Rennard SI, Fogarty C, Kelsen S, Long W, Ramsdell J, Allison J, Mahler D, Saadeh C, Siler T, Snell P, Korenblat P, Smith W, Kaye M, Mandel M, Andrews C, Prabhu R, Donohue JF, Watt R, Lo KH, Schlenker-Herceg R, Barnathan ES, Murray J (on behalf of the COPD Investigators)
Am J Respir Crit Care Med. 2007;175:926-934.
Rationale
Chronic obstructive pulmonary disease (COPD) is a progressive, smoking-related, inflammatory lung disease in which tumor necrosis factor-[alpha] is overexpressed and has been suggested to play a pathogenic role.
Objective.
To determine if infliximab, an anti-TNF-[alpha] antibody, results in clinical benefit and has an acceptable safety profile in patients with moderate to severe COPD.
Methods.
In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study, subjects with moderate to severe COPD received infliximab (3 mg/kg [n = 78] or 5 mg/kg [n = 79]) or placebo (n = 77) at Weeks 0, 2, 6, 12, 18, and 24. Efficacy, health status, and safety were assessed through Week 44.
Measurements and Main Results.
Infliximab was generally well tolerated, but showed no treatment benefit as measured by the primary endpoint, Chronic Respiratory Questionnaire total score. Similarly, there was no change in secondary measures, including prebronchodilator FEV1, 6-min walk distance, SF-36 physical score, transition dyspnea index, or moderate-to-severe COPD exacerbations. Post hoc analysis revealed that subjects who were younger or cachectic showed improvement in the 6-min walk distance. Malignancies were diagnosed during the study in 9 of 157 infliximab-treated subjects versus 1 of 77 placebo-treated subjects. No opportunistic infections were observed, and there were no differences in the occurrence of antibiotic-requiring infections, although the incidence of pneumonia was higher in infliximab-treated subjects. No infection-related mortality was observed. Higher proportions of infliximab-treated subjects discontinued the study agent due to adverse events (20-27%) than did placebo-treated subjects (9%).
Conclusions.
Subjects with moderate to severe COPD did not benefit from treatment with infliximab. Although not statistically significant, more cases of cancer and pneumonia were observed in the infliximab-treated subjects. The impact of infliximab on malignancy risk in patients with COPD needs to be further elucidated.
Editor's Comment.
New treatments for COPD are urgently needed, and there are data to suggest that TNF-[alpha] blockade may have an important role in modifying the pathogenesis of emphysema. This is based on the observation that TNF-[alpha] levels are increased insputum from patients with COPD, TNF-receptor knockout mice may be protected from developing emphysema if exposed to cigarette smoke, and some features of emphysema are exaggerated in mice with overexpression of this cytokine. On the other hand, humans with emphysema do not show an increase in blood TNF-[alpha], and one small earlier study failed to find a benefit from TNF-[alpha] blockade. This article describes an ambitious study in more than 200 subjects with moderate to severe COPD who received infliximab or placebo infusions over a 6-month period. Neither the primary end point, Chronic Respiratory Questionnaire scores, nor any of the secondary end points showed any evidence of improvement with this therapy. This study highlights both the widespread frustration with the currently available treatments for COPD and the complexities of pathogenesis that are unlikely to resolve with blockade of one cytokine, regardless of how central or biologically plausible its role may appear to be.
SK