West Coast Editor

Off-label sales of InterMune Inc.'s Actimmune for idiopathic pulmonary fibrosis likely will take a hit from the stoppage of Phase III trials, but the company could rebound on positive data later this year from an earlier-stage study with ITMN-191, a protease inhibitor for hepatitis C virus.

For IPF, investors also are looking with increased interest at pirfenidone, a small-molecule p38-gamma inhibitor that chalked up positive Phase III data - for the first time ever in that indication - near the end of last year in Japan.

Shares of InterMune (NASDAQ:ITMN) dropped 22 percent Tuesday, or $5.90, to close at $22.15, after the company scrapped the Phase III trial testing Actimmune (interferon gamma-1b) against IPF because an independent data monitoring board found lack of survival benefit compared to placebo.

Actimmune, marketed for chronic granulomatous disease and severe, malignant osteopetrosis, fizzled a year ago in Phase III trials against ovarian cancer, and InterMune stopped all oncology research with the drug then. (See BioWorld Today, Feb. 6, 2007.)

Dan Welch, president and CEO of Brisbane, Calif.-based InterMune, said Tuesday that the outlook for future explorations with Actimmune is "very limited, if at all." In the 826-patient IPF trial, the panel found no statistically significant difference between treatment groups in overall mortality (14.5 percent for Actimmune, 12.7 percent for placebo), and adverse events proved similar to prior studies.

Nothing is approved in the U.S. or Europe for IPF, characterized by thickening and scarring of lung tissue. The fatal disease strikes most often between ages 50 and 70, and the average life expectancy after diagnosis is between five and six years. It's apparently started by inflammation, but researchers still are looking for the cause.

Late last year, InterMune's stock jumped about 30 percent on word from Japanese rights-holder Shionogi & Co. Ltd. that Phase III studies with pirfenidone significantly inhibited worsening of lung function at high and low doses. Pirfenidone is undergoing Phase III tests in an InterMune program that Welch described as "quite similar in many respects."

The endpoint in the Japanese trial was vital capacity, and in the InterMune study it is forced vital capacity, "a slightly different test, but substantially the same in terms of clinical relevance," Welch said.

Dosing levels in the two trials are almost exactly the same, taking into account that Japanese people are 20 percent to 25 percent lighter than Americans and Europeans. And IPF is diagnosed in a similar way for both trials, since experts in America and Europe set up the guidelines used in Japan. InterMune's trial is eight weeks longer than Shionogi's, but that is considered beneficial in a progressive, deteriorating illness such as IPF. The main wild card is the potentially result-skewing genetic variance between Japanese patients and others, but researchers don't know of any differences, metabolic or otherwise, that could have an effect, Welch told BioWorld Today.

Meanwhile, viral kinetic data from InterMune's 14-day, Phase Ib study with ITMN-191 for HCV are expected in the second half of this year, and the Phase Ia trial is slated for completion in the first half. Last fall, the NS3/4A protease inhibitor became the subject of a potential $530 million deal with F. Hoffmann-La Roche Ltd., of Basel, Switzerland. (See BioWorld Today, Oct. 18, 2006.)

"Phase Ib data would be what I would call the money data, [regarding] how investors see this and, frankly, how we do as well," Welch said.

With ITMN-191, Roche and InterMune hope for an edge over telaprevir (also known as VX-950), the protease inhibitor in the works from Vertex Pharmaceuticals Inc., of Cambridge, Mass., as well as Kenilworth, N.J.-based Schering-Plough Corp.'s SCH 503034. InterMune has claimed greater potency for its compound, plus a more favorable dosing schedule - twice daily rather than three times per day.

At the end of last year, Vertex said results from an interim safety analysis of the Phase IIb PROVE 1 trial showed 65 of 74 patients (88 percent) came up with undetectable HCV RNA levels (less than 10 IU/mL) at week 12, compared to 17 of 33 patients (52 percent) in the control arm.

While Tuesday's InterMune sell-off might provide an opportunity for investors, they may vary on where to place the most value. Pirfenidone's Phase III effort has exposed about 1,000 patients to the drug, and the IPF market is "kind of like [the market for pulmonary arterial hypertension], but three to five times the size of PAH, which is already $1 billion," Welch noted. "That's a big market, and we'd be all alone there." HCV is a strong opportunity, too, although ITMN-191 is earlier in development and carries the risk of the unknown.