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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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December 1, 2010

Resveratrol (SRT501): Development Halted

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Posted by Derek

Back in May, GlaxoSmithKline halted a trial of SRT501, which is a formulation of resveratrol, in myeloma. Now the folks at the Myeloma Beacon site are the first with the news that the company has halted all further development:

According to a GlaxoSmithKline spokesperson, an internal analysis of the kidney failure cases has concluded that they “most likely were due to the underlying disease … However, the formulation of SRT501 was not well tolerated, and side effects of nausea / vomiting / diarrhea may have indirectly led to dehydration, which exacerbated the development of the acute [kidney] failure.”

For this reason, the company decided to halt further development of SRT501 in multiple myeloma. The SRT501 formulation of resveratrol “may only offer minimal efficacy,” explained the Glaxo spokesperson, while increasing the chances of kidney failure. . .

. . .In a separate statement to The Myeloma Beacon, a Glaxo spokesperson explained the rationale for the company’s decision to halt all development of SRT501. Ending all work on SRT501, the spokesperson said, will allow Glaxo to focus its resources on the development of drugs that act similarly to SRT501, but have more favorable properties. The spokesperson mentioned, in particular, SRT2104 and SRT2379 as drugs similar to SRT501 that the company is developing.

These compounds are still a bit of a mystery - they've been in the clinical trial registry for a while, and are certainly the subject of active investigation, but we don't know how they fit into the whole activation-of-SIRT1 brouhaha. They haven't been challenged by the critics of the work, nor specifically defended by GSK, so we're just going to have to see how they perform out there in the real world (which was always going to be the final word, anyway).

But this would appear to be it for resveratrol itself in the real world, as far as GSK's concerned. Hey, does this mean that they'll let their two former Sirtris execs start selling it again on the side, now that they have no interest in the parent compound? One doubts it. But why not?

Comments (27) + TrackBacks (0) | Category: Aging and Lifespan | Cancer | Clinical Trials


COMMENTS

1. ChemCynic on December 1, 2010 9:12 AM writes...

Not surprised. Besides you can get resveratrol cheaper than any drug formulation: get yourself some Franzia or Carlo Rossi. Since when did GSK become GNC? Selling wine extracts and fish oil!

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2. Fizzby on December 1, 2010 9:19 AM writes...

What's the over/under on Westphal's continued employment with GSK?

Probably about 2 months less than that of Moncef.

If Westphal ever gets Pharma money again I'm quitting the indusrry and becoming a dog walker.

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3. anchor on December 1, 2010 9:55 AM writes...

Derek: We have covered this subject matter on many occasions in your blog and we know that end was coming (purely on the basis of med chem and at best dubious biology). The foot dragging by GSK in my belief is that- simply not knowing as to how to exit from this muddle with reputation intact. Suffice it to say that longer this drag on, the more dim-witted they look (for all that $$$ spent).

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4. TTU76 on December 1, 2010 1:25 PM writes...

Oh, we've got trouble, right here in River City.

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5. BoredChemist on December 1, 2010 4:16 PM writes...

Anybody: When did GSK become such a train wreck of pharma company? Have friends there who would prefer to be somewhere else but are just thankful to have jobs nowadays.

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6. Anonymous on December 2, 2010 4:26 AM writes...

I don't see why ending SRT501 would imply that the other compounds will be failures. GSK has been trying to ditch SRT501 for a long time, but the evolving story has been strange.

1) In 2007, Sinclair and Co. show that SRT501 controlled diabetes in a small trial prior to GSK buying Sirtris. There was no mention of kidney problems with that group. Was that a poor study or fraud?

3) In April 2008, GSK buys Sirtris.

2) In June 2008, Sinclair was quoted in Wired saying that Sirtris' resveratrol was in phase II trials and: When it [must be SRT501] hits the market in four or five hears, he said, "It’ll be on the market as a diabetes drug. It’ll have to sell for $3 or $4 a pill, in order to stay competitive." That's an odd thing to say

3) Westphal says in 2008 that they are moving beyond SRT501.

4)SRT501 was in a colon cancer trial in 2009 but the results that came in December where never published in 2010.

5)In April 2010, GSK stopped SRT501 in the MM trial because of kidney problems, but it looks like there were no more problems that what occurs in mm patients.

6) In summer 2010, Westphal tries to sell SRT501 (250mg) for about $2 a day and was stopped by GSK the day the story went out. It isn't clear how long that institute was selling since not well known. GSK then later says it can't stop the sale of SRT501, but it isn't being sold. Also strange.

7)GSK ends SRT501 in the MM study but previously allowed patients who wanted to take it to continue. GSK says there are several reasons they are discontinuing SRT501 is because of the efficay safety ratio. This is about the only way they can say that they don't really want to use SRT501 because they wouldn't make much money off of it.

8) Sincliar and Westphal are both taking SRT501 but haven't said how much.

None of this suggests the other compounds will fail.

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7. Arnold Goldstein on December 2, 2010 6:04 AM writes...

It is important to bear in mind that SRT501 is a synthetic form of the molecule, produced either by fermentation or organic chemical engineering. Secondly it is not pure resveratrol at all. It is complexed with another material, probably cyclodextrin or tween 80, to make it more water soluble. Synthetic resveratrol sometimes contains either remnants of the bacteria or yeast which has been modified to produce the molecule or other, what are known as, "unknowns" which show up on an HPLC fingerprint of the molecule. Some researchers have reported instances of mild toxicity associated with synthetic resveratrol. I do not believe that there are any reports of such toxicity related to natural resveratrol.

A recently published study by the Albert Einstein Med Ctr. using biotivia transmax, a purified form of natural resveratrol, found no toxicity or adverse effects even at a high dose. The human clinical trial did find enhanced metabolic function and improved insulin resistance, two important benefits to diabetic and pre diabetic patients.

If there are any lessons here at all regarding resveratrol itself they are:
1. Avoid synthetic resveratrol, or any complex of resveratrol with cyclodextrin or Tween (another solubility agent) and
2. Stay away from micronized resveratrol. No study has proven any advantages to this form of resveratrol.

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8. Derek Lowe on December 2, 2010 8:05 AM writes...

The above comment (Arnold Goldstein) makes very little sense. Resveratrol's structure is not complex, and synthetic material is completely identical with the naturally-derived compound. And I can assure you that it's not being produced by "bacteria or yeast".

I have heard that SRT501 is the cyclodextrin complex of resveratrol, although I don't know that for sure. But the reason people use cyclodextrin is to get higher and more reproducible blood levels of a compound. The same goes for micronization.

What you're saying is that GSK (either deliberately or stupidly) developed a less useful (and, you're implying, less pure and more toxic) form of the drug compared to the compound by itself. But while they may have been wrong-headed in buying Sirtris (the jury's still out), they do have a lot of very competent drug development people, so I don't think much of this theory.

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9. cancer_man on December 2, 2010 2:53 PM writes...

Goldstein is just wrong. SRT501 is not synthetic resveratrol. You only have to read the patent to see this.

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10. Anonymous on December 2, 2010 9:42 PM writes...

SRT501: an exquisitely polished turd that was bought by a company that was struggling and needed a fix. Poor decision making on the part of the buyer....

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11. TTG on December 2, 2010 9:53 PM writes...

@ anon.
you said "GSK has been trying to ditch SRT501 for a long time..." This is epecially true since Westphall left Sirtis. But why?? Because GSK does not want resveratrol to be a competitor with its New Chemical Entities. My belief, from studying resveratrol daily for 10 years, is that one could take less than 500 mg of SRT501 per day and see significant health benefits - especially with regard to heart health, colon health, and brain health. I have little respect for GSK...because they are a distorter of information...by this I mean, stating that one has to take mega doses to see health benefits, all in order to make its 'more potent' NCE's more desireable is not admirable. Westphal, Sinclair, and Dipp tried to do something good by starting the Healthy Lifespan Institute to sell resveratrol but were smacked down. They are not stupid, and know the benefits of Res, so don't take GSK's MM actions to mean anything but profit protection.

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12. Anonymous on December 2, 2010 11:56 PM writes...

Westphal said in October 2008: “I think ultimately, from a pharmaceutical- company perspective, a patented, composition-of-matter compound that is 1,000 times more potent is going to be more attractive than reformulated resveratrol, so definitely our focus is more on the NCEs.”

Sinclair hasn't been consistent about resveratrol. He said in early 2007 that he was taking resveratrol, that he thought it was perfectly safe, but didn't recommend others start at that time. Then he told a reporter about the same time that he had been taking 300mg of Longevinex (resveratrol with quercetin) a day for 3 years based on his weiht. He then started taking SRT501 but also helped to formulate Vivix in 2008.Lut his enthusiasm for resveratrol at a Shaklee (makers of Vivix) event seemed genuine.

But in a couple of early 2009 interviews, Sinclair implied thousands who take resveratrol are doing a long term experiment on themselves and that to get the effects found in mice people "might need to consume up to 5 grams a day" That BusinessWeek article had many errors so maybe Sinclair was misquoted, but he was discouraging resveratrol use with the previous comment. Months later, Sinclair then wrote an ebook on resveratrol with another Harvard researcher, giving the advice to stay at 250mg a day or under if someone wants to start.

The Westphal and Dipp episode seems odd. Selling 250mg SRT501 at under $2 would have shaken up the resveratrol market. But were they quietly selling the 250mg SRT501 to people who may have also wanted to try SRT501 and then announce the sales through xconomy.com assuming GSK would tell them to stop? It looks suspicious because no other resveratrol vender required customers to buy in 6 month or 1 year bulk. But bulk makes sense if you think your early customers are friends or aquaintences who have been asking you to sell them some SRT501.

Based on what I've read over the past few years, including what Sinclair has said and was taking, 100mg to 500mg is the beneficial range, maybe 250mg to 500mg.

Permalink to Comment

13. Anonymous on December 2, 2010 11:57 PM writes...


It would be interesting to talk to one of the MM patients who wanted to continue taking SRT501 as GSK said...

Why did GSK go ahead with the SRT501 cancer trials in the first place?

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14. alig on December 3, 2010 8:14 AM writes...

Any of you taking low-dose resveratrol out there want to contact me? I have some alkaline water to sell you. It has the same amount of data backing up its health benefits.

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15. BoredChemist on December 3, 2010 10:19 AM writes...

So, how long will it be before GSK starts advertising anatomy/performance-enhancing herbal remedies on late-night TV or Telemundo?

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16. Terrence on December 3, 2010 9:20 PM writes...

@ alig,
what is your definition of 'low dose'? anything under the 5000 mg. micronized, and served in HPMC/DOSS? Talk about overdoing it.

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17. Anonymous on December 4, 2010 12:29 AM writes...

"Any of you taking low-dose resveratrol out there want to contact me? I have some alkaline water to sell you. It has the same amount of data backing up its health benefits."

I might. But do you have hundreds of studies showing health benefits of alakline water on mice? Do you have a video showing a fat mouse who drank alakaline water run twice as far as a fat mouse drinking tap water?

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18. Spiny Norman on December 4, 2010 2:33 PM writes...

TTG@11: What, exactly, do you mean by "studying?" Because I think that what you mean when when you use this word is not what the scientists here mean when they use the same word.

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19. Watcher on December 4, 2010 10:53 PM writes...

Well, this looks like the beginning of the public release of a predictable slow, agonizing, painful death watch, the start of what will turn out to be the Sirtris end-game.

What is so maddening, is the amount of money that changed hands for nothing gained, and with many jobs lost within GSK as a direct and admitted need to help pay for the business decision fiasco.

Westphall, Dipp, Witty, Slaoui, and Vallence all should be fired.

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20. Anonymous on December 6, 2010 12:11 AM writes...

I still don't follow the logic that it means anything for GSK since it was almost certain they were never going to market SRT501. We never saw the results of SRT501 for either cancer study, and diabetics taking SRT1 in 2007 didn't seem to have any kidney problems, or none were reported.

Their "efficacy/safety" statement was vague to be almost meaningless unless they release the results of all of the SRT501 studies, which they will never do.

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21. Anonymous on December 6, 2010 11:02 AM writes...

#11 TTG.

Your conclusions are fallacious.

True: Westphal, Dipp, Sinclair are not stupid.
True: They know exactly how effective resveratrol is.
True: GSK, like every business, is trying to make money.

Unstated but also true: Westphal, Dipp, Sinclair are trying to make money.

Those 4 statements have NOTHING to do with your conclusion that the three principles "tried to do something good" by starting the Healthy Lifespan Institute. Unless, of course, you believe that making money is good. Which it is.

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22. Bixbyte on January 5, 2011 1:07 AM writes...

My wife and I have been dosing on 1,500 milligrams per day 98 and 99% Resveratrol prepared liquid ultrasonically mix with HPMC and PG3350 for years.
We have not experienced any kidney damage.
My wife and I are living proof RES helps slow aging.

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23. Ian on January 11, 2011 9:14 PM writes...

As a pharmacist you will see many legitimate studies of resveratrol posted on pub med using low dosages and showing excellent results . The Natural is used in the studies. You can not patent it. The water analogy was silly. GSK can not compete with the natural. Game over for them.

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24. Ian on January 11, 2011 9:14 PM writes...

As a pharmacist you will see many legitimate studies of resveratrol posted on pub med using low dosages and showing excellent results . The Natural is used in the studies. You can not patent it. The water analogy was silly. GSK can not compete with the natural. Game over for them.

Permalink to Comment

25. Ian on January 11, 2011 9:15 PM writes...

As a pharmacist you will see many legitimate studies of resveratrol posted on pub med using low dosages and showing excellent results . The Natural is used in the studies. You can not patent it. The water analogy was silly. GSK can not compete with the natural. Game over for them.

Permalink to Comment

26. Ian on January 11, 2011 9:16 PM writes...

As a pharmacist you will see many legitimate studies of resveratrol posted on pub med using low dosages and showing excellent results . The Natural is used in the studies. You can not patent it. The water analogy was silly. GSK can not compete with the natural. Game over for them.

Permalink to Comment