Pirfenidone reduces disease progression of IPF

Pirfenidone (Esbriet), an oral antifibrotic therapy, was able to reduce progression of idiopathic pulmonary fibrosis (IPF) and reduce the risk of mortality, according to phase 3 trial results presented at the American Thoracic Society International Conference in San Diego.

The phase 3 trial results of ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis) showed that pirfenidone significantly reduced disease progression, as measured by lung function, exercise tolerance, and progression-free survival, when compared with placebo in patients with IPF, according to the May 18^th online report in the New England Journal of Medicine. The trial was sponsored by the manufacturer, InterMune.

IPF is a chronic, progressive disease that results in lung scarring and affects approximately 80,000 Americans. Mostly older adults have been diagnosed with the disorder that typically has a 3- to 5-year survival rate. Until now, there have been no effective drug therapies, according to lead author, Talmadge E. King, Jr., MD.

“We’ve looked at many drugs [since 1979]-drugs that we thought would be effective, and none of them worked,” explained Dr King, professor and chairman, Department of Medicine, University of California, San Francisco. “This is the first treatment that reduced the disease progression and had an effect on mortality-either all-cause mortality or more importantly from the IPF itself.

“When we looked at that in the pooled analysis with a bigger population to study, we were surprised at how robust this drug seems to be at reducing the risk of mortality,” said Dr King, who referred to 3 other trials of pirfenidone for IPF in the recently published NEJM study. These included a trial conducted in Japan and two multinational studies known as CAPACITY 004 and 006. The CAPACITY 006 study did not meet the end point of lung function, as measured by change in percentage of predicted forced vital capacity (FVC).

After reviewing the three trials in 2010, FDA declined approval of pirfenidone for the treatment of IPF, and requested an additional study, known as the ASCEND trial. In the ASCEND trial, 555 patients with IPF received either oral pirfenidone at a dose of 2403 mg daily or placebo for 52 weeks. Most patients were aged 65 years or older, white, and male. The mean baseline FVC in the pirfenidone group was 67.8±11.2% of the predicted value and 68.6±10.9% of the predicted value in the placebo-controlled group.

The primary end point was FVC change from baseline or death. The secondary end points were 6-minute walk distance, progression-free survival, dyspnea, and death from any cause or from IPF.

At 52 weeks, 46 patients (16.5%) in the pirfenidone group had a decline of 10 percentage points or more in the percentage of the predicted FVC or died, compared with 88 (31.8%) in the placebo group. In addition, 63 patients (22.7%) who were treated with pirfenidone had no decline in the percentage of the predicted FVC, compared with 27 patients (9.7%) in the placebo group.

In terms of secondary end points at 52 weeks, 72 patients (25.9%) in the pirfenidone group had a decrease of 50 m or more in the 6-minute walk distance or died, compared with 99 patients (35.7%) in the placebo group. There was no significant difference between the two groups in terms of dyspnea or all-cause mortality at 52 weeks, explained Dr. King and his colleagues in the journal article.

“In the prespecified analysis of all-cause mortality in the pooled population of 1,247 patients (555 from the ASCEND study and 692 from the CAPACITY studies), pirfenidone reduced the risk of death at 1 year by 48%, as compared with placebo,” Dr King and his colleagues noted. “In addition, in the pooled population, the risk of death from idiopathic pulmonary fibrosis at 1 year was reduced 68% in the pirfenidone group, as compared with the placebo group.”

The most common adverse events in the pirfenidone group were gastrointestinal and skin-related, with most being mild to moderate in severity. Adverse events led to 40 patients (14.4%) of the pirfenidone group and 30 patients (10.8%) in the placebo group to withdraw from the ASCEND study.