An update and appraisal of the cilomilast Phase III clinical development programme for chronic obstructive pulmonary disease

Abstract

Cilomilast (Ariflo, SB 207499) is an orally active, second-generation phosphodiesterase (PDE) 4 inhibitor that is being developed by GlaxoSmithkline for the treatment of chronic obstructive pulmonary disease (COPD). The results of Phase I and Phase II studies have demonstrated that cilomilast significantly improves lung function and quality of life to a clinically meaningful extent, which has led to a comprehensive Phase III programme of research evaluating efficacy, safety and mechanism of action. However, the results of those Phase III studies are unremarkable and disappointing, raising doubt over the future of cilomilast as a novel therapy for COPD. This review summarizes data obtained from the Phase III clinical development programme, highlights some of the potential concerns both specific to cilomilast and to PDE4 inhibitors in general and assesses the likelihood that cilomilast will reach the market.

Figure 1

Results of one Phase II (no. 32) and four independent Phase III efficacy trials (nos 39, 156, 091 and 042) in Europe (EU) and North America (NA) of the effect of oral cilomilast on clinic forced expiratory volume in 1 s (FEV₁) in patients with chronic obstructive pulmonary disease. (a) Subjects entered a 2-week placebo run-in before being randomized (double-blind) to receive cilomilast (5 mg, n = 109; 10 mg, n = 102; 15 mg, n = 107; bid) or placebo (n = 106) for 6 weeks. At defined times after treatment trough (predose) FEV₁ was measured. Results with 15 mg cilomilast (bid) are shown. (b–e) Subjects entered a 4-week placebo run-in before being randomized (double-blind) to receive cilomilast (15 mg bid; ○) or placebo (•) for 24 weeks. At the indicated times after treatment trough (predose) FEV₁ was measured. At the end of the trial the average FEV₁ was calculated and an endpoint (EP) measurement made. NB: the ordinate shows the mean change from baseline in clinic FEV₁, which was modest (0–∼60 ml). Data are taken from references [19, 21]. See text for further details. *Statistically significant improvement in lung function relative to placebo

Figure 2

Percentage of adverse events reported in all controlled asthma and chronic obstructive pulmonary disease clinical trials. The number of subjects that received cilomilast or placebo were: 0 (n = 1802), 2.5 mg (n = 72), 5 mg (n = 366), 10 mg (n = 437) 15 mg (n = 2475). Data taken from reference [40]