InterMune Announces Additional Pirfenidone Data in Idiopathic Pulmonary Fibrosis

SAN DIEGO, May 20, 2014 /PRNewswire/ -- 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:

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

About the Ongoing Open-Label Studies
Study 002 is a compassionate-use study in the United States in patients with either IPF or secondary pulmonary fibrosis.  Study 012 "RECAP" is a multinational open-label extension study in patients who completed either of the two CAPACITY studies or the ASCEND study. Data from these ongoing open-label studies included in this comprehensive safety assessment are based on the interim data cut-off date of April 29, 2011. 

About ASCEND
ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF) is a multinational, randomized, double-blind, placebo-controlled Phase 3 trial designed to evaluate the safety and efficacy of pirfenidone in patients with IPF.  Patients (N=555) were randomly assigned 1:1 to receive oral pirfenidone (2403 mg/day) or placebo and were enrolled at 127 centers in the United States, Australia, Brazil, Croatia, Israel, Mexico, New Zealand, Peru and Singapore.

More than 95 percent of eligible patients (those patients who remained on blinded pirfenidone or placebo therapy) who completed the ASCEND study decided to enter the open-label RECAP extension study. RECAP is a study in which all patients receive pirfenidone.  RECAP also includes patients rolled over from the company's prior CAPACITY studies which completed in late 2008 and enrolled 779 patients in two Phase 3 studies. RECAP provides valuable long-term safety data that further expands the already large safety database for pirfenidone in patients with IPF.

About CAPACITY
Pirfenidone has been studied in multiple Phase 3 clinical trials in patients with IPF, including the two Phase 3 CAPACITY trials sponsored by InterMune.

The CAPACITY program consisted of two concurrent 72-week trials which enrolled a total of 779 patients. Both trials were multinational, randomized, double-blind, and placebo-controlled. The studies were designed to evaluate the safety and efficacy of pirfenidone in IPF patients with mild to moderate impairment in lung function. The primary endpoint in both studies was the change from Baseline to Week 72 in percent predicted FVC. This endpoint was met with statistical significance in CAPACITY 2 (p=0.001). The secondary endpoints of PFS and categorical change in FVC also achieved statistical significance (p<0.05). Although the primary endpoint was not met in CAPACITY 1 (p=0.501), supportive evidence of a pirfenidone treatment effect was observed on a number of measures, including percent predicted FVC at weeks 24, 36 and 48, and on 6MWD.

Pirfenidone demonstrated a favorable safety profile and was generally well tolerated in both CAPACITY studies. The most frequent side effects reported were photosensitivity rash, gastrointestinal symptoms such as nausea and dyspepsia, and dizziness.

About Pirfenidone
Pirfenidone is an orally active, anti-fibrotic agent that inhibits the synthesis of TGF-beta, a chemical mediator that controls many cell functions including proliferation and differentiation, and plays a key role in fibrosis.  Pirfenidone also inhibits the synthesis of TNF-alpha, a cytokine that is known to have an active role in inflammation.

On February 28, 2011, the European Commission (EC) granted marketing authorization for Esbriet® (pirfenidone) for the treatment of adults with mild to moderate IPF.  The approval authorized marketing of Esbriet in all 28 EU member states.  Esbriet has since been approved for marketing in Norway and Iceland.  In 2011, InterMune launched commercial sales of pirfenidone in Germany under the trade name Esbriet, and Esbriet is now also commercially available in various European countries, including key markets such as France, Italy and the UK.

On October 1, 2012, Health Canada approved Esbriet for the treatment of mild to moderate IPF in adult patients.  Health Canada designated Esbriet for Priority Review and completed the accelerated review according to target guidelines of 180 days.  InterMune launched Esbriet in Canada in January 2013.

Pirfenidone has been marketed as Pirespa® since 2008 in Japan and since 2012 in South Korea by Shionogi & Co. Ltd.  Under different trade names, pirfenidone is also approved for the treatment of IPF in China, India, Argentina and Mexico.

Pirfenidone is not approved for sale in the United States.

About IPF
Idiopathic pulmonary fibrosis (IPF) is an irreversible and ultimately fatal disease characterized by progressive loss of lung function due to fibrosis (scarring) in the lungs, which hinders the ability of lungs to absorb oxygen. IPF inevitably causes shortness of breath, and a deterioration in lung function and exercise tolerance. IPF patients follow different and unpredictable clinical courses and it is not possible to predict if a patient will progress slowly or rapidly, or when the rate of decline may change. Periods of transient clinical stability in IPF, when they occur, inevitably give way to continued disease progression. The median survival time from diagnosis is two to five years, with a five-year survival rate of approximately 20-40 percent, which makes IPF more rapidly lethal than many malignancies, including breast, ovarian and colorectal cancers. IPF typically occurs in patients over the age of 45, and tends to affect slightly more men than women.

About InterMune
InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and orphan fibrotic diseases.  In pulmonology, the company is focused on therapies for the treatment of idiopathic pulmonary fibrosis (IPF), a progressive, irreversible, unpredictable and ultimately fatal lung disease.  Pirfenidone is approved for marketing by InterMune in the EU and Canada under the trade name Esbriet®.  Pirfenidone is not approved for sale in the United States.  InterMune's research programs are focused on the discovery of targeted, small-molecule therapeutics and biomarkers to treat and monitor serious pulmonary and fibrotic diseases.  For additional information about InterMune and its R&D pipeline, please visit www.intermune.com.

Forward-Looking Statements
This news release contains forward-looking statements within the meaning of section 21E of the Securities Exchange Act of 1934, as amended, that reflect InterMune's judgment and involve risks and uncertainties as of the date of this release, including without limitation the potential for pirfenidone to be approved as a medicine to IPF patients in the United States. All forward-looking statements and other information included in this press release are based on information available to InterMune as of the date hereof, and InterMune assumes no obligation to update any such forward-looking statements or information. InterMune's actual results could differ materially from those described in InterMune's forward-looking statements.

Other factors that could cause or contribute to such differences include, but are not limited to, those discussed in detail under the heading "Risk Factors" in InterMune's most recent annual report on Form 10-K filed with the Securities and Exchange Commission (SEC) on February 24, 2014 (the "Form 10-K") and other periodic reports filed with the SEC, including but not limited to the following: (i) the risks related to the uncertain, lengthy and expensive clinical development process for the company's product candidates, including having no unexpected safety, toxicology, clinical or other issues and having no unexpected clinical trial results such as unexpected new clinical data and unexpected additional analysis of existing clinical data; (ii) risks related to the regulatory process for the company's product candidates, including the possibility that the results of the new 52-week Phase 3 clinical trial (ASCEND) having an FVC endpoint may not be satisfactory to the FDA for InterMune to receive regulatory approval for pirfenidone in the United States; (iii) risks related to unexpected regulatory actions or delays, in particular in connection with our planned resubmission of a Class 2 NDA with the FDA seeking approval of pirfenidone or other government regulation generally; (iv) risks related to our ability to successfully launch and commercialize pirfenidone in the United States, if approved by the FDA and (v) InterMune's ability to obtain or maintain patent or other proprietary intellectual property protections. The risks and other factors discussed above should be considered only in connection with the fully discussed risks and other factors discussed in detail in the Form 10-K and InterMune's other periodic reports filed with the SEC, all of which are available via InterMune's web site at www.intermune.com.

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SOURCE InterMune, Inc.

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