Israeli Science: News from Rehovoth
- MULTIPLE SCLEROSIS: FDA RECOMMENDATION FOR NEW DRUG
- LEPTIN: POTENTIAL WEIGHT-LOSS DRUG LINKED TO ADULT DIABETES?
NEW DRUG RECEIVES RECOMMENDATION OF FDA ADMINISTRATION ADVISORY COMMITTEE
REHOVOT, Israel -- An advisory committee convened by the U.S. Food and
Drug Administration recommended on September 1996, that the FDA approve the
Israeli drug copolymer-1, to be marketed under the brand name COPAXONE®, for
treatment of patients with relapsing-remitting multiple sclerosis.
Following the recommendation, the FDA is expected to grant approval for the
marketing of the drug in the U.S. within the next few weeks. Copolymer-1
(COPAXONE®) is a protein-like molecule originally synthesized by Prof. Michael
Sela, Prof. Ruth Arnon and Dr. Dvora Teitelbaum of the Weizmann Institute of
Science in Rehovot, Israel.
Yeda Research & Development Co., which deals with the commercialization of
Weizmann Institute research, granted exclusive rights for manufacturing and for
marketing copolymer-1 (COPAXONE®) throughout the world to Teva Pharmaceutical
Industries Ltd., Israel.
The drug was further developed by Teva, with the participation of physicians
and researchers from Israel and other countries. Clinical trials carried out in
recent years have shown that copolymer-1 reduces the number of attacks in
patients with the relapsing-remitting form of multiple sclerosis, and that it
ameliorates the condition of people in the early stages of this disease.
Moreover, the drug produces almost no negative side effects.
Copolymer-1 was first clinically investigated at the Hadassah-Hebrew
University Medical Center in Jerusalem and the Albert Einstein College of
Medicine in New York, and follow-up trials were conducted at various other
research centers. In a decisive double-blind trial carried out between 1991 and
1994, copolymer-1 was tried on several hundred patients in eleven U.S.
hospitals. Following the success of these trials, a request for marketing
approval for the drug was filed last year with the FDA, and, as noted above, a
recommendation for such approval has just been granted.
Multiple sclerosis is an autoimmune disease that
occurs when the body's immune system erroneously attacks the protective myelin
coating around nerve fibers in the central nervous system. Once this coating is
destroyed, signals sent along these nerves are slowed down, and at times stopped
altogether. As a result, body movement becomes difficult, and partial or
complete paralysis may set in.
Copolymer-1 (COPAXONE®) blocks this process in two ways: it prevents the
immune-system "attacker" cells from recognizing the myelin coating, thus warding
off their attack, and it also triggers the production of immune-system
suppressor cells that inhibit the action of the destructive attackers.
Multiple sclerosis is a devastating disease affecting mainly young people
approaching the prime of their lives. Approximately 1 million people suffer from
it around the world, including some 300,000 patients in the US and an additional
350,000 in Europe.
Prof. Arnon holds the Paul Ehrlich Chair of Immunology and Prof. Sela, the W.
Garfield Weston Chair of Immunology.
LEPTIN: POTENTIAL WEIGHT-LOSS DRUG MAY BE LINKED TO ADULT DIABETES
REHOVOT, Israel November 13, 1996 Leptin, the protein that made
headlines two years ago when it was found to reduce obesity in mice,may be a
cause of adult-onset diabetes in humans, according to a new Weizmann Institute
of Science study.
The study, to be published in the November 15 edition of Science, found that
high levels of leptin disrupt some of the activities of insulin, the hormone
that controls blood sugar levels. Since obese humans unlike the genetically
obese mice that received so much publicity are known to have high leptin levels
in their blood, this finding may explain why overweight people have a tendency
to develop adult-onset, or Type II, diabetes. It may also point the way towards
developing new treatments for Type II diabetes, which is the most common form of
diabetes and mostly strikes overweight people over the age of 40.
Moreover, this research suggests that if leptin is developed into a weight-loss
drug in the future, it should be used with caution because it may cause the user
to develop diabetes-related symptoms.
"We know that overweight people have higher levels of leptin. We also know
that these people have a tendency towards adult-onset diabetes, and that no one
is sure exactly what causes this type of diabetes," said research head Prof.
Menachem Rubinstein, of the Molecular Genetics Department.
"We have now shown that excessive leptin leads to reduced activity by insulin.
All the evidence now points to the probability that excessive leptin may be one
of the causes of Type II diabetes, although it is probably not the only cause.
More studies are needed to examine the link between excess leptin and diabetes,
and to determine whether anything can be done about it."
Leptin, a protein produced in fat cells, raises body temperature and lowers food
intake. It was first identified in 1994 by scientists who found that it was
absent in genetically obese mice, and that daily leptin injections caused the
animals to eat less and to lose weight. This research generated great hopes for
leptin's development as a weight-reduction drug for human consumption.
However, further studies introduced a cautionary note, finding that injecting
leptin works mainly on obese mice with agenetic defect that results in an
absence of leptin. Genetically normal obese mice as well as obese humans
actually have excess leptin levels. (So far, no humans are known to have a
genetically caused absence of leptin.)
Rubinstein's study now sounds a further warning, and points to a new avenue
of research that will investigate the connection between leptin and adult-onset
diabetes. In this form of diabetes, insulin production is usually normal but
blood sugar levels are not under proper control.
Balancing blood sugar levels Insulin keeps blood sugar levels balanced in
several ways: when glucose from a meal enters the bloodstream, insulin ensures
it is converted into glycogen and fat, stored for later use. Insulin also
ensures that the stored fat is not released and turned back into glucose, a
process known as gluconeogenesis, until it is needed. This double-valve process
is a finely tuned balancing act that goes on minute by minute, ensuring that
cells get a constant amount of energy and that blood sugar levels are not
subject to wild fluctuations.
Working with cells derived from human liver and using a quantity of leptin
similar to that present in the blood of obese individuals, Rubinstein and
colleagues Dr. Batya Cohen and Dr. Daniela Novick found that while leptin does
not affect insulin's first function, it does significantly suppress its ability
to slow down gluconeogenesis a process which, in the body, would cause raised
blood sugar levels.
How leptin affects insulin Leptin, insulin and other "messenger" proteins act
by binding with specific receptors on a cell's membrane, rather like a ship
docking, setting off a cascade of processes inside the cell. Leptin's main
receptor is in the brain's hypothalamus region, but there are also leptin
receptors in the liver, heart, lungs and many other organs, and their workings
had not been studied.
Rubinstein's team focused on the leptin receptor in the liver, and found that
when leptin binds to liver cells, the resulting cascade affects a key protein
involved in insulin's own cascade, the insulin receptor substrate 1 (IRS-1),
stopping it from becoming phosphorylated (the process in which phosphate
molecules attach to the protein). This failure caused several processes to take
place, the net effect of which was that a much greater amount of gluconeogenesis
Prof. Rubinstein holds the Maurice and Edna Weiss Chair of Cytokines
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