SAN DIEGO — The antifibrotic pirfenidone reduces disease progression and mortality and improves progression-free survival in patients with idiopathic pulmonary fibrosis, according to a new phase 3 study.
Two previous phase 3 trials of pirfenidone arrived at conflicting results; one showed that pirfenidone slows disease progression (Eur Respir J. 2010;35:821-829) and the other failed to meet its end point (Lancet. 2011;377:1760-1769). Those results prompted the US Food and Drug Administration to request an additional phase 3 trial to determine the effectiveness of the drug.
"The trends were in the right direction [in the negative trial] but the placebo group was a bit different. It also didn't have enough statistical power," said Talmadge King, MD, professor of internal medicine at the University of California, San Francisco, during a press conference.
In the Assessment of Pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis (ASCEND) study, Dr. King and his colleagues narrowed the selection criteria for study inclusion. "They were pretty subtle changes, but at the end of the day, I think they mattered," said Dr. King.
The results were presented here at the American Thoracic Society 2014 International Conference and published online simultaneously in the New England Journal of Medicine.
Pirfenidone is an antifibrotic drug that inhibits the synthesis of transforming growth factor (TGF)-beta, which plays a role in cell proliferation and differentiation.
In the ASCEND study, 278 patients with idiopathic pulmonary fibrosis were randomized to receive pirfenidone 2403 mg/day for 52 weeks, and 277 were randomized to receive placebo.
The primary end point was forced vital capacity. Secondary end points were distance walked in the 6-minute walk test, progression-free survival, dyspnea, all-cause mortality, and disease-specific mortality.
The proportion of patients who had an absolute reduction of at least 10% in predicted forced vital capacity or who died was 47.9% less in the pirfenidone group than in the placebo group. In addition, the mean decrease in forced vital capacity from baseline was lower in the pirfenidone group than in the placebo group (235 vs 428 mL P < .001)
The proportion of patients who had no decline in forced vital capacity was 132.5% higher in the pirfenidone group than in the placebo group (P < .001).
There was also less decline in the 6-minute walk test distance in the pirfenidone group than in the placebo group (P = .04), and better progression-free survival (P < .001).
There was no significant difference in dyspnea scores (P = .16), all-cause mortality (P = .10), or disease-specific mortality (P = .23) between the 2 groups.
However, in a pooled analysis of data from this trial and the 2 previous phase 3 trials, overall risk for death at 52 weeks was lower in the pirfenidone than the placebo group (hazard ratio, 0.52; 95% confidence interval, 0.31 - 0.87; P = .01). In addition, pirfenidone improved all-cause mortality (P = .01) and disease-specific mortality (P =.006).
In the ASCEND trial, gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group, but they rarely led to treatment discontinuation.
Pirfenidone is not a cure, but the news is positive for patients with idiopathic pulmonary fibrosis who have a very poor prognosis. "We have something that slows the rate of decline," said Dr. Talmadge.
A caveat is that this study looks at surrogate markers rather than survival, said Jesse Roman, MD, professor of medicine at the University of Louisville in Kentucky, who was involved in the negative trial of pirfenidone.
"That's what many studies are doing, but you can't always equate that to survival," Dr. Roman told Medscape Medical News.
"The idea that we may be able to change the outcome in patients with idiopathic pulmonary fibrosis is novel and very exciting to people in the community," said Gary Hunninghake, MD, assistant professor of medicine at Harvard Medical School and Brigham and Women's Hospital in Boston, who attended the session.
However, although the lung function data were encouraging, the news wasn't all good, he told Medscape Medical News. For example, the drug has gastrointestinal and rash adverse effects that can be bad enough to cause drug discontinuation, and patients on the drug didn't necessarily perceive an improvement.
"It's difficult when we have a drug that improves the outcome for patients but they can't perceive that. Ultimately, we want to see more than this," said Dr. Hunninghake.
The study was funded by InterMune. Dr. King reports relationships with Boehringer Ingelheim, Daiichi Sankyo Pharma, and Immune Works. Dr. Roman and Dr. Hunninghake have disclosed no relevant financial relationships.
American Thoracic Society (ATS) 2014 International Conference. Presented May 18, 2014.
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Cite this: Pirfenidone Slows Decline in Idiopathic Pulmonary Fibrosis - Medscape - May 21, 2014.