GlaxoSmithKline now has their eye on a specific compound in wine and berries, called resveratrol.

This amazing natural ingredient has been shown to slow aging in lab animals. Glaxo is offering $720 million in cash for a biotech company that was co-founded by the same researcher who did the resveratrol studies. The company, Sirtris, watched its stock jump 81.9 percent on release of the offer.

The active ingredients in resveratrol are enzymes called sirtuins. The researcher said that these enzymes could treat many of the major diseases in a “safe, natural way.”

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GlaxoSmithKline deal latest in flurry of local purchases

By Todd Wallack, Globe Staff | April 23, 2008

Sirtris Pharmaceuticals Inc., the Cambridge biotech company that has attracted national attention for trying to use drugs based on an extract in red wine to fight diabetes and other age-related diseases, is being sold to British pharmaceuticals giant GlaxoSmithKline PLC for $720 million, the companies said late yesterday.

The purchase price of $22.50 per share is nearly double the company’s closing price yesterday of $12.23, and more than double its initial offering price of $10 per share in May 2007.

The sale is the latest example of a Bay State biotech getting scooped up by a big drug company. Just two weeks ago, Japan’s Takeda Pharmaceutical Co. bought Millennium Pharmaceuticals Inc., the state’s third largest biotech, for $8.8 billion, making it the biggest deal in the history of the state’s biotech industry. Last fall, Pfizer Inc. bought Coley Pharmaceutical Group in Wellesley for $164 million. And Bristol-Myers Squibb Co. bought Adnexus Therapeutics for $430 million.

Many of the companies, like Sirtris, are relatively young but have a promising pipeline of experimental drugs that could one day become blockbusters. Large drug companies have been aggressively scouting for biotech companies to fill their pipelines as patents on their old, established drugs expire.

“This kind of transaction has become increasingly common,” said Glen Giovannetti, global biotechnology leader for accounting firm Ernst & Young in Boston. “It’s a reflection of how healthy the local start-up market is in terms of new companies being formed around exciting technologies.”

The sale also marks the latest success for Sirtris chief executive Christoph Westphal, a former venture capitalist who previously cofounded Alnylam Pharmaceuticals Inc. and Momenta Pharmaceuticals Inc. in Cambridge.

GlaxoSmithKline says it plans to continue to operate Sirtris as an autonomous drug discovery unit, with Westphal and the rest of the management team at the helm. And Westphal said he plans to stick with the company for the long term, despite his history of starting one venture after another, because of its potential to attack aging-related diseases.

“This is probably going to be one of the most important things I’ve done in my life,” Westphal said. “This is a unique moment in drug discovery.”

Though Sirtris is at least four years away from bringing any drugs to market, Westphal has dazzled investors and the media with tantalizing research that resveratrol, a compound found in red wine, might be able to stimulate enzymes called sirtuins that appear to play a key role in aging.

In 2006, the company published a scientific paper reporting that resveratrol reduces fat and boosts endurance by activating a key sirtuin. And last year, Sirtris teamed with Harvard for another study that found two other sirtuins protect against cell damage, opening up another possible mechanism to slow the effects of aging.

Westphal has often wowed audiences with pictures of mice and monkeys who look years younger after their sirtuins have been activated through a calorie-restricted diet, something that might be similarly possible with drugs that have the same effect.

Sirtris, founded in 2004, is in the early stages of testing a reformulation of resveratrol to treat Type 2 diabetes. But Sirtris eventually hopes to develop drugs to treat a number of aging-related diseases, such as cancer.

And though Westphal is careful to say the company is focused on treating specific diseases – not aging – many articles have suggested Sirtris could be on the verge of discovering the fountain of youth. Just last month, the company was featured in a Barbara Walters television special on ABC called “Live to be 150, Can You Do It?”

As part of GlaxoSmithKline, Westphal said Sirtris, which has close to 60 employees, will have deep pockets to step up its resources without needing to do additional fund-raising.

“We’re stepping on the gas,” Westphal said, adding that GlaxoSmithKline is committed to Sirtris’s vision and will be a good research partner. “It’s a wonderful thing for Boston biotech.”

SAN FRANCISCO, WIRED MAGAZINE — For the first time, scientists have proof in human subjects that a derivative of an ingredient in red wine combats some symptoms of aging. Sirtris Pharmaceuticals announced the results here on Monday at the JPMorgan Healthcare Conference.

Resveratol, naturally found in red wine, stimulates a gene known as SIRT1, which has been linked with extended lifespans in rodents. The new study is the first time similar effects have been replicated in humans.

“We believe that this is the first time that a drug candidate has shown efficacy in a disease of aging by targeting the genes that control aging,” said Christoph Westphal, CEO of Sirtris.

Sirtris was co-founded by David Sinclair, a Harvard Medical School researcher, who discovered SIRT1’s role in regulating lifespan. His early work was in yeast, and he later showed that stimulating SIRT1 through a calorie-restricted diet helped animals live longer. Then, Sinclair found resveratol, which stimulates the same gene with results similar to calorie-restriction but without the diet. Resveratrol’s effects in mice touched off a storm of excitement among people, including Sinclair, who began taking the drug in its over-the-counter form hoping to extend their lifespans.

Sirtris’ proprietary formulation of the drug significantly reduced blood sugar in 67 diabetic patients as compared with a placebo group. The results are an important milestone in bringing resveratrol-related drugs to market.

The study, however, ran just 28 days and had conservative goals: to measure whether a resveratol formulation called SRT501, which is five times easier for the body to use than naturally occurring resveratol, was safe and had some activity in humans. Getting the drug through the regulatory process will take until at least 2012, the company said.

The results partially answer skeptics like Steven Austad, a cellular biologist and longevity researcher at the University of Texas, who expressed doubts about the impact of resveratol in humans to Wired News last year after mouse studies showed longevity gains.

“People in the research community tend to think of mice as small little furry humans with long tails, but they’re not,” Austad said at the time. “We don’t know what it will do.”

Sirtris can now say it does know what SRT501 does, at least for a small number of patients over a short period of time: It works.

Patients in the trial were given 2,500 or 5,000 milligrams of the drug in liquid form. Both groups had positive outcomes with no side effects. Westphal said during a question-and-answer session following his presentation at the JP Morgan Healthcare Conference that the unusually high doses were necessary because resveratrol is not a very potent molecule.

That’s why the company is also working with other molecules — potential drugs — that are unrelated to resveratrol but also stimulate the SIRT1 gene. Some of the molecules could be up to 1,000 times more potent than resveratrol, he added.

Still, SRT501 was effective enough that Sirtris is continuing to push the drug through clinical trials.

“Based on the positive results, and the fact that there are a lot of desirable characteristics to SRT501, we’ve initiated a Phase IIa study combining SRT501 with the most common diabetic drug, metformin,” said Westphal. “Those data are back in the second half of this year.”

Sirtris had an initial public offering of its stock back in May of 2007 and is up 23 percent since that time. Following the clinical trial announcement, the stock gained 1.5 percent in after-hours trading.

Scientists have found that resveratrol works on a gene called SERT1 that controls the aging process. The company that is making a synthetic version of resveratrol is in Phase One of clinical trials.

Pittsboro, NC, April 08, 2008 –(PR.com)– Cutting edge research was presented on a TV special on ABC called “Live to be 150… Can You Do It?” Several new technologies are getting people closer to the quest to live longer and healthier lives.

Dr. David Sinclair, a founder of Sirtris Pharmaceuticals and a professor at Harvard Medical School, talked about a specific gene that is activated by resveratrol that slows the aging process. Resveratrol is an antioxidant found in several fruits. Muscadine grapes, which grow in the Southeastern US, were found to have especially high concentrations of natural resveratrol.

Dr. Sinclair stated, “Resveratrol works on a gene called SERT1, and this is the gene that controls the aging process.” With the gene activated by a high dose of resveratrol, the mice ran twice as far as the untreated mice. He noted, “They didn’t get heart disease, cancer, even osteoporosis and they lived thirty percent longer.”

Sirtris Pharmaceuticals is in Phase I clinical trials with a synthetic form of resveratrol. However, a muscadine grape seed supplement with a high level of resveratrol is available today. Resveratrol, Inc; a nutraceutical company based in Rose Hill, North Carolina, produces NutraGrape(TM), which is available online at www.nutragrape.com.

Target Health Inc. advises that before taking any OTC supplements, you should consult with and get an okay from your doctor.

About Resveratrol, Inc.
Resveratrol, Inc. is a nutraceutical company that makes NutraGrape(TM) and NutraGrape’s The Vine® products from Muscadine grape seeds. The company was founded by Duplin Winery in 1998 and is headquartered in Rose Hill, N.C.

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Wednesday April 2, 12:00 pm ET

CAMBRIDGE, Mass.–(BUSINESS WIRE)–Sirtris Pharmaceuticals, Inc. (NASDAQ: SIRT – News), a biopharmaceutical company focused on discovering and developing small molecule drugs to treat diseases of aging, announced that the United States Food and Drug Administration has granted the company orphan-drug designation for resveratrol in the treatment of MELAS syndrome (Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes). Orphan-drug designation for resveratrol in MELAS syndrome provides Sirtris with seven years of marketing exclusivity upon receipt of FDA approval.

“MELAS can have a devastating effect on the quality of life of patients and their families,” says Professor Patrick Chinnery of Newcastle University, who is leading a MELAS Phase 1b clinical trial in the United Kingdom with SRT501, Sirtris’ proprietary formulation of resveratrol. “Finding treatments for MELAS and the many other mitochondrial-related illnesses is essential,” says Chinnery, whose focus is the treatment and research of mitochondrial disorders.

“Many diseases of aging, such as Type 2 Diabetes, exhibit impaired mitochondrial function,” says Peter Elliott, PhD, Sirtris Senior Vice President of Development. “As we target SIRT1, a gene tied to the aging process and improved mitochondrial function, we hope to develop new therapies for diseases like MELAS and Type 2 Diabetes.”

“We are extremely pleased to have received orphan-drug designation in MELAS,” says Christoph Westphal, MD, PhD, CEO and Vice Chair, Sirtris Pharmaceuticals, Inc. “Clinical testing with SRT501 in this mitochondrial disorder offers the potential to provide an exciting, novel treatment option for the future.”

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Source: Sirtris Pharmaceuticals, Inc.

MELAS is a progressive and fatal disorder with no known treatments. The earliest symptoms include muscle weakness, fatigue, recurrent headaches and seizures. The reported age of onset varies between 3 and 40 years, with most patients presenting between the ages of 5 to 15 years. The syndrome can manifest as stroke-like episodes in patients under 20 years of age. Seizures, dementia, impaired muscular function and neurodegeneration can be observed as the disease progresses. MELAS patients also have high glucose levels and approximately 30 percent have Type 2 Diabetes.

MELAS is caused by a point mutation in mitochondrial DNA, leading to the development of poorly functioning mitochondria, which supply cellular energy. The diagnosis can be confirmed through genetic testing.

In preclinical testing, activation of the SIRT1 enzyme with SRT501 has been shown to increase the number and function of mitochondria. SRT501 has also been shown to be safe and well-tolerated in two earlier human Phase 1a clinical trials. In a Phase 1b clinical trial with Type 2 Diabetes patients naïve to treatment, SRT501 was shown to be safe and to significantly lower glucose at the two-hour time point in an oral glucose tolerance test conducted as part of the 28 day trial.

The Phase 1b trial for MELAS conducted at Newcastle University is designed to test the primary endpoints of safety and pharmacokinetics of SRT501 in patients with MELAS. SRT501 is being administered to a group of 15 patients once daily for three months and an additional group of five patients will receive a placebo. Secondary endpoints include exercise tolerance, and fasting blood glucose and insulin levels. Sirtris expects data from this trial in the first half of 2009.

The United States Orphan Drug Act of 1983 was created to provide incentives for companies to develop and market treatments for diseases affecting fewer than 200,000 people in the United States. Under the Orphan Drug Act, more than 300 new drugs have been developed and approved.

Sirtris plans to seek orphan drug status for SRT501 in Europe.

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 aging, including metabolic diseases such as Type 2 Diabetes. Our drug candidates are designed to mimic certain beneficial health effects of calorie restriction, without requiring a change in eating habits, by activation of sirtuins, a recently discovered class of enzymes that the Company believes control the aging process. Sirtris Pharmaceuticals is engaged in human clinical trials for Type 2 Diabetes, and is planning similar trials in cancer, another age-related disease. Sirtris is also engaged in a human clinical trial for MELAS, a mitochondrial disorder. The company’s headquarters are in Cambridge, Massachusetts.

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Doctors do agree that something in red wine appears to help your heart.. Recent research has indicated a substance called resveratrol, which is found in the skin and seeds of grapes used to make wine, has promising heart-healthy benefits.

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1b trial for the mitochondrial disorder MELAS

Red wine in particular seems to have even more heart-health benefits than other types of alcohol, according to a large Danish study from 2000. The study, known as the Copenhagen City Heart Study, found that those who drank red wine had about half the risk of dying of heart disease as those who didn’t.

Additional studies have given mixed results — some confirming the Danish finding, others showing red wine isn’t any better than beer, white wine or liquor for heart health. As a result, the American Heart Association says there’s no clear evidence yet that red wine is superior to other forms of alcohol when it comes to possible heart-health benefits.

The pro-red wine studies suggest antioxidants in red wine called polyphenols help protect the lining of blood vessels in your heart. These antioxidants come in two main forms: flavonoids and nonflavonoids.

* Flavonoids. These antioxidants are found in a variety of foods, including oranges, apples, onions, tea and cocoa. Other types of alcohol, such as white wine and beer, contain small amounts, too, but red wine has higher levels.
* Nonflavonoids. These antioxidants found in red wine have recently been of particular interest because they appear to help prevent arteries from becoming clogged with fatty blockages. However, these studies mostly involved mice — not humans. Resveratrol is the nonflavonoid that researchers are most interested in.

Resveratrol in red wine

Some researchers believe that resveratrol might be the key ingredient in red wine that helps prevent damage to blood vessels, reduces “bad” cholesterol and prevents blood clots.

Research in mice given resveratrol has indicated that the antioxidant might also help protect them from obesity and diabetes, both of which are strong risk factors for heart disease. However, those findings were reported only in mice, not in people. In addition, to achieve the dose of resveratrol used in the mice studies, a person would have to consume 100 to 1,000 bottles of red wine a day.

Some companies sell supplements containing resveratrol. However, doctors caution that not enough is known about resveratrol’s effects to endorse resveratrol supplements. Research into the potential heart-health benefits of resveratrol is continuing.
Resveratrol in grapes and other foods

The resveratrol in red wine comes from the skin of grapes used to make wine. Because red wine is fermented with grape skins longer than is white wine, red wine contains more resveratrol. Simply eating grapes, or drinking grape juice, has been suggested as one way to get resveratrol without drinking alcohol. Some studies have suggested that red and purple grape juices have some of the same heart-healthy benefits of red wine.

Other foods that contain some resveratrol include peanuts, blueberries and cranberries. It’s not yet known how beneficial eating grapes or other foods might be compared with drinking red wine when it comes to promoting heart health. The amount of resveratrol in food and red wine can vary widely.

Rochester researchers showed for the first time that a natural antioxidant found in grape skins and red wine can help destroy pancreatic cancer cells by reaching to the cell’s core energy source, or mitochondria, and crippling its function.

The study is published in the March edition of the journal, Advances in Experimental Medicine and Biology.

The study also showed that when the pancreatic cancer cells were doubly assaulted — pre-treated with the antioxidant, resveratrol, and irradiated — the combination induced a type of cell death called apoptosis, an important goal of cancer therapy.

The research has many implications for patients, said lead author Paul Okunieff, M.D., chief of Radiation Oncology at the James P. Wilmot Cancer Center at the University of Rochester Medical Center.

Although red wine consumption during chemotherapy or radiation treatment has not been well studied, it is not “contraindicated,” Okunieff said. In other words, if a patient already drinks red wine moderately, most physicians would not tell the patient to give it up during treatment. Perhaps a better choice, Okunieff said, would be to drink as much red or purple grape juice as desired.

Yet despite widespread interest in antioxidants, some physicians are concerned antioxidants might end up protecting tumors. Okunieff’s study showed there is little evidence to support that fear. In fact, the research suggests resveratrol not only reaches its intended target, injuring the nexus of malignant cells, but at the same time protects normal tissue from the harmful effects of radiation.

“Antioxidant research is very active and very seductive right now,” Okunieff said. “The challenge lies in finding the right concentration and how it works inside the cell. In this case, we’ve discovered an important part of that equation. Resveratrol seems to have a therapeutic gain by making tumor cells more sensitive to radiation and making normal tissue less sensitive.”

Resveratrol is known for its ability to protect plants from bacteria and fungi. Purified versions have been described in scientific journals as potential anti-cancer, anti-inflammatory and anti-atherogenic agents, and for their ability to modulate cell growth. Other well-known antioxidants derived from natural sources include caffeine, melatonin, flavonoids, polyphenols, and vitamins C and E.

A flurry of antioxidant studies in recent years has not proven how and why they work at the cellular level. At the suggestion of a young scientist in his lab, Okunieff began studying resveratrol as a tumor sensitizer. That’s when they discovered its link to the mitochondria.

The discovery is critical because, like the cell nucleus, the mitochondria contains its own DNA and has the ability to continuously supply the cell with energy when functioning properly. Stopping the energy flow theoretically stops the cancer.

Researchers divided pancreatic cancer cells into two groups: cells treated without resveratrol, or with resveratrol, at a relatively high dose of 50 mg/ml, in combination with ionizing radiation. (The resveratrol concentration in red wine can be as high as 30 mg/ml, the study said, and higher doses are expected to be safe as long as a physician is monitoring.)

They evaluated the mitochondria function of the cells treated with resveratrol, and also measured apoptosis (cell death), the level of reactive oxygen species in the cells, and how the cell membranes responded to the antioxidant.

Laboratory experiments showed that resveratrol:

* Reduced the function of proteins in the pancreatic cancer cell membranes that are responsible for pumping chemotherapy out of the cell, making the cells chemo-sensitive.
* Triggered the production of reactive oxygen species (ROS), which are substances circulating in the human body that have been implicated in a number of diseases: when ROS is increased, cells burn out and die.
* Caused apoptosis, which is likely the result of increased ROS.
* Depolarized the mitochondrial membranes, which indicates a decrease in the cell’s potential to function. Radiation alone does not injure the mitochondrial membrane as much.

The team also wanted to investigate why pancreatic cancer cells seem to be particularly resistant to chemotherapy. The pancreas, a gland located deep in the abdomen, produces insulin and regulates sugar, and pumps or channels powerful digestive enzymes into the duodenum. This natural pumping process, however, ends up ridding the needed chemotherapy from cells in the pancreas. But just as reseveratrol interferes with the cancer cells’ energy source, it also may decrease the power available to pump chemotherapy out of the cell.

“While additional studies are needed,” Okunieff said, “this research indicates that resveratrol has a promising future as part of the treatment for cancer.”

In the same journal, Okunieff and his group also reviewed why resveratrol protects normal tissue, and found that antioxidants can be designed to take advantage of certain biochemical properties or cellular targets, making them more effective.

http://www.urmc.rochester.edu/

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This week, an FDA advisory panel will review a recommendation to put a warning on flu drugs Tamiflu and Relenza that says there have been “psychiatric events observed in some patients.” The companies who make the drugs have both responded that they’ve found no causal link between their drugs and “psychiatric events.” Even the FDA has mixed feelings about it, which it may resolve this week.