The phase 3 REACH trial investigating Fulcrum Therapeutics’ losmapimod in patients with facioscapulohumeral muscular dystrophy remains on track with topline data anticipated in the fourth quarter of 2024.
Patrick Horn MD, PhD
(Credit: Fulcrum)
Although losmapimod (Fulcrum Therapeutics) did not meet its primary end point in the phase 2b ReDUX4 trial (NCT04003974), findings showed improvements in structural and functional outcomes in patients with facioscapulohumeral muscular dystrophy (FSHD) treated with the investigational agent. These results, newly published in The Lancet Neurology, informed the design and choice of efficacy end points of the ongoing phase 3 REACH study (NCT05397470) assessing losmapimod in adults with FSHD.1,2
Among 80 patients in the trial (losmapimod, n = 40; placebo, n = 40; men, n = 54; women n = 26; White, n = 70; mean age, 45.7 [SD, 12.5]), investigators noted no change from baseline in the primary end point of DUX4 activity in either the placebo (least squares [LS] mean, 0.40; SE, 0.65) or the losmapimod (LS mean, 0.83; SE, 0.61) groups, with no significant difference observed between the groups (0.43; SE, 0.56; 95%, CI –1.04 to 1.89; P = .56). Notably, authors also observed no significant differences between losmapimod and placebo of the primary end point in the prespecified subgroup analyses.
“The publication of these results, which informed the design and choice of efficacy endpoints in our phase 3 clinical trial, also provide important validation for the therapeutic potential of losmapimod," Patrick Horn MD, PhD, chief medical officer at Fulcrum, said in a statement.2 "Looking ahead, we remain on track to report topline data for REACH in the fourth quarter of 2024, which will bring us one step closer to addressing the high unmet needs of the FSHD patient community. With an unwavering commitment to our patients, we continue to take important steps toward a potential NDA filing and commercial launch for losmapimod.”
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ReDUX4 is a randomized, double-blind, placebo-controlled phase 2b trial performed at 17 neurology centers in Canada, France, Spain, and the United States between Aug 27, 2019, and Feb 27, 2020. The trial included adults aged between 18 and 65 years with type 1 FSHD, who had a Ricci clinical severity score between 2 and 4 and had at least 1 skeletal muscle judged using MRI to be suitable for biopsy. Investigators randomized participants 1:1 to either oral losmapimod 15 mg twice a day or a matching placebo for 48 weeks through an interactive response technology system. The primary end point, measured by quantitative RT-PCR, was the change from baseline to either week 16 or 36 in DUX4-driven gene expression in skeletal muscle biopsy samples and secondary end points included safety and tolerability.
"Losmapimod is an oral small molecule with rapid distribution in skeletal muscle. It inhibits p38 MAP kinase, a regulator of DUX4 expression whose aberrant activation causes FSHD," the Fulcrum team told NeurologyLive®. "The ReDUX4 trial has provided important evidence supporting reachable workspace (RWS) as a sensitive functional outcome measure to assess the loss of upper extremity function in FSHD as well as the use of MRI-assessed change in fat infiltration as a useful structural end point."
Treatment-emergent adverse events (TEAEs) were more common in the participants who received losmapimod (n = 29) compared with those on placebo (n = 23). Authors reported drug-related TEAEs in 9 patients on losmapimod and 2 patients on placebo. In the losmapimod group, only 2 patients each had treatment-related rashes, dyspepsia, and increased alanine aminotransferase concentrations. Notably, skin and subcutaneous TEAEs were more frequently reported in the losmapimod group (n = 8) compared with the placebo group (n = 1). In both groups, the site principal investigator or subinvestigators rated most of the AEs as mild or moderate in severity. In the placebo group, authors had no reports of severe or serious TEAEs. Only 2 patients had severe TEAEs occur in the losmapimod group (alcohol poisoning and suicide attempt; postoperative wound infection) which were not considered treatment related by investigators.
"Substantial variability of DUX4-driven gene expression was seen at both baseline and after treatment in both losmapimod and placebo arms. Possible drivers for the high variability include (1) the stochastic nature of DUX4 expression in myonuclei; (2) the heterogeneity in composition of biopsy samples which included muscle, fibrotic tissue, and fat, and (3); the imprecision of the biopsy procedure," the Fulcrum team added. "Preclinical studies showed that compared with inactive control, losmapimod decreased DUX4 target gene expression and markers of apoptosis in FSHD muscle cells. ReDUX4 provided valuable lessons on which clinical and patient reported outcomes are able to quantify disease progression and are sensitive to change in FSHD."
All told, limitations of ReDUX4 included the small sample and enrollment of patients with type 1 FSHD only. Another limitation of the trial noted by the investigators was the use of end points for which the sensitivity to change further needed to be established in the clinic. Also, authors noted missing data at week 48 which may have created a potential bias in the efficacy analysis. Moreover, the researchers noted that some of the exploratory clinical assessments used did not capture the differences over time or between losmapimod and placebo and thus, are deemed not sensitive enough to capture differences in the disease progression.
"Fulcrum Therapeutics is currently conducting the REACH trial, a phase 3 randomized, double-blind, placebo-controlled, 48-week study of the efficacy and safety of losmapimod in FSHD, evaluating losmapimod effect on markers of disease progression in a larger patient population. The study enrolled 260 patients with FSHD type 1 and FSHD type 2 across Europe and North America. Topline results of this study are expected in Q4 2024," the company told NeurologyLive. "The primary end point in the REACH phase 3 trial is RWS. Secondary end points include patients reported outcomes, change in fat infiltration in selected muscles as measured by MRI, and safety and tolerability."
