SAN FRANCISCO—Does current multiple sclerosis (MS) therapy reduce a patient’s long-term disability? According to John H. Noseworthy, MD, “We know that the approved drugs delay the first relapse and reduce relapses by 18% to 30% for up to two to four years, but 10 years after the approval of interferon, there is still no evidence for a meaningful effect on disability beyond the first two to three years of treatment … and that early effect on disability is limited, at best.”

Dr. Noseworthy, Professor and Chair of the Department of Neurology at the Mayo Clinic College of Medicine and Mayo Foundation in Rochester, Minnesota, emphasized that even in the short term, the approved drugs have modest benefit. “Some of the therapies help, at least for a while,” but clinically meaningful long-term data are lacking, he said at the Sixth Annual Outcomes Research Meeting at the 128th Annual Meeting of the American Neurological Association. From a statistical point of view, the number needed to treat (NNT) informs on the size of the benefit. For patients with so-called clinically isolated syndromes (eg, patients at an increased risk for MS), “one must treat seven patients with interferons to prevent one from developing clinically definite MS at three years. For relapsing-remitting MS, one must treat nine patients to prevent even one patient from having one relapse at one year or eight patients to prevent any measurable change in Expanded Disability Status Scale (EDSS) in one patient at two years. For actively progressing MS, one must treat 11 patients with mitoxantrone to reduce one patient’s change in EDSS of 1.0 points at two years. A caveat to these calculations is that randomized controlled trials are an enriched sample chosen with a high risk of achieving the outcome, and the NNT in practice may far exceed the numbers predicted by randomized controlled trials.”

Dr. Noseworthy pointed out that other drugs have shown short-term benefit, but by the end of the trial the initial benefit was lost. “In MS trials, follow-up of at least two years is needed to determine that any treatment benefit will persist. Long-term follow-up (preferably beyond five years) is particularly important in a disease like MS, which has a variable clinical course.”

The issue of whether MS treatment prevents long-term disability is not merely academic, Dr. Noseworthy said. The drugs are administered parenterally and can have adverse effects. One must also address the cost/benefit ratio—MS drugs cost more than $1 billion per year in the United States—to determine whether MS therapies provide meaningful protection against delayed disability.

Dr. Noseworthy suggested a number of strategies. “Possibilities include extension trials, long-term randomized trials, nonrandomized inception cohort studies, data registries, meta-analyses and systematic reviews of existing data, continued short-term randomized controlled trials looking for large effects, or waiting for a convincing breakthrough in basic research leading to definitive, hypothesis-driven trials,” he said.

For example, it is known that axonal injury occurs in early inflammatory MS, but it is not clear whether progression of the disease is caused by this inflammatory-mediated axonal injury. If it is, then therapies designed to decrease the inflammation may have a long-term beneficial effect. However, if disease progression is independent of inflammation, then anti-inflammatory therapies may not decrease long-term disability. Dr. Noseworthy predicted that neurologists would be much more willing to embrace short-term evidence if they were somehow certain that these short-term benefits would be sustained.

Dr. Noseworthy conceded that although long-term trials are the ideal way to obtain long-term data, multiple obstacles stand in the way of their completion, including enormous cost, dropouts, lack of interest from the pharmaceutical industry, consent bias, competing treatments, lack of blinding, limited number of hypotheses that can be tested, and difficulty in choosing treatment and controls. Inception cohort trials have many strengths, such as providing natural history data and external validity since patients are not excluded, but cohort trials are limited because they are nonrandomized and unblinded and the data analysis is complex. Extension trials—another approach—are biased because they include patients who are already doing well; patients who are not doing well tend to drop out before the extension trial begins.

An additional problem comes from the tools used to assess MS trial data, Dr. Noseworthy said. The widely used EDSS has significant limitations. It is ordinal rather than continuous, nonlinear, unreliable, and insensitive to certain important clinical changes, such as in arm function or cognition. In addition, the EDSS correlates poorly with MRI changes.

A new assessment tool, the MS Functional Composite (MSFC) has good reliability and partial concurrent validity with MRI and quality of life, and also partially predicts EDSS score, Dr. Noseworthy said. The MSFC consists of three parts: ambulation to 25 feet, upper-limb timed nine-hole peg test, and cognition (Paced Auditory Serial Addition Test).

Dr. Noseworthy stressed, however, that the main current limitation, in his view, was not the sensitivity of the measurement tools but rather the lack of evidence that the current treatments are powerful enough to deliver prolonged benefit. Until more long-term data are available, Dr. Noseworthy advised, “Be cautious about short-term results in clinical trials for MS.”

NR

—Andrew Wilner, MD

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