losmapimod (FTX-1821) / GSK, Fulcrum Therap, Sanofi - LARVOL DELTA

Deciphering Facioscapulohumeral Dystrophy in the clinical trials era: where are we now? (PubMed, Acta Myol) - "Clinical trials, such as Losmapimod, show promise in slowing muscle degeneration, though results remain inconsistent...Ongoing research is needed to clarify pathogenesis and identify reliable biomarkers. Future therapeutic strategies should focus on precision medicine, integrating genetic, clinical, and imaging data to optimize patient stratification and treatment efficacy."

Journal • Review • Genetic Disorders • Muscular Dystrophy • DUX4

The participants' perspective on facioscapulohumeral muscular dystrophy trials in The Netherlands - A qualitative study. (PubMed, J Neuromuscul Dis) - "The first trials with potentially disease-modifying therapies have started, including a phase ll open-label study and a phase lll double-blind randomized placebo-controlled trial assessing the safety and efficacy of losmapimod...Recommendations consisted of more frequent updates on the overall progress and results of the trials. This study presents the participants' perspective on FSHD trials, providing important key findings for future clinical trial design, study site practices and patient education."

Journal • CNS Disorders • Muscular Dystrophy

Fulcrum Therapeutics Announces Recent Business Highlights and Financial Results for Fourth Quarter and Full Year 2024 (GlobeNewswire) - "Patient enrollment and site activation continues to progress in the Phase 1b PIONEER trial evaluating pociredir in patients with SCD. Fulcrum has enrolled 10 patients in the 12 mg dose cohort, and plans to share data from the 12 mg dose cohort in mid-2025 and from the 20 mg dose cohort by the end of 2025. Fulcrum continues to advance its program for the potential treatment of inherited aplastic anemias, such as Diamond-Blackfan anemia (DBA), Shwachman-Diamond syndrome, and Fanconi anemia, and plans to submit an IND for DBA during the fourth quarter of 2025. Consistent with our commitment to share full trial results with patients, study investigators, and the broader FSHD community, data from the Phase 3 REACH trial evaluating losmapimod in patients with Facioscapulohumeral Muscular Dystrophy will be presented on March 19th at the 2025 MDA Conference being held in Dallas, Texas."

IND • P1 data • P3 data • Trial status • Aplastic Anemia • Muscular Dystrophy • Sickle Cell Disease

Efficacy and Safety of Losmapimod in Treating Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) With Open-Label Extension (OLE) (clinicaltrials.gov) - P2 | N=76 | Terminated | Sponsor: Fulcrum Therapeutics | Trial completion date: Jan 2026 ➔ Nov 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Oct 2025 ➔ Nov 2024; Sponsor Decision

Trial completion date • Trial primary completion date • Trial termination • Muscular Dystrophy

Efficacy and Safety of Losmapimod in Treating Participants With Facioscapulohumeral Muscular Dystrophy (FSHD) (REACH) (clinicaltrials.gov) - P3 | N=260 | Terminated | Sponsor: Fulcrum Therapeutics | Trial completion date: Jan 2026 ➔ Nov 2024 | Active, not recruiting ➔ Terminated; Sponsor Decision

Trial completion date • Trial termination • Muscular Dystrophy

Evaluation of Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments of Losmapimod for FSHD1 With Extension (clinicaltrials.gov) - P2 | N=14 | Terminated | Sponsor: Fulcrum Therapeutics | Trial completion date: Jan 2026 ➔ Oct 2024 | Active, not recruiting ➔ Terminated | Trial primary completion date: Oct 2025 ➔ Oct 2024; Sponsor Decision

Biomarker • Trial completion date • Trial primary completion date • Trial termination • Muscular Dystrophy • DUX4

Temporal variation in p38-mediated regulation of DUX4 in facioscapulohumeral muscular dystrophy. (PubMed, Sci Rep) - "In xenograft studies, p38α/β inhibition by losmapimod failed to suppress DUX4 target gene expression in late FSHD xenografts. Our results show that while p38 is critical for DUX4 expression during early myogenesis, later in myogenesis a significant level of DUX4 expression is independent of p38α/β activity."

Journal • Muscular Dystrophy • DUX4 • MAPK14

Losmapimod ameliorates doxorubicin-induced cardiotoxicity through attenuating senescence and inflammatory pathways. (PubMed, Biomed Pharmacother) - "LOSM significantly increased mitofusin2 gene expression, which may enhance mitochondrial fusion. These findings underscore the potential therapeutic efficacy of p38 MAPK inhibition, exemplified by LOSM, in ameliorating DOX-induced cardiotoxicity, senescence, and inflammation."

Journal • Cardiovascular • Inflammation • CDKN1A • CXCL1 • IL6 • MFN2

Pirfenidone Prevents Heart Fibrosis during Chronic Chagas Disease Cardiomyopathy. (PubMed, Int J Mol Sci) - "Therefore, we sought to analyze the effect of inhibitors of TGF-β (pirfenidone), p38-MAPK (losmapimod) and c-Jun (SP600125) on the modulation of collagen deposition in cardiac fibroblasts (CF) and in vivo models of T. cruzi chronic infection. Assays of chronic infection of mice with T. cruzi have shown a reduction in heart collagen by pirfenidone. These results propose a novel approach to fibrosis therapy in CD, with the prospect of repurposing pirfenidone to prevent the onset of ECM accumulation in the hearts of the patients."

Journal • Cardiomyopathy • Cardiovascular • Fibrosis • Immunology • Infectious Disease • TGFB1

An open-label pilot study of losmapimod to evaluate the safety, tolerability, and changes in biomarker and clinical outcome assessments in participants with facioscapulohumeral muscular dystrophy type 1. (PubMed, J Neurol Sci) - P2 | "Losmapimod was well tolerated and may be a promising new treatment for FSHD; a larger phase 3 study is ongoing."

Biomarker • Clinical data • Journal • Genetic Disorders • Muscular Dystrophy • DUX4

Losmapimod, a p38 Small Molecule Inhibitor, Selectively Inhibits the DUX4 Program Without Negatively Impacting Myogenesis in FSHD (New Directions 2024) - No abstract available

DUX4

Safety and efficacy of losmapimod in facioscapulohumeral muscular dystrophy (ReDUX4): a randomised, double-blind, placebo-controlled phase 2b trial. (PubMed, Lancet Neurol) - P2 | "Although losmapimod did not significantly change DUX4-driven gene expression, it was associated with potential improvements in prespecified structural outcomes (muscle fat infiltration), functional outcomes (reachable workspace, a measure of shoulder girdle function), and patient-reported global impression of change compared with placebo. These findings have informed the design and choice of efficacy endpoints for a phase 3 study of losmapimod in adults with facioscapulohumeral muscular dystrophy."

Journal • P2b data • Infectious Disease • Muscular Dystrophy • Myositis • DUX4

Safety and Tolerability of Losmapimod for the Treatment of FSHD (AAN 2024) - "Losmapimod administered up to 15 mg BID in >100 subjects with FSHD1 for up to 96 weeks has been generally well-tolerated; the benefit-risk profile of losmapimod for the treatment of FSHD remains positive and favorable."

Clinical • Atopic Dermatitis • CNS Disorders • Dermatology • Immunology • Infectious Disease • Musculoskeletal Pain • Novel Coronavirus Disease • Pain

Facioscapulohumeral Muscular Dystrophy (FSHD) Disease Progression and Losmapimod Efficacy Assessed by Reachable Workspace in Both Arms (MDA 2024) - "These results support the potential benefits of using total RSA with weight averaged over both arms as a clinical endpoint. This bilateral assessment of RSA provides a robust measure of FSHD functional impairment and disease progression, aligning with secondary endpoints of muscle strength and structure."

Clinical • Muscular Dystrophy

Losmapimod, a p38 Small Molecule Inhibitor, Selectively Inhibits the DUX4 Program Without Negatively Impacting Myogenesis in FSHD (MDA 2024) - "It was observed that only a small number of genes were differentially expressed after treatment with the majority being targets of DUX4, with no negative impact on key drivers of myogenic programing. These in vitro findings highlight the potential of Losmapimod for the treatment of FSHD, a condition that today has no approved therapies."

DUX4

Vitamin D inhibits p38 MAPK and senescence-associated inflammatory mediator secretion by senescent fibroblasts that impacts immune responses during ageing. (PubMed, Aging Cell) - "Furthermore, transcriptomic analysis of skin biopsies from older subjects after vitamin D supplementation shows that vitamin D inhibits the same inflammatory pathways in response to saline as the specific p38 inhibitor, losmapimod, which also enhances immunity in the skin of older subjects. Vitamin D supplementation therefore may enhance immunity during ageing in part by blocking p38 MAPK signalling and in turn inhibit SASP production from senescent cells in vivo."

Journal • Herpes Zoster • Varicella Zoster

Apabetalone, a Clinical-Stage, Selective BET Inhibitor, Opposes DUX4 Target Gene Expression in Primary Human FSHD Muscle Cells. (PubMed, Biomedicines) - "Using primary human skeletal muscle cells from FSHD type 1 patients, we evaluated apabetalone for its ability to counter DUX4's deleterious effects and compared it with the pan-BET inhibitor JQ1, and the p38 MAPK inhibitor-and DUX4 transcriptional repressor-losmapimod. Losmapimod also reduced expression of DUX4 target genes but differed in its impact on FSHD-associated pathways. These findings demonstrate that apabetalone inhibits DUX4 target gene expression and reverses transcriptional programs that contribute to FSHD pathology, making this drug a promising candidate therapeutic for FSHD."

Journal • Muscular Dystrophy • DUX4

Efficacy and Safety of Losmapimod in Treating Participants With Facioscapulohumeral Muscular Dystrophy (FSHD) (REACH) (clinicaltrials.gov) - P3 | N=260 | Active, not recruiting | Sponsor: Fulcrum Therapeutics | Recruiting ➔ Active, not recruiting

Enrollment closed • Muscular Dystrophy

Fulcrum Announces Completion of Enrollment in the Phase 3 REACH Clinical Trial of Losmapimod in Facioscapulohumeral Muscular Dystrophy (FSHD) (GlobeNewswire) - "Fulcrum Therapeutics, Inc...today announced that it has completed enrollment in REACH, a Phase 3 clinical trial evaluating losmapimod in patients with FSHD at sites in the United States, Canada, and Europe....We expect to report topline data from REACH in the fourth quarter of 2024, bringing us one step closer to potentially delivering the first FDA-approved therapy for FSHD.'"

Enrollment closed • P3 data: top line • Muscular Dystrophy

Antinociceptive properties of losmapimod in two acute pain models in rats: behavioural analysis, immunohistochemistry, dose response, and comparison with usual analgesic drugs. (PubMed, BJA Open) - "Losmapimod (12 mg kg) was compared with paracetamol, ketamine, and morphine using thermal and mechanical stimulation after carrageenan injection. Losmapimod appears to be a promising drug in severe acute pain conditions. Losmapimod could also be helpful for postoperative pain control, as suggested by its effect after plantar incision."

Journal • Preclinical • Pain

Safety and tolerability of Losmapimod for the treatment of FSHD (WMS 2023) - No abstract available

Clinical

Comparison of Quantitative Mass Spectrometric Methods for Drug Target Identification by Thermal Proteome Profiling. (PubMed, J Proteome Res) - "Label-free DIA approaches, and particularly the library-free mode in DIA-NN, were comparable of TMT-DDA in their ability to detect target engagement of losmapimod with MAPK14 and one of its downstream targets, MAPKAPK3. Using DIA for thermal shift quantitation is a cost-effective alternative to labeled quantitation in the TPP pipeline."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • MAPK14

Treatment of Facioscapulohumeral Muscular Dystrophy (FSHD): A Systematic Review. (PubMed, Cureus) - "Vitamin C, vitamin E, zinc gluconate, and selenomethionine showed significant improvement in the maximal voluntary contraction and endurance limit time of quadriceps muscle. At the same time, diltiazem and MYO-029 demonstrate no improvement in function, strength, or muscle mass. Losmapimod, currently in phase I of the ReDUX4 trial, showed promising results. Peradventure, more clinical trials are still needed to address this subject. Nevertheless, this review provides a clear and concise update on the treatment for this disease."

Journal • Review • Muscular Dystrophy

Evaluation of Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments of Losmapimod for FSHD1 With Extension (clinicaltrials.gov) - P2 | N=14 | Active, not recruiting | Sponsor: Fulcrum Therapeutics | Trial completion date: Jan 2024 ➔ Jan 2026 | Trial primary completion date: Jan 2024 ➔ Oct 2025

Biomarker • Trial completion date • Trial primary completion date • Muscular Dystrophy

Efficacy and Safety of Losmapimod in Treating Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) With Open-Label Extension (OLE) (clinicaltrials.gov) - P2 | N=76 | Active, not recruiting | Sponsor: Fulcrum Therapeutics | Trial completion date: Feb 2025 ➔ Jan 2026 | Trial primary completion date: Feb 2024 ➔ Oct 2025

Trial completion date • Trial primary completion date • Muscular Dystrophy