UM finds promise in unlikely MS drug

THE BALTIMORE SUN

The first drug to offer hope to people suffering from multiple sclerosis has its roots in failure -- almost a decade of experimental results so disappointing that many scientists urged abandoning the approach altogether.

But two physicians with the University of Maryland Medical Center looked at failure and saw possibilities.

And now, their perseverance seems to have borne fruit. Test results show the drug, beta interferon, lessens the severity and frequency of attacks of multiple sclerosis in many patients who are in the early stages of the disease.

"This is a very exciting time for MS research," said Dr. Kenneth P. Johnson, who along with Dr. Hillel S. Panitch, directed beta interferon research at the University of Maryland Medical Center. "It will cut down on the number of attacks and cut down on the disability."

The Food and Drug Administration is expected to decide soon whether to heed an advisory panel's recommendation and grant commercial approval to beta interferon, which is made by Chiron Corp. and marketed by Berlex Laboratories.

So far, testing has focused on patients with mild to moderate symptoms that come and go in cycles known as relapses and remissions. There are approximately 300,000 MS patients in the United States; for now, the drug appears suited for roughly one-third of them.

While the FDA is observing its usual silence during the final review of an experimental drug, observers believe approval is a near certainty.

Dr. Johnson recalls many times in the past decade when friends, noting the string of frustrations over studies into the broader family of interferons, politely suggested that he look elsewhere for answers to the nerve-wasting disease.

"Virtually no one else had any interest in the interferons," said Dr. Johnson, chief of neurology at Maryland. "We tried it. It didn't work. We showed it didn't work. It was time to move onto other things."

How it works

Beta interferon seems to suppress the underlying cause of multiple sclerosis -- errant attacks by the immune system on nerve fibers of the brain and spinal cord. The attacks destroy myelin, the protective covering around nerve fibers. This causes a confusing "cross-talk" between fibers, and slows the signals that control such functions as movement, balance, feeling and sight.

The effects vary greatly. Some people become paralyzed in a few years. Most, however, experience occasional episodes of weakness, numbness, slurred speech, poor balance and impaired vision that are followed by remissions that can last several months or years.

These patients can remain active for years and, in many cases, for their entire lives. But while the symptoms tend to subside between attacks, each assault on the nervous system leaves patients more impaired than before.

This is why the recent findings on beta interferon are important. The hope is that patients will not only suffer fewer attacks but that residual nerve damage will accumulate more slowly. This could give people more time before they become disabled.

While no one views the drug as a cure, a cautious excitement has grown among MS patients and researchers because of its potential to give patients more time between attacks, reduce their severity and slow the progression of the disease.

The basis for their enthusiasm is a three-year study of 372 patients at 11 institutions in the United States and Canada, including the University of Maryland. The patients were divided into three equal groups -- one receiving a high dose of beta interferon, one a moderate dose and another a placebo.

The high dose worked best. Patients taking it had one-third fewer attacks than those taking a placebo. Over three years, that group went an average of 264 days before their first attack, compared with 147 days for those in the placebo group. And the attacks were less severe, causing less weakness, numbness and vision problems.

Additionally, 36 people in the high-dose group went through a two-year period with no attacks at all -- twice the number in the group taking a placebo.

Perhaps most surprising were the results of magnetic resonance images that were taken of patients every year.

The pictures showed that areas of damaged brain tissue shrank slightly in the high-dose group; in contrast, the areas grew 20 percent in the placebo group.

This doesn't mean the high-dose patients were improving, Dr. Johnson said. But it could be physical evidence that the course of the disease had slowed.

Volunteer's success story

"Obviously, I'm hoping for a cure someday," said Martha Krebs, a 34-year-old Germantown woman who was first diagnosed in 1987 after episodes of poor vision, fatigue, lethargy and numbness. "But in the meantime, I am going to do whatever I can to help myself and others."

In the three years since she volunteered for the study, she has not suffered a single attack. But to preserve the study's objectivity, none of the volunteers have yet been told which preparation they are taking. So it is possible she is taking a placebo and is experiencing one of the unpredictably long remissions with which some patients are blessed.

Interferons are a family of naturally occurring proteins unleashed by the immune system to combat viral infection and other insults to the body. Around 1980, a flurry of excitement over their potential to battle cancer made them the molecules of the moment.

Dr. Johnson and Dr. Panitch, who were then working at the University of California at San Francisco, saw a different possibility -- that interferon injections could be used to combat multiple sclerosis. In a small clinical trial, they tried one of the interferons -- alpha interferon -- on the theory that some people didn't produce enough, and that boosting the supply could protect nerves from assault.

The drug seemed to bring about modest improvements in some patients, but with side effects of fever, chills, muscle aches and fatigue. A reduced dose didn't work. The side effects disappeared, but so did the benefits.

But the two doctors were encouraged by the small improvements they saw in those first patients. New production techniques were also making interferons easier to obtain.

In 1981, Dr. Johnson moved to the University of Maryland Medical Center, which was then gaining the reputation as a major center of multiple sclerosis treatment and research. It wasn't long before the Massachusetts biotechnology company, Biogen, approached him about trying another interferon -- gamma interferon.

Eighteen patients received injections of gamma interferon, and the results were dramatic. Dramatically bad.

Seven of the patients developed multiple sclerosis attacks in the first month, an extraordinarily high rate. By that time, many scientists were writing off interferons.

"Some saw the gamma interferon study as a disaster," Dr. Panitch said. "We saw it as something that told us a tremendous amount."

If injections of gamma interferon exacerbated the disease, they surmised, perhaps attacks of multiple sclerosis occurred when the immune system, on its own, unleashed the protein against the nervous system. They looked for something to inhibit the attacks.

That inhibitor turned out to be another member of the interferon family -- beta interferons. A pilot study of 30 patients showed encouraging results, and that led to the much larger study reported this month in the journal Neurology.

Cautious optimism

"This is probably the most significant treatment finding for MS in the last 25 years, particularly if you look at the underlying disease course rather than symptomatic management," said Dr. Stephen Reingold, vice president for research and medical programs for the National Multiple Sclerosis Society.

He cautioned, however, that the drug has been shown effective only for early-stage patients. And, he said, it will take years to learn whether the drug truly slows the downward course of the disease.

The next experiment, which should begin in the coming year, will test the drug on people who are suffering constant symptoms rather than a wax-and-wane pattern.

In the meantime, patients with early disease cling to hope.

"They've always said this is not a cure, but it can help retard the progression of the illness," said Ms. Krebs. "My hope is that the drug gets approved, insurance pays for it and life goes on."

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