Research Updates
FIRST MONOCLONAL ANTIBODY TREATMENT
FOR MULTIPLE SCLEROSIS APPROVED
FDA News FOR-107, 11/23/04
FDA today licensed a new biological approach to treat patients with relapsing forms of Multiple Sclerosis (MS) to reduce the frequency of symptom flare-ups or exacerbations of the disease. MS is a chronic often disabling disease of the brain and spinal cord.
Natalizumab, the new product, is a monoclonal antibody bioengineered from part of a mouse antibody to loosely resemble a human antibody. It is being marketed under the tradename Tysabri. The product is given intravenously once a month in a physician's office.
According to the Multiple Sclerosis Association of America, approximately 350,00 individuals have been diagnosed with M.S. in the U.S., with an estimated 10,000 new cases diagnosed each year. The most common form of MS at the time of initial diagnosis is a relapsing-remitting form, in which acute symptoms or worsening of neurological function (referred to as "relapses," "attacks," or "exacerbations") occur intermittently. The symptoms can diminish or disappear for months or years between relapses.
Although the cause of MS is unknown, it is widely considered to be an autoimmune disease in which the person's immune system attacks the brain and/or spinal cord. Tysabri appears to work by binding to these immune system cells, thus preventing them from traveling to the brain where they can cause damage.
Antibodies are proteins produced by a person's immune system to fight foreign substances, such as infections. Monoclonal antibodies, such as natalizumab, can be produced in large quantities in cell culture in a laboratory setting. They can be designed to bind to proteins in the body's normal cells. By recognizing and attaching these proteins, monoclonal antibodies can interfere with (or alter) normal or abnormal cellular responses. In this way, monoclonal antibodies may be used in the treatment of certain diseases such as MS.
"This innovative treatment for multiple sclerosis represents a new approach to treating MS - exciting news for patients with this serious disease," said Dr. Lester M. Crawford, Acting FDA Commissioner. "While we eagerly await long-term results from ongoing clinical trials, we have reason to believe that Tysabri will significantly reduce relapses in MS."
The approval of Tysabri is based on positive results seen in patients after one year of treatment. This product received accelerated approval because it appears to provide substantial benefits for patients with a serious disease. As part of that approval, the manufacturer has committed to continuing its trials of this product for another year.
Tysabri was evaluated for safety and efficacy in two ongoing randomized, double-blind, placebo-controlled trials in patients with relapsing forms of MS. In the first clinical trial of the product's safety and efficacy, the drug reduced the frequency of relapses by 66 percent relative to placebo.
In a second trial, patients who had been treated with Avonex (interferon beta-1a), an approved treatment for MS, but who had experienced one or more relapses while on Avonex, were randomized to receive Tysabri or placebo. Avonex was continued throughout the study for both groups. In this trial, natalizumab reduced the frequency of relapses by 54 percent relative to placebo.
The most frequently reported serious adverse reactions were infections, including pneumonia, temporary hypersensitivity reactions (such as rash, fever, low blood pressure, an chest pain), depression, and gallstones. These serious adverse reactions were uncommon. Common adverse reactions were generally mild and included non-serious infections (such as urinary tract, lower respiratory tract, GI system, and vaginal infections), headache, depression, joint pains, and menstrual disorders.
VITAMIN BOOST
Condensed from Science News 10/9,16/04
Janet Raloff
The story of Vitamin D would appear simple. Take in enough sun or drink enough fortified milk to get the recommended daily amount, and you'll have strong bones. Take a supplement, if you want insurance. But recent studies from around the world have revealed that the sunshine vitamin's role in health is far more complex. More than just protecting bone, vitamin D is proving to preserve muscle strength and to give people some protection against deadly diseases including multiple sclerosis (MS), diabetes, and even cancer.
What's now clear is that vitamin D is a potent force in regulating cell growth, immunity, and energy metabolism, observes David Fieldman of Stanford University School of Medicine. He's the editor of a new 1,300-page compilation of research findings from more than 100 labs working on this substance (2004, Vitamin D, Academic Press). Not only is the vitamin gaining increasing respect as a governor of health, he notes, but it's also serving as the model for drugs that might tame a range of recalcitrant diseases.
Ironically, observes bone-metabolism specialist Robert P. Heaney of Creighton University Medical Center in Omaha, Neb., vitamin D is a misnomer. "A vitamin is an essential food constituent that the body can't make," he explains, but people have the capacity right in their skin to provide all the vitamin D they need from a cholesterol-like precursor.
Once vitamin D is available, the body converts it first into 25-hydroxy vitamin D and then into 1,25-dihydroxy vitamin D (1,25-D). This final form, which is actually a hormone, is the only active variety, Researchers loosely refer to all three substances in this biochemical cascade as "vitamin D."
Other correlations between vitamin D and health have captured researchers' attention. Kassandra L. Munger of the Harvard School of Public Health in Boston recently presented evidence of what appears to be a protective effect of vitamin D against MS. In two ongoing studies of 187,500 U.S. nurses, women getting at least 400 IU of vitamin D per day showed only 60% the risk of developing MS compared with women getting less of the vitamin, Munger and her colleagues reported in the Jan 13 Neurology. These findings not only confirmed a link seen earlier in animals but also fit with several long-standing geographic observations. The incidence of MS and other autoimmune diseases--in which a person's immune system attacks part of his or her own body-- tends to be rare near the equator, where ultraviolet light from the sun is intense and people produce abundant vitamin D.
Over the years Cantorna's team has shown in animal models of MS, lupus, inflammatory bowel disease, and type 1 diabetes that autoimmune systems diminish or disappear after the animal receives either 1, 25-D or chemical analogs of it. The group has even shown, in a mouse study, that such drugs can prevent rejection of a transplanted heart. Cantorna and others have turned to 1,25-D analogs for potential therapeutic applications of vitamin D because excessive amounts of 1,25-D can raise blood-calcium concentrations to toxic levels, which can lead to kidney stones and heart disease.
Today, during much or all of the year, a large share of the U.S. population doesn't even come close to achieving 200 to 600 IU of vitamin D daily. That is the minimum vitamin D intake recommended in 1997 by the National Academies' Food and Nutrition Board, which sets the guidelines for vitamins. However, most recent research on Vitamin D suggests that many of its health-promoting actions may require far higher dosage. At issue, however, is how much. Until this issue can be addressed, it is far safer to stay within the National Academies' recommended dosage. This is for information only, and needs to be discussed with your doctor.
YOGA REDUCES FATIGUE IN MS SUFFERERS, REPORT SHOWS
13 WVEC Medical (Tues., 7/6/04)
When Beth Adamusik was diagnosed with multiple sclerosis (MS) 10 years ago, she felt like she was given a death sentence. "I was devastated, I used to cry constantly, I was a mess, I thought my life was over," says Beth.
Beth's initial symptoms included temporary blindness. She lost her sensation of touch, from the tips of her toes to her head. She was completely numb. "It was horrifying, I had three kids, my youngest was two," says Beth.
After receiving her diagnosis, Beth struggled to regain control of her life, both physically and mentally. Once an athlete, Beth was hungry to get her body moving again. She discovered yoga. "It has transformed me, it has given me back my life," says Beth.
In fact, recent research published in the Journal of Neurology demonstrated that yoga significantly reduces fatigue in people battling MS. The study also clearly demonstrated that yoga postures can be modified for use among people with MS who have disabilities caused by their condition and that yoga can be done safely and effectively.
"Yoga is a form of movement and exercise and it incorporates deep breathing, poses, some stretching, relaxation and all of those things are beneficial to people with MS," says Debbie Hertz of the National Multiple Sclerosis Society.
Just like there is insulating material around an electrical wire, nerves in the central nervous system, the brain and spinal cord also have an insulating material called myelin. With MS, myelin is destroyed and replaced by scars of hardened "sclerotic" patches of tissue. Such lesions are called "plaques", and appear in multiple places within the central nervous system.
In addition to extreme fatigue, many people with MS can have blurred vision, loss of balance, poor coordination, slurred speech, tremors, numbness, even paralysis. These problems could be permanent. Frequently though, they come and go.
Beth's yoga teacher, Martin Bland, has been working with people who have MS, for the last 15 years. "In yoga class, it's not just the skeleton, it's not just the muscles, it's the organs and glands that get stimulated, their whole respiratory system gets stronger," says Martin.
Beth, who does yoga stretches religiously every morning, says it has not only helped her conquer her fatigue, but it has also helped with equilibrium.
"It's about balance, it teaches you how to [balance] from your core, how to balance the whole upper body and then strengthen the lower body, it's been amazing," says Beth.
The National Multiple Sclerosis Society urges every one to first consult with their physician before beginning any kind of exercise program.
TRIAL OF ARICEPT AND A NEW
MS-LIKE MODEL
Nat. M.S. Soc. (11/08/04)
Results Published from Study of Aricept in MS
The results of a study on Aricept (donepezil hydrochloride, Pfizer, Inc.) - an oral medication shown to improve memory in Alzheimer's disease - in 69 people with MS have been published in full in the November 9 issue of Neurology (2004;63:1579-1585). Dr. Lauren Krupp and colleagues (State University of New York at Stony Brook) originally reported these results at the Annual Meeting of the American Academy of Neurology in 2003. They found that 35 persons on Aricept for 24 weeks showed significantly greater improvements on ability to recall a list of words, and in clinician and patient reports, than 34 subjects taking inactive placebo.
Cognitive changes often occur in MS, commonly problems with memory. In an accompanying editorial, Drs. P. Murali Doraiswamy (Duke University, Durham) and Stephen M. Rao (Medical College of Wisconsin, Milwaukee) commented that the investigators "... have now set the gold standard for the next generation of cognitive enhancer trials in MS," adding that testing the long-term effectiveness of such drugs is a priority. "It is hoped that such studies in the near future will lead to increased treatment of options for this debilitating disorder." In fact, a large study is underway to confirm the safety and benefits of Aricept for improving memory in MS.
RESEARCHERS EXPLORE A NEW MODEL OF
MS-LIKE DISEASE
Nat. M.S. Soc. (11/08/04)
Researchers have developed a new animal model for studying how damage occurs in MS and how to exploit the body's own capabilities for repair. MS occurs when the immune system attacks the brain and spinal cord, damaging myelin insulation on the underlying nerve fibers. Limited repair does occur, but these capabilities have been difficult to assess, for one, because in the standard animal model of MS-like disease - known as EAE, or experimental autoimmune encephalomyelitis - areas of myelin damage (lesions) occur in many various and unpredictable locations.
Now, Dr. Martin Kerschensteiner (Harvard University, Cambridge) and colleagues have developed a "targeted" EAE model, which they present in the October 18 issue of The Journal of Experimental Medicine (2004 Oct. 18;200(8):1027-38), In this model, the authors caused a single lesion in the spinal cords of rats, and observed that nerve fibers were able to regenerate and repair themselves in several ways. This study provides a framework for understanding the repair capabilities inherent to the nervous system, and for developing future therapeutic strategies for MS that take advantage of this capacity for self-repair.
TRIAL TESTS DIABETES DRUG IN
TREATMENT OF MULTIPLE SCLEROSIS
Pharma Investments (Ventures & Law Weekly, 07/04/04)
Researchers at the University of Illinois (UIC) at Chicago are launching a clinical trial to determine whether a drug commonly used for diabetes might be effective in treating multiple sclerosis, an autoimmune disease that affects 350,000 Americans.
In an animal model of the disease, the researchers found that the drug reduced the inflammation of nervous tissue that occurs with multiple sclerosis and prevents the aberrant immune response that ends up destroying the body's own brain and spinal cord.
"At present, few medications have been approved by the Food and Drug Administration for the treatment of multiple sclerosis," said Douglas Feinstein, associate professor of anesthesiology in the UIC College of Medicine. "These drugs are only partially effective, and none help significantly in the later, progressive forms of the disease. The drugs also have undesirable side effects, and they need to be injected, making them difficult to administer."
The drug being tested, called pioglitazone, is prescribed for the treatment of type 2 diabetes. Marketed by Takeda Pharmaceuticals North America, pioglitazone "sensitizes" the body's cells to insulin, a hormone produced by the pancreas that lets sugar into cells so that it can be converted into energy. People with type 2 diabetes are unable to use insulin efficiently, leading to elevated blood sugar levels (hyperglycemia) and tissue damage.
Research has shown that drugs like pioglitazone not only raise the levels of certain proteins involved in the uptake an metabolism of glucose but also lower the levels of other molecules involved in the immune response and inflammation.
"It is amazing that this drug, at least in animal tests, has shown a dramatic effect on two different targets of multiple sclerosis, namely the immune system and the inflammation process," Feinstein said. Feinstein also noted that the drug is available as a tablet, simplifying its administration.
The clinical trial will enroll about 30 patients with relapsing remitting multiple sclerosis, the most common form of the disease. People with this type of multiple sclerosis experience episodes of acute worsening of neurological function, followed by partial or complete recovery. In most patients, the disease will eventually change into a chronic, persistent form, with symptoms worsening throughout life.
Participants in the trial will take a 30 mg dose of pioglitazone daily for a period of 18 months, during which they will be monitored for any side effects or changes in their symptoms.
"At this stage in the drug trial, we are simply trying to determine whether the drug is safe and can be tolerated by people with multiple sclerosis," Feinstein said. "But we'll also be doing neurological examinations and biochemical analyses of blood samples, looking for signs of inflammation and immune cell activation to determine whether the drug is having any effect on symptoms of the disease."
Employing UIC's state-of-the-art magnetic resonance imaging technology, the researchers will do a series of three brain scans over the course of the trial to look for changes in the cerebral lesions associated with multiple sclerosis.
In the United States, health care costs for multiple sclerosis are second only to those for Alzheimer disease.
The study is funded by Takeda Pharmaceuticals North America.
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