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Pfizer Scores FDA Nod for Lung Cancer Drug Crizotinib (Xalkori)

FDA has given the regulatory nod to crizotinib, Pfizer’s ALK inhibitor that has proven very effective in the small portion of the population whose lung cancer is driven by the protein.

Pfizer says the drug, to be sold under the brand name Xalkori, will cost $9,600 per month, and it will provide assistance so that patient co-pays will not exceed $100. It’s the first in a handful of new drugs Pfizer is counting on to help offset the sales drain when the patent expires this fall on its blockbuster cholesterol drug Lipitor.

The approval is notable as the second drug/diagnostic combo to get the FDA green light in recent weeks—Plexxikon/Roche’s melanoma treatment Zelboraf is the other.

Also notable? We call the compound an ALK-inhibitor, but scientists didn’t start out looking for an ALK-inhibitor. Work on crizotinib originated at Sugen, a South San Francisco-based biotech first bought by Pharmacia, which was later acquired by Pfizer. Sugen chemists were intent on finding a molecule that blocked c-Met, a protein implicated in tumor metastasis. They had already struck upon a promising amino pyridine scaffold by the time their activities were moved into Pfizer’s La Jolla site, where lead optimization took place.

An optimized molecule, billed as a c-Met inhibitor, was put into clinical trials. Then, as we wrote last year, scientific discovery and serendipity converged to change the course of the drug’s development:

Researchers led by Hiroyuki Mano, a professor of functional genomics at Japan’s Jichi Medical University, found that when a certain chromosome inverted, a fusion occurred in lung cancer cells between the echinoderm microtubule-associated proteinlike 4 (EML4) gene and the ALK gene. The researchers found that the fusion caused tumor formation in mice. A subsequent test determined that about 7% of lung cancer patients had this fusion gene. In a paper published in Nature, the researchers concluded that ALK would make a good drug target (Nature 2007, 448, 561).

As it happened, Pfizer had just learned it had an ALK inhibitor on its hands. The company and Massachusetts General Hospital had evaluated results from large biochemical and cell-based screens to see whether crizotinib was hitting targets other than c-Met, says James Christensen, director of translational research in Pfizer’s oncology unit. Upon characterizing the hits, the collaborators found that it was blocking ALK’s activity.

Better, crizotinib was just as good at blocking ALK as it was at shutting down c-Met. Pfizer scientists believe the dual activity is due to a similarity in a residue on each protein. Specifically, both c-Met and ALK have a particular tyrosine within one of the three phosphorylation sites, called the activation loop, which seems to be responsible for the compound’s activity.

All in all, pretty cool science that has translated into a very promising treatment for some lung cancer patients.

5 Comments

  • Aug 30th 201113:08
    by Deborah

    I thought you might be interested in this MD Anderson Cancer Center video on new research on lung cancer: http://www.youtube.com/watch?v=cVOlOT81hFM. It’s particularly important to patients who cannot have surgery for an early stage lung cancer – they can now benefit from a new radiation therapy technology called stereotactic radiation therapy (STARS).

  • Sep 1st 201101:09
    by Greg Pawelski

    With the lastest press release from Pfizer about their new drug Xalkori, the queston of whether to consider spending $3,000 or more for a cell-based functional profiling test gets more interesting. The drug will cost $9,600 per patient per month and the gene test for it will cost $1,500 per patient. A biotech executive states the real cost of the drug is $9,600 plus 25 ALK tests, because that’s how many patients will need to be screened for one to actually get Xalkori.

    There are lots of things which determine if drugs work, beyond the existence of a given target (like ALK). Does the drug even get into the cancer cell? Does it get pumped out of the cell? Does the cell have ways of escaping drug effects? Can cells repair damage caused by the drug? Do combinations of drugs work in ways which can’t be predicted on the basis of static gene expression patterns?

    Tumor biology is a lot more complex than we’d like it to be. Cancer is more complex than its gene signature. Many common forms of cancer present as a host of mutated cells, each with a host of mutations. And they’re genetically unstable, constantly changing. That’s why so many cancers relapse after initially successful treatment. You kill off the tumor cells that can be killed off, but that may just give the ones that are left a free reign.

    The idea of searching for clinical responders by testing for a single gene mutation seems like a nice theoretical idea, but you may have to test for dozens of protein expressions that may be involved in determining sensitivity/resistance to a given drug. Because if you miss just one, that might be the one which continues cancer growth. And at $1,500 a pop, that’s a lot of dough, on top of the inflated price of the single drug!

    The key to understanding the genome is understanding how cells work. The ultimate driver is “functional” pre-testing (is the cell being killed regardless of the mechanism) as opposed to “target” pre-testing (does the cell express a particular target that the drug is supposed to be attacking). While a “target” test tells you whether or not to give “one” drug, a “functional” pre-test can find other compounds and combinations and can recommend them, all from the one test.

  • Sep 17th 201109:09
    by nalinee agarwal

    how can we get this drug in the Indian Market

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