Losmapimod

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Chemical compound

title: "Losmapimod" type: doc version: 1 created: 2026-02-28 author: "Wikipedia contributors" status: active scope: public tags: ["protein-kinase-inhibitors", "orphan-drugs", "neopentyl-compounds", "disubstituted-pyridines"] description: "Chemical compound" topic_path: "general/protein-kinase-inhibitors" source: "https://en.wikipedia.org/wiki/Losmapimod" license: "CC BY-SA 4.0" wikipedia_page_id: 0 wikipedia_revision_id: 0

::summary Chemical compound ::

| Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 444926440 | IUPAC_name = 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)pyridine-3-carboxamide | image = Losmapimod.svg | image_class = skin-invert-image

| tradename = | pregnancy_AU = | pregnancy_US = | pregnancy_category = | legal_AU = | legal_CA = | legal_UK = | legal_US = Investigational New Drug | legal_status = | routes_of_administration =

| bioavailability = | protein_bound = | metabolism = | elimination_half-life = | excretion =

| IUPHAR_ligand = 7835 | CAS_number_Ref = | CAS_number = 585543-15-3 | ATC_prefix = | ATC_suffix = | PubChem = 11552706 | DrugBank_Ref = | DrugBank = | UNII_Ref = | UNII = F2DQF16BXE | ChEMBL_Ref = | ChEMBL = 1088752 | KEGG_Ref = | KEGG = D09639 | ChemSpiderID_Ref = | ChemSpiderID = 9727484

| C=22 | H=26 | F=1 |N=3 | O=2 | smiles = C3CC3NC(=O)c(cc(F)c1C)cc1-c(cc2)ncc2C(=O)NCC(C)(C)C | StdInChI_Ref = | StdInChI = 1S/C22H26FN3O2/c1-13-17(9-15(10-18(13)23)21(28)26-16-6-7-16)19-8-5-14(11-24-19)20(27)25-12-22(2,3)4/h5,8-11,16H,6-7,12H2,1-4H3,(H,25,27)(H,26,28) | StdInChIKey_Ref = | StdInChIKey = KKYABQBFGDZVNQ-UHFFFAOYSA-N

Losmapimod (GW856553X) is an investigational drug that reached stage III clinical trials for multiple medical conditions, but did not prove efficacy. It was most recently in development by Fulcrum Therapeutics for the treatment of facioscapulohumeral muscular dystrophy (FSHD). Losmapimod selectively inhibits enzymes p38α/β mitogen-activated protein kinases (MAPKs), which are modulators of DUX4 expression and mediators of inflammation.

Historical Investigations

Losmapimod was discovered and unsuccessfully developed by GSK for treating multiple medical conditions. Despite failing to prove efficacy, GSK clinical trials showed that losmapimod is generally well tolerated across more than 3,500 subjects.

GSK investigated losmapimod as a therapeutic for patients post-myocardial infarction (heart attack). Despite phase II clinical trials the phase IIIA clinical trial (LATITUDE) failed to show significantly improved clinical outcomes. In October 2015 GSK announced cancelling the planned phase IIIB trial, but would "evaluate all options for future development."

GSK investigated losmapimod as a therapeutic for COPD, but multiple phase II clinical trials failed to show that losmapimod improves exercise tolerance, lung function, arterial inflammation, endothelial function, or rate of COPD exacerbations in subjects with COPD. GSK terminated development of losmapimod for COPD in 2016.

GSK investigated losmapimod as a therapeutic for major depressive disorder (MDD) on the basis of depression being correlated with elevated pro-inflammatory cytokines. Phase II clinical trials failed to show a significant improvement in depression symptoms and biomarkers.

In 2019 Fulcrum therapeutics acquired from GSK the rights to losmapimod. Fulcrum identified p38α/β MAPK inhibitors as potent suppressors of DUX4 expression, the de-suppression of which is accepted as the cause FSHD, and then chose to develop losmapimod for FSHD due to "substantial and attractive preclinical and clinical data" from previous GlaxoSmithKline (GSK) clinical trials. Although a 2021 phase IIb clinical trial showed slowing of muscle deterioration, a 2024 phase III clinical trial failed to demonstrate efficacy.

References

References

  1. (October 2009). "p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression". Journal of Medicinal Chemistry.
  2. "FORM S-1 REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933 FULCRUM THERAPEUTICS, INC.". Securities and Exchange Commission.
  3. (January 2014). "Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial". The Lancet. Respiratory Medicine.
  4. (2018). "The p38 mitogen activated protein kinase inhibitor losmapimod in chronic obstructive pulmonary disease patients with systemic inflammation, stratified by fibrinogen: A randomised double-blind placebo-controlled trial". PLOS ONE.
  5. {{ClinicalTrialsGov. NCT00474864. Study To Evaluate The Effects Of GW856553 On Endothelial Function/Vascular Compliance In Subjects With Dyslipidaemia.
  6. {{ClinicalTrialsGov. NCT00633022. A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging
  7. {{ClinicalTrialsGov. NCT00910962. Study to Evaluate the Safety of 12 Weeks of Dosing With GW856553 and Its Effects on Inflammatory Markers, Infarct Size, and Cardiac Function in Subjects With Myocardial Infarction Without ST-segment Elevation (Solstice)
  8. (February 2011). "Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia". Circulation.
  9. (September 2012). "Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis". JACC. Cardiovascular Imaging.
  10. (September 2014). "Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial". Lancet.
  11. {{ClinicalTrialsGov. NCT02145468. A Phase 3 Clinical Outcomes Study to Compare the Incidence of Major Adverse Cardiovascular Events in Subjects Presenting With Acute Coronary Syndrome Treated With Losmapimod Compared to Placebo (LATITUDE-TIMI 60)
  12. (April 2016). "Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial". JAMA.
  13. (27 October 2015). "GSK provides update on LATITUDE-TIMI 60 (losmapimod cardiovascular study)". GSK.
  14. {{ClinicalTrialsGov. NCT01218126. Randomised, Double-Blind, Placebo-Controlled, Parallel-Group, Multi-centre, Dose Ranging Study to Evaluate the Efficacy and Safety of Losmapimod Tablets Administered Twice Daily Compared With Placebo for 24 Weeks in Adult Subjects With Chronic Obstructive Pulmonary Disease (COPD)
  15. {{ClinicalTrialsGov. NCT01541852. Losmapimod in Chronic Obstructive Pulmonary Disease Patients Stratified by Fibrinogen. (EVOLUTION)
  16. {{ClinicalTrialsGov. NCT02299375. Safety and Efficacy Study of Losmapimod (GW856553) in Frequently Exacerbating Participants With Chronic Obstructive Pulmonary Disease (COPD)
  17. (September 2017). "Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical benefits in COPD". Respiratory Medicine.
  18. (Oct 26, 2016). "GlaxoSmithKline Terminates Development of Losmapimod for COPD". BioSpace.
  19. (Oct 26, 2016). "GSK drops a pair of late-stage candidates in COPD, HIV". FierceBiotech.
  20. (June 2014). "Evaluation of antidepressant properties of the p38 MAP kinase inhibitor losmapimod (GW856553) in Major Depressive Disorder: Results from two randomised, placebo-controlled, double-blind, multicentre studies using a Bayesian approach". Journal of Psychopharmacology.
  21. {{ClinicalTrialsGov. NCT00569062. A Study of GW856553X For the Treatment of Depression
  22. {{ClinicalTrialsGov. NCT00976560. Clinical Study to Test a New Drug to Treat Major Depression
  23. (23 April 2019). "Fulcrum Therapeutics Acquires Global Rights to Losmapimod, a Potential Disease-Modifying Therapy for Facioscapulohumeral Muscular Dystrophy". BioSpace.
  24. (2021-06-24). "ReDUX4 trial result exceeds expectations".
  25. "Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD)". United States National Library of Medicine.
  26. {{ClinicalTrialsGov. NCT04003974. Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) (FSHD)
  27. "Fulcrum's losmapimod fails interim analysis in muscle wasting trial". FierceBiotech.
  28. {{ClinicalTrialsGov. NCT04004000. Evaluation of Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments of Losmapimod for FSHD1

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protein-kinase-inhibitorsorphan-drugsneopentyl-compoundsdisubstituted-pyridines