Pirfenidone Improves Survival in Idiopathic Pulmonary Fibrosis

Recently published study results, when combined with results from previous clinical trials, show treatment with the antifibrotic drug pirfenidone slows disease progression and improves survival in patients with idiopathic pulmonary fibrosis (IPF). These findings, if they lead the FDA to reevaluate and approve this drug, could be a game changer for patients with IPF, a disease marked by a high mortality rate and few treatment options.

During a session yesterday at the 2014 American Thoracic Society International Conference, Talmadge E. King, Jr, MD, the Julius R. Krevans Distinguished Professor in Internal Medicine and Chair of the UCSF Department of Medicine, reviewed data from the ASCEND study, a phase 3 clinical trial designed to confirm the effect of treatment with the oral antifibrotic agent pirfenidone on disease progression in patients with idiopathic pulmonary fibrosis (IPF). There have been three previous phase 3 studies of pirfenidone in patients with IPF: the Shionogi study (n=275) and the CAPACITY 004 and CAPACITY 006 trials (combined total enrollment n=779).

The ASCEND trial was conducted at 127 sites in 9 countries. Unlike the earlier studies, this trial used centralized assessments of certain data, in particular to assure an accurate diagnosis of IPF using High Resolution Computed Tomography (HRCT). More than 90% of patients referred by the sites as being eligible were confirmed as having IPF by HRCT. A total of 555 subjects were randomized and 93.5% and 94.6% of patients completed the study for pirfenidone and placebo treatment, respectively.

The primary endpoint was the change in forced vital capacity (FVC) between baseline and 52 weeks on treatment. The main secondary endpoints were change in 6-minute walk distance (6MWD) test and progression-free survival (PFS). Additional secondary endpoints were all-cause mortality, IFP-related mortality, treatment-emergent mortality, and dyspnea.

The primary endpoint was pre-specified as the decline in FVC over the 52-week trial period or death. In the study, nearly one-fourth (23%) of patients treated with pirfenidone experienced no decline in FVC, compared with only 9% of patients who received placebo. There was a very high statistical significance of p<0.00001 for the efficacy of pirfenidone over placebo. Investigators conducted various alternative statistical tests, with proven validity, and the results confirmed the robustness of the findings. The pirfenidone effects on reducing IPF disease progression persisted over the full 52-week study period.

Treatment with pirfenidone was also associated with a significant reduction in the decline in 6MWD at week 52. Overall PFS was also improved in patients treated with pirfenidone comared to placebo.

When the researchers analyzed the combined data from the ASCEND trial and the two CAPACITY trials (n=692), they found a significant decrease in mortality for pirfenidone-treated patients versus placebo (p=0.011).

Treatment effects were consistent across all subgroups which suggested that pooling the data from the three studies was acceptable.

Adverse events more common for pirfenidone treatment were principally gastrointestinal and skin-related, as expected from the earlier studies. These were typically mild to moderate in severity and infrequently led to treatment discontinuation. There were fewer serious adverse events in the pirfenidone-treated group. Safety outcomes were consistent when comparing ASCEND data with the pooled data.

The session also featured a discussion of the results among a panel of pulmonologists and respiratory medicine specialists that included:

• Harold Collard, MD, associate professor of medicine in UCSF's Division of Pulmonary and Critical Care Medicine and the Director of the Interstitial Lung Disease Program at UCSF
• Ganesh Raghu, MD, professor of medicine in the Division of Pulmonary and Critical Care Medicine and director of the Interstitial Lung Disease/Sarcoid/Pulmonary Fibrosis Program at University of Washington Medicine
• Martin Kolb, MD, associate professor, division of respirology, in the department of medicine at McMaster University, Ontario, Canada

Collard asked the panel if there were any issues with pooling the data. One panelist replied with a resounding, “No!” There was no further discussion on this point.

He then asked whether the findings from these studies were representative of IPF. Raghu said that this sort of question was very difficult to answer for controlled clinical trials in many disease categories. Kolb thought it looked like a very “clean” study population, given that 94-95% of eligible candidates were confirmed as having IPF by the central reviewers upon examining the HRCT results.

An audience member remarked upon the fact that 9.3% of placebo-treated patients remained stable (no decline in FVC) compared to 23% of those in the treatment arm. Collard asked if there could be some subgroup causing this discrepancy. King said he could not answer this but the phenomenon was very interesting, as this number was very high compared to other studies.

Another questioner asked if there were differences in the responses to placebo between patients in the ASCEND and CAPACITY trials. King replied that there were no discernable differences in the placebo effects between the studies.

Raghu asked how they could properly evaluate patients in routine clinical practice without having access to the spectrum of tests available to the central assessors in the ASCEND trial. King addressed the issue as to whether the central assessment was really necessary given that they confirmed the diagnosis of IPF in more than 90% of the candidates referred by the investigators. The team did go back and check the CT scans to see whether patients with emphysema and obstructive lung diseases had been properly excluded from the trial. He was confident that IPF was the predominant disease in the patients randomized to the ASCEND trial.