A promising anti-inflammatory drug failed to improve symptoms of moderate to severe chronic obstructive pulmonary disease, or COPD, in a large, multi-center trial.
The results of the randomized, double-blind, placebo-controlled trial of infliximab were published in the first issue of the May American Journal of Respiratory and Critical Care Medicine, published by the American Thoracic Society.
According to an editorial commenting on the research, the failure of the infliximab to provide any therapeutic benefit in COPD patients was unexpected because the drug has proven effective in treating other inflammatory diseases, particularly rheumatoid arthritis and Crohn's disease.
COPD is the fourth-leading cause of death of men and women in the United States and the world. It is projected to become the third-leading cause of death, after heart disease and cancer, by 2015.
Stephen I. Rennard, M.D., of the University of Nebraska Medical Center in Omaha, led a team of researchers at 41 U.S. medical centers that enrolled 234 subjects in the study. Patients receiving infliximab were randomly selected to receive the drug in doses of 3 mg/kg or 5 mg/kg six times during a six-month period of time.
At the end of six months, there was no meaningful difference in the quality of life among those taking the drug and those taking the placebo as measured by the Chronic Respiratory Questionnaire (CRQ). The questionnaire, which was the primary endpoint, assesses health-related quality of life in patients with functionally limiting chronic lung disease.
There were also no differences among the three groups in secondary efficacy endpoints as measured by FEV1, 6-minute walk distance, the transition dyspnea index and the number of exacerbations requiring a doctor or hospital visit.
According to the authors, the results of the study were surprising for a number of reasons. Infliximab is an anti-tumor necrosis factor TNF-á, and a number of studies have reported increased production of TNF in COPD patients. This increased production has been linked to weight loss, muscle weakness and muscle loss.
In addition, animal studies supported the prospect using the drug in COPD. When TNF-á was infused into rats, they developed emphysema, which, along with chronic bronchitis, makes up most COPD cases. When the TNF-á receptor was turned off in mice, they were less likely than mice that had not be genetically altered to develop emphysema when exposed to chronic cigarette smoke.
The latest study, however, did confirm a recently reported pilot study that found no improvement among the 14 COPD patients given infliximab.
In attempting to explain the disappointing results, the study authors speculate that, despite infliximab's efficacy in treating other inflammatory diseases, it may not be effective in COPD because other mediators, in addition to TNF-á, are necessary to cause COPD. They also concede that six months may simply be too short a time period to see improvement.
However, an increased number of malignancies observed in infliximab-treated subjects, the authors said, raised concern about the safety of this drug in lung patients. Although the malignancies may have been present when the patients enrolled in the study, "the possibility that infliximab contributed to the progession, and thus the diagnosis, of malignancies remains a serious concern."
This safety issue, coupled with the "resoundingly negative results," make in unlikely that a longer trial will be undertaken, according to the accompanying editorial.