ATS 2009: Pirfenidone for Idiopathic Pulmonary Fibrosis Displays Contradictory Results in 2 Trials

Kristina Rebelo

May 27, 2009

May 27, 2009 (San Diego, California) — In the investigational phase 3 CAPACITY studies (CAP1 and CAP2) of pirfenidone for idiopathic pulmonary fibrosis (IPF), treatment with the oral antifibrotic and anti-inflammatory agent resulted in a significantly smaller loss of lung function after 72 weeks than placebo in one study, but the other almost identical trial did not show such a benefit, according to results released here at ATS 2009: the American Thoracic Society International Conference.

Pirfenidone is described as an orally active small-molecule drug. In vitro evidence has shown that it can modify disease course by inhibiting collagen synthesis, downregulating production of multiple cytokines, and decreasing fibroblast proliferation in response to cytokines. In the CAP2 study, both doses of pirfenidone significantly reduced (P < .05) loss of lung capacity, compared with placebo, in IPF patients with mild-to-moderate impairment in lung function. Pirfenidone has previously demonstrated activity in other fibrotic conditions, such as in the lung, kidney, and liver.

The ambitious studies featured 779 patients (344 in CAP1 and 435 in CAP2) who were enrolled at sites in North America (75%), Europe, and Australia. CAP1 patients were randomly assigned in a 1:1 ratio to receive a daily dose of pirfenidone 2403 mg or placebo. CAP 2 patients were randomly assigned in a 2:2:1 ratio to receive a daily dose of pirfenidone 2403 mg, placebo, or pirfenidone 1197 mg, respectively, administered in 3 divided doses; the lower-dose group provided safety and tolerability data.

Although the treatment phase is complete, only the blinded preliminary data were presented. The study group was primarily made up of white men (mean age, 66 years). High-resolution computed tomography scans met the criteria for a definite diagnosis of IPF in more than 90% of patients; the remaining subjects were diagnosed through biopsy.

The primary end point was change in percent predicted forced vital capacity (FVC) at week 72; it achieved statistical significance in CAP2 (P = .001). Secondary end points of progression-free survival and categorical change in FVC achieved statistical significance. The additional end point of efficacy did not reach statistical significance; however, data support a treatment effect. It was the primary end point in the earlier CAP1 (P = .501) that was not met; however, supportive evidence of a pirfenidone treatment effect was nonetheless observed.

Statistically Significant and Clinically Meaningful

"CAP2 has been shown to be statistically significant and clinically meaningful," said Paul W. Noble, MD, FCCP, presenter and cochair of the CAPACITY program that designed the trials' protocols, to an overflow crowd of physicians eager to learn the results of the CAPACITY trials. Dr. Noble is a physician/scientist, professor of medicine, and chief of the Division of Pulmonary, Allergy and Critical Care Medicine at Duke University School of Medicine in Durham, North Carolina.

Dr. Noble discussed data from CAPACITY in the area of dose-effect, mean change in FVC volume, and the 6-minute walk test distance (32 meters), which he said was "statistically significant as early as week 24."

In a press release, CAPACITY cochair Roland du Bois, MD, professor of medicine at National Jewish Health in Denver, Colorado, said: "When taken in the context of the urgent unmet need for new medicines to treat IPF patients, the collective efficacy and safety data from the 2 CAPACITY studies, corroborated by a similar study in Japan (where it was approved in 2008 and is sold by Shionogi), make a case for the use of pirfenidone in this disease setting."

As for adverse events, Dr. Noble said that "there were no real disparities between the groups." The more common adverse events for pirfenidone, compared with placebo, were primarily rash, fatigue, gastrointestinal symptoms, vomiting, nausea, dyspepsia, dizziness, and diarrhea; 2 patients —1 in CAP 1 and the other in CAP2 — developed a severe rash. The incidence of IPF-related deaths during the treatment period was lower among those in the CAP1 and CAP2 groups than among those in the placebo group.

"Our opinion is that CAP2 demonstrated statistically significant and meaningful effects on the primary end point of change in percentage predicted FVC and the secondary end point that treatment was safe and generally well tolerated, with similar [adverse events] in both groups," said Dr. Noble.

Contradictory Results

After the presentation, during the question-and-answer session, Dr. Noble received numerous compliments, in the form of "excellent trial" and "well done." His results also garnered comments about the "contradictory results between the 2 trials," the "quality-of-life issues," and the "marginal effects" in CAP2.

John Heffner, MD, past president of the American Thoracic Society and professor of medicine at Oregon Health & Science University in Portland, who attended the presentation, told Medscape Pulmonary Medicine after the session that he found the study "encouraging but not definitive."

He said: "We clinicians are desperate to find — and our patients are eager to get — a glimmer of hope, so any study that shows any statistically significant and important clinical evidence of positive effect on this deadly disease is warmly welcomed."

Dr. Heffner praised the study as having been "well designed."

"It gave us the opportunity to assess any potential benefit of the drug; the findings encourage us that this agent probably limits or slows the course of the disease," he said. "But where we are with this disease is perhaps where we were with the earliest stages of chemotherapy discovery for cancer. Now we use combination drugs and we've had to develop one drug after another from a family of drugs that showed some positive effect. When we found drugs that had a positive effect, we had to learn to use them in combination."

He continued: "This is the first drug that demonstrates any benefit, but it clearly will not be a cure or sufficient by itself to offer patients major benefit. But in discovering the positive effect of this drug, we perhaps can find other drugs that can be used in combination or [modify the] pirfenidone structure so we can find more effective medications."

Dr. Noble reports that he is a paid consultant for InterMune, Inc, which funded the research. Dr. Heffner has disclosed no relevant financial relationships.

ATS 2009: American Thoracic Society International Conference: Abstract 216. Presented May 17 and 19, 2009.

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