Losmapimod Explained

Losmapimod (GW856553X) is an investigational drug being developed by Fulcrum Therapeutics for the treatment of facioscapulohumeral muscular dystrophy (FSHD); a phase III clinical trial is pending approval. Losmapimod selectively inhibits enzymes p38α/β mitogen-activated protein kinases (MAPKs), which are modulators of DUX4 expression and mediators of inflammation.^[1]

Potential treatment for FSHD

Fulcrum Therapeutics, a Massachusetts-based biotechnology company, identified p38α/β MAPK inhibitors as potent suppressors of DUX4 expression, the de-suppression of which is accepted as the cause FSHD. Among p38α/β MAPK inhibitors, Fulcrum chose losmapimod as its preferred developmental candidate due to its "substantial and attractive preclinical and clinical data" from previous GlaxoSmithKline (GSK) clinical trials.

As Fulcrum discovered the potential utility of p38 MAPK inhibition in treating FSHD, a Saint Louis University (SLU) research group independently arrived at the same conclusion.^{[2] [3]} The SLU research group found that p38α and p38β isoforms independently contribute to DUX4 expression, which indicates potential gain in exploring isoform specific (p38α or p38β) inhibition to balance therapeutic effects with side effects.

A theoretical limitation of losmapimod is that p38 kinase inhibition could impair myogenesis, the opposite effect of what is desired. Facio Therapies, a Dutch pharmaceutical company with their own drug candidate for FSHD, announced that they had eliminated p38 kinase inhibitors (including losmapimod) as a developmental candidate because p38 kinase inhibitors resulted in impaired myotube formation on their drug development platform.^{[4] [5]} Indeed, others have found that p38α abrogation impairs myotube formation.^[6] However, Fulcrum found that p38 kinase inhibition did not impair myotube fusion at levels sufficient for DUX4 reduction.^[7]

Fulcrum development timeline

• March 2022: Fulcrum announced plan for a phase III clinical trial for treatment of FSHD, named REACH.^[8] Unlike the previous trial, the primary endpoint will be reachable workspace.
• June 2021: Results of a randomized controlled phase IIb clinical trial, named ReDUX4, showed statistically significant slowing of muscle function deterioration, albeit biomarkers were unchanged. Further trials are pending.^{[9] [10] [11]}
• March 2021: Fulcrum announced discontinuation of LOSVID due to challenges with enrollment and the rapidly evolving environment of COVID-19 treatment.^[12]
• June 2020: Fulcrum announced applying to the FDA to initiate a phase III clinical trial, LOSVID, for losmapimod in treatment of COVID-19. Recent evidence indicates that p38 MAPK inhibition could be therapeutic, possibly by attenuating the exaggerated inflammatory response following SARS-CoV-2 infection.^[13]
• January 2020: Fulcrum announced receiving orphan drug status for losmapimod.
• October 2019: Fulcrum announced preliminary results of their phase 1 clinical trial of losmapimod. Oral dosing of losmapimod demonstrated sustained muscle tissue drug concentrations that in preclinical in vitro studies had shown effective in reducing DUX4 levels.^[14]
• April 2019: Fulcrum acquired from GSK the global rights to losmapimod.^[15]

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.^{[16] [17] [18]}

GSK investigated losmapimod as a therapeutic for patients post-myocardial infarction (heart attack). Despite phase II clinical trials^{[19] [20] [21]} the phase IIIA clinical trial (LATITUDE) failed to show significantly improved clinical outcomes.^[22] In October 2015 GSK announced cancelling the planned phase IIIB trial, but would "evaluate all options for future development."^[23]

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^[24] in subjects with COPD. GSK terminated development of losmapimod for COPD in 2016.^{[25] [26]}

GSK investigated losmapimod as a therapeutic for major depressive disorder (MDD) on the basis of depression being correlated with elevated pro-inflammatory cytokines.^[27] Phase II clinical trials failed to show a significant improvement in depression symptoms and biomarkers.

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. Oliva J, Galasinski S, Richey A, Campbell AE, Meyers MJ, Modi N, Zhong JW, Tawil R, Tapscott SJ, Sverdrup FM . 6 . Clinically Advanced p38 Inhibitors Suppress DUX4 Expression in Cellular and Animal Models of Facioscapulohumeral Muscular Dystrophy . The Journal of Pharmacology and Experimental Therapeutics . 370 . 2 . 219–230 . August 2019 . 31189728 . 6652132 . 10.1124/jpet.119.259663 .
3. News: In Lab, SLU Research Halts Toxic Protein Linked to Muscular Dystrophy . 26 October 2019 . www.newswise.com . Newswise . 23 October 2019.
4. News: Facio to present at the World Muscle Society Congress . 9 November 2019 . Facio Therapies . 30 September 2019.
5. News: Facio reveals novel mechanism targeting the cause of FSHD . 9 November 2019 . Facio Therapies . 24 June 2019.
6. Perdiguero E, Ruiz-Bonilla V, Gresh L, Hui L, Ballestar E, Sousa-Victor P, Baeza-Raja B, Jardí M, Bosch-Comas A, Esteller M, Caelles C, Serrano AL, Wagner EF, Muñoz-Cánoves P . 6 . Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation . The EMBO Journal . 26 . 5 . 1245–56 . March 2007 . 17304211 . 1817635 . 10.1038/sj.emboj.7601587 .
7. Rojas LA, Valentine E, Accorsi A, Maglio J, Shen N, Robertson A, Kazmirski S, Rahl P, Tawil R, Cadavid D, Thompson LA . 6 . P38α Regulates Expression of DUX4 in Facioscapulohumeral Muscular Dystrophy . bioRxiv . 12 July 2019 . 700195 . 10.1101/700195 . 9 November 2019 . en. free .
8. News: Fulcrum announces Phase 3 trial of losmapimod . 3 March 2022 . FSHD Society . 3 March 2022 . https://web.archive.org/web/20220303235110/https://www.fshdsociety.org/2022/03/03/fulcrum-announces-phase-3-trial-of-losmapimod/ . 3 March 2022.
9. 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.
10. 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.
11. News: Fulcrum's losmapimod fails interim analysis in muscle wasting trial . FierceBiotech . en.
12. News: Inc . Fulcrum Therapeutics . Fulcrum Therapeutics Reports Recent Business Highlights and Fourth Quarter and Full Year 2020 Financial Results . 4 March 2022 . GlobeNewswire News Room . 4 March 2021 . https://web.archive.org/web/20210304120323/https://www.globenewswire.com/news-release/2021/03/04/2186976/0/en/Fulcrum-Therapeutics-Reports-Recent-Business-Highlights-and-Fourth-Quarter-and-Full-Year-2020-Financial-Results.html . 4 March 2021 . en.
13. Web site: Losmapimod as potential COVID-19 treatment? . FSHD Society . 10 June 2020 . https://web.archive.org/web/20200610163811/https://www.fshdsociety.org/2020/06/10/losmapimod-as-potential-covid-19-treatment/?fbclid=IwAR1pemUbJa76klnqVhwl-mHvGWwnjChlrL-4lm6y8YqpSgJx3d_1TbBZ60g . 10 June 2020 . 10 June 2020.
14. News: Fulcrum Therapeutics Announced Results of Phase 1 Clinical Trial of Losmapimod in FSHD . GlobeNewswire News Room . 4 October 2019.
15. Web site: Fulcrum Therapeutics Acquires Global Rights to Losmapimod, a Potential Disease-Modifying Therapy for Facioscapulohumeral Muscular Dystrophy . BioSpace . 23 April 2019 .
16. 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.
17. 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 .
18. 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 .
19. 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 .
20. 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 .
21. 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 .
22. 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 .
23. News: GSK provides update on LATITUDE-TIMI 60 (losmapimod cardiovascular study) . 12 August 2019 . GSK . 27 October 2015.
24. 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 .
25. News: Keown . Alex . vanc . GlaxoSmithKline Terminates Development of Losmapimod for COPD . 11 August 2019 . BioSpace . Oct 26, 2016.
26. News: Lawrence . Stacy . vanc . GSK drops a pair of late-stage candidates in COPD, HIV . 11 August 2019 . FierceBiotech . Oct 26, 2016 . en.
27. 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 .