InterMune was left with a mixed bag when it released its major Phase III program of pirfenidone in idiopathic pulmonary fibrosis, which yielded conflicting primary endpoint results. But the company thinks there are enough tricks in that bag to win FDA approval, given the urgent unmet medical need, support from pooled data analyses, strong showings on the secondary endpoints and a separate pivotal trial from Japan.

On Feb. 3, Brisbane, Calif.-based InterMune released long-awaited Phase III results for the anti-fibrotic, anti-inflammatory treatment and indicated that plans to submit an NDA in the U.S and a marketing authorization application in Europe this year remain on track.

Pirfenidone missed its primary endpoint of slowing decline in forced expiratory vital capacity, a standard measure of lung function, after 72 weeks of treatment in the CAPACITY-1 trial, but met that endpoint in the similarly-designed CAPACITY-2 study. The drug proved safe and generally well-tolerated in both studies.

Looking at the "totality of the data," InterMune believes the overall treatment effect was similar in both studies. The firm plans to use a pooled analysis of the CAPACITY trials in its regulatory submissions, and also submit a positive trial from its Japanese partner, Shionogi.

In October 2008, Shionogi received approval for pirfenidone in Japan, where it is marketed under the trade name Pirespa . InterMune says the Phase III trial that supported the Japanese application also could be used for the FDA filing. However, some investors have been concerned that high dropout rates in the Japanese trial could cause trouble with FDA.

"Had we achieved our primary endpoint for both IPF studies, the regulatory strategy would be somewhat more straightforward," said CEO Daniel Welch, during a Feb. 3 investors' call explaining the results.

"However, we believe that the collective efficacy and safety data on pirfenidone from our two CAPACITY studies, corroborated by Shionogi's Phase III study, provide very strong support that pirfenidone may play a meaningful role in the management of patients suffering from IPF, a lethal disease for which no treatment exists," the executive said.

Consequently, the company plans to prepare both an NDA and an MAA as soon as possible.

Data set may be a "hard sell" with FDA

Some analysts were optimistic overall about pirfenidone's regulatory prospects, even though the primary endpoint was missed in one of the key trials.

"The mixed data set may be a hard sell to the FDA, but given the severity of the disease and the lack of effective treatment options, outright rejection may have a lower probability than similar results in a different indication," ThinkEquity analyst Jason Kolbert concluded in a Feb. 3 note.

A disease of unknown origin, IPF causes inflammation and scarring, worsening progressively over time (¹ Also see "InterMune’s Idiopathic Pulmonary Fibrosis Push Continues As Actimmune Sales Slump" - Pink Sheet, 8 February, 2008.). The five-year survival rate is only about 20 percent. Currently there are no FDA-approved treatments for IPF, which afflicts an estimated 250,000 in the U.S. and Europe. There are 30,000 new cases of IPF every year in the U.S., compared to 6,000 cases of the better-known pulmonary arterial hypertension. In 2008, the market for PAH therapies reached an estimated $900 million in the U.S. and $1.6 billion worldwide.

Kolbert estimated a 65 percent probability that pirfenidone will be approved in the U.S. and valued the treatment at $575 million, based on a conservative estimate that it could garner 30 percent of the market of mild and severe IPF patients.

Oppenheimer analyst Brian Abrahams commented that the inconsistencies in CAPACITY study results will "complicate the regulatory pathway," but then added: "Given the unmet need, we believe there is a reasonable chance of FDA approval."

Exploratory data analyses bolster application, firm says

InterMune's Phase III program consisted of the two randomized, placebo-controlled, international CAPACITY trials, which had near-identical designs. The primary endpoint related to change in forced vital capacity; secondary endpoints included various measures of lung function, progression-free survival, exercise tolerance and patient-reported outcomes.

In the CAPACITY 1 study of 344 patients, pirfenidone missed the FVC primary endpoint but did achieve a statistically significant effect in one secondary endpoint - the six-minute walk test measure - compared with placebo. In the CAPACITY 2 study of 435 patients, the drug met the FVC endpoint at 72 weeks and also met key secondary endpoints related to PFS and a categorical change in FVC.

An exploratory "repeated measures" analysis showing change over time compared to baseline suggested that pirfenidone reduced the decline in FVC in both studies. Medication effects were strongest around the 48-week mark.

Furthermore, an exploratory pooled analysis of secondary endpoints for both studies showed good effects in PFS, categorical FVC change and the six-minute walk test.

"The totality of the data from these two studies suggests that pirfenidone has a positive treatment effect on patients with IPF," the company concluded.

Kolbert noted that "totality of the data" is his "least-favorite catch phrase in the world of drug development."

"In recent years, the FDA seems less interested in 'the totality of the data' and more focused on the primary endpoints of a given trial. The totality of the pirfenidone data seems to show a very modest treatment effect," he wrote.

However, Kolbert also noted the treatment's benign treatment profile will work in its favor. Serious adverse event rates were similar between patients on pirfenidone and placebo. Nausea, rash, fatigue, dyspepsia and dizziness were the most commonly reported side effects in the treatment arm.

The company says the reasons behind the different study results are unclear but one hypothesis is that differences in patient populations played a role. Walk test results and higher rates of oxygen use in the CAPACITY 1 patients and walk test results suggest those patients had more severe illness.

In an interview, Chief Medical Officer Steve Porter acknowledged that the patients in CAPACITY 1 were a bit sicker than their counterparts in CAPACITY 2 in some measures, but declined to attribute the outcome mainly to these differences.

Porter noted the significance of the progression-free survival results and said when drugs first are being developed for a particular disease, there often is a lot of uncertainty about what is achievable in terms of design and endpoints.

Typically in these cases, regulatory authorities have offered wider latitude when it comes to application review, he said.

-Emily Hayes (e.hayes@elsevier.com)

InterMune Bullish On Pirfenidone NDA Despite Mixed Study Results

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