SAN DIEGO – Pirfenidone, an oral antifibrotic therapy not yet for sale in the United States, helped preserve lung function, exercise tolerance, and progression-free survival in patients with idiopathic pulmonary fibrosis, according to phase III results published online May 18 in the New England Journal of Medicine and presented by Dr. Talmadge King Jr. at an international conference of the American Thoracic Society.
The study randomized 278 patients to 2,403 mg of pirfenidone daily and 277 patients to placebo. There were no significant baseline differences between groups; the mean baseline forced vital capacity (FVC) was about 68% of predicted in both arms.
Dr. Talmadge King
At 52 weeks, 16.5% of pirfenidone patients vs. 31.8% of placebo patients had a decline of 10% or more in their predicted FVC or had died. Conversely, 22.7% of pirfenidone patients vs. 9.7% of placebo patients had no FVC decline. The mean FVC decline from baseline was 235 mL in the pirfenidone group and 428 mL in the placebo group. Also at 52 weeks, fewer pirfenidone patients had a drop of 50 m or more in their 6-minute walk test (16.5% vs. 19.5%). All of the differences were statistically significant, the investigators reported (N. Eng. J. Med. 2014 May 18 [doi: 10.1056/NEJMoa1402582]).
There also were fewer deaths in the pirfenidone group, but the difference was not significant (4.0% vs. 7.2%; P = .10), including three (1.1%) deaths from idiopathic pulmonary fibrosis in the pirfenidone group and seven (2.5%) in the placebo group (P = .23).
Overall, the advantage of pirfenidone "was evident by week 13 and increased throughout the duration of the trial. ... We found that pirfenidone as compared with placebo reduced disease progression in patients with idiopathic pulmonary fibrosis. Treatment was generally safe, had an acceptable side-effect profile, and was associated with fewer deaths," said the investigators, led by Dr. King, chair of the department of medicine at the University of California, San Francisco.
"We enrolled patients with mild to moderate physiological impairment; the degree to which our findings can be generalized to a population of patients with advanced disease is therefore uncertain," they noted.
The study was funded by the California biotech company InterMune to support its Food and Drug Administration application. The company currently markets the agent in Europe and Canada.
It’s the fourth phase III trial for pirfenidone; two of the earlier trials showed an FVC benefit, but a third did not, leading the FDA to request another investigation. To "confirm the effect of pirfenidone," the investigators adjusted their study design to include "centralized procedures for diagnosis, spirometry, and adjudication of deaths" and to enroll patients at higher risk for disease progression. They also limited the trial to 1 year.
Pirfenidone did significantly reduce the risk of death at 1 year when the new results were pooled with results from earlier studies (hazard ratio, 0.52; 95% confidence interval, 0.31-0.87; P = .01).
About 80% of the subjects in both treatment arms were men. The large majority of subjects were white, and about 70% were over age 65.
About 14% of pirfenidone patients and 10.8% of placebo patients quit the study because of side effects, most commonly worsening of idiopathic pulmonary fibrosis in 1.1% of pirfenidone patients and 5.4% of placebo patients. Grade 3 (severe or medically significant but not immediately life-threatening) gastrointestinal adverse events were reported in 5.4% of pirfenidone patients and 1.4% of placebo patients. Grade 3 skin-related adverse events were reported in 1.8% of pirfenidone patients and 0.4% of placebo patients. Liver enzyme elevations three times the normal limit occurred in 2.9% of pirfenidone patients and 0.7% of placebo patients.
Also, six pirfenidone patients discontinued to undergo lung transplant, vs. one placebo patient.
The study was funded by InterMune, the maker of pirfenidone. Dr. King reported personal fees from InterMune and other companies. Three of his 16 coauthors are InterMune employees, and almost all of the rest reported personal payments or grants from the company, as well as other pharmaceutical companies.