Losmapimod

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Losmapimod
Losmapimod.svg
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Legal status
Identifiers
  • 6-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-N-(2,2-dimethylpropyl)pyridine-3-carboxamide
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.158.124 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H26FN3O2
Molar mass 383.467 g·mol−1
3D model (JSmol)
  • C3CC3NC(=O)c(cc(F)c1C)cc1-c(cc2)ncc2C(=O)NCC(C)(C)C
  • InChI=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) X mark.svgN
  • Key:KKYABQBFGDZVNQ-UHFFFAOYSA-N X mark.svgN
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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.[ citation needed ]

Related Research Articles

A mitogen-activated protein kinase is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.

<span class="mw-page-title-main">Facioscapulohumeral muscular dystrophy</span> Muscular degenerative disease of the face, shoulder blades, and upper arms

Facioscapulohumeral muscular dystrophy (FSHD) is a type of muscular dystrophy, a group of heritable diseases that cause degeneration of muscle and progressive weakness. Per the name, FSHD tends to sequentially weaken the muscles of the face, those that position the scapula, and those overlying the humerus bone of the upper arm. These areas can be spared, and muscles of other areas usually are affected, especially those of the chest, abdomen, spine, and shin. Almost any skeletal muscle can be affected in advanced disease. Abnormally positioned, termed 'winged', scapulas are common, as is the inability to lift the foot, known as foot drop. The two sides of the body are often affected unequally. Weakness typically manifests at ages 15–30 years. FSHD can also cause hearing loss and blood vessel abnormalities at the back of the eye.

Mitogen Activated Protein (MAP) kinase kinase kinase is a serine/threonine-specific protein kinase which acts upon MAP kinase kinase. Subsequently, MAP kinase kinase activates MAP kinase. Several types of MAPKKK can exist but are mainly characterized by the MAP kinases they activate. MAPKKKs are stimulated by a large range of stimuli, primarily environmental and intracellular stressors. MAPKKK is responsible for various cell functions such as cell proliferation, cell differentiation, and apoptosis. The duration and intensity of signals determine which pathway ensues. Additionally, the use of protein scaffolds helps to place the MAPKKK in close proximity with its substrate to allow for a reaction. Lastly, because MAPKKK is involved in a series of several pathways, it has been used as a therapeutic target for cancer, amyloidosis, and neurodegenerative diseases. In humans, there are at least 19 genes which encode MAP kinase kinase kinases:

p38 mitogen-activated protein kinases are a class of mitogen-activated protein kinases (MAPKs) that are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in cell differentiation, apoptosis and autophagy. Persistent activation of the p38 MAPK pathway in muscle satellite cells due to ageing, impairs muscle regeneration.

Mitogen-activated protein kinase kinase is a dual-specificity kinase enzyme which phosphorylates mitogen-activated protein kinase (MAPK).

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Phosphoinositide 3-kinase inhibitors are a class of medical drugs that are mainly used to treat advanced cancers. They function by inhibiting one or more of the phosphoinositide 3-kinase (PI3K) enzymes, which are part of the PI3K/AKT/mTOR pathway. This signal pathway regulates cellular functions such as growth and survival. It is strictly regulated in healthy cells, but is always active in many cancer cells, allowing the cancer cells to better survive and multiply. PI3K inhibitors block the PI3K/AKT/mTOR pathway and thus slow down cancer growth. They are examples of a targeted therapy. While PI3K inhibitors are an effective treatment, they can have very severe side effects and are therefore only used if other treatments have failed or are not suitable.

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Pirfenidone, sold under the brand name Pirespa among others, is a medication used for the treatment of idiopathic pulmonary fibrosis. It works by reducing lung fibrosis through downregulation of the production of growth factors and procollagens I and II.

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Ifetroban is a potent and selective thromboxane receptor antagonist. It has been studied in animal models for the treatment of cancer metastasis, myocardial ischemia, hypertension, stroke, thrombosis, cardiomyopathy, and for its effects on platelets. Clinical trials are evaluating the therapeutic safety and efficacy of oral ifetroban capsules for the treatment of cancer metastasis, cardiovascular disease, aspirin exacerbated respiratory disease, systemic sclerosis, and Duchenne muscular dystrophy.

Givinostat, sold under the brand name Duvyzat is a medication used for the treatment of Duchenne muscular dystrophy. It is a histone deacetylase inhibitor with potential anti-inflammatory, anti-angiogenic, and antineoplastic activities. It is a histone deacetylase (HDAC) inhibitor that works by targeting pathogenic processes to reduce inflammation and loss of muscle.

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Nintedanib, sold under the brand names Ofev and Vargatef, is an oral medication used for the treatment of idiopathic pulmonary fibrosis and along with other medications for some types of non-small-cell lung cancer.

A MEK inhibitor is a chemical or drug that inhibits the mitogen-activated protein kinase kinase enzymes MEK1 and/or MEK2. They can be used to affect the MAPK/ERK pathway which is often overactive in some cancers.

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Ralimetinib (LY2228820) is a small molecule experimental cancer drug in development by Eli Lilly. Although originally thought to be a p38 mitogen-activated protein kinase (MAPK) inhibitor, it has since been reported that it acts instead as an epidermal growth factor receptor (EGFR) inhibitor.

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<span class="mw-page-title-main">NJK14047</span> Chemical compound

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<span class="mw-page-title-main">Pamapimod</span> Investigational drug

Pamapimod is an investigational drug which is being evaluated for the treatment of autoimmune diseases. It is a p38 mitogen-activated protein kinase inhibitor. It has been evaluated in a phase 2 clinical trial for the treatment of rheumatoid arthritis, but was found not to be effective. It has subsequently been investigated as a possible treatment for osteoarthritis.

References

  1. ↑ Aston NM, Bamborough P, Buckton JB, Edwards CD, Holmes DS, Jones KL, et al. (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. 52 (20): 6257–69. doi:10.1021/jm9004779. PMID   19772287.
  2. 1 2 "FORM S-1 REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933 FULCRUM THERAPEUTICS, INC". www.sec.gov. Securities and Exchange Commission. Retrieved 26 October 2019.
  3. 1 2 3 Watz H, Barnacle H, Hartley BF, Chan R (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. 2 (1): 63–72. doi:10.1016/S2213-2600(13)70200-5. PMID   24461903.
  4. 1 2 3 Fisk M, Cheriyan J, Mohan D, Forman J, Mäki-Petäjä KM, McEniery CM, et al. (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. 13 (3): e0194197. Bibcode:2018PLoSO..1394197F. doi: 10.1371/journal.pone.0194197 . PMC   5863984 . PMID   29566026.
  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. ↑ Cheriyan J, Webb AJ, Sarov-Blat L, Elkhawad M, Wallace SM, Mäki-Petäjä KM, et al. (February 2011). "Inhibition of p38 mitogen-activated protein kinase improves nitric oxide-mediated vasodilatation and reduces inflammation in hypercholesterolemia". Circulation. 123 (5): 515–23. doi: 10.1161/CIRCULATIONAHA.110.971986 . PMID   21262998. S2CID   25095165.
  9. ↑ Elkhawad M, Rudd JH, Sarov-Blat L, Cai G, Wells R, Davies LC, et al. (September 2012). "Effects of p38 mitogen-activated protein kinase inhibition on vascular and systemic inflammation in patients with atherosclerosis". JACC. Cardiovascular Imaging. 5 (9): 911–22. doi: 10.1016/j.jcmg.2012.02.016 . PMID   22974804.
  10. ↑ Newby LK, Marber MS, Melloni C, Sarov-Blat L, Aberle LH, Aylward PE, et al. (September 2014). "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. doi:10.1016/S0140-6736(14)60417-7. PMID   24930728. S2CID   38041584.
  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. ↑ O'Donoghue ML, Glaser R, Cavender MA, Aylward PE, Bonaca MP, Budaj A, et al. (April 2016). "Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction: A Randomized Clinical Trial". JAMA. 315 (15): 1591–9. doi: 10.1001/jama.2016.3609 . PMID   27043082.
  13. ↑ "GSK provides update on LATITUDE-TIMI 60 (losmapimod cardiovascular study)". GSK. 27 October 2015. Retrieved 12 August 2019.
  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. ↑ Pascoe S, Costa M, Marks-Konczalik J, McKie E, Yang S, Scherbovsky PS (September 2017). "Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical benefits in COPD". Respiratory Medicine. 130: 20–26. doi: 10.1016/j.rmed.2017.07.002 . PMID   29206629.
  18. ↑ Keown A (26 October 2016). "GlaxoSmithKline Terminates Development of Losmapimod for COPD". BioSpace. Retrieved 11 August 2019.
  19. ↑ Lawrence S (26 October 2016). "GSK drops a pair of late-stage candidates in COPD, HIV". FierceBiotech. Retrieved 11 August 2019.
  20. 1 2 Inamdar A, Merlo-Pich E, Gee M, Makumi C, Mistry P, Robertson J, et al. (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. 28 (6): 570–81. doi:10.1177/0269881114529377. PMID   24699061. S2CID   1370216.
  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. ↑ "Fulcrum Therapeutics Acquires Global Rights to Losmapimod, a Potential Disease-Modifying Therapy for Facioscapulohumeral Muscular Dystrophy". BioSpace. 23 April 2019.
  24. ↑ "ReDUX4 trial result exceeds expectations". FSHD Society. Wayback Machine. 24 June 2021. Archived from the original on 26 June 2021. Retrieved 26 June 2021.
  25. ↑ "Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD)". ClinicalTrials.gov. United States National Library of Medicine. Retrieved 12 August 2019.
  26. ↑ Clinical trial number NCT04003974 for "Efficacy and Safety of Losmapimod in Subjects With Facioscapulohumeral Muscular Dystrophy (FSHD) (FSHD)" at ClinicalTrials.gov
  27. ↑ "Fulcrum's losmapimod fails interim analysis in muscle wasting trial". FierceBiotech.
  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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