Introduction

William H. Stuart, MD, Medical Director, MS Center of Atlanta, Georgia

Multiple Sclerosis (MS) was once a therapeutically neglected disease. Now, people affected by MS are increasingly receiving benefit from drugs developed through the efforts of the biotech/pharmaceutical industry. There is a sense of immediacy for MS patients and their physicians, as evidence consistently points to the early phase of this illness being the most responsive to therapy. This fact was demonstrated by the CHAMPS trial (Controlled High Risk Avonex® Multiple Sclerosis Prevention Study), a study conducted over the last two years in 50 different sites across the US and Canada. The New England Journal of Medicine published the CHAMPS results on September 28, 2000.

Patients, physicians, and the industry, alike, must resolve to work together to continue this momentum with newer drugs and drug combinations in order to most effectively serve the multiple sclerosis patient population.

CHAMPS Results

Over the past decade, new disease-modifying treatments have become available for people with relapsing-remitting multiple sclerosis (RRMS). These treatments, sometimes called the ABC drugs (Avonex®, Betaseron®, and Copaxone®), are the first ones that have been able to slow the progression of MS and reduce the number of relapses. People with MS may be reluctant to take an ABC drug because they feel relatively well in between relapses. However, a wealth of evidence shows that treatment with disease-modifying drugs slows the progress of further deterioration in people with MS, including those who are not obviously sick.

A new study shows that even in people who have not yet developed MS, but have very early signs of the disease, treatment with Avonex® can delay progression to full-blown MS. The study, called CHAMPS (Controlled High Risk Subjects Avonex® Multiple Sclerosis Prevention Study), was recently published in the New England Journal of Medicine (Vol. 343, Issue 13); it included 383 patients who experienced an isolated neurologic event that was suggestive of MS and who had at least one MS lesion in their brain as seen on magnetic resonance imaging (MRI). Study subjects were between the ages of 18 and 50 and were treated at 50 sites in the US and Canada.

"Avonex® has shown a global efficacy by delaying disease progression, decreasing the relapse rate, and reducing MRI disease activity, brain atrophy, and cognitive dysfunction for patients with RRMS," stated Drs. Lawrence Jacobs and Jack H. Simon, who presented the 18-month results at the 52nd Annual Academy of Neurology. Dr. Jacobs is Professor of Neurology at the University of Buffalo, and Dr. Simon is Professor of Radiology and Neurology and MRI Chief at the University of Colorado.

Subjects in both arms of the study were pretreated with intravenous steroids and were then randomized to receive either Avonex® 30 mcg or a placebo look-alike injection once a week. The demographics (age, gender) and disease characteristics of both arms were well-balanced, except that those in the Avonex® arm had slightly more evidence of MS activity in their brains as seen on MRI compared to the placebo group. This slight imbalance would, if anything, bias the results against Avonex®, but the final results showed that Avonex® was significantly better than placebo in delaying progression to clinically definite MS.

At the end of the study, patients treated with Avonex® were 44 percent less likely to convert to clinically-definite MS compared to those treated with placebo. MRI brain scans performed at 18 months showed that patients treated with Avonex® had a 57 percent reduction in the mean number of new or enlarging MS lesions, a 91 percent reduction in the size of their MS lesions, a 67 percent reduction in the mean number of enhancing lesions (i.e., disease activity), and a 66 percent reduction in the volume of enhancing lesions. All four of these measurements were highly statistically significant compared to placebo (p < 0.0001), which bolsters the validity of these findings. Furthermore, at 18 months, 47 percent of those treated with Avonex® had no new or enlarging MS lesions compared with only 18 percent of those in the placebo group.

Interestingly, although some patients in the placebo group did not have any additional neurological events suggestive of MS over the course of the study, their brain MRI scans revealed up to 63 new or enlarging lesions, which means that the disease continues to progress without any overt symptoms. Even if a person with MS looks well, the disease continues its relentless course.

The CHAMPS study also validates the use of brain MRI scans to follow MS patients and to monitor their responses to treatment. Brain MRI scans are helpful, especially early in the course of disease when a patient may have no overt signs of deterioration.

"From years of experience, we've known that you can identify MS on the basis of [patient] MRIs, and the CHAMPS trial, as well as other trials, now show these are reliable data," said Dr. Simon.

Results of CHAMPS were so robust in favor of Avonex® treatment compared to placebo when analyzed at 18 months, that an independent safety and monitoring committee concluded that withholding Avonex® treatment from the placebo group would be unethical. At this point in time, the majority of patients who entered the study and were randomized to Avonex®, have completed at least two years of treatment on the study.

A number of large, convincing studies have shown that MS should be treated early in the course of disease. This is the first study to show that "earlier is better than just 'early'. The major message from this study is that the disease is active right from the first symptoms and should be treated right from the first symptoms," stated R. Philip Kinkel, MD, Medical Director of the Mellen Center at the Cleveland Clinic Foundation and one of the investigators for CHAMPS. "At the Cleveland Clinic, we start Avonex® immediately in a person with a first attack and one or more symptomatic MRI lesions," he added. Dr. Kinkel presented the 24-month results of CHAMPS at the ECTRIMS meeting in Toulouse, France, in September of 2000.

Analysis of 24-month results showed that all of the benefits reported at 18 months in the Avonex®-treated group persisted. Although these results are encouraging, researchers plan to mount a second study to address the issue of what happens to patients treated with Avonex® over the longer term. The new study, called CHAMPIONS (CHAMPS in Ongoing Neurologic Surveillance) will include the original CHAMPS patients and follow their responses to continuing treatment with Avonex® over five more years.

Some people argue against treating patients with just one isolated attack suggestive of MS, maintaining that this represents "benign" disease. Dr. Kinkel said, "Benign disease is a myth. The vast majority of patients with MS who appear to have so-called benign disease have other symptoms that are compromising-including fatigue and cognitive problems." He said that the evidence for early treatment is much more convincing than any argument against it. He urged physicians to consider early treatment of any person who presents with one neurological attack suggestive of MS and MRI evidence of one or more active MS lesions.