February 25, 2014
InterMune, Inc. today announced that top-line data from ASCEND, a Phase 3 trial evaluating pirfenidone in patients with idiopathic pulmonary fibrosis (IPF), demonstrated that pirfenidone significantly reduced IPF disease progression 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 six-minute walk test distance (6MWD) change (p=0.0360) and progression-free survival (PFS) (p=0.0001).
“We are pleased to report these top-line ASCEND Phase 3 results,” said Dan Welch, Chairman, Chief Executive Officer and President of InterMune. “Based on the strength of the ASCEND results, InterMune is preparing a resubmission of our New Drug Application for pirfenidone to the U.S. Food and Drug Administration (FDA), which we expect to submit by early third quarter of this year. We would like to thank our collaborators, patients and their families for their participation in ASCEND and their contributions to IPF research.”
The magnitude of the treatment effect of pirfenidone was measured by comparing the proportion of patients in the pirfenidone and placebo groups experiencing either a clinically meaningful change in FVC, or death. A 10% decline in FVC in an individual IPF patient is considered clinically meaningful and strongly predicts mortality. At Week 52, 16.5% of patients in the pirfenidone group experienced an FVC decline of 10% or more or death, compared with 31.8% in the placebo group, representing a 47.9% reduction in the proportion of patients who experienced a meaningful change in FVC or death. Additionally, at Week 52 the data demonstrated that 22.7% of patients in the pirfenidone group experienced no decline in FVC, compared with 9.7% in the placebo group, representing a 132.5% increase in the proportion of patients whose FVC did not decrease between Baseline and Week 52.
Dr. Talmadge King, Chair, Department of Medicine, University of California San Francisco and Co-chair of the ASCEND protocol steering committee, said, “IPF is an unpredictable, debilitating and ultimately fatal disease, and safe and effective treatments are desperately needed to alter the course of this challenging and complex condition. The ASCEND data demonstrated that pirfenidone significantly reduced decline in lung function and significantly increased the proportion of patients who had no decline, which is an important advance in the field. The results for 6MWT distance, PFS and mortality provide important supportive evidence of pirfenidone’s efficacy.”
Key Secondary Endpoints
The ASCEND protocol pre-specified 6MWD and PFS as the two key secondary endpoints. Change from Baseline to Week 52 in 6MWD is a measure of exercise tolerance. A 50-meter decrement in walk distance is considered an independent predictor of mortality in an individual patient with IPF. In ASCEND, pirfenidone reduced by 27.5% the proportion of patients who experienced a decline in 6MWD of 50 meters or greater (p=0.0360).
PFS is a measure of time before death or a disease-progression event. A PFS event was defined in the protocol as any of the following: death, percent predicted FVC decrement of 10% or greater or 6MWD decrement of 50 meters or greater. In ASCEND, pirfenidone reduced the risk of death or disease progression by 43% compared to placebo (Hazard Ratio [HR]=0.57; 95% confidence interval, 0.43-0.77; p=0.0001).
Safety and Tolerability
In ASCEND, pirfenidone showed a favorable safety profile and was generally well tolerated.
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 percentage of patients discontinuing treatment due to an adverse event was 14.4% in the pirfenidone group and 10.8% in the placebo group. Serious adverse events (SAEs) were reported in 19.8% of patients in the pirfenidone group and 24.9% in the placebo group. Hospitalizations due to respiratory, thoracic and mediastinal SAEs were reported in 3.6% of patients in the pirfenidone group and 11.2% in the placebo group.
The most common AEs with higher incidence in the pirfenidone group were primarily gastrointestinal (e.g., nausea and dyspepsia) and skin-related (e.g., rash). The GI and rash AEs were generally mild to moderate in severity, manageable, reversible and only infrequently led to treatment discontinuations.
Elevations of aminotransferase levels at least 3 times the upper limit of normal occurred in 2.9% of pirfenidone patients (including one case associated with a bilirubin increase) vs. 0.7% of placebo patients. In general, these elevations occurred early, were manageable and reversible, and were similar to those observed in previous pirfenidone studies.
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.
“These results from the ASCEND trial provide compelling evidence of a clinically meaningful treatment effect of pirfenidone with generally favorable safety and tolerability findings, which is very encouraging for patients suffering from this fatal and relentless disease,” said Paul W. Noble, Chair, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, Calif. and Co-chair of the ASCEND protocol steering committee. “Importantly, the overall safety observations from ASCEND complement and corroborate the robust safety database that already exists from the InterMune-sponsored clinical studies of pirfenidone and extensive post-marketing experience outside the United States.”
See the full press release here.