InterMune, Inc., a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and orphan fibrotic diseases, has resubmitted its pirfenidone New Drug Application (NDA) to the US Food and Drug Administration (FDA) in response to a Complete Response Letter (CRL) received in May 2010.  Pirfenidone is being developed for the treatment of adult patients with idiopathic pulmonary fibrosis (IPF).

"We are pleased to have resubmitted the pirfenidone NDA and look forward to our interactions with the FDA," said Dan Welch, chairman, chief executive officer and president of InterMune.  "The final steps in preparing the resubmission were completed very smoothly and efficiently, allowing us to complete the process somewhat earlier than expected.  If the FDA grants approval of our NDA within the six-month review period of an NDA resubmission, we would be ready to launch pirfenidone in the first quarter of 2015."

Under the Prescription Drug User Fee Act (PDUFA), the FDA has 74 days after receipt of an NDA to evaluate the submission in order to determine if it is sufficiently complete.  If in this 74-day period the FDA determines that the submission is complete, the review clock will be deemed to have started as of the date that the resubmission was initially received by the FDA.  As the resubmission of an efficacy supplement, the submission of the ASCEND data represents a Class 2 resubmission that has a target FDA review of six months under PDUFA V.

In May 2010, InterMune received a CRL from the FDA.  In the CRL, the FDA recommended an additional Phase 3 clinical trial to support the efficacy of pirfenidone.  Since the receipt of the CRL, InterMune has conducted the Phase 3 ASCEND trial of pirfenidone in IPF, and results of that trial were presented on May 18, 2014, at the meeting of the American Thoracic Society and were published on-line the same day in the New England Journal of Medicine.  The NDA resubmission includes the ASCEND Clinical Study Report as well as the pooled analyses of efficacy and mortality from the three InterMune phase 3 trials: ASCEND and the previous Phase 3 CAPACITY trials (004 and 006).  Additionally, the NDA resubmission includes a safety update of approximately 15,000 patients including clinical studies and the extensive post-marketing experience of pirfenidone collected since 2008.

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 the United States, Australia, Brazil, Croatia, Israel, Mexico, New Zealand, Peru and Singapore.

The CAPACITY programme consisted of two concurrent 72-week trials (studies 004 and 006) 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 study 004 (p=0.001).  The primary endpoint was not met in study 006 (p=0.501).

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.

On February 28, 2011, the European Commission (EC) granted marketing authorization for Esbriet (pirfenidone) for the treatment of adults with mild to moderate IPF.  The approval authorized marketing of Esbriet in all 28 EU member states.  Esbriet has since been approved for marketing in Norway and Iceland.  In 2011, InterMune launched commercial sales of pirfenidone in Germany under the trade name Esbriet, and Esbriet is now also commercially available in various European countries, including key markets such as France, Italy and the UK.

On October 1, 2012, Health Canada approved Esbriet for the treatment of mild to moderate IPF in adult patients.  Health Canada designated Esbriet for Priority Review and completed the accelerated review according to target guidelines of 180 days.  InterMune launched Esbriet in Canada in January 2013.

Pirfenidone has been marketed as Pirespa since 2008 in Japan and since 2012 in South Korea by Shionogi & Co. Ltd.  Under different trade names, pirfenidone is also approved for the treatment of IPF in China, India, Argentina and Mexico.

Pirfenidone is not approved for sale in the United States.

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.