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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 15, 2010

Sirtuin Scenarios

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Posted by Derek

So, after reading what Pfizer has to say about Sirtris (and by extension, about GlaxoSmithKline's heavy investment in them), let's go over the possibilities. What happened, and what's going on?

We'll start out with the first branch point: either Pfizer (and Amgen) are right that there's trouble with the Sirtris assays and compounds (Reality A, I'll call it), or they're wrong (Reality B). For the rest of this piece, I'm going to assume that they're right, because I think that this is almost certainly the case. At least two separate groups of competent investigators have reported trouble, and that's good enough for me. (We'll discuss the implications of that in a bit).

Now we come to the second branch point: either Glaxo did enough due diligence to be aware of the problems (scenario A1) or they didn't realize them at the time of the deal (scenario A2). If A1 is the case, then we'd have to assume that the most likely consequence (A1a) is that Sirtris had other non-public assets that did check out, and that GSK's management felt that these justified the purchase. (A1b would be the scenario where GSK was well aware of the Sirtris problems, knew also that they didn't have anything else to offer, and bought them anyway, which doesn't make sense). These assets could have been other compounds, and/or a leg up on the complicated biology of this field. The difficulty with that line of thinking is that having found the fundamental assay problems with the Sirtris work, the GSK people would surely have been much more cautious about drawing sweeping conclusions about the rest of the company's intellectual property.

If A2 is the case, then we're looking at sheer fecklessness on the part of GSK's upper management. I'd like to be able to rule this out, but there have been other deals in the history of this industry that make that hard to do. I have witnessed at least one such personally. One problem is that these deals tend to be initiated near the highest levels of a company, and these people are not always the most technically savvy (or up-to-date) members of an organization. Even with a science background, the CEO of a large company does not have the time to be a scientist. (I'm reminded of Peter O'Toole's character in My Favorite Year: "I'm not an actor - I'm a movie star!"

Overall, though, I find it hard to believe that no one would have noticed the reported problems at all, which leads me to favor what I'll call scenario A3: the problems with the Sirtris assays may well have been known/realized at the lower scientific levels of GSK's organization, but these concerns may not have made it to the top in a sufficiently timely or vigorous manner. The deal would have gone through under its own momentum, then, in a flurry of last-minute misgivings which would have been hard to distinguish from the usual butterflies that accompany any large transaction or the preliminary stirrings of buyer's remorse. The sorts of reasons advanced in the A1 paragraph above would have been used to justify pushing ahead. With that in mind, this scenario could be broken down further into A3a, where Sirtris also had some other assets that the rest of us haven't seen, and A3b, where they didn't. I think that A3a is more likely, since that would have provided some of the momentum to get the deal done regardless. A3b is basically A2 with different timing and slightly less cluelessness.

So where do things go from here? That obviously depends on which of those three realities obtains. If A1 (specifically A1a) is the case, then GSK plows ahead with their secret Sirtris assets and compounds, and good luck to all concerned. It's worth keeping in mind that sirtuins are quite interesting and important, and that it's an area worth investigating on its own merits. (Pfizer and Amgen, among others, must think so too; that's the only reason that they would have been trying to replicate the Sirtris work).

If A2 is the real story, well, I'm very sorry to hear it. A lot of people seem ready to believe this one, partly because of anger over the layoffs the company has been going through. The most likely consequence of A2 is that $720 million dollars disappears, never to yield anything that's of use to anyone, so I hope that this isn't what happened.

And if, as I think, A3 is what actually happened, then that sort of depends on whether we're looking at A3a or A3b. If the former, then Glaxo overpaid, but has a fighting chance to redeem itself. If the latter, then Glaxo not only overpaid, but (as with A2) is in danger of losing its whole investment as well. We'll all find out.

But we may not find out very quickly. GSK has (like many other companies) a tendency to be rather close-mouthed about the progress of some of its research. When I worked in the nuclear receptor field, we all were very interested in the fate of a particular Glaxo compound, the first selective PPAR-delta ligand to go into the clinic. The company had talked about some animal and preclinical data, but we knew that they were taking it into humans (after all, it was listed that way in their pipeline updates). But it stayed listed like that. . .and stayed. . .and stayed. . .until, as the months and years passed, it became obvious to even the most optimistic observer that the compound's development was (at the very least) extremely complicated, and (more likely) had actually quietly ceased a good while before, albeit with no change in its public status.

In this case, now that these doubts have come up, GSK has a real interest in pointing out any success it may have. If its sirtuin compounds go into the clinic and just sort of hang there, that will probably be an even worse sign than usual. And if no sirtuin compounds even go into the clinic at all, well, the question has answered itself. I hope that's not what happens.

Comments (61) + TrackBacks (0) | Category: Aging and Lifespan | Clinical Trials | Diabetes and Obesity | Drug Development


COMMENTS

1. UK Chemist on January 15, 2010 9:21 AM writes...

I'm sure many of us who have been on due diligence activities have seen examples where the team recommend not to do the deal and were over-ruled by senior managment.I wonder if anyone has examples where the team were wrong and senior managment were right.I certainly dont' have any.

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2. Ed on January 15, 2010 9:27 AM writes...

If compounds are listed as being in the pipeline, surely NYSE/SEC or LSE/FSA listing rules must stipulate that information provided to investors must be accurate, and thus compounds that aren't being actively developed must be shown to be dropped?

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3. Doug on January 15, 2010 9:29 AM writes...

Hi Derek, my apologies in advance. My comment is not related to Sirtuin, but about recent layoffs in the industry. At least one of the scientist in Wyeth (Pearl River) committed suicide, and another one in Groton tried to kill his wife. It has been brutal for the scientists and researchers who were let go. And it seems (correct me if wrong) the scientists and researchers have no saying at all about their own fate in a company. My question is why there are no unions in our industry. Are there any historical reasons? I am not personally agreeing with everything a union represents. But the scientists/researchers need to have a voice in the management of the company. The massive layoffs are partly the results of years' miss management and over expansion in the big pharms.

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4. Anonymous on January 15, 2010 9:32 AM writes...

Well, SRT2104 is in clinical trials

http://clinicaltrials.gov/ct2/results?term=SRT2104

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5. Tok on January 15, 2010 9:37 AM writes...

Doug,

Sorry but unions don't work for research. The union's most powerful tool is a strike. It would take about 10 years for a industry wide strike to have enough effect to warrant attention. Every one of those 10 years would bring record breaking profits for these companies since they're not paying for R&D. By that time, everything will be in China and India.

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6. Jose on January 15, 2010 9:47 AM writes...

"and thus compounds that aren't being actively developed must be shown to be dropped?"

I think the devil lies in the detail of how exactly one defines "actively" developed in this case. Sure, a janitor could be sifting through boxes for "storage" or, one associate biologist is still running some assays in a quiet corner, or some poor bloke in formulations is playing with Tween 80... or.... yup, that's active!

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7. Chemjobber on January 15, 2010 9:59 AM writes...

"At least one of the scientist in Wyeth (Pearl River) committed suicide, and another one in Groton tried to kill his wife."

Link, please?

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8. emjeff on January 15, 2010 10:03 AM writes...

Unions worked real well for the auto industry. It is astounding to me that anyone in this day and age thinks that the reply to global competition is to create a class of entitled workers with no accountability.

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9. darwin on January 15, 2010 10:12 AM writes...

I HAVE PEOPLE SKILLS!!!!

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10. The Pharmacoepidemiologist on January 15, 2010 10:19 AM writes...

The sirtuins have lots of intracellular actions. One such action concerns the regulation of mitochondrial activity; potentially, a signal might be given for mitochondrial inactivation or, perhaps, disintegration. If this happens in the liver, heart or brain, then death of the subject comes into play. Bottom line: the biological effects of sirtuins may be quite different in lab or clinical setting, as compared to a post-marketing approval one. The latter might be fraught with noxious effects missed during clinical development. At that point, no matter what GSK paid, it will have been too much.

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11. Hap on January 15, 2010 10:20 AM writes...

5) Other than the fact that (for a variety of reasons) lots of chemists don't necessarily want unions to work, I am sort of surprised that unions managed to work at all. My first thought is that a lot of the cases where unions were effective depended on having conditions that localized the workforce (mining, for example - you can ship people in but it's probably hard and you have to run a gauntlet), which doesn't exist for anything relying on information rather than physical materials.

If companies want to ship drug discovery overseas, well, they'll do it anyway, though it seems like an extended suicide note for everyone other than the people in charge who'll walk away with lots of cash before Chinese and Indian drug companies eat their companies' breakfasts, lunches, and dinners. If there aren't any jobs in manufacturing, and no jobs in info or technical skill, where will the money coming from to pay service employees, and who will actually have the money to buy anyone's products? It'll be harder as well to convince people to gain technical skills if it seems like a long road to penury, and then I wonder where the economy will manage to go (other than "into a deep hole").

It just seems like too many people are indicating that GSK had enough info to not buy Sirtris and ignored it, anyway. Any drug candidates coming from Sirtris would be suspect - if their core technology was so flawed, then it would be hard to trust that the rest of their drug discovery was effective enough to deliver a high-value drug candidate. Torcetrapib should give one an idea what can happen to even the best drug candidates, anyway (the ones that everyone thinks are lead-pipe cinches) - buying candidates you don't know if you can trust at all seems like a really expensive lottery ticket. If you're depending on luck without any knowledge at all, well, you're probably hosed.

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13. Mike G on January 15, 2010 10:26 AM writes...

What about a scenario (a variation on A2) in which GSK, having little natural products expertise, relied heavily on Sirtris' data package and/or research methods (assay formats, etc). After all, Sirtris is the expert in reservatrol pharmacology, so it makes sense that GSK might defer to them at least for mechanistic due diligence. I'm wondering if this sort of over-reliance on licensee data is becoming a common practice in areas where pathways and targets are unprecedented?

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14. Hap on January 15, 2010 10:27 AM writes...

Unions worked real well for the auto industry. It is astounding to me that anyone in this day and age thinks that the reply to global competition is to create a class of entitled workers with no accountability.

Um, what would CEO's be, at this point? It's not exactly an endorsement of the idea of unions, but it sure looks like the current situation. Apparently, someone didn't mind the idea of creating an entitled class of workers at stockholders' expense with no accountability as a way to make companies "globally competitive".

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15. Annonymous on January 15, 2010 10:31 AM writes...

Chemjobber - here is one of the incidents http://www.theday.com/article/20091118/NWS02/311189914

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16. FMC on January 15, 2010 10:33 AM writes...

@ 8, no I am not a liberal. However, what we are appearing to create is a class of companies with no accountability. This is no whining, but I think some checks and balances would be good.

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17. alig on January 15, 2010 10:39 AM writes...

It is A2. While I was not in the room when the due diligence was discussed with upper management, I know some of the people who did the due diligence. Within days of the deal being made, they were flabbergasted that they had been completely ignored by upper management. GSK had an internal SIRT1 program before the deal, but all the hits turned out to be artifacts of the assay. So the scientists at the bench knew to look for this.

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18. Chemjobber on January 15, 2010 11:10 AM writes...

Um, wow. That's terrible.

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19. ex GSK on January 15, 2010 11:11 AM writes...

alig is completely correct.

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20. Hap on January 15, 2010 11:29 AM writes...

Do you mean A1b (GSK knew of the problems, at least in general with sirtuin assays, and ignored that possibility with Sirtris), or have I misunderstood this?

It's not really fair to say that all CEOs form a privileged class, but there seems to be an awful lot of incentives for some that make at least a subset of them appear to be a privileged class.

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21. darwin on January 15, 2010 11:38 AM writes...

Ward-stop being so hard on the Beaver.

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22. retread on January 15, 2010 11:56 AM writes...

"I'll call scenario A3: the problems with the Sirtris assays may well have been known/realized at the lower scientific levels of GSK's organization, but these concerns may not have made it to the top in a sufficiently timely or vigorous manner."

This may just be typical of large organizations. Here's a blast from the past based on personal experience. In 1968 the USA had half a million men in Vietnam. The Army needed lots of docs to take care of them and their motto was "If you can practice medicine outside the army you can practice it inside the army". There was no 4F for docs nor were there medical excuses. This meant that all newly minted MDs would spend two years during or after residency training in the service. Fortunately (for me) the Army was short of neurologists in 1968, so with just one year of residency (instead of the usual 3) under my belt I was sent to one of their best hospitals (Fitzsimons) to work under an excellent and seasoned neurologist (Col. Halbert Herman Schwamb -- whose name alone scared the hell out of me).

The tour of duty in Vietnam was 1 year for everyone, so docs who had been there for their first of two years got their pick of where to go for their final year. Naturally, Fitzsimons was one of their top picks, so the place was full of them.

The army had something called the 'body count' which meant the number of Viet Cong (and possibly civilian) bodies they could find. It gave a number, which was increasing with each passing month. It showed we were winning. However not one of the returning 2 year docs I talked to (and I talked to a lot of them) thought we were winning. Most thought we were losing, and badly. They were of course right.

Since most of the 2 year docs were not career military (like myself) they didn't send anything up the chain of command. I can tell you that it would have been career destroying for a West Point grad coming back as a very junior officer to say this to the higher ups (who were either blind or stupid e.g. Westmoreland). Hopefully this is not the way it was at GSK.

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23. okemist on January 15, 2010 12:08 PM writes...

First off my heart goes out to all who have experienced layoffs in recent months, especially those who are suffering emotionally.
Next there are several ways to profit from aquiring new technology, Dereks past employer did a $500M 5 yr deal that got 0.0 compounds developed, but reaped a large profit in equity. There are other ways to profit beside producing a blockbuster api.
And C, all you anti-union, think you are managers because you have PhD's wouldn't be eliligble to be in a union. I have felt for ages that associate scientists should have union protections with far too many reasons than should be listed here.

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24. Phoenix70 on January 15, 2010 12:47 PM writes...

@ retread

I have a little different take or "tangent" on scenario A3. I *was* one of those West Point grads ('67) in 'nam in 1970. I worked for an organization called the Phoenix Program. A required report called the HES report, which basically stated what regions were controlled by the good guys vs the bad guys, had to be periodically submitted up the chain of command starting from the grunts on the ground. Regardless of what you envisioned, these reports were factual when generated (and not career destroying - at least to me), but as I found out later, were systematically inflated in favor of the good guys as they moved up through the chain of command. By the time they reached the Commanding General (Gen. Abrams by that time), these reports were totally distorted. Gen. Abrams was relying on bad data in order to make decisions and recommendations.

I am wondering if the same case could not be made about the decision made by GSK to make this purchase....i.e., he was making the decision based on inaccurate data that was inflated as it moved up the ranks.

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25. Me on January 15, 2010 12:47 PM writes...

I had a friend who worked at Sirtris for a year and left before a GSK bought the company. A friend had to deal with outsourced workers in China for ... Do you think that Sirtris created other assets with those workers in China?

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26. partial agonist on January 15, 2010 1:04 PM writes...

It is my understanding that chemistry at Sirtris was heavily outcourced to China, but that the biology was all "inside" and largely not outsourced. I think the chemistry leaders at Sirtris were telling the Chinese contractors exactly what to make, so they would likely not have generated additional assets.

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27. Cellbio on January 15, 2010 1:15 PM writes...

Derek,

Nice post as always, but I think you apply too much logic, and perhaps underestimate the way in which "leaders" of these organizations utilize group think and adhere to beliefs that reason and logic show to be unfounded. Kind of like religion.

Regarding logic, no doubt that most readers here fit Kant's belief that we act rationally; 'Act according to the maxim that you will to be a universal law', or something to that effect. But, our oft loathed MBA's fit to Hume's belief that we are driven by emotion, and logic is only the window dressing constructed after the fact to justify our actions. Did I mention religion?

And then the very common working of the mind, coupled with large egos, makes it very difficult for scientists, to derail ingrained beliefs. Examples of this sort of belief system include the broadly held view that low fat diets are healthy despite studies which show no benefit. People know it to be true because they know it to be true through social belief systems (Dr. Koop's authority and knowledge cascade), which cannot be easily changed by fact. When our leaders know something works, and is the fountain of youth after all, then scientists pointing out details like assay artifacts, studies which fail to confirm, existing data which unravel the logic, well, these concerns are from the chorus of dissenting voices that that lack the vision of the true believers. The data are not heard because the messenger is deemed to not have the big pisture. The "truth" can always be confirmed by other's who also have the knowledge, offsetting the dissenters in numbers if not logic. Kind of like the Gnostic movement in early Christianity, to ring the religion bell again.

I have seen this several times. In fact, I and others did stand up "in a sufficiently timely or vigorous manner", only to be uninvited from further participation. Classic emperor's new clothes behavior. In fact, these experiences lead me to reread the fables, which I find more valuable for corporate life than religion. Though, the power to smite down would come in handy.

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28. Kay on January 15, 2010 1:27 PM writes...

I was at GSK at the time of the Sirtris purchase, and another complicating factor was that GSK was in the middle of layoffs at the time it went through. The layoff process at GSK lasted for months and involved a lot of hoop-jumping and reorganizing and moving from one department to another, so a lot of the scientists at GSK at the time were focused on the layoff process, even if they weren't personally affected.

As far as unions, after working in pharma for 15 years, I ended up in the federal government after my last layoff. I'm now part of a union, much to my surprise. It doesn't affect my work, except that I don't have the constant fear of layoffs that became such a huge part of my life during my last 4-5 years in pharma. Some people think that the fear of losing your job at any moment makes you work harder, but it just made me less able to focus. I feel that I'm much more productive now (much like I was when I first started working in pharma, when layoffs weren't a constant backdrop in every job.) And the people I work with in the government are equally dedicated and hard working to those that I worked with in pharma.

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29. bamh1d on January 15, 2010 1:49 PM writes...

@13
Actually, until about 10-15 years ago GSK had one of the premier natural products programs in the industry. However, I imagine that by now most if not all of those people are elsewhere.

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30. anon the II on January 15, 2010 2:28 PM writes...

@bamh1d

Was that the "G" part or the "SK" part that had the good natural products groups? I'm guessing it was the "SK" part. I don't remember seeing natural products papers from the "G" part in the past.

Most of the pharma industry got rid of their natural products groups in the '90s for a variety of reasons.

Some thought that combinatorial chemistry would take it's place (wrong).

Some thought combinatorial chemistry and natural products chemistry were the same thing (really wrong).

Some thought it was most useful for antibiotics and they weren't doing antibiotics anymore (sorta correct).

Some saw a huge amount of work constantly re-finding the same molecules (also kinda correct).

Most saw the other companies doing it and so they did too (best answer).

There were a lot of reasons that all pharma should have kept a small group around doing natural products chemistry. You could probably have supported the whole industry's worth for 40 years for $720M.

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31. JAB on January 15, 2010 3:02 PM writes...

@anon the II #30

Amen to your last statement that $720M could support the whole NP in pharma, maybe not for 40 years but for quite a while.

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32. retread on January 15, 2010 4:18 PM writes...

#24: Phoenix70:

Fascinating. I had almost no contact with line officers in my two years at Fitzsimons -- while all docs were officers, there were few soldier type officers on the post. The people we did take care of who'd been in 'Nam were pretty badly hurt (or they wouldn't have been there) and most were draftees.

Your comment also explains why LBJ acted the way he did. He wasn't getting decent information. I do recall one officer I talked to who said it was his job to 'win the war with maps'. If he drew a circle around two known enemy troop concentrations or controlled areas, the number of such was decreased by 50%. I was never sure if he was kidding or not.

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33. dearieme on January 15, 2010 4:56 PM writes...

"$720 million dollars disappears, never to yield anything that's of use to anyone." But it ends up in someone's pocket, Derek.

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34. NIgel on January 15, 2010 5:55 PM writes...

Even if resveratrol does not directly activate SIRT1, SIRT1 IS activated when I take resveratrol orally - so why do I care? I don't. I just look at the ends and not the means.

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35. cancer_man on January 15, 2010 7:47 PM writes...

This point is the same as the guy working in the Harvard lab made against Lowe's original post. And unless Sitris fudged the data, SRT501 was shown to be safe and effective at 2.5g a day for lowering glucose in diabetics in a phase II trial. I guess SRT501 is too similar to resveratrol for GSK to make money off of ot, but if the pfizer study is correct, then SRT501 isn't activating SIRT1 either, but something impressive seems to be happening.

Here is one response from GSK:

[GSK questions the validity of the Pfizer team's findings. The researchers "set out to prove a negative and fall short of achieving that objective while adding little scientific insight to a complicated and emerging area of biology", a representative wrote in an email to New Scientist.]

[ "It may be that resveratrol-like compounds are going to be therapeutically useful in people," Kaeberlein says.]

http://www.newscientist.com/article/dn18396-stay-young-on-red-wine-drugs-think-again.html


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36. sgcox on January 15, 2010 8:18 PM writes...

I am just a bench scientist and not intimately familiar with regulation and legal issues of drug development. Still, the GSK "sirt1 activator" went into clinical trials, three phase I studies are completed. Several are in progress and one PhaseII is recruitng. Once again, I might be mistaken but Phase I purpose (one of several) is to determine the maximum tolerated dose. That means that some people in the higher dosage cohort must have experienced some dose limiting toxicity (hopefully not long lasting and not very severe).
Now, I understand that people sigh the concent form and are paid (some pitifull sum of money).
Yet, it is all done on the premise of the good faith and genuine attempt to develop a new medication.
But, as it becomes painfully clear, GSK knew it is all fake. Several papers have been published on the subject, and not just recent Pfizer and Amgen but also couple of academia papers exposing the dodgy assay well before the Sirtuis purchase. Still, GSK went ahead despite the objections from their own scientists . That means GSK, either without properly testing clinical candidates (according to the procedures of allarmingly contradictinng research studies) or filfully ignoring the data, deliberately cause people suffering without any clout of developing the genuine drug.
It all smells of a plain criminal act on the part of GSK management to me.

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37. Lazarus on January 15, 2010 9:47 PM writes...

Or it's all for show, they've had great success and only the politicians will live forever :)

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38. Anonymous on January 15, 2010 11:55 PM writes...

Nigel is absolutely right.
At the end of the day it is the physiology that matters and resveratrol increases lifespan in every animal tested while clearly benefiting in nearly all animal models of disease.

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39. Anonymous on January 16, 2010 12:16 AM writes...

The compounds were already in the clinic when the purchase went through. It is amazing some of the shit you see in phase I. Hell, even the pos elesclomol made in to phase III before people figured out it was killing patients.

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40. MTK on January 16, 2010 9:05 AM writes...

sgcox,

Probably a stretch to call it a criminal act.

a)whatever clinical plan they had and data to support that clinical plan were filed in a IND which the FDA obviously cleared.

b)although some earlier groups had published similar reports, the fact the Amgen and Pfizer went through with their own work and got it published after the clinical trials started would probably be defense enough that GSK was working in good faith.

c)whatever adverse effects were found in Phase I would have had to been predictable at the tested dosaages from the animal studies to rise to criminality, IMO, otherwise nearly every failed clinical trial could be considered criminal.

Now if GSK didn't provide pre-clinical data to the FDA that would have predicted the observed toxicity at the dosages used in the clinic, then yeah, it could be criminal. Otherwise, I don't see it.

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41. Jose on January 16, 2010 9:47 AM writes...

Wow, I was unfamiliar with elesclomol: a bis-(thiocarbonyl hydrazine amide) monstrosity?!?! it doesn't get much uglier than that and still get anywhere near humans.

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42. alig on January 16, 2010 10:27 AM writes...

Jose, Elesclomol was another brillant purchase by Moncef & Patrick over the objections of internal scientists. The Head of GSK's Oncology CEDD (not just some guy in the lab) objected to this purchase, but was overruled and it probably contributed to his firing. The boys up top don't like being disagreed with. At least this mistake only cost GSK ~$200 mil (+ a well respected oncologist).

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43. Anonymous on January 16, 2010 11:12 AM writes...

Alig@17's description of a diligence team that identified the problems but which was overruled by upper management is certainly not an uncommon scenario.

GSK was likely not the only potential buyer to whom Sirtris hawked their compounds so I would imagine there were other diligence teams who knew exactly what Sirtris had. Apparently in those organizations the recommendations were actually followed.

The eventual outcome looks to be a loss for GSK. There is the possibility that GSK will get lucky either through other unreported pharmacology with the Sirtris compounds or by developing genuine sirtuin activators based on Sirtris' IP though this seems unlikely.

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44. TFox on January 16, 2010 12:42 PM writes...

Nigel@34, Anonymous@37:
Absolutely, whether it works in vivo is the critical question. But does it? I remember when I heard Sinclair talk there were a number of lines of evidence, all making a beautifully coherent story. Have these results been reproduced by others? Pfizer tried in mouse, and got nothing.

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45. Samuel Adams on January 16, 2010 1:07 PM writes...

Last night, I had a few beers and looked up the structure of elesclomol. I had to ask myself - how many beers would it take to convince a leadership team to put that compound into development?

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46. Anonymous on January 16, 2010 4:13 PM writes...

just because a compound *looks* ugly (elesclomol) it doesn't necessarily mean it's going to be crap. After all, Metformin is about as ugly as they come....

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47. milkshake on January 16, 2010 4:55 PM writes...

elesclomol: for a cancer drug its not that bad - compare it with the classical chemo agents -alkylators from the mustard gas category, cis-platinum or mitoxanthrone.

I think you would have a difficulty developing something like this as a arthritis or Parkinson medication because of the safety, but then again, many popular soda brands contain brominated vegetable oil and a polychlorinated carbohydrate (Splenda) as a flavoring agents.

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48. ex-GSK2 on January 16, 2010 5:39 PM writes...

Derek, Here's another scenario based on my eye witness account: There is a competition for the next head of R&D at GSK leading up to Tachi Yamada's move to the Gates Foundation. Moncef S (business development)is competing with Peter G (SVP Discovery Research) for the role. Moncef convinces the board that externalizing R&D will not only lower costs but it will increase quality - just look at all the great biotech drugs. Peter G sticks to his vision of 'industrializing' drug discovery with HTS, high-throughput chemistry and biology to lower the cost of testing hypotheses in humans, believing that one way through our lack of understanding of human biology is to do more, smart experiments. For lots of reasons, political and business, Moncef wins the job on his platform of "Everyone elses scientists are smarter than ours" and proceeds to throw R&D into an endless series of re-organizations starting with purging all of Peter G's direct reports and destroying Peter's part of the company - where $$$$$ had been invested during the previous regime.

Moncef could not resist Sirtris because it fits his vision of reality and what he sold the board to get his job - the purchase was self-affirming. He probably also enjoyed being able to roll-over the GSK due diligence team (who had similar data to what was published by Amgen) because their objections were counter to the 'big picture' judgement he had already reached. The 50% reduction in R&D scientists at GSK under his 'leadership' give him more $$$ to continue the fantasy. He also has no small molecule DD experience (immunologist - vaccine business - business development) and his attitude toward chemists is contemptuous at best.

Once started down this road, you can't get to fussy about the quality of the deals, or you won't make any. Competition for anything that doesn't reek of decay is fierce.

Internal innovation takes courage, persevervance and belief in people. It also takes stability. No doubt Moncef will be nestled into a golden retirement long before his strategy either succeeds or fails and the next 'leader' with the simple solution will be having a go at the helm. No board wants to hear that drug discovery is just HARD and it takes time - longer than any manager, good or bad gets to stick around.

There is a thin line between being a visionary and being delusional - I think following the data is the only way to stay on the right side of the line in drug discovery.

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49. cancer_man on January 16, 2010 7:11 PM writes...

There are still pieces that don't make sense to me. If Sinclair and Westphal knew that nothing important was likely to come out of Sitris *after* they got their $8 million and $25 million, wouldn't you think they would want to avoid 60 Minutes last January? Or if interviewed stick much closer with the SRT501 diabetes results and not add "We think this has the potential to change healthcare", etc.

I also remember Sinclair acknowledging that SIRT1 may not be the pathway last fall, yet around the same time he said a series of papers will be published in coming months (from August 2009) and that the "results are promising."

Maybe they don't have much or have nothing, but it's interesting that the Pfizer study confirmed what was already suspected and released right before the new set of sitris papers is expected to be released.

Betting on scenerio A3a unless nothing materializes by spring.

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50. me too! on January 17, 2010 6:32 PM writes...

@27, CellBio.

Same experience. Did a quick read of the knowledge around the target that one of the biotechs we were evaluating was aiming for, and felt that the target wasn't clear, and the area messy. Made my recommendation to the uppers, and have never been asked to evaluate again. Heh.

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51. befuddled on January 18, 2010 8:48 AM writes...

Just to play devil's advocate, there are reasons for an exec to be skeptical of some of the advice given by the scientists on the inside. After all, if you make some big acquisition, it will probably mean decreasing their budgets, their responsibilities, and perhaps, their jobs.

And it is to a large extent the failure of internal drug development that has made such acquisitions attractive.

Which makes it a difficult position for an exec who, even if he has a scientific background, can't possibly be current with all the relevant issues.

Now, that being said, making hard decisions well is why they get the big bucks. And by and large, they don't appear to be earning them.

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52. exGSK2 on January 18, 2010 10:28 AM writes...

befuddled - take a look at: Munos, B., Lessons from 60 years of pharmaceutical innovation. Nat Rev Drug Discov 2009, 8 (12), 959-68.

The 'problem' with drug discovery is that no one is very good at it - big pharma is about as successful as biotech - not less.

Actually, drug discovery does work - it is just less successful than needed to achieve the >10% growth per year that the market wants to see and the products end up being pretty expensive to recover the cost of attrition.

Having seen a few drugs go from my lab to the market, the miracle is that any of them survived the 3-4 regimes (heads of R&D, name of the company etc...) that came & went during the 10-15 years of the discovery to market life-cycle of a project. There is a flaw in the system when the people who set the long-term strategy have a half-lfe much less than that of a single project. How does an organization learn to do better? Answer - it doesn't, any 'new' idea displaces the previous hyperbolic panacea and the scientists who actually know drug discovery labor on at the coal-face and hope the most recent 'solution' doesn't screw-up their project.

Do I hear an 'amen'?

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53. Anonymous on January 18, 2010 12:40 PM writes...

Maybe there should be another scenario to consider: GSK also bought Genelabs for (a paltry) $57 million not too long after buying Sirtris. Genelabs had DHEA in phase III for lupus at the time. (And what a gem that was!) Both reversetrol and DHEA are available OTC at your neighborhood GNC store. Maybe Moncef and Patrick have invested heavily in Ares Management which owns GNC or, perhaps, they think that medicinal chemists are superfluous and everything can just be bought at the GNC. I'm sure Witty wouldn't know the difference.

Actually, in their defense, GSK announced in the press release that they were buying Genelabs for their Hep C expertise, not to get DHEA. Funny though, I couldn't find any Hep C development programs on their website over a year later. And, I seem to recall some recent reports of their competitors compounds currently going into phase III that had eliminated said virus in (infected) patients. Hmmmm.

I hope Moncef and Patrick have a plan on how to market their drug, which is apparently still in the preclinical stage, to patients who have already been cured. Or maybe reversetrol can treat Hep C and DHEA will extend life? Or maybe I'm just failing to grasp something that can only be gleaned by those bold enough to piss away $767 million bucks. I wonder if their bonuses were bigger than the A.I.G. execs.

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54. Hap on January 19, 2010 10:25 AM writes...

Except, GSK can't control resveratrol's use, and if you don't know what it's doing (the assays that Sirtuin specializes in don't work, as claimed by both Amgen and Pfizer), you can't make analogs of it that you could sell and patent (you can't even start to design or test them). If you don't understand anything other than resveratrol does something good, then what in the hell did GSK pay $720M for?

I don't have to buy resveratrol from GNC (and considering their "supplement shill" shtick, I don't know what I would buy from them) and while it might help them if resveratrol does something good, I don't think anyone would make enough money from them to make this deal not suck.

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55. David on January 19, 2010 2:03 PM writes...

Here's something I don't understand about development programs for resveratrol analogues: How can you ever run a clinical trial? You'd need to ensure that the placebo group isn't getting a therapeutic dose of resveratrol from other places. Would you restrict entry to patients who don't drink wine and don't eat grape products? It's fine if a chemist can make a compound marginally better than the naturally ocurring one, but what if it's not feasible to conduct a definitive trial?

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56. Dave_n on January 19, 2010 3:30 PM writes...

Re GSK's NP groups. The first removal of the then SK NP group was in 1985 when the antibiotic groups were fired, followed later by removal of the antitumor group that still did a little NP work. This was in the SKF and SKB era. Then the Glaxo side disposed of their group as MerLion in Singapore and GSK now have nothing. I should know the dates quite ell, as I was part of the 1985 crew. Amusingly (sarcasm) SKF almost purchased Glaxo in the very early 1980s as the H2 antagonists were just coming on line and Glaxo had a competitor but was on its beam ends at that time. Often wonder how things would have transpired in later years

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57. Dave_n on January 19, 2010 3:31 PM writes...

Re GSK's NP groups. The first removal of the then SK NP group was in 1985 when the antibiotic groups were fired, followed later by removal of the antitumor group that still did a little NP work. This was in the SKF and SKB era. Then the Glaxo side disposed of their group as MerLion in Singapore and GSK now have nothing. I should know the dates quite ell, as I was part of the 1985 crew. Amusingly (sarcasm) SKF almost purchased Glaxo in the very early 1980s as the H2 antagonists were just coming on line and Glaxo had a competitor but was on its beam ends at that time. Often wonder how things would have transpired in later years

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58. anon on January 30, 2010 4:07 PM writes...

It seems to me that the timeline proves that this was fraud by Sirtris.

The two JBC papers showing that SIRT1 activation by resveratrol was an assay artifact were published in 2005. But the Nature paper describing the "next generation" Sirtris compounds (discovered using the same assay) wasn't published until 2007, and GSK did not buy Sirtris until 2008. It is inconceivable that Sirtris scientists were not highly aware of the JBC papers...after all, resveratrol was their clinical candidate. So they must have tried other assays and discovered that their new compounds were also false positives. But they published the compounds in Nature anyway and then sold the company for $720 million.

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59. sgcox on February 15, 2010 8:00 AM writes...

Good, now this discussion makes the Nat. Chem. Biol. news !
http://www.nature.com/nchembio/journal/v6/n3/pdf/nchembio.330.pdf

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60. CynthiaG on August 19, 2010 10:55 AM writes...

Hi, Derek. Please forgive the belated comment, but I am wondering if, in light of the recent J. Biol. Chem. article (1), you intend to follow up on this story. Even based on a quick skim, the article is impressive, which should be expected with Ross, an excellent enzymologist, leading the charge. I will note that enzyme activation is not always so easily grasped by non-biochemists, and especially non-enzymologists, so the earlier results proferred by Pfizer et al. may very well be the result of less than optimal experimental design and interpretation.

(1) Han Dai et al., "SIRT1 activation by small molecules - kinetic and biophysical evidence for direct interaction of enzyme and activator. J Biol Chem in press; see also GlaxoSmithKline strikes back over anti-ageing pills.

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61. anonymous on May 18, 2011 11:23 PM writes...

This is a belated comment but I agree with CynthiaG.
After hearing David Sinclair give his side of the story during Barshop Institute for Longevity and Aging Studies:
2010 Barshop Institute student days lecture, They looked at the Pfizer et al stance and proved them wrong.

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