Assistant Managing Editor

Executives of Brisbane, Calif.-based InterMune Inc. disclosed details for the upcoming confirmatory trial needed for U.S. approval of idiopathic pulmonary fibrosis (IPF) drug Esbriet (pirfenidone) and told analysts Thursday that they believe some fine-tuning to the trial design could help the drug finally clear the FDA.

"We've learned a lot" over the past several years, said Bill Bradford, senior vice president of clinical sciences and biometrics, during the company's analyst day. During that time, the company has conducted multiple IPF trials, including two Phase III studies, designated CAPACITY 1 and CAPACITY 2.

Though only one of those studies hit its endpoint, InterMune found that pooled data from both studies reached statistical significance. The firm filed a new drug application (NDA) on those data, betting that the unmet need in IPF, a rare lung scarring disease for which there are no approved therapies, would help sway the FDA. But, despite a positive panel review, the agency rejected the NDA, apparently holding to the rigid two-successful-studies requirement for approval.

InterMune has had better luck overseas, winning a European nod earlier this year, with plans to start rolling out the drug in September. In light of the European approval, some analysts had predicted the company might appeal the FDA's decision, especially after Gilead Sciences Inc.'s endothelin receptor antagonist ambrisentan, the only other late-stage contender in IPF, disappointed in Phase III late last year. (See BioWorld Today, Dec. 27, 2011, and March 4, 2011.)

But the company opted, instead, to conduct the confirmatory study as required. There are some changes, however. The study is "specifically designed to fully address the FDA's complete response letter," Bradford said.

The new trial, designated ASCEND (Assessment of Pirfenidone to Confirm Efficacy and Safety in IPF), will be of shorter duration than the previous CAPACITY studies – 52 weeks vs. 72. Post hoc analyses of the earlier studies indicated that Esbriet's effect was more pronounced earlier in treatment.

InterMune also has modified the patient population criteria, requiring patients more likely to experience forced vital capacity (FVC) decline and looking for a more homogenous group. Analysis of the CAPACITY data using the new ASCEND criteria showed a 6 percent absolute FVC difference at week 48, compared to the 3 percent reported from CAPACITY results. And the six-minute walk test would have shown improvements of 42 meters vs. 20 meters in CAPACITY had the tighter recruitment criteria been used in those studies.

A total of 500 subjects will be enrolled in ASCEND, and the primary endpoint will measure the difference in FVC from baseline and is 97 percent powered. Secondary endpoints will include the six-minute walk test, progression-free survival (defined s death, percentage of FVC declines of 10 percent of greater and six-minute walk test declines of 50 m or greater). The study also will measure all-cause mortality and on-treatment IPF-related deaths and rates, with those datasets pooled with the earlier studies, as well as dyspnea.

The ASCEND trial will not be conducted under a special protocol assessment (SPA). CEO Dan Welch cited the need for flexibility and added that getting an SPA would have delayed Esbriet's U.S. development by "quarters."

InterMune expects to enroll the first patient in the study next month. Assuming the trial proceeds as planned, it's expected to be fully enrolled in the first half of 2012, with results expected in mid-2013 and the NDA resubmission in the second half of 2013. That puts possible FDA approval in the first half of 2014.

Wells Fargo analyst Brian Abrahams noted in a research report that the use of "post hoc analyses to guide future study design is risky," and is estimating a 50 percent probability of success. He added, however, that Thursday's presentation "should remind the Street that there is value to the U.S. program."

There are about 100,000 patients with IPF in the U.S., and about two-thirds suffer from mild to moderate disease, the populations for which Esbriet likely would win approval first.

The delay, however, could give time for competing products to catch up. Johnson & Johnson, of New Brunswick, N.J., expects Phase II data from its antibody candidate CNTO-888 early next year. CNTO-888 is designed to target human CC chemokine ligand 2.

There's also Stromedix Inc., of Cambridge, Mass., which is preparing for Phase II testing of STX-100, a monoclonal antibody targeting integrin alpha(v)beta6, and Malvern, Pa.-based Promedior Inc., which recently completed Phase I testing with PRM-151, a recombinant form of human pantraxin-2 protein. ImmuneWorks Inc., of Indianapolis, started a Phase I trial last year of IW001, an oral solution of Type V collagen.

In Europe, at least, InterMune has a good head start. Esbriet also has orphan designation in that region, which provides 10 years of marketing exclusivity.

Data from ASCEND study is expected to provide added support to the company's commercialization efforts in Europe, where IPF affects about 110,000 people in the top 10 markets. InterMune, which is commercializing on its own in Europe, plans to launch first in Germany in September and follow with launches in France, Spain and Italy in the first half of 2012 and the UK in mid-2012.

Pricing has not yet been set, but analysts are expecting a $40,000 to $45,000 annual range, the same as oral therapies for similarly rare disease pulmonary arterial hypertension.

Shares of InterMune (NASDAQ:ITMN) fell $1.24, to close Thursday at $36.31, though part of that reaction might have been to news that insiders at the company filed to sell 755,054 shares, valued at about $29 million.

InterMune, which reported a net loss of $32.1 million, or 57 cents per share for the first quarter, had about $254.3 million in the bank as of March 31.