Patricia F. Fitzpatrick Dimond Ph.D. Technical Editor of Clinical OMICs President of BioInsight Communications

GSK shelled out $720 million for Sirtris but admits that the new science needs validation.

Just what did GlaxoSmithKline (GSK) get for its dime when, in 2008, it dropped $720 million (or 72 billion dimes) to buy Sirtris Pharmaceuticals? It gained small molecule antiaging drugs that work, according to Sirtris, by mimicking some of the beneficial effects of caloric restriction mediated by resveratrol, a compound found in some red wines.

Founded in 2004, Sirtris went public in May 2007 and continues as an independent discovery performance unit within GSK. The buyout was another giant coup for Sirtris founder and Boston biotech entrepreneur Christoph Westphal, M.D., Ph.D. He reportedly could earn up to $25 million from the deal as well as a $2 million bonus to stay on for four years to run Sirtris/GSK. All the investors involved also made a bunch of money. Dr. Westphal has consistently done well for his investors: He co-founded and was CEO of Alnylam Pharmaceuticals, Momenta Pharmaceuticals, as well as Acceleron Pharma and was also co-founder of Concert Pharmaceuticals.

GSK believes that it got a good deal, with Sirtris’ drug candidates adding to GSK’s metabolic-disease drug pipeline. The company said that the acquisition reflected its strategy of pursuing the best new science to bring novel medicines to patients and value to its pipeline. But two research papers recently called into question some basics of the new science underlying Sirtris’ drug candidates. Such confounding results highlight the complexity of SIRT1 activation, the mechanism behind Sirtris’ antiaging candidates.

Yay and Nays for SIRT1 Activation as an Antiaging Tool

A group of investigators at Amgen concluded that “the pharmacological effects of resveratrol in various models are unlikely to be mediated by a direct enhancement of the catalytic activity of the SIRT1 enzyme. In consequence, our data challenge the overall utility of resveratrol as a pharmacological tool to directly activate SIRT1.”

Separately, Pfizer found in in vitro studies using synthetic and natural substrates that SRT1720, SRT2183, SRT1460, and resveratrol did not directly activate SIRT1; SRT1720, SRT2183, and SRT1460 were all identified by Sirtris as candidates at some point. The investigators also found that the compounds were highly promiscuous in their interaction. Additionally, their study of SRT1750’s in vivo efficacy in high fat ob/ob mice did not find a decrease in plasma glucose at comparable dose levels to those used by Sirtris and discovered an increased food intake and weight gain in the treated mice. Higher doses of the drug intended to increase glucose tolerance resulted in three dead mice.

These findings directly contradict the work of David Sinclair, Ph.D., of Harvard Medical School and a Sirtris founding scientist. With regard to Pfizer’s findings, Dr. Sinclair commented, “Purity of the compounds that were used in their study cannot be ascertained due to the lack of data provided. The publication also does not cite nor discuss multiple scientific publications that are in direct contrast to their primary conclusions. As such it is unclear how to place this work in perspective of what has been found by other investigators.”

A large body of basic research does indeed support the nomination of SIRT1 activators as antiaging drugs. SIRT1 activation has profound metabolic effects: It regulates glucose or lipid metabolism through its deacetylase activity for over two dozen known substrates and has a positive role in the metabolic pathway through its direct or indirect involvement in insulin signaling. It also stimulates glucose-dependent insulin secretion from pancreatic β cells and directly stimulates insulin-signaling pathways in insulin-sensitive organs. SIRT1 also reportedly influences adiponectin secretion, inflammatory responses, gluconeogenesis, and levels of reactive oxygen species, which together contribute to the development of insulin resistance.

The importance of SIRT1 is evidenced by the fact that inactivation of SIRT1 has significant consequences: Inbred knockout mice lacking SIRT1 show developmental defects, have a low survival rate, and have a significantly shorter lifespan compared with wild-type mice.

Sirtris based its small molecule drug development programs on basic research conducted by Dr. Sinclair and Leonard Guarente, Ph.D., of MIT who showed that caloric restriction in animals, long known to extend life, is associated with SIRT1 activity. The company’s mouse studies showed that resveratrol “induces gene-expression patterns in multiple tissues that parallel those induced by dietary restriction.”

The study also found a significant increase in lifespan in both the resveratrol-treated group on a high-calorie diet and the resveratrol-treated group on a calorie-restriction diet. The treatments, however, did not extend lifespan in mice on a standard diet. The resveratrol-treated mice did show markers for improved cardiovascular health and reduced aortic stiffness, according to the company.

These findings, the company noted, support the idea that resveratrol can mimic many effects of dietary restriction in vivo. Sirtris said that it has developed thousands of small molecules with much greater potency than resveratrol, allowing administration in much smaller doses. Increasing SIRT1 activity, either by transgenic overexpression of the SIRT1 gene in mice or by pharmacological activation by small molecule activators like resveratrol and SRT1720, the synthetic resveratrol, reportedly delayed the onset and reduced the incidence of age-related diseases such as type 2 diabetes. Sirtris also reported that SRT1720 improved whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle, and the liver.

Based on its research, Sirtris is forging ahead with its Sirtuin program with NCEs that are reportedly chemically distinct from and more potent in vivo than resveratrol. In January 2008, the company announced that its first product to enter the clinic, SRT501, was “found to be safe and well tolerated and to significantly lower glucose in an oral glucose-tolerance test conducted as part of a 28-day Phase Ib clinical study in patients with type 2 diabetes.” In April 2008, the company said that the FDA granted resveratrol orphan drug designation as a treatment of MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). Since then neither GSK nor Sirtris has put out a press release related to its Sirtuin program, but Jamie Morgan, spokesperson for GSK, told GEN that the firm plans a pipeline update shortly.

Nascent Field Is in Need of Validation

And the Sirtuin story will grow more and more complicated. In 2009, MIT’s Dr. Guarente published a study in Genes and Development reporting that sirtuins bring about the effects of calorie restriction on a brain system known as the somatotropic signaling axis, which controls growth and influences lifespan length. “The new study,” Dr. Sinclair commented, “fills in an important missing piece of the sirtuin puzzle—how sirtuins act in the brain to mediate the effects of calorie restriction. Until this paper, the focus has been on tissues like muscles and liver and other organs that control metabolism.” 

Richard Miller, professor of pathology at the University of Michigan Medical School Institute of Gerontology, pointed out, however, that Dr. Guarente’s study did not link SIRT1 knockout with shorter lifespan or declining health. The relationship between sirtuins and longevity, he said, is “more complicated than people had hoped would be the case.” He thinks that sirtuins are likely one of many cell-signaling systems that influence aging.

In an April 2008 interview with Forbes about why GSK acquired Sirtris, Patrick Vallance, head of drug discovery at GSK, said “Like a lot of areas of science, it’s got its controversies, and like many biotechs in this stage with a good pathway, this hasn’t been proven yet. It has to be proven with a medicine.”

Patricia F. Dimond, Ph.D., is a principal at BioInsight Consulting. Email: [email protected].

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