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The Efficacy and Safety of Cilomilast in COPD

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Abstract

The aim of this review is to present the clinical data on the efficacy and safety of cilomilast in patients with chronic obstructive pulmonary disease (COPD). Over 6000 COPD patients received cilomilast during an extensive clinical development programme performed by GlaxoSmithKline (GSK).

Five phase III randomized, double-blind, placebo-controlled, parallel-group pivotal studies were conducted in poorly reversible patients (<15% or <200 mL improvement over baseline in forced expiratory volume in 1 second (FEV1) after salbutamol). Patients were randomized to receive oral cilomilast 15 mg (n = 2088) or placebo (n = 1408) twice daily for 24 weeks. The co-primary efficacy variables were changes from baseline in trough (predose) FEV1 and in total score of the St George’s Respiratory Questionnaire (SGRQ).

Additional studies were performed to investigate the anti-inflammatory actions of cilomilast by measuring inflammatory cells and mediators in biopsies and induced sputum; to assess the long-term effects of cilomilast; to assess the cardiac safety of cilomilast; and to assess the efficacy of cilomilast on hyperinflation. Results from one of the phase III and from one supportive study have been previously published.

In the phase III pivotal studies, when averaged over 24 weeks, the mean change from baseline in FEV1 in the cilomilast group showed improvement compared with placebo in all studies (range 24–44 mL treatment difference). When averaged over 24 weeks, there was a similar improvement in the mean total SGRQ score in both treatment groups with a decrease ranging from −1.8 to −4.2 units in the cilomilast group and 0.4 to −4.9 units in the placebo group. Only one study, however, showed both a statistically and clinically meaningful difference between the two treatment groups (treatment difference −4.1 units; p < 0.001). Although cilomilast was shown to reduce COPD exacerbations in some of these studies, there was no effect on the incidence of COPD exacerbations in a study specifically powered to detect a difference compared with placebo.

No significant change was found in the primary endpoints of the anti-inflammatory studies, although some anti-inflammatory activity was detected, including a reduction in tissue CD8+ T lymphocytes and CD68+ macrophages in airway biopsies. In addition, studies did not demonstrate a consistent significant effect of cilomilast on hyperinflation.

In all studies, adverse events associated with the gastrointestinal body system were reported more frequently in the cilomilast group than the placebo group and predominantly occurred within the first 2 weeks of initiating cilomilast therapy.

During the cilomilast development programme a number of different endpoints were investigated to characterize the efficacy and safety of this second-generation phosphodiesterase 4 inhibitor. Safety assessments throughout the late-phase programme did not reveal any evidence of serious safety concerns with the use of cilomilast. Previous studies in phase II and early phase III had shown improvements in efficacy endpoints and some evidence of an anti-inflammatory mechanism of action. However, subsequent phase III studies failed to definitively confirm the earlier programme results, which led to termination of the development of cilomilast.

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Acknowledgements

The authors acknowledge technical support from Diana Jones, a professional medical writer, who was compensated by GlaxoSmithKline (GSK), in the preparation of this manuscript.

SR has had or currently has a number of relationships with companies who provide products and/or services relevant to outpatient management of chronic obstructive pulmonary disease. These relationships include serving as a consultant, advising regarding clinical trials, speaking at continuing medical education programmes and performing funded research both at basic and clinical levels. He does not own stock in any pharmaceutical companies. In the last 3 years, SR has received laboratory and industry grants from Almirall, Altana, Astellas, Centocor, GSK, Nabi, Novartis and Pfizer; has served on consultancy and advisory boards for Adams, Almirall, Altana, AstraZeneca, Bend, Biolipox, Centocor, Critical Therapeutics, Dey, GSK, ICOS, Johnson & Johnson, Novartis, Ono Pharma, Parengenix, Pfizer, Roche, Sankyo, Sanofi, Schering-Plough and Talecris; and has received speakers fees from AstraZeneca, Boehringer Ingelheim, GSK, Osuka and Pfizer. AM is an employee of GSK (clinical) and owns stock and stock options in GSK. FB is an employee of GSK (clinical) and holds stock options with GSK. KR has been consulting, participated in Advisory Board meetings and received lecture fees from AstraZenica, Boehringer, Chiesi Pharmaceuticals, Pfizer, Novartis, AltanaPharma, MSD and GSK. The Department of Pulmonology, and thereby Professor Rabe as head of the department, has received grants from Novartis, AstraZeneca, Boehrigner Ingelheim, Roche and GSK between 2005 and 2008 and has a grant pending from Polen. NL has been an employee of GSK (statistician) since 2003. KK is an employee of GSK (clinical) and holds stock options in GSK. NS, WGC and YZ have no conflicts of interest.

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Authors and Affiliations

  1. Pulmonary and Critical Care Medicine, University of Nebraska Medical Center, Omaha, Nebraska, 68198-5885, USA

    Stephen Rennard

  2. GlaxoSmithKline, Research Triangle Park, North Carolina, USA

    Katharine Knobil, Andrea Morris, Nicholas Locantore & Frank Barnhart

  3. Leiden University Medical Centre, Leiden, the Netherlands

    Klaus F. Rabe

  4. Mount Sinai School of Medicine, New York City, New York, USA

    Neil Schachter

  5. Medical University of Genoa, Genoa, Italy

    Walter G. Canonica

  6. Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China

    Yuanjue Zhu

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  1. Stephen Rennard
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Rennard, S., Knobil, K., Rabe, K.F. et al. The Efficacy and Safety of Cilomilast in COPD. Drugs 68 (Suppl 2), 3–57 (2008). https://doi.org/10.2165/0003495-200868002-00002

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