Investigational p38 inhibitors for the treatment of chronic obstructive pulmonary disease

P Norman - Expert opinion on investigational drugs, 2015 - Taylor & Francis
P Norman
Expert opinion on investigational drugs, 2015Taylor & Francis
Introduction: The p38 protein kinases, in particular p38α and p38β, regulate the production
of multiple inflammatory mediators. Consequentially, considerable effort has been focused
on trying to develop p38 inhibitors for the treatment of inflammatory diseases. Some 20 p38
inhibitors have progressed to clinical development, mostly for the treatment of rheumatoid
arthritis, but with little success. Increasingly, interest has turned to their use in other
indications and notably chronic obstructive pulmonary disease (COPD). Areas covered: In …
Introduction: The p38 protein kinases, in particular p38α and p38β, regulate the production of multiple inflammatory mediators. Consequentially, considerable effort has been focused on trying to develop p38 inhibitors for the treatment of inflammatory diseases. Some 20 p38 inhibitors have progressed to clinical development, mostly for the treatment of rheumatoid arthritis, but with little success. Increasingly, interest has turned to their use in other indications and notably chronic obstructive pulmonary disease (COPD).
Areas covered: In this review, the author discusses the eight p38 inhibitors that have been clinically evaluated. Acumapimod is the only one of four orally delivered inhibitors that remains in active development while Phase II results of PH-797804 and losmapimod are compared. The activity of two inhibitors designed for inhaled delivery, RV-568 and PF-03715455, is compared but little is known about AZD-7624 or the discontinued GSK-610677.
Expert opinion: Results from animal models provide a clear rationale for developing p38 inhibitors for COPD, and appear to be (partially) validated by the efficacy seen with PH-797804 and losmapimod. Inhaled delivery provides the opportunity to enhance p38 inhibition in the lung while reducing unwanted systemic effects of p38 inhibition. Validation of this hypothesis should come from the results of the recently completed Phase II study with RV-568.
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