Despite mixed results from its two pivotal Phase III trials, InterMune submitted an electronic NDA for its proposed idiopathic pulmonary fibrosis drug pirfenidone on Nov. 4.

The compound already has been approved in Japan, where it is marketed by InterMune's partner Shionogi as Pirespa .

The drug was shown in preclinical and in vitro testing to inhibit collagen synthesis, down-regulate profibrotic cytokines and decrease fibroblast proliferation. It met the primary efficacy endpoint - change in predicted forced vital capacity at week 72 - in the Phase III CAPACITY 2 trial, but missed statistical significance in the CAPACITY 1 study (Also see "InterMune Bullish On Pirfenidone NDA Despite Mixed Study Results" - Pink Sheet, 4 February, 2009.).

The NDA filing, which requests a priority review since IPF is a major unmet medical need with no approved treatment in the U.S., is backed by those two trials, including pooled data analysis of secondary endpoints and strong safety profile.

In an interview, InterMune CEO Dan Welch said his firm also plans to file a Medication Authorization Application in Europe for the drug during the first quarter of 2010.

In CAPACITY 2, pirfenidone produced a mean change in predicted FVC of -6.49 percent at week 72, compared with -9.55 percent for placebo (p = 0.001). However, in CAPACITY 1, the drug produced a mean change in FVC of -6.49 percent while placebo showed a mean change of -7.23 percent (p = 0.501). While the data showed a treatment effect, the difference in efficacy compared with placebo did not achieve statistical significance.

Approval of the drug in Japan was based on a separate study conducted by Shionogi in which pirfenidone did meet statistical significance in the primary endpoint. Welch noted that the results of the Japanese trial are included in the FDA filing, but not as a pivotal study database like the data from the two CAPACITY trials. Japanese authorities approved the drug in October 2008.

Strong safety and tolerability profile back filing

The Brisbane, Calif.-based biotech, however, hopes that FDA will be swayed by the drug's very strong tolerance and safety data derived from four trials - the two CAPACITY trials, plus two ongoing open-label trials. RECAP is an open-label extension that has enrolled 603 patients (out of 779 total) from the two CAPACITY studies, while PIPF-002 is a long-term, open-label trial involving 83 IPF patients.

At the European Respiratory Society Annual Congress in September, InterMune reported that the majority of adverse events in the trials were mild to moderate, with relatively few patients discontinuing treatment. The rate of serious adverse events was similar in the pirfenidone and placebo arms of the two pivotal trials, the company added. Meanwhile, the open-label studies have demonstrated that long-term pirfenidone therapy is safe and generally well-tolerated.

In an Oct. 8 analysis following a meeting with InterMune, Lazard Capital Markets analyst Terence Flynn predicted the varied outcomes of the two CAPACITY trials, as well as questions about the clinical benefit of slowing FVC decline, would lead FDA to seek an advisory committee review of pirfenidone.

Welch said InterMune had only had administrative discussions about the filing with FDA so far. "We have not had a conversation on the data, per se, [but] we look forward to that conversation as the review begins."

InterMune clearly is pinning some of its hopes on the lack of any treatment or therapy for IPF, combined with the disease's high mortality rate. Median survival time from diagnosis is two to five years, with a five-year survival rate of approximately 20 percent. IPF is estimated to afflict 200,000 people in the U.S. and EU, with 30,000 new cases reported annually in each market.

Welch said the economic value of the first-to-market opportunity for pirfenidone, if approved, could not be estimated until pricing considerations begin. But, "if pirfenidone is approved, I would suspect that a large portion of IPF patients who meet the terms of the approved label will receive pirfenidone, because it is a deadly disease [and] there is nothing approved," Welch noted. "I think the uptake could be reasonably quick and, depending upon the price, could be a very attractive opportunity for InterMune in terms of economic opportunity."

Beyond Shionogi, InterMune plans to seek other partners for the drug. Welch said that process is ongoing with "multinational pharmaceutical companies" having expressed interest and new potential suitors materializing on a regular basis.

-Joseph Haas (j.haas@elsevier.com)

InterMune Files NDA For IPF Drug Despite Mixed Pivotal Trial Results

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