title: Safety and efficacy of an inhaled epidermal growth factor receptor inhibitor (BIBW 2948 BS) in chronic obstructive pulmonary disease.
abstract: BACKGROUND
  Epidermal growth factor receptor (EGFR) activation is implicated in mucin hypersecretion in chronic obstructive pulmonary disease (COPD).
  
  
  OBJECTIVE
  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.
  
  
  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 FEV(1). 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 microm(3)/microm(2); 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).
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
authors.forename: Prescott G
authors.initials: PG
authors.lastname: Woodruff
authors.forename: Michael
authors.initials: M
authors.lastname: Wolff
authors.forename: Jens M
authors.initials: JM
authors.lastname: Hohlfeld
authors.forename: Norbert
authors.initials: N
authors.lastname: Krug
authors.forename: Mark T
authors.initials: MT
authors.lastname: Dransfield
authors.forename: E Rand
authors.initials: ER
authors.lastname: Sutherland
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Criner
authors.forename: Victor
authors.initials: V
authors.lastname: Kim
authors.forename: Antje
authors.initials: A
authors.lastname: Prasse
authors.forename: Michael C
authors.initials: MC
authors.lastname: Nivens
authors.forename: Kay
authors.initials: K
authors.lastname: Tetzlaff
authors.forename: Ralf
authors.initials: R
authors.lastname: Heilker
authors.forename: John V
authors.initials: JV
authors.lastname: Fahy
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D001999:Bronchoscopy; D004311:Double-Blind Method; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009077:Mucins / Q000378:metabolism; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D009077:Mucins; D004815:Epidermal Growth Factor; D066246:ErbB Receptors