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GlaxoSmithKline Halts All Further Development Of Resveratrol Drug SRT501

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Published: Nov 30, 2010 3:28 pm

GlaxoSmithKline has announced that it is halting all further development of its proprietary formulation of resveratrol known as SRT501.

A key factor in this decision, according to the company, was that it no longer feels the drug offers an adequate efficacy / safety trade-off as a potential treatment for multiple myeloma.

Earlier this year, Glaxo suspended its Phase 2 trial of SRT501 in multiple myeloma because several patients in the trial developed kidney failure.

At the time, it was unclear if the kidney failure cases were due to SRT501, or if they were a natural consequence of the patients’ multiple myeloma. The form of kidney failure that was observed – cast nephropathy – is a common complication of multiple myeloma, so much so that it is often described as “myeloma kidney.”

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 terminate the Phase 2 trial of SRT501 in multiple myeloma and halt development of the drug as a potential myeloma treatment. The SRT501 formulation of resveratrol “may only offer minimal efficacy,” explained the Glaxo spokesperson, while increasing the chances of kidney failure.

It is currently uncertain why GlaxoSmithKline decided to terminate all further development of SRT501.  The company could have ended trials of the drug as a possible myeloma treatment, but continued to test the drug in trials for other diseases.  [See Update #2 below.]

The resveratrol in SRT501 is from a plant-based source. It is micronized, or milled into very small uniform particles, to maximize uptake into the body. Patients in the SRT501 multiple myeloma trial received a relatively high dose of resveratrol – 5 grams of SRT501 – once per day.

Resveratrol is a molecule found in small quantities in the skin of red grapes and in red wine. It is thought to be the source of red wine’s reported health benefits.

Previous studies have indicated that resveratrol may be effective at killing cancer cells, including multiple myeloma cells.

Scientific evidence for these claims has been controversial and confined mostly to the laboratory. The SRT501 trial was the first attempt to determine the effectiveness of resveratrol in treating multiple myeloma patients.

Update #1 (November 30, 2010; 4:10 pm) -  The full text of GlaxoSmithKline's statement to The Myeloma Beacon regarding its decision to halt further development of SRT501 is as follows:

GSK will terminate its phase IIa study of SRT501 in advanced multiple myeloma. We have taken this decision following a comprehensive analysis of the data which suggested this formulation of resveratrol may only offer minimal efficacy while having a potential to indirectly exacerbate a renal complication  common in this patient population.

This same analysis also reviewed the cases of acute renal failure in five study patients, which had triggered the suspension of new patient enrolment in April this year. This analysis concluded that these renal failure cases were most likely due to the underlying disease, as kidney complications related to myeloma occur in up to 50% of cases. 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 renal failure.

Investigators and regulators in the UK and Denmark, where the study was being conducted, were consulted on the analysis of the data and unanimously supported the decision to terminate the trial at this time.  There are no further plans to develop SRT501.

Update #2 (November 30, 2010; 5:30 pm) - 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. Neither of these drugs, however, is currently being tested as a potential treatment for multiple myeloma.

The full Glaxo statement to the Beacon on this matter was as follows: "We are focusing our efforts now on more selective SIRT1 activator compounds that have no chemical relationship to SRT501 and more favorable drug-like properties.  Currently we have two of these latest generation compounds (SRT2104 and SRT2379) in several exploratory clinical trials."

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  • Ronda Harrison said:

    This is not particularly surprising. The highly modified version of resveratrol called SRT501 which Glaxo was testing is a corruption of the natural resveratrol molecule created by Glaxo to allow them to patent it and control the distribution through pharmaceutical channels.

    The lesson here is that when a big pharma takes a safe and effective natural compound and modifies it for profit the results are often to destroy the desirable properties of the natural version without adding to its efficacy.

  • Ed Holliday said:

    As I see it the dilemma for Glaxo, was always that the products they are developing already exist in safe effective natural, inexpensive form. Given, his synthetic analogs may be more potent or targeted against specific metabolic pathways and transcription factors, but there exist other stilbenes such as pterostilbene with superior such properties. Biotivia transmax, the concentrated resveratrol being used in the human trials at a number of medical schools, has been extensively tested and shown to be non toxic even at a high dose and is available now, not five to seven years from now which is normal for new pharmaceuticals. Synthetic analogs historically have been shown to be somewhat unpredictable in effect and safety. Why not simply stick with the natural form? To succeed from this point forward Glaxo will have to come up with sythetic versions of resveratrol that are shown to be clearly superior to resveratrol itself and just as safe. So far this has not happened.

  • Dr Susanne Fleming said:

    One of the issues that several researchers have voiced concern over is the practice of micronizing resveratrol. This practice results in a very rapid but short-lived spike in resveratrol blood plasma concentration, effectively multiplying the dose initially but dramatically lowering the half life of the resveratrol and its metabolites overall. The optimum particle size according to our trials is approximately 65 microns.

    The sellers of so-called micronized resveratrol should be required to take these products off the market until their supplements are declared safe. No toxic effects have been reported with respect to normally granulated resveratrol however.

  • HannaO said:

    Ronda you are spot on! Well said.

    I understand that it is important to figure out how much of a natural product to take for it to be effective. I also get that we need to make a product bio-available.

    I wish there was a group that raised millions of dollars to hire the brightest and best of various specialists including the "ancient medicine" specialists to conduct our own clinical trials. They would test natural products that, once we knew how much to take and how to take it, would not make millions for drug companies. They might include brewer's yeast, curcumin, green tea, cranberries, garlic, etc.

    We already raise millions of dollars for cancer research. Why can't we do the same to fund natural solutions? For now, keep making your green juices and throw in some red grapes once in a while. Grapes that aren't GMO or full of pesticides.

  • Istvan Zoltan PhD said:

    This may help to make funding for studies on the natural form of resveratrol a bit more forthcoming. The Albert Einstein study on pre diabetes is being expanded in collaboration with the Mayo Clinic soon and a new human clinical trial using transmax to treat beta thalassemia patients in Italy will begin in January, but given the remarkable results seen in the 3500 studies done as of July of 2010, far more human clinical data would go a long way to confirming or moderating the effect of resveratrol on inflammation, cancer, apoptosis,neurological protection, and the so-called diseases of aging. Bringing the focus back to the natural molecule is one possible benefit to this decision by Glaxo.

  • Chuck said:

    I think everyone needs to be very clear on something ... SRT501 *is* resveratrol. It's not some "synthetic analog." It's not some "corruption of the natural resveratrol molecule." It's resveratrol from a plant source that's been ground down to really fine particles.

    Yes, the high bioavailability of the finely milled resveratrol in SRT501 may play an important role in why patients taking it developed the side effects that contributed to their developing kidney failure. It's possible, therefore, that other resveratrol products that deliver the product in different ways may have different outcomes than observed with SRT501.

    But the reality remains that, in the first clinical trial of resveratrol in myeloma patients, the product had sufficient side effect issues and not enough efficacy that the manufacturer punted on developing the drug further.

    So to those of you who have parachuted into this site to peddle your own version of resveratrol (I'm looking at you, Ed Holliday), I say: Stop the blatant disinformation campaign, and give us *hard* data supporting the use of your resveratrol concoction as a myeloma treatment.

  • AWJourn said:

    As someone who has written about some of the mis-truths spread by anti-aging entrepreneurs, I have to agree with Chuck. This notion that pharma companies don't work with natural substances because they can't patent them is just wrong--it's a misconception that only confuses patients. And when I read about the troubles with SRT501, it worries me that so many consumers are taking super-potent resveratrol that they're buying from companies claiming it's perfectly natural. Just because something comes from nature doesn't mean it's safe. I would urge anyone who is self-medicating with huge doses of resveratrol to think twice.

  • Bixbyte said:

    My wife have been dosing on HUGE doses of Resveratrol 98 and 99% pure for over three Years. I have increased the bioavailability of the Resveratrol by ultrasonicating with HPMC and PG3350. Yes, we both have a Resveratrol plasma spike once a day.
    Visit us sometime and see the results for yourself.

    Happy New Years!