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BRISBANE, California - InterMune, Inc. (NASDAQ: ITMN) 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).
Additional Secondary Endpoints
Three additional secondary endpoints were pre-specified in the ASCEND protocol: all-cause mortality, treatment-emergent IPF-related mortality and change from Baseline to Week 52 in dyspnea (shortness of breath). The two mortality analyses were pre-specified for both the ASCEND study and the pooled population of the ASCEND study and the previous Phase 3 CAPACITY studies through 52 weeks. Due to the relatively low overall mortality rate in patient populations in the time frames studied in a single IPF study such as ASCEND, pooled analyses of ASCEND and CAPACITY data provide more statistical power and a more precise estimate of the treatment effect of pirfenidone on mortality.
In the pre-specified mortality analysis of the ASCEND study alone, there were fewer events of all-cause mortality (HR=0.55, log rank p=0.1045) and of treatment-emergent IPF-related mortality (HR=0.44, log rank p=0.2258) in the pirfenidone group compared to the placebo group. ASCEND was not powered to show a difference on these endpoints. The relationship of death to IPF was determined in ASCEND by a blinded adjudication committee.
The pre-specified analyses of the pooled population (N=1,247) across ASCEND and the two Phase 3 CAPACITY studies (taking CAPACITY mortality data through Week 52) 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, in the pooled population 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).
The secondary endpoint of dyspnea, measured by the UCSD SOBQ questionnaire, was not achieved (p=0.1577).
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."
InterMune intends to present additional data from the ASCEND study at the 2014 American Thoracic Society International Conference in May.
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.
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 Esbriet® (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.
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.
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, the only medicine approved for IPF anywhere in the world, 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 but has completed three Phase 3 clinical trials to support regulatory registration 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.
Conference Call and Webcast Details
InterMune will host a live webcast of a conference call today at 8:00 a.m. EST to discuss the top-line ASCEND Phase 3 results. Interested investors and others may participate in the conference call by dialing 800-738-1032 (U.S.) or +1-212-231-2905 (international), conference ID# 21709573. A replay of the webcast and teleconference will be available approximately three 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 800-633-8284 (U.S.) or +1 402-977-9140 (international), and entering conference ID# 21709573.
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 InterMune's expectations regarding the timing for resubmission of its new drug application with the FDA for pirfenidone; the potential to make pirfenidone available as a medicine to IPF patients in the United States and InterMune's intention to present additional data on the ASCEND trial at the American Thoracic Society meeting in May 2014. 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 21, 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.
SOURCE InterMune, Inc.