for a puzzling disease
To be diagnosed with multiple sclerosis (MS) is to find yourself on ground that is shifting under your feet—and to know that even if the shifting stops, it may well resume with a vengeance.One out of every 500 Albertans lives on this uncertain ground. For every man with MS, there are two women who have the disease, and the average age at diagnosis is 30. In a province with a young population like Alberta’s, MS touches many lives.
“Probably 50 percent of us know someone or are related to someone who has MS,” says neurologist Dr. Luanne Metz, Director of the Multiple Sclerosis Clinic at Calgary’s Foothills Hospital and a member of the University of Calgary’s MS Research Team. “The burden MS creates for people who have the disease, for their families, for the healthcare system, and for community resources is very, very heavy.”
Physicians and scientists are all too aware that what they have to offer those who suffer from MS is limited. Current treatments include glatiramer acetate (Copaxone) and interferon-beta (Avonex, Betaseron, and Rebif). If started early enough, all of these drugs delay the permanent neurological injury that occurs with the disease. None of them, however, will cure MS or stop its progress.
The challenge for MS researchers is not just to develop brand new drugs—an enormously costly and time-consuming undertaking—but also to understand how the existing drugs work and how those mechanisms can be improved. “Understanding how drugs work in MS is very important in that it leads not only to a better understanding of what drugs are targeting, but it also helps to unravel some of the causes of what is happening in the disease,” says Dr. V. Wee Yong, an AHFMR Senior Scholar and a colleague of Dr. Metz’s on the MS Research Team. “Our aim is to help boost the efficacy of currently available drugs and, in so doing, to discover new therapeutics.”
Stalking the medicine chest
Dr. Yong and his colleagues at the University of Calgary are optimistic that they will soon be able to add another treatment to the MS medicine chest. Dr. Yong has been working with matrix metalloproteinases (MMPs), a family of proteins associated with inflammation in the central nervous system, and with the class of drugs known as matrix metalloproteinase inhibitors, which curb the effects of the proteins. “MMPs,” he says, “are the bad guys in MS.”
Interferon-beta is an MMP inhibitor that works by decreasing the amount of MMPs that leukocytes (white blood cells) produce, a discovery first published by the Yong laboratory. Copaxone works through a different mechanism: “We know that interferon-beta affects MMPs in one manner, and we are looking at drugs that are already in use which affect MMPs by other mechanisms,” Dr. Yong explains. “If we can find other drugs with MMP-inhibitory activity, then we can use them to supplement the effects of the existing MS drugs. We’ll be able to launch a multi-pronged attack on MMPs using interferon-beta and the second MMP inhibitor. Because these drugs are already on the market and have a proven safety record, it will be easier to get approval for their clinical use in MS patients. We have a candidate that has shown promise in animal models.”
The MS team hopes to have clinical trials underway in about a year. To bring the drug to a Phase I trial, they have applied for funding through a new Canadian Institutes of Health Research (CIHR) grant competition for interdisciplinary teams of health researchers. The team is one of only 32 out of 179 groups—and the only MS research team—to have proceeded to the next stage of the highly competitive and lucrative awards. The winning teams, which will be announced in January 2001, will receive an estimated $1 million per year over a five-year period.
Testing new drugs
When the trials get underway, Dr. Metz is certain there will be no shortage of willing participants. “What we’re trying to do is see if we can make the effect of current treatments better by combination therapy.” However, even if that doesn’t prove to be the case, showing that this drug is effective on its own—as this one was in the animal model—will also be important.
MS patients will tell you that interferon and Copaxone have significant downsides: They must be administered by injection, either daily or every other day, and may be associated with irritation at injection sites. Also, interferon frequently has unpleasant side effects, including flu-like symptoms. These are enough of an incentive that some people with MS opt out of treatment. What makes Dr. Yong’s drug particularly appealing is that it is taken by mouth and is considerably less expensive than interferon or Copaxone, which cost a staggering $12,500 to $21,000 per patient per year. Dr. Metz says her clinic follows about 500 patients on injectable therapy.
“If we can show that combination therapy is more effective, we will be adding little to the current cost of treatment; whereas, if we show that this drug alone has similar efficacy and safety to current treatments, then the cost of treatment could be more in the range of $1,000 per patient per year,” she says. “Greater therapeutic effectiveness, as we are hoping for from combination therapy, would then mean that patients get greater clinical benefits, and Alberta Health and Wellness gets more benefit for every dollar spent. On the other hand, a less expensive, equivalent therapy would mean that we could treat more people, and there would be more money available for other treatments. Even if we can show that this treatment is as good as the other treatments, then, at the very least, we can save money.”
Dr. Wee Yong is an AHFMR Senior Scholar, and Associate Professor in the Departments of Oncology and Clinical Neurosciences at the University of Calgary. He is a Medical Research Council of Canada Scientist and a member of the Medical Advisory Committee of the Multiple Sclerosis Society of Canada.
He also receives support from the Canadian Institutes of Health Research (formerly the Medical Research Council of Canada), the Multiple Sclerosis Society of Canada, Teva Pharmaceutical Industries Ltd. (Israel), and Osprey Pharmaceuticals Ltd. (Calgary).The MS Research Team at the University of Calgary includes: Dr. Wee Yong, Dr. Luanne Metz, Dr. Christopher Power, Dr. Robert Bell, Dr. Scott Patten, Dr. Ross Mitchell, Dr. Michael Yeung, Dr. David Patry, and Dr. William Murphy.
How MS drugs work
A colleague describes Dr. Wee Yong as “an international star” at understanding the mechanisms of the drugs used to treat multiple sclerosis. Indeed, as a consultant for Teva Pharmaceutical Industries, an Israeli company, he regularly packs his bags and heads off to explain to neurologists around North America exactly what those drugs do on a cellular level.
Like interferon-beta and glatiramer acetate (Copaxone), the current mainstays of MS treatment, the drug that Dr. Yong and the MS research team at the University of Calgary are hoping to bring to clinical trials in the next year acts as an inhibitor to the family of proteins known as matrix metalloproteinases (MMPs).
“MMPs act on a number of levels,” Dr. Yong explains. “They help leukocytes [white blood cells] to traffic into the brain, and they produce inflammation when the cells go into the central nervous system. MMPs can also harm components within the brain, and there is evidence that they can degrade myelin and kill neurons. An MMP inhibitor would reduce the infiltration of leukocytes into the brain, curb the neuro-inflammation, and negate the toxicity of MMPs.”