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

Biomarkers in facioscapulohumeral muscular dystrophy. (PubMed, Curr Opin Neurol) - "Facing the genetic and phenotypic complexity of FSHD, robust biomarkers must be used to assess the efficacy of the experimental treatments, and individuals must be selected and stratified to minimize variability, in order to prepare for future clinical trials."

Biomarker • Journal • Muscular Dystrophy • Myositis • DUX4

Responsiveness to Change of Quantitative Whole-Body MRI in FSHD: Results From ReDUX4 OLE (ICNMD 2026) - "These biomarkers were included as secondary endpoints in a 48-week phase 2b study of Losmapimod (ReDUX4) in FSHD with an optional open label extension (OLE) study. Whole-body quantitative MRI were acquired using fat-water separated imaging (Dixon)... Describing progression in heterogenous and slowly progressing diseases such as neuromuscular disorders is challenging and increases both cost and complexity in drug development. By utilizing whole-body MRI to identify muscles with an increased likelihood of near-term progression, the responsiveness of the biomarkers can increase significantly, potentially enabling earlier detection of disease progression or treatment response."

CNS Disorders

Identification of compounds that repress DUX4 expression in facioscapulohumeral muscular dystrophy. (PubMed, Sci Rep) - "Despite this, at low doses C06 was an equally effective and more specific repressor of DUX4 than losmapimod, which is a robust and specific p38 inhibitor...Thus, C06 is a useful tool for potent and specific DUX4 suppression, and a viable candidate for further development. Our results highlight both the utility and limitations of AI for targeted drug discovery, and the importance of using an FSHD-specific functional screening strategy for selecting relevant candidates."

Journal • Muscular Dystrophy • DUX4

Losmapimod, an Oral Anti-p38 MAP Kinase, Demonstrates Anti-Neuropathic and Anti-Inflammatory Effects in Rat Acute Pain. (PubMed, J Clin Med) - "Losmapimod was also compared with gabapentin, their respective ED50 were determined, and their interaction was studied using an isobolographic approach. The anti-inflammatory characteristics of losmapimod were assessed from day 0 to day 5 after carrageenan injection in the rat hind paw and compared with those of ketoprofen, ketamine, and morphine using paw oedema volume... Losmapimod showed anti neuropathic properties at the very early stage of neuropathic pain and potent anti-inflammatory properties. As previous studies have highlighted the excellent tolerance of losmapimod in human populations, this drug seems promising for acute postoperative pain, which combines both acute neuropathic and inflammatory mechanisms."

Journal • Preclinical • Inflammation • Neuralgia • Pain

Time-programmed Losmapimod release enhances ANXA1-associated efferocytosis for diabetic wound repair. (PubMed, J Control Release) - "Gain- and loss-of-function studies in macrophages, together with in vivo pharmacological modulation, implicated ANXA1-related signaling as an important contributor to these effects. Together, these findings support a local, time-programmed pro-resolution biomaterial strategy for diabetic wound repair and identify macrophage clearance-associated remodeling as a relevant therapeutic axis."

Journal • Fibrosis

Identification of compounds that repress DUX4 expression in facioscapulohumeral muscular dystrophy. (PubMed, bioRxiv) - "Despite this, at low doses C06 was an equally effective and more specific repressor of DUX4 than losmapimod, which is a robust and specific p38 inhibitor. Thus, C06 is a useful tool for potent and specific DUX4 suppression, and a viable candidate for further development. Our results highlight both the utility and limitations of AI for targeted drug discovery, and the importance of using an FSHD-specific functional screening strategy for selecting relevant candidates."

Journal • Muscular Dystrophy • DUX4

A randomized, double-blind, placebo-controlled study of losmapimod in patients with facioscapulohumeral muscular dystrophy: Results of the REACH study. (PubMed, J Neuromuscul Dis) - P3 | "Losmapimod was generally well tolerated with a favorable safety profile at a dose of 15 mg twice daily. Although none of the efficacy endpoints were met, study design and data from the study may inform future studies of FSHD therapies."

Clinical • Journal • Muscular Dystrophy • DUX4

Epoxy-oxylipins direct monocyte fate in inflammatory resolution in humans. (PubMed, Nat Commun) - "GSK2256294, a selective sEH inhibitor specifically elevates 12,13-EpOME and 14,15-EET...We find that 12,13-EpOME blocks the transition of classical to intermediate monocytes in a p38 MAPK-dependent manner, results that are recapitulated when blocking p38 MAPK in vitro and when administering the p38 MAPK inhibitor losmapimod in vivo to healthy volunteers. Furthermore, fewer intermediate monocytes are observed at the site of inflammation, accompanied by reduced tissue CD4 T cells. Hence, we have mapped the expression, activity and function of epoxy-oxylipins in human inflammation revealing new mechanisms of monocyte differentiation and resolution biology."

Journal • Inflammation • Pain • CD4

Drug Development. (PubMed, Alzheimers Dement) - "IPAA enables rapid preclinical assessment of target pathways with confidence for impact on AD pathology prior to clinical trials. Our findings highlight the critical role of protein kinase networks, particularly the p38 MAPK-MK2 axis, in driving AD pathology in humans."

Journal • Alzheimer's Disease • CNS Disorders • Aβ42 • CDC20 • CDH1 • YAP1

A multi-ancestry meta genome-wide association study of migraine among veterans: associations with traumatic brain injury, depression, and post-traumatic stress disorder. (PubMed, Mol Psychiatry) - "Despite high genetic correlations with neuropsychiatric disorders - including post-traumatic stress disorder, depression, and traumatic brain injury - Mendelian randomization analyses found no causal links. Finally, we prioritized potential migraine drug targets, including losmapimod (which reduces production of toxic DUX4 protein) and TLR4 antagonists."

Journal • CNS Disorders • Depression • Mental Retardation • Migraine • Pain • Post-traumatic Stress Disorder • Psychiatry • Vascular Neurology • ASXL1 • CELF4 • DUX4 • MVP • SPOCD1 • TLR4

Early anti-inflammatory therapy in acute myocardial infarction: A network meta-analysis of timing-dependent effects in 23 randomized trials and 28,220 patients. (PubMed, Atherosclerosis) - "This network meta-analysis demonstrates that anti-inflammatory therapy improves outcomes in AMI only when initiated early. Colchicine and anakinra were the only effective agents, highlighting a narrow therapeutic window and supporting a time-sensitive approach to inflammation-targeted treatment in AMI."

Journal • Retrospective data • Cardiovascular • Congestive Heart Failure • Heart Failure • Infectious Disease • Inflammation • Myocardial Infarction • IL1B

The recent clinical trial of losmapimod for the treatment of facioscapulohumeral muscular dystrophy. (PubMed, Neuromuscul Disord) - "This raises concerns about the relevance of in vitro models for drug testing. The failure of losmapimod underscores the need for better disease models, such as xenografts, and a deeper understanding of DUX4 regulation, before advancing future therapies to clinical trials."

Journal • Review • Muscular Dystrophy • DUX4

Precision installation of silyl synthetic handles within arenes by regiocontrolled ruthenium C(sp 2)-H functionalization. (PubMed, Nat Catal) - "Significantly, the regiodivergent installation of silylmethyl synthetic handles allows for the synthesis of the pharmaceutical losmapimod and could further be applied in direct late-stage functionalizations. Mechanistically, an essential role for biscyclometallated ruthenium(II) species has been found, with the formation of intermediate ruthenium(III) species indicated by paramagnetic NMR experiments. These synthetic inventions and mechanistic elucidations signify a transformative step within ruthenium-catalysed C(sp 2)-H functionalization, enabling diverse syntheses and providing a framework for future development."

Journal

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