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|Results of Two Phase 3 CAPACITY Studies of Pirfenidone in IPF Presented at American Thoracic Society (ATS)|
-- Results of new analyses of efficacy and safety reported -
-- Conference Call and Webcast at 9 p.m. EDT (6 p.m. PDT) -
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). The secondary endpoints of progression-free survival (PFS) and categorical change in FVC were also met with statistical significance. 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, including the primary endpoint. Pirfenidone was safe and generally well tolerated in both CAPACITY studies. InterMune is preparing a New Drug Application (NDA) expected to be submitted to the FDA in the summer of 2009, to be followed by a Marketing Authorization Application (MAA) submission to the EMEA around the end of 2009.
Dr. Noble commented on the results, "CAPACITY 2 demonstrated a statistically significant and clinically meaningful effect on both the primary endpoint of change in percent predicted FVC and secondary endpoints of progression-free survival and categorical change in percent predicted FVC. While CAPACITY 1 did not achieve statistical significance on the primary endpoint, the results were generally consistent with and supportive of CAPACITY 2. Further, the treatment effect observed in the CAPACITY studies was generally consistent with that observed in the Phase 3 study of pirfenidone in IPF patients conducted by Shionogi & Co. Ltd. in Japan."
Dr. Roland du Bois, Professor of Medicine at National Jewish Health, Denver, Colo., and CAPACITY co-chair also commented on the CAPACITY results. "When taken in the context of the urgent unmet medical need for new medicines to treat IPF patients, the collective efficacy and safety data from the two CAPACITY studies, corroborated by a similar study in Japan, make a case for the use of pirfenidone in this disease setting."
Primary Efficacy 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 an exploratory analysis that interrogated the time course of the pirfenidone treatment effect. The results of an exploratory repeated measures analysis of ranked change from baseline, assessing treatment effect over the full duration of the study showed that pirfenidone reduced the decline in FVC in both studies (CAPACITY 2, p=0.004 and CAPACITY 1, p=0.001).
Secondary Efficacy Endpoint Results
In CAPACITY 2, treatment with pirfenidone 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 DLco. In CAPACITY 1, pirfenidone treatment was associated with a treatment 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.
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=0.001). Although pooled analyses of secondary endpoints were pre-specified in the study protocols, these analyses are nonetheless considered exploratory because the primary endpoint of both studies was not met.
The pooled analysis of Categorical FVC Change showed that 30% fewer patients experienced a 10% or greater decrease in FVC at week 72 in the pirfenidone group than in the placebo group. This magnitude of decline is considered clinically meaningful as a 10% decline in percent predicted FVC has been shown in multiple studies to be an independent predictor of mortality in patients with IPF. In addition, 40% more patients in the pirfenidone group did not experience a decline in percent predicted FVC at week 72 versus baseline compared to those who received placebo.
While the studies were not powered to demonstrate an effect on overall survival, a pre-specified exploratory endpoint, the pooled hazard ratio (pirfenidone: placebo) was 0.77 (p=0.326).
ADDITIONAL EXPLORATORY EFFICACY RESULTS REPORTED AT ATS
The ATS presentation highlighted new efficacy data from CAPACITY pertaining to dose-effect relationships, mean change in FVC volume and Six-Minute Walk Test distance.
In the CAPACITY 2 study, 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. The lower dose of pirfenidone in CAPACITY 2 was included to explore dose-effect relationships in a descriptive fashion. Dr. Noble reported at the ATS meeting data on the low-dose pirfenidone group for the efficacy outcome measures of change in percent predicted FVC, PFS and DLco. On each of these outcome measures, the effect of 1197 mg was intermediate as compared to placebo and 2403 mg pirfenidone, indicative of a consistent dose-effect relationship. Similarly, a dose-response relationship was observed on a number of safety outcome measures.
Change in FVC Volume
Pre-specified analyses of change in FVC were based on percent predicted FVC and not volume. Given the clinical interest in FVC volume, data on change in this parameter were reported at ATS. Similar to the results of the primary endpoint analysis, evidence of a pirfenidone treatment effect on this endpoint was observed at all six assessment periods, including Week 72, in CAPACITY 2, and at all four of the assessment periods through Week 48 in CAPACITY 1, but not at Week 72. An analysis of pooled data from the two CAPACITY studies showed that placebo-treated patients experienced a mean of 76 mL more decline in FVC than patients who received pirfenidone at Week 72. At Week 48, patients who received pirfenidone experienced a mean of 169 mL less FVC decline compared to placebo in CAPACITY 2 (p=0.002) and a mean of 54 mL less FVC decline in CAPACITY 1 (p=0.006). This pattern of change is consistent with that observed at Week 52 in the Phase 3 study of pirfenidone conducted by Shionogi.
Categorical Analysis of Change in Six-Minute Walk Test (6MWT) Distance
Post-hoc analyses of data from the 826-patient INSPIRE trial suggested that patients experiencing a 50-meter decrement in distance walked during the 6MWT at six months had an approximately 2.5-fold increased risk in mortality. Using this threshold, 33% and 47% of pirfenidone and placebo patients, respectively, in CAPACITY 1 (p=0.013), and 37% and 47% of pirfenidone and placebo patients, respectively, in CAPACITY 2 (p=0.032) experienced this magnitude of change. In a pooled analysis, 35% and 47% of pirfenidone and placebo patients, respectively, experienced a change that exceeded this threshold (p=0.001).
Safety and Tolerability Results
Safety data presented for both studies showed that pirfenidone given as 2403 mg per day 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, of patients did so in CAPACITY 1. The percentage of patients discontinuing treatment due to an adverse event across both studies combined was 15% and 9% in the pirfenidone and placebo groups, respectively.
There was no difference between pirfenidone and placebo in the percentage of patients who experienced a serious adverse event (SAE). An SAE was reported by 35% and 33% of pirfenidone and placebo groups, respectively, in CAPACITY 2 and by 31% and 30%, respectively, in CAPACITY 1. While there was a slightly higher incidence of Grade 3 adverse events in the pirfenidone groups in both studies, there was no difference in overall Grade 4 adverse events between pirfenidone and placebo.
The pattern of adverse events was in general comparable to that observed in previous clinical studies of pirfenidone. The most common adverse events in the pirfenidone group as compared to placebo 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 experienced a severe rash.
ADDITIONAL SAFETY RESULTS REPORTED
The ATS presentation reported new safety data from the CAPACITY studies pertaining to the incidence and cause of deaths, treatment discontinuations due to adverse events and laboratory tests.
Incidence and Cause of Deaths
Analysis of the incidence and cause of death revealed that fewer patients in the pirfenidone 2403 mg group compared with placebo died during the treatment period, defined as the time from the first dose until 28 days after the last dose of study treatment. In CAPACITY 1, 5.3% of patients in the pirfenidone group died during the treatment period, compared with 8.7% in the placebo group. In CAPACITY 2, 5.7% of patients in the pirfenidone group died during the treatment period, compared with 8.0% in the placebo group.
The incidence of IPF-related deaths during treatment was also lower among patients treated with pirfenidone. IPF-related deaths occurred during the treatment period in 4.1% of patients in the pirfenidone group and 8.1% of patients in the placebo group in CAPACITY 1. IPF-related deaths occurred during the treatment period in 2.9% of pirfenidone group and 6.3% of patients in the placebo group in CAPACITY 2.
Treatment Discontinuation due to Adverse Events
Pirfenidone was safe and generally well tolerated. Relatively few adverse events resulted in treatment discontinuations. The percentage of patients in the 2403 mg pirfenidone and placebo groups across both CAPACITY studies who discontinued treatment (pirfenidone/placebo) due to various adverse events were as follows: IPF (2.9/2.6); rash (1.4/0); nausea (1.4/0); bladder cancer (0.9/0); photosensitivity reaction (0.9/0.3); respiratory failure (0.9/0.3) and weight decrease (0.6/0).
A total of 30 laboratory tests were regularly performed in CAPACITY. The incidence of grade 3/4 laboratory abnormalities was similar between treatment groups in both studies. In six of the tests, Grade 3/4 abnormalities were noted slightly more frequently in patients treated with pirfenidone (phosphate elevation, hyponatremia, lymphopenia, ALT elevation, AST elevation and cholesterol elevation). Of these laboratory abnormalities in pirfenidone patients, all but one case each of hyponatremia and lymphopenia were Grade 3. In four of the laboratory tests, Grade 3/4 abnormalities were noted slightly more frequently in patients treated with placebo (urate elevation, hyperkalemia, amylase elevation and creatine kinase elevation). Both the incidence of grade 3/4 lab abnormalities and the differences observed between treatment groups on all tests were small.
Regarding the overall safety results, Dr. du Bois commented, "The safety and tolerability of pirfenidone was reassuring. The principal side effects experienced by patients in the studies were gastrointestinal discomfort and photo-sensitivity, both of which were manageable in the majority of patients."
Dr. Noble concluded, "The efficacy and safety findings of CAPACITY were generally consistent with those observed in the Phase 3 study in IPF patients conducted by Shionogi in Japan. Collectively, these three Phase 3 studies give us a very good sense of the impact that pirfenidone has on the progression of IPF over at least one year."
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.
Regarding RECAP, 603 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.
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(R) by Shionogi in that country.
Idiopathic pulmonary fibrosis (IPF) is a disabling and ultimately fatal disease that affects approximately 200,000 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.
InterMune will host a teleconference and webcast, with accompanying slide presentation, this evening at 9:00 p.m. EDT (6:00 p.m. PDT), in which Dr. Noble will present his oral presentation of the CAPACITY results and accompanying slides.
To access the live teleconference, dial 888-799-0528 (U.S.) or 973-200-3372 (international), conference ID# 97738057. 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# 97738057.
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.
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, the interpretation of the CAPACITY clinical data, including certain exploratory analyses conducted by the Company with respect to such data 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. 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 these data, in combination with the other efficacy analyses 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 one or more scientific publications. 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 16, 2009 (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.
SOURCE InterMune, Inc.