Multiple Sclerosis: Betaseron and Beyond
Few years ago the Food and Drug Administration (FDA) approved Betaseron (interferon beta-1b) as the first and only agent for the treatment of multiple sclerosis (MS). This approval was a beacon of hope for the more than 300,000 Americans who are afflicted with this central nervous system disease which usually first appears in young adulthood and which disables by causing problems with vision, strength, coordination, speech, bladder control, sensation, or other faculties governed by the eyes, brain, or spinal cord.
MS is characterized by multiple, scattered sites of inflammation (lesions) within the central nervous system, which occur at irregular intervals of time and which produce attacks of variable neurologic symptoms, depending on exactly which site in the brain, optic nerves, or spinal cord is newly affected. The inflammatory lesions appear to be caused not by an infection, but by an abnormal autoimmune process in which the body's immune system is reacting inappropriately to parts of the central nervous system as though they are foreign tissue. Usually the individual lesions and the resultant symptoms subside somewhat, but they leave hardened (sclerotic) plaques in the nervous system.
The ultimate disability in MS is dictated by the frequency, severity, and exact location of these lesions and the resultant plaques. Therefore, most of the strategies for long-term treatment of MS have been directed at modifying the immune system to make new attacks (exacerbations) less frequent and less severe. Numerous trials of drugs expected to suppress the immune system have shown only minimal benefit, particularly when weighed against the risks of immunosuppression. However, one of the drugs, Betaseron (a naturally occurring human protein which affects the immune system), produced a significant decrease in the frequency of the exacerbations reported by patients and slowed the appearance of new lesions on the MRI brain scans. This led to its FDA approval, even though the drug has some important limitations:
1. Betaseron is not a cure for MS.
This is not a surprise, because the experimental clinical data on which the FDA approval was based suggested that the patients treated with alternate-day injections of the high dose of Betaseron still experienced about two-thirds the number of MS exacerbations experienced by the patients treated with placebo injections. Some patients treated with Betaseron have done remarkably well, in the sense that they have had very minimal side effects, a glowing sense of well-being, and no discernible exacerbations. On the other hand, other patients seem to have had an acceleration of the frequency of their exacerbations, even to the point of having to discontinue Betaseron. The majority of the patients fall somewhere in the middle: they feel reasonably well compared to their pre-Betaseron experience, and they are committed at present to keeping up with Betaseron, because they feel it is the "right thing to do."
2. Betaseron is not for everyone with MS.
The stated indications for Betaseron are "to reduce the frequency of clinical exacerbations in ambulatory patients with relapsing-remitting multiple sclerosis." This is a somewhat artificial restriction imposed by the population pool chosen to be subjects for the two-year clinical trial submitted to the FDA. We certainly have regarded patients with progressive MS and patients who are not ambulatory also to be possible candidates for Betaseron.
More importantly, individual patients have made very sound decisions to not start Betaseron or to discontinue Betaseron, based on how troubled they are by their disease, on their informed assessment of how beneficial the treatment is likely to be, and on their readiness to accept some of the side effects. These side effects include the substantial cost (about $10,000 per year); the almost universal flu-like aching, fever, and malaise which most patients experience for many hours after each injection for the first few months; and (rarely) exaggerated skin lesions at the injection sites. Fortunately, we are learning ways to decrease each of these adverse effects of Betaseron injections.
3. Betaseron is a first-generation MS treatment.
Because Betaseron is not the perfect treatment for MS, already there is substantial pressure to do better. The first question asked by patients who are not going to start Betaseron, or who are going to discontinue it, is: "What else is available?" This has caused us to revisit some of the previously tested drug treatments for MS, mainly immunosuppressant drugs such as azathioprine, cyclophosphamide, and methotrexate. These drugs do not require formal FDA approval for the treatment of MS, because they are already released for other purposes. We do know that there were some guardedly encouraging results in previous trials with these drugs, and currently they are appropriate candidate drugs for long-term treatment of MS. In addition, there have been some suggestions that short-term treatment with steroids, long a mainstay of "reactive" treatment for new exacerbations, may actually have a protective effect for as long as a year, if the steroids are administered in a massive intravenous dose.
A number of new drugs are in the process of gaining FDA approval for the treatment of MS. These include a chemically modified form of interferon beta-1b and a totally different drug, copolymer 1, which has been under investigation for many years. This is an exciting period in the treatment of MS: even if there is not a perfect cure in the near future, it is likely that we will have several drugs to choose among, either singly or in combination, when tailoring a treatment program for patients with different forms of MS.
Dr. Lowenthal, whose special interests include neuromuscular disorders and neuroimmunology, is chair, section of neurology and neurosurgery, at the Sansum Medical Clinic in Santa Barbara, California USA. A graduate of Harvard College and of the University of Chicago School of Medicine, he completed his neurology residency training at the University of California, San Francisco. He is a Fellow of the American Academy of Neurology and he is chair of the California Medical Association's section on neurology.
For additional information on Multiple Sclerosis, go to:
MS Direct -- Multiple Sclerosis Support
MS Crossroads: links on web about multiple sclerosis (MS).
National Multiple Sclerosis Society
733 Third Avenue
New York, NY 10017-3288
Telephone: (212) 986-3240
FAX: (212) 986-7981
Toll-Free Information Line: 1-800-LEARN MS
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