title: Safety and tolerability of an oral MMP-9 and -12 inhibitor, AZD1236, in patients with moderate-to-severe COPD: a randomised controlled 6-week trial.
abstract: BACKGROUND
  Matrix metalloproteinases (MMPs) have been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). This phase IIa study investigated the safety and tolerability of oral AZD1236, an MMP-9 and MMP-12 inhibitor, in patients with COPD. Efficacy analyses were included on an exploratory basis.
  
  
  METHODS
  This was a multinational, randomised, double-blind, parallel-group study conducted in 74 men and women aged ≥40 years with stable moderate-to-severe COPD. After a 2-week run-in period, patients received oral AZD1236 75 mg, or matching placebo, twice daily for 6 weeks (on top of background medication with short-acting bronchodilators and/or inhaled corticosteroids, if applicable). In addition to safety and tolerability endpoints (AEs, vital signs and laboratory assessments) efficacy was assessed as a secondary objective (spirometry, 6MWT, BODE index and biomarkers in blood and urine. Clinical COPD Questionnaire (CCQ), peak expiratory flow (PEF) and daily diary cards of symptom severity were completed by the patients.
  
  
  RESULTS
  The incidence of adverse events (AEs) was similar in AZD1236 and placebo recipients; 28 in 13 patients (37%) and 21 in 17 patients (44%), respectively; the difference in actual number reported accounted for primarily by mild AEs in the AZD1236 group. The most commonly experienced AEs in both groups were COPD exacerbations, headache and viral infections. One patient in the AZD1236 group experienced a serious AE of interstitial nephritis (comprising of acute renal failure, rash, fever and blood eosinophilia) considered to be related to treatment. After 6 weeks, AZD1236 had demonstrated no significant effect on lung function, 6MWT, BODE index or biomarkers compared with placebo. No meaningful differences were observed in patient-reported CCQ score, PEF, COPD symptoms or use of rescue medication.
  
  
  CONCLUSIONS
  For most of these COPD patients, with the particular exception of one who experienced a serious AE, AZD1236 at 75 mg twice daily was generally well tolerated and had an acceptable safety profile. Therapeutic efficacy could not be demonstrated, possibly due to the stable disease and background medications of the patients enrolled in this small, short-term study.
authors.affiliation: Pulmonary Research Institute at Hospital Grosshansdorf, Centre for Pneumology and Thoracic Surgery, Woehrendamm 80, Grosshansdorf, Germany. magnussen@pulmoresearch.de
authors.forename: Helgo
authors.initials: H
authors.lastname: Magnussen
authors.forename: Henrik
authors.initials: H
authors.lastname: Watz
authors.forename: Anne
authors.initials: A
authors.lastname: Kirsten
authors.forename: Millie
authors.initials: M
authors.lastname: Wang
authors.forename: Heather
authors.initials: H
authors.lastname: Wray
authors.forename: Viktoria
authors.initials: V
authors.lastname: Samuelsson
authors.forename: John
authors.initials: J
authors.lastname: Mo
authors.forename: Richard
authors.initials: R
authors.lastname: Kay
mesh_terms: D000368:Aged; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D010366:Peak Expiratory Flow Rate; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires; D016896:Treatment Outcome
chemical_list: D061965:Matrix Metalloproteinase Inhibitors