Single doses of p38 MAP kinase inhibitors or prednisolone affect CRP and IL-6 in patients with active Rheumatoid Arthritis (RA)

Abstract

Purpose: To investigate the effects of single doses of losmapimod, dilmapimod (inhibitors of p38 MAPK) and prednisolone on biomarkers of systemic inflammation (serum C-reactive protein (CRP) and interleukin (IL)-6) in subjects with active rheumatoid arthritis (RA). Methods: Two randomized, double blind, placebo controlled, parallel group, single dose studies investigated the CRP and IL-6 dose-response relationships for losmapimod (study A) and dilmapimod and prednisolone (study B) in patients with active RA on stable weekly doses of methotrexate. CRP, IL-6 and other exploratory biomarkers were measured in blood at baseline and up to 72 hours post-dosing. Results: In study A, 51 subjects were randomized to receive losmapimod (7.5, 20 and 60 mg) or placebo and in study B, 77 subjects were randomized to receive dilmapimod (7.5, 15 and 25 mg) or prednisolone (10, 20 and 50 mg) or placebo. Single doses of prednisolone caused a decrease in circulating IL-6 detectable at 3 and 24 hours post-dose as well as a CRP single-dose relationship at 48 hours post-dose in patients with active RA. All doses of losmapimod produced a statistically significant reduction in serum IL-6, 3 hours post-dose but had no effect on CRP. Dilmapimod had no effect on IL-6 or CRP at any dose or time.

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

“…A clinical trial simulation using a placebo dataset ( n =895) from the GSK aggregated paroxetine database (Gomeni and Merlo Pich, 2007) indicated that for a study with n =12 per arm the probability of obtaining Bech results similar to those obtained in Study 574 was around 1% (unpublished). This assessment, together with new evidence for the effects of losmapimod in other patients with inflammatory disorders (Elkhawad et al, 2012; Lukey et al, 2012), produced enough confidence to attempt replication of the treatment effect in a larger and adequately powered trial. Study 009 was designed using the results of trial 574 as Bayesian prior.…”

Identification of p38β as a Therapeutic Target for the Treatment of Sézary Syndrome

“…The clinical benefit of inhibiting p38 has been explored for chronic inflammation associated with chronic obstructive pulmonary disease (COPD), cardiovascular disease, rheumatoid arthritis (RA), nerve pain, and most recently solid tumors ( Anand et al 2011 ; ClinicalTrials.gov 2012 ; Lukey et al 2012 ). Our observations in CTCL cell lines and patient samples indicate that p38 may also be a therapeutic target in this disease as well.…”

A Randomized Dose-Escalation Study of the Safety and Anti-Inflammatory Activity of the p38 Mitogen-Activated Protein Kinase Inhibitor Dilmapimod in Severe Trauma Subjects at Risk for Acute Respiratory Distress Syndrome

“…The plasma concentration of dilmapimod increased approximately proportionally to the increase in dose, and both the 7.5 mg and 10 mg 24-hour continuous infusion regimen seemed superior to the 4-hour infusion regimens in maintaining therapeutic concentrations of dilmapimod within the range required to achieve 50% inhibition of TNF-α expression (IC50) (37). Although both 24-hour dosing regimens yielded more consistent blood dilmapimod concentrations, the 10-mg dosing arm yielded a greater proportion of levels above the therapeutic range than the 7.5-mg dosing arm.…”