The immunosuppressant drug pirfenidone was shown to modestly reduce lung function decline in patients with idiopathic pulmonary fibrosis, according to results from two phase III randomized, placebo-controlled trials.
The trials, enrolling 779 patients of both sexes aged 40-80 years at 110 sites worldwide, are the largest to date of pirfenidone in this patient group. Idiopathic pulmonary fibrosis (IPF), a progressive lung disease that is generally fatal within 5 years, is classified as an orphan disease for which there are few treatment options.
The results, published online May 14 in the Lancet (doi:10.1016/S0140- 6736[11]60405-4), show a "clinically meaningful benefit" for people with IPF, wrote the investigators, led by Dr. Paul W. Noble, professor of medicine and chief of the pulmonary, allergy, and critical care medicine division at Duke University, Durham, N.C.
The trials, both sponsored by InterMune and similar in design, evaluated pirfenidone at different doses over a period of 72 weeks, with the primary end point being change from baseline in percentage predicted forced vital capacity (FVC). Secondary end points were progression-free survival and 6-minute walk test results.
In the first trial, 435 patients were randomized to receive pirfenidone 2,403 mg/day, pirfenidone 1,197 mg/day, or placebo. In the second trial, 344 patients were randomized to pirfenidone 2,403 mg/day or placebo.
The first study showed an 8.4% decline in mean FVC in the pirfenidone group, compared with 12.4% in the placebo group after 72 weeks. In the second study, the difference between groups in FVC change at week 72 was not significant (9.0% for pirfenidone vs. 9.6% for placebo). However, the investigators noted, a "consistent pirfenidone effect was apparent until week 48 (P = .005) and in an analysis of all study time points (P = .007)" in the second study.
In a pooled analysis of both studies, the pirfenidone group saw fewer overall deaths (19, or 6%) than the placebo group (29, or 8%) and fewer deaths related to idiopathic pulmonary fibrosis (12, or 3%, with treatment, compared with 25, or 7%, with placebo). However, the trials were not powered to assess mortality. In both trials, the treatment groups saw significantly more adverse effects, including nausea, dyspepsia, vomiting, anorexia, photosensitivity, rash, and dizziness.
In a pooled analysis looking at FVC change, "pirfenidone reduced the proportion of patients with a 10% or more decrement by 30% compared with placebo," Dr. Noble and his colleagues wrote, noting that a 10% or greater decline is considered to be predictive of death in clinical practice. "Moreover, pirfenidone was associated with a 26% reduction in the risk of death or disease progression in analyses of progression-free survival, a 31% reduced mean decline in [6-minute walk test] at week 72, and a consistently favorable direction of effect on mortality, despite the trials not being powered to assess mortality," they wrote.
Dr. Noble and his colleagues acknowledged as limitations their enrollment of patients with mild to moderate disease and few comorbidities, meaning the results "cannot necessarily be generalized to the broader population of patients." Also, they noted, "the lack of adjustment for multiple statistical testing has the potential for overinterpretation of the results." Safety and tolerance beyond 72 weeks were not measured.
In an editorial accompanying the report, Dr. Demosthenes Bouros of Democritus University of Thrace in Alexandropolis, Greece, wrote that pirfenidone "could be appropriate in patients who are willing to accept possible adverse consequences even if expected benefits are small." Successful treatment of IPF "is likely to require a combination of therapies targeting several pathways involved in fibroproliferation," Dr. Bouros said (Lancet 2011 May 14 [doi:10.1016/S0140- 6736(11)60546-1]).
Pirfenidone has been licensed in Japan since 2008 for the treatment of IPF, and in February, the European Medicines Agency recommended marketing authorization throughout the European Union for pirfenidone, based in part on preliminary findings from the same two phase III trials.
Pirfenidone has not been approved by the U.S. Food and Drug Administration for patients with IPF. Earlier this month, despite a favorable 9-3 vote by its expert panel, the agency said it would need to see evidence from additional trials before approving pirfenidone.
Dr. Noble and his colleagues’ research was funded by InterMune, pirfenidone’s manufacturer. InterMune was involved with the study design, data collection, data analysis, writing, analysis, and maintenance of the data. Dr. Noble disclosed having served as an investigator for InterMune, and all but 2 of his 11 coauthors disclosed relationships with InterMune or are employees of InterMune. Dr. Bouros declared that he had no relevant financial disclosures.