Despite Positive Advisory Committee Vote, InterMune Gets Complete Response For Pirfenidone

FDA requests an additional efficacy trial, not surprising given that the IPF drug met the primary endpoint in only one of two Phase III trials.

FDA seems to be holding tightly to its regulatory standards in issuing a "complete response" letter for InterMune's pirfenidone May 4, requesting an additional efficacy trial for the idiopathic pulmonary fibrosis drug.

InterMune had been anticipating approval, following a somewhat mixed but still largely positive outcome of an advisory committee meeting. However, the panel's mixed vote reflected conflicting efficacy findings from two Phase III trials and FDA's request indicates that the agency is requiring a second positive trial as confirmatory evidence.

Pirfenidone, to be marketed as Esbriet if approved, is a dual inhibitor of TGF-beta synthesis and TNG-alpha synthesis and would be the first approved drug for IPF in the U.S. The drug is already approved in Japan, where InterMune's marketing partner Shionogi sells it as Pirespa , and also has been filed for approval with the European Medicines Agency.

During a March 9 meeting of FDA's Pulmonary-Allergy Drugs Advisory Committee, panelists voted 9-3 in favor of the drug's approval, with multiple members noting the lack of any drug therapy for the progressive and fatal disease. The current standard of care for IPF is lung transplant. However, the vote was tighter (7-5) on whether pirfenidone had demonstrated efficacy in reducing decline in lung function for IPF patients (Also see "Despite Mixed Views On Efficacy Data, Advisory Committee Recommends Approval Of InterMune's Pirfenidone" - Pink Sheet, 9 Mar, 2010.).

The two pivotal trials for pirfenidone had a primary endpoint of absolute change from baseline in percent predicted vital capacity at week 72 of treatment. The drug met statistical significance for that measure in the PIPF-004 trial, with treatment-arm patients experiencing a decline of 8 percent in FVC compared with a 12.4 percent decrease in the placebo arm. However, in the PIPF-006 trial, pirfenidone slightly outperformed placebo (-9.0 percent to -9.6 percent), but not enough to show a treatment effect (Also see "Pirfenidone Panel Highlights Difficulty Of Selecting Primary Endpoint In IPF" - Pink Sheet, 15 Mar, 2010.).

During an investor call May 4, InterMune CEO Dan Welch expressed disappointment over FDA's decision, especially since the advisory committee had advocated for approval. He was unable to offer many details on what the requested new trial might entail, saying InterMune had requested a meeting with FDA that probably would occur within 60 to 90 days.

"After that meeting, I think we'll have a better idea of what they meant and what they said in their complete response letter," Welch said.

FVC or different endpoint possible in new trial

Chief Medical Officer Steve Porter added that a number of potential approaches to the trial were mentioned in FDA's letter, including another study using FVC as an endpoint or one measured by a mortality indicator. At the advisory committee meeting, FDA expressed preference for seeing a mortality analysis.

The company also plans to raise with FDA the possibility of using the Shionogi trial that helped get pirfenidone approved in Japan, Welch reported. InterMune explained that it had previously submitted the trial report, but not the patient-level data.

Asked if there were any other issues cited in the letter, Welch said there were a few but none that by themselves would be meaningful to any timelines for approval. However, another efficacy study would have a significant impact on time to approval - the company noted that its Phase III trials began enrolling patients in April 2006 and reported data in January 2009.

With pirfenidone potentially facing a long delay before U.S. approval, the door could be open for another company to reach market first with an IPF drug. Among the possibilities are currently marketed pulmonary arterial hypertension drugs, such as Actelion's Tracleer and Gilead Sciences' Letairis , which are being studied in IPF (Also see "InterMune Likely First To Market In IPF, But Other Firms Poised To Follow" - Pink Sheet, 22 Mar, 2010.).

As IPF is an orphan condition, pirfenidone had the potential to be the first drug to tap a potential billion-dollar-plus market that is "completely up for grabs," Robert W. Baird analyst Thomas Russo asserted in an April 30 note on InterMune.

"Its orphan drug nature offers seven and 10 years of exclusivity in the U.S. and Europe, respectively, and can likely support price points in the $30,000-$50,000 range," he wrote. "The likelihood that future drugs entering the space would be added on, rather than competing for share, is also favorable to the first mover. Our feedback from the medical community suggests very high intent to prescribe any approved therapy to these patients with no other effective options."

-Joseph Haas ([email protected])