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InterMune Offers Added Pirfenidone Data in Idiopathic Pulmonary Fibrosis, Says Endpoint Was Met with Statistical Significance in Capacity 2

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InterMune, Inc. (NASDAQ: ITMN) today announced that results of analyses of pooled data from the ASCEND trial and the two previous Phase 3 CAPACITY trials evaluating pirfenidone in patients with idiopathic pulmonary fibrosis (IPF) were presented at the 2014 International Conference of the American Thoracic Society (ATS) in San Diego, Calif.  In addition, long-term safety results in patients with IPF receiving treatment with pirfenidone for a median duration of 2.6 years and a maximum duration of 7.7 years were published in the current edition of the journal Respirology.  Pirfenidone is not approved for sale in the United States.

Exploratory Analyses of Pooled Data from ASCEND and CAPACITY New efficacy results from analyses conducted on the pooled population from the ASCEND trial and the two previous Phase 3 CAPACITY studies (004 and 006), in addition to the previously reported results of the Phase 3 study ASCEND and the prespecified pooled analyses of mortality, were presented  at the ATS Symposium "Skyfall: Late Breaking Trials in Idiopathic Pulmonary Fibrosis."  The similar study designs, patient populations and clinical efficacy outcomes across these three independent global Phase 3 studies justify the pooling of study results, allowing a comprehensive analysis of outcomes from a large data set (N = 1,247).  The primary objective of these new analyses of the prespecified primary and secondary efficacy endpoints in ASCEND, conducted on the large pooled population, is to provide a more precise estimate of the magnitude of the pirfenidone treatment effect.  Pooled analyses were conducted at Week 52, the time of the primary endpoint assessment in ASCEND, and also at Week 72, the time of the primary endpoint assessment in CAPACITY.  These Week 72 analyses provide insight into the persistence of the pirfenidone treatment effect. 

These analyses were presented by Dr. Talmadge King, Professor and Chair, Department of Medicine, University of California, San Francisco and Co-chair of the ASCEND protocol steering committee, and complement earlier reports about the ASCEND or CAPACITY studies  alone.  Earlier at ATS, the ASCEND study was featured in the New England Journal of Medicine's symposium and published on-line in the New England Journal of Medicine on May 18.  The ASCEND data will be published in the journal's May 29 print issue.

Results of ASCEND were the subject of a May 18 investor press release and webcast and therefore won't be commented on in this press release.  

Pooled Analyses at One Year

Forced Vital Capacity (FVC) The magnitude of treatment effect of pirfenidone on FVC across all three Phase 3 studies 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 predictive of mortality.  At one year, the pooled analysis showed that compared to placebo, pirfenidone reduced by 43.8% the proportion of patients who experienced a meaningful decline in FVC or death (rank ANCOVA p<0.0001).

6-Minute Walk Distance (6MWD), Progression-Free Survival (PFS) and Dyspnea Several secondary endpoints, including change from baseline in 6MWD, PFS, and dyspnea, were analyzed in the pooled population.  6MWD is a measure of exercise tolerance, and a 50-meter decrement in walk distance is an independent predictor of mortality in an individual patient with IPF.  At one year, the pooled analysis showed that compared to placebo, pirfenidone reduced by 28.7% the proportion of patients who experienced a decline in 6MWD of 50 meters or greater or died (rank ANCOVA p=0.0004).

PFS is a measure of time before death or disease-progression.  Disease progression was defined as a percent predicted FVC decrement of 10% or greater or 6MWD decrement of 50 meters or greater.  At one year, the pooled analysis showed that compared to placebo, pirfenidone reduced the risk of death or disease progression by 38% (Hazard Ratio [HR] 0.62; 95% confidence interval [CI], 0.51-0.75; p<0.0001).

An analysis of dyspnea (shortness of breath) in the pooled population showed a difference favoring pirfenidone at one year;  24.0% of patients in the pirfenidone group experienced a >20 point worsening in UCSD SOBQ score or death, compared with 31.4% of patients in the placebo group (relative difference, 23.7%; p=0.0471).  There was no significant difference between groups in dyspnea scores in any of the individual studies.

Mortality As reported on May 18, at Week 52, the pre-specified analysis from the ASCEND study of the pooled population of the ASCEND and CAPACITY trials showed that the risk of all-cause mortality was reduced by 48% in the pirfenidone group compared to the placebo group (HR 0.52, log rank p=0.0107).  Additionally, the risk of treatment-emergent IPF-related death in the pirfenidone group compared to placebo was reduced by 68% (HR 0.32, log rank p=0.0061). 

Exploratory Week 72 Pooled Analyses Analyses of the following clinical outcomes were performed on the pooled data from the ASCEND and CAPACITY studies through 72 weeks (the CAPACITY endpoint).  These analyses showed a magnitude of treatment effect of pirfenidone in the range of 43% to 57% and were statistically significant favoring pirfenidone:

o FVC decline >/= 10% or death o Progression-free survival o All-cause mortality o Treatment-emergent all-cause mortality o IPF-related mortality o Treatment-emergent IPF-related mortality

Pooled Phase 3 Safety Analyses In the pooled Phase 3 data set of ASCEND and CAPACITY, the profiles of adverse events (AEs) (treatment-emergent, Grade 3 or 4), serious adverse events (SAEs) and AEs leading to discontinuation were similar to those observed in ASCEND alone as were reported in the company's press release of May 18. 

Long-term Pirfenidone Safety Data Published in Respirology A comprehensive assessment of the long-term safety and tolerability of pirfenidone in patients with IPF was performed in an integrated population from four clinical trials (n=789) evaluating pirfenidone in patients with IPF.  The results of this analysis were reported on May 18 in the journal Respirology.  All patients who were randomized to treatment with pirfenidone 2403 mg/d in the Phase 3 CAPACITY studies (Studies 004 and 006) and all patients who received at least one dose of pirfenidone in one of two ongoing open-label studies (Studies 002 and 012) in patients with IPF were included in the analysis.  Safety outcomes were evaluated from baseline until 28 days after the last dose of study drug.  

According to the published study, the comprehensive safety and tolerability analysis demonstrated that treatment with pirfenidone for up to 7.7 years presented a favorable safety profile and was generally well tolerated.  The median duration of exposure to pirfenidone was 2.6 years (range, 1 week–7.7 years) and the cumulative total exposure was 2,059 person exposure years (PEY).  Gastrointestinal and skin-related events were the most commonly reported adverse events.  These included nausea (40%), dyspepsia (21%), vomiting (18%) and rash (26%).  These events were generally mild to moderate in severity, decreased in incidence over the first several months of therapy and rarely led to treatment discontinuation. 

"Our long-term safety analysis is extremely robust given the large study population and overall duration of treatment exposure, which is unique for novel agents for orphan diseases," said Dominique Valeyre M.D., of the Hôpital Avicenne, Bobigny, France, and lead author of the Respirology paper. "These data provide further evidence to support the long-term clinical use of pirfenidone in patients with idiopathic pulmonary fibrosis."

Analysis of new onset adverse events by 6-month intervals demonstrated that gastrointestinal and skin-related adverse events tended to occur early in the course of treatment. The incidence of new onset gastrointestinal and skin-related events declined after the first 6 months and remained low during subsequent intervals.

Elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) of more than three times the upper limit of normal (3 X ULN) occurred in 2.7% of patients. The adjusted incidence of AST/ALT elevations was 1.7 per 100 PEY.  These elevations were generally transient, reversible, and without significant clinical consequence.

Worsening IPF (8.7%) was the most common event leading to treatment discontinuation.  The only other adverse events that resulted in treatment discontinuation in >1% of patients were nausea (2.3%), rash (1.6%), and respiratory failure (1.3%).

A total of 18.8% patients died during the period of observation. Treatment-emergent deaths, defined as deaths occurring after the first dose and within 28 days of the last dose of study drug, occurred in 15.6% of patients; of these, 11.2% were assessed by the investigator as IPF-related.  The adjusted incidence of treatment emergent death, defined as treatment emergent deaths per 100 PEY, was 6.0 for all-cause death and 4.3 for IPF-related death.

Investor Conference Call and Webcast Details

InterMune will host a live webcast today at 8:00 p.m. EDT (5:00 p.m. PDT) to discuss the additional pirfenidone data in IPF presented in the SKYFALL session.  Interested investors and others may participate in the conference call by dialing 844-825-0513 (U.S.) or 484-365-2934 (international), conference ID# 43741688.  A replay of the webcast and teleconference will be available approximately two hours after the call.

To access the webcast, please log on to the company's website at www.intermune.com at least 15 minutes prior to the start of the call to ensure adequate time for any software downloads that may be required.

A telephonic replay will be available for 10 business days following the call and can be accessed by dialing 855-859-2056 (U.S.) or 404-537-3406 (international), and entering the conference ID# 43741688.  

Posted-In: News FDA Press Releases

 

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