Fulcrum Therapeutics Announces Interim Analysis Data from its ReDUX4 Trial in Facioscapulohumeral Muscular Dystrophy (FSHD)
Reduction in DUX4-driven gene expression observed in biopsies with highest baseline levels of DUX4-driven gene expression
Topline data on-track for Q1 2021 with full data in Q2 2021
Company to review clinical data on second quarter earnings call today at 8:00am ET
CAMBRIDGE, Mass., Aug. 11, 2020 (GLOBE NEWSWIRE) -- Fulcrum Therapeutics, Inc. (Nasdaq: FULC), a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases, today announced results from a pre-specified interim analysis of the primary endpoint of the Phase 2 ReDUX4 trial in subjects with facioscapulohumeral muscular dystrophy (FSHD). The primary endpoint is the reduction from baseline of DUX4-driven gene expression in affected skeletal muscle after subjects have been treated with losmapimod or placebo. Secondary and exploratory endpoints were not assessed as part of this analysis. Results from the interim analysis in the first 29 randomized subjects indicate that DUX4-driven gene expression did not show a separation from placebo at 16 weeks. However, in a pre-specified sensitivity analysis, those with the highest pre-treatment DUX4-driven gene expression in their muscle biopsy sample showed a 38-fold reduction in DUX4-driven gene expression following treatment with losmapimod compared to a 5.4 fold reduction with placebo.
FSHD is a rare, progressive and disabling disease for which there are no approved treatments. FSHD is caused by aberrant expression of DUX4 in skeletal muscle, resulting in the inappropriate presence of the DUX4 protein, which causes the death of muscle and its replacement by fat. In preparatory studies, the range of DUX4 expression levels within affected muscles throughout a patient’s body have been shown to be relatively stable over time at the site of a muscle biopsy.
“Preliminary evidence from our interim analysis suggests that muscles with higher DUX4-driven gene expression in pre-treatment biopsies show greater reduction of DUX4-driven gene expression following treatment with losmapimod compared to placebo. These results, which provide evidence of the ability of losmapimod to reduce DUX4-driven gene expression, are very encouraging,” said Robert J. Gould, Ph.D., president and chief executive officer. “This initial data represents the first time a treatment is being evaluated to impact the root cause of FSHD in a placebo-controlled trial and are helping to inform our longer-term clinical strategy for losmapimod. We look forward to further leveraging the open label study to evaluate the long-term effects of losmapimod in additional FSHD subjects. We remain on track to share topline results on the primary endpoint in the first quarter of 2021 and full data, including all secondary and exploratory endpoints, in the second quarter of 2021.”
Interim Analysis Summary
The interim results included an analysis of the first 29 subjects who completed their 16-week biopsy out of the 80 subjects enrolled. Pharmacokinetics, demographics and the primary endpoint were assessed. Subjects were randomized to receive an oral dose of losmapimod 15mg (n=15) or placebo (n=14) twice per day. While results showed a significant reduction in DUX4-driven gene expression in the muscle biopsies of subjects whose baseline biopsy showed the highest levels of DUX4 gene expression (38-fold decrease with losmapimod, n=3, and 5.4 fold-decrease with placebo, n=5), the population level data analysis of the reduction in DUX4-driven gene expression from all 29 subjects did not show a separation of losmapimod from placebo (3.7 fold increase with losmapimod, n=15, and 2.8 fold increase with placebo, n=14). Results indicate that muscle biopsies within the higher levels of DUX4-driven gene expression may be needed to observe a reduction from baseline.
|Interim Analysis Results |
|Interim Analysis Results |
(Highest Expressing Muscle Biopsies)*
|Sample Size||Fold change (Δ CT)||Sample Size||Fold change (Δ CT)|
* Highest expressing muscle biopsies represent the top quartile of biopsies assessed based on baseline DUX4-driven gene expression.
Losmapimod was generally well tolerated with no serious drug-related adverse events (SAEs) reported. The interim analysis was not powered for statistical significance and did not include individual patient level data. ReDUX4 remains blinded.
“One of the critical factors in patients with FSHD is that there can be significant variability in the magnitude of DUX4-driven gene expression at the site of each pre-treatment needle biopsy,” said Diego Cadavid, MD, Fulcrum’s senior vice president, clinical development. “The initial observation of greater reduction by losmapimod over placebo in DUX4-driven gene expression in the biopsied muscles with the highest baseline expression may represent the potential losmapimod has to treat the root cause of the disease. We’re excited about the study progress and look forward to the final analysis.”
ReDUX4 is a randomized, double-blind, placebo-controlled multicenter international Phase 2b clinical trial in 80 subjects with FSHD to investigate the efficacy and safety of oral administration of losmapimod 15 mg twice per day. The primary endpoint is to evaluate the reduction of DUX4-driven gene expression in affected skeletal muscle biopsies. The original design of ReDUX4 included a muscle biopsy at week 16 during the 24-week treatment period followed by an open label extension.
As a result of the COVID-19 pandemic, Fulcrum announced in May 2020 that the trial had been extended from 24 to 48 weeks through a protocol amendment to ensure the safety of the subjects and to allow for the opportunity for a biopsy at week 16 as originally intended or at week 36.
The extension from 24 to 48 weeks also allows for a longer assessment in a placebo-controlled design of the skeletal muscle MRI secondary endpoint and the various exploratory clinical endpoints, such as reachable workspace, FSHD-Timed Up and GO, muscle function measures and patient reported outcomes. Topline data from approximately 80 patients is expected in the first quarter of 2021. Approximately 68 subjects remain active in the randomized portion of the trial and 12 remain active in the open label extension.
FSHD is characterized by progressive skeletal muscle loss that initially causes weakness in muscles in the face, shoulders, arms and trunk, and progresses to weakness throughout the lower body. Skeletal muscle weakness results in significant physical limitations, including an inability to smile and difficulty using arms for activities, with many patients ultimately becoming dependent upon the use of a wheelchair for daily mobility.
FSHD is caused by mis-expression of DUX4 in skeletal muscle, resulting in the presence of DUX4 proteins that are toxic to muscle tissue. Normally, DUX4-driven gene expression is limited to early embryonic development, after which time the DUX4 gene is silenced. In people with FSHD, the DUX4 gene is turned “on” as a result of a genetic mutation. The result is death of muscle and its replacement by fat, leading to skeletal muscle weakness and progressive disability. There are no approved therapies for FSHD, one of the most common forms of muscular dystrophy, with an estimated patient population of 16,000 to 38,000 in the United States alone.
Losmapimod is a selective p38α/β mitogen activated protein kinase (MAPK) inhibitor that was exclusively in-licensed from GSK by Fulcrum Therapeutics following Fulcrum’s discovery of the role of p38α/β inhibitors in the reduction of DUX4 expression and an extensive review of known compounds. Utilizing its internal product engine, Fulcrum discovered that inhibition of p38α/β reduced expression of the DUX4 gene in muscle cells derived from patients with FSHD. Researchers at Fulcrum also believe that losmapimod has the potential to treat COVID-19 by reducing the acute exaggerated pro-inflammatory responses to SARS-CoV-2 infection and restoring the antigen-specific immune responses needed for viral clearance, potentially leading to improved clinical outcomes. Losmapimod has been evaluated in more than 3,600 subjects in clinical research across multiple indications, including in several Phase 2 trials and a large Phase 3 trial in acute myocardial infarction. No safety signals were attributed to losmapimod in any of these trials. In 2020, the Company received U.S. and European Orphan Drug Designation for losmapimod for the treatment of FSHD. Fulcrum is currently conducting Phase 2 trials investigating the safety, tolerability, and efficacy of losmapimod to treat the root cause of FSHD and initiating a Phase 3 trial investigating the safety, tolerability, and efficacy of losmapimod to treat hospitalized patients with COVID-19.
About Fulcrum Therapeutics
Fulcrum Therapeutics is a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases in areas of high unmet medical need. Fulcrum’s proprietary product engine identifies drug targets which can modulate gene expression to treat the known root cause of gene mis-expression. The company has advanced losmapimod to Phase 2 clinical development for the treatment of facioscapulohumeral muscular dystrophy (FSHD) and is advancing losmapimod to Phase 3 for the treatment of COVID-19. Fulcrum also anticipates filing an IND in the third quarter with initiation of a clinical trial in the fourth quarter of 2020 with FTX-6058 for the treatment of sickle cell disease.
Please visit www.fulcrumtx.com.
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