INTERFERON BETA THERAPY
AND MS DISEASE PROGRESSION:
CLINICAL TRIALS SUPPORT EARLY TREATMENT

SAN DIEGO—For decades, therapies could only ease the symptoms of multiple sclerosis. The prospect of slowing or even stopping disease progression emerged with the introduction of the interferon betas, immunomodulatory drugs that were demonstrated to reduce the physical disability, relapse rate, lesion burden, and cognitive decline associated with multiple sclerosis. Following the Food and Drug Administration (FDA) approval of interferon beta-1b and interferon beta-1a for relapsing-remitting multiple sclerosis just a few years ago, several large multicenter trials began to study whether these drugs could provide benefits in patients over the long run, as well as in patients with earlier and later stages of the disease. The findings from three Phase III clinical trials were presented at the 52nd Annual Meeting of the American Academy of Neurology.

REDUCING LESIONS AND THE RATE OF CONVERSION

At the time of their first episode of multiple sclerosis, "more than half of patients are likely to carry clinically silent brain lesions on MRI [magnetic resonance imaging]," said Lawrence D. Jacobs, MD, from the Department of Neurology at the Buffalo General Hospital in New York. Of these patients, a great majority will go on to develop a second episode of clinically definite multiple sclerosis, he added. Dr. Jacobs and his colleagues demonstrated that treatment with interferon beta-1a is capable of reducing the rate of conversion of these patients at risk for clinically definite multiple sclerosis, as well as reducing the development of lesions on MRI.

A cohort of 383 subjects enrolled in 50 centers throughout the United States and Canada and were randomly assigned to receive interferon beta-1a (30 µg, intramuscularly once per week) or matched placebo. All of the patients (age range, 18 to 50) had a first acute demyelinating clinical event—such as optic neuritis, spinal cord syndrome, or brainstem cerebellar syndrome—and had evidence of two or more clinically silent T2- weighted MRI lesions greater than 3 mm at baseline. Neurologic exams were scheduled every six months and also within seven days after a suggested relapse.

By six months, the rate of developing clinically definite multiple sclerosis was greatly reduced in the patients who were treated with interferon beta-1a, said Dr. Jacobs. At three years, the researchers calculated a 43% reduction in the rate of conversion. "This was the first time such an effect has been shown in a high-risk group of patients," Dr. Jacobs said, and added that interferon beta-1a was well tolerated and had a rapid onset of action that persisted throughout the duration of the study. "These findings emphasize the value of [obtaining] an MRI at the time of first clinical syndrome," he said, "in order to identify high-risk patients who may benefit from treatment."

MONITORING DISEASE PROGRESSION WITH MRI

Whether or not MRI can be used as a surrogate measure of clinical activity is still debated, but there is a belief that MRI can help select patients for treatment. In fact, this particular trial relied on MRI to identify patients at risk for developing clinically definite multiple sclerosis and monitor the effects of treatment with interferon beta-1a, said Jack H. Simon, MD, from the Neuroradiology/MRI Department at the University of Colorado Health Sciences Center, Denver.

In the cohort described above, neuroimaging scans were acquired at baseline and at six, 12, and 18 month in patients who had not yet developed clinically definite multiple sclerosis. At baseline, the treated group had slightly larger lesion sizes and a slightly higher likelihood of having one or more enhancing lesions than the placebo group. "These differences were not significant," Dr. Simon said, adding that this potential bias served to underscore the profound beneficial effects associated with interferon beta-1a treatment in the final analysis.

By six months, the interferon beta-1a treated patients demonstrated a reduced number and volume of both T2 lesions and gadolinium-enhancing lesions. The treatment effects became more significant over time, Dr. Simon said. By 18 months, there was a 91% reduction in T2 hyperintense lesion volume, a 57% reduction in the number of new or enlarged hyperintense lesions, and a 67% reduction in the number of gadolinium—enhancing lesions. According to these findings, MRI can be used to monitor the course and response to treatment of early multiple sclerosis, he said.

LASTING BENEFITS FOR RELAPSING-REMITTING MULTIPLE SCLEROSIS

New data from the PRISMS (Prevention of Relapses and Disability by Interferon Beta-1a Subcutaneously in Multiple Sclerosis) trial pointed to a continued benefit on both clinical and MRI parameters for at least four years in patients with relapsing-remitting multiple sclerosis. The long-term effects of interferon beta-1a were greater than previously thought, said Mark S. Freedman, MD, from the University of Ottawa, the Ottawa Hospital-General Campus, Ontario. Dr. Freedman and his colleagues demonstrated a dose effect, with high-dose interferon beta-1a being superior to low-dose in slowing disease progression, minimizing relapses, and reducing MRI activity. There was an advantage in starting the treatment earlier, he said, but added that "delaying therapy offered no advantage, but a benefit could still be seen."

The study cohort consisted of 560 patients who were enrolled in 22 centers in nine countries. "The original two-year study was extended to four years … to examine the long-term safety and efficacy" of interferon beta-1a as well as to compare the high and low dosing regimens, Dr. Freedman explained. At the beginning of the study, patients were randomized to receive high-dose (44 µg) interferon beta-1a, low-dose (22 µg) interferon beta-1a, or placebo. At 24 months, the placebo patients were re-randomized to receive a high or low dose for the remainder of the study. Treatments were administered three times a week, and clinical evaluations were scheduled every six months.

As in the original results, there was a rapid reduction in relapse rate among the placebo patients who were re-randomized to receive interferon beta-1a, Dr. Freedman said. This "translated into about a 53% reduction in relapse rate" for both dosing regimens, he said, and suggested that "the burden of disease built up in the first two years could be rapidly diminished after treatment exposure." Similarly, both dosing regimens of interferon beta-1a markedly diminished the MRI active lesion development and the accumulation of lesion burden over time when compared with placebo.

The patients who had been taking high-dose interferon beta-1a from the very beginning of the study showed the lowest relapse rate overall, Dr. Freedman reported. However, the placebo patients who were switched to a high dose caught up quickly to patients who had been taking the low dose right from the start, he pointed out. Surprisingly, there was no difference between the patients who had taken low doses of interferon beta-1a for two years and those who had taken low doses for four years. Those who were taking the high dose from the start, however, stayed ahead of those patients who switched to high-dose therapy after two years on placebo. This study provides both clinical and MRI evidence demonstrating the benefits of long-term interferon beta-1a treatment, Dr. Freedman said.

CONFLICTING FINDINGS IN SECONDARY PROGRESSIVE MULTIPLE SCLEROSIS

In 1998, the European Study Group reported the efficacy of interferon beta-1b in secondary progressive multiple sclerosis. This pivotal study demonstrated a significant delay in the time-to-onset of sustained worsening on the Kurtzke Expanded Disability Status Scale (EDSS), suggesting interferon beta-1b can successfully treat patients in later stages of the disease. Using a similar trial design, the North American Study Group, led by Donald E. Goodkin, MD, Medical Director of the University of California San Francisco/Mount Zion Multiple Sclerosis Center, attempted to extend the results of the European trial by studying two dosing regimens in a second cohort of patients with secondary progressive multiple sclerosis.

A total of 939 patients enrolled in 35 study centers throughout North America were randomly assigned to receive interferon beta-1b at 8 MIU, interferon beta-1b at 5 MIU/m2 (mean dose, 9.6 MIU), or placebo. The treatments were administered subcutaneously every other day. All patients (age range, 18 to 65) had clinically definite multiple sclerosis for two or more years (EDSS score range, 3.0 to 6.5). Entry criteria included having a progressive course for six or more months and an increase of one or more EDSS points during the two years prior to study. All patients were examined every 12 weeks for three years and a subgroup of 163 patients completed monthly gadolinium-enhanced MRI scans to measure active lesion rates.

In contrast to the earlier European study results, the North American study did not find a favorable effect for interferon beta-1b with regard to the primary outcome, which was defined as the time to progression of sustained disability, said Dr. Goodkin. Although the baseline EDSS scores were the same in the two cohorts, he explained, treated patients in the North American cohort failed to decrease the time up to maintaining an increased EDSS score for at least six months.

Although interferon beta-1b treatment did not affect progression to sustained disability, treatment effects were seen in most of the secondary clinical and imaging endpoints, Dr. Goodkin said. The results were very similar between the European and North American cohorts, he said, with respect to annual relapse rate, MRI activity, and lesion burden. Relapses in the treated patients, he reported, "were reduced in severity and duration." In addition, treated patients had a lower annual progression of T2 lesion volume and a reduction in the number of new gadolinium-enhancing lesions. "The interferon beta-1b efficacy was not influenced by the presence of neutralizing antibodies," Dr. Goodkin said, and added that both doses of interferon beta-1b were well tolerated.

SAME STUDY DESIGN, DIFFERENT POPULATIONS?

Given that the North American and European trials were conducted similarly, the divergent results with respect to EDSS scores have "given us the opportunity to ask why are these results are different," said Henry F. McFarland, MD, Chief of the Neuroimmunology Branch at the National Institutes of Health in Bethesda, Maryland. Using statistical modeling, Dr. McFarland and his colleagues considered three possible explanations: chance, EDSS measurement error, or a biological difference between the two study cohorts.

Chance alone was quickly ruled out, Dr. McFarland said, since there was only a 2% probability that chance alone could account for the divergent study results. The degree of variability in EDSS measurements, he continued, was 10% greater in the North American study. This suggested that there was some difference in the use of the EDSS instrument, he said. According to Dr. McFarland, the most likely explanation for the divergent results is that the two studies involved different patient populations.

Examination of the patient characteristics suggested that the European Study Group targeted a secondary progressive population "skewed towards more relapsing or active characteristics," Dr. McFarland said. When the cohorts were compared, the researchers found that the European patients had a higher relapse rate both before and during the study. Analysis of MRI scans, he continued, also revealed an increased number of gadolinium-enhancing lesions in the European cohort.

BEYOND THE TREATMENT THRESHOLD?

Studies on the natural history of multiple sclerosis indicate that in some secondary progressive patients, the frequency of relapses and active lesions spontaneously declines despite gradual progression of disability. The underlying pathology of these clinical and imaging changes are not fully understood, Dr. McFarland said during a panel discussion with Dr. Goodkin, and added that along with individual differences, these progressive changes could explain the varying success rates observed with therapy. And, according to Dr. Goodkin, it is conceivable that patients enrolled in the North American trial were "too far down the pathway of secondary progressive multiple sclerosis to benefit."

Interferon beta-1b most likely "targets the relatively early steps in lesion development," Dr. Goodkin said, and added that this immunomodulatory agent may have less benefit in patients who have severe tissue destruction, axonal loss, and irreversible myelin loss. In other words, patients who continue to have an inflammatory component in their disease progression are more likely to respond to interferon beta-1b treatment, he proposed.

In an attempt to pinpoint any factors that could predict treatment outcome, Dr. McFarland and his colleagues created a statistical model to compare 11 characteristics between the North American and European study cohorts. Eight of the 11 characteristics were found to be significantly different, he said, but noted that no one single factor could be considered a disease modifier. It was clear, he said, that the biological properties of these two populations were different. Future studies are needed to define in more detail the type of patients who should be receiving this form of treatment, he concluded.

—Shauna Kubose
Senior Associate Editor

Suggested Reading
Kappos L, Moeri D, Radue EW, et al. Predictive value of gadolinium-enhanced magnetic resonance imaging for relapse rate and changes in disability or impairment in multiple sclerosis: a meta-analysis. Gadolinium MRI Meta-analysis Group. Lancet. 1999;353:964-969.
Placebo-controlled multicentre randomised trial of interferon beta-1b in treatment of secondary progressive multiple sclerosis. European Study Group on interferon beta-1b in secondary progressive multiple sclerosis. Lancet. 1998;352:1491-1497.
Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. PRISMS (Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) Study Group. Lancet. 1998; 352:1498-1504.

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