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Iressa the poster child for personalized medicine?

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Color me not surprised

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Those who caught my presentation at the first Minyanfest in Crested Butte or read my subsequent articles ("Death of the Blockbuster Drug" and Minyan Mailbag - Targeted therapies) are likely not too surprised at the results announced today by AstraZeneca (AZN). They announced their targeted lung cancer drug Iressa failed to show a survival benefit in a study that enrolled 1700 lung cancer patients.

The study didn't fail because Iressa is a bad drug. The study failed because AstraZeneca designed the trial poorly. Iressa clearly works in a small subset of patients. These patients are often terribly, irreversibly ill. They take Iressa and see symptom improvement almost immediately. It's quite remarkable to hear patients and doctors speak of the experience.

Initial research published last June hinted at a way to determine in advance which patients will respond to Iressa. About 10% of lung cancer patients have a certain type of protein marker that seems predictive of successful Iressa use. Iressa is a targeted drug meant to act on this marker, so this makes perfect sense.

The problem is AZN wants to be able to market Iressa to all lung cancer patients. They believed the marker necessary for Iressa to work was far more prevalent than it actually is. They figured by running a large trial the positive signal from those who have this marker would drown out the negative statistical signal from those who don't. Three times now, this has not worked.

If you remember my discussions of targeted therapies, you know one of the things I cautioned about was companies trying to stretch the utility of a targeted therapy across an entire patient population. Companies do this to try to maximize the market size for a particular drug, despite there being little chance the drug works in patients without the target.

AZN tried to do just that, and got slapped. AZN will need to run additional studies to confirm early research about the predictive protein marker. Then they'll need to run another clinical trial enrolling only patients with this marker. The trial will have two goals: Validate Iressa for this patient population and validate a test for this protein marker.

I sincerely hope AZN sticks with Iressa. This drug, when given to the right patients, works remarkably well. The disincentive is that a drug that many considered to be a blockbuster (>$1B in sales) will now likely only sell $100-200M per year. That may sound like a lot to you and I, but it will take a very long time before AZN ever makes any money from the drug.

I also note there is a broader subtext to this story. Management of the oncology section at the FDA approved this drug only after Dr. Mark McClellan forced them to follow the recommendation of a panel of clinicians (the ODAC panel). After Dr. McClellan left, the oncology section managers have gone on something of a rampage. Genta (GNTA) and Allos Therapeutics (ALTH) were the first to feel the sting of this backlash in the May 2004 ODAC panel meeting I've described previously (preview, post-mortem) . That backlash continued in a recent ODAC panel meeting where the FDA violated the written letter of the law and asked an ODAC panel to compare a drug up for approval against drugs not currently approved for the indication in question. In short, sending a drug - especially a modern, targeted therapy - to the oncology section has been something of a crap shoot as companies can't be certain whether their applications will be judged fairly or whether the FDA will choose to make an example out of them.

It may be this result from the Iressa trial will embolden these wayward FDA staffers. It makes it even more important President Bush appoint an FDA Commissioner sooner rather than later. Regulatory predictability is crucial for both biotech companies and biotech investors and that's not something we have in the oncology sector right now.

If the FDA asks AZN to pull Iressa from the market - which is completely within the realm of possibility, though it would be unprecedented - this will reverberate through biotech valuations. If the FDA instead leaves Iressa on the market, asking AZN to quickly run studies to determine the proper patient population, then it will be a signal of sanity from the oncology division at the FDA. The latter is the proper path for the FDA to take, but I fear the former is more likely.
No positions in stocks mentioned.

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