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

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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 FEV1 at end of treatment. TDI, symptoms, and blood inflammatory biomarkers were measured. FEV1 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<0.05) in all studies. Plasma fibrinogen decreased by 10 to 15% (p<0.05) in the two studies in which it was measured. The most common PH-associated side effect was rash. A disproportionate incidence of atrial fibrillation (AF) was observed in two studies with no apparent dose-relationship. PH dose dependently prolonged QTcF interval. In summary, PH improved FEV1; 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.

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