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Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: Twitter: Dereklowe

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August 12, 2010

Resveratrol (SRT501): Buy Now - Why Wait?

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Posted by Derek

Update - see below for more on this story. GSK has reacted quickly. . .

Now this seems rather odd. According to Xconomy, two former Sirtris higher-ups have formed a nonprofit foundation which is selling resveratrol online.

Michelle Dipp, a Sirtris-turned-Glaxo executive, confirmed that the nonprofit that she and former Sirtris CEO Christoph Westphal co-founded last year has started online sales of resveratrol. Dipp leads the effort on the off hours when she isn’t doing her main job as senior vice president of Glaxo’s Center of Excellence for External Drug Discovery.

While the group is charging $540 for a one-year supply of resveratrol, Dipp says that the nonprofit is selling the supplements for cost and is not profiting from the sales.

And thanks to Hatch-Waxman, since this is being offered as a "dietary supplement", hey, it can go straight into people - people with $540, anyway:

To be clear, this resveratrol operation is a volunteer effort that Dipp and Westphal do on the side. Both are still employees of Glaxo, and they have also started a Boston venture firm called Longwood Founders Fund with fellow Sirtris co-founder Rich Aldrich.

“Our main business is brining new drugs to patients through our work at Longwood and (Glaxo),” says Dipp, who is president of the Healthy Lifespan Institute. “But there was so much demand for (resveratrol).”

I really don't know what to make of this. This formulation of resveratrol would appear to be basically SRT501, which has been involved in a number of clinical trials (and unexpectedly dropped out of one not too long ago). I can't recall another case where an investigational drug has also been sold as a dietary supplement, by some of the same people, who are working both for the company funding the trials and for a nonprofit foundation. I mean, what if GSK/Sirtris find a clinically relevant use for resveratrol? Why buy it from them if you can get it at cost? Or would all that change if SRT501 gets FDA approval? Makes a person's head hurt, it does. . .

Update - GSK has now asked Dipp and Westphal to resign from their institute, saying that they didn't realize that they were selling resveratrol. That didn't take long!

Comments (69) + TrackBacks (0) | Category: Aging and Lifespan | Clinical Trials


1. PharmaHeretic on August 12, 2010 12:23 PM writes...

Snake oil.. reloaded. But after fiascoes such as- COX-2 inhibitors, Ezetimibe, Olanzapine and other atypicals, Varenicline, SSRIs (paroxetine).. the pharma industry has also lost its credibility.

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2. processchemist on August 12, 2010 12:28 PM writes...


maybe I'm wrong, but I remember some FDA directive or US law that says that as soon the ingredient of a dietary supplement enters clinical trials can't be no more used as nutraceutical. Can you confirm it?

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3. milkshake on August 12, 2010 12:44 PM writes...

I suppose the next turn in the crackpot saga will be a late night advert explaining that big pharma and big government are conspiring to keep this revolutionary research about a natural healing power away from the patients

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4. processchemist on August 12, 2010 1:02 PM writes...

Having worked (during better times) on projects for a company entirely focused on natural products and semisynthetic derivatives, I witnessed to the death of a project with a natural antocyanoside as candidate (indication: support to chemiotherapies), then tried (with good results) their formulation for sore throath, largely based on antocyans (I'm still waiting for his approval, it was fantastic).
But the resveratrol saga, with this new development, leaves me perplexed, to use mild terms.

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5. Terry on August 12, 2010 1:20 PM writes...

This is an indication to me that this resveratrol thing has legs. Why on earth would two very respected scientists put their reputations on the line if they truly did not believe the resveratrol and SIRT1 activation is for real.

This is good news. Many very good human resveratrol studies have been rolling out recently with more to follow.

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6. John on August 12, 2010 1:50 PM writes...

I believe some of the people involved in omega-3 trials are also pushing the same products on the side. Presumably they'd slap a fancy label on the side if it ever reached NDA.

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7. john on August 12, 2010 1:51 PM writes...

A recent article came out from a group at Kansas which demonstrated low doses of resveratrol were driving cancer cell growth in some cell lines. These doses were much lower than those needed to see the inhibitory effects, it was specific to cell lines and acted through stimulation of the NF-KB pathways. The authors were surprised by the result but I thought the data looked good at least no red flags came up, though I am trained as a chemist.
Reference is Mol Carcinog 2010 49(8)750-759

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8. john on August 12, 2010 1:53 PM writes...

A recent article came out from a group at Kansas which demonstrated low doses of resveratrol were driving cancer cell growth in some cell lines. These doses were much lower than those needed to see the inhibitory effects, it was specific to cell lines and acted through stimulation of the NF-KB pathways. The authors were surprised by the result but I thought the data looked good at least no red flags came up, though I am trained as a chemist.
Reference is Mol Carcinog 2010 49(8)750-759

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9. Henning Makholm on August 12, 2010 2:14 PM writes...

processchemist: "maybe I'm wrong, but I remember some FDA directive or US law that says that as soon the ingredient of a dietary supplement enters clinical trials can't be no more used as nutraceutical."

Try googling for "clinical trial" "vitamin C". Based on your result, what does your theory predict about the legality of selling vitamin C as a dietary supplement?

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10. LAM on August 12, 2010 2:31 PM writes...

The conflict of interest of the former Sirtris executives, now GSK senior managers, is expanding. They all should be summarily fired from GSK immediately. Letting them stay in their GSK positions gives us all insight into GSK's current management style and amazing ability to continue to misfocus.

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11. Skeptic on August 12, 2010 2:41 PM writes...

"...selling resveratrol online"

Makes you wonder about all those ex-med chems taking on huge education loans so they can get those hot protected jobs in pharmacy and regulatory affairs. Add on the coming VAT's and I think bankrupt Grandma is going to give up the fascinating cell biology discussions with the local pharmacist and go with the cheaper product from the underground operators.

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12. Virgil on August 12, 2010 3:29 PM writes...

Critical distinction to be made... Are they selling resveratrol (as the website claims), or are they selling SRT501? The latter is not resveratrol but some weird formulation of it (to increase bioavailabilty IIRC). Thus, they can continue to sell resveratrol because this is not the same composition-of-matter that's in the clinical trials and covered by glaxo/sirtris patents. In the same way they can continue to study SRT501 in clinical trials because presumably they convinced someone at the FDA that it's a different entity to the over-the-counter nutriceutical.

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13. Terry on August 12, 2010 3:59 PM writes...

They are selling micronized resveratrol. I think Ms. Dipp was not telling the truthiness.

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14. Anonymous on August 12, 2010 5:02 PM writes...

@Derek - "I mean, what if GSK/Sirtris find a clinically relevant use for resveratrol?"

I'm just dying here! Thanks so much for the laugh! After yesterday's post on new job prospects for chemists, I needed one. That was a joke right?

She's in charge of external drug discovery at GSK AND The Healthy Lifespan Institute? You can't pay for irony like this.

Dr. Dipp: You are the weakest link! Goodbye.

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15. AR on August 12, 2010 5:57 PM writes...

Storms ahead for resveratrol? The compound is plenty toxic to hepatocytes and other cell types. Perhaps this will be the final straw that pushes the FDA to start regulating nutritional supplements when enough resveratrol popping consumers present with fulminate hepatitis.

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16. TFox on August 12, 2010 6:20 PM writes...

Sounds expensive. 30 seconds on Froogle finds products with the same specs (30 250mg capsules) at less than half the price per bottle. I guess it's the "completely synthetic process" that makes the difference. I doubt that's a benefit, though, most consumers in the health supplement market seem to like the word "natural". China price for the bulk product, extracted from natural sources, might be 10x lower -- I got a quote at < $600/kg when I was curious a couple years ago, compared to $6/g from this outfit.

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17. UPDATE on August 12, 2010 8:01 PM writes...

Whoops.....they should have been foreced to resign from GSK, which would have allowed them to retain their well considered positions with Healthy LifeSpan. Both are so slimy, which fits with trying to sell snake-oil.

Glaxo Slaps Former Sirtris Execs

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18. cancer_man on August 12, 2010 8:06 PM writes...

Why would one assume that Dipp was "not telling the truthiness"? This looks like SRT501, which Sirtris claims is 5 times as potent as resveratrol. At $1.50 for 250mg, that is about what you'd expect 250mg of SRT501 to cost if not for profit. Healthy Lifespan Institute can still sell it as resveratrol even though a formulation.

GSK clearly doesn't want to have anything to do with SRT501 since focusing on the NCEs, but does it make more sense to have a non profit sell it than let it drop? Both Sinclair and Westphal say they are taking SRT501, so if there is good news in a forthcoming paper, a lot of people will start buying it.

I'm sure resveratrol vendors have been nervous about GSK selling SRT501 even though most assumed it would never happen because it couldn't generate enough profit when competing with regular resveratrol.

And now they are selling it at cost. This could easily put a large hole in vendor's sales. Is the goal to later get FDA approval and then be the only brand to have that?

Westphal said a few weeks ago that a paper will soon be publishedthat will get as much publicity as the Pfizer paper.

It is likely that more will come out on this story in the near future.

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19. cancer_man on August 12, 2010 8:18 PM writes...

I just read post #17. See! I was right about more coming out in the near future.

"GSK [Glaxo] was not aware that the Healthy Lifespan Institute was selling a resveratrol formulation on the Internet. The company has instructed the GSK employees to cease their association with this activity and Michelle Dipp and Christoph Westphal will be resigning their positions on the board of Healthy Lifespan," said Glaxo spokeswoman Sarah Alspacham in a statement emailed to TheStreet.

Am I the only one who thinks this was all staged?

Permalink to Comment

20. Anonymous on August 12, 2010 8:27 PM writes...

Several yrs of revenue from this product may in fact allow GSK to recover the ca. 780 million $ that they spent in the acquisition of sirtris.

Funny how things progress. It's almost predictable. The best layed plans of mice and men....

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21. And Pigs Fly on August 12, 2010 8:42 PM writes...


Staged? By who? Who gains? Only Westphal and Depp, stroaking their egos, promoting their concepts without supporting science. Sounds a lot like the basis of Sirtris.

Pharma R&D has enough problems. It does not need this type of irresponsible management, leadership, as "the newest future" as well. GSK was foolish. They should take this as an opportunity to rid themselves of both "Sr. Executives", and get back to science being the driver of new drugs, not make believe advertising.

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22. cancer_man on August 12, 2010 9:07 PM writes...

I don't understand the motives of anyone in this. SRT501 has already been shown to be effective against diabetes. How is that junk science?

Westphal is a multimilionaire. He needs his ego stroked by selling something similar to SRT501 as a non-profit?

Westphal and Dipp are empoyees of GSK and GSK was obvlious to what they were doing?

There must be some twist to this strange story, and I think we'll know in a few weeks

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23. qetzal on August 12, 2010 9:51 PM writes...

@processchemist (#2) & Henning Makholm (#9),

I commented on this point earlier today, but it seems the spam filter ate my post. I'll try again without the hyperlinks this time. Apologies to all if this ends up being a repost.

21 USC 321 (ff)(3)(B)(ii) states:

The term "dietary supplement" does not include an article authorized for investigation as a new drug, antibiotic, or biological for which substantial clinical investigations have been instituted and for which the existence of such investigations has been made public, which was not before such approval, certification, licensing, or authorization marketed as a dietary supplement or as a food unless the Secretary, in the Secretary's discretion, has issued a regulation, after notice and comment, finding that the article would be lawful under this chapter.

I found that because FDA actually cited it in a letter to another company wanting to market resveratrol as a supplement:

FDA has carefully considered the information in your notification and other published reports in the scientific literature and has made the following determinations. First, trans-Resveratrol is excluded from the definition of a "dietary supplement" under 21 U.S.C. 321(ff)(3)(B) because it is an article authorized for investigation as a new drug for which substantial clinical investigations have been instituted and made public in the U. S. The purpose of this research underway is to investigate the use of trans-Resveratrol in combination with nucleoside analogs in the treatment of human immunodeficiency virus infection.

FDA authorized trans-Resveratrol (which is also known as "resveratrol" or 3,5,4'-trihydroxystilbene) to be an investigational new drug on January 30,200l. The Dietary Supplement Health and Education Act (DSHEA) of 1994 defined a "new dietary ingredient" as one that was marketed in the U.S. on or after October 15, 1994. This office does not have any information that indicates that trans-Resveratrol was legally marketed as a dietary ingredient in the U.S. before October 15, 1994.

The FDA letter was from 2001, but unless they've changed their view on this (and I couldn't find anything to suggest they have), it seems that processchemist is right.

Permalink to Comment

24. processchemist on August 13, 2010 1:55 AM writes...


ok, I got it. They're playing this one on a fringe: "dietary supplement" stands for "formulation". So if SRT501 is not simple micronized resveratrol, but a more complex formulation, it's all legal.


Beware of chinese products coming from extraction. It's usually really hard to obtain from China standardized extraction products with a complete analytical profile (potency, heavy metals, residual solvents etc), so in this case lower prices mean lower safety. With a totally synthetic product usually things are smoother (but, sourcing from china, any "BSE/TSE free" and "Non animal origin" declaration must be trusted at your own risk).

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25. Anonymous on August 13, 2010 2:12 AM writes...

What suprises me is that these two get to keep their GSK positions. If these allegations are true, it would seem to have been both a huge conflict of interest, and an ethical conflict that surely, no proper pharma company would want to be associated with in any way.

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26. dvizard on August 13, 2010 3:00 AM writes...

@terry #7: quite simply because they realized that selling snake oil is just way more likely to make them money than doing actual research.

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27. profiler on August 13, 2010 3:59 AM writes...

"I can't recall another case where an investigational drug has also been sold as a dietary supplement"

here's another example, similarly strange:

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28. fWindPharmer on August 13, 2010 5:28 AM writes...

Thanks for pointing this one out, Derek. A really nice insight into how the WindPharm is run, makes me glad I'm out of it!

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29. alig on August 13, 2010 6:58 AM writes...

@ Cancer_man "SRT501 has already been shown to be effective against diabetes."

Umm, no it hasn't. It is still in phase II and it likely to never progress beyond that.

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30. Terry on August 13, 2010 8:32 AM writes...

First of all,
There is no indication that resveratrol is snake oil - just the opposite. Human trials are revealing that it has incredible health benefits - and at low doses (e.g. 40 mg./day)

Second of all,
the Healthy Lifespan Institute was NOT selling SRT501 so Dipp was not telling the truthiness.

Drs. Sinclair and Westphal are taking resveratrol daily, not SRT 501

SRT501 can be copied without violating patents. All it is is micronized resveratrol in an emulsifier. Not real complex.

Permalink to Comment

31. Terry on August 13, 2010 8:34 AM writes...

First of all,
There is no indication that resveratrol is snake oil - just the opposite. Human trials are revealing that it has incredible health benefits - and at low doses (e.g. 40 mg./day)

Second of all,
the Healthy Lifespan Institute was NOT selling SRT501 so Dipp was not telling the truthiness.

Drs. Sinclair and Westphal are taking resveratrol daily, not SRT 501

SRT501 can be copied without violating patents. All it is is micronized resveratrol in an emulsifier. Not real complex.

Permalink to Comment

32. David Stipp on August 13, 2010 8:46 AM writes...

The nutraceutical brouhaha surrounding the Health Lifespan Institute is interesting, but the real news this week on the resvertrol/SIRT1 front appeared in JBC: See

Permalink to Comment

33. cancer_man on August 13, 2010 8:56 AM writes...

SRT501 was shown to be effective in a phase II trial. That is still an impressive display of effectiveness at 5000mg a day.

1) Sinclair was taking Longevinex for years before taking something else, believed to be SRT501. How do you know this is false?

2) What human trial has ever shown benefits at 40mg/day? Effectiveness against pre diabetes was with 1000mg. A heart benefit was seen at around 200mg to 350mg.

3)Again, how do you know Dipp is lying?

4)Selling SRT501 would be a patent violation.

Permalink to Comment

34. Peej on August 13, 2010 9:06 AM writes...

"First of all,
There is no indication that resveratrol is snake oil - just the opposite. Human trials are revealing that it has incredible health benefits - and at low doses (e.g. 40 mg./day)"

Thats exactly the kind of sentence that tells me that this stuff IS snake oil. "Incredible" health benefits, huh?

Permalink to Comment

35. Resveratrol Receptor on August 13, 2010 9:27 AM writes...

In other news, Sirtris finally published a JBC paper on how STACS "work". I haven't read it yet, but am sure looking forward to seeing kilograms of lipstick on a pig. (A quick skim suggests that it will be a gripping read for chemists/enzymologists).

Permalink to Comment

36. processchemist on August 13, 2010 9:40 AM writes...

@David Stipp

The jbc cited has currently no structures nor additional information about the synthesis of the STACs.
I remember that one of the problems of original Sirtris work was the chemistry: the original syntheses were retested without success, and the described products, once synthetized and correctly characterized did not show the declared activity.
I think that details can be found in a previous post about Sirtris/resveratrol.

Permalink to Comment

37. David Stipp on August 13, 2010 9:55 AM writes...

To processchemist: In my copy of the JBC paper, the structures of 24 STACs are shown in Fig. 1.

Permalink to Comment

38. alig on August 13, 2010 10:05 AM writes...

@cancer_man does not list any complete phase II studies of SRT501 in diabetes. Can you provide the study number? There was a phase I study which showed some indication of maybe a benefit at 5g per day, but no follow up studies are complete. But hell, Avandia showed a benefit in several phase III & IV studies on thousands of patients and we all know how that turned out when used in practice. So go on, believe SRT501 works because it showed some activity in

Permalink to Comment

39. processchemist on August 13, 2010 10:06 AM writes...

@David Stipp

Yes, my fault. But for such a controverse matter the chemical problems will not be solved until someone else repeats syntheses and biological tests (or until some STAC will be approved from FDA).

Permalink to Comment

40. David Stipp on August 13, 2010 10:14 AM writes...

To processchemist: I totally agree with you that the controversy won't go away based on one study by a biotech with a big stake in its outcome. But I think that if significant clinical benefit is shown in trials with STACs, the debate will die down and become largely moot -- I don't think it will necessarily take FDA approval to swing the tide of public opinion. Whether that will happen is beyond me at this point -- I'm an agnostic on whether Sirtris's drugs will work in people, merely watching with great interest to see how this plays out.

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41. Pearl on August 13, 2010 11:13 AM writes...

Mr. Stipp,
Interesting piece. Thanks for posting.
Not sure if you are aware of this but resveratrol acticates most (if not all) of the sirtuin genes -1 through 7. Studies are finding that Sirt1 is not the only winner in the class.

Permalink to Comment

42. David Stipp on August 13, 2010 11:21 AM writes...

To Pearl: I've seen some limited evidence that resveratrol can induce expression of SIRT3 and SIRT4 (reviewed in ) , but I don't know of data showing it can activate SIRT enzymes other than SIRT1.

Permalink to Comment

43. bbooooooya on August 13, 2010 11:41 AM writes...

neurochem's alzhemed, which flushed out of a phase 3 trial for alzheimer's a few years ago, is now a nutracetical being sold by bellus.


Permalink to Comment

44. qetzal on August 13, 2010 12:39 PM writes...

processchemist (#24):


ok, I got it. They're playing this one on a fringe: "dietary supplement" stands for "formulation". So if SRT501 is not simple micronized resveratrol, but a more complex formulation, it's all legal.

I apologize. In exerpting what I considered the relevant part of 21USC321(ff), I seem to have made the meaning a bit ambiguous. If you read the whole paragraph, it essentially says that the term "dietary supplement" means a product that (1) contains a dietary ingredient (e.g. vitamin, mineral, etc.), (2) is intended for ingestion, and (3) does not include an approved or investigational drug. IOW, it's not that the term "dietary supplement" can't include an investigational drug. It's that the supplement product cannot include "an article authorized for investigation as a new drug."

So, as I read that, it means you can't bypass the rules simply by claiming that your supplement is a different formulation of the same active. Just like you can't dope your supplement with sildenafil and claim it's legal because it's not the same formulation as Viagra.

Since the spam filter seems not to like me, I won't link to the text of the law. If you want to read it for yourself, google "usc," click the "United States Code: Main Page" link (~ 10th hit), search for "21USC321," & click "TEXT" for the first hit. Scroll down to paragraph (ff).

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45. CabSav on August 13, 2010 12:52 PM writes...

Dr Double Dipp?

Red red wine you make me feel so grand
I feel a million dollars when your just in my hand

Permalink to Comment

46. ronathan richardson on August 13, 2010 1:06 PM writes...

For the record, red yeast rice is a nutraceutical OTC with a pretty good content of mevacolin, a statin. It's really just sort of shows the awkwardness of the industry and intellectual property--the people that deserve to be paid are the people that put up hundreds of millions for clinical trials. This is why I think the NIH should pay for and run clinical trials on any agents that show serious preclinically. Not that that would be possible, but in an ideal world.

Permalink to Comment

47. Anonymous BMS Researcher on August 13, 2010 2:42 PM writes...

I don't have a dog in this fight, and most of what little I know about resveratrol I learned from this blog or from the news media. So I don't really have an opinion about the stuff myself.

But any thread containing phrases like "kilograms of lipstick on a pig" is a fun thread to read!

Permalink to Comment

48. cancer_man on August 13, 2010 7:38 PM writes...

The effectiveness of SRT501 on diabetes was shown in a phase 1b trial, not II as I thought. Still, SRTFF501, not an NCE, showed effectiveness in a study of 100 with Type 2 diabetes.

Permalink to Comment

49. cancer_man on August 13, 2010 7:50 PM writes...

To Derek:

In light of the new JBC article on resveratrol/Sirt1, could you post which scenerio you think is most likely?

"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."

Or have the odds increased that at least one compound will be effective?

Permalink to Comment

50. RKN on August 13, 2010 8:57 PM writes...


Last time I looked only one or two companies sold the active isomer of resveratrol (rsv). When exposed to light rsv quickly changes to a therapeutically inactive isomer. The company I purchased from (Longevinex) said their rsv supplement contained >95% active isomer. Supposedly verified by mass spectrometry by independent labs. Cheaper versions don't contain any active isomer.

Permalink to Comment

51. Ricola on August 14, 2010 3:52 PM writes...

Concerning this matter, on Health Blog:

" August 13, 2010, 12:44 PM ET

GlaxoSmithKline Tells Execs to Leave Nonprofit Selling Resveratrol Supplements

Until very recently, if you went to the website of the nonprofit Healthy Lifespan Institute you’d be able to click on a tab to purchase a resveratrol supplement for $540 per year. The tab is gone, and the nonprofit’s co-founders have left the organization — the latter action at the request of GlaxoSmithKline."


Permalink to Comment

52. Sili on August 15, 2010 6:24 AM writes...

Why on earth would two very respected scientists put their reputations on the line if they truly did not believe the resveratrol and SIRT1 activation is for real.
I believe that's the operative word. Permalink to Comment

53. Anonymous on August 16, 2010 9:19 AM writes...

Why on earth would two very respected scientists put their reputations on the line if they truly did not believe the resveratrol and SIRT1 activation is for real.

Ummm --- respected scientists? Reputations as moneymakers is enhanced. Can you say "show me the money"?

Permalink to Comment

54. non-chemist on August 16, 2010 9:45 AM writes...

Michelle Dipp's Wikipedia page could do with some updating.

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55. Anonymous on August 17, 2010 9:57 PM writes...


She's looking pretty good on that website!! Must be the Resveratrol kicking in.

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56. Anonymous on August 19, 2010 12:09 PM writes...

The fact that Westphal's wife works at xconomy must make for some interesting dinner conversation:

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57. cancer_man on August 19, 2010 9:00 PM writes...

(middle of Nature article)

"The (Pfizer, etc) papers did a lot of damage to a lot of people," says Ross Stein, a scientist at Sirtris and lead author on the company's new rebuttal1.

Test-tube discrepancies
The debate revolves around a laboratory test Sirtris used to assess whether or not a particular drug increases SIRT1 activity. When activated, SIRT1 strips acetyl groups from cellular proteins including histone proteins, which silences gene transcription and is thought to be involved in its anti-ageing effects. To measure this process, researchers used an acetylated protein fragment containing a fluorescent tag. When activated, SIRT1 deacetylates this peptide causing the tag to glow. The Sirtris scientists reasoned that more fluorescence means greater SIRT1 activity.

The critics, however, found that resveratrol and the other Sirtris drugs activate SIRT1 only when the fluorescent tag is present.

After the Pfizer paper came out, GSK defended its SIRT1 test and the drugs the company found using it. The firm claimed that test-tube conditions did not totally capture the complex biochemistry of SIRT1 in living cells.

Moreover, the drugs seemed to work in mice. Resveratrol protected rodents from the ill effects of a high-fat diet5, and a potent resveratrol mimic made obese mice and rats more sensitive to insulin, suggesting that the drug could be effective against type 2 diabetes6.

Off-target effects
To address lingering doubts, the Sirtris researchers took a closer look at how the drugs interact with SIRT1 and that infamous fluorescent tag. The researchers concede that their drugs can bind to the tagged peptide but contend that this interaction can't alone explain why the drugs activate SIRT1.

If the action of the drugs were due only to the fluorescent tag, Stein says, the stronger the activation of SIRT1, the more strongly the drugs would bind to the tagged peptide. "We have a number of compounds that do not bind to the peptide but are great activators of SIRT1," he says.

Stein and his team also found that Sirtris's drugs could activate SIRT1 even when a fluorescent tag wasn't used to measure deacetylation. However, the researchers agree that an extra chemical group on the peptide is important for SIRT1 activation. Stein suggests that some natural cofactor acts in this capacity in living cells.

"Although this is possible, there is no evidence to believe that this might be true," says Ronen Marmorstein, a biochemist at the Wistar Institute in Philadelphia, Pennsylvania, who remains sceptical that the Sirtris drugs directly activate SIRT1.

Joseph Baur, a molecular biologist at the University of Pennsylvania and former member of Sirtris cofounder David Sinclair's lab, doesn't rule out the possibility that the fluorescent tag mimics a natural SIRT1 cofactor. However, he says, "this is difficult to test, and nearly impossible to disprove".

Kaeberlein, whose team found that SIRT1 activation depends on the fluorescent tag, says that the latest paper does not settle his doubts about whether resveratrol and the other Sirtris drugs activate SIRT1. He notes, however, that resveratrol has many targets other than SIRT1 and it need not directly activate SIRT1 to improve health. "It may be that many of these other compounds have similar off-target effects."

Stein remains confident that the Sitris compounds exert their effects by activating SIRT1, but admits that his team doesn't know everything about how the drugs might act.

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58. Anon on August 21, 2010 9:24 AM writes...

1) Interesting, that the new Sirtris data did not exist until recently, despite all their initial claims for evidence of the claimed activation mechanism.
2) It is great that RS is confident, with caveats, but he is not without a history of controversy in previous career settings.
3) Kaeberlein is right in pointing out that the Sirtris compounds are not target selective, and that any observed cellular or in vivo activity could be due to off-target effects. This has been pointed out repeatedly to Sirtris by GSK staff who are knowledgable about the compounds' characterization, going back to before GSK's purchase of Sirtris. The whole thing tends to be ignored, denied by Sirtris...a type of street-corner shell-game of deception (where is the pea?).

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59. cancer_man on August 21, 2010 7:02 PM writes...

#1 is interesting.

It is also interesting that Derek hasn't commented on the new paper after over a week. Maybe next week.

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60. Trista Morrison on August 23, 2010 2:44 PM writes...

There are other examples of products that are both drugs and supplements. Here's a BioWorld Insight article on that topic:

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61. curious on August 23, 2010 11:43 PM writes...

Some parts of this story don't add up.

First, what is the incentive for Westphal to sell at cost? The Healthy Life Span wouldn't benefit either.

Second, only they were selling in 6 month packages. Why would they do this since all other vendors sell in one month packages?

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62. watcher on August 24, 2010 1:02 PM writes...

curious, #61:

Packaging or repackaging can be easily accomodated. It's done all the time for little cost. Small, unimportant detail.

They have been saying that Healthy Life Span was non-profit. Nice, slick positioning to make themselves look good.

But "at cost" can be all relative. What is included in the bookkeeping for their "cost"? Leading you to think one way, but is that what they were proposing to do?

I've not seen anything about (denying) any proposed compensation for people who were involved in management and/or their board of directors. Seeing how these folks operate, can only assume that they would have gotten a nice compensation for the level of their contribution and use of their names on the web-site. So, it all makes perfect sense to me.

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63. curiosity on August 24, 2010 10:09 PM writes...

I realize that "at cost" is a somewhat loose phrase, but it is usually understood as just costs of labor and capital. Certainly directors like Westphal and Dipp would be excluded from gain in this case.

I also don't see how it makes them look especially good to sell it. Westphal just got $20 million from GSK and looks "good enough" just starting something called the Healthy Lifespan Institute.

Selling in 6 months packages is strange and no other vendor does this. I don't see evidence that any was actually sold, either. Westphal may have correctly thought that once it is known that they have a version of SRT501 for sale that customers would trurst his name and buy in bulk. But again "at cost..." Why? just a Good Samaritain getting out SRT501 to the little people at a cheaper price than GSK would have even though it seems they didn't plan on selling it?

Did Westphal and Dipp really think GSK wouldn't have a say about selling a version of SRT501? But even stranger, the spokesperson said GSK couldn't stop The HLI from selling it. So what is up?

Far from a clear story to me, and I bet resveratrol sellers worried it would take market share away from them.

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64. watcher on August 25, 2010 9:05 PM writes...

You are trying too hard, overthinking this.

For someone like CW, there's never enough money, power, influence, visibility, importance. Never. Take home $20m, turn around and look for the next deal. People like CW and MD work by different rules, expectations, boundaries than most of the rest of us...sometimes they get away with it for a long time with honorable legacies, sometimes they get caught and lost in history's maze, sometimes they become infamous (aka, Ponzi, Madoff).

GSK had no legal way to stop HLI from selling appropriate patent protection. BUT, they could insist that THEIR employees avoid any apparent conflict of acted to ask that CW and MD separate from the conflict by resigning from HLI. I don't know if they have indeed left HLI, or instead if they agreed for HLI not to sell SRT501, which would have in essence accomplished the same objective to remove the conflict of interest between CW and MD as employees of GSK.

This raises one question, which is the actual purpose, function, activities of HLI (as distinct from their stated mission statement. And whatever that may be, can they actually exist without CW? Doubtful.

Nonetheless, this is only a side show of the larger scientific, strategic, ethical, honesty in disclosure debate around the characteristics of various claimed unique activators of the sirtuins. Let's not get lost in the less important minutiae.

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65. curiosity on August 26, 2010 8:10 PM writes...

To #63:

"You are trying too hard, overthinking this....Let's not get lost in the less important minutiae."

I don't sell resveratrol, but I don't think what happened is trivial in that market. First, Westphal may certainly want more wealth, fame and power, but how does selling a version of SRT501 for a non-profit and at cost accomplish any of those?

SRT501 that they claim they were selling or about to sell is supposedly 5 times as potent as resvertrol alone. If so, that would likely completely change the resveratrol market.

I've read that it isn't hard to make SRT501 and that GSK does have a patent on it, so it can't be sold by anyone but GSK. Westphal must have known that.

We also don't know how the Sirtis compounds would stack up to resveratrol at high doses if they eventually are successful. Why has Sinclair taken 300-400mg of a blend of resveratrol for 4 years based on his weight then recommend people stay at or under 250mg, which was the same unit Westphal said they were going to sell of something like SRT501.

I read that Westphal and Dipp left the HLI, an organization that hasn't seemed to have much purpose.

Overall, a really suspicious story.

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66. Anonymous on August 26, 2010 10:48 PM writes...

# 64 is spot on. Must be an insider LOL just kidding!

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67. Confused on September 8, 2010 7:34 AM writes...

Not a doctor just want to know after reading all of these comments, is Resveratrol safe and when will it be made available to the general public?

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68. casa on November 17, 2010 12:46 PM writes...

excellent blog

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69. Jacob on September 13, 2011 2:43 PM writes...

Odd, here we are what about a year later after all the hub bub has quieted down and along comes the publication of a phase 1 trial on this same stuff.

What's one to think?

Cancer Prev Res (Phila). 2011 Sep;4(9):1419-25. Epub 2011 Jun 16.
Phase I Randomized, Double-Blind Pilot Study of Micronized Resveratrol (SRT501) in Patients with Hepatic Metastases--Safety, Pharmacokinetics, and Pharmacodynamics.
Howells LM, Berry DP, Elliott PJ, Jacobson EW, Hoffmann E, Hegarty B, Brown K, Steward WP, Gescher AJ.

Department of Cancer Studies and Molecular Medicine, Robert Kilpatrick Clinical Sciences Building, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom.

The phytochemical resveratrol has undergone extensive preclinical investigation for its putative cancer chemopreventive properties. Low systemic availability of the parent compound due to rapid and extensive metabolism may confound its usefulness as a potential agent to prevent malignancies in organs remote from the site of absorption. Micronization allows increased drug absorption, thus increasing availability. Here we describe a pilot study of SRT501, micronized resveratrol, given as 5.0 g daily for 14 days, to patients with colorectal cancer and hepatic metastases scheduled to undergo hepatectomy. The purpose of the study was to assess the safety, pharmacokinetics, and pharmacodynamics of the formulation. SRT501 was found to be well tolerated. Mean plasma resveratrol levels following a single dose of SRT501 administration were 1,942 ± 1,422 ng/mL, exceeding those published for equivalent doses of nonmicronized resveratrol by 3.6-fold. Resveratrol was detectable in hepatic tissue following SRT501 administration (up to 2,287 ng/g). Cleaved caspase-3, a marker of apoptosis, significantly increased by 39% in malignant hepatic tissue following SRT501 treatment compared with tissue from the placebo-treated patients. SRT501 warrants further clinical exploration to assess its potential clinical utility. Cancer Prev Res; 4(9); 1419-25. ©2011 AACR.

[PubMed - in process]

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