Pirfenidone

Description

Pirfenidone is an orally active, small molecule drug 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. It also inhibits the synthesis of TNF-alpha, a cytokine that is known to have an active role in inflammation. Pirfenidone has demonstrated activity in multiple fibrotic conditions, including those of the lung, kidney and liver.

InterMune licensed certain rights to pirfenidone from Marnac, Inc. and its co-licensor, KDL GmbH, in 2002. In 2007 the company purchased from Marnac and KDL the rights to sell the compound under the patents in the United States, Europe and other territories, except in Japan, Taiwan and South Korea, where rights to the molecule were licensed to Shionogi & Co. Ltd. of Japan. In October of 2008, pirfenidone was approved for use in Japan for patients with idiopathic pulmonary fibrosis (IPF), where it is marketed as Pirespa® by Shionogi & Co.

Clinical Trial Results

Pirfenidone has been studied in multiple Phase 2 and Phase 3 clinical trials in patients with IPF, including the two Phase 3 CAPACITY trials, conducted by InterMune, as well as a Phase 3 trial designed and conducted by Shionogi. In May of 2009, InterMune reported results from the two Phase 3 CAPACITY studies evaluating pirfenidone in patients with IPF, at the International Conference of the American Thoracic Society (ATS) in San Diego. Additional analyses of the CAPACITY results were presented in September 2009 at the Annual Congress of the European Respiratory Society (ERS) in Vienna, Austria.

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 each study was the absolute mean change from baseline to week 72 in percent predicted forced vital capacity (FVC). This endpoint 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 (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 six-minute walk test (6MWT) distance.

Pirfenidone was safe and generally well tolerated in both CAPACITY studies, the most frequent side effects reported being photosensitivity rash, gastrointestinal symptoms such as nausea and dyspepsia, and dizziness. Patients completing the CAPACITY trials were allowed to enroll in RECAP, an ongoing open-label roll-over study from CAPACITY to evaluate the long-term safety of pirfenidone in patients with IPF. In RECAP, all patients receive pirfenidone.

Regulatory Status

Pirfenidone has been granted Orphan Drug and Fast Track designation by the FDA, and also has been granted Orphan Drug status in Europe.

On November 4, 2009, InterMune submitted a New Drug Application (NDA) for pirfenidone to the U.S. FDA, seeking approval to market pirfenidone for the treatment of patients with IPF to reduce the rate of decline in lung function. On January 4, 2010, InterMune announced that the FDA had granted Priority Review designation to the pirfenidone NDA. Priority Review designation may be granted by the FDA to an NDA for drugs that have the potential to offer major advances in treatment, or provide a treatment where no adequate therapy exists. Based on the Prescription Drug User Fee Act (PDUFA), the FDA set an action date for the NDA of May 4, 2010. On May 4, 2010, the FDA issued a complete response letter with regard to the pirfenidone NDA, requesting an additional clinical trial to support the efficacy of pirfenidone in IPF. In January 2011 InterMune reported that, as recommended by the FDA in its complete response letter, the company currently plans to conduct a new Phase 3 clinical study that would demonstrate a clinically meaningful effect on forced vital capacity, with a target of enrolling the first patient in the study in June of 2011.

On March 2, 2010, InterMune announced that it had submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA), seeking approval to market pirfenidone for the treatment of IPF patients in the European Union. The MAA for pirfenidone was validated on March 24, 2010, indicating that the application was complete and that the review process had begun. On December 17, 2010, InterMune announced that the Committee for Medicinal Products for Human Use (CHMP) of the EMA had adopted a positive opinion recommending the granting of the MAA. The CHMP is the scientific body of the EMA responsible for reviewing all Marketing Authorization Applications for new medicines. On March 3, 2011, InterMune announced that the European Commission (EC) had granted marketing authorization for Esbriet® (pirfenidone). Esbriet is indicated in adults for the treatment of mild to moderate idiopathic pulmonary fibrosis. InterMune currently plans to launch Esbriet on timelines consistent with normal regulatory and reimbursement processes in the various member nations of the European Union, with the first launch expected in 2011.

Investigational, not an FDA-approved product.