Terra Sigillata

GlaxoSmithKline to buy Sirtris

Just a little blurb in my local paper this morning that is making a big splash in the stock market: international pharma giant GSK is purchasing Cambridge, MA-based Sirtris Pharmaceuticals Inc. for an estimated US$720 million.

Glaxo plans to bolster its pipeline with Sirtris’s experimental biotechnology treatments targeting aging-related diseases.

In early trading, Sirtris shares gained 81.6 percent to $22.21 while Glaxo shares added 19 cents to $43.92.

Apparently I should’ve gone immediately from my morning bathroom newspaper reading to my online stock purchase website. Instead, you get a blogpost.

As we wrote here in November 2006, the pipeline at Sirtris is based upon the work of Dr David Sinclair and his mentor, Dr Leonard Guarente, the latter of whom operates a competing company, Elixir Pharmaceuticals.

The investigators had been searching for chemicals that would mimic the life-prolonging effect of caloric restriction in yeast and rodents. Of interest to me was that the red wine antioxidant compound, resveratrol, popped out as an active compound from their screening. Resveratrol appears to act as an activator of the SIRT1 family of histone deacetylases, known also as sirtuins, that control insulin sensitivity and mitochondrial bioenergetics. These effects have been shown to enhance longevity but also have applications in the treatment of type II diabetes and obesity.


The problem with resveratrol as a drug is that it has poor oral bioavailability – that means that when taken orally, not enough of the drug gets into the bloodstream to have effects consistent with effects observed in yeast culture (in Sinclair’s animal studies, unrealistically high doses were given to rodents). Instead, Sirtris has generated semi-synthetic analogs of resveratrol and other compounds that have much better potency and bioavailability that are 1) more likely to become a real drug and 2) comprise patentable intellectual property.

Others more knowledgable than I will comment on the mechanisms of action of these compounds and their link to age-prolongation, diabetes, and obesity.

But I wanted to give readers one concrete example of a situation where Big Pharma has become interested in bringing to market a technology originally developed under the realm complementary and alternative medicine (CAM). Dietary supplement companies have been selling resveratrol for more than a decade, despite the fact that most of it ends up in the municipal wastewater stream. However, the ability of Sirtris to build upon the promise of resveratrol in the laboratory and generate drug-like molecules that can be given to rodents (and, hopefully, humans) in realistic doses has led to a significant financial investment by one of the biggest players in the international pharmaceutical industry.

Hence, when hardcore basic science is brought to bear on natural products used in complementary and alternative medicine, real advances in pharmacotherapy can result. In this case, questionable “medicine” stands a chance to become real, evidence-based medicine.

And when naysayers and conspiracy theorists complain that pharma is only interested in squelching natural medicines, we can use this case as an example of where pharma found enough support in the science to justify a major investment. Sirtuin modifying agents may still crash and burn in the clinic, but this buyout is evidence that natural products still serve as a great source for novel biological activities.

An Aside
Looking back on my old post, I was reminded that my interest in sirtuin-mediated longevity therapies was stimulated by a beer-fueled discussion with journalist, author, and Intersection blogger, Chris Mooney. My laboratory has dabbled in epigenetics of gene regulation due to natural product-mediated histone modifications and Chris reminded me that he had written a freelance article on Sinclair and sirtuins back in January 2004. The link to the article itself is now dead, including its assocaited comment thread, but here is what I wrote following Chris’ visit to Pharmboy land a year-and-a-half ago:
The section of the article under the header, “Raise Your Glass,” makes for some impressive, prescient writing by Mooney that holds up today:

Resveratrol, Sinclair finds, also activates the human analog of Sir2p, known as SIRT1, when tested on cultured human cells in the laboratory. The central question now, wrote Sinclair, is, “Do sirtuin activators extend life span in higher organisms?”

Sinclair says he thinks the answer might be yes. What’s more, he says that soon-to-be-published research will describe a previously unknown connection between the IGF-1/insulin and Sir2 pathways. At several meetings in 2003, researchers in the United States and the Netherlands reported that SIRT1 controls the activity of a set of specialized proteins in the insulin/IGF-1 signaling pathways that control gene activity. These proteins, in turn, appear to turn on genes that defend cells against so-called oxidative damage, which occurs when the chemically unstable byproducts of metabolism relentlessly assault our DNA and cellular machinery. This finding is particularly exciting because many scientists believe that oxidative damage fuels cell deterioration and thus aging.

Given the hint of such linkages, and looking ahead to 2004, Sinclair says we might be reaching a point of convergence between a body of research concerning genes that control longevity and an even more vast body of research on calorie restriction. “Things are pointing towards a day, maybe not too far in the future, where we would have final proof that these two fields have merged,” he says.

I had a good laugh, as I’m sure Chris will as well, from an anonymous commenter who wrote then:

Chris Mooney is just one gullible guy. But then he listens to the experts who, so far, haven’t come up with a single thing to advance longevity or slow aging. Instead we see Olshansky and Binstock quibbling about anti-aging medicines. The idea prevails that somehow advances in pharmacology and stem cell research is going to make a big or even just a minor difference when, so far, there is no evidence that either will make one iota of difference.

It’s always been impressive to me to see scientific hypotheses ideas hold up and bear out over years or decades. But having spent a few days with Mooney and learn of his drive and intellect made me realize also how impressive it is to see the hunches of a good science journalist hold up and bear fruit nearly three years later.

. . .and net a controversial scientific idea $720 million another two years later.

P.S. My British buddy Jack/Insider at Pharmagossip gets up earlier than I.

Comments

  1. #1 Doc Bushwell
    April 23, 2008

    Very interesting news, Abel! Pharma-dr has never lost interest in natural products. However, the scaled-up synthesis of a pure compound with 20 chiral centers is daunting to say the least! That said, natural products can provide the template for rational drug design in a number of ways as you have highlighted here.

    comment on the mechanisms of action of these compounds and their link to age-prolongation, diabetes, and obesity.

    A fascinating subject! The mechanism of action, of course, depends on whether one aims toward allosteric interactions with the SIRT proteins as activators or antagonists or if one blocks the active site of the enzyme directly. Keep in mind that there are multiple SIRTs in humans with apparently different function. Also, the product of the enzyme, O-acetyl ADP-ribose, may be a signaling molecule in and of itself. Maybe I should slap a little review on the Refuge on this intriguing class of enzymes.

    As a little aside, a friend and former colleague is a director at Sirtris. I’ll have to get the nitty gritty news from him.

  2. #2 Joe
    April 24, 2008

    APB wrote “Dietary supplement companies have been selling resveratrol for more than a decade, despite the fact that most of it ends up in the municipal wastewater stream.”

    As I understand this- some in vitro activity was observed and supplement manufacturers put inactive products on the market. Am I wrong? If I am right, it is another example of disreputable activity on the part of said manufacturers.

    This is a good example of pharmacology moving ahead. We know that drugs are available in nature, we just don’t know where (how reliable is ethnobotany?), or how to identify many (for lack of cheap, rapid screening).

  3. #3 Abel Pharmboy
    April 24, 2008

    Doc B, you are likely to have already seen that Derek Lowe has an optimistic post on the purchase at In the Pipeline. Among his points, he raises the question of how one does a Phase II trial for life extension – what’s the surrogate marker?

    Joe, the current law permits supplement companies to put inactive compounds on the market. I’ll be inclined to call that unethical rather than disreputable but I agree that it is still wrong regardless.