randomized, double-blind, placebo-controlled, 48-week study of the efficacy and safety of losmapimod in subjects with FSHD:ReDUX4. Presented at: 2022 AAN Annual Meeting; April 2-7; Seattle, Washington. Abstract 2824
2. Fulcrum Therapeutics announces REACH, a phase 3 clinical trial of losmapimod in facioscapulohumeral muscular dystrophy (FSHD). News release. Fulcrum Therapeutics. March 3, 2022. Accessed April 8, 2022. https://www.biospace.com/article/releases/fulcrum-therapeutics-announces-reach-a-phase-3-clinical-trial-of-losmapimod-in-facioscapulohumeral-muscular-dystrophy-fshd-/