In statements to Fierce Biotech and to the Myeloma Beacon, GlaxoSmihtKline (GSK) said that it has stopped all development of its proprietary resveratrol formulation SRT501. Thanks also to the “In the Pipeline” blog for the information on the Myeloma Beacon statement.
As you all may recall, GSK acquired the sirtuin-pathway specialty company Sirtris (Cambridge, MA) for $720 million in June 2008. This gave GSK ownership of Sirtris’ sirtuin modulator drugs, including SRT501. GSK also appointed Christoph Westphal, then CEO of Sirtris, as the Senior Vice President of GSK’s Centre of Excellence in External Drug Discovery (CEEDD), and Michelle Dipp, then vice president of business development at Sirtris, as Vice President and the head of the US CEEDD at GSK.
According to the Fierce Biotech article, the precipitating factor in GSK’s decision to halt development of SRT501 was the result of a Phase 2a study of the drug in advanced multiple myeloma. The company suspended the study after several patients developed kidney failure. GSK said that in its analysis, the company concluded that SRT501 “may only offer minimal efficacy while having a potential to indirectly exacerbate a renal complication common in this patient population.” It then said that the company has “no further plans to develop SRT501.”
Instead, GSK intends to focus on development of Sirtris’ non-resveratrol synthetic selective sirtuin 1 (SIRT1) activators, which in addition to their greater potency, have more favorably drug-like properties. In its statement to the Myeloma Beacon, GSK in particular mentioned SRT2104 and SRT2379 as the focus of its continuing activity. According to the Sirtris website, SRT2104 is in Phase 2 studies in metabolic and cardiovascular disease, and SRT2379 is in Phase 1 studies in healthy volunteers. Neither compound is currently being tested in cancer.
We discussed Sirtris’ SIRT1 activators in the context of the anti-aging biology field, in a February 10, 2010 blog post. In summary, the mechanism of action of reseveratrol and of Sirtris/GSK’s sirtuin activators is unclear. They apparently activate multiple targets, and they may not be direct SIRT1 activators at all. Nevertheless, Sirtris’ studies of these compounds in mice indicate that they have efficacy in treatment of metabolic diseases. The Phase 2 clinical trials in humans are still ongoing.
To complicate matters further, a study published in the journal Diabetes in March 2010 by NIH researcher Jay H. Chung and his colleagues indicates that resveratrol works indirectly, via the energy sensor AMP-activated protein kinase (AMPK), to activate sirtuins. Since activation of AMPK increases fatty acid oxidation and upregulates mitochondrial biogenesis, the effect of resveratrol on AMPK may be more important than its more indirect activation of sirtuins, at least in the case of metabolic diseases.
Thus Sirtris/GSK’s “sirtuin activators” are under a cloud.
However, as we discussed in our blog posts of November 8, 2009 and February 10, 2010, basic research on anti-aging biology has yielded ample material for drug discovery which may eventually lead to novel treatments for metabolic diseases, and perhaps for other conditions such as various cancers. For example, several companies are developing AMPK activator drugs. Thus there are other avenues for harnessing basic research on anti-aging pathways to discover and develop novel drugs for multiple conditions, even if the Sirtris compounds prove to be a dead end.
>>911 >resveratrol works indirectly, via the energy sensor AMP-activated protein kinase (AMPK), to activate sirtuins. >Since activation of AMPK increases fatty acid oxidation and upregulates mitochondrial biogenesis, the effect of resveratrol on AMPK >may be more important than its more indirect activation of sirtuins, at least in the case of metabolic diseases.
>>923 Longevinexについて、Biotiviaはこんな発表をしている Recent study by Resveratrol Partners shows that Longevinex suppressed SirT1 activation and had no effect on the other 6 Sirtuins Resveratrol Partners is a start up California company that sells a supplement called Longevinex. This product consists of a combination of low dose Resveratrol, Quercetin and rice bran as filler. The company recently released results of a study they commissioned on the gene activation effects of Longevinex.
The results of this study strongly contradict the company's own emphatic claim that Longevinex activates the Sirt1 gene. In fact, the study data clearly confirms that low dose Resveratrol combined with Quercetin does not activate the SirT1 gene nor does it activate any of the other sirtuins. According to their own findings this combination resulted in a startling reduction of Sirt1 activation by a factor of 1.7 times.
This conclusion definitively validates Biotivia's position that, 1. A high dose of quality Trans-Resveratrol is required to obtain SirT1 activation and, 2. Quercetin suppresses SirT1 transcription.
Below are excerpts taken directly from the Longevinex study. In the study Longevinex is referred to as NCM.
The mammalian sirtuin proteins are proposed to be critical mediators of the effect of CR and Resveratrol; of the seven sirtuin genes identified in mice, only Sirt1 was changed by any treatment in this study (decreased -1.7-fold by Longevinex from the microarray;)
Moreover, Sirt1 expression was significantly decreased in expression
in the Longevinex mice from the microarray data (Figure 2D) and Sirt1 expression was not changed by any treatment according to the RT-PCR data
The ability of Transmax and Bioforte to activate the SirT1 gene was confirmed by the National Advertising Division of the National Better Business Bureau in their decision pursuant to Longevinex's complaint against Biotivia in February of this year. We here at Biotivia feel extremely gratified that once again our reliance upon peer reviewed scientific evidence and strict adherence to quality control and sound product design have been vindicated. http://www.biotivia.com/company/news/longevinexsupressedsirt1.html
I started taking Biotivia 500mg one year ago. The first thing I noticed was that I started getting tired more quickly when running or cross-country skiing. Because of that I stopped taking resveratrol for a week or two and then started again. Later I also stopped for a while and felt better during those breaks.
In May I noticed my hair is getting grey (I was 42). I had made some dietary changes too (for example started using more cacao and less coffee) and also had started to take 5000IU of D3 daily first time ever. I can't be sure that resveratrol caused the greying of my hair but it's on the list of suspects.
I continued to take resveratrol (mostly 250mg now) until last December and then stopped. Right now I'm trying the tips on this forum for reversing grey hair. Maybe later I will start again taking resveratrol but it will be a small dose of 50-175mg. Currently my view for any supplement is that the dose should be low, just providing the amount we are missing because of not eating optimal diet. High dose is unnatural and will have consequences.
This resveratrol manufacturer says the optimal dose is 175mg:
これも入れたがよくない? The effects of resveratrol are currently a topic of numerous animal and human studies. Its effects on the lifespan of many model organisms remain controversial,with uncertain effects in fruit flies, nematode worms,[1] and short-lived fish. In mouse and rat experiments, anticancer, anti-inflammatory, blood sugar-lowering and other beneficial cardiovascular effects of resveratrol have been reported. These results have yet to be replicated in humans. In the only positive human trial, extremely high doses (3?5 g) of resveratrol, in a proprietary formulation designed to enhance its bioavailability, significantly lowered blood sugar. This 28-day Phase 1b study was conducted privately in India by pharmaceutical company Sirtris, and was announced in an investors conference in 2008. However, although it has been alluded to in review articles, the study itself has never been published in a peer-reviewed scientific publication. Despite mainstream press alleging resveratrol's anti-aging effects,"there are no accepted data to form a scientific basis for the application of these claims to mammals"(see Life-extension section below). There are also a number of potential dangers posed by resveratrol