- CAPACITY 2 Meets Primary and Key Secondary Endpoints -
- CAPACITY 1 Misses Primary Endpoint, Provides Supportive Data -
- Company Preparing to Submit NDA and MAA -
InterMune, Inc. (Nasdaq: ITMN ) today announced results from the two Phase 3 CAPACITY studies evaluating pirfenidone in patients with idiopathic pulmonary fibrosis (IPF).
The primary endpoint of change in percent predicted Forced Vital Capacity (FVC) at Week 72 was met with statistical significance in CAPACITY 2 (p=0.001), along with the secondary endpoints of categorical change in FVC and progression-free survival (PFS). The primary endpoint was not met in CAPACITY 1 (p=0.501), but supportive evidence of a pirfenidone treatment effect was observed on a number of measures.
Pirfenidone was safe and generally well tolerated in both CAPACITY studies. The company is preparing a New Drug Application (NDA) for submission to the FDA, to be followed by a Marketing Authorization Application (MAA) submission to the EMEA.
Dan Welch, Chairman, Chief Executive Officer and President of InterMune, said, "We are very pleased by the overall efficacy and safety of pirfenidone in the treatment of IPF provided by the two CAPACITY studies. In CAPACITY 2, pirfenidone demonstrated a robust treatment effect on the primary endpoint and key secondary endpoints. Although the effect of pirfenidone did not achieve statistical significance on the primary endpoint in CAPACITY 1, the overall treatment effect of pirfenidone was in many respects similar in both studies. The totality of the data from these two studies suggests that pirfenidone has a positive treatment effect on patients with IPF. We believe that the efficacy data from both of the CAPACITY studies as well as Shionogi's Phase 3 study, the compelling safety and tolerability profile observed in CAPACITY, together with the urgent unmet medical need for new medicines to treat IPF strongly support our decision to move forward with our NDA and an MAA submissions for pirfenidone as soon as possible. IPF is a disease that is more lethal than almost every form of cancer, affects almost 250,000 Americans and Europeans combined, and for which there are no medicines approved for their treatment."
Primary Endpoint Results
The primary endpoint of both CAPACITY studies was change in percent predicted Forced Vital Capacity (FVC) after 72 weeks of treatment, evaluated with a nonparametric rank ANCOVA. In the CAPACITY 2 study, the primary endpoint was met (p = 0.001). In CAPACITY 1, the primary endpoint was not met (p= 0.501). An exploratory analysis of pooled primary endpoint data from both studies using the pre-specified primary endpoint test statistic from a nonparametric rank ANCOVA resulted in a P value of 0.005.
A pre-specified repeated measures analysis of the primary endpoint was used to obtain a least squares mean estimate (LS mean) of the magnitude of the treatment effect. The LS mean change in percent predicted FVC at Week 72 was -6.5% and -9.6% in the pirfenidone and placebo groups, respectively, in CAPACITY 2, and -6.5% and -7.2%, respectively, in CAPACITY 1. This represents a relative reduction of 32% in CAPACITY 2 and 10% in CAPACITY 1.
To better understand the primary efficacy outcome, InterMune conducted a series of exploratory analyses interrogating the time course of treatment effect. An exploratory repeated measures analysis of ranked change from baseline, assessing treatment effect over the full duration of the study suggested pirfenidone reduced the decline in FVC in both studies (CAPACITY 2 p = 0.004 and CAPACITY 1 p = 0.001). In both studies, the magnitude of treatment effect generally was most pronounced in the first 48 weeks of treatment. For example, in CAPACITY 2 and CAPACITY 1 the Week 48 rank ANCOVA p values were 0.001 and 0.005; the relative reductions in LS means from the repeated measures analysis were 46% and 29%, respectively. The difference between the CAPACITY 2 and CAPACITY 1 primary endpoint results at Week 72 may have been due to a modest attenuation in the rate of FVC decline in the placebo group subsequent to Week 48 in CAPACITY 1.
Secondary Endpoint Results
In CAPACITY 2, pirfenidone treatment was associated with a statistically significant effect on the pre-specified secondary endpoints of PFS (p = 0.023) and Categorical Change in FVC (p = 0.001) when compared to placebo. A PFS event was defined in the study protocol as the time to death, a 10% decrease in FVC or a 15% decrease in DL(CO). In CAPACITY 1, pirfenidone treatment was associated with a statistically significant effect in the pre-specified secondary endpoint of Six-Minute Walk Test distance (p = 0.001) when compared to placebo. There were no other statistically significant findings on any of the other pre-specified secondary endpoints in either study and pirfenidone treatment was not associated with a worse outcome on any endpoints.
Although pooled analyses of secondary endpoints were pre-specified in the study protocol, these analyses are nonetheless considered exploratory because the primary endpoint of both studies was not met. Analyses of pooled data for the pre-specified secondary endpoints of both CAPACITY studies showed a treatment effect favoring pirfenidone on three: PFS (p = 0.029); Categorical FVC Change (p = 0.003) and Six-Minute Walk Test distance (p = 0.004). While the studies were not powered to demonstrate an effect on overall survival, the pooled hazard ratio (pirfenidone: placebo) was 0.78 (p= 0.326).
Safety and Tolerability Results
Safety data from both studies show that pirfenidone was safe and generally well tolerated. In CAPACITY 2, 83% and 90% of surviving, lung transplant-free patients completed therapy per protocol in the pirfenidone and placebo groups, respectively, and 82% and 90%, respectively, in CAPACITY 1. The percentage of patients discontinuing treatment due to an adverse event was 12% and 8% in the pirfenidone and placebo groups, respectively, in CAPACITY 2, and 14% and 8%, respectively, in CAPACITY 1.
There was no difference between pirfenidone and placebo in the percentage of patients that experienced a serious adverse event (SAE). An SAE was reported in 35% and 33% of pirfenidone and placebo groups, respectively, in CAPACITY 2 and in 31% and 30%, respectively, in CAPACITY 1. In both studies, the incidence of Grade 3 or Grade 4 laboratory abnormalities was similar between patients treated with pirfenidone or placebo.
The pattern of adverse events was in general comparable to that observed in previous clinical studies of pirfenidone. The most common adverse events occurring more than 1.5 times in the pirfenidone 2403 mg group as compared to placebo in either study were nausea (35% vs. 18% in CAPACITY 2 and 38% vs. 16% in CAPACITY 1), rash (31% vs. 10% and 34% vs. 13%), fatigue (28% vs. 21% and 33% vs. 20%), diarrhea (25% vs. 17% and 33% vs. 21%), dyspepsia (17% vs. 9% and 21% vs. 6%), and dizziness (19% vs. 10% and 18% vs. 10%). Rash was generally mild to moderate in both studies; only 2 patients (1 in each CAPACITY study) receiving pirfenidone 2403 mg experienced a severe rash, and only 4 patients in each study discontinued study treatment due to a rash or photosensitivity. There was no difference in the incidence of skin cancer between patients treated with pirfenidone or placebo.
Low-dose Treatment Group
A low-dose group at 1197 mg per day was included in CAPACITY 2 to explore dose-response relationships in a descriptive fashion. In general, on efficacy outcome measures the low-dose group showed a demonstrable, but more modest treatment effect than the high-dose group. Regarding safety, low-dose pirfenidone was also safe and generally well tolerated with overall fewer side effects than the high-dose group.
Steve Porter, M.D., Ph.D., Chief Medical Officer of InterMune, said, "While the primary endpoint was met in just one of two CAPACITY studies, there are significant consistencies across the two studies in the overall treatment effect of pirfenidone on lung function and exercise tolerance. In addition, the Study Week 48 results from both CAPACITY studies are consistent with those of the primary efficacy endpoint, change in Vital Capacity at Week 52, in the Shionogi Phase 3 study. Considering the favorable safety profile of pirfenidone and the lack of any approved treatment options for IPF patients, we believe the collective data suggest pirfenidone may play a meaningful role in the management of patients suffering from this devastating disease."
Dr. Porter continued, "We are greatly indebted to the many patients, health care providers and study personnel who dedicated themselves to the successful conduct of the CAPACITY program and enabled us to deliver high quality data."
About CAPACITY and RECAP
The CAPACITY program consisted of two multinational, randomized, double-blind, placebo-controlled Phase 3 trials, named CAPACITY 1 and CAPACITY 2, designed to evaluate the safety and efficacy of pirfenidone in IPF patients with mild to moderate impairment in lung function. The primary endpoint of both trials was change in percent predicted Forced Vital Capacity (FVC) after 72 weeks of treatment evaluated with a nonparametric rank ANCOVA analysis. Both trials enrolled patients in North America, Europe and Australia with roughly 75% of the total 779 patients enrolled in North America.
CAPACITY 1 enrolled a total of 344 patients. Patients were randomized 1:1 to receive a total daily dose of 2403 mg pirfenidone, or placebo. CAPACITY 2 enrolled a total of 435 patients, and patients were randomized 2:2:1 to receive a total daily dose of 2403 mg pirfenidone, or placebo, or a total daily dose of 1197 mg pirfenidone, respectively, administered in three divided doses. The lower dose of pirfenidone in CAPACITY 2 provided safety and tolerability data. The pre-specified statistical analysis plan did not call for this low-dose group to be used in any analyses of efficacy. The pooled analyses of the primary and secondary efficacy outcome measures were based on a combined analysis of the 2403 mg group compared with the placebo group across both studies and were considered exploratory.
Enrollment of both trials was completed in less than 13 months following randomization of the first patient into the program in late April 2006. Ninety-seven percent (97%) of all patients in the two CAPACITY studies who were living and had not received a lung transplant, completed their Week 72 study visit.
Each trial in CAPACITY was designed to have greater than 95% statistical power to detect a 50% reduction in the rate of FVC progression compared to placebo after 72 weeks of treatment and greater than 85% statistical power to detect a 40% reduction after the same period, when compared to placebo. The pre-specified secondary endpoints of CAPACITY were:
1. Time to worsening of IPF, defined as time to acute IPF
exacerbation, IPF-related death, lung transplant or respiratory
hospitalization, whichever comes first
2. Progression-free survival defined as time to the first occurrence
of either of the following (as compared to the patient's
baseline):
-- 10% absolute decline in percent predicted FVC, or
-- 15% absolute decline in percent predicted Hb-corrected
DL(CO), or
-- Death
In the case of FVC or DL(CO), the decline must be confirmed at
two consecutive visits at least 6 weeks apart.
3. Categorical assessment of absolute change from Baseline to Week
72 in percent predicted FVC
4. Change from Baseline to Week 72 in dyspnea measured by the
University of California at San Diego Shortness-of-Breath
Questionnaire (UCSD SOBQ)
5. Change from Baseline to Week 72 in the percent predicted
Hb-corrected DL(CO)
6. Change from Baseline to Week 72 in the worst oxygen saturation by
pulse oximetry (SpO2) measurement observed during the Six-Minute
Walk Test
7. Change from Baseline to Week 72 in distance walked in the Six-
Minute Walk Test
Regarding RECAP, all eligible patients from CAPACITY have been enrolled in this on-going open-label roll-over study from CAPACITY to evaluate the long-term safety of pirfenidone in patients with IPF.
The results of CAPACITY will be presented at the 2009 International Conference of the American Thoracic Society (ATS) in San Diego, and InterMune plans to publish the results of CAPACITY in a peer-reviewed journal.
About Pirfenidone
Preclinical and in-vitro evidence had shown that pirfenidone inhibits collagen synthesis, down-regulates profibrotic cytokines and decreases fibroblast proliferation. Prior to the current results, data were presented from one Phase 3 study and four Phase 2 clinical trials in more than 400 patients which suggested that pirfenidone may positively affect lung function and disease progression in patients with IPF. In those clinical studies, pirfenidone was generally safe and well tolerated with the most frequent side effects reported being photosensitivity rash and gastrointestinal symptoms. In October of 2008, pirfenidone was approved for use in IPF patients in Japan and is marketed as Pirespa® by Shionogi in that country.
About the Marnac Agreement
In November 2007, InterMune concluded an agreement with Marnac, Inc. and with co-licensor KDL GmbH, the licensors for pirfenidone. The agreement involved the acquisition of patents and the elimination of all future royalties due to Marnac in exchange for total upfront payments of $13.5 million. Contingent acquisition payments of up to an additional $53.5 million would be made by InterMune only upon successful achievement of certain clinical development and regulatory milestones. InterMune provided additional details of this agreement in its press release dated November 26, 2007.
About IPF
Idiopathic pulmonary fibrosis (IPF) is a disabling and ultimately fatal disease that affects approximately 250,000 people in the United States and Europe combined, with approximately 30,000 new cases reported per year in each of the United States and Europe.
IPF is characterized by inflammation and scarring (fibrosis) in the lungs, hindering the ability to process oxygen and causing shortness of breath (dyspnea) and cough and is a progressive disease, meaning that over time, lung scarring and symptoms increase in severity. The median survival time from diagnosis is two to five years, with a five-year survival rate of approximately 20%. Patients diagnosed with IPF are usually between the ages of 40 and 70, with a median age of 63 years and the disease tends to affect slightly more men than women. There are no medicines approved by the FDA or EMEA for the treatment of IPF.
Webcast Details
InterMune will host a teleconference and webcast, with accompanying slide presentation, today at 8:00 a.m. EST to discuss results from the CAPACITY program.
To access the live teleconference, dial 888-799-0528 (U.S.) or 973-200-3372 (international), conference ID# 84164912. To access the live audio webcast of the conference call, please log on to the investor relations page of the company's website at www.intermune.com. The company recommends logging on to the site 15 minutes prior to the start of the presentation in order to register or download any necessary software.
A replay of the webcast and teleconference will be available approximately three hours after the call. The teleconference replay will be available for 10 business days following the call and can be accessed by dialing 800-642-1687 (U.S.) or 706-645-9291 (international), and entering the conference ID# 84164912.
About InterMune
InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and hepatology. InterMune has a pipeline portfolio addressing idiopathic pulmonary fibrosis (IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio includes the Phase 3 program, CAPACITY, which is evaluating pirfenidone as a possible therapeutic candidate for the treatment of patients with IPF, RECAP, an open-label extension study from CAPACITY and a research program focused on small molecules for the treatment of pulmonary disease. The hepatology portfolio includes the HCV protease inhibitor compound ITMN-191 (referred to as R7227 at Roche, its development partner) in Phase 1b, a second-generation HCV protease inhibitor research program, and a research program evaluating new targets in hepatology. 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 statements related to anticipated product development timelines and the likelihood of regulatory success. 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. The top-line efficacy, safety and tolerability data reported in this press release are from analyses of the highest areas of interest to the company based on the prior clinical experience with pirfenidone in IPF patients. Pirfenidone failed to achieve statistical significance on the primary endpoint in one of its two pivotal clinical trials and there can be no assurance that the regulatory authorities in either the United States or Europe will grant regulatory approval based upon the efficacy data from a single pivotal trial, in combination with the other efficacy and safety results the company currently intends to submit in support of its NDA and MAA filings. Further analyses of the CAPACITY results will be conducted in the future and additional observations may be made which may lead to material change in the company's current regulatory strategy for pirfenidone, including a decision by the company not to proceed with either or both of its regulatory submissions in the United States and Europe. These analyses and observations will be included in a presentation of the CAPACITY data that the company expects to make at the American Thoracic Society (ATS) in the second quarter of 2009, and/or in a scientific publication. 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 SEC on March 14, 2008 (the "Form 10-K") and other periodic reports filed with the SEC, including the following: (i) risks related to the long, expensive and uncertain clinical development and regulatory process, including having no unexpected safety, toxicology, clinical or other issues or delays in anticipated timing of the regulatory approval process; (ii) risks related to failure to achieve the clinical trial results required to commercialize our product candidates; and (iii) risks related to timely patient enrollment and retention in clinical trials. 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.