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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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« The Collapse of Complexity | Main | Another Proposal For the Scientific Literature »

May 3, 2010

SRT501 - A Trial Suspended

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Posted by Derek

A comment to this post on the Sirtris compound saga just had me checking Clinicaltrials.gov. And indeed the commenter is correct: a trial against myeloma of a combination of Velcade (bortezomib) and SRT501, which I believe is reformulated resveratrol itself, was suspended as of April 22 for "unexpected safety concerns".

There's no way of knowing what those are, and it's worth keeping in mind that a number of other studies have been completed with SRT501. But since there's been (as far as I can tell) no mention of this trial's halt anywhere, I thought it worth noting.

Comments (35) + TrackBacks (0) | Category: Aging and Lifespan | Cancer | Clinical Trials


COMMENTS

1. John on May 3, 2010 10:40 AM writes...

There really needs to be some form of mandated outcome disclosure. Half the trials I see on clinicaltrials.gov are terminated without explanation, and I'm pretty sure it's not because they couldn't meet enrollment.

Permalink to Comment

2. weirdo on May 3, 2010 10:56 AM writes...

"mandated outcome disclosure"

Why?

If the molecule becomes a drug, then yes, I agree with you. I believe the FDA agrees as well. But probably 90% of the molecules tested never get marketed. So why mandate disclosure?

("for the greater good"?)

Permalink to Comment

3. lynn on May 3, 2010 11:50 AM writes...

I think one of the big problems in drug discovery and development, from screening to clinical trials, is the failure to disclose why things fail - so that others might learn from those failures. One hopes the company that endured the failure would learn from it - if it survives. But broader disclosure, publication, whatever, could further general progress. This could apply to academic research as well. I was at a meeting recently where academics and industry types talked about drug discovery (in antibacterials). The academics were suggesting lots of screening ideas and other approaches they felt were novel. Industry folks were frustrated in saying, "oh yeah, we did that - it didn't work" - or "good screen but no hits." The academics didn't want to hear that because there were no publications to support the claims (fair enough). But who publishes negative results? Still - at least for clinical trials, where a lot of money and, possibly, lives are at stake, it would seem wise to disclose results. Not so much for the public but for progress in the field.

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4. Terrance on May 3, 2010 12:11 PM writes...

Maybe Sirtris 'wanted' to discontinue the study because it can't make money on SRT501. It wants to focus on its proprietary molecules instead. It is interesting that the study was suspended on the day that Westphal left Sirtris.

Permalink to Comment

5. Sili on May 3, 2010 12:22 PM writes...

"mandated outcome disclosure"

Why?

If the molecule becomes a drug, then yes, I agree with you. I believe the FDA agrees as well. But probably 90% of the molecules tested never get marketed. So why mandate disclosure?

("for the greater good"?)


Because people have contributed their bodies to further the knowledge of mankind. To take a high horse look at it.

More practically, in an attempt to reduce waste. If you have a result, you might as well put it out there to stop others using time and resources going down blind roads.

Permalink to Comment

6. J-bone on May 3, 2010 12:57 PM writes...

On the topic of disclosing things so others don't go following the same path, some of us in grad school joked about starting a journal called "The Journal of Failed Experiments" or something like that. Could definitely benefit some people to see that a reaction they're trying has already caused someone else to run their head into a wall. I probably could have used it a lot (and filled it quite a bit).

Permalink to Comment

7. anchor on May 3, 2010 1:22 PM writes...

I hope this will be the final nail on the coffin. Many (backed by solid research) concluded long back that the whole Sirtris compound saga was fraudulent science brimming with irrational exuberance. What a colossal waste of $$$$ and science. For all we know the guilty went un-punished. People who did initial honor must come back (to CBS 60 min.) and tell the rest of the World that it was all farce

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8. Ed on May 3, 2010 1:34 PM writes...

Lynn, I have tried to publish "negative" results. This was of an HTS program that we couldn't generate any reliable leads from, but with no shortage of hits. We were trying to disclose our efforts in hit to lead chemistry (all in micromolar region) and would also have disclosed every HTS hit that we found.

We felt that other groups working in the area might have been able to look on our results with new eyes and/or put it together with what they already knew to move the field forward (at which point we obviously might jump back in again). I should add that this was a novel oncology target in which the state of the art was at that time ridiculous non-drug like inhibitors active in the micromolar region (enzyme, not cell).

The paper was flat out rejected - even though I felt I managed to write quite a nice "story". Journals (even mid-tier ones) just don't seem to be interested in publishing such "negative" work.

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9. Hap on May 3, 2010 1:38 PM writes...

If the Sirtris work is bogus, there'll be plenty of time to drive in the spikes. I thought, though, that resveratrol was a distinctly undrug-like compound - it's possible that lots of things rather than simply its effect on the desired receptors might have caused the problems, and so the performance of better (at least, more druglike) compounds would be better to assess the state of Sirtris's art.

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10. hibob on May 3, 2010 2:05 PM writes...

"mandated outcome disclosure." ... We need them to actually register the trials first. About half of all clinical trials over the past few years weren't properly registered. Of those that were, many of the submissions weren't made until after data collection had begun; sometimes it had probably even been completed. I think legally tying IRBs' and P.I.s' human trial privileges to the filing of registrations complete with primary outcomes and power analyses before the start (let alone the end) of patient enrollment would be a good way to stop some of the waste. Especially for the post-approval studies, where there's a bit less scrutiny. If A researcher data mines their results until they randomly find one with a low (and now incorrectly calculated) p-value and then reports it as if it was the original primary outcome they were searching for, the best possible result is someone else has to conduct an expensive trial on human beings to prove the treatment is actually useless. We would be much better off if publishing a clinical trial result (animal as well as human) required a description of the original planned data set and outcomes, and a walkthrough of any changes made to the protocol after the trial started.

Permalink to Comment

11. noname on May 3, 2010 2:37 PM writes...

Two comments:

One: There already is a journal of non-reproducible results. It's called Tetrahedron Letters.

Two: Don't forget that the other half of this clinical cocktail was a free boronic acid, a drug already known to be quite toxic. If the trial was indeed halted for tox reasons, blaming the tox on resveratrol is a bit like blaming the Jonestown deaths on Kool-Aid mix.

Permalink to Comment

12. Hap on May 3, 2010 5:04 PM writes...

1) Shouldn't Velcade's toxicity be a known, though?

2) If Velcade's so toxic that you won't be able to see the resveratrol's toxicity, then what's the point of the trial?

Permalink to Comment

13. cancer_,man on May 3, 2010 6:02 PM writes...

I know of only two SRT501 trials that have been completed. A Phase I safety trial and a successful diabetes trial at 2.5g of SRT501/day.

The liver/colon cancer trial was completed four months ago. At what point should we assume SRT501 wasn't effective if nothing is published?

Permalink to Comment

14. Kira on May 3, 2010 7:55 PM writes...

@Hap - forgive a confused layman's question, but why do you say that resveratrol is "undrug-like"? Is there something about its structure that makes it problematic?

(I find lurking here highly educational, but I admit my med-chem background is otherwise nonexistent.)

Permalink to Comment

15. partial agonist on May 4, 2010 7:57 AM writes...

Kira, resveratrol has 3 phenol groups. Phenols are notorious for having short duration of action because they undergo glucuronide formation which then results rapid clearance. Sulfate formation is another modification/clearance pathway.

As a result, generally polyphenols have very short half-lives in vivo. Sometimes having a phenol to limit half-life is good- see short acting beta agonists like albuterol.

Polyphenols often are also quite promiscuous in binding. Those of us who do high throughput screening know that a lot of polyphenols, including flavenoids, seem to have double digit micromolar affinity for a whole host of targets and are difficult to optimize for the needed level of potency and selectivity. We learn to largely ignore them as hits because they are hard to make leads.

Permalink to Comment

16. Marty on May 4, 2010 8:56 AM writes...

I seem to have landed in a blog populated by medical/chem researchers. I'd like to add a thought from a very different perspective. I am a multiple myeloma patient - and running out of drug options. I have participated in clinical trials, and understand why a drug company wants to keep their cards close to their vests in case they have a big win on their hands. But if there is a failure, the idea that there is no mandatory outcome disclosure appalls me. We patients need you all to learn from failures. What a colossal waste of precious resources and TIME if researchers are doomed to investigating pathways that unbeknownst to them have already failed. Yes, this is personal. My life is at stake. I'm on Velcade for the second time around, already having built resistance to it once. I have a bottle of high potency resveratrol in my drug cabinet, trying to decide whether to "add" it to my Velcade. And now I can't know why I SHOULDN'T do that. We're real, we patients. We
aren't just statistics. We really want to stay alive, and we need your expertise to do it. What is interesting science for you, what is a win or a dead end... for me is life or death.

Permalink to Comment

17. Hap on May 4, 2010 9:49 AM writes...

#14: What he/she (partial agonist) said.

Permalink to Comment

18. David on May 4, 2010 10:51 AM writes...

Marty:
According to the WSJ this was the reason for the suspension:
"GlaxoSmithKline spokeswoman Sarah Alspach said Tuesday that a number of trial participants developed a complication generally associated with myeloma. New-patient enrollment has been put on hold while the company analyzes the data and determines its next steps."

Also,keep in mind that the participants are taking 5 GRAMS of resveratrol per day - an enormouse amount.

Best wishes.

Permalink to Comment

19. Anonymous on May 4, 2010 11:11 AM writes...

It is a bit too late to discuss whether resveratrol is drug-like or not.

Permalink to Comment

20. phillip on May 4, 2010 11:35 AM writes...

Why would they suspend the trial for adverse events that weren't drug related? Is that normal? Or is it more diversionary BS?

Permalink to Comment

21. skeptic on May 4, 2010 12:03 PM writes...

One thing that is ignored on the blogs about Sirtris' compounds is their widely ranging lack of specificiy. It has been shown, ignored by Westphal cronies, and reluctantlly admitted by some at Sirtris, that various compounds of interest have demonstrated off-target potencies that can be comparable or even stronger than the affinity to the desired target. As a result, many of the cell based or even animal pharmacology results can be attributed to these alternative target interactions. I am aware of at least one situation where studies conducted outside of Sirtris demonstrated a biological effect preclinically in vivo that was consistent with a well-know alternative target's effects, only to later find that Sirtris had known of this alternative target interactions all along, but had not divulged the information until pressured. These distributions of alternative molecular interactions may explain the early Sirtirs claims of differing biological effects for different structures. All the remarkable biologies could have very little to do with the primary, advertise, intended target(s).

Most who work diligently in drug discovery sciences and particularly in the related biologies, strive for explanations and hypotheses that make sense. Yes, at times, the stories are changed and revised based on new, emerging information. It's all part of the scientific method. What some in Sirtris would like us to believe is that their compounds change these rules, they are different and do remarkable things, and since they are labeled as inhibitors of their claimed pathway that they then must be working biologically through such pathways to give observed results. Sounds eerily similar to the arrogance expressd by many in the investment world of the late '90s and '06 to '08 that financial rules had changed. We know all too well how that has turned out.

For those who follow classical scientific principals, these concepts the claims by Sirtris are largely rubbish. And unfortunately, it is that type of bunk that has been promoted by Sirtris, bought by some upper managers in GSK (but not necessarily the scientist in the GSK lines), and is now much of the basis of the ongoing blogs & attention given to this entire area.

The bottom line still is the same, if it seems unreasonable, unfathomable , non-scientific snake oil, then most likely it is unreasonable, unfathomable snake oil. In trying to be balanced, within the snake-oils of the world, once in a while something might actually be of medicinal value--as natural products (aka snake oils) can be of therapeutic value and / or provide leads to newer, better drug therapies! An the end, this could be the ultimate legacy of the Sirtris experience and the hubris of Westphall and company.

Permalink to Comment

22. Anon on May 4, 2010 1:21 PM writes...

Good point Phillip. I think this whole thing is BS - they have to create a reason for the existance of their new compounds somehow. And 5 grams of resveratrol per day plus the other drug? Wow.

Also, they suspended on the day Westphal left the company. That is a bit strange.

Permalink to Comment

23. skeptic on May 4, 2010 1:45 PM writes...

22, Anon:

On Westphal: not at all a surprise. Sirtris was sold to GSK for a very nice, unfathonmable sum. He has more than achieved and executed the type of exit strategy that is the goal of all VCs. It is actually surprising that he did not resign sooner, except that it may have reflected poorly on his image as a Sr. VP within GSK.

His new position as head of SR1, as well as the growing hype around his personal VC group, the Longwood Founders Fund, makes is prudent for him to escape Sirtris before this house-of-cards collapses.

Permalink to Comment

24. Vince on May 4, 2010 2:22 PM writes...

Fantastic post skeptic. I find it amazingly frustrating as someone who works with in-vivo models to see abstract 'black-box' effectiveness yet no reasonable mechanistic explanation offered.

Permalink to Comment

25. skeptic on May 4, 2010 3:59 PM writes...

24:
Thanks. The whole story on Sirtris may never be assembled and told in one place. But conducting science still must make scientific sense. Basic tenants should still hold and if a proposed story line seems to good to be true, then.......

Permalink to Comment

26. Anon on May 4, 2010 4:05 PM writes...

From Glaxo "Patients who were on the study were informed of the development and were asked to re-consent if they wished to continue on the trial. She said some patients had continued on the study."

So, it appears that only New applicants are not being allowed in? And some patients are continuing? Maybe, they should lower the dose a bit. 5 Grams!

Permalink to Comment

27. cancer_man on May 4, 2010 6:08 PM writes...

@skeptic
Are you saying the SRT501 study on diabetics that showed success at 2.5g is fake? If not, then you are claiming that SRT501 is sometimes snakeoil -and sometimes not?

@Anon
There is no way to know if 5g of SRT501 is too much. Also, the SRT501 liver/colon cancer study was completed and not suspended, and those patients also took 5g.

Permalink to Comment

28. Cellbio on May 4, 2010 6:41 PM writes...

Skeptic, your post was a refreshing dose of rationale thought and accurate assessment, thanks.

Permalink to Comment

29. cancer_man on May 4, 2010 7:08 PM writes...

I'd still like to see Skeptic argue that the SRT501 diabetes trial was in fact a failure. Most snakeoil doesn't significantly lower glucose levels in diabetics.


There is this comment to consider as well from January:

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

Permalink to Comment

30. Ronathan richardson on May 4, 2010 7:49 PM writes...

http://www.ncbi.nlm.nih.gov/pubmed/19934007
Can we all just agree that resveratrol is an AMPK activator, probably weaker than metformin, with some off target effects that aren't clear. Given that a swath of recent data suggests that metformin has anti-cancer potential, the next logical step in this ridiculous saga is that there will be a couple weakly positive trials, which GSK will denote as STRONG CLINICAL SIGNIFICANCE, and the world of translational medicine will pat itself on the back without having improved any patient's lives.

(Note that I'm not ruling out that Sirtris/GSK knew these things were AMPK activators and that they would give a positive clinical trial as a result of that but because of the woo, would get a million prescriptions a year anyway).

Permalink to Comment

31. Anon on May 4, 2010 7:51 PM writes...

From Bloomberg: Five of 24 patients in the trial developed cast nephropathy, a type of kidney damage that can stem from multiple myeloma and lead to organ failure, said Jo Revill, a spokeswoman for the London-based drugmaker.

Glaxo previously completed two studies of the drug in diabetics and saw no signs of the complication, Revill said today in a telephone interview.

Permalink to Comment

32. Anon on May 4, 2010 9:02 PM writes...

Cast nephropathy is also known as "myeloma kidney" and is 'common' with myeloma. As such, why would Glaxo suspend a trial based on symptoms that are common with the disease? This is odd to say the least.

Permalink to Comment

33. Kira on May 5, 2010 2:11 PM writes...

Thanks for the explanation, partial agonist!

...and to get back on track, might they have been concerned about toxicity in the patients with cast nephropathy? If they had to alter the treatment for five patients--well, 24 is a pretty small number to begin with.

Permalink to Comment

34. Myeloma Beacon on May 7, 2010 8:33 AM writes...

We published late last night a number of new details about the suspended SRT501 trial. For example, the five patients who developed kidney problems during the trial were taking just SRT501 at the time they developed kidney issues. Also, the dose that was used during the trial was sufficiently high that it caused nausea and vomiting in some patients, which may have been a key factor causing the observed renal failure. The article can be found here: http://www.myelomabeacon.com/news/2010/05/06/suspended-resveratrol-clinical-trial-more-details-emerge

Permalink to Comment

35. Spiny Norman on May 8, 2010 9:29 PM writes...

http://www.jbc.org/content/285/11/8340.abstract

SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1

Abstract
Sirtuins catalyze NAD+-dependent protein deacetylation and are critical regulators of transcription, apoptosis, metabolism, and aging. There are seven human sirtuins (SIRT1–7), and SIRT1 has been implicated as a key mediator of the pathways downstream of calorie restriction that have been shown to delay the onset and reduce the incidence of age-related diseases such as type 2 diabetes. Increasing SIRT1 activity, either by transgenic overexpression of the Sirt1 gene in mice or by pharmacological activation by small molecule activators resveratrol and SRT1720, has shown beneficial effects in rodent models of type 2 diabetes, indicating that SIRT1 may represent an attractive therapeutic target. Herein, we have assessed purported SIRT1 activators by employing biochemical assays utilizing native substrates, including a p53-derived peptide substrate lacking a fluorophore as well as the purified native full-length protein substrates p53 and acetyl-CoA synthetase1. SRT1720, its structurally related compounds SRT2183 and SRT1460, and resveratrol do not lead to apparent activation of SIRT1 with native peptide or full-length protein substrates, whereas they do activate SIRT1 with peptide substrate containing a covalently attached fluorophore. Employing NMR, surface plasmon resonance, and isothermal calorimetry techniques, we provide evidence that these compounds directly interact with fluorophore-containing peptide substrates. Furthermore, we demonstrate that SRT1720 neither lowers plasma glucose nor improves mitochondrial capacity in mice fed a high fat diet. SRT1720, SRT2183, SRT1460, and resveratrol exhibit multiple off-target activities against receptors, enzymes, transporters, and ion channels. Taken together, we conclude that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

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