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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: Twitter: Dereklowe

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June 23, 2010

Exelixis Gets a Compound Back

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Posted by Derek

Exelixis has long been a bit of a puzzle to outside observers. The company has developed a number of clinical candidates in oncology (many of them kinase inhibitors, I believe). In fact, for a while there, they seemed to have developed more clinical candidates than a company that size should have been able to manage. It was a bit alarming to employees of larger companies in the area.

And figuring out what the structures of these things were wasn't so easy, either. I once had the unenviable assignment of trying to break down a stack of their patent applications to see if I could find the lead structure for one of their compounds, and after a week or so I had to concede. None of my usual tricks worked - untangling and charting out the synthetic pathways from the experimental section to see the common threads, looking for sudden upticks in the amounts of intermediates or final compounds being prepared, looking to see if some compounds had been more completely characterized than others, and so on. No, these folks had done a fine job of sweeping up after themselves, and over the years I've run into other people who came to the same conclusion.

The company has had a long relationship with Bristol-Myers Squibb. There have been many twists and turns, but in 2008 the companies agreed to develop a compound called XL-139. (You won't quite be able to figure it out from that Exelixis page, but that announcement also marked the end of one of the broader agreements that the two companies had signed). Later that year came an announcement (also on that link above) about two more kinase inhibitors, XL-184 and XL-281, whose status hadn't been resolved earlier.

Now comes word that XL-184 has been returned to Exelixis. The press release, as press releases will, makes it seem as if the problem was that the compound was just too darn good:

"Given the recent progress of BMS' wholly-owned oncology pipeline and positive data generated by XL184, Exelixis and BMS were not able to align on the scope, breadth and pace of the ongoing clinical development of XL184."

They say that they're pleased to have the chance to develop the compound outside the meddling influence of BMS (well, not quite in those words naturally). But I'll bet they're not pleased to have to do it without BMS cash. Having the drug sent back makes you think that the larger company put it in the category of "Nothing we can't live without", although it's true that XL-184 is surely worth more to Exelixis. (Development of the other compound, XL-281, is apparently continuing).

My guess is that kinase inhibitors of this sort just look a lot less attractive than they did a few years ago. Several of them have made it to market, and while they can be profitable, the field is getting crowded. Mind you, they're all different from each other, but sorting out what works in the clinic is a long process. None of them seem (so far) to do anything dramatic against the most common tumor types. (Here's a recent article on just that problem). What Exelixis will make of XL-184 remains a mystery, probably to them just as much as to anyone else.

Comments (12) + TrackBacks (0) | Category: Cancer | Drug Development


1. Ed on June 23, 2010 7:39 AM writes...

IIRC Exelixis had an oncology compound targeting AKT/PKB that was in and out of the clinic before the patent app even published!

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2. bbooooooya on June 23, 2010 7:47 AM writes...

No no, EXEL has it right, this is positive! They now get 100% of future economics!

nope, not at all another example of money wasted by big pharma (though probably cheaper than had BMS discovered/developed it)

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3. CRH on June 23, 2010 8:29 AM writes...

So, BMS is paying "severance" for this "displaced" compound and only 3 months at that...

"As part of the termination agreement, BMS will shell out $17 million, a figure that would have covered its financial contribution to the drug’s development over the next three months."

To bbooooooya: Do you think EXEL is going to retain 100% of future economics? There is no way they bring this to market alone.

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4. Sally on June 23, 2010 8:42 AM writes...

XL 184 inhibits VEGF, MET and RET.

BMS already have a VEGF/FGFR inhibitor in phase III development for liver cancer that is looking promising - it's called brivanib.

XL 184's leading indication is medullary thyroid cancer, which is very slow growing and not a huge market.

Ergo, given the focus on brivanib at recent investor meetings (it got a mention whereas XL 184 was hardly to be seen), it's no surprise they gave XL 184 back to Exelixis. It's a little unfortunate, as they were previously ditched at the alter by GSK on the same compound.

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5. bbooooooya on June 23, 2010 8:43 AM writes...

"Do you think EXEL is going to retain 100% of future economics?"

I'm pretty sure they'll try to repartner. Maybe it will work....would not bet on it

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6. alig on June 23, 2010 10:10 AM writes...

As Sally points out, this compound was returned to Exelixis by GSK two years ago, was then resold to BMS and now returned again without much progress down the clinical path. My guess is this compound is going nowhere. Does Exelixis ever kill a compound?

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7. mad on June 23, 2010 11:35 AM writes...

Hard to know without the data but often its "worth the money" for some big pharma to delay drugs to time better with there current pattants . This doest alwasy fit the timelines of the small company (or the people who may benefit from these drugs!) and in fact the smaller companies can go out of bussiness in the delay time then the big guys can scoop up the compounds again. it the case here?

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8. Greggers on June 23, 2010 12:47 PM writes...

Exelixis should just sell the company and be done with it.

But then again, Scangos wouldn't be able to rob shareholders blind to the tune of $1 mill a year in his own personal fleecing salary if he sold the company - so don't expect it.

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9. Jiri Voller on June 28, 2010 9:57 AM writes...

"And figuring out what the structures of these things were wasn't so easy, either. .... None of my usual tricks worked."

Derek, would you mind to write a blog post in that you would demonstrate "deciphering" a composition of matter patent? I guess many of your readers would enjoy that. Are there any articles/books related to the this sort of magic? Thanks.

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10. pete on June 30, 2010 1:59 PM writes...

#8 Greggers

And now it appears, Scangos will be off to work his magic at Biogen. Curious choice, that.

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11. pwtros on July 1, 2010 1:44 PM writes...

Interesting career path for Scangos

Bayer Exelixis Biogen

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12. annette bak on October 13, 2010 8:07 PM writes...

I was formerly a group leader for the preformulation group at Amgen, MA.

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