Antifibrotic Drug Promising in Idiopathic Pulmonary Fibrosis

Laurie Barclay, MD

May 17, 2011

May 17, 2011 — The novel antifibrotic and anti-inflammatory drug pirfenidone lowers the rate of lung function decline in patients with idiopathic pulmonary fibrosis, according to the results of 2 concurrent randomized trials reported Online First May 14 in The Lancet.

"Idiopathic pulmonary fibrosis remains a progressive and fatal disorder, and no treatment so far has been shown to be efficacious, despite several clinical trials in the past decade," write Paul W. Noble, MD, from Duke University Medical Center in Durham, North Carolina. "The orphan status of idiopathic pulmonary fibrosis, heterogeneity in rates of disease progression, and lack of a precedent for regulatory approval complicate efforts to develop novel treatments."

The CAPACITY programme consisted of 2 concurrent trials (004 and 006) designed to confirm findings from a phase 2 study showing that pirfenidone reduced deterioration in lung function in patients with idiopathic pulmonary fibrosis. At 110 centers in Australia, Europe, and North America, patients aged 40 to 80 years with idiopathic pulmonary fibrosis were randomly assigned to receive oral pirfenidone (2403 mg/day in both studies as well as 1197 mg/day in 004 divided in 3 oral doses daily) or placebo for at least 72 weeks.

Randomization was computer generated and stratified by region, and all study personnel were blinded to treatment allocation. The main study outcome was change in percentage predicted forced vital capacity (FVC) at week 72, with analysis by intent-to-treat.

In study 004, pirfenidone was associated with reduced decline in FVC (P = .001), with greater effects noted in the 2403-mg/day group vs the 1197-mg/day group. There was an 8.4% decline in mean FVC in the pirfenidone group vs 12.4% in the placebo group, and decline was 10% or more in 20% of 174 patients in the pirfenidone group vs 35% of 174 patients in the placebo group. There was a significant treatment effect at all time points from week 24 and in an analysis over all study time points (P = .0007).

In study 006, the difference between groups in FVC change at week 72 was not significant, but there was a consistent pirfenidone effect until week 48 (P = .005) and in an analysis of all study time points (P = .007).

Compared with patients in the placebo group, those in the pirfenidone 2403-mg/day group had higher incidences of nausea (36% vs 17%), dyspepsia (19% vs 7%), vomiting (14% vs 4%), anorexia (11% vs 4%), photosensitivity (12% vs 2%), rash (32% vs 12%), and dizziness (18% vs 10%). All-cause mortality and death rates from idiopathic pulmonary fibrosis were lower in the pirfenidone 2403-mg/day groups vs the placebo groups (6% vs 8% and 3% vs 7%, respectively).

"The data show pirfenidone has a favourable benefit risk profile and represents an appropriate treatment option for patients with idiopathic pulmonary fibrosis," the study authors write.

Limitations of this study include lack of generalizability to patients with severe idiopathic pulmonary fibrosis and many comorbidities, inability to determine the effect of concurrent therapies, lack of adjustment for multiple statistical testing, and treatment limited to 72 weeks.

In an accompanying comment, Demosthenes Bouros, from Medical School, Democritus University of Thrace in Alexandroupolis, Greece, notes that no drug is currently approved for use in idiopathic pulmonary fibrosis in the United States.

"Pirfenidone could be appropriate in patients who are willing to accept possible adverse consequences even if expected benefits are small," Dr. Bouros writes. "Although the successful treatment of idiopathic pulmonary fibrosis is likely to require a combination of therapies targeting several pathways involved in fibroproliferation (panel), pirfenidone is so far the only approved drug that will be commercially available in Europe, raising hopes for many patients with this life-threatening lung disease."

InterMune supported this study and employs 2 of its authors. Some of the other study authors have disclosed various financial relationships with Actelion, Boehringer-Ingelheim, InterMune, Novartis, Centocor, Gilead, Bayer, MondoBiotech, ImmuneWorks, Arresto, Celgene, and/or the National Institutes of Health Idiopathic Pulmonary Fibrosis Network. Dr. Bouros has disclosed no financial relationships.

Lancet. Published online May 14, 2011. Abstract


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