Results from the Phase 3 ASCEND study evaluating pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) were presented recently at the International Conference of the American Thoracic Society (ATS) in San Diego, and published on-line in the New England Journal of Medicine.
In ASCEND, pirfenidone significantly reduced decline in lung function as measured by change in percent predicted forced vital capacity (FVC) from Baseline to Week 52 (rank ANCOVA p<0.000001). Additionally, significant treatment effects were demonstrated on both of the key secondary endpoints of change in six-minute walk distance (6MWD) (p=0.0360) and progression-free survival (PFS) (p=0.0001). The secondary endpoint of dyspnea (shortness of breath) was not met. In ASCEND, treatment with pirfenidone was associated with fewer deaths although the study was not powered for and did not reach statistical significance on mortality. A pre-specified analysis of the pooled population from ASCEND and the two Phase 3 CAPACITY studies showed that the risk of all-cause mortality was reduced by 48% at Week 52 in the pirfenidone group compared to the placebo group (Hazard Ratio [HR] 0.52, log rank p=0.0107). In ASCEND, treatment with pirfenidone showed a favorable safety profile and was generally well tolerated.
Dr Talmadge King, Professor and Chair, Department of Medicine, University of California, San Francisco and Co-chair of the ASCEND protocol steering committee, presented the ASCEND results. He said: "Pirfenidone, as compared with placebo, reduced disease progression, as reflected by lung function, exercise tolerance, and progression-free survival in patients with idiopathic pulmonary fibrosis. Treatment was associated with an acceptable side effect profile and fewer deaths."
IPF is a chronic, progressive, and irreversible lung disease characterised by scarring in the lungs, which hinders a person's ability to breathe. The median survival time from diagnosis is two to five years, which makes IPF more rapidly lethal than many malignancies, including breast, ovarian and colorectal cancers.
The pre-specified analysis of the ASCEND study alone showed fewer all-cause and treatment-emergent IPF-related deaths in the pirfenidone group compared to the placebo group. 4% of patients in the pirfenidone group and 7.2% of patients in the placebo group died during the study (HR 0.55; 95% CI 0.26 to 1.15; p=0.1045). Treatment-emergent IPF-related deaths occurred in 1.1% and 2.5% of patients in the pirfenidone and placebo groups, respectively (HR 0.44; 95% CI 0.11 to 1.72; p=0.2258). The relationship of death to IPF was determined in ASCEND by a blinded adjudication committee.
The pre-specified analyses of mortality in the pooled population (N=1,247) from ASCEND and the two Phase 3 CAPACITY studies showed that the risk of all-cause mortality was reduced by 48% at Week 52 in the pirfenidone group compared to the placebo group (HR 0.52; 95% CI 0.31–0.87; p=0.0107). Additionally, in the pooled population the risk of treatment-emergent IPF-related death in the pirfenidone group compared to placebo was reduced by 68% at Week 52 (HR 0.32; 95% CI 0.14–0.76; p=0.0061).
A total of 93.5% and 94.6% of patients completed the study, died or had a lung transplant by study day 365 in the pirfenidone and placebo groups, respectively. The most common adverse events with higher incidence in the pirfenidone group were gastrointestinal (e.g., nausea and dyspepsia) and skin-related (e.g., rash). The gastrointestinal and rash adverse events were generally mild to moderate in severity, manageable, reversible and only infrequently led to treatment discontinuations. A Grade III gastrointestinal adverse event was experienced in 5.4% and 1.4% of patients in the pirfenidone and placebo groups, respectively. A Grade III skin-related adverse event was experienced in 1.8% of patients in the pirfenidone group compared with 0.4% of patients in the placebo group. No patients in either group experienced a Grade IV gastrointestinal or skin-related event.
Serious adverse events (SAEs) were reported in 19.8% of patients in the pirfenidone group and 24.9% in the placebo group. The most common serious adverse event was worsening of idiopathic pulmonary fibrosis (2.5% of patients in the pirfenidone group vs. 9.7% in the placebo group). There were fewer deaths in the pirfenidone group compared with placebo (2.9% vs. 5.4%).
The safety and tolerability profile of pirfenidone was generally consistent with observations from the previous Phase 3 CAPACITY studies, open-label extension studies and post-marketing experience.
"The results from the ASCEND trial reinforce the favorable safety and tolerability profile observed in previous studies of pirfenidone and through real-world experience where it is currently marketed," said Dr. Paul W. Noble, Chair, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, Calif. and Co-chair of the ASCEND protocol steering committee. "As a treating physician, I am pleased that there is such a robust and thorough assessment of the safety and tolerability of pirfenidone, a medicine that may play an important role in managing patients with IPF."