Replies to post #47367 on Biotech Values

[DewDiligence]

> SIRT – What a low key offering from hype-minded guys. They had articles everywhere.<

Indeed they did. Not only a gazillion articles on the company per se, but several articles the concept behind it, e.g. #msg-19420460.

[DewDiligence]

Elixir Pharmaceuticals Presents Additional Preclinical Data Demonstrating the Potential of Ghrelin Antagonism to Regulate Metabolism, Body Weight and Glycemic Control

[The company Elixir is most often compared to is SIRT, which recently IPO’d. How long until Elixir does the same?]

http://biz.yahoo.com/bw/070605/20070605006074.html?.v=1

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Tuesday June 5, 12:16 pm ET

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Elixir Pharmaceuticals, Inc., announced today new preclinical data confirming ghrelin antagonism as a potential method for regulating metabolism, decreasing body weight and managing blood glucose. The data were presented in poster sessions during ENDO 07, The Endocrine Society's 89th Annual Meeting, being held in Toronto, Canada. Elixir is focused on the development of drugs to treat and prevent metabolic disease, as well as prevent age-related diseases, based on targets identified in the pathways regulating aging.

Ghrelin is a key metabolic regulator that is known to stimulate appetite and food consumption and is believed to play a key role in metabolism and energy storage. Ghrelin is a naturally occurring hormone secreted by the stomach, which acts primarily at the level of the hypothalamus in the brain.

In the first presentation, Elixir scientists explored whether ghrelin exerts a direct effect on adipocytes (fat cells) and if the effect is mediated through ghrelin receptor (GhrR) mRNA expression in these cells. To assess this, the scientists first examined ghrelin signaling by measuring insulin sensitivity in mouse adipocyte cell lines that were treated with ghrelin for four days. Scientists also assessed the expression of GhrR mRNA in adipose tissue, isolated adipocytes from mice, and the mouse adipocyte cell-line. The results showed GhrR was detected in the isolated adipocytes and mouse adipocyte cell lines, suggesting ghrelin acts directly through its receptor on adipocytes to regulate energy homeostasis. Moreover, the reduction of insulin signaling in adipocytes by chronic ghrelin treatment provides a possible mechanism for increased insulin sensitivity in GhrR knockout mice.

In two additional tandem presentations, Elixir scientists showed that, compared to control mice, GhrR knockout mice resisted the development of diabetes and obesity associated with a high-fat diet. The presentations further showed that treatment of wild type diabetic and obese mice with a small molecule ghrelin antagonist recapitulated the effects seen in the knockout mice.

In a first series of experiments, Elixir scientists examined the impact of a high-fat diet on fuel utilization and metabolic flexibility in GhrR knockout mice. Increased metabolic flexibility is associated with increased insulin sensitivity and a resistance to diabetes. As expected, long-term exposure to a high-fat diet caused an overall decrease in metabolic flexibility in the wild type mice; however, this trend was reversed in the GhrR knockout mice fed the same diet.

In another series of experiments, GhrR knockout mice were fed a high-fat diet for 15 weeks, with their body weight and food intake monitored throughout the experiment. The results showed after 15 weeks on the diet, the GhrR knockout mice gained 10 percent less weight than the wild type control mice. Additionally, the knockout mice had lower blood glucose, insulin and HbA1c levels. These results indicate the knockout mice are less prone to the development of diabetes.

The scientists then compared the results of the GhrR knockout mice to those obtained with mice treated twice a day for up to 56 days with one of the Company's potent, small molecule GhrR antagonists. As with the GhrR knockout mice, the antagonist-treated mice showed improved glucose and insulin control compared to the mice treated with vehicle. In addition, the GhrR antagonist treatment resulted in a significant reduction in liver fat content with no evidence of liver toxicity relative to the mice vehicle-treated mice.

"Ghrelin antagonism represents one of the most intriguing new targets for addressing metabolic disorders such as Type 2 diabetes, obesity and other metabolic disorders. Our compilation of preclinical data, including these presentations, has shown it is possible to improve glucose control, decrease fat, including in the liver, and to regulate metabolism through the inhibition of ghrelin," stated Peter DiStefano, Ph.D., Chief Scientific Officer. "EX-1350, our small molecule ghrelin antagonist, is currently undergoing IND-enabling studies, with the goal of initiating first-in-man clinical studies in early 2008."

Amongst metabolic diseases, diabetes and obesity are at epidemic proportions in the U.S. and represent an enormous unmet medical need. According to the International Diabetes Federation, Type 2 diabetes affects 195 million people worldwide and the number of sufferers could top 330 million by 2025.

Elixir has filed broad intellectual property protection on all aspects of the ghrelin antagonist program including composition of matter protection covering five novel compound classes and their therapeutic uses.

About Elixir Pharmaceuticals

Elixir is a Cambridge, MA-based biopharmaceutical company focused on developing and commercializing drugs to treat and prevent metabolic disease, prevent age-related diseases, ultimately extending the quality and length of human life.

In addition to its ghrelin antagonist program, the Company has leveraged its knowledge of ghrelin biology and pharmacology by licensing a small molecule ghrelin agonist (designated EX-1314) from Bristol-Myers Squibb Company in April 2005. EX-1314 binds selectively to the ghrelin receptor and mimics the body's naturally occurring ghrelin. In doing so this novel, orally available agent is capable of stimulating appetite, gastric motility and the release of growth hormone. Elixir is currently in IND-enabling studies with EX-1314 targeting a variety of therapeutic indications.

Further, in March 2006, Elixir in-licensed North and South American rights to Glufast® (mitiglinide calcium hydrate), an insulin secretagogue, which lowers post-meal glucose levels by improving the body's own ability to produce insulin. Already marketed in Japan, Glufast has undergone extensive clinical development demonstrating the product's ability to safely and effectively treat Type 2 diabetes.

Elixir has also developed expertise and a broad IP portfolio of more than twenty patents and patent applications related to the Sirtuin class of proteins, including small molecular weight SIRT1 activators and inhibitors. The Company's own R&D efforts and those of its numerous research partners utilizing modulators of SIRT1 (a human sirtuin) have significantly extended the SIRT knowledge base in recent years. Elixir is also actively pursuing drug discovery efforts focused on other key targets, such as AMP-activated kinase (AMPK) and the INDY gene, both of which have been implicated in the regulation of aging and metabolism in a variety of organisms. More information about Elixir is available at http://www.elixirpharm.com/
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[DewDiligence]

SIRT
One of Biotech's Brightest Players Is Now a Free Agent

http://www.boston.com/business/globe/articles/2007/11/04

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By Scott Kirsner
November 4, 2007

In September, when Elixir Pharmaceuticals Inc. said it intended to raise $86 million in an initial public offering, one name was conspicuously missing from the company's filing: Lenny Guarente, the Massachusetts Institute of Technology professor who cofounded Elixir in 1999.

Some think that Guarente's scientific work could one day win a Nobel Prize. So it was odd he'd resigned from Elixir exactly a year earlier.

Elixir is one of two Cambridge companies founded to commercialize the science behind the mechanism that makes humans age and doles out diseases like diabetes, cancer, and Parkinson's along with our decrepitude. The other company is Sirtris Pharmaceuticals Inc., which went public last May, raising $60 million.

Not coincidentally, Sirtris is now romancing Guarente. Now that Guarente's one-year noncompete agreement with Elixir has expired, Sirtris chief executive Christoph Westphal has been trying to lure him onto Sirtris's scientific advisory board.

Westphal said the company is interested in Guarente because "everyone who's a leader in the sirtuin space," the area of science both Elixir and Sirtris were founded to explore, is on Sirtris's advisory board. "I think Lenny's going to win the Nobel Prize some day for finding genes related to the aging process," said Westphal, a former venture capitalist who sports a PhD and an MD, but is not a master of understatement.

The rivalry between the two companies has been endlessly explored in the press.

Elixir was founded first, by Guarente and another researcher at the University of California at San Francisco, Cynthia Kenyon. Kenyon was looking at a gene that seemed to extend the lifespan of worms, and Guarente was studying yeast. Guarente honed in on a gene known as Sir2 (its name led to the term "sirtuins," which describes a group of enzymes produced by genes like Sir2) and invited David Sinclair, a researcher he'd mentored, to join the company.

Sinclair passed, but later joined Westphal, Alkermes Inc. chairman Richard Pops, and others to start Sirtris.

Elixir raised a phenomenal amount of private capital in its hunt to find chemicals that would be able to dial in human sirtuin levels, ideally having an impact on age-related diseases. Guarente believes tweaking sirtuin levels may mimic the effects of drastic calorie restriction - without requiring you to eat less - which has been shown to produce older, healthier mice.

No one thought it would be wise to design a Food and Drug Administration trial to prove the company discovered a drug that extended human lifespan; that would take too long [LOL]. But Guarente and others at Elixir alluded to the possibility of a few extra years as a pleasant potential side effect.

In the company's recent filing with the Securities and Exchange Commission, Elixir said it racked up $82 million in losses since its founding in 1999. Much of that was fronted by Oxford Bioscience Partners and MPM Capital, two Boston-based venture firms.

But over time, Elixir's backers began to get impatient with how long it was taking to discover drugs that might have an impact on sirtuins. (Red wine contains a substance called resveratrol that can activate sirtuins - but in too small a dose to be useful.) So Jonathan Fleming and Ansbert Gadicke, two venture capitalists who served on Elixir's board, decided to bring in a new chairman and CEO who had more experience getting drugs to market quickly.

Vaughn Kaillian, former chairman of Millennium Pharmaceuticals, became Elixir's chairman. And in 2004, William Heiden, a former Schering-Plough executive, became CEO. Slowly, work related to the sirtuins was shifted to the back burner.

Last year, Elixir licensed a diabetes drug already approved in Japan, Glufast, with an intention of getting it blessed in the United States by the FDA. Glufast helps lower the high glucose levels diabetics can experience immediately after eating. Elixir's plan is to build its own sales force to market the drug.

Sirtris, meanwhile, was branding itself as the "leading sirtuin therapeutics company" and hurtling toward an IPO.

But some in the local life sciences industry, including Elixir's backers, grumble that Sirtris went public based on scant clinical data. Sirtris's first drug candidate, dubbed SRT501, is a proprietary formulation of resveratrol - far more concentrated than what you'd get from a couple of cases of red wine. It's currently being tested in India on patients suffering from Type 2 diabetes whose blood sugar levels aren't well-managed by currently available drugs in a trial that should last through the end of 2008.

Sirtris also has no alliances with major drug companies, a normal way for young biotechs to bring in early revenue. But Westphal says that is part of the plan, explaining the company wants to prove it has found drugs that can affect sirtuins, and then establish partnerships when the company has better negotiating leverage.

Coincidentally, Sirtris is headquartered in a building that was once home to Alnylam Pharmaceuticals, a company Westphal helped start while he was at Polaris Venture Partners. Alnylam went public by scooping up many of the researchers and much of their intellectual property related to RNA interference, an approach to blocking the effect of the genes that trigger diseases. This included work done by Craig Mello and Andrew Fire, who shared last year's Nobel Prize in medicine.

"Christoph's playbook is a direct copycat of the Alnylam playbook," says a person close to Elixir. "He can go tell the world that he's got all the important players."

Over the last three years, Guarente had been getting frustrated that Elixir wasn't interested in his latest patents. The company, as he saw it, was getting "very conservative," focusing most of its resources on Glufast.

And, he says, when he'd file a new patent, it was Sirtris, not Elixir, that was licensing it from MIT. But Elixir wouldn't allow Guarente to consult for Sirtris, so he resigned from the company.

"I just really wanted to do something more adventurous," he says. An arrangement with Sirtris hasn't been finalized, and Guarente says there's a chance he might create a new start-up instead.

But just as he was when founding Elixir, Guarente is still convinced that sirtuins have huge potential. And potential, whether grand or mundane, is what fuels the biotech industry.

"What's emerging is that extending life and forestalling diseases are coupled," Guarente says. "If you have a drug that will do the first, it'll also do the second."
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[DewDiligence]

GSK Acquires SIRT at 85% Premium to Market

[SIRT, which IPO’d at $10/share in mid 2007, is not your typical young biotech company. Even in its toned down presentations to investors, SIRT was in a class by itself (#msg-25929302) in content, style, and general polish. This buyout is unfortunate insofar as I had hoped to eventually establish a position; had SIRT remained independent, I think it would’ve represented one of the bona fide moon shots in the biotech universe. The effective deal price is about $620M net of SIRT’s cash on hand.]

http://biz.yahoo.com/prnews/080422/netu127.html

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GlaxoSmithKline to Acquire Sirtris Pharmaceuticals, a World Leader in 'Sirtuin' Research and Development

Tuesday April 22, 4:37 pm ET

LONDON, PHILADELPHIA AND CAMBRIDGE, Mass., April 22 /PRNewswire-FirstCall/ -- GlaxoSmithKline (NYSE: GSK ) and Sirtris Pharmaceuticals Incorporated (Nasdaq: SIRT ) announced today that they have entered into a definitive agreement pursuant to which GlaxoSmithKline will acquire Sirtris Pharmaceuticals for approximately USD720 million (or approx. GBP362 million) through a cash tender offer of USD22.50 (or approx. GBP11.33) per share.

Through the acquisition of Sirtris, GSK will significantly enhance its metabolic, neurology, immunology and inflammation research efforts by establishing a presence in the field of sirtuins, a recently discovered class of enzymes that are believed to be involved in the ageing process. Sirtris Pharmaceuticals has established a drug discovery capability to exploit sirtuin modulation for the treatment of human disease, an approach that has the potential to generate multiple clinically and commercially important products. Their focus to date has been on the development of SIRT1 activators for the treatment of Type 2 Diabetes Mellitus (T2DM).

"Modulation of this family of enzymes is a potentially transformative science that could address diseases associated with metabolism and ageing such as diabetes, muscle wasting, and neurodegeneration," commented Moncef Slaoui, Chairman GSK R&D. "This acquisition continues GSK's strategy of pursuing the best new science, externally or internally, to bring new medicines to patients and value to the GSK pipeline. Our intent is to retain all Sirtris employees and continue the entrepreneurial and innovative culture they created."

Sirtris will become part of GSK's Drug Discovery organisation, while continuing to operate from laboratories in Cambridge, Massachusetts as an autonomous drug discovery unit. Christoph Westphal, CEO and Vice Chair of Sirtris and the management team will continue to lead this autonomous unit.

Dr. Westphal commented, "We have built a dynamic and scientifically-driven organisation. We expect this transaction will accelerate our vision to target sirtuins to treat diseases of metabolism and ageing and deliver tremendous value to patients, our shareholders and our employees. We look forward to working with GlaxoSmithKline and their world-class research, development and commercialisation organisation."

Under the agreement, a subsidiary of GSK will commence a cash tender offer to purchase all of the outstanding shares of Sirtris, at USD22.50 (or approx. GBP11.33) per share followed by a second step merger in which any untendered Sirtris shares would be acquired at the same price per share. All outstanding stock options will be cancelled with holders receiving the excess of the transactions price over the exercise price. The acquisition has been approved by the board of directors of each company and is subject to customary closing conditions, including the tender of at least a majority of Sirtris's shares and clearance under the Hart-Scott-Rodino Antitrust Improvements Act. The parties anticipate that the tender offer will be commenced in early May and close in the second quarter of 2008.

About GSK

GSK -- one of the world's leading research-based pharmaceutical and healthcare companies -- is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For company information including a copy of this announcement and details of the company's updated product development pipeline, visit GSK at http://www.gsk.com.

About Sirtris Pharmaceuticals

Sirtris Pharmaceuticals is a biopharmaceutical company focused on discovering and developing proprietary, orally available, small molecule drugs with the potential to treat diseases associated with ageing, including metabolic diseases such as Type 2 Diabetes. Our drug candidates are designed to mimic certain beneficial health effects of calorie restriction by activation of sirtuins, a recently discovered class of enzymes that the Company believes control the ageing process. The company's headquarters are in Cambridge, Massachusetts.
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