Resveratrol
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.
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