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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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In the Pipeline: Don't miss Derek Lowe's excellent commentary on drug discovery and the pharma industry in general at In the Pipeline

In the Pipeline

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January 28, 2014

Dacomitinib Doesn't Come Through

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Posted by Derek

Lest you think that it's only small companies that wipe out in Phase III oncology trials, consider Pfizer's news yesterday about dacomitinib. Two Phase III studies in non-small cell lung cancer (NSCLC) missed their endpoints, a real problem for a compound that was supposed to be one of the showpieces of the company oncology portfolio.

The compound (structure here) is another of the current crop of irreversible kinase inhibitors (which is one reason why 2013's crop of approved drugs looked a bit odd). In this case, it's picking up Cys773, on the edge of the ATP binding pocket. The compound hits across the HER kinase family, and we have now found out that that's not enough for this variety of lung cancer, at any rate. It had looked more promising in Phase II (don't they all), so we can assume that a lot of what-went-wronging has been going on at Pfizer, both to keep from repeating this experience and to figure out if there are some identifiable patient subsets that might be worth following up on.

Even if there are, dacomitinib is not going to be the drug that Pfizer hoped for. That drug would have hit the survival endpoints in these two trials.

Comments (17) + TrackBacks (0) | Category: Cancer | Clinical Trials


COMMENTS

1. road on January 28, 2014 9:18 AM writes...

Any understanding of why this compound failed where afatinib succeeded? The mechanism seems identical, suggesting that hitting across the HER kinase family IS enough for NSCLC...

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2. David Borhani on January 28, 2014 10:12 AM writes...

@1: Trial design differences, that will make little difference in a larger, marketed sample of patients?

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3. RTW on January 28, 2014 11:13 AM writes...

As someone that worked towards the preclinical discovery of this drug, to say I am astounded is an understatement! I guess I would have to agree with @2. David! I think it must have had something to do with the trial design or analysis. I suspect they will find a sub population were this worked very well. NSCLC is a hard nut to crack. It may prove to be much better in mCRC or Breast Cancer in the long run.

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4. alig on January 28, 2014 11:26 AM writes...

Afatinib was approved to treat patients with the EGFR del mutant or L858R mutant. It doesn't look like either of these trials selected for patients with the mutation. It does look like they have a trial still running that selects for mutant positive patients. Smaller market, but bigger chance for success.

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5. Anonymous on January 28, 2014 11:41 AM writes...

Derek,

how much $$ for the "sponsored" hyperlink on the 'structure here'?

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6. Anonymous on January 28, 2014 11:52 AM writes...

@5

Why don't you write an entry on wikipedia on dacomitinib, so Derek can use his traditional structure reference?

Permalink to Comment

7. RTW on January 28, 2014 12:21 PM writes...

@6 A Wiki article is a good idea. Perhaps I could do so. I have enough preclinical references to its discovery. Not a lot of clinical development resources however. I Not sure what Pfizer's position on such would be though since I no longer work for them.

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8. anon the II on January 28, 2014 12:42 PM writes...

@5

Actually, it's pretty cool that Selleckchem provides an 1H-NMR. When you write up that wikipedia entry, could you include the NMR, too?

Thanks

Permalink to Comment

9. Derek Lowe on January 28, 2014 12:48 PM writes...

#5, the only reason I linked to Selleck was that there's no Wikipedia article, as #6 guessed. No kickback involved. I get a commission on Amazon links around here (as I state from time to time), but there's no money changing hands behind the scenes around here.

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10. Hap on January 28, 2014 1:47 PM writes...

Now that sounds like a lucrative side career. Next thing you know, Dr. Lowe would be doing infomercials:

"I'm a drug chemist and a famous blogger, but even I can't do everything. And when I need failed drug candidates, I reach for my Xzylplurg catalog, because they're known throughout the galaxy for quality synthesis at reasonable prices. They even offer galactic currency transfers at low cost."

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11. Philip on January 28, 2014 3:57 PM writes...

What functionality binds to the cysteine? Is it the Michael acceptor?

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12. chacao on January 28, 2014 3:59 PM writes...

@9

And why would anyone have to defend getting some $'s for great articles/blog posts?

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13. road on January 28, 2014 5:24 PM writes...

@11 - yes.

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14. Pennpenn on January 28, 2014 6:20 PM writes...

@10: These messages were brought to you by Zarkon & Yipslarg.

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15. Moody Blue on January 29, 2014 1:27 PM writes...

@ #5 if it would make you happy use the link below instead:
http://www.ama-assn.org/resources/doc/usan/dacomitinib.pdf

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16. MB on February 2, 2014 3:27 AM writes...

Oh look another molecule that fails to work against a cell surface receptor. When will Pharma and practically all of science realize that 99% of models of cell surface proteins are horrifically wrong? Nearly 100% of all cell surface proteins are glycosylated, yet if you look at the proteins being modeled for in silico models, glycans are completely missing. The same goes for tyrosine kinases. If you just add one bisecting Glcnac on N-linked glycans to a receptor like EGFR you can significantly inhibit metasasis.

Nearly all GPCRS are glycosylated. Nearly 30% of the entire mw of ion channels, another favorite target for pharma, comes from glycosylation. Compounds are failing because all of your models are flat out wrong. Protein conformations and binding pocket geometries are substantially altered by glycosylation as well as overall protein function, trafficking, and half life. Next time you are working on a project that involves a cell surface receptor ask yourself where are the sugars? Ignore them and you'll find yourself designing the wrong molecule based on a crystal structure, geometries, and protein functions that are all wrong (most protein crystal structures acquired after removing glycans if one cam manage to even get a structure of a cell surface protein).

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17. Willy jones on February 17, 2014 8:51 AM writes...

This medicine Dacomitinib together with PD0325901 is supposed to cure advanced colon cancer with KRAS protein but Pfizer is not releasing these to the Anthonie van Leeuwenhoek hospital in Amsterdam. Does anyone know the precise reason?

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