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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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January 26, 2010

A Storm in a Teacup

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Posted by Derek

So says GlaxoSmithKline CEO Andrew Witty about the Sirtris controversy - see this Forbes story for more. I hope he's right. I actually would like to see good things come out of sirtuin research - the biology's clearly interesting enough. And I would like to think that GSK didn't blow $720 million, because we could all use that sort of money these days. This story will only be settled for sure in the clinic, with the agents the GSK is developing. Good luck to them. I fear that they might need it, but I hope that they don't.

Comments (14) + TrackBacks (0) | Category: Aging and Lifespan


1. Hap on January 26, 2010 11:11 AM writes...

$720M makes a heck of a cup of tea - on the other hand, if drugs cost $1B to develop, well, it's less than one failed drug's cost to Phase III.

Of course, if it turns out that GSK ignored its own people to buy snake oil (or was extremely incompetent in vetting said oil), well, then that makes it hard to trust anything its management says or does. I can see why its management would prefer people forget about this ASAP.

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2. Anonymous on January 26, 2010 11:37 AM writes...

It is so revealing that Witty, Guarente, and Sinclair never dispute the primary claim of the Pfizer paper -- that the Sirtris compounds do not activate Sirt1 directly, and therefore that the whole story about "1000-fold more potent resveratrol" that was widely publicized (in Nature, NY Times, 60 minutes, etc...) is a complete fabrication. If the Pfizer group were actually wrong, you would think they would have a more convincing response than to basically tell everyone to forget about it (its "a storm in a teacup" and "neither surprising nor worrisome.") So, they are basically acknowledging that the whole thing is a fraud, without coming out a directly saying it.

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3. Anonymous on January 26, 2010 12:00 PM writes...

I love it when CEOs try to conflate low quality science with high risk science in an effort to reassure shareholders. High risk research is research based in a solid premise that still likely won't work for a myriad of as yet unpredictable reasons. Low quality research is research based on fiction. As demomnstrated in these reecent papers, the Sirt1 compounds are the latter.

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4. Cellbio on January 26, 2010 1:11 PM writes...

#3, love your post. I think the lost distinction you refer to is a root cause of a lot of poor decisions: VC funding blunders, Pharma deal jokes, executive decisions and less clear thinking of project leaders. Can't tell you the number of times I've seen the central premise of a project proven untrue without effect on project priority or resourcing, due in large part to the 'what the heck, most things fail anyway' dismissal of negative data. Especially if the decision maker is weak in scientific thinking, and the premise offered a tonic in the style of snake oil salesman, cure what ails you, fountain of youth stuff.

Hmmm, if Ponce de Leon were around today, would he be an entrepreneur, VC or pharma exec? I read that it may not be accurate that he looked for the fountain of youth, but rather, from Wikipedia, "Most historians hold that the search for gold and the expansion of the Spanish Empire were far more imperative than the any potential search for the fountain." So I'll go with Pharma exec.

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5. juju124 on January 26, 2010 1:34 PM writes...

Perhaps Glaxo should have listened to what has been said earlier

Science is the belief in the ignorance of experts-Richard Feynman

The establishment defends itself by complicating everything to the point of incomprehensibility- FRED Hoyle

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6. GM on January 26, 2010 2:54 PM writes...

The additional question to be addresed, which I think is very important is: Is the deal worth $720 million? If the market valued Sirtris' at $12 dollars a share, why would some pay $22 dollars a share (about 84% premium, as pointed out in other articles). Were other companies trying to acquire Sirtris? Which could explain why GSK has to up their offer. I heard Roche offered $20 million.

And I guess the other questions is" what is the opportunity cost to GSK? What would GSK R&D be doing with $720 million? I bet you it's probably 7 years worth of R&D with 100 to 150 employees. You tell me if GSK thinks this deal is far more better than what 150 scientist internal can do in 7 years?

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7. CMCguy on January 26, 2010 3:07 PM writes...

#4 Cellbio if criteria was only "search for gold" motivation I would strongly assign de Leon as a modern VC. Since added "empire building" element does sound more like many Pharma Mangers/Execs so would vote with you.

Someone on another thread suggested VCs being good at distinguishing potential success of Research Projects but IMO majority VCs may be good at making money but their scientific awareness is often worse than a lot of the Pharma Execs. Most VCs can generally afford to hire in appropriate consultants to evaluate projects/companies potentials but as with all Due Diligence there are wrong calls and disappointments.

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8. The Pharmacoepidemiologist on January 26, 2010 7:39 PM writes...

Don't be too surprised if the sirtuins end up as major players in drug-induced hepatotoxicity.

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9. Anonymous on January 26, 2010 10:23 PM writes...

Derek deserves a lot of credit for forcing this story into the mainstream press. It's pretty obvious that Forbes and Nature wouldn't be covering the Sirtris scandal if not for the relentless posting on this blog.

Great work, way to keep them honest!

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10. AR on January 27, 2010 12:32 PM writes...

Thank-you pharmacoepidemiologist! Every in vitro hepatotoxicity test I’ve run using resveratrol shows this stuff to have a thin therapeutic margin. These include some fairly specific toxicity mechanism of action studies. It’s been difficult to find any animal safety study information to review, despite people writing to this board claiming the in vivo toxicity was minimal at moderate doses. I’d sure like to have some Cmax data to sort this out.

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11. retread on January 28, 2010 6:16 PM writes...

A very interesting new technique (with the acronym DARTS -- for Drug Affinity Responsive Target Stability) was described at the end of last year [ Proc. Natl. Acad. Sci. vol. 106 pp. 21984 - 21989 '09 ] The technique is based on the idea that binding of a drug to a protein diminishes the number of conformations available to the protein drug complex (as opposed to the free protein). This is held to render the protein more resistant to proteolytic degradation. So you can use the test to find out where a given drug is going (not just to the target you hoped it would) without modifying the drug or the protein.

The relevance to the sirtuins and resveratrol, is that resveratrol binds to proteins of the eukaryotic translation initiation machinery.

It would be interesting to know what the pharmacologists reading this think of the technique.

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12. cancer_man on January 30, 2010 2:10 AM writes...

By the way, the Sirtis/GSK colon-liver cancer study using 5g of SRT501 just ended a few weeks ago. Does anyone know when we might expect to see results? If SRT501 turns out to not be effective, does the study dissapear?

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13. RenegadeSci on February 18, 2010 6:49 PM writes...

One of the privileges of the FDA is to report on studies for the betterment of the public. If a company does a private study, then they don't have to publish. Unsuccessful FDA studies happen all the time, and can be found online.

The SRT501 should still work. The effects of Tres are real in the studies, but the mechanism was an artifact. The problem was compounded when Sirt1 is activated when Res is administered to cells, but AMPK may be the true target. NIH investigators recently came out with a great paper which shows evidence to this. So the Sirt1 activators may not have the effect they wanted, but resveratrol actual is not disproven. Resveratrol may just act on a specific subunit of AMPK.

It seems more logical that the effects that have been seen with resveratrol are based on AMPK. Upregulation of Sirt1 is not a neuroprotectant, and AMPK is. Etc.

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14. RenegadeSci on February 19, 2010 2:59 PM writes...

Also, the only evidence I can find of Sirt1 being the target of Resveratrol is the screen and microarrays. A microarray won't give you gene order, and the screen was wrong. My genetics professor will be making her students read these papers, for certain.

So much fun.

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