Washington Editor

SILVER SPRING, Md. - An FDA advisory panel Tuesday backed approval of InterMune Inc.'s pirfenidone as a treatment for idiopathic pulmonary fibrosis (IPF), a progressive, irreversible, ultimately fatal disease that affects about 5 million people worldwide, including 100,000 Americans.

The FDA's Pulmonary-Allergy Drugs Advisory Committee voted 9 to 3 to approve pirfenidone as a therapy to reduce the decline in lung function in patients with IPF.

"We are very excited by the vote and by the discussion," InterMune Chief Medical Officer Steven Porter told reporters after the meeting. "The data spoke for itself," he said.

Although one of InterMune's two Phase III studies missed its primary endpoint, the FDA's Pulmonary-Allergy Drugs Advisory Committee voted 7 to 5 that the pooled data showed substantial evidence that pirfenidone provides a clinically meaningful efficacy benefit in reducing decline in lung function in IPF.

The committee also voted 9 to 3 that pirfenidone's safety had been adequately assessed, despite some concerns about one potential case of drug-related serious liver injury and serious adverse gastrointestinal and skin events. Many on the panel urged InterMune to create a patient registry to track long-term safety data.

InterMune has proposed a risk evaluation and mitigation strategy (REMS) plan for pirfenidone, but the REMS currently does not include a registry, Porter told reporters. "We are certainly open to the FDA about whatever is appropriate," he said. Porter noted that InterMune has about six years of safety data collected.

The company currently has two ongoing follow-up studies. "That's a rich source of additional safety data," Porter said. "It is open for discussion with the agency in terms of what further data they want and that they feel is important."

Porter noted during the meeting that the adverse gastrointestinal and skin events, such as rash and photosensitivity reactions, in the firm's clinical trials were mild to moderate and rarely led to treatment discontinuation. Those events were alleviated by adjusting the patient's dosage of pirfenidone, he added. To avoid the adverse gastrointestinal events, InterMune has proposed labeling recommendations for pirfenidone to be taken with food. The firm's proposed labeling also recommends use of sun protection measures and advises prescribers to temporarily modify dosages of the drug when necessary.

Porter emphasized that no cases of Steven's-Johnson syndrome or anaphylactic reactions were reported during InterMune's studies. In addition, no hospitalizations due to the skin reactions were reported.

There currently are no treatments approved in the U.S. for IPF, a disease for which the cause is unknown but the condition has been known to run in families.

Osaka, Japan-based Shionogi & Co. Ltd., however, received approval of pirfenidone in October 2008 in Japan, where the drug is sold as Pirespa.

Panelist Leslie Hendeles, professor of pharmacy and pediatrics at the University of Florida, said that although he voted that InterMune's studies had failed to show evidence of substantial efficacy, he backed the drug's approval because "If I got this disease, I would be on the next Delta flight to Japan."

Panelist Karen Gottesman, the committee's patient representative, said she also was not convinced of the drug's efficacy, but she voted in favor of approval to provide patients "a smidgen of hope."

The median survival in patients with IPF is about three to five years. There were more than 175,000 IPF-related deaths from 1992 to 2003 - a rate higher than many cancers, said Ron du Bois, professor of medicine at National Jewish Health. IPF causes irreversible honeycomb-like lesions and scarring on the lungs, he said, characterizing patients' experience as slowly suffocating as though their lungs were filling with Jello.

While patients with IPF generally are treated off-label with corticosteroids and immunosuppressive agents, there is no evidence to support the efficacy of those drugs, du Bois said. Lung transplants also have been an option for survival, but because IPF strikes people generally in their 40s or later, age and comorbidities often make many patients ineligible for the procedure.

There have been few adequate controlled clinical trials of drugs in IPF, he noted. InterMune's pirfenidone program, he insisted, was a "vanguard" of the study process and conduct in the disease. Du Bois argued that InterMune not only took into account the nature of IPF, but also used the "most appropriate" primary endpoint.

Because of a paucity of IPF-related research for therapies and no regulatory history, the FDA has been grappling with determining an appropriate clinical trial endpoint.

InterMune used the absolute change in percent predicted in forced vital capacity (FVC) from baseline to week 72 as its primary efficacy endpoint, despite the agency recommending against doing so.

Regulators had argued that mortality was the "ideal" primary endpoint, and that FVC was not an established surrogate for mortality.

InterMune's Phase III PIPF-004 (CAPACITY 2) trial showed that 20 percent of patients treated with pirfenidone at the 2,403-mg daily dosage had a 10 percent or greater decline in FVC compared with 35 percent taking a placebo, which was statistically significant in favor of treatment, said Bill Bradford, senior vice president of clinical science and biometrics.

However, InterMune's Phase III PIPF-006 (CAPACITY 1) failed to duplicate those results, which Bradford said was "perplexing." He said the company was unable to explain the differences in the two studies' results.

Nonetheless, he said, at time points through week 48 of PIPF-006, there was "clear evidence" of a pirfenidone treatment effect of a generally similar magnitude in the two studies. Plus, Bradford added, the repeated measures analysis of percent predicted FVC change with averaging across all study time point resulted in a statistically persuasive finding for both PIPF-004 and PIPF-006.

Bradford also argued that the reduction in the proportion of pirfenidone-treated patients experiencing a decrement of 50 meters or more in the six-minute-walk test was "clinically meaningful" and a "strong prognosticator" for mortality outcome.

Trading of Brisbane, Calif.-based InterMune's shares (NASDAQ:ITMN) were suspended Tuesday, but the stock in afterhours trading rose more than 60 percent.

Published  March 10, 2010