19 replies to this topic

[VP.]

In a possible setback for scientists attempting to make drugs out of a substance found in red wine, GlaxoSmithKline PLC said a clinical trial of one drug in cancer patients has been halted due to safety concerns.

Glaxo acquired the drug in 2008 when it paid $720 million for Sirtris Pharmaceuticals, a biotech company in Cambridge, Mass. The drug, known as SRT501, contains a reformulated version of resveratrol, a substance found in low quantities in red wine.
Glaxo said Tuesday it has halted a small trial in multiple myeloma, a cancer of the plasma cells in bone marrow, because some patients developed a complication called cast nephropathy, a condition that can cause kidney failure.

George Vlasuk, chief executive of Sirtris, said in a phone interview that the complication is common in multiple myeloma patients and "may or may not be related to" the drug. Glaxo halted the trial "out of an abundance of caution" while it studies the data further, he said.

Dr. Vlasuk said Tuesday that the compounds "do activate SIRT1" and that Glaxo and Sirtris plan to publish a paper soon to clarify their case. He also raised questions about the way Pfizer tested the compounds' efficacy on blood-glucose levels, and said Pfizer's result "is not consistent with at least six papers published by independent laboratories that appear in the scientific literature."

"We're very confident in not only the science we're doing but we're also very confident in the direction we're going in," Dr. Vlasuk said. "With that said, we're still trying to understand at the molecular level how these compounds actually work."
http://online.wsj.co...s_LEFTWhatsNews

[tunt01]

doesn't surprise me in the least.

[niner]

Wow, not even the NCEs, just good ole resveratrol! Well, maybe cast nephropathy is common in MM, but it doesn't look good for GSK. There are a lot of other resveratrol cancer trials going on, aren't there? It will be interesting to see if the awesomely palindromic SirtriS can beat back the ogres of Pfizer.

[Anthony_Loera]

Here is a quote from Bloomberg:

http://www.bloomberg...id=asLl7NcxtEc8

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.

I was reading about it yesterday here:
http://pipeline.cora...l_suspended.php

here are some quotes:

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.

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!

From the quotes, I am not sure if it was do to Velcade's toxicity (maybe?), Resveratrol at 5 grams (probably not), or that patients that signed up for the study where at the tipping point and developed nephropathy...

How toxic is Velcade again? And doesn't it cause Kidney failure or nephropathy by itself as possible side effect of that drug? In the past we have known that resveratrol does increase the strength or length of some medications. It's certainly possible, this could have happened here as well, while using 5 grams a day with Velcade (which is a cancer med that can be toxic).


It is funny, but combinations of resveratrol with ceramides are also being considered. Here is an April study:
http://www.ncbi.nlm....7?dopt=Abstract

Edited by Anthony_Loera, 05 May 2010 - 12:36 PM.

[tunt01]

I read the In The Pipeline comments also. They aren't obligated to release the data. But we know that resveratrol is nephrotoxic at high doses, and putting the blame on Velcade alone seems to be a "hopeful" conclusion. High dose resveratrol is just plain bad.

Edited by prophets, 05 May 2010 - 03:18 PM.

[drmz]

I read the In The Pipeline comments also. They aren't obligated to release the data. But we know that resveratrol is nephrotoxic at high doses, and putting the blame on Velcade alone seems to be a "hopeful" conclusion. High dose resveratrol is just plain bad.

Yep it is just plain bad. Too bad Anthony keeps promoting high dosing at any cost. I would do the same if i was a wonder pill retailer.

Edited by drmz, 05 May 2010 - 03:37 PM.

[Anthony_Loera]

drmz,

Nephrotoxic? It appears most studies show the opposite:
http://scholar.googl...m...o=&as_vis=1

Maybe it was this one at 3 grams/kg? That amounts to 180 grams a day. As you know, anything is toxic at high enough amounts, even water. So this is quite unrealistic. http://toxsci.oxford...t/full/82/2/614

I do not promote 180 grams a day, I also do not promote Sirtris's 5 grams of micronized resveratrol in cyclodextrin a day. No one even makes this available to the public..


Did you know that we have low dose capsules ranging from 100mg, 250mg, 300mg, 500mg, and 1000mg for everyone young and old?

Cheers
A

Edited by Anthony_Loera, 05 May 2010 - 05:58 PM.

[zorba990]

Key phrase above : ""reformulated version of resveratrol"

I read the In The Pipeline comments also. They aren't obligated to release the data. But we know that resveratrol is nephrotoxic at high doses, and putting the blame on Velcade alone seems to be a "hopeful" conclusion. High dose resveratrol is just plain bad.

Yep it is just plain bad. Too bad Anthony keeps promoting high dosing at any cost. I would do the same if i was a wonder pill retailer.

[tunt01]

http://toxsci.oxford...t/full/82/2/614

kidney toxicity. is this substantially more than in human trials? yes. BUT

not everyone is the same. some people have predisposed issues with their kidneys, other supplements which can act as co-factors in kidney damage (similar to Velcade's potential role). And I would remind all that one person calculated Nitro 250 as having a peak plasma load equivalent to ~4.5grams of resveratrol. That would be higher than what was used in a now terminated clinical trial.

Does that make it better? In my opinion, no. Is it due to Velcade's role? Can't say with certainty. Should anyone be taking high dose resveratrol? IMO, it's a bad idea.

Edited by prophets, 05 May 2010 - 04:53 PM.

[Anthony_Loera]

Prophets,

our estimate is not 18x, but about 5x. Stevei (or you) really do not know our exact formulation to make any solid estimates.
In the end, your opinion is just that...an opinion. While we have to deal with label claims, the FDA, and the FTC.

So, about 5x stands.

(Seriously according to the resveratrol tox study a minimum of 48 capsules would be needed, if we calculate 1 gram per kg at the 5x estimate...). At 3g per kg (which is when the issues were noted in the study) it would still take 144 capsules a day!

None of these are realistic or supported in any way.
Again, our 5x estimate still stands, and our products are very safe indeed.

Cheers
A

Edited by Anthony_Loera, 05 May 2010 - 05:25 PM.

[mikeinnaples]

Yep it is just plain bad. Too bad Anthony keeps promoting high dosing at any cost. I would do the same if i was a wonder pill retailer.

High dosage? The largest I can find on the website is 1 gram.

Can you provide me a link to high dosage promotion so I can see it for myself?

Thanks

[Ringostarr]

Not to get off subject but the reason we are even talking about this is that Sirtris basically has misinformed the public about how much resveratrol is needed for health benefits - all in order to make the case for its NCE's. Very shady indeed.

[Anthony_Loera]

I actually find this pretty interesting, and think GSK and Pfizer will continue to fight it out:

Dr. Vlasuk said Tuesday that the compounds "do activate SIRT1" and that Glaxo and Sirtris plan to publish a paper soon to clarify their case. He also raised questions about the way Pfizer tested the compounds' efficacy on blood-glucose levels, and said Pfizer's result "is not consistent with at least six papers published by independent laboratories that appear in the scientific literature."

As a side note, velcade is toxic enough to be limited to small milligram doses.

Here are interesting PDFs for folks on Velcade (bortezomib):
http://velcadesearch...INFORMATION.pdf
http://www.community...les/0408480.pdf



Cheers

A

Edited by Anthony_Loera, 05 May 2010 - 06:19 PM.

[maxwatt]

I read the In The Pipeline comments also. They aren't obligated to release the data. But we know that resveratrol is nephrotoxic at high doses, and putting the blame on Velcade alone seems to be a "hopeful" conclusion. High dose resveratrol is just plain bad.

Yep it is just plain bad. Too bad Anthony keeps promoting high dosing at any cost. I would do the same if i was a wonder pill retailer.

If I was a retailer, I would promote LOW doses, as this would greatly reduce my costs. And if I could fill up the rest of the capsule with hedge clippings or waste material from rice bran processing, and sell it as part of a miracle combination at low cost and high markup, I would do that too. I think Anthony responds to public demand, and his formulations have pretty much followed the demands and (sometimes) speculations of users in this group.

As far as the Multiple Myeloma study goes, the only thing it definitely hints at is that resveratrol does not make an effective treatment for Myeloma. This was also the conclusion a year ago among Myeloma patients in one of their newsgroups, and in Margaret's Corner blog.

I wonder if they'll ever do a study vis-a-vis arthritis, something I found moderate doses of resveratrol very effective at controlling, much more so than any anti-arthritis drug I've been prescribed. Or maybe that's why it isn't being tested; prescription and OTC NSAIDs are already profitable and this would cut into their sales.

Just so we speak the same language, here is my classification of dosages:

< 10 mg Minuscule
< 100 mg Minute
< 250 mg LOW
<= 500 mg MODERATE
<= 1 gram HIGH
<= 2 grams VERY HIGH
<= 5 grams Pharmaceutical
<=7 grams Maniacal
>7 grams Thaumaturgical

As Oscar Wild may have said, one man's Meade is another man's Persian.

[tunt01]

I actually find this pretty interesting, and think GSK and Pfizer will continue to fight it out:

honestly, it means nothing other than PR/saving face for the efforts of GSK's top mgmt. If they were to say, "OK, we agree Pfizer is right," the CEO could be out on his ass the next day for having botched a $800 M acquisition. they will see it through one way or another, even if it takes 2-3 more years for "certainty" of failure.

it's all talk and BS for Moncef & his cornies until they have positive clinical results. they onus is on them, not pfizer.

[ken_akiba]

Resveratrol is great because its popularity in the West keeps Japan weed free :-)
- For those who may not know, Resveratrol is derived from a rather ugly weed called Japanese knotweed -

Other than that, I hardly see much benefit from it. Resveratrol has been approved as Kampo medicine (Folk medicine) from 80's in Japan, but has never been popular till today.
- Folk medicine is governed in Japan and Kampo doctors need license to practice it -

Edit: Personally I think it is silly to attribute French Paradox to Resveratrol.

Edited by ken_akiba, 05 May 2010 - 08:41 PM.

[niner]

I read the In The Pipeline comments also. They aren't obligated to release the data. But we know that resveratrol is nephrotoxic at high doses, and putting the blame on Velcade alone seems to be a "hopeful" conclusion. High dose resveratrol is just plain bad.

Well, Velcade is known to be pretty nasty, and resveratrol isn't, if one considers this fairly long list of resveratrol clinical trials. The same study that found kidney problems in rats at a human equivalent dose a half a pound a day also declared that the NOAEL was 300mpk! I can't call resveratrol "toxic" on that basis. Cast nephropathy is sometimes called "myeloma kidney", according to one of the In the Pipeline commenters. Before I could draw any sort of conclusion from this, I would want to know what the cast nephropathy rate was for people with MM who get Velcade alone. With a study of only 24 patients, it's not terrifically highly powered. Is this a case where if one less patient (4 instead of 5) had gotten the complication, everything would have looked normal? We just don't know. There really aren't any conclusions I can draw from this event in the absence of more information.

[ken_akiba]

My apologies. I'm deleting the post because I need more digging.

OK

http://www.sirtrisph...m/pipeline.html

Excerpt:
SRT501, a formulation of resveratrol with roughly five times higher bioavailability than the natural product.
Completed Phase IIa trial in Type 2 Diabetes (Elliott et al. Drugs Future 2009, 34, 291-295.).
Currently under way with a Phase IIa trial in oncology.

http://journals.prou...t...96&p_IsPs=N

This is the url for the upper mentioned Elliott et al. Drugs Future 2009, 34, 291-295.
They are asking $100 for a copy, no thanks. Judging from near total lack of press release on the result of this study, I wouldn't expect stellar result.

http://www.sirtrisph...s-diabetes.html

Here they mention SRT501 study together with metformin. I can't find the result anywhere. Maybe included in the above $100 article? Though outline of the article doesn't mention metformin.


Now back to this thread's topic (the suspended Phase IIa oncology trial)

First, excerpt from Reuters' story:
http://www.reuters.c...E6435A620100504

The mid-stage Phase II study, conducted in Britain and Denmark, was assessing the safety and tolerability of SRT501 with or without the established cancer drug Velcade from Takeda Pharmaceutical.

Second, excerpt from Bloomberg's:
http://preview.bloom...ney-damage.html

The study is being done to evaluate the safety of the treatment alone and in combination with Takeda Pharmaceutical Co.'s Valcade....

Now pay attention to the phrase "with or without" and "alone and in combination with".
In other words, they were doing two studies: One with SRT501 alone (Let's call it trail A) and the other one, Velcade + SRT501 (Let's call it trial B)

What is conspicuously missing from Bloomberg's and Reuters' report is that,
Is it trial A or trial B that resulted in (or could not prevent) development of Cast Nephropathy?

I would say both trials or at least trial A (SRT501 alone). Had Cast Nephropathy developed only in trial B (Velcade + SRT501), they would have made it clear that trial A (SRT501 alone) prevented development of Cast Nephropathy and they would have not suspended trial A.

Summing up,
1. Administering SRT501, in best scenario, failed preventing development of Cast Nephropathy and in worst scenario, Administering SRT501 fueled development of Cast Nephropathy.
2. In all likelyhood, SRT501 did not exhibit synergistic enhancement to Velcade's efficacy (or possibly even lowered efficacy of Velcade).

Edited by ken_akiba, 06 May 2010 - 04:33 AM.

[tunt01]

http://twitter.com/R...ses/13549842596

Sinclair chips in his remark. It's not entirely clear which drug he's talking about, but w/e.

[unglued]

... Sirtris representatives also have told the Beacon that all patients who experienced kidney failure during the trial were being treated with only SRT501 when their kidney problems developed.
...
“This was most likely a manifestation of the underlying myeloma.” Dr. Jacobson noted that SRT501 has not caused a single case of kidney failure in any of the previous trials of the drug, which involved some 340 healthy persons, colon cancer patients, and diabetes patients. “We have never seen another case of [kidney] failure except in this myeloma study.”
...
Representatives from Sirtris emphasized in their discussions with the Beacon that the SRT501 myeloma trial has not been stopped. Although new participants are not being recruited at this time, evaluation of SRT501 and its efficacy will continue. “The trial was not stopped. The trial remains active,” said Vlasuk. “We are simply, out of an abundance of caution, trying to understand if SRT501 is actually providing a benefit to these patients. If we determine that’s the case, or at least that it doesn’t have an adverse safety finding, we will continue with this trial.”
...
According to Dr. Nelson Leung, a kidney specialist at the Mayo Clinic in Rochester, Minnesota, cast nephropathy is a common complication of multiple myeloma. It occurs when excess protein blocks the kidney, resulting in kidney failure, and it affects 15 to 30 percent of myeloma patients.
...
Patients in the SRT501 trial were required to have normal kidney function prior to the trial in order to participate in it. Due to the relatively high dose of SRT501 used in the study, however, some participants experienced nausea and vomiting, which could have led to dehydration.
...
“In a patient who was prone to the renal failure from their [myeloma symptoms], ” said Dr. Jacobson, “dehydration could have tipped the balance. That could have been an indirect precipitating cause of the kidney problems.”

-- The Myeloma Beacon, May 6

All of which contradicts some speculation in a L***nex press release of May 4:

The drug trial was designed for some patients to take a resveratrol-based drug alone (SRT501 Sirtris Pharmaceuticals) and other patients in combination with bortezomib (Velcade), a toxic cancer drug. Without greater transparency as to the suspected cause of the safety problem, consumers are left to guess whether it was the drug, resveratrol, or their combination that prompted the study to be closed down.

Apparently Sirtris believes it was neither the drug nor resveratrol, but the disease, possibly combined with dehydration from the 5 grams of resveratrol. And they haven't closed down the trial, just suspended enrolling new subjects.