Systemic inhibition of p38 MAPK improves lung function and inflammatory markers in moderate-severe COPD

COPD is characterized by inflammation and lung function decline. p38 MAPK inhibition may be an anti-inflammatory therapeutic approach to COPD. The efficacy and safety of PH-797804 (PH), a potent, selective oral p38 inhibitor, was tested in three studies including patients with GOLD stage II/III COPD. Studies were randomized, double-blind, placebo-controlled, parallel-group, and of 6–12 weeks duration; with differing concomitant COPD treatment (PRN short-acting bronchodilators (SABD); tiotropium (TIO, 18 mg QD); or salmeterol/fluticasone combination (SFC, BID)). PH doses ranged from 0.25–10 mg QD, with 6 mg being common to all studies. The common primary endpoint was placebo-adjusted change from baseline in trough FEV 1 at end of treatment. TDI, symptoms, and blood inflammatory biomarkers were measured. FEV 1 was improved in all studies, which varied with background treatment (Table). Symptoms and TDI were inconsistently improved across studies. Plasma hs-CRP decreased by 40 to 43% (p 1 ; decreased systemic anti-inflammatory biomarkers; and produced adverse events both known (i.e., rash) and not known (i.e., AF and QTc prolongation) to be associated with p38 inhibition. Supported by Pfizer, Inc.