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The FDA demonstrated staunch independence from its advisory committees last night with a refusal to approve Intermune’s (NASDAQ:ITMN) pirfenidone (Esbriet), a drug that many believed was set to be the first agent to reach the market to specifically treat the fatal and debilitating lung disease, idiopathic pulmonary fibrosis (IPF).

Although a panel of experts convened to assess the product earlier this year voted for approval the regulator remains unconvinced of pirfenidone’s efficacy, an understandable stance considering the mixed results from the pivotal programme, with only one of the two trials meeting its primary endpoint. The FDA has asked for another clinical trial to allay its concerns, the shape and scope of which will determine exactly how big a setback this is for Intermune. On the stock market, however, damage was swiftly inflicted, with the company losing three-quarters of its value, $2bn, in early trade.

Long delay?

Speaking on a conference call yesterday Intermune executives could add little information as to what the FDA still wants to see, pending a meeting which should take place in the next couple of months. The complete response letter the company received was “broad”, they said, requesting another clinical trial without setting out precise details.

A potential sticking point could have been the use of forced vital capacity (FVC), a measure of lung function that was chosen as the primary endpoint in pirfenidone’s clinical programme called Capacity. There have always been questions about the relevance of this measure, with experts suggesting that a survival primary endpoint might have been more relevant (Pirfenidone outlook not quite so rosy for InterMune, May 23, 2008).

Progression free survival was a secondary endpoint in both trials, but was met in only one of them, the larger Capacity 2 trial (Mixed pirfenidone data improves InterMune's capacity, February 3, 2009).

Whether the FDA wants to see another successful FVC trial or a more conclusive survival benefit established will make a big difference to the length of delay Intermune is facing; clearly the latter will take longer to establish. The two Capacity trials took between two-and-a-half and three years to complete, so Intermune is potentially looking at a long wait in getting pirfenidone to market.

Shorter time lines?

There are a couple of outcomes that might make these timelines substantially shorter.

Firstly, the FDA could decide it will accept a much shorter lung function trial, say 52-weeks, for example.

Secondly, there is another phase III data set that could be mined. Shionogi, which licensed pirfenidone for the Japanese market, won approval back in 2008 on the back of a trial that showed a significant improvement in FVC. Intermune indicated yesterday that the FDA has not ruled out using this data set, the drawback being the information is in Japanese and needs translating and transferring into a usable form.

Another possible bright spot on the horizon is European approval, a decision on which is due in the first half of next year, and could go more positively than the US decision.

Nosedive

Overall, however, the outlook for the California company just took a big nosedive. Analysts had pencilled in a launch this year and sales reaching the magical billion dollar mark by 2015, underlining the potential seen in pirfenidone.

The biggest disappointment is of course for patients with IPF, who have a life expectancy of up to five years and few options open to them (Therapeutic focus - Behind Tracleer pulmonary fibrosis pipeline is a trickle, January 18, 2010).

The fact that Intermune shares had almost quadrupled in value since the beginning of March, closing at an eight year high of $48.14 two weeks ago, illustrates the level of confidence in pirfenidone’s approval. It seems that cautionary comments made by the FDA in briefing documents ahead of the panel, pointing out that it normally requires more than one trial to demonstrate efficacy, even for orphan drugs like pirfenidone, should have been heeded more closely. Shares in Intermune were trading at $11 in early trade today.

For now, however, the outcome of talks with the FDA is the most important event on the horizon for the company.

Source: Intermune Left Gasping by FDA Rejection of Pirfenidone