InterMune, Inc. 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.
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