Key Point

The novel anti-inflammatory, antioxidant, and antifibrotic agent pirfenidone may reduce exacerbations and improve lung function in IPF patients.

TOKYO—New research suggests that pirfenidone, a novel agent with anti-inflammatory, antioxidant, and antifibrotic properties, may improve lung function and reduce the number of acute exacerbations in patients with idiopathic pulmonary fibrosis (IPF). In fact, the study was terminated early because the reduction in exacerbations was so significant that the review board wanted to allow all participants to take the drug.¹

STEM CELLS TESTED

Ganesh Raghu, MD, and colleagues randomized 107 corticosteroid-naïve IPF patients to receive treatment with pirfenidone or placebo; follow-up lasted nine months. All patients were on a dose-titration schedule of 200 mg three times a day for the first two days, 400 mg three times a day for the next two days, and 600 mg three times a day (maximum dose) for the last three days. The maximum dose was maintained throughout the study in patients who tolerated it. Patients not tolerating the maximum dose received a reduced dose. Primary end points included the difference in the change of the lowest oxygen saturation by pulse oximetry during two six-minute exercise tests administered at baseline and again at six months. Secondary end points included lung function (vital capacity [VC]) and episodes of acute IPF exacerbation. According to the authors, “The most striking and clinically important findings noted were that the episodes of acute exacerbation of IPF manifested exclusively in the placebo group and there was a lesser decline in change in VC in patients receiving pirfenidone.”

SECONDARY END POINTS IMPROVE

There were no statistically significant differences between groups in the change in oxygen saturation during the six-minute exercise test (the primary end point), though the pirfenidone group did show an increase from baseline, versus a decrease in the placebo group. The patients in the pirfenidone group, however, experienced significant improvements in the secondary end points. At nine months, the difference in decline of VC between groups was –0.13 L in the placebo group and –0.03 L in the treatment group. Ground-glass and reticular opacities on high-resolution CTs were reduced in 15% of pirfenidone patients versus 7% of placebo patients.

Most importantly, none of the pirfenidone recipients experienced an acute IPF exacerbation during nine months. In contrast, 14% of placebo recipients had an exacerbation (one of whom died). Because of these data, the study was aborted and the drug was given to placebo patients. “The implication of the prevention of acute exacerbation by pirfenidone is potentially crucial for the prognosis of IPF, as these episodes often have a fatal outcome despite aggressive levels of supportive care in the [ICU],” stressed the authors.

Compliance rates at both six and nine months were similar between groups: About 85% of pirfenidone and 81% of placebo patients were compliant at six months, and 78% of both groups were adherent at nine months. Pirfenidone, however, was not without adverse effects; in fact, about half of the patients were taking a reduced dose at nine months due to side effects. The most common of these were photosensitivity, vomiting, fever, and hepatic dysfunction. Most of these symptoms disappeared once the medication was decreased or stopped.

WHAT DOES THE FUTURE HOLD?

“An efficacious treatment regimen for IPF is long overdue,” wrote the authors. In an accompanying editorial, Roland M. du Bois, MD, cited some dismal results for trials of interferon-γ and mentioned that studies involving antitumor necrosis factor-α and antiendothelin dual-receptor antagonists are on the horizon.² Although the pirfenidone study looks promising, Dr. du Bois cited the end point issue and asked, “What is the most appropriate measure of change to be used in clinical trials?” The study authors acknowledge that their primary end point needs to be validated, and the clinical relevance of other outcome measures must be determined in order for treatments to be tested effectively. “IPF has a mortality greater than some cancers,” maintained Dr. du Bois. “We need to follow the model of cancer trials: comparison of current ‘best therapy’ with novel drugs,” in large trials that are powered to provide answers.

—Tamara Gibb

References
1. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2005;171:1040-1047.
2. du Bois RM. Is idiopathic pulmonary fibrosis now treatable? Am J Respir Crit Care Med. 2005;171:939-940.

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