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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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57. anon on January 12, 2010 6:25 PM writes...

who will pay for such a fail?

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58. Hap on January 12, 2010 6:25 PM writes...

On second thought, someone else chose Kindler. Someone else pays the CEOs and the other executive to run the companies for the short-term, and designs the incentives for them to do so. I don't know who in fact those people are (thus what their backgrounds are) and they probably should have more to answer for (at least to their stockholders and employees) than many of the current executives.

It seems like the emphasis from pharma is to sell what you have rather than actually to make anything worth selling. That didn't seem to be the case in the past, nor does it seem to be consistent with long-term survival (well, as anything other than a parasite). I don't know why that is or who to blame. It's easier to blame people outside the field for those strategies, but it may or may not be accurate.

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59. BigSky on January 12, 2010 6:52 PM writes...

Anonymous #42 also brings up a great point. The incentives to shade your vision can be large whether you hail from academia or industry or biotech. The currency differs but it bears noting that everyone has a price for their integrity.

It's just that those with a lower price seem to do better.

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60. Gordon on January 12, 2010 7:25 PM writes...

Seems like GSK is following Pfizer's business model , which is akin to looting a corpses pockets after killing him in the back alley.

1. Merge with a company
2. Layoff internal scientists to pay for it
3. Layoff scientists from merged company (generating the corpse)
4. Promote compounds and clinical assets from merged company over internal programs (looting the pockets).

Are any corporate Boards paying attention?

Seems like every big Pharma is pursuing the same model.

Gotta be good news for the small biotechs struggling in this cash-poor, VC averse environment.

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61. TEM on January 12, 2010 8:22 PM writes...

Ok, So what will the guilty parties do now?

Will Nature and Science force retractions?
Will GSK's board send Cristoph, Moncef & Patrick packing?
Will GSK shareholders, employees and former employees take this news kindly?
Will Harvard retrack Sinclair's tenure status?
Will Harvard and MIT initiate and complete a formal review of Sinclair's published research?
What will they do if they find evidence of data fabrication?
Will the NIH and other grant awarding bodies stem the bloodletting and blacklist Sinclair?
Lot's of questions. Waiting for the answers.

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62. provocateur on January 12, 2010 9:42 PM writes...

I saw the mice running on treadmills.Assuming they did not cheat there how do u xplain it?

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63. retread on January 12, 2010 9:48 PM writes...

60 minutes, 60 minutes, take me Lord.

I spent an inordinate amount of time reassuring my patients that some of their spectacular material was flat out wrong. (things like the mercury in dental fillings causing MS etc. etc.). I'd cringe any time they did anything medical (which was fairly often). I felt like I was cleaning up after the elephants, each patient had to be reassured individually.

Fortunately, people give big media like this far less credence than they did in the 70s and 80s, particularly after the Dan Rather debacle.

TV was regarded as synonymous with truth back then. 30 years ago, the only I ever did that impressed my kids was appearing on the local feed of the Jerry Lewis Telethon when I was running a muscular dystrophy clinic.

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64. cancer_man on January 12, 2010 10:04 PM writes...

So how about 60 Minutes' recent report , "Body Parts"? That also bunk just because CBS reported it?

Sinclair still maintained this summer that forthcoming articles will show that the compounds are promising. Maybe, maybe not, but it seems premature to insist that this line of drugs is doomed.

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65. Jose on January 12, 2010 10:14 PM writes...

A very wise boss (with decades of drug discovery experience back in the days when it was a science) told me, "Any time someone shows you polyphenols, run away as fast as possible. They always light up assays but can never be optimized."

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66. Anonymous on January 12, 2010 10:17 PM writes...

The supposed activation of sirtuins by resveratrol was reported in the literature to be almost certainly a rather simple assay artifact years prior to the recent Amgen and Pfizer publications and even the Sirtris purchase.


A 2007 poster from Cisbio refers in passing to resveratrol's "artificial effect" and a 2005 JBC paper first raised the alarm.

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67. researchfella on January 12, 2010 11:24 PM writes...

High credit goes to the Pfizer researchers (and their management) for spending the extra effort to determine what was wrong with the Sirtris assay, etc. and re-checking the animal studies, and - most importantly - publishing the results. Most organizations would have just killed the project and kept quiet.

Since many reviewers and journals don't seem to be doing their jobs very effectively, i.e., to challenge questionable results, we desperately need studies like the Pfizer work (and earlier Amgen work) to be carried out and published.

Next time, hopefully it won't take so long for publications to appear to counter some bogus results. Didn't anybody else try to repeat the resveratrol animal studies?

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68. Terry on January 12, 2010 11:26 PM writes...

Remember that Resveratrol is structrually unrelated the the NCE's the Sirtris is developing. Don't lump resveratrol into the same category. There are numerous studies showing the health benefits of resveratrol in both human and animal models - regardless of how or why these benefits occur resveratrol is still a very promising and safe agent in moderate doses.

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69. Jason on January 12, 2010 11:35 PM writes...

Yikes. $720 million here, $720 million there, and soon you're talking real money.

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70. cancer_man on January 13, 2010 12:39 AM writes...

First, how are we so sure the Pfizer study is valid based on what scientists are saying about shody peer reviewed papers in journals?

Assuming the Pfizer scientists are correct, how do we know that the supposed killer app, SRT2104, doesn't activate SRT1 or why are we to assume it is D.O.A. since it wasn't included in the study?

Again, dancing on GSK's grave seems premature.

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71. Chairman of the Bored on January 13, 2010 12:41 AM writes...

#58 Hap

The people to whom you refer are called the "Board of Directors" and especially the Chair, which sometimes is also the CEO.

Stockholders are supposed to the "real" owners of a publicly traded company, but we all know how that works out.

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72. Vince on January 13, 2010 1:24 AM writes...

Why did they run the in-vivo work for 18 days according to the methods, but present data for only 14?

Also, 14 days? Sinclair's 2006 paper had a data set that was over 110 weeks, during which a strong divergence was seen only after 60wks in the HFD. I can't even compare the Pfizer data to Sinclair's as he truncated the data before 55wks: the entire Pfizer timeline is only 10wks (P65-P74)


Why do the control mice on a normal diet have a higher "average food intake" than the heavier, HFD mice? I know why, but utilizing "grams," sans caloric content, is just shoddy. This applies doubly so when your model is Leptin-defecient ob/ob mice. Also shoddy is adding in the excel interpolated values from a discrete set that is that small.

Great work from those "medicinal chemists who started their careers on animal models," eh?

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73. Roseisarose on January 13, 2010 2:05 AM writes...

As a former Glaxo, GW and finally GSK scientist, who thought Tachi Yamada was an idiot, I was soon begging the the 'Good Old days" once Moncef and Patrick came along. Their stupidity was only matched by their arrogance and ego.

Sirtris is just one of their stupid moves and came at the same time they kicked a number of their excellent scientists in the ass and out of GSK, myself included. Both of these jokers aren't fit to run a corner drug store let alone what USED to be a great company. YES, we told both Moncef and Patrick that Sirtris had NOTHING but NO, they knew better! Morons....

For me, this wine (WHINE) tastes extra sweet!!!

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74. Jack Friday on January 13, 2010 3:29 AM writes...

Hey there GSK - wanna buy a bridge?

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75. sgcox on January 13, 2010 6:05 AM writes...

Funny thing, Sirtris is still patenting the same crap, see WO/2010/003048

In the biology assay section, the detection method is NMR but substrate peptide is fluorophore labeled. Wonder why...

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76. srp on January 13, 2010 6:07 AM writes...

You guys just aren't doing enough lateral thinking. Obviously the plan is to dose patients with both the compound and the fluorescent peptide. Activity and specificity problems solved!

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77. Thomas McEntee on January 13, 2010 6:32 AM writes...

Is ANY COMPANY in the US or Europe doing corporate R&D in pharma and biotech the way it ought to be done? I read these posts and comments and wonder what factors makes a company go off the rails. I worked for companies that had leaders with egos and mistresses, companies that acquired other companies and did well with their acquisitions, companies that spent years chasing promises well beyond their time. Who in pharma, and I'll include biotech, is doing it right? What are the chances of some scientific Warren Buffett picking up the pieces and putting them back together to do it right?

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78. PhytoDoc on January 13, 2010 6:58 AM writes...

As I wrote over one year ago:

As I see it the dilemma for Sirtris, and now Glaxo, is that the products they are developing already exist in effective natural, inexpensive form. Given, his synthetic analogs may be more potent or targeted against specific conditions however biotivia transmax the concentrated resveratrol being used in the human trials, is available now and has been shown in peer reviewed studies to be safe and effective. Synthetic analogs historically have been shown to be somewhat unpredictable in effect and safety. Why not simply stick with the natural form? It is here now and does not require an expensive physician's appointment. To succeed Glaxo will have to come up with synthetic versions of resveratrol that are shown to be clearly superior to resveratrol itself and just as safe. In the meantime Sinclair has taken to insisting that people wait for his pharmaceutical version of resveratrol to be approved and hinting that only this product will provide the real health benefits already clearly associated with Transmax.

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79. PhytoDoc on January 13, 2010 7:59 AM writes...

As I wrote over one year ago:

As I see it the dilemma for Sirtris, and now Glaxo, is that the products they are developing already exist in effective natural, inexpensive form. Given, his synthetic analogs may be more potent or targeted against specific conditions however biotivia transmax the concentrated resveratrol being used in the human trials, is available now and has been shown in peer reviewed studies to be safe and effective. Synthetic analogs historically have been shown to be somewhat unpredictable in effect and safety. Why not simply stick with the natural form? It is here now and does not require an expensive physician's appointment. To succeed Glaxo will have to come up with synthetic versions of resveratrol that are shown to be clearly superior to resveratrol itself and just as safe. In the meantime Sinclair has taken to insisting that people wait for his pharmaceutical version of resveratrol to be approved and hinting that only this product will provide the real health benefits already clearly associated with Transmax.

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80. PhytoDoc on January 13, 2010 8:06 AM writes...

As I wrote over one year ago:

As I see it the dilemma for Sirtris, and now Glaxo, is that the products they are developing already exist in effective natural, inexpensive form. Given, his synthetic analogs may be more potent or targeted against specific conditions however biotivia transmax the concentrated resveratrol being used in the human trials, is available now and has been shown in peer reviewed studies to be safe and effective. Synthetic analogs historically have been shown to be somewhat unpredictable in effect and safety. Why not simply stick with the natural form? It is here now and does not require an expensive physician's appointment. To succeed Glaxo will have to come up with synthetic versions of resveratrol that are shown to be clearly superior to resveratrol itself and just as safe. In the meantime Sinclair has taken to insisting that people wait for his pharmaceutical version of resveratrol to be approved and hinting that only this product will provide the real health benefits already clearly associated with Transmax.

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81. PhytoDoc on January 13, 2010 8:10 AM writes...

As I wrote over one year ago:

As I see it the dilemma for Sirtris, and now Glaxo, is that the products they are developing already exist in effective natural, inexpensive form. Given, his synthetic analogs may be more potent or targeted against specific conditions however biotivia transmax the concentrated resveratrol being used in the human trials, is available now and has been shown in peer reviewed studies to be safe and effective. Synthetic analogs historically have been shown to be somewhat unpredictable in effect and safety. Why not simply stick with the natural form? It is here now and does not require an expensive physician's appointment. To succeed Glaxo will have to come up with synthetic versions of resveratrol that are shown to be clearly superior to resveratrol itself and just as safe. In the meantime Sinclair has taken to insisting that people wait for his pharmaceutical version of resveratrol to be approved and hinting that only this product will provide the real health benefits already clearly associated with Transmax.

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82. DanJo on January 13, 2010 8:38 AM writes...

Re #75 (sgcox)..Interesting point..If by some miracle these compounds do progress the patents may be invalid!

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83. DrSnowboard on January 13, 2010 9:03 AM writes...

Phytodoc: Clearly your product does little for your stutter..Or is it your short term memory?

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84. partial agonist on January 13, 2010 9:29 AM writes...

phytodoc, "Why not simply stick with the natural form?"

Because "natural" is not synonymous with "safe and effective"

There are a lot of natural toxins, and there are also many natural products-inspired drugs that were modified from their natual form to be safer and/or more effective than the extract that initially got people excited.

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85. Fred on January 13, 2010 10:16 AM writes...

Don't forget that turd-like Synta oncology compound GSK snapped at a year or two befoee the Sirtris deal....

I played it just right, myself (as an investor); doubled my money on SIRT-- then SOLD.

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86. RKN on January 13, 2010 12:12 PM writes...

Damn, that explains the grade of B I received when I journal clubbed the first Nature paper by the Sinclair group on the efficacy of Resv in mice.

Maybe I should appeal.

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87. Ed on January 13, 2010 1:10 PM writes...

Cleaning Solution

Saturate conc H2SO4 with Potassium dichromate

Will clean anything

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88. MedInformaticsMD on January 13, 2010 1:38 PM writes...

Sili wrote at 45, "MedInformaticsMD, do I dare check your link this time, or should I drink first?"

Yes.

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89. Anonymous on January 13, 2010 4:21 PM writes...

So when I see any press release that includes the concept "similar to the action of reservatrol" is probably in trouble right from the get-go, eh?

======================================
Contact: Nick Zagorski
nzagorski@asbmb.org
301-634-7366
American Society for Biochemistry and Molecular Biology
Thyme oil can inhibit COX2 and suppress inflammation
Appearing in the January 2010 issue of JLR

For those who do not drink, researchers have found that six essential oils –from thyme, clove, rose, eucalyptus, fennel and bergamot—can suppress the inflammatory COX-2 enzyme, in a manner similar to resveratrol, the chemical linked with the health benefits of red wine. They also identified that the chemical carvacrol was primarily responsible for this suppressive activity.

These findings, appearing in the January issue of Journal of Lipid Research, provide more understanding of the health benefits of many botanical oils and provide a new avenue for anti-inflammatory drugs.
=============================================

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90. Dr. Manhattan on January 13, 2010 4:46 PM 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).

Geez, Derek, I thought I was the only one who has read (and reread) those stories. They would make a fine film in the right hands...

"The fatter toad waxes on the kine's coleslaw"

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91. Anonymous on January 13, 2010 6:41 PM writes...

"Is ANY COMPANY in the US or Europe doing corporate R&D in pharma and biotech the way it ought to be done?"

Genentech...............and MAYBE the parent company will keep it that way. We shall see.

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92. kurt9 on January 13, 2010 8:05 PM writes...

The Sirtis work as been kept quite proprietary. However, there is a considerable amount of independent research that does support the claims of resveratrol itself, even if the Sirtis research turns out to be flawed.

At worse, the Sirtis compound will be no better than the generic resveratrol supplement that is available now. If this is the case, then GSK has thrown away considerable money on a fool's errand.

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93. cancer_man on January 13, 2010 9:48 PM writes...

Still no guess as to why SRT 2104 wasn't analyzed along with the rest? It is obvious that this will be a thereputic failure?

Also, any reason GSK's shares haven't fallen on the news?

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94. OnAnonAnon on January 13, 2010 9:55 PM writes...

"Buy new stir bars."
Seems the easiest approach.

I was going to suggest stirring it overnight in a concentrated solution of EDTA (even several changes of same).

As to aqua regia, it's a good way to get rid of gold too.
http:// en.wikipedia.org/wiki/Aqua_regia

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95. Anthony on January 13, 2010 11:19 PM writes...

I enjoyed reading through some of the posts and comments. I will add a few comments and queries of my own.

I think that these research results are pertinent and worth reading. However, I think we (society) will soon be able to discern exactly what, if anything, both resveratrol and the SIRT drugs do in vivo. For the former, the NIH, in vivo studies should provide us with a wealth of information on the health benefits (if any) of resveratrol. For my part, I think that the stillbene might have some cardio-protective benefits.

As for the SIRT drugs, one of these chemicals is currently in clinical trials (Phase IIb?). We should get more info. on its effectiveness or impotence in the next couple of years.

In the end, I think GSK and SIRTRIS took some risks in moving ahead so quickly on the development of the SIRT drugs. If the SIRT drugs make it through trials, they will garner praise for their foresight and courage (or impetuousness). If these drugs fail, GSK and SIRT will be castigated for rushing things.

At the same time, David Sinclair and GSK have spent a great deal of time promoting these drugs. I can't recall any other chemical that was as highly hyped prior to its entry into Stage III trials. This marketing scheme will pay significant dividends if the drugs pass Phase III trials and vice verse if they fail.

In the end, GSK, SIRT, Sinclair, et al made (and continue to make) choices which carried a higher than usual degree of risk but at the same time promised a huge return (for society and for the companies involved) if successful. I can't fault them for taking this course.

On another note, I don't think we can fault GSK for buying SIRT. The company took a calculated risk by purchasing SIRT without waiting for a bevy of supporting data from other researchers. First, GSK (and everyone else assumed and still assumes) that any Sirtuin activators will be a blockbuster (if they are true CR mimetics). Second, GSK figured that it would have had to pay a lot more than $700 million for the company if it took a cautious approach and the data came in to support Sinclair's findings. Third, considering GSK's cash flow and size, $700 million is sizable but not earth shattering.

One more quick note, GSK is a large, multi-national company with research facilities in a host of different countries. Further, it contains numerous subsidiary companies. I would argue that GSK is more closely akin to a confederation of cultures than representative of any one cultural type. Therefore, I am not sure how the SIRT situation ties into the company's culture.

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96. cancer_man on January 14, 2010 2:23 AM writes...

I saw this comment on another page Lowe was on:

Having worked one of the Harvard labs that did the pioneering work on sirtuins, I can assure you threre is a lot more to this story than you are letting on. For one, SIRT-1 is just one of many sirtuin proteins that GSK has access to as a result of the Sirtris deal. SIRT-6 knockout mice have a profound premature aging phenotype, and SIRT-6 has also been shown to modify several of the pathways involved in insulin signaling. While I agree that the Pfizer data is troubling, I think we are a long way from justifiably writing off the sirtuin family of proteins.

Long GSK

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97. TEM on January 14, 2010 3:35 AM writes...

Hey cancer_man,

Concerning your #80 post, The simple answer is that the Pfizer folks performed the proper controlled experiment just like Kaeberlein et al, Dumas et al & Beher et al. Ever wonder why the Sirtris group used fluor labelled peptides in all their assays? Because they could not get the advertised "Activation" using standard acetylated peptides. Ever look at the original Resveratrol longevity curves? Always looked fishy to me. I think there was a whole bunch of cool aide passed around and guess what, these same folks got rich. Probably was a whole lotta winking and nudging going on. With $720,000000.00 at stake, who could blame them. This is not rocket science kids. It's not science at all!

Regarding all the pioneering work on Sirtuins(post 96), I'm sorry to say it all has the stink of Sinclair and Guarente on it. I need to take a shower.

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98. Anonymous on January 14, 2010 5:02 AM writes...

#93
"Still no guess as to why SRT 2104 wasn't analyzed along with the rest? It is obvious that this will be a thereputic failure?"

SRT2104 was not in that Nature paper.
Was SRT2104 structure actually disclosed ?
Could not find it.

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99. another anon on January 14, 2010 9:07 AM writes...

why do I agree with Alig #14? Simple. I watched numerous other similar inlicensing deals get made over the objections of internal scientists. And all of the ones I saw failed, for the reasons that had been identified.

Rather than outsource discovery, GSK should outsource decision-making.

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100. alig on January 14, 2010 9:11 AM writes...

RE: Anthony
"On another note, I don't think we can fault GSK for buying SIRT. The company took a calculated risk by purchasing SIRT without waiting for a bevy of supporting data from other researchers."

GSK scientists had data which refuted the Sirtris claims yet they were ignored by management. GSK was well aware that artifacts of the assay were the only hits coming from screens. Moncef and Patrick made an idiotic purchase because they have no experience in drug discovery and ignored the people who had decades of experience. This is the same story with Elesclomol, it was purchased despite the internal GSK scientists saying it was shit. It seemed like the head of Oncology CEDD was fired because he dared question their purchase of Elesclomol. When will Witty wake up and replace Moncef? Just because JP put Moncef in place doesn't mean you have to keep him Witty. Wake up and grow some balls.

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101. partial agonist on January 14, 2010 9:55 AM writes...

SRT-2104 does not appear to be a disclosed structure.

At least Scifinder & Pubmed had no hits, Google Scholar has papers referring to it with no structure, Google has press releases without structures and lots of clincal trial enrollment information (phase IIa). Oddly one would think that phase I data would be published with structures, but I could not turn it up.

One can guess a structire based upon their patents, but as far as I know the exact structure is not disclosed publicly.

If one were very nice you could assume that the "latest and greatest" is unlike its predecessors, but one would more logically assume that it just has better PK and/or a little more "potency".

What is odd, whether GSK did due diligence or not with regard to the acquisition, you would think that there would have to be lots of due diligence internally and under FDA scrutiny when they were approved to go into phase IIa and when they apparently started the trials sometime last year.

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102. TEM on January 14, 2010 10:01 AM writes...

If you have never experienced the full persuasive spin power of Christof and David, you cannot understand how they orchestrated this disaster. C&D could collect your urine, repackage it and sell it back to you all the while convincing you it's the next new blockbuster. Hmmm not too far from what really happened. This was a back room deal that has never involved science.

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103. SynChem on January 14, 2010 4:10 PM writes...

When I lose my "big pfarma" job to outsourcing I am going to start my own biotech, not to discover actually anything, but to swindle some big bucks from "big pfarma". Since I have spent years in "big pfarma" I know what buzzwords to use to sell them the crap we will "invent" in a potential "billion dollar indication" and we will fake ourselves some really nice data to go along with it. Who is with me!

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104. cancer_man on January 14, 2010 4:17 PM writes...

"Dr. Gallagher said that unpublished tests in mice showed that another chemical mimic, SRT-1720, increased both health and lifespan; after two years, twice as many mice taking the drug were alive compared with the undosed animals."

Anyone know of this study the New York Times reported on in sep 2009?

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105. anon on January 14, 2010 4:21 PM writes...

The "hotter" the science, the "higher profile" the lab/PI, the more "respectable" the journal, the fewer the number of other labs that have reproduced the results, the more work you better put into confirming results before spending real money. In the area of siRNA delivery, Nature is notorious for publishing developments that have not been reproduced.

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106. anonymous2 on January 14, 2010 4:27 PM writes...

There is a frequent logical error cropping up in several of these comments (Anthony & Cancer_man) - GSK did not 'buy' sirtuins as a target class, they bought a company with some compounds that were claimed to activate a member of the class. Once the association b/t the compounds and the target has been invalidated (as it was internally at GSK before the purchase), what are you buying? Expertise on this target class? - perhaps, but given the fact that Sirtris bungled the association b/t their compounds and the molecular target, the expertise doesn't seem that deep (at least in drug discovery). As a medicinal chemist I often see more biologically based scientists equating a compound with the target in an exclusive manner that is almost never justified. Once you are in the clinic, you are testing a compound, not its putative molecular target. Sometimes the result you get fits your preconceptions of the role of the target in biology, often not - and we seldom know whether its b/c we really didn't understand the biology or b/c the compound has other activities (usually both of these are true).

The logic of buying a company based on artifactual data (repeating - this was known in GSK before the deal was closed) escapes me. 'High-risk' doesn't mean ignoring what you know, it means accepting the fact that what you don't know may invalidate your hypothesis.

Drug discovery depends on risk-taking and serendipity, but if you abandon the scientific process of using the data that you do have, then you are lost. When I started in this business >20 years ago, I believed in wishful thinking but no one trusted me with $720M to dry the water from behind my ears - much less giving me the authority to fire 100's of scientists to fund my learnings.

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107. cancer_man on January 14, 2010 8:59 PM writes...

I'm not sure where I've been illogical in pointing out problems with respect to assuming this has never been anything but hype and the GSK got taken. Maybe so, but in no particular order:

1) 'jwbrush' claims he was working on sirituins in a Harvard lab and commented on Lowe's article (same blog post): " I can assure you threre is a lot more to this story than you are letting on." That's pretty strong. Also, "For one, SIRT-1 is just one of many sirtuin proteins that GSK has access to as a result of the Sirtris deal. I think we are a long way from justifiably writing off the sirtuin family of proteins." (This is the kind of unknown that I suspected.)

2)I haven't seen anyone respond to #72 Vince who argues there are "shoddy" elements in Pfizer's study.

3. Why hasn't GSK stock price dropped at all on the news? It's a big company, but you'd think if the Sirtuis are now widely regarded as worthless among those in the field, that there would be at least a short term drop. Maybe all that will work effectively will be SRT501, but GSK can't make money on that. Again, the price should already be dropping somewhat.

4. If SIRT1 isn't activated by resveratrol either, Sirtuis still may be able to increase the effectiveness despite the compounds also not activating SIRT1.


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108. sgcox on January 15, 2010 5:45 AM writes...

Actually, it is going down right now, as more and more stockbrokers and investors scroll down the JBC advanced publications.
LoL!

http://uk.finance.yahoo.com/q?s=GSK.L

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109. Tok on January 15, 2010 9:01 AM writes...

#91 anonymous - So Genentech's model of having just enough PhDs oversee all the work being outsourced to China is the successful model? Huh, that's unfortunate.

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111. Anonymous on January 15, 2010 9:46 AM writes...

Of course I am joking !
What else can I do after reading point 3 of #107 ?

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112. anonaswell on January 15, 2010 4:40 PM writes...

I'd not expect this to dent GSK shares to be honest considering the fact that, while this scientfic car crash may have landed on some investors' desks, on the same day GSK also posted having shipped $1.4Bn of flu vaccine in Q4.
As to the science, well the recent Pfizer paper says conclusively and in no uncertain terms what many people had already either written (for example Amgen) or thought for a long time. Let's keep an eye on this and also on what the opportunities may be for inhibitors of these enzymes for specific indications. No false positives there according to the Pfizer paper.

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113. cancer_man on January 15, 2010 7:03 PM writes...

Shares drop all the time on very bad news. They might not drop if the news is somewhat. So either:

a. the news isn't as bad as most think here

b. the news is quite bad but investors largely assumed that the compounds might not produce anything and/or GSK is so large that this failure is trivial.

c. the news is quite bad but other good news about GSK offsets it.

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114. TEM on January 16, 2010 10:43 AM writes...

112. anonaswell make an excellent point. A well characterized inhibitor of SirT1, SEN0014196(EX-527) is now in the news as a treatment for Huntington's disease.

http://www.sienabiotech.com/newsSiBi.jsp#

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115. Bill Sardi on January 20, 2010 4:39 AM writes...

The idea of single gene-targeted drugs, like Sirtuin1 stimulators, only diminishes the value of small molecules. Single gene-targeted drugs like Erbitux and Gleevec have only produced modest benefit. Aging and chronic disease involve many genes.

In this regard, a global gene array study was performed by Weindruch and colleagues which showed that calorie restriction, the unequivocal life-prolonging intervention, significantly differentiated 198 genes in laboratory mice. Resveratrol differentiated 225 genes, and an array of small molecules strikingly differentiated 1711 genes.

There is a growing body of evidence that low-dose combinations of small molecules, such as provided in red wine, exert a far greater biological effect.

What Sirtris did was to ask the world to hold its breath for their 1000-fold Sirtuin1 activators, called "new chemical entities." (NCEs)

Sirtris then conducted a human study in India that employed mega-doses, 2500 and 5000 mg, which are known to exert pro-oxidant effects, release copper, selectively induce apoptosis in tumor cells, and would be more appropriate for cancer treatment. But this high dose was used among human subjects with metabolic disease, with very transient benefit.

Why did Sirtris test an inappropriate dose? Was this an intentional set up for the NCEs, which now appear to have fallen into disfavor? This leaves Sirtis holding SRT501, which is simply micronized, stabilized, emulsified trans resveratrol. There are many similar offerings available as dietary supplements.

Of note, at least one of the NCEs on Sirtris pipeline list was removed without explanation, prior to this recent study by Pfizer scientists.

Other studies also seem to indicate over-activation of Sirtuin1 may be deleterious.

The problem here is that nature points to synergistic action as evidenced in wine, while the FDA wants single molecules to be tested as drugs.

Resveratrol still awes. But its real value appears to be realized when combined with other small molecules.

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116. laughing on January 21, 2010 3:08 PM writes...

Yup, GSK made another stupid mistake buying Praecis too. Nothing more than Phage display preferentially selecting for hydrophobic residues, yet they bought their line of BS too.

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117. Taber on January 27, 2010 4:41 PM writes...

Resveratrol is one big marketing hype...don't believe the hype, they are only after your $

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118. RenegadeSci on January 30, 2010 8:01 PM writes...

They do sill have SRT501, which is their 3-5g dose Resveratrol/lipid metabolism inhibitor formulation. With the raw material costs coming down their could be a large enough market.

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119. Concerned_chemist on January 31, 2010 6:01 AM writes...

This doesn't give me a warm fuzzy feeling at all.

Anyone know who the wife & mistress names are?

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120. Michael Cleary on February 1, 2010 6:41 AM writes...

We at the ResQ Club left resveratrol behind long ago as it has a quite a narrow and limiting value in its enzyme activity with CYP1B1. We have a broader spectrum of polyphenols from tangerines, strawberries, cranberries, blueberries and blackberries that are able to halt unwanted mitosis at the onset.
Find out more about these effective compounds micleary@talktalk.net

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121. Robert Endover on February 3, 2010 8:42 AM writes...

GSK bought a total turkey! Doesn't surprise me in the least! Roseisarose, comment 73 said it all and named the names. I just wonder who he might be!!

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122. noname on February 3, 2010 4:58 PM writes...

#116 Laughing-

The Praecis folks are still there after 3 years. They published that Nat Chem Biol paper last year. My company is getting interested in that sort of approach to PPI's and other intractable targets. How do you know it's all BS?

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123. sriram on March 15, 2010 12:36 PM writes...

hi everyone. i was aboutr to do some thing with this sirtuin using a computational approach. but i lost interest because of some controversies. my proffessor wanted to work badly on resveratrol/sirtuin thing. gave this project to some guy. now that this news has reached after two months. i consider myself lucky that i didnt work on some crap for months together. thankgod.....ha ha iam working in a project where i will sort of get some useful answers that poor guy now has to leave that project.....ha ha ha ha ha

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124. Anonymous on December 31, 2010 1:43 PM writes...

If you are critical of Longevinex at this point, please look at the upcoming results of the latest study. It shows that Longevinex is safe at ANY dose, is heart attack preventative and reduces fatalities.

The pharmaceutical industry as a whole hates all of the over the counter natural remedies that are disease preventative. They alternate strategies of FUD (fear, uncertainty and doubt) where supplements are worthless with "supplements are dangerous and must be regulated by the FDA."

They either want want to control the access and use of supplements for profitability reasons or destroy the industry for the same reason. The pharmaceutical companies know that supplements are proven to be disease preventative and that fact scares them because their businesses are based on disease management.

GSK competitors want to discredit Longevinex because they believe products like it will destroy their business.

The only problem with the the success of Longevinex in the latest study is that it is now likely that Longevinex will be pulled from the OTC market. I believe that GSK will lobby the FDA to regulate resveratrol and Longevinex as a prescription only drug. After all, GSK is a pharmaceutical company.

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125. Goldorak on October 9, 2011 2:14 PM writes...

I searched for sirtuin inhibitors during my Ph.D thesis in 2004 using different assays - among others an assay using a fluorescent peptide.
Beside a large number of inhibitors, I discovered also "activators of the sirtris-type": only activation using fluorescent peptides.
A large number of academic experts in the field like Jung, Baumeister, Denu, Yoshida gave me the hint not to continue on the field of the activators - and today I can say that they were right.
However, I checked my lab journal for activators (all unpublished):
@GSK: if there is any interest to purchase some of them please let me know

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