Exubera (inhaled Human Insulin) Approved By European Commission

Pfizer Inc said today that the European Commission has approved Exubera (inhaled human insulin) for the treatment of adults with type 1 and type 2 diabetes. Exubera is the first non-injectable, inhalable form of insulin to be approved since the discovery of insulin in the 1920s, and represents a major advance in diabetes treatment.

According to the World Health Organization (WHO), diabetes has reached epidemic proportions and affects approximately 48 million people in Europe alone. People with diabetes often suffer from debilitating complications due to uncontrolled blood sugar levels including heart disease, amputation, blindness and kidney failure. The direct healthcare costs associated with diabetes are estimated to be around $286 billion worldwide, with the majority of these costs linked to treating diabetes-related complications.

Since its discovery more than 80 years ago, insulin has been the gold standard treatment for diabetes. In order to achieve tight blood sugar control, insulin is often administered before meals to mimic the body's natural insulin response to food. Healthcare providers and patients have been reluctant to initiate or intensify insulin therapy when it is required due to the need for daily injections.

“Exubera is a major, first-of-its-kind, medical breakthrough that marks another critical step forward in the treatment of diabetes, a disease that has taken an enormous human and economic toll worldwide,” said Hank McKinnell, Pfizer chairman and chief executive officer. “The global incidence of diabetes is currently at epidemic levels. Millions of patients are not achieving or maintaining acceptable blood sugar levels, despite the availability of current therapies. Exubera meets a critical medical need by offering a highly effective and needle-free alternative to diabetes pills and insulin injections to manage this complicated, debilitating disease.”

Exubera is a fast-acting, dry powder formulation of human insulin that is inhaled into the lungs via the mouth before meals using a simple-to-use, hand-held device that does not require batteries or electricity. The device, which weighs four ounces and is about the size of a carrying case for a pair of eye glasses, is designed to deliver an accurate and precise dose of insulin each time it is used.

Exubera is the result of one of the most rigorous and innovative diabetes development programs ever and Pfizer's investment now stands at over $1 billion. Pfizer invested in two state-of-the-art manufacturing facilities -- the world's largest insulin plant in Frankfurt, Germany, and a high-tech facility in Terre Haute, Indiana, U.S. -- well ahead of regulatory actions, so that the product can reach patients as quickly as possible.

The efficacy and safety profile of Exubera was studied in more than 2,500 adults with type 1 and type 2 diabetes for an average duration of 20 months. In studies in adults with type 1 or type 2 diabetes, Exubera was shown to be as effective as injectable insulin in achieving glycemic control. In adults with type 2 diabetes who are not sufficiently controlled with commonly used oral therapies, Exubera has been shown to provide greater improvements in glycemic control. In addition, patients who took Exubera reported greater overall treatment satisfaction and acceptance compared to insulin injections or oral therapies.

"This is really good news for physicians and patients. It is truly a clinical and scientific milestone -- being able to give insulin without needles," said Chantal Mathieu, Professor of Endocrinology, University of Leuven, Belgium. "Physicians face many challenges with insulin therapy due to patients' reluctance to take injections, which up until now, was the only way to take insulin. With Exubera, patients now have another opportunity to take control of their blood sugar and take an active role in managing this complicated disease."

About Exubera

To further support the effective use of Exubera, Pfizer is investing in extensive educational programs to support healthcare professionals and patients.

Exubera is a product of a collaboration between Pfizer Inc and Nektar Therapeutics. Pfizer recently reached an agreement to acquire the sanofi-aventis worldwide rights to Exubera. The two companies were previously in a worldwide alliance to co-develop, co-promote and co-manufacture Exubera.

In the European Union, Exubera has been approved for the treatment of adults with type 2 diabetes (greater than 18 years of age) not adequately controlled with oral antidiabetic agents and requiring insulin therapy. Exubera is also indicated for the treatment of adult patients with type 1 diabetes mellitus, in addition to long or intermediate acting injectable insulin, for whom the potential benefits of adding inhaled insulin outweigh the potential safety concerns.

Exubera is pending approval in the U.S. In September 2005, the U.S. Food and Drug Administration (FDA) Advisory Committee recommended that Exubera should be approved for the treatment of adults with type 1 and type 2 diabetes.

There are two major forms of diabetes -- type 1 and type 2. In type 1, which typically develops in childhood, the insulin-producing cells in the pancreas have been destroyed leading to a complete lack of insulin. In type 2 diabetes, the most common and progressive form of the disease, the body does not effectively use nor produce enough insulin to manage blood sugar levels, and eventually most people with type 2 diabetes will need insulin to achieve blood sugar control.

Important Safety Information about Exubera

The safety profile and tolerability of Exubera have been extensively studied in clinical trials. Adverse events throughout the clinical development program were generally mild to moderate, and discontinuation rates were low.

Patients should not take Exubera if they have poorly controlled or unstable lung disease, or if they smoke or have stopped smoking less than six months prior to starting Exubera treatment. If a patient starts smoking or resumes smoking, he or she must stop using Exubera and see a health care provider about a different treatment.

Before starting treatment with Exubera, a health care provider will carry out a simple test to check lung function. The test involves exhaling into a measuring device. This will help to find out if Exubera is the right treatment for individual patients. Once a patient starts treatment, it is recommended that a health care provider should check lung function again at six months (see full prescribing information).

A small decrease in lung function may occur during Exubera treatment although symptoms might not be noticeable. This change occurs within the first months of treatment and should not worsen as treatment is continued.

Like all medicines, Exubera can cause side effects. As with all forms of insulin, a possible side effect of Exubera is low blood sugar levels.

Some patients have reported a mild cough while taking Exubera, which occurred within seconds to minutes after Exubera inhalation. Coughing occurred less frequently as patients continued to use Exubera.

Consecutive inhalation of three 1mg unit dose blisters causes a significantly higher insulin exposure than inhalation of one 3mg unit dose blister. Therefore, three 1mg unit dose blisters should not be substituted for one 3mg unit dose blister.

http://www.www.pfizer.com

Eating And Body Weight Regulated By Specific Neurons

Researchers at Yale School of Medicine provide direct evidence that two parts of a neuronal system, one that promotes eating and another that suppresses eating, are critical for the acute regulation of eating and body weight, according to a study published online in the September 11 issue of Nature Neuroscience.

The paper makes it clear that the agouti-related peptide-expressing (AgRP) neurons are mandatory for eating. "Previous studies showed that the brain, particularly the hypothalamus, is responsible for the regulation of eating," said co-senior author Tamas Horvath, chair and associate professor in the Section of Comparative Medicine, and associate professor in neurobiology and the Department of Obstetrics, Gynecology & Reproductive Sciences. "But until now, no experimental evidence was available to prove that AgRP neurons are critical for acute regulation of eating."

Horvath's collaborator Jens Bruening of the University of Cologne in Germany introduced the avian diphtheria toxin receptor into neurons in the feeding support system of transgenic mice. When the animals were adults, two injections of toxin caused the specific cell population to die within 48 hours, impairing the mouse's ability to eat and resulting in acute anorexia. These mice also showed marked reduction in blood glucose, plasma insulin and Leptin concentrations.

"Our results confirm the hypothesis that these two systems are critical for eating and the cessation of eating," said Horvath. "Previous transgenic approaches failed to provide this proof because of compensatory mechanisms that could operate during development. None of those actually knocked out neuronal function. In this case, however, neurons are gone and there is no time to replace their function."

In explaining the significance of the finding, Horvath said, "It is important to ensure that the multibillion dollar academic and pharmaceutical approach against metabolic disorders is leaning in the right direction. The approach in general could also eventually lead to specific destruction of cells in other kinds of diseases."

Other authors on the study included Eva Gropp, Marya Shanabrough, Erzsebet Borak, Allison W. Xu, Ruth Janoschek, Thorsten Buch, Leona Plum, Nina Balthasar, Brigitte Hampel, Ari Waisman, Gregory S. Barsh, and co-senior author Jens Bruning.


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Citation: Nature Neuroscience, Published online September 11, in print: October 2005 Vol. 8 No. 10
Editor's Note: The original news release can be found

Compound In Wine Reduces Levels Of Alzheimer's Disease-causing Peptides

A study published in the November 11 issue of the Journal of Biological Chemistry shows that resveratrol, a compound found in grapes and red wine, lowers the levels of the amyloid-beta peptides which cause the telltale senile plaques of Alzheimer's disease.

"Resveratrol is a natural polyphenol occurring in abundance in several plants, including grapes, berries and peanuts," explains study author Philippe Marambaud. "The polyphenol is found in high concentrations in red wines. The highest concentration of resveratrol has been reported in wines prepared from Pinot Noir grapes. Generally, white wines contain 1% to 5% of the resveratrol content present in most red wines."

One of the characteristic features of Alzheimer's disease is the deposition of amyloid-beta peptides in the brain. Philippe Marambaud and his colleagues at the Litwin-Zucker Research Center for the Study of Alzheimer's Disease and Memory Disorders in Manhasset, New York, administered resveratrol to cells which produce human amyloid-beta and tested the compound's effectiveness by monitoring amyloid-beta levels inside and outside the cells. They found that levels of amyloid-beta in the treated cells were much lower than those in untreated cells.

The researchers believe the compound acts by stimulating the degradation of amyloid-beta peptides by the proteasome, a barrel-shaped multi-protein complex that can specifically digest proteins into short polypeptides and amino acids.

However, eating grapes may not be a cure for Alzheimer's disease. "It is difficult to know whether the anti-amyloidogenic effect of resveratrol observed in cell culture systems can support the beneficial effect of specific diets such as eating grapes," cautions Marambaud. "Resveratrol in grapes may never reach the concentrations required to obtain the effect observed in our studies. Grapes and wine however contain more than 600 different components, including well-characterized antioxidant molecules. Therefore, we cannot exclude the possibility that several compounds work in synergy with small amounts of resveratrol to slow down the progression of the neurodegenerative process in humans."

Following up on their studies, Marambaud and his colleagues are trying to figure out how resveratrol exerts its effects in order to develop similar compounds to use in fighting Alzheimer's disease. "Our long-term goal is now to elucidate the exact molecular mechanisms involved in the beneficial properties of resveratrol as a necessary prerequisite to the identification of novel molecular targets and therapeutic approaches," says Marambaud. "The observation that resveratrol has a strong anti-amyloidogenic activity is a powerful starting point for screening analogues of resveratrol for more active and more stable compounds, a task in which our laboratory is actively involved. We have already obtained analogues of resveratrol that are 20 times more potent than the original natural compound. We are now aiming to find more stable analogues and to test them in vivo in mice."

Additional good news is that resveratrol may also be effective in fighting other human amyloid-related diseases such as Huntington's, Parkinson's and prion diseases. Studies by a group at the Institut National de la Santé et de la Recherche Médicale in Paris, France headed by Christian Néri have recently shown that resveratrol may protect neurons against amyloid-like polyglutamines, a hallmark of Huntington's disease.


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The American Society for Biochemistry and Molecular Biology (ASBMB) is a nonprofit scientific and educational organization with over 11,000 members in the United States and internationally. Most members teach and conduct research at colleges and universities. Others conduct research in various government laboratories, nonprofit research institutions, and industry.
Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for Experimental Biology. The Society's primary purpose is to advance the sciences of biochemistry and molecular biology through its publications, the Journal of Biological Chemistry, the Journal of Lipid Research, Molecular and Cellular Proteomics, and Biochemistry and Molecular Biology Education, and the holding of scientific meetings.
For more information about ASBMB, see the Society's website at www.asbmb.org.
________________________________
This story has been adapted from a news release issued by American Society for Biochemistry and Molecular Biology.

http://www.sciencedaily.com/releases/2005/11/051104085054.htm

For Great Diabetes Care, Remember Your ABCs!

Taking good care of your diabetes can be complex and confusing. This handy list will make remembering all the steps you need to take as easy as A B C D E F G H I!


A is for A1C.

The A1C ("A-one-C") test—short for hemoglobin A1c—measures your average blood glucose (sugar) over the past 3 months.

Suggested target: Below 7
How often: At least twice a year

A is also for albuminuria.

Albuminuria means protein in the urine. A test that measures your urine microalbumin-to-creatinine ratio can detect kidney disease very early, when it can usually be stopped. This can prevent dialysis or kidney transplantation later on.

Suggested target: Below 30
How often: At least once a year

And, finally, A is for aspirin.

Taking low-dose aspirin every day can help prevent heart attacks and strokes. Children and young adults with no history of heart disease should not take aspirin without a doctor’s order, nor should some older adults. Check with your doctor before starting daily aspirin.



B is for blood pressure.

High blood pressure makes your heart work too hard and can cause damage to your kidneys and eyes.

Suggested target: Below 130/80
How often: At every visit


C is for cholesterol.

Bad cholesterol, or LDL, builds up and clogs your arteries, leading to heart attacks and strokes.
Suggested LDL target: Below 100

How often: At least once a year


D is for diabetes education.

Help your doctor help you. The more you know about how food, exercise, and medicines affect your diabetes control, the better you and your doctor can work together to make any needed changes.

Suggested resources: Dietitians, nurse diabetes educators
How often: Ongoing


E is for eye exam.

Regular eye exams can catch diabetic eye disease early enough to prevent eventual blindness.

How often: At least once a year


F is for foot care

Keep an eye on your feet. If you have nerve disease and can’t feel your feet, your feet can’t tell you when something is wrong.

How often: Check your feet daily. Remind your doctor to check them at every visit. Get an extensive foot exam once a year.


G is for glucose (sugar) monitoring.

If you know when your blood sugar level is too high or too low, you’ll know better how to treat it.

How often: Decide with your doctor.


H is for staying healthy.

For people with diabetes, getting the flu or pneumonia can lead to serious complications. Avoid them by getting vaccinated.

How often: Flu vaccine, every year; pneumonia, at least once.


I is for identifying special medical needs.

Complications are complicated. As they occur, your doctor may need to send you to various specialists. Voicing your health concerns at every visit can help your doctor spot trouble and get any extra help you need quickly.

How often: When needed

Footnotes
Permission is granted to reproduce this material for nonprofit educational purposes. Written permission is required for all other purposes. 7/03

http://clinical.diabetesjournals.org/

Mechanism Underlying Response To Targeted Therapy For Kidney Cancer, UCLA

Article Date: 15 Jan 2006 - 13pm (UK)



UCLA researchers knew - based on two clinical trials - that a subset of kidney cancer patients responded well to an experimental targeted therapy, but they didn't know why. If they could determine the mechanism behind the response, they would be able to predict which patients would respond and personalize their treatment accordingly.

Extrapolating from the clinical responses, Jonsson Cancer Center scientists uncovered the cascade of molecular events by which the cancer cells in a subset of patients became sensitized to the experimental drug CCI-779. Armed with this information, UCLA researchers are developing a test to identify which patients will benefit from receiving CCI-779.

The research, published this month in Nature Medicine, takes researchers a step closer to personalized medicine - treating cancer patients not with a one-size-fits-all therapy but with a treatment based on the specific molecular signature of their cancer cells.

"We knew there were certain kidney cancer patients who responded to this drug, but we didn't know the mechanism behind the response," said George Thomas, first author of the study, an assistant professor of pathology and a Jonsson Cancer Center researcher. "We had to determine the mechanism of response so we could identify the responders."

Thomas, with Jonsson Cancer Center researchers Dr. Ingo Mellinghoff and Dr. Charles Sawyers, discovered that human kidney cancer cells that had lost the tumor suppressor gene Von Hippel Lindau (VHL) were more sensitive to the growth inhibitory effects of CCI-779. One of the main functions of VHL is to regulate a protein called hypoxia inducible factor (HIF). When patients lost VHL, they had high levels of HIF. Thomas said the cancer cells became dependent on HIF to grow, so high levels of the protein gave the cancer cells a growth advantage.

CCI-779 had previously been tested at UCLA in prostate cancer patients and researchers knew it targeted the mTOR protein. Previous studies also had shown that inhibitors of mTOR also might inhibit HIF.

"We theorized that by inhibiting mTOR, which contributes to HIF levels, we might be able to significantly reduce HIF and remove the growth advantage the cancer cells had," Thomas said. "Because we now know the mechanism that is fueling the growth of the cancer cells, we can identify patients who will respond to this drug."

About 50 to 70 percent of kidney cancer patients have lost VHL, Thomas said. Their tumors, therefore, will have high levels of HIF and likely will respond to the drug. This finding could potentially help about 20,000 kidney cancer patients every year.

Typically, scientists seeking a target for a new cancer therapy start work in cell lines and then advance to laboratory animals to test their theories. Working backward from responses in clinical trials is unusual, Thomas said. Responses observed in clinical studies led researchers back to the laboratory. Their laboratory findings will be tested in further clinical studies, bringing the observation full circle, from the patient to the lab and back to the patient again.

In this case, CCI-779 was being tested at UCLA in a Phase I study on patients with a variety of advanced cancers. Researchers noted that patients with kidney cancer seemed to respond better to the drug than patients with other cancer types. That led to a Phase II study solely in kidney cancer patients. That study showed that a subset of patients had a complete response, while a high percentage experienced partial responses or had their disease stabilize, meaning it was no longer growing.

Thomas predicted that CCI-779 would probably be most effective when given in combination with other therapies because it "in kidney cancer, it stops the tumor cells from growing, it doesn't kill them." It could be paired with conventional chemotherapy or with another targeted therapy, such as an angiogenesis inhibitor, which cuts off the independent blood supply that cancers need to grow and flourish. The CCI-779 would stop the growth of the cancer, and the chemotherapy would be used to kill the cancer cells or the angiogenesis inhibitor could be administered to cut off the blood supply to the tumor, stopping the flow of oxygen and nutrients that the tumor needs to survive.

Standard of care for kidney cancer is almost always removal of part or the entire kidney, so that tissue could be tested for the molecular signature that indicates response to CCI-779. Doctors could then decide on what treatment to use in those likely to respond to the drug.

A secondary study finding determined that the drug's efficacy can be monitored quickly using positron emission tomography (PET). Because HIF also regulates glucose transport in cells, UCLA researchers theorized that the kidney cancer cells, with their high levels of HIF, would take in a standard PET imaging probe at high levels. If that proved true, the PET scan would show that the cancer cells had increased levels of the probe. Using laboratory animals, researchers determined that kidney cancer cells were indeed better at taking up the probe, allowing the cancer cells to be monitored by PET scanning. Just 24 hours after treatment with CCI-779, intake of the PET probe levels dropped in the cancer cells, meaning HIF levels were falling and the drug was working.

"If we can use PET scanning to follow response, patients won't need repeated invasive tests," Thomas said. "This would save them from getting an added surgical procedure. And we can see, in a very short time, probably in less than a week, whether the drug is working."

The study was a collaboration of researchers from the Jonsson Cancer Center, the Crump Institute for Molecular Imaging, the Howard Hughes Medical Institute and the UCLA departments of pathology, urology, medicine and molecular and medical pharmacology.

UCLA's Jonsson Comprehensive Cancer Center comprises more than 240 researchers and clinicians engaged in research, prevention, detection, control, treatment and education. One of the nation's largest comprehensive cancer centers, the Jonsson center is dedicated to promoting research and translating the results into leading-edge clinical studies. In July 2005, the Jonsson Cancer Center was named the best cancer center in the western United States by U.S. News & World Report, a ranking it has held for six consecutive years.

For more information on the Jonsson Cancer Center, visit our web site at:

http://www.cancer.mednet.ucla.edu.

http://www.medicalnewstoday.com/