InterMune said today its idiopathic pulmonary fibrosis (IPF) drug candidate pirfenidone met its primary endpoint in a Phase III ASCEND clinical trial of significantly reduced disease progression, as well as both secondary endpoints in the study.

Based on those results, InterMune is preparing to resubmit to the FDA its NDA for pirfenidone—an application Chairman and CEO Dan Welch said the company expects to submit “by early third quarter.”

Pirfenidone, marketed overseas as Esbriet®, is approved in the European Union and Canada, as well as Argentina, China, India, Japan, Mexico, and South Korea. FDA rejected pirfenidone in 2010, insisting on another Phase III trial after an advisory committee recommended approval of the drug, but by a 9–3 margin.

Top-line data from ASCEND released by InterMune showed that at 52 weeks from the start of treatment, 16.5% of patients treated with pirfenidone experienced a decline in forced vital capacity (FVC) of 10% or more or death, compared with 31.8% in a comparator group treated with placebo—a 47.9% reduction in the proportion of patients who experienced a meaningful change in FVC or death. Also at week 52, 22.7% of patients in the pirfenidone group experienced no decline in FVC, compared with 9.7% in the placebo group—a 132.5% increase in the proportion of patients whose FVC did not decrease between baseline and a year later.

“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,” Talmadge King, M.D., chair of the Department of Medicine at University of California, San Francisco, and co-chair of the ASCEND protocol steering committee, said in a statement. 

InterMune said significant treatment effects were seen in both of the key secondary endpoints of six-minute walk test distance (6MWD) change and progression-free survival. In ASCEND, pirfenidone reduced by 27.5% the proportion of patients experiencing a decline in 6MWD of 50 meters or greater. The experimental drug was also found to reduce the risk of death or disease progression by 43% compared to placebo.

“The results for 6MWT distance, PFS and mortality provide important supportive evidence of pirfenidone’s efficacy,” Dr. Talmadge added.

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 shortness of breath.  While there were fewer events of all-cause mortality and treatment-emergent IPF-related mortality in pirfenidone patients compared with placebo, ASCEND could not show the difference on these endpoints, with a blinded adjudication committee determining the relationship of death to IPF.

Because of the relatively low overall mortality rate in patient populations in the time frames studied in ASCEND and other single studies, researchers sought more statistical power and a more precise estimate of the treatment effect of pirfenidone on mortality. To achieve both, researchers analyzed some effects of the drug candidate on a patient population pooled from ASCEND and an earlier pair of earlier Phase III studies known as CAPACITY.

Analyses of the pooled population across ASCEND and CAPACITY showed that the risk of all-cause mortality was reduced after 52 weeks by 48% in the pirfenidone group compared to the placebo group.  Also, in the pooled population the risk of treatment-emergent IPF-related death in the pirfenidone group compared to placebo was reduced by 68%.

However, the secondary endpoint of dyspnea, measured by a UC San Diego Shortness of Breath questionnaire, was not achieved.

Pirfenidone showed a favorable safety profile and was generally well tolerated in ASCEND, InterMune said. The percentage of patients ending treatment due to an adverse event was 14.4% for pirfenidone and 10.8% for placebo.  However, the percentage of serious adverse events (SAEs) reported in pirfenidone patients (19.8%) was smaller than the placebo group (24.9%). Also smaller was the percentage of hospitalizations due to respiratory, thoracic and mediastinal SAEs among pirfenidone patients (3.6%) compared with 11.2% among patients taking placebo.

Welch said additional ASCEND data will be presented in May at the 2014 American Thoracic Society International Conference. 

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