Losmapimod Explained

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] the phase IIIA clinical trial (LATITUDE) failed to show significantly improved clinical outcomes.[8] In October 2015 GSK announced cancelling the planned phase IIIB trial, but would "evaluate all options for future development."[9]

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[10] in subjects with COPD. GSK terminated development of losmapimod for COPD in 2016.[11] [12]

GSK investigated losmapimod as a therapeutic for major depressive disorder (MDD) on the basis of depression being correlated with elevated pro-inflammatory cytokines.[13] 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.[14] 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,[15] [16] [17] a 2024 phase III clinical trial failed to demonstrate efficacy.

Notes and References

  1. Aston NM, Bamborough P, Buckton JB, Edwards CD, Holmes DS, Jones KL, Patel VK, Smee PA, Somers DO, Vitulli G, Walker AL . 6 . p38alpha mitogen-activated protein kinase inhibitors: optimization of a series of biphenylamides to give a molecule suitable for clinical progression . Journal of Medicinal Chemistry . 52 . 20 . 6257–69 . October 2009 . 19772287 . 10.1021/jm9004779 .
  2. Web site: FORM S-1 REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933 FULCRUM THERAPEUTICS, INC. . www.sec.gov . Securities and Exchange Commission . 26 October 2019.
  3. Watz H, Barnacle H, Hartley BF, Chan R . 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 . 2 . 1 . 63–72 . January 2014 . 24461903 . 10.1016/S2213-2600(13)70200-5 .
  4. Fisk M, Cheriyan J, Mohan D, Forman J, Mäki-Petäjä KM, McEniery CM, Fuld J, Rudd JH, Hopkinson NS, Lomas DA, Cockcroft JR, Tal-Singer R, Polkey MI, Wilkinson IB . 6 . 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 . 13 . 3 . e0194197 . 2018 . 29566026 . 5863984 . 10.1371/journal.pone.0194197 . 2018PLoSO..1394197F . free .
  5. Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Mäki-Petäjä KM, Collier DJ, Morgan J, Fang Z, Willette RN, Lepore JJ, Cockcroft JR, Sprecher DL, Wilkinson IB . 25095165 . 6 . Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia . Circulation . 123 . 5 . 515–23 . February 2011 . 21262998 . 10.1161/CIRCULATIONAHA.110.971986 . free .
  6. Elkhawad M, Rudd JH, Sarov-Blat L, Cai G, Wells R, Davies LC, Collier DJ, Marber MS, Choudhury RP, Fayad ZA, Tawakol A, Gleeson FV, Lepore JJ, Davis B, Willette RN, Wilkinson IB, Sprecher DL, Cheriyan J . 6 . Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis . JACC. Cardiovascular Imaging . 5 . 9 . 911–22 . September 2012 . 22974804 . 10.1016/j.jcmg.2012.02.016 . free .
  7. Newby LK, Marber MS, Melloni C, Sarov-Blat L, Aberle LH, Aylward PE, Cai G, de Winter RJ, Hamm CW, Heitner JF, Kim R, Lerman A, Patel MR, Tanguay JF, Lepore JJ, Al-Khalidi HR, Sprecher DL, Granger CB . 38041584 . 6 . Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial . Lancet . 384 . 9949 . 1187–95 . September 2014 . 24930728 . 10.1016/S0140-6736(14)60417-7 .
  8. O'Donoghue ML, Glaser R, Cavender MA, Aylward PE, Bonaca MP, Budaj A, Davies RY, Dellborg M, Fox KA, Gutierrez JA, Hamm C, Kiss RG, Kovar F, Kuder JF, Im KA, Lepore JJ, Lopez-Sendon JL, Ophuis TO, Parkhomenko A, Shannon JB, Spinar J, Tanguay JF, Ruda M, Steg PG, Theroux P, Wiviott SD, Laws I, Sabatine MS, Morrow DA . 6 . Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial . JAMA . 315 . 15 . 1591–9 . April 2016 . 27043082 . 10.1001/jama.2016.3609 . free .
  9. News: GSK provides update on LATITUDE-TIMI 60 (losmapimod cardiovascular study) . 12 August 2019 . GSK . 27 October 2015.
  10. Pascoe S, Costa M, Marks-Konczalik J, McKie E, Yang S, Scherbovsky PS . Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical benefits in COPD . Respiratory Medicine . 130 . 20–26 . September 2017 . 29206629 . 10.1016/j.rmed.2017.07.002 . free .
  11. News: Keown . Alex . vanc . GlaxoSmithKline Terminates Development of Losmapimod for COPD . 11 August 2019 . BioSpace . Oct 26, 2016.
  12. News: Lawrence . Stacy . vanc . GSK drops a pair of late-stage candidates in COPD, HIV . 11 August 2019 . FierceBiotech . Oct 26, 2016 . en.
  13. Inamdar A, Merlo-Pich E, Gee M, Makumi C, Mistry P, Robertson J, Steinberg E, Zamuner S, Learned S, Alexander R, Ratti E . 1370216 . 6 . 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 . 28 . 6 . 570–81 . June 2014 . 24699061 . 10.1177/0269881114529377 .
  14. Web site: Fulcrum Therapeutics Acquires Global Rights to Losmapimod, a Potential Disease-Modifying Therapy for Facioscapulohumeral Muscular Dystrophy . BioSpace . 23 April 2019 .
  15. Web site: ReDUX4 trial result exceeds expectations . FSHD Society . 26 June 2021 . https://web.archive.org/web/20210626171442/https://www.fshdsociety.org/2021/06/24/redux4-trial-result-exceeds-expectations/ . 26 June 2021 . Wayback Machine . 2021-06-24.
  16. Web site: Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) . ClinicalTrials.gov . United States National Library of Medicine . 12 August 2019 . en.
  17. News: Fulcrum's losmapimod fails interim analysis in muscle wasting trial . FierceBiotech . en.

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