Using nature to fight MS.

USING Nature TO FIGHT MS

A major two-year clinical trial of one form of interferon--a natural substance produced by the body--is under way at 10 medical centers in the U.S. and Canada. Participating clinicians are hopeful that the results, expected around mid-1991, will match the early promise shown by the agent.

Interferon is made continually by the body to combat viruses. Since it can suppress an abnormal immune response, which MS is thought to be, interferon has been considered a good candidate for clinical trials. It is also being used in AIDS research.

Three different types of interferon have now been manufactured in a "recombinant" form through gene cloning techniques: alpha, beta and gamma. Dr. Kenneth Johnson, chairman of neurology and rehabilitation at the University of Maryland, has closely followed trials of all three types since 1980. In that year a preliminary study of alpha interferon done at the University of California, San Francisco, Stanford University, and the Scripps Clinic showed some benefit; but the side effects--malaise, fever, joint pain, loss of appetite, injection site pain--made long-term use prohibitive.

"In this first society-funded trial we saw a trend toward a drop in numbers of MS attacks among young, relapsing-remitting patients," Dr. Johnson told INSIDE MS. "We knew we were onto something with interferon, but the alpha type was probably not going to be it because of the side effects."

Then, in 1984 Dr. Johnson and a colleague, Dr. Hillel Panitch, were approached to do a trial of recombinant gamma interferon. "This type of interferon stimulates Ia antigens of the immune system," Dr. Johnson explains. "So when you give gamma interferon you intensify the antigen signal within the brain and increase the inflammatory response.

"As it turned out, of 18 people who got interferon, seven exacerbated within one month. We had to stop the study immediately. But it told us a lot about the immune system and the central role of gamma interferon in MS."

Since 1984, Dr. Johnson says, one fundamental plank of MS research has been the idea that if something could be done to control the body's output of gamma interferon, it might be possible to prevent MS attacks. "Well, it turns out that beta and alpha interferon both block many of the effects of gamma interferon. So we had a new rationale for using them."

Since alpha's side effects were now well known, it was decided to run a pilot trial with beta interferon, to learn whether the agent was safe and at what dose it could be tolerated.

The trial, begun in 1986 and still continuing, focused on 30 young patients with relapsing-remitting disease.

"We are treating these patients with 45 million units of beta interferon three times a week, which is a lot of interferon," comments Dr. Johnson. "But after the first two months--which are a little rocky--patients have absolutely no side effects with these doses. Again, we find a trend toward fewer MS attacks in the group, but the number of patients is too small to make a value judgment. Significantly, all the patients have asked to continue in the trial, which they have been allowed to do."

Most recently, Dr. Johnson and other interested clinicians decided to go all out in a 10-center trial (see box) of 350 patients. The study, which is supported by Triton Bioscience Inc. of Alameda, Calif., will consist of three patient groups (all with relapsing-remitting disease): one that gets beta interferon in doses of 45 million units every other day (rather than three times a week), a second group that gets a comparatively low dose of 9 million units, and a third group that gets placebo. Patients will give themselves subcutaneous injections on alternate days for two years.

From the beginning, teams at various centers have tagged immunological studies to the interferon trials to learn what was happening on a cellular level. "We at Maryland and Dr. Robert Knobler at Jefferson Medical College have found that patients getting beta interferon produce much less gamma interferon," says Dr. Johnson. "That's exactly the kind of thing we want to have happen. And Dr. Barry Arnason at the University of Chicago has found an increase in suppressor T-cell activity in beta interferon studies; this, too, we feel is a positive aspect of therapy."

Other studies will be part of the project. Dr. John Whitaker at the University of Alabama is studying myelin basic protein fragments in patients' urine to chart the course of demyelination. The University of British Columbia's Donald Paty plans to do magnetic resonance imaging scans on both interferon and placebo patients every six weeks. The images should yield important data.

Additional beta interferon trials are currently taking place at the Dent Institute in Buffalo, the University of Rochester (NY), Walter Reed Hospital in Washington, D.C., the VA Wadsworth Medical Center in Los Angeles, and the Hospital Neurologique in Lyon, France.