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Safety and Efficacy of an Inhaled Epidermal Growth Factor Receptor Inhibitor (BIBW 2948 BS) in Chronic Obstructive Pulmonary Disease

¹ Division of Pulmonary and Critical Care Medicine, Department of Medicine, and ² Cardiovascular Research Institute, University of California San Francisco, San Francisco, California; ³ Department of Lead Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany; ⁴ Department of Clinical Research Respiratory, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, Connecticut; ⁵ Fraunhofer Institute Toxicology and Experimental Medicine (ITEM), Hannover, Germany; ⁶ UAB Lung and Health Center, Birmingham, Alabama; ⁷ National Jewish Health, Denver, Colorado; ⁸ Temple University School of Medicine, Philadelphia, Pennsylvania; ⁹ Department of Pneumology, University Medical Center Freiburg, Freiburg im Breisgau; and ¹⁰ Department of Sports Medicine, Medical Clinic and Policlinic, University of Tuebingen, Tuebingen, Germany

Correspondence and requests for reprints should be addressed to John Fahy, M.D., M.Sc., 505 Parnassus Avenue, M1307, Box 0130, San Francisco, CA 94143-0130. E-mail: john.fahy{at}ucsf.edu

Rationale: Epidermal growth factor receptor (EGFR) activation is implicated in mucin hypersecretion in chronic obstructive pulmonary disease (COPD).

Objectives: To investigate the safety and efficacy of an inhaled EGFR antagonist (BIBW 2948) in COPD.

Methods: Multicenter, double-blind, placebo-controlled trial of 4 weeks of treatment with two doses of BIBW 2948 (15 and 30 mg twice a day) on safety and mucin-related outcomes in 48 patients with COPD. The effect of BIBW 2948 on EGFR activation in airway epithelial cells was assessed using an ex vivo assay. Efficacy measures included the volume of mucin in the airway epithelium (Vs mu,bala) in bronchial biopsies and the expression of mucin genes in bronchial brushings.

Measurements and Main Results: Inhaled BIBW 2948 induced a dose-related inhibition of EGFR internalization (reflecting decreased EGFR activation) in epithelial cells from treated subjects. However, BIBW 2948 was associated with a dose-related increase in adverse events, including reversible liver enzyme elevation (n = 2), and reduction in FEV₁. The changes in mucin stores and mucin gene expression were not significantly different in the pooled BIBW 2948 group versus placebo (volume of mucin per surface area of basal lamina = 0.22 ± 7.11 vs. 0.47 ± 8.06 µm³/µm²; P = 0.93). However, in the 30 mg twice a day group, the reduction in epithelial mucin stores was greatest in subjects with the greatest degree of EGFR inhibition (Pearson r = 0.98; 95% confidence interval, 0.71–0.99).

Conclusions: Four-week treatment with BIBW 2948 did not significantly decrease epithelial mucin stores and was poorly tolerated in patients with COPD. Ex vivo analyses suggest that higher doses may be more effective at both EGFR inhibition and decreases in mucin stores but that adverse events should be expected.

Clinical trial registered with www.clinicaltrials.gov (NCT00423137).

Key Words: chronic obstructive pulmonary disease • chronic bronchitis • epidermal growth factor receptor • mucins

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Basic research implicates epidermal growth factor receptor (EGFR) activation in the pathogenesis of mucin hypersecretion in chronic obstructive pulmonary disease (COPD). What This Study Adds to the Field Four-week treatment with the EGFR antagonist BIBW 2948 did not significantly decrease epithelial mucin stores and was poorly tolerated in patients with COPD. Ex vivo analyses suggest that higher doses may be more effective at both EGFR inhibition and decreases in mucin stores, but that adverse events should be expected.

 

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