CAMBRIDGE, Mass.—Fulcrum Therapeutics Inc., a biopharmaceutical company focused on genetically defined rare diseases, is seeking to break new ground with losmapimod in facioscapulohumeral muscular dystrophy (FSHD), a rare form of muscular dystrophy. Losmapimod is a selective p38α/β mitogen activated protein kinase (MAPK) inhibitor.
Fulcrum has two trials underway for the compound at present, both of which were initiated late in 2019. ReDUX4 is a Phase 2b clinical trial meant to assess the safety and efficacy of losmapimod in addressing the underlying cause of FSHD. ReDUX4 is a randomized, double-blind, placebo-controlled, 24-week study to evaluate losmapimod’s ability to reduce DUX4-driven gene expression as measured by a subset of DUX4-regulated gene transcripts in skeletal muscle biopsies. In conjunction with ReDUX4, Fulcrum also launched a 52-week open-label study.
In October, the company reported preliminary results from Phase 1 clinical trial of losmapimod in FSHD, which were also presented at the 24th International Annual Congress of the World Muscle Society. The trial sought to determine losmapimod’s safety and efficacy in healthy volunteers as well as FSHD patients, in addition to determining repeated dose pharmacokinetics and target engagement in FSHD patients. The drug candidate demonstrated similar tolerability, safety and pharmacokinetics in both healthy participants and FSHD patients, with dose-dependent pharmacokinetics and target engagement in blood.
In FSHD patients, losmapimod dosing led to dose-dependent concentrations in skeletal muscle, and an oral 15 mg dose taken twice a day resulted in sustained drug concentrations that led to a significant reduction of DUX4-driven gene expression in preclinical models of human FSHD myotubes (muscle fibers).
It’s encouraging progress for a drug that failed its first indication. Fulcrum in-licensed losmapimod from GlaxosmithKline after the compound fell short in acute coronary syndrome.
“Losmapimod has previously been shown to have adequate safety and tolerability in over 3,500 patients and healthy volunteers across multiple indications, with no safety signals attributed to the drug in those trials. Until now, losmapimod had not been tested in patients with FSHD, nor was it known if it was muscle-penetrant in humans,” Dr. Michelle Mellion, medical director at Fulcrum Therapeutics, commented in a press release. “The preliminary results from our Phase 1 clinical trial of losmapimod in patients with FSHD indicate that losmapimod was generally well tolerated and achieved dose-dependent concentrations in plasma and muscle believed to be adequate for efficacy based on preclinical pharmacology studies.”
Mis-expression of DUX4 has been found to be the key to FSHD. While this gene is usually only expressed in embryonic development and then silenced, in FSHD it remains active and overexpressed, which results in muscle tissue degenerating and being replaced by fat. This progressive disease leads to a loss of skeletal muscle, which results in increasing physical disability.
Dr. Peter Jones—who is the Mick Hitchcock, Ph.D. Endowed Chair in Medical Biochemistry and an associate professor of pharmacology at University of Nevada, Reno School of Medicine—is a leading researcher into genetics and epigenetics related to muscle development and disease. In a report on FSHD and the role of DUX4 in the disease, Jones explained that FSHD is the result of genetic alterations at Chr 4q35. Specifically, deletions at Chr 4q result in FSHD1, while mutations at Chr 18p result in FSHD2. Regardless of the form, however, epigenetic dysregulation is common across all forms of the disease.
As noted in the presentation, “DUX4 encodes an early developmentally active transcription factor that is silent in healthy somatic cells,” and as a result, “DUX4 expression is aberrantly increased in FSHD skeletal muscle.” While most muscle diseases are the result of a loss-of-function mutation, FSHD is a gain-of-function disease. When DUX4 expression was modulated in experiments, they found that dose-dependent increases in DUX4 expression in skeletal muscle resulted in decreased muscle function and strength, and an increase in muscle histopathology.
“This is a devastating, progressive disease and unfortunately one where there are no drugs currently approved, and there are no industry-sponsored programs in the clinic, so it’s an area where there’s just tremendous unmet need for patients,” says Bryan Stuart, chief operating officer at Fulcrum. He tells DDNews that the trials for losmapimod are advancing “right on schedule,” and the company anticipates presenting top-line data in the third quarter of the year.
FSHD isn’t the only muscle disease that Fulcrum is looking into, however. The company has discovery-stage programs underway to identify and validate targets in several other diseases, including Duchenne muscular dystrophy, Friedreich ataxia, myotonic dystrophy 1 and α-Synucleinopathies.