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|InterMune Reports Phase 3 ASCEND Trial Results of Pirfenidone in Idiopathic Pulmonary Fibrosis (IPF)|
"We are pleased to report these top-line ASCEND Phase 3 results," said
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.
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
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
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
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.
Pirfenidone has been marketed as Pirespa® since 2008 in
Pirfenidone is not approved for sale in
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.
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