Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial.
BACKGROUND
There is a pressing need for new forms of treatment for COPD. Based on the known pathophysiology of COPD, inhibition of matrix metalloproteinases is a theoretically promising approach. This Phase IIa study evaluated the effects of AZD1236, a selective MMP-9 and MMP-12 inhibitor, on the biomarkers of inflammation and emphysematous lung tissue degradation in patients with moderate-to-severe COPD.


METHODS
This was a multinational, randomized, double-blind, placebo-controlled signal-searching study conducted in men and women aged ≥40 years with stable moderate-to-severe COPD. After a 2-6-week period to eliminate any remaining effects of previous medication, 55 patients received oral AZD1236 75 mg or matching placebo twice daily for 6 weeks. Differential cell count and TNF-α levels in induced sputum and 24-h urinary desmosine excretion were the main study variables, but a range of exploratory biomarkers was also assessed in induced sputum, blood and urine. Secondary variables included lung function and patient-recorded Clinical COPD Questionnaire (CCQ) responses and diary records of symptoms, adverse events, use of rescue medication and AZD1236 plasma concentrations.


RESULTS
The majority of variables showed little change compared to placebo although there was a possible, but not statistically significant reduction in urinary desmosine excretion and reductions in the number and percentage of lymphocytes in sputum and blood with AZD1236. No effect was seen on clinical parameters after 6 weeks of treatment. The proportion of patients experiencing adverse events was similar in both treatment groups.


CONCLUSIONS
AZD1236 dosed orally at 75 mg twice daily was generally well tolerated over 6 weeks in patients with moderate-to-severe COPD. No clinical efficacy of AZD1236 was demonstrated in this short-term signal-searching study, although possible evidence of an impact on desmosine may suggest the potential value of selective inhibitors of MMPs in the treatment of COPD in longer term trials.
Department of Respiratory Diseases, Århus University Hospital, Nørrebrogade 44, DK-8000 Århus C, Denmark. ronadahl@rm.dk
Ronald
R
Dahl
Ingrid
I
Titlestad
Ari
A
Lindqvist
Pascal
P
Wielders
Heather
H
Wray
Millie
M
Wang
Viktoria
V
Samuelsson
John
J
Mo
Alison
A
Holt
D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D003895:Desmosine / Q000652:urine; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D012129:Respiratory Function Tests; D012720:Severity of Illness Index; D016896:Treatment Outcome
D015415:Biomarkers; D061965:Matrix Metalloproteinase Inhibitors; D003895:Desmosine