Infliximab Shows No Benefit in COPD

OMAHA, Neb., May 2 -- Infliximab (Remicade), the tumor necrosis-factor alpha inhibitor, has proved ineffective for moderate to severe chronic obstructive pulmonary disease.

Patients who received the drug also had higher rates of pneumonia and cancer than those who received a placebo, reported Stephen Rennard, M.D., of the University of Nebraska Medical Center here in the first May issue of the American Journal of Respiratory and Critical Care Medicine.

The combination of lack of efficacy and safety concerns was similar to two studies reported just a day earlier in trials of patients with polymyalgia rheumatica and giant cell arteritis.

(Infliximab Fails Test in Two Rheumatologic Diseases)

Dr. Rennard and colleagues enrolled 234 COPD patients from 41 U.S. centers from January 2003 through January 2004, and randomized them to placebo or infliximab at either 3 mg/kg of body weight or 5 mg/kg.

The primary endpoint of the study was a clinically and statistically significant change in the Chronic Respiratory Questionnaire total score after 24 weeks of treatment. The researchers also considered secondary endpoints, including change in the six-minute walk distance and forced expiratory volume in one second (FEV₁).

However, they said, "no therapeutic benefit was observed" in either the primary outcome variable or any of the secondary endpoints.

On the other hand, although infliximab was generally well-tolerated, they found:

• Adverse events were the most common reason for stopping treatment, with 9.1% of placebo patients, 27.3% of low-dose infliximab patients, and 20.0% of high-dose infliximab patients discontinuing before week 24.
• COPD exacerbation was the most frequent adverse event, occurring in 41.6% of placebo patients and 36.4% and 38.8% of low- and high-dose infliximab patients respectively.
• One placebo patient suffered pneumonia (1.3%), compared with four (5.2%) and six (7.5%) respectively in the low- and high-dose infliximab groups. The differences were not significant.
• Malignancies were reported in 10 patients during the study -- one in the placebo group, five in the low-dose infliximab group, and four in the high-dose infliximab group. The differences were not statistically significant.

The increased number of malignancies in the infliximab-treated patients "raises concerns," the investigators said, although because of the small size of the sample the strength of the safety signal remains unclear.

"Nevertheless, the possibility that infliximab contributed to the progression, and thus the diagnosis, of malignancies remains a serious concern," they said.

The combination of the safety issues and the lack of efficacy means that the study "clearly does not support the use of infliximab routinely in moderate to severe COPD," the researchers concluded.

The COPD result was surprising because a number of lines of evidence had led investigators to think that TNF-alpha plays a role in the pathogenesis of the disease.

Infliximab is approved for use in rheumatoid arthritis and Crohn's disease, in which inflammation also play a major role. But in COPD, Dr. Rennard and colleagues said, it may be that other cytokines also play a role, so that blocking TNF-alpha has no effect.

The result, combined with the negative findings in polymyalgia rheumatica and giant cell arteritis, "tells you that all inflammation is not the same," Dr. Rennard said.

Since infliximab is approved for use in rheumatoid arthritis, he said, it's possible some physicians and patients may consider an off-label use for other inflammatory conditions.

"Indiscriminate off-label use is clearly not warranted," Dr. Rennard warned.

Another possible explanation for the COPD failure, the researchers said, might be that a six-month study was too short to demonstrate efficacy.

But in view of the "resoundingly negative results," a longer trial is unlikely, commented Peter Barnes, D.Sc., of Imperial College, London, in an accompanying editorial. The safety concerns raised by the investigators also work against the possibility of a longer trial, he said.

Dr. Rennard reported financial relationships with Centocor, AstraZeneca, GlaxoSmithKline, Altana, Dey, Inspire, Pfizer, Roche, Sanofi, and Novartis. He has a pending patent on the use of PDE4 inhibitors in repair and is a co-inventor of the patent owned by the University of Nebraska Medical Center.

Charles Fogarty, M.D., of Spartanburg Pharmaceutical Research in Spartanburg, S.C., reported financial relationships with Centocor. Steven Kelsen, M.D., of Temple University Medical Center in Philadelphia, reports financial relationships with GlaxoSmithKline and Genentech. Constantine Saadeh, M.D., of the Amarillo Center for Clinical Research in Amarillo, Tex., reported lecture fees from Pfizer. Thomas Siler, M.D., of Midwest Chest Consultants, P.C., in St. Charles, Mo., reported financial relationships with Boehringer Ingelheim, Pfizer, GlaxoSmithKline, Sepracor, Centocor, Altana, AstraZeneca, and Dey. Phillip Korenblat, M.D., of The Clinical Research Center, LLC, in St. Louis, reported a financial relationship with Centocor and owning more than ,000 in stock from Johnson & Johnson. James F. Donohue, M.D., of the University of North Carolina at Chapel Hill, is principal investigator on studies which Centocor is financing through the university.

Four of the authors -- Rosemary Watt, Kim Hung Lo, Rozsa Schlenker-Herceg, and Elliot S. Barnathan -- are employees of Centocor. The remaining authors do not have a financial relationship with a commercial entity that has an interest in the subject of the study.

Dr. Barnes reported financial relationships with GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Novartis, Scios, Altana, and Pfizer, which all have an interest in new therapies for COPD.