Investigational, not an FDA-approved product
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. Pirfenidone is approved for marketing in 30 European countries (28 in EU plus Norway and Iceland) and Canada under the InterMune trade name Esbriet® and in Japan and South Korea where it is marketed by Shionogi & Co. Ltd under the trade name Pirespa®. Under different trade names, pirfenidone is also approved for the treatment of IPF in China, India, and Argentina. Pirfenidone is not approved for marketing in the United States but InterMune intends to resubmit the pirfenidone New Drug Application (NDA) to the U.S. FDA early in the third quarter of 2014 to support regulatory registration in the United States.
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, the ASCEND Phase 3 trial, as well as a Phase 3 trial designed and conducted by Shionogi.
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). The primary endpoint was not met in CAPACITY 1 (p=0.501).
In the CAPACITY studies, pirfenidone showed a favorable safety profile and was 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.
InterMune reported top-line results from the Phase 3 “ASCEND” trial in February 2014. ASCEND, a randomized, double-blind, placebo-controlled trial that enrolled 555 patients, was conducted to support marketing approval of pirfenidone in the United States.
ASCEND data confirmed observations from other clinical studies that pirfenidone significantly reduced IPF disease progression as measured by change in percent predicted forced vital capacity (FVC) from Baseline to Week 52 (rank ANCOVA p<0.000001). Additionally, significant treatment effects were demonstrated on both of the key secondary endpoints of six-minute walk test distance change (p=0.0360) and progression-free survival (p=0.0001). A pre-specified analysis 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 ASCEND, pirfenidone showed a favorable safety profile and was generally well tolerated.
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 would conduct a new Phase 3 clinical study that would demonstrate a clinically meaningful effect on forced vital capacity. The first patient was enrolled in the study, referred to as the "ASCEND" study, in July of 2011 and enrollment was completed in January 2013. Top-line results from ASCEND were reported in February 2014, as noted above. InterMune currently intends to resubmit the pirfenidone NDA to the FDA early in the third quarter of 2014.
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. 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.
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.