Losmapimod

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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.[1]

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.[2][3][4]

GSK investigated losmapimod as a therapeutic for patients post-myocardial infarction (heart attack). Despite phase II clinical trials[5][6][7][8][9][10] the phase IIIA clinical trial (LATITUDE)[11] failed to show significantly improved clinical outcomes.[12] In October 2015 GSK announced cancelling the planned phase IIIB trial, but would "evaluate all options for future development."[13]

GSK investigated losmapimod as a therapeutic for COPD, but multiple phase II clinical trials[14][15][16] failed to show that losmapimod improves exercise tolerance,[3] lung function,[3] arterial inflammation,[4] endothelial function,[4] or rate of COPD exacerbations[17] in subjects with COPD. GSK terminated development of losmapimod for COPD in 2016.[18][19]

GSK investigated losmapimod as a therapeutic for major depressive disorder (MDD) on the basis of depression being correlated with elevated pro-inflammatory cytokines.[20] Phase II clinical trials[21][22] failed to show a significant improvement in depression symptoms and biomarkers.[20]

In 2019 Fulcrum therapeutics acquired from GSK the rights to losmapimod.[23] 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.[2] Although a 2021 phase IIb clinical trial showed slowing of muscle deterioration,[24][25][26][27][28] a 2024 phase III clinical trial failed to demonstrate efficacy.Script error: No such module "Unsubst".

References

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  1. ↑ Script error: No such module "Citation/CS1".
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  4. ↑ a b c Script error: No such module "Citation/CS1".
  5. ↑ Clinical trial number NCT00474864 for "Study To Evaluate The Effects Of GW856553 On Endothelial Function/Vascular Compliance In Subjects With Dyslipidaemia." at ClinicalTrials.gov
  6. ↑ Clinical trial number NCT00633022 for "A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging" at ClinicalTrials.gov
  7. ↑ Clinical trial number NCT00910962 for "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)" at ClinicalTrials.gov
  8. ↑ Script error: No such module "Citation/CS1".
  9. ↑ Script error: No such module "Citation/CS1".
  10. ↑ Script error: No such module "Citation/CS1".
  11. ↑ Clinical trial number NCT02145468 for "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)" at ClinicalTrials.gov
  12. ↑ Script error: No such module "Citation/CS1".
  13. ↑ Script error: No such module "citation/CS1".
  14. ↑ Clinical trial number NCT01218126 for "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)" at ClinicalTrials.gov
  15. ↑ Clinical trial number NCT01541852 for "Losmapimod in Chronic Obstructive Pulmonary Disease Patients Stratified by Fibrinogen. (EVOLUTION)" at ClinicalTrials.gov
  16. ↑ Clinical trial number NCT02299375 for "Safety and Efficacy Study of Losmapimod (GW856553) in Frequently Exacerbating Participants With Chronic Obstructive Pulmonary Disease (COPD)" at ClinicalTrials.gov
  17. ↑ Script error: No such module "Citation/CS1".
  18. ↑ Script error: No such module "citation/CS1".
  19. ↑ Script error: No such module "citation/CS1".
  20. ↑ a b Script error: No such module "Citation/CS1".
  21. ↑ Clinical trial number NCT00569062 for "A Study of GW856553X For the Treatment of Depression" at ClinicalTrials.gov
  22. ↑ Clinical trial number NCT00976560 for "Clinical Study to Test a New Drug to Treat Major Depression" at ClinicalTrials.gov
  23. ↑ Script error: No such module "citation/CS1".
  24. ↑ Script error: No such module "citation/CS1".
  25. ↑ Script error: No such module "citation/CS1".
  26. ↑ Clinical trial number NCT04003974 for "Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) (FSHD)" at ClinicalTrials.gov
  27. ↑ Script error: No such module "citation/CS1".
  28. ↑ Clinical trial number NCT04004000 for "Evaluation of Safety, Tolerability, and Changes in Biomarker and Clinical Outcome Assessments of Losmapimod for FSHD1" at ClinicalTrials.gov

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