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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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April 28, 2010

Sirtris's Compounds: Everyone Agrees?

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Posted by Derek

Christoph Westphal gave what by all accounts was a very interesting talk at the recent Bio-IT conference. And considering his track record in company formation, he's well worth listening to. But concerning the recent controversy over the compounds and results from his most recent success (Sirtris), I found this part of his speech. . .well, interesting:

"There’s a debate in the academic world,” Westphal acknowledged. “We don’t know the specific molecular mechanism of why you need a specific substrate on the in vitro screen to find Sirt1 activators. Pfizer, Amgen, GSK, Sirtris, everyone in academia agrees on that. Then the question is: Is the mechanism direct on SIRT1 or indirect on SIRT1? Everyone in the field agrees our molecules have beneficial effects in animals, and I hope they will in man soon. The specifics of the mechanism are under debate. This kind of thing will be debated for ten years.”

Emphasis mine. And I emphasize that part because Pfizer specifically tested one of the highlighted Sirtris compounds, SRT1720, and was unable to reproduce the in vivo effects. So no, I wouldn't say that "everyone agrees" on this point. Not quite.

Westphal says that there's another paper in press that might be able to clear things up a bit, so we'll see what that one has to say. And he's right that the clinical results are what will really settle these questions - but we're going to have to wait a while for those. For now, agreement on a lot of key points remains hard to come by. . .

Comments (36) + TrackBacks (0) | Category: Aging and Lifespan | Business and Markets


COMMENTS

1. lewis robinson on April 28, 2010 8:57 AM writes...

People have been proposing this sort of the for 20+ years. Here's one from the recent past.

[ Proc. Natl. Acad. Sci. vol. 101 pp. 14091 - 14096 '04 ] Human cells can make morphine and other opiate alkaloids. They were identified by gas chromatography/tandem mass sepctroscopy. It has been thought that although opiates can be found in the body (at nanoMolar concentrations) they were of dietary origin. Not so, a neuroblastoma cell line grown in an18-Oxygen isotope atmosphere had morphine found by the same technique with 4 more mass units (there are 3 oxygens in morphine so it should have been 6 units higher). Nonetheless, a fairly convincing demonstration of biosynthetic capacity.

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2. sgcox on April 28, 2010 9:25 AM writes...

"...He announced his resignation as Sirtris CEO the very next day..."

Don't think he actually has much trust in it.

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3. Hap on April 28, 2010 9:32 AM writes...

It's not all that encouraging to see that they either don't care what other people's responses are (they can't be right) or are being dishonest (since it's plainly false).

I also don't really understand what the point of the money spent on Sirtris is if you have no idea whether the compounds act by sirtuin-mediated pathways - if that's the case, Sirtris's IP didn't get GSK much that they couldn't have gotten without them and with the $720M that they spent buying Sirtris (though I'd guess the latter explains the former - that would be a conclusion the Sirtris people would prefer GSK not make).

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4. Will on April 28, 2010 9:54 AM writes...

I saw the new CEO of Sirtus George Vlasuk present at the Arizona SBS conference about two weeks ago.

His talk was basically a point by point rebuttal to the Pfizer JBC paper.

By the look of it- the Sirtus group retrospectively went back and found a peptide substrate that worked with the Sirtus molecules (albeit very weakly).

This was obviously a non-physiological substrate (6 or 7 mer).

Therefore they claim that their molecules are Sirt activators- and Pfizer, Amgen, etc.. don't understand Sirt biology the way that Sirtus does.

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5. anon the II on April 28, 2010 10:04 AM writes...

This is so damned depressing. The unfortunate truth is that the "Westphal"'s are the successful people in this industry. And the money that these guys are sucking out of the industry could employ a whole bunch of talented, hard-working and honest scientists for a long time. I think I've said it here before that once DTC moved the industry from being science-dominated to marketing-dominated, our fate was sealed. The successful people are the ones who can spin and spin and spin. It's just a game to them.

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6. MTK on April 29, 2010 1:33 PM writes...

Anon the II,

Let me play the contrarian here. Westphal is a success story with no sarcasm. And the capital generated was being used to employ people.

Sirtris stockholders just didn't take the money, close up shop, and run to the islands. It was used to employ people and conduct research. The money that the VC's and initial investors make will be put into new ventures and companies that will also employ people. Sure some of it will go to vacation homes in Hamptons, but the majority of it will go back into the system in some form.

I wouldn't be so quick to dismiss the Westphals of the world.

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7. Hap on April 29, 2010 1:55 PM writes...

But it could have been used for better research too, both from GSK and from the companies that would have been funded instead.

If you can't trust their research, why can you trust their investments?

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8. MTK on April 29, 2010 5:26 PM writes...

Perhaps, Hap, perhaps.

Westphal's words and the title of the post remind me of a song

"Cause everybody knows, that nobody really knows,
just how to make it work or how to ease the hurt.
We've heard it all before, that everybody knows
how to make it right, I wish we gave it one more try
One more try
Cause everybody knows, but nobody really knows."

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9. Hap on April 29, 2010 6:03 PM writes...

Yeah, that's about right. Alternatively,

"When a distinguished but elderly scientist states that something is possible, he is almost certainly right. When he states that something is impossible, he is probably wrong."

The less-than-refeshing honesty isn't encouraging though.

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10. Ray on April 29, 2010 6:41 PM writes...

Anybody on this board have a view on taking resveratrol as a supplement? If so please share. I've been taking 350mg since I read about Sirtris. Its since become a craze and my doubts are increasing. This story doesn't help.

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11. Open Eyes on April 29, 2010 7:38 PM writes...

To #6 MTK:

You need to get the picture right and your total facts straight. It was acknowledged internally that part of GSK's restructuring in 2008 / 2009 involved fired dozens of staff in R&D to create funds to help pay for the Sirtris deal. Almost certainly, more positions were let go by GSK to fund the deal than are being employed in Cambridge.

For many inside GSK seeing this very sad drama play out in slow motion has been demoralizing. Interactions with staff from other sites with those in Cambridge remain difficult, data that has been stated as available by Sirtris has turned out to be non-existent, attitudes in Cambridge remain defensive. Many staff at the core GSK R&D sites want to have nothing to do with the Sirtis staff, their compounds, or their activities, seeing the entire scheme as professionally, scientifically, & ethically reprehensible.

What is most unfortunate is that many inside R&D in GSK who remain interested in trying to make new drugs, who cooperate and work toward group goals & objectives, have been treated as pariahs in favor of those who talk the talk, but don't know what is involved to walk the walk. Sirtris is held by management all the way to Witty as the prototype of the future of drug discovery. In cases where well respected staff have spoken with balanced perspective that may have not completely absorbed the Sirtis centric view, staff positions have been rapidly replaced by Westphal supporters or eliminated.

Adding insult to injury, Westphal was recently appointed to head SR-One, the company's long running venture group, while at the same time continuing as a partner of Longwood Founders Fund, a privately held venture capital group. The two hats clearly are a confict of interest in being able to have impartial evaluations of funding opportunities for the best interest of GSK vs. further padding the pockets of C. Westphal and his other VC partners.

Those like Westphal are no different from the greedy, arrogant, self-abosrbed, unreflective members of investment firms such as Goldman. Their ultimate goal is simply to re-arrange paper in moving money from wherever they can get it into their pockets.

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12. MTK on April 30, 2010 7:07 AM writes...

#11

Did Sirtris have scientists employed? Did they not raise money from investors and VC's to pay those scientists? Now that the investors and VC's have gotten a return on their investment will that money not be reinvested in new ventures employing new scientists? Did not GSK cut the jobs within GSK, because it certainly wasn't Sirtris.

I have no idea if the net outcome in jobs is negative or positive and neither do you, because that money will go into other future ventures that will hire people.

You know what gets me. People who blame the Westphal's of the world for their woes. People who characterize a man they probably have never met and don't know in the least as arrogant, greedy, self-absorbed, and unreflective. They have no idea about the character of the human being. They blame him for job losses, when the reality is he's created jobs. GSK is the one that cut the jobs, not Sirtris.

Don't like his ilk? Fine. Since you are clearly a better human being than westphal, then live up to your own higher principles and not work for any company that has been funded by VC's or started by such greedy, arrogant, self-absorbed people who would (gasp!) look to get a return on their investment. Good luck in your consulting career where you'll add so much more value.

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13. MTK on April 30, 2010 7:40 AM writes...

And another thing #11...

All your complaints are essentially with GSK management as far as I can tell. So who do you take out on? The Sirtris folks, of course. You refuse to cooperate with them. You stamp your feet, hold your breath, and don't want to have anything to do "with the Sirtis staff, their compounds, or their activities".

Bravo, sir. That'll show 'em.

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14. Anonymous on April 30, 2010 7:59 AM writes...

MTK, do you approve of boiler stock rooms or Ponzi schemes ?
Sirtris folk are not that different. Selling assay artifacts (knownly) is a fraud IMHO

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15. Anonymous on April 30, 2010 8:18 AM writes...

MTK:

You've missed the whole point. The criticism of Sirtris is based on the fact that their drugs in development are pure snake-oil. The science supporting their candidates is so sloppy and has been so thoroughly refuted in the published literature, it is impossible to continue to promote this stuff without willfully rejecting reality.

It doesn't matter how many people Sirtris employs or how the VC's invest their profits. If research money spent at Sirtris is going toward supporting something that is a total scientific fraud, then this is a deadweight loss for society. If productive resources at GSK were redirected to Sirtris to further advance this fraud, then that is a further loss to society.

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16. noname on April 30, 2010 8:43 AM writes...

Knownly?

The Sirtris scientists are just like the rest of us. They worked hard, they used their brains, they acted as a team, and they solved the scientific questions they were asked to solve. In fact, they probably did so more efficiently than GSK scientists could have, because of the intrinsic efficiencies of small organizations. That efficiency is what Witty et al are touting, "doing more with less."

Unfortunately, while the R&D model was right, the science was wrong. I don't know exactly what was said in the diligence meetings but people on both sides of the deal seemed to have dropped the ball. Someone at the upper levels of Sirtris should have constantly been playing the contrarian, questioning everything. Likewise at GSK. As far as Westphal, I'm guessing he formed a narrative of success and excitement that noone wanted to puncture with data. On the one hand it is the role of the CEO to cheerlead the troops, keep them positive, and drive them towards the value point. On the other hand, they do a disservice if the vision is simply profit based on sloppy science.

In the end, Westphal is wounded. Particularly if the SRT compounds crash and burnm I predict he is out of GSK before Moncef. He will certainly not survive a change in R&D head unless something big happens with the compounds. Then you have to wonder, will the next start-up want him as CEO, despite the track record, with a sullied reputation in the eyes of the customer big pharma? Likewise will VCs want him as their gold sniffer, given that big pharma will view his discoveries with suspicion.

He probably will just end up on the beach. A bad ending to this story leaves him nowhere else to go.

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17. Anonymous on April 30, 2010 9:02 AM writes...

"He probably will just end up on the beach. A bad ending to this story leaves him nowhere else to go."

Not at all... Sirtris people are climbing the GSK hierarchy, and this AFTER the papers exposing the sloppiness of Sirtris biology and chemistry.

@MTK:
all criticism here is about great success based on dubious science (while the GSK guys that developed Tykerb are out of the game).

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18. Hap on April 30, 2010 9:26 AM writes...

Perhaps this is another example of "Bad money chases out good."

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19. Anon on April 30, 2010 10:03 AM writes...

MTK:

It would be one thing if Sirtis would still be standing alone to prove hypotheses and claims. But when others were told they had to leave jobs at GSK to pay for the deal, when the big bucks needed to conduct clinical trials as the ultimate determiner to resolve the debate now comes from GSK, the two are no longer independent.

With multiple examples where those doing experiments at Sirtris repeatedly having refused to show GSKers results from experiments, when data that was claimed to exist later turned out not to have been determined and only to be divulged after much harranging, the scientists have proven themselves to be equally culpable, sad as that is to say. Fair or not, from the outside looking in, everyone becomes tainted since it is impossible to know who is ever telling the truth. By the way, it seems that more recent disclosures seem coincident upon departure of original Sirtris scientists and those assuming responsibilities being more forthcoming.

Don't get this wrong. I am a big supporter of biotechs, startups, VC funding and understand concepts of "exit strategies" to get return of investment. But, not to the extent of endlessly promoting & defending poor science for the purpose of ego & personal image.

#16: Only if it were so easy to isolate the Westphal's of the world. Take a look at the members of the board along with the VCs providing financial backing to Concert Pharmaceuticals.

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20. Petros on April 30, 2010 11:14 AM writes...

Looking at some of the stories on sirtris I googled MIchelle Dipp, founder and now VP for GSK's CEDD for external discovery.

She is 33 and her only experience of industry has been at Sirtris!

http://www.xconomy.com/boston/2010/04/22/sirtris-vet-michelle-dipp-takes-over-key-role-at-glaxo-as-westphal-returns-to-vc/

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21. MTK on April 30, 2010 11:54 AM writes...

#15,

I'm not missing the whole point at all. Here's the story as put out by #11. a) GSK buys Sirtris for $720M. b) GSK lays off people to afford Sirtris. c)Sirtris' science stinks, d) Sirtris CEO is an arrogant, greedy, self-absorbed and unreflective, e)#11 refuses to play ball with new colleagues who came from Sirtris because they're to blame for layoffs.

This, of course, completely fails to acknowledge that GSK signed an industry leading 67 deals in 08-09 alone. I don't know the cost of all these deals, along with more recent ones, but Synta, Concert, NanoBio, Targacept, Anacora, and Isis alone cost $220M in upfront payments. that doesn't include future milestone payments which could be in the billions. (And no those milestones don't start at FDA approval.) That's just for 10% of the deals they have made. The tip of the iceberg.

Sirtris, regardless of whether they sold snake oil or not, is not the reason for the layoffs at GSK, merely symptomatic. They are one, maybe the single priciest one to date, but still just one of dozens of deals made by GSK management, all of which have to be paid for. Sirtris in itself did not lead to the layoffs and reorganization despite characterizations to the contrary.

So why did GSK management feel the need to turn so decidedly to the outside in general, not just to Sirtris?

I'm sure y'all have your opinions, but let me give you one incorrect answer. Because some arrogant, greedy, self-absorbed, unreflective SOB named Westphal hoodwinked GSK costing me my job.

Like it or not, the Westphals of the world are right now the primary hirers of scientists. I would not be so rash as to demonize them nor shun earnest and sincere people working for them simply due to association. You may soon be one of them.

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22. Hap on April 30, 2010 1:18 PM writes...

To buy snake oil, doesn't someone have to sell it? The fact that people at GSK were not diligent enough (or had other incentives) to fully vet the deal doesn't excuse selling something you either don't have sufficient evidence to claim works or know isn't what you claim. And none of this excuses either Sirtris's or GSK's management not being able to tell the truth after the fact, and hosing the investors and others in GSK.

People who drive the formation of companies aren't bad in themselves - they're driven by the same things other people are, and help to create the value everyone wants. Being dishonest in the service of your ends, though, is supposed to be frowned upon, whether individual, small company, or big company. The fact that lots of money is generated by the dishonesty doesn't make it any less wrong, or any less destructive.

There might be something in the sirtuin pathway of use, and hence a reason for the company and employees to still believe in their goals. It's never right to be dishonest to serve that end. When people do so, it makes it appear less likely that the people leading the company actually believe those goals (and thus that the company can actually do something useful towards that end). It is counterproductive on lots of levels - it tells your employees that they should wonder whether management has any faith in them or their mission, makes their new employers look bad, and angers their investors. A fine bit of work.

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23. MTK on April 30, 2010 2:26 PM writes...

Hap,

I agree wholeheartedly.

But...

Do we know that they are being intentionally dishonest? Being shoddy and being fraudalent are completely different things. One can have honest differences in opinion and also honestly come to different conclusions based on factual data. Or one can have misguided faith, but sincerely believe in it. All of these are mistakes. We all make them. That doesn't make one a bad person, that makes one human.

I could be wrong, but I don't see the whole sirtuin story as out and out dishonesty. I view it, so far, as faulty conclusions based on sketchy experimentation.

My beef here is with wholesale condemnation of a person's character, because folks are blaming the Sirtris deal for GSK layoffs, which let's be honest, is exactly what is happening. Of course, this ignores all the other deals including one for Reliant which GSK paid $1.65B.

For all I know, Christoph Westphal may be a bad person. Or he might be the greatest guy around. I have no idea. I've never met the man.

Here's what I do know. He has co-founded four companies which currently employ about 500 people directly. He's provided a healthy return to investors who have undoubtedly used the funds in other companies employing other people. He's still working in a VC capacity providing others with the necessary capital to get their companies going and employing people. He could easily just be sitting back and doing nothing.

Does this make him a great guy? No. But it does make him and people like him important to the future of our industry.

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24. Anon on April 30, 2010 3:15 PM writes...

MTK:

Ahhhh ....

it is all now so clear, so very simple .....

people who deliberately defend poor science but make a bundle at the expense of many innocent others should be honored and respected .....

yes, so very very clear .....

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25. Hap on April 30, 2010 3:37 PM writes...

I don't know how honest Westphal has been, or rather how honest Sirtris has been (and how much that can be mapped onto any one person in particular). Saying that "Everyone in the field agrees that our compounds have beneficial effects in animals" is clearly wrong - Pfizer and Amgen have said so in print. P and A could be wrong, but it's obvious they don't agree. He could have said something else - "Our data shows that these compunds work in animals, and we believe that further research and clinical data will bear that out", for example. There is a utility to supposing unanimity, but if isn't true, well, then you do the best you can with what you have.

A lot of the complaints, though, probably don't come on to Westphal so much as Sirtris in general - the problems with the assays seem unresolved and highly problematic (if you have to use a fluorescent marker in NMR assays, as someone noted in one of the previous posts, something's probably wrong, or there needs to be a good explanation). That could be sloppiness for Sirtris or it could be wrong (there might be something in P or A's work that is incorrect). The problem, and what makes Sirtris look dishonest, is that the statements of people responding to those issues rely on either insult (you don't know what you have - well, if you published better procedures, so that we could, that might be a defensible counterargument, but...) or wish fulfillment (no, the contrary data is wrong, or isn't what it says). Mistakes people can understand, but spin, not as much. Spin makes people think that what you've got is less than you're saying (which is its intent), and is not as forgivable. That may be necessary for investors, but in itself, that's a problem.

If investing in biotech/small companies becomes a con game, dependent on how well companies can fool people or keep them in the dark, who does that benefit? It doesn't benefit small companies unless they're willing to be dishonest (the supplement game). It doesn't benefit the big companies that might want to purchase them, because it may cost them significant money to get to the point where they can even look at real data to see what's real and what's spin. It doesn't benefit investors, because most of them will get taken. It doesn't benefit employees, because if spin, and not substance, is what matters, then their fates have nothing to do with what they can actually do for their employer, since it may not care. It doesn't likely benefit people in general, because there's little reason for companies to produce actual products, or at least less of one than under a more honest system. Overall, the likely outcomes seem bad for almost everyone except the dishonest.

Permalink to Comment

26. MTK on April 30, 2010 3:53 PM writes...

#24,

where did I say he should be honored and respected? I said he was important to the industry. I made it quite clear that I make no judgments about him as a person.

As for making a bundle at the expense of the innocent...who exactly are these innocents that would have retained their jobs if not for Sirtris?

As I pointed out earlier, GSK made 67 deals in two years. Sirtris was one. It even wasn't the biggest one, that would be Reliant at $1.65B. Six other deals in my simple search revealed $220M more in upfront payments. That's a $36mil/deal average. That leaves 60 or so unaccounted. Let's say those averaged a paltry $10mil in upfront payments, that means a conservative estimate of $2.4B in deals outside of Sirtris. Now let's throw in the revenue lost from Avandia sales. In 2006 Avandia sold $2.5B, in 2009 $1.2B. Over the last three years it's about $2.5B in revenue losses even if sales had stayed static vs. 2006.

And did you not happen to see that the every other Big Pharma company has had massive layoffs also?

Oh, I see. Despite losing billions in Avandia revenue, spending at least another $2.4B on dozens of other deals, and the fact that every other Big Pharma was la