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Derek Lowe The 2002 Model

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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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April 16, 2014

One and Done

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Posted by Derek

Matthew Herper has a good piece in Forbes on Robert Duggan and Pharmacyclics. In the course of it, we learn this interesting (and perhaps disturbing) bit of information:

Second acts in the biotech business are hard: 56% of the drug firms that received an FDA approval between 1950 and 2011 did so only once.

And I hate to say it, but the article does not inspire confidence in Duggan's ability to break that trend. It's surely no coincidence that the profile mentions in its first paragraph that he's a major donor to the Church of Scientology, and maybe it's just my own prejudices, but when I hear that, I'm pretty much done with thinking that a person can make rational decisions.

Comments (24) + TrackBacks (0) | Category: Drug Industry History


1. Henry's cat on April 16, 2014 9:47 AM writes...

OK in oncology we're less picky, but when you see a Michael Acceptor pass as a drug you start to wonder what compounds we have discarded over the last couple of decades because "we don't DO nitro groups, man"...

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2. ADCchem on April 16, 2014 10:17 AM writes...

"Once in command Duggan charged a nine-person committee with advising him on how to proceed with Xcytrin. The vote came back 9-0 that Xcytrin was done. Duggan still believes Xcytrin would have succeeded if Miller had run the right trials."

Normally I would say this was just a quote from someone who never did drug discovery before, and was just an arrogant millionaire.

One arm of the trial lead to 15 months life extension vs 10 months and was found to be statistically insignificant.

But in the North American arm they were given the treatment earlier after only 4 weeks of tumor identification and had an overall survival rate of 24 months compared to 8 months and it was found to be statistically significant.

It probably would have been approved if they had did the rest of the study like the North American counterpart as the FDA declined approval based on statistical significance.

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3. Anonymous on April 16, 2014 10:36 AM writes...

I suggest looking at that "second acts" observation the other way around:

44% of the companies that received one FDA approval would get at least one more.

Obviously there are all sorts of confounding factors in there, like companies that disappeared because they were acquired for that one drug. But it seems to me that the odds for a "second act" are a lot better than for a brand new company.

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4. Ted on April 16, 2014 10:41 AM writes...

@1: Trisenox is approved, and it's even tougher to get folks to say, "we DO arsenate groups, man"...


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5. Biff on April 16, 2014 10:53 AM writes...

Never mind the Scientology -- whenever I encounter a 69 year old man with jet black hair and eye brows, even when (or perhaps especially when) they are CEOs, "I'm pretty much done with thinking that a person can make rational decisions."

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6. David Young MD on April 16, 2014 11:16 AM writes...

Well, Imbruvica is just the first of several Bruton Kinase Inhibitors to make it on the market. But first does make a difference, for the FDA does not like to approve "me too" drugs in oncology and the other inhibitors will have to go for a different indication. And in the meantime, Pharmacyclics will rake in their millions (billions actually). I have yet to start a patient on Imbruvica but the FDA made the indication easy to prescribe so it may not be long before someone in our office prescribes it. If it is as well tolerated as they say, then it will become a popular go-to drug... except for the cost. (Lower the cost and let us all use it?) Finding another anticancer drug with so few side effects is a real challenge.

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7. Curt F. on April 16, 2014 11:19 AM writes...

What makes you so sure that anyone working in the biotech drug space is capable of making rational decisions?

(Asked only slight in jest.)

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8. Medchem on April 16, 2014 12:00 PM writes...

If you ask me, 56% is NOT bad at all!

"56% of the drug firms that received an FDA approval between 1950 and 2011 did so only once."

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9. Anon on April 16, 2014 12:14 PM writes...

IMO, 56% freaking amazing considering a biotech's second therapy is using the same technology/approach as their first drug. It seems that large cap companies have trouble even with their diversified strategies (or it is because of their diversified strategies?...)

As far as Duggan, he is just a man with money who played roulette and won. He didn't have anything to do with the R&D or regulatory work.

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10. molecular architectl on April 16, 2014 12:32 PM writes...

As a key member of the Celera team that designed Imbruvia (ibrutinib), I'm thrilled that it was approved and is helping patients. It saddens me that our own CEO and his cronies didn't have the faith in us to continue pushing it to the clinic. Pharmacyclics did hire several of our biologists but none of the chemists who were directly involved in the BTK program. From their patents, it appears that they synthesized several hundred analogs but found none with a better combination of activity, selectivity, and safety. Pharmacyclics did a masterful job of shepherding the compound through trials.

Based on this one case, I'd conclude that their prior management had talent for identifying good molecules for sale and that Duggan's team knows drug development and clinical trial design. What's not clear is whether they have any real capability for drug discovery and optimization.

And #1, that michael acceptor is key to ibrutinib's selectivity. It's not particularly reactive outside of the binding site. Initial binding selectivity is controlled by the "gatekeeper" residue which then positions the acrylamide to react with the cysteine. Only a very small handful of kinases have a cysteine residue in position to add to it. Inhibition is irreversible and knocks out almost all BTK activity.

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11. Anon2 on April 16, 2014 12:50 PM writes...

#10-- Congrats on ibrutinib. It looks like it is going to be a game-changing blockbuster for multiple fields of medicine.

Did you work with Robert Booth at Celera? Very savvy of Pharmacyclics to pick him up.

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12. Medchem on April 16, 2014 1:00 PM writes...

No 9

I've come to appreciate the capital side of things in pharma. As much as I hate to admit, the businessmen are every bit as important as the scientists, if not more.

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13. Medchem on April 16, 2014 1:08 PM writes...

A case in point would be our colleague of entry No 10. They did a beautiful scientific job, but only got unemployment at the end. The science was a success, their businessmen failed.

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14. Old Timer on April 16, 2014 1:17 PM writes...

"...he's a major donor to the Church of Scientology, and... when I hear that, I'm pretty much done with thinking that a person can make rational decisions."

That is an appropriate way to think about all religious people! Although, it seems the younger the religion, the less rational the individual.

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15. molecular architectl on April 16, 2014 1:37 PM writes...

#11 Yes, Robert Booth was our head of research at Celera. I wasn't aware that he was at Pharmacyclics. The last I knew, Robert and some of our other top folks formed ViroBay and he was also a partner with a VC firm.

#13 Yes, we did some beautiful science. The molecule was designed specifically to inhibit BTK and worked as designed. Our reward was unemployment, which in my case, lasted far too long. I miss the excitement of those days, we had a great scientific team at Celera.

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16. Miramon on April 16, 2014 2:07 PM writes...

> and maybe it's just my own prejudices

Honestly, I think when you use a qualifier like that you undercut your own opinions.

Either the CoS is a cynical group of criminals shielding themselves from prosecution with the assumed mantle of a ludicrous religion or they're not. I think from your comments you agree with me that they are, though, and that's not prejudice, that's reasoned judgment, based on myriad facts. So why pretend you might be mistaken? To be polite to scientologist readers?

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17. Medchem on April 16, 2014 2:10 PM writes...

molecular architectl:

I hope you're happily employed now and doing what you enjoy doing.

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18. annon on April 16, 2014 2:36 PM writes...

To me, this is one of those "yeah, tell me something new" moments. (I'm actually surprised that the number achieving another approved drug is as high as 40%).

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19. ScientistSailor on April 16, 2014 9:39 PM writes...

I wonder how many of the 46% that got more than one drug approved discovered both vs in-licence one or more of them?

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20. molecular architect on April 17, 2014 9:18 AM writes...

#17 Medchem - Thanks for the good wishes. Yes, I landed at a Federal Agency (which I won't name but I'm sure you can guess) whose upper management is mostly physicians and ex-academics who labor under the illusion that they are experts at drug discovery/development. It's low pressure, as safe as a job can be today, and I have unlimited access to the scientific literature and great seminars but I miss the excitement of my former career. The pace of work is glacial, the decision making process is unbelievably bureaucratic and the upper management clueless but it's a job until retirement. There's quite a few of us Pharma refugees here now, but our opinions seem to have very little effect on any discovery/development decisions. Frustrating.

I had fun at Celera and, unlike most med chemists, I had a direct role in a drug that was approved. Personally satisfying but all the money went to Duggan's pockets, none to mine. No surprise, since society doesn't value us chemists anymore.

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21. Medchem on April 17, 2014 11:33 AM writes...

molecular architect:

That's good to know! Like you said, you can't beat a federal agency like yours in terms of job security. I totally relate to everything you said, which is why I quit big pharma to try to start something on my own. It's been difficult, and I liken it to the Matrix experience: take the blue bill, go back to a comfortable but boring life; take the red bill, jump down the rabbit hole and see where the real world takes you. One has to choose which life he wants.

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22. milkshake on April 17, 2014 1:20 PM writes...

Molecular architect: At this point it would be worth mentioning how Celera former site in SSF (Axys Pharma) got closed. I am still amazed that no-one actually had the balls to class action sue - because you got lied to and the cheated out of severance, in the most blatant way. My ex-colleagues in SSF took Pfizerto court for far less (and won a settlement). You got all nuked and paved over.

I am glad to have left before the bitter end: I liked my chemistry colleagues at Celera but I have to say that the higher management was the most odious bunch that I encountered throughout the industry.

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23. Phil on April 18, 2014 8:56 AM writes...

It has always been better to be lucky than smart. When you have millions and milions to invest, you get a lot of opportunities to be lucky.

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24. matt on April 19, 2014 3:17 AM writes...

Tried to reply earlier, but the site wasn't responding.

Sure, Robert Duggan comes across as someone who doesn't know much about pharmaceuticals. But 1) he got a group of advisors who were knowledgeable, 2) he asked their advice about the drug for which he bought the company, and apparently (from what followed) made it clear he wanted to hear honestly, 3) they had the guts to tell him what he didn't want to hear, and 4) he listened to them and took their advice.

Sounds to me he's ahead of many big pharma CEOs, who talk a lot smarter, but don't execute those four points nearly as well as Duggan. That is, they choose advisors from the latest managerial buzzthink industry rather than experienced pharma heads; they surround themselves with yes-people; they "team-build" with this ego-stroking group; and they shoot any bad-news messengers, which by result of the previous have to be outsiders who are willing to tell it like it is.

That doesn't mean that he'll crank out a lot more successful drugs, unfortunately--I imagine there may well be a handful of very good pharmaceutical heads-of-company whose candidates just don't pan out, or who happen to be trying to raise cash at the wrong time or in an unpopular part of the market.

I think there is room for a leader like Eisenhower, who was never considered the smartest guy in the room, but who nonetheless had a knack for making the right (tough) decisions based on listening to straight talk from opinionated but knowledgeable advisors. And for managing the egos of such a group during the day-to-day slog. Different from the FDR/JFK/Steve Jobs "visionary" model, but still effective.

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