A NEW VIEW of Progressive MS.

Some leading MS experts now consider progressive MS to be a treatable disease. By the time this magazine goes to press, this opinion may be backed by the first FDA approval of a drug for secondary-progressive MS. In the meantime, expert recommendations about "off-label" therapies are changing how progressive MS is approached by many medical professionals.

InsideMS spoke to Dr. Donald Goodkin, associate professor of neurology at the University of California at San Francisco and medical director of the Mt. Zion MS Center at USF Hospital. He is worldfamous as an MS physician and researcher with particular interest in progressive MS.

Moving into a better future for progressive MS

"Nearly half of all patients who begin with relapsing-remitting MS will convert to a secondary-progressive form within 10 years of their first symptom," Dr. Goodkin said. "Progressive MS is common, and disability is significant in this group. Approximately 50% of people with secondary-progressive MS will continue to be able to walk on their own--and 50% will require assistance. People in the second group have a higher risk of needing a wheelchair permanently.

"For many years, we had no disease-modifying options to offer people with secondary-progressive MS. Over the past 2 years, this has changed. I now consider secondary-progressive MS a treatable disease, even though the treatments are not curative. There is evidence from some Phase III placebo-controlled trials that indicate interferon beta (sold as Betaseron or Avonex) and mitoxantrone (Novantrone) may reduce relapses, delay the onset of sustained progression of disability, and reduce MRI activity in people with secondary-progressive MS."

MRI activity Dr. Goodkin mentions refers to the evidence of active disease as seen on certain MRI scans. In the 1980s, MRI scanning enabled researchers to discover that early in the disease, MS is actively damaging myelin in the central nervous system, whether the individual is experiencing an attack of symptoms or not.

What is progressive MS, exactly?

Like nearly everything else about MS, the answer's not simple.

Progressive from the start

A small number of people with MS (15%, perhaps) never have a remission when their symptoms go away. Their MS slowly gets worse. Or it may stop and stabilize at any time. They may also have attacks when symptoms get dramatically worse (earning the name "progressive-relapsing"). But whether MS stops and starts up again, stops altogether, or just goes on steadily, people in this group don't have recoveries. They have "primary-progressive" MS. The patterns look like those in Figure 1, next page.

[Figure 1 ILLUSTRATION OMITTED]

Secondary-progressive

This kind of MS develops in people who have been living with relapsing-remitting MS for a while. At some unpredictable point, the division between attack and recovery (which might have been a bit gray already) becomes truly blurred. Symptoms that once arrived only during attacks move in permanently. Some people stop having clear-cut attacks; their disease worsens slowly just like primary-progressive MS. Others slowly get worse, but have attacks too, every now and then. Again, it is important to remember that MS can stabilize at any time. The patterns look like those illustrated in Figure 2, at right.

[Figure 2 ILLUSTRATION OMITTED]

Completing the picture

To get a handle on the whole picture, one needs to look at relapsing-remitting MS too. This is the most common form of MS at the time of diagnosis. The person has dramatic attacks of symptoms. These attacks are called "relapses" or "episodes" or "flares". The $64,000 term is "exacerbations". All these terms mean exactly the same thing: a period when symptoms become much more severe and new symptoms develop.

A relapse ends when the person recovers. The disease "remits" and there are weeks, months, or even years when symptoms quiet down. Sometimes remission is complete. The weakness, incoordination, loss of vision--whatever has happened--all go away. Some people feel completely normal during their remissions. But others deal with odd sensations of prickling or heaviness, fatigue, pain, vertigo, difficulty concentrating, and other symptoms. There are many MS symptoms that may (or may not!) come and go as part of everyday life. Even so, remission means the big stuff has gone away and the person's abilities return, though sometimes the abilities are not quite as good as they were. When scientists codify relapsing-remitting MS, the patterns look like those in Figure 3, next page.

[Figure 3 ILLUSTRATION OMITTED]

Who's got what?

The diagrams show 3 different names and 6 different patterns. Three drugs--Avonex, Betaseron, and Copaxone--have been approved by the FDA for controlling 2 of them, based on data from large-scale clinical trials. All these trials used reduction in the number of attacks as one of the benchmarks of success. Since many people with progressive MS have no attacks, people with progressive disease were not part of these trials. Thus the FDA had no data on effectiveness in progressive MS, one way or the other. Approval was restricted to what the trials showed, and treatment recommendations are based on that. But sometimes life is not as neat as a diagram.

"Suppose you have secondary-progressive MS with relapses," Dr. Goodkin said. "On paper, this pattern looks very different from the 2 patterns of relapsing-remitting MS. But, like most patients, you come to see me at the beginning of a new attack. I see you, you're treated, and now you're doing well. I don't see you again until the beginning of another attack. I notice then that your disability is worse than it was. But I don't know if it progressed gradually (as in secondary-progressive MS) or if it's a leftover, a symptom from your last attack that never completely resolved (which would be relapsing-remitting MS, with incomplete recovery). So in practice it's very difficult for me to distinguish the pattern with complete clarity. Many of my colleagues admit they can't do it either."

Fitting treatments to individuals

Although people with relapsing-remitting MS are eligible for the FDA-approved ABCs, some people in this group have many repeated attacks despite these medications. Dr. Goodkin and other MS clinicians are talking treatment cues from clinical trials, only one of which has been submitted to the FDA. These studies, many conducted in Europe, show that 3 other treatments may also reduce the number of attacks in relapsing MS. (They have a mixed record on delaying disability.) They are Novantrone, intravenous immunoglobulin or MG, and Imuran (azathioprine). All are being used "off-label" to treat people with relapsing-remitting MS that has not responded to A, B, or C.

"If a treatment is approved for other indications, a baseline of safety has been established, and doctors can use it for MS if they want to," Dr. Goodkin explained. "They have to be cautious. They have to follow these patients very carefully. And because the use is `off-label', some insurance companies may not reimburse for the treatments."

Those are powerful cautions. However, a great many drugs that are known to relieve symptoms of MS were originally approved for something else and are used "off-label". This is true not only for progressive forms of MS, but also for therapies that treat symptoms and improve life for people with all forms of MS. For example, MS fatigue can be successfully treated with amantadine, a drug the FDA approved for Parkinson's disease. The painful sensation of a tight band around the upper chest can be calmed with carbamazepine, a drug approved for control of epileptic seizures. The list goes on and on.

"Off-label" is the norm

For patients with secondary-progressive MS who have relapses, Dr. Goodkin and his colleagues routinely use Betaseron or Avonex "off-label", following the results of clinical trials in Europe, which showed that these drugs can reduce disease activity.

"If patients continue to experience disease activity on these therapies, we'll consider Novantrone as an alternative," Dr. Goodkin said. "And if this doesn't work, there are still others. But the data aren't quite as convincing. The first is methotrexate, taken orally once a week. The second is Copaxone. The third is monthly or every-other-month intravenous methylprednisolone, which is a steroid. The fourth is intravenous immunoglobulin or IVIG. A fifth possibility is Cytoxan (or cyclophosphamide), which some studies show to be effective and others indicate has no Clear benefit. I put this one in a separate category because of the conflicting data," he concluded.

"The picture is slightly different for people with secondary-progressive MS with no relapses. There are 2 treatments known to slow progression of disability for some of these patients, as shown in studies done in Europe," Dr. Goodkin said. "The first is Betaseron, which is now approved in Europe and Canada for people with this form of progressive MS. The second is Novantrone, which has been recommended for approval in the U.S. by FDA advisors. There are 3 more treatments that we think have some potential for people in this group: methotrexate, Copaxone, and intravenous methylprednisolone. The data supporting these drugs are not as strong as those for Novatrone or Betaseron. The studies were much smaller. But if a person is not responding to the other options, I will consider them.

"Not every doctor does the same things I do, but I think there is a growing consensus that this approach is rational."

The bottom line is good news

Treating MS symptoms continues to be extremely important in all kinds of MS. Controlling bladder problems, fatigue, spasticity, pain, and other problems makes a major difference in how people with MS feel from day to day Now it is increasingly possible to blunt the underlying disease as well. Here's how Dr. Goodkin summed it up: "It is no longer true that doctors have nothing to offer when MS progresses. But it is true that we need to develop better treatments."

Work on that is under way, in laboratories and clinics around the world.

RELATED ARTICLE: Some Current Clinical Trials of Treatments for Progressive Forms of MS

Large Multicenter Trials

WHAT                BETASERON for secondary-progressive MS
WHERE               At 35 sites in the U.S. and Canada
HOW MANY PEOPLE     939 people
EXPECTED DATE
OF COMPLETION       Stopped early (in September 1999); results
                    announced on May 1, 2000

Note: Use in secondary-progressive MS is now approved in Canada,
Europe, and Australia based on European trials; see page 31 for
results of this North American study.

WHAT                AVONEX for secondary-progressive MS
WHERE               At sites in the U.S., Canada, and Europe
HOW MANY PEOPLE     440 people
EXPECTED DATE
OF COMPLETION       Expected to finish in 2001

WHAT                IVIG (intravenous immunoglobulin) for
                    secondary-progressive MS
WHERE               At sites in Europe and Canada
HOW MANY PEOPLE     310 people
EXPECTED DATE
OF COMPLETION       Expected to finish in 2001

WHAT                COPAXONE for primary-progressive MS
WHERE               At sites in the U.S. and Canada
HOW MANY PEOPLE     900 people
EXPECTED DATE
OF COMPLETION       Expected to finish in 2002

Note: This study is still recruiting volunteers.
Call 1-877-758-7766 for more information.

WHAT                PHLOGENZYM, a combination of 3 enzymes,
                    for progressive-relapsing MS
                    and relapsing-remitting MS
WHERE               At approximately 21 sites in Europe
HOW MANY PEOPLE     280 people
EXPECTED DATE
OF COMPLETION       Completion date uncertain; trial may not have
                    produced clear results

Large Single-Center Trial

WHAT                T-CELL VACCINATION for secondary-progressive MS
WHERE               At the University of Southern California
HOW MANY PEOPLE     80 people
EXPECTED DATE
OF COMPLETION       Expected to finish in 2002

Note: This study is jointly supported by the National MS Society
and the National Institutes of Health.

Small Preliminary or Pilot Studies

WHAT                AVONEX for primary-progressive MS
WHERE               At 1 site in London, U.K.
HOW MANY PEOPLE     50 people
EXPECTED DATE
OF COMPLETION       Expected to finish in 2000

WHAT                MICELLAR PACLITAXEL, an immune-response
                    inhibitor that slows growth
                    of the cells that create scarring, for
                    secondary-progressive MS
WHERE               At 7 sites in Canada
HOW MANY PEOPLE     29 people
EXPECTED DATE
OF COMPLETION       Expected to finish in 2000

Note: Preliminary results have encouraged Angiotech Corporation
to begin planning a multicenter study involving 190 people.

WHAT                CELLCEPT (mycophenolate mofetil), a drug
                    that prevents rejection of transplants, for
                    secondary-progressive MS
WHERE               At 2 sites in the U.S.
HOW MANY PEOPLE     30 people
EXPECTED DATE
OF COMPLETION       Expected to finish by March 2001

For more information on clinical trials of MS therapies, as well as background on various types of trials, call your chapter at 1-800-FIGHT MS (option #1) and ask for a copy of Research Highlights, Winter/Spring 2000, or log on to <www.nmss.org> and go to the Research section.

Martha King is editor of this magazine.