Phase II Study of Single/Repeated Doses of Acumapimod (BCT197) to Treat Acute Exacerbations of COPD.

Mitogen-activated protein kinase p38 is a key regulator in the inflammation pathway and is activated in the lungs of chronic obstructive pulmonary disease (COPD) patients. Acumapimod is a potent, selective, oral, p38 inhibitor under investigation for treatment of acute exacerbations of COPD (AECOPD). In this Phase II, double-blind, randomized, placebo-controlled dose-exploration study of acumapimod in patients with moderate or severe AECOPD (NCT01332097), patients presenting with AECOPD were randomized to receive single-dose acumapimod (20 mg or 75 mg) on Day 1, repeated single-dose acumapimod (20 mg or 75 mg) on Days 1 and 6, oral prednisone 40 mg (10 days), or placebo. Primary outcome: improvement in forced expiratory volume in 1 s (FEV) versus placebo at Day 5 (single doses) and Day 10 (repeated doses).  = 183 patients were randomized; 169 (92%) patients completed the study. Although the primary endpoint (FEV at Day 10) was not met ( = 0.082), there was a significant improvement in FEV with acumapimod repeat-dose 75 mg versus placebo at Day 8 ( = 0.022) which, though not a prespecified endpoint, was part of an overall trend. Differences at lower doses did not achieve significance. Mean change in FEV AUC from baseline to Day 14 in the 75 mg repeat-dose group was significantly higher versus placebo ( = 0.02), prednisone ( = 0.01), and 20 mg single-dose groups ( = 0.015) (post-hoc analysis). EXACT-PRO showed numerical differences versus placebo that did not reach significance. Acumapimod was well tolerated. In conclusion, repeated single-dose acumapimod showed a clinically relevant improvement in FEV over placebo at Day 8, along with consistent numerical differences in EXACT-PRO. These data can be used to determine dose regimens for a proof-of-clinical-concept trial.