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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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January 12, 2010

The Sirtris Compounds: Worthless? Really?

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Posted by Derek

As followers of the drug industry know, GlaxoSmithKline famously paid $720 million to buy Sirtris Pharmaceuticals in 2008. Sirtris is the most high-profile shop working on sirtuins and resveratrol-like pharmacology, which subject has received a massive amount of press (some accurate, some scrambled). I've been following the story with interest, since the literature has me convinced that the aging process can indeed be modified in a number of model organisms, which makes me think that it could be in humans as well. And I also feel sure that advances in this area could lead to many profound medical, social, and economic effects. (GSK, though, is going after diabetes first with the Sirtris deal, I should add - among other reasons, the FDA has no regulatory framework whatsoever for an antigeronic, if I can coin a word.)

But whatever the state of the anti-aging field, doubts have crept in about the wisdom of the Sirtris purchase. Last fall, a group at Amgen published a study suggesting that some of the SIRT1/resveratrol connections might be due an an experimental artifact caused by a particular fluorescent peptide. Now a group at Pfizer has piled on in the Journal of Biological Chemistry. They're looking over resveratrol and a series of sirtuin activators described by the Sirtris group in Nature.

And unfortunately, they also find trouble due to fluorogenic peptides. The TAMRA fluorophore on their peptide substrates seems to pervert the assay. While the Sirtris compounds looked like activators initially, switching to the native peptide substrates showed them to be worthless. Further study (calorimetry) showed that the activator compounds bind to a complex of SIRT1 and the fluorescent peptide substrate, but not to SIRT1 itself (or in the presence of native substrate without the fluorogenic group). That's not good.

But worse is to come:

"Despite a lack of evidence for the Sirtris series of compounds as direct SIRT1 activators, we investigated whether the in vivo efficacy demonstrated by SRT1720 in several rodent models diabetes could be validated and attributed to indirect activation of SIRT1. We therefore attempted to reproduce the in vivo efficacy for SRT1720 in mouse models of type 2 diabetes previously shown. . ."

That word "attempted" should tell you what comes next. The reported high dose of the compound (100 mpk) resulted in weight effects and death. The reported low dose (30 mpk) showed no effects at all on any diabetic parameters, but instead seemed to lead to increased feeding and weight gain. To complete the debacle, the Pfizer group screened the Sirtris compounds through a broad panel of assays, and found that all of them hit a number of other targets (and appear significantly worse than resvertarol itself, which is no one's idea of a clean compound to start with).

Basically, these folks have thrown down the gauntlet: they claim that the reported Sirtris compounds do not do what they are claimed to do, neither in vitro nor in vivo, and are worthless as model compounds for anything in this area of study. So what is GSK going to have to say about this? And what, if this paper is at all accurate, did they buy with their $720 million?

Comments (125) + TrackBacks (0) | Category: Aging and Lifespan | Business and Markets | Drug Assays


COMMENTS

1. Superted on January 12, 2010 8:54 AM writes...

You would hope that GSK performed the kind of studies that the Pfizer group have done as part of their due diligence. So either:
a) GSK did the studies but got different results.
b) Sirtris has some other compounds that GSK know about but they've not published anything on them yet.
c) GSK screwed up big time and didn't do any of their own studies with Sitris compounds to confirm the data.

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2. Jose on January 12, 2010 9:02 AM writes...

A startup with shoddy validation on their assays? Nahhh, say it ain't so!

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3. darwin on January 12, 2010 9:07 AM writes...

The outcome of any due diligence is only as good as the company's willingness to heed data rather than decide in a predetermined fashion to "fill a development gap".

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4. J-bone on January 12, 2010 9:21 AM writes...

The outcome of any due diligence is only as good as the company's willingness to heed data rather than decide in a predetermined fashion to "fill a development gap".

So you're saying industry is exactly like academia? Shocking.

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5. anon the II on January 12, 2010 9:21 AM writes...

So here's the problem and it's really simple. There are some medicinal chemists who started their careers on animal models and watched as the pharma industry switched over to biochemical models as a first line assay in the '80's. They watch as program after program dredged up this class of polyphenolic compounds as leads and they watched as group after group spent a lot of money and time optimizing these things to somewhere between 0.2 and 2 uM IC-50's. Glaxo doesn't have many of those older chemists. They built up their US programs in the late 80's, so new hires (those currently under 50) probably never learned this stuff and they've earlyretired (my verb) anyone who might. The natural products group from SK (of GSK) is long gone. So basically they didn't have anyone around to protect them from the academic vultures from Harvard with their silk tongues and "new discoveries".

The pharmaceutical industry has destroyed so much institutional knowledge over the last decade that it makes the Taliban, blowing up temples, look like high school pranksters.

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6. NH_chem on January 12, 2010 9:29 AM writes...

Find an idea that the press can understand (i.e. drinking red wine is good) and then move forward and pass go, collect (in this case) $720M......I am jealous that I did not come up with this!

Perhaps I can find a way for beer to make you live longer, start a company, and.......

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7. David P on January 12, 2010 9:54 AM writes...

Was it just me or was there a detectable amount of giggling and smugness in the Pfizer report?

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8. Vader on January 12, 2010 10:08 AM writes...

"the FDA has no regulatory framework whatsoever for an antigeronic, if I can coin a word."

Frank Herbert used the phrase "geriatric drug", but that always seemed backwards. And an antigeronic that you get by digging it out of a howling desert full of hostile animals the size of the Goodyear Blimp has obvious disadvantages over one you get by guzzling red wine.

What did they get for their $720 million? A Pascal's Wager. It is their nature that they rarely pay off.

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9. Hap on January 12, 2010 10:13 AM writes...

Usually, though, academics don't need to "fill their pipelines" as much, and when they do, it doesn't usually cost them $720M to do it. (If it cost Harvard or Scripps that much to recruit professors, then they probably wouldn't be able to do it.) Academics don't need to boost their stock price to impress analysts who don't know better, after all. They also don't usually have to buy companies to do research in a specific area. The cost of academics ignoring data is lower, but the likelihood of others uncovering their ignorance is higher (because lots of other groups will probably jump on their results).

Was GSK just asleep, driven by a need to impress someone, or is it possible Pfizer and Amgen have it wrong?

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10. gyges on January 12, 2010 10:13 AM writes...

# 5 anon II

brilliant post, well done.

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11. Hap on January 12, 2010 10:19 AM writes...

Well, if the probability of a payoff for Pascal's Wager is 1/infinity, then it seems like following it is a successful business model only for people who can't do math. I thought that was one of the skills MBAs had in spades.

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12. PharmaHeretic on January 12, 2010 10:22 AM writes...

Pfizer.. why so glum.

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13. anchor on January 12, 2010 10:22 AM writes...

.. So what is GSK going to have to say about this?

Very simple... and that is it will cost thousands of their employess to recoup the cost. Wall street is impressed..and all is forgotten.

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14. alig on January 12, 2010 10:22 AM writes...

The Scientists at GSK told management the compounds were shit during due diligence. GSK's management (Moncef Slaoui & Patrick Vallance) ignored their internal scientists and bought the company anyway (for too much money even if the compounds were real). This is part of Moncef's overall strategy of trusting external scientists more than internal ones (just look where they are investing). The blame lies squarely at Moncef's feet for this debacle.

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15. Anon on January 12, 2010 10:27 AM writes...

"And what, if this paper is at all accurate, did they buy with their $720 million?"

Fools & their money are soon parted?

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16. RB Woodweird on January 12, 2010 10:33 AM writes...

@Hap-
"I thought that was one of the skills MBAs had in spades."

The only math the MBA schools seem to teach is how to plot the bonus as a function of headcount reduction.

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17. MedInformaticsMD on January 12, 2010 10:36 AM writes...

Having suffered fools almost my entire professional life, except perhaps as a physician in a public transit authority where my concerns were listened to due to the - er, very public nature and difficulty spinning about massive transit accidents, I have a story for every occasion.

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18. GM on January 12, 2010 10:39 AM writes...

To Hap's (# 11) comment...what has this got to do with MBAs? Why is it that everything that goes bad in big pharma is MBAs fault. For the records, Both Moncef and Partrick, the top GSK guys who bought Sirtris don't hold MBAs, they holw scientic PhDs.

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19. Kismet on January 12, 2010 10:41 AM writes...

Any estaimtes when the FDA will cave in and when we'll get regulation allowing pharma companies to develop said 'antigeronic' drugs?

However, I am not sure any company would want to attempt making such a drug. After all, wouldn't it need to be much safer than usual drugs and if you add in the cost of the necessary long term tests, it'd be extremely risky, no?

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20. DC on January 12, 2010 10:42 AM writes...

Sorry off-topic question for the chemists here, what's the best way to clean metallic residues (MnO2, Pt/C, etc) off stirrer bars? I can't seem to get the black dust off and I wouldn't want trace amounts of these guys hanging around in other reactions. Thanks!!

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21. anon again on January 12, 2010 10:45 AM writes...

For a good discussion of antigerones, the social and economic effects and how to launch one, read John Wyndham's 'Trouble with Lichen' Its a good sci-fi, but who knows in the future...

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22. Anonymous on January 12, 2010 10:51 AM writes...

@ nr 14: were the GSK scientists just saying 'these compounds are crap' because they didn't like the look of them, or because they had the data to prove it?

@22: Aqua regia usually does the trick. Failing that, try conc sulphuric acid and H2O2 (but be very careful of the exotherm!)

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23. Anonymous on January 12, 2010 10:53 AM writes...

#14 Alig is absolutely correct

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24. Hap on January 12, 2010 11:03 AM writes...

Well, because if you're making a decision for business reasons and not scientific ones, MBAs are usually the people to go to. Of course, maybe if the people running GSK were making business decisons but didn't have good enough knowledge to do so, that might have been the problem.

The general anathema towards MBAs is because the decisions killing pharma don't seem to have been done on the basis of scientific input or long-term business well-being but on the "sack-the-company-and-run" ethos, an ethos likely to be best held by outsiders with business skills (MBAs), though it could also be held by pharma managers with lots of (the wrong) incentives and no consciences. I was also referencing a Sunday Dilbert strip from about ten(?) years ago (10/27/1996).

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25. bad wolf on January 12, 2010 11:28 AM writes...

They ("anti-geronics") were also termed "anagathics" in an old RPG (Traveller) as i recall, although i can't find an independant source for the term or a derivation.

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26. barry on January 12, 2010 11:38 AM writes...

re: DC
Stir them overnight in aqua regia. If the black was a metal, that'll take it off. Then be sure to wash/sonicate them thoroughly in ammonium hydroxide. You wouldn't want to leave traces of aqua regia anywhere.

As to antigeronics, the FDA was asked about human growth hormone for geriatrics. They famously replied that "geriatric frailty is not a disease, and we're not in the tonic business". Of course they could define "geriatric frailty" as a disease, and that might change the market value of IP in several growth factors overnight, depending on clinical results.

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27. Derek Lowe on January 12, 2010 11:41 AM writes...

#25 - the term "anti-agathic" first appears, to my knowledge, in the "Cities in Flight" science fiction stories by James Blish (an enjoyable read, by the way). I think he coined the word. I didn't use it here because that would, I think, mean "anti-death", rather than anti-aging.

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28. oMan on January 12, 2010 11:46 AM writes...

Anon the II (#5): brillliant. Institutional self-lobotomy tends not to be successful.

Value of natural products expertise was not just the chance of a product, but the cross-categorical experience. Hard to explain, let alone justify, to the perky consultants when they come around to "identify the synergistic opportunities."

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29. anonymous2 on January 12, 2010 11:48 AM writes...

Alig & anonymous are perhaps amoung the happy band that know GSK as a good place to be from - at least for scientists and others that base decisions on data. GSK's current R&D exec decided that external innovation was the 'answer' (in fact this is the line that Moncef sold the board to win his job) and have proceeded to ignore all internal concerns about quality/validity during due diligence - painting any dissenters with the "not invented here" brush - leading to the current situation. Not trusting (and insisting) that your own scientists to be as good as external is a self-fulfilling nightmare.

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30. DLIB on January 12, 2010 11:59 AM writes...

A little ironic that several years before that they were on the verge of funding my startup which would have provided them with calorimeters capable of primary screening. The VP ( Drake Eggleston at the time ) liked it and it moved through Bus Dev til all the champions got laid off ( including eventually the VP ) and then Bus Dev dropped it. A much smaller investment could have prevented this debacle. Sadly the champions of calorimetry in companies have very little clout.

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31. anonymous 2 on January 12, 2010 12:00 PM writes...

Alig (14) is absolutely correct and is perhaps amoung the happy band of scientists and other data-based decision makers who view GSK as a great place to be from. The GSK R&D exec has pronounced all external innovation as better than internal and they steamroll over all dissenters with the 'not invented here' mantra. Unfortunately there is no accountability for such decisions and the current crew will be floating gracefully into retirement hanging from their golden parachutes while all the scientists they fired to fund this deal and others are plugging along - hopefully improving human health with their efforts.

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32. LongGoneButStillWatchingInHorror on January 12, 2010 12:15 PM writes...

Alig has it spot on. When I was around half of what they bought in was cack, and the other half wasn't much better (I would love to name my absolute favourite example but I best not!). In a couple of cases the internal due diligence just seemed to get ignored completely, it was madness.

A lot of it is driven by 'peer pressure'. ie "Oooohhhh if we don't buy this (ridiculously overpriced) asset then (equally dim) company x might beat us to it" Cue panicky rash decision.

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33. Anonymous on January 12, 2010 12:22 PM writes...

EEK! regarding the sulfuric acid and hydrogen peroxide...watchout for the exotherm is an understatement! This is known as piranha solution and it will react VIOLENTLY if it comes in contact with organic materials. Do a scifinder search on it first and likely the top hits are about unpleasant lab accidents that have occurred using this mixture. I would buy new stir bars before I tried cleaning them with this. Even if you know how to handle this appropriately, I would imagine you work around other people who might not and that is how accidents happen...

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34. FMC on January 12, 2010 12:35 PM writes...

Doesn't this remind us all a little of the siRNA purchase by Merck? A lot of dough paid, so far no returns if I am not mistaken...

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35. JC on January 12, 2010 12:43 PM writes...

I find conc HCl cleans most residues well particularly iron but if ur that worried buy new ones.

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36. MTK on January 12, 2010 12:59 PM writes...

So what alig is saying, and others confirming, is that this seeming debacle has nothing to do with lack of institutional knowledge or lack of old-school scientists as anon the II suggested. At the same time, you can't blame the faceless "MBAs" either, since the two principals within GSK are Ph.D.s, not MBAs.

So it sounds like lack of institutional hearing combined with personal hubris that led to all this.

Interesting.

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37. anon the II on January 12, 2010 1:06 PM writes...

My apologies to the fine chemists at GSK who saw the Sirtris deal for what it was. Maybe I should have said that "Glaxo doesn't have many of those older chemists left and they're not listening to them anyway".

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38. Hap on January 12, 2010 1:07 PM writes...

Perhaps they are trying to prove that scientists can be bad executives too. While that would be a useful point to make, committing mass suicide is perhaps not the best way to make it.

Is this the time to bring up Santayana?

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39. Anonymous on January 12, 2010 1:54 PM writes...

"So what is GSK going to have to say about this? And what, if this paper is at all accurate, did they buy with their $720 million?"

What are they going to say about this? I'll give you an idea: The corporate sycophant that currently runs diabetes/metabolic research at GSK is going to punish any internal scientists (most already displaced) who might speak up about this and concurrently justify and praise any decision ever made by the Slaoui/Vallance team to anyone who will listen. They, in turn, will promote him/her again for making them look better. And GSK will continue to spiral the drain with their management holding the stopper ensuring there's a loud sucking sound accompanying the death of all their research efforts. And the exact same type of thing would happen at every single other large pharma as well. Don’t fool yourselfs.

And they really didn't pay for them anyway- they just fired 2/3 of their cardiovascular research group and 1/2 of their metabolic research group right after buying Sirtris, from what I heard. It probably came out as a wash.

Afterall, everyone knows that the talent and wisdom of those "earlyretired" sods paled in comparison to all the geniuses at biotechs who could polish a turd and sell it to big pharma. Now THAT takes talent. 'Hey, look what I bought at GNC! Wonder if some idiot will buy it for a lot of money?' Cue up Slaoui and Vallance......it's your time guys.

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40. abzyme on January 12, 2010 2:02 PM writes...

Anon the II is right to mourn the loss of good medicinal chemists and institutional knowledge at GSK. However, from my personal experience (published before the Amgen and Pfizer studies), all that was needed to avoid self-delusion and the delusion of others was to apply scientific rigor and a knowledge of enzymology. It was clear from the outset that polyphenols as SIRT "activators" was a stretch, and carefully designed control experiments flagged these and similar compounds as artifacts of the fluorescent assay.

Missing a piece of the $720m hurt, but I'm glad I didn't "follow the money".

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41. Zak on January 12, 2010 2:15 PM writes...

Moncef was probably screwing his girlfriend/employee on the company jet to pay much attention to the science of this deal.

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42. Anonymous on January 12, 2010 2:18 PM writes...

Usually, though, academics don't need to "fill their pipelines" as much, and when they do, it doesn't usually cost them $720M to do it. (If it cost Harvard or Scripps that much to recruit professors, then they probably wouldn't be able to do it.) Academics don't need to boost their stock price to impress analysts who don't know better, after all. They also don't usually have to buy companies to do research in a specific area. The cost of academics ignoring data is lower, but the likelihood of others uncovering their ignorance is higher (because lots of other groups will probably jump on their results).

The currency in academia not dollars, it's ego and bragging rights. At the center of all the recent publication controversies lies a professor's willingness to overlook facts that are glaring him in the face so he can get A) a prestigious publication in a high impact journal or B) many, many publications that will significantly extend the length of his CV and the publication section of his research group webpage.

Those of you that went to grad school undoubtedly experienced a sudden increase in pressure when you were close to publishing, and most of that pressure was probably not self-imposed. If at any point you were to tell your PI that a route had failed or that your reaction only worked for a very small population of substrates rather than several, I can almost guarantee that the response was not a friendly invitation to chat and find a new route or project, but more along the lines of "make it work".

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43. You're Pfizered on January 12, 2010 2:22 PM writes...

Gotta agree with #33. Buy new stir bars.

#34-SIRNA. I recall when that place was Ribozyme Pharmaceuticals, based in Boulder, before it tanked. Sirna was a smoke-and-mirrors Phoenix rising from those ashes, put together by a VC team that made themselves a whole lot of money when Merck drank the Kool-Aid.

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44. GM on January 12, 2010 2:36 PM writes...

@ Hap...you may be missing a point when you direct your comments to MBAs. I'll encourage you to find out the background of the leaders behind this deal. Most of them hold scientifi PhDs. MBAs are responsible for big pharma troubles.

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45. Sili on January 12, 2010 2:37 PM writes...

MedInformaticsMD, do I dare check your link this time, or should I drink first?

Pirañha was popular for clean glass frits in the organic lab next door, but they did take it to the 'gas lab' where the hood had a teflon bottom, rather than steel. Having once sulfonated a stirrer bar, I too have to ask if they're really that expensive that they need to be saved at any cost? If leaving them in nitric acid for a while doesn't do it, then just move on. Funnels and frits are more suited for saving I'm sure.

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46. Petros on January 12, 2010 2:39 PM writes...

Re #14 Alig

Patrick Vallance is Head of Drug Discovery for GSK - that part of the pipeline that runs from the initial chemical hit against a target through developing the medicine and testing it to "proof of concept" in the clinic.

Prior to joining GSK in May 2006 he was a clinical academic and led the Division of Medicine at UCL. He has over 20 years experience of clinical medicine - general internal medicine, cardiovascular medicine and clinical pharmacology - and has an international reputation as a vascular biologist and clinician scientist.

Moncef Slaoui
http://www.ft.com/cms/s/0/4e5d5864-a857-11dc-9485-0000779fd2ac.html?nclick_check=1

So little drug development experience from either executive

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47. where are the retractions? on January 12, 2010 2:57 PM writes...

So many of the sirtuin papers by David Sinclair (and now Sirtris) have been shown to be false. But none of these papers have been retracted. What does it take? Is there anything that will shame the editors at Nature into retracting this garbage?

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48. cj on January 12, 2010 3:20 PM writes...

Re #46 Petros, # 14 alig
Vallance systematically removed all chemists, biologists and clinicians with drug discovery experience and surrounded himself with ass kissing sycophants. He and Slaoui created a scientifically uninspired, oppressive culture.

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49. anonymous2 on January 12, 2010 3:58 PM writes...

GSK enzymologists pretty much did the Amgen experiments while running an internal program but were ignored during due diligence. While Moncef & Patrick may have PhD's, neither has any small molecule drug discovery experience and cj (48) has it about right - actual knowledge of drug discovery (much less having successfully done it) was/is fatal to your career at GSK with these two in charge - unless you are willing to pucker up & agree with them. Personally, I wouldn't follow them out of a burning building.

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50. 2mrklr on January 12, 2010 3:59 PM writes...

I recall about a year ago that the resveratrol / Sirtris story was featured on 60 Minutes (perhaps Morely Safer had a personal interest in the possibility of treatments for aging?) and I recall Christoph Westphal wearing a lab coat (which I'm sure he does on a daily basis) while being interviewed. He's still the Sr. VP for the "Centre of Excellence in External Drug Discovery" - must be kind of awkward, but I would assume his share of that $720 MM will pay for some consolation to his ego, or to treatments for any related insomnia (yeah, right).

So Morely, if you're reading, where's the follow-up? Given the current media interest on 1) the cost of healthcare and 2) Executive Greed, one would think that there's enough to fill up a couple of slots before andy Rooney (who likely also has a personal interest in this topic).

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51. TAK on January 12, 2010 4:24 PM writes...

I knew about the resveratrol issues, but I was holding out hope that the Sirtris compounds were more legitimate. There was no excuse for them to not do the proper experiments with these compounds after the issues with resveratrol were clearly proven.

Does anyone know of any sirtuin activators in the literature that are legitimate? That work in the abscence of fluorescently tagged peptide substrates?

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52. anon the II on January 12, 2010 4:25 PM writes...

2mrklr has a point. Maybe we should cut the Glaxo executives a little slack. The Sirtris guys were able to reel in those piranha journalists from 60 minutes. I've seen those 60 minutes guys tear world leaders apart and the Sirtris crowd had them eating out of their hands. What chance did a couple of mere pharma execs have with talent like that?

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53. partial agonist on January 12, 2010 4:31 PM writes...

I have heard via the grapevine that people at Lilly also tried to replicate the Sirtris results, which isn't surprising given their stake in diabetes treatment, and also saw fluorophore-dependent effects that indicated the "hits" were an artifact.

Pfizer going to the extent to replicte the non-existant in vivo results was maybe overkill but it adds nails to the coffin.

Nobody ever paid 720 million for cold fusion,did they? There seems to be about as much here...

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54. Sili on January 12, 2010 4:37 PM writes...

I completely forgot my initial complaint ...

I'm not an animal 'rights' fanatic, but I do think animal welfare counts. So it annoys me to learn that some significant amount of rodents have been wasted doing poorly designed experiments that then had to be redone only to demonstrate uselessness. Aside from the waste of 'life' it seems to be a stupid waste of resources as well, since I (unlike apparently some of the nutcases) know that animal tests are difficult and cost and arm and a leg.

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55. Wuot on January 12, 2010 4:37 PM writes...

mba’s get lots of obedience training best from the top schools and once the direction gets set by their managers the analytics follows in high pursuit. we have seen too many seemingly astute analytics go bad. lies dam lies and analytics.

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56. Hap on January 12, 2010 5:59 PM writes...

You mean, like Kindler?

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