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.
Pro-inflammatory cytokines (PICs) may play important pathophysiological roles in some forms of Major Depressive Disorder (MDD). The p38 MAPK inhibitor losmapimod (GW856553) attenuates the pro-inflammatory response in humans by reducing PIC production. Losmapimod (7.5 mg BD) was administered for 6 weeks in two randomised, placebo-controlled trials in subjects with MDD enriched with symptoms of loss of energy/interest and psychomotor retardation (Studies 574 and 009). Primary efficacy endpoints were the Bech 6-item depression subscale of the HAMD-17 (the 'Bech,') for Study 009; and the Bech, Inventory of Depressive Symptomatology-Clinician Rated (IDS-C), HAMD-17, and Quick Inventory of Depressive Symptomatology (self-rated) (QIDS-SR) for Study 574. Key cytokine biomarker levels were also measured. Study 574 (n=24) was terminated prematurely in light of emerging data from an internal study in rheumatoid arthritis. Efficacy results available at termination favoured losmapimod (Bech, 6 weeks: endpoint drug vs. placebo difference = -4.10; 95% CI, -7.36, -0.83; p=0.017). A subsequent study, Study 009 (n=128), designed using a Bayesian approach based on a prior derived from Study 574, showed no advantage for losmapimod (Bech, 6 weeks: endpoint drug vs. placebo difference = 1.11; 95% credible interval, -0.22, 2.50). Biomarker data showed no significant changes. In conclusion 7.5 mg BID losmapimod was not effective in MDD.
Neurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline R&D Ltd, Harlow, Essex, UK The first two authors equally contributed to the work here reported Present address: Takeda Development Centre Europe Ltd., London, UK amir.inamdar@takeda.com.
Amir
A
Inamdar
Neurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline R&D Ltd, Verona, Italy The first two authors equally contributed to the work here reported Present address: Neuroscience DTA, F. Hoffman-la Roche, Basel, Switzerland.
Emilio
E
Merlo-Pich
Neurosciences Medicines Development Centre, GlaxoSmithKline R&D Ltd, Harlow, Essex, UK.
Michelle
M
Gee
Neurosciences Medicines Development Centre, GlaxoSmithKline R&D Ltd, Durham, NC, USA.
Clare
C
Makumi
Discovery Biometrics, GlaxoSmithKline R&D Ltd, Harlow, Essex, UK.
Prafull
P
Mistry
Discovery Biometrics, GlaxoSmithKline R&D Ltd, Harlow, Essex, UK.
Jon
J
Robertson
Neurosciences Medicines Development Centre, GlaxoSmithKline R&D Ltd, Durham, NC, USA.
Erik
E
Steinberg
Clinical Pharmacology Modelling and Simulation, GlaxoSmithKline R&D Ltd, Verona, Italy.
Stefano
S
Zamuner
Neurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline R&D Ltd, Durham, NC, USA.
Susan
S
Learned
Neurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline R&D Ltd, Verona, Italy.
Robert
R
Alexander
Neurosciences Centre for Excellence in Drug Discovery, GlaxoSmithKline R&D Ltd, Verona, Italy.
Emiliangelo
E
Ratti
D000293:Adolescent; D000328:Adult; D000339:Affect / Q000187:drug effects*; D000928:Antidepressive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001499:Bayes Theorem; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D003521:Cyclopropanes / Q000009:adverse effects / Q000627:therapeutic use*; D016207:Cytokines / Q000097:blood; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology / Q000523:psychology; D004311:Double-Blind Method; D057239:Early Termination of Clinical Trials; D005060:Europe; D005260:Female; D006801:Humans; D007194:India; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D011725:Pyridines / Q000009:adverse effects / Q000627:therapeutic use*; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D000928:Antidepressive Agents; D015415:Biomarkers; D003521:Cyclopropanes; D016207:Cytokines; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases
Cytokines; major depressive disorder; p38 MAPK