Neurology & Psychiatry · 1993
Interferon beta-1b for relapsing-remitting MS
Interferon Beta Multiple Sclerosis Study Group
Through the 1970s and 1980s, multiple sclerosis was managed almost entirely with corticosteroids for relapses and supportive care for accumulating disability. No drug had been shown to alter the underlying disease course. The pathophysiology of MS was understood well enough to suggest that immune modulation might help, but clinical trials of azathioprine, cyclophosphamide, and various interferons had produced inconsistent results. Interferon beta attracted interest because of its antiviral and immunomodulatory properties, and early phase 2 data were encouraging enough to justify a large phase 3 study.
The Interferon Beta Multiple Sclerosis Study Group enrolled 372 patients with relapsing-remitting disease at 11 centers across North America. Patients were randomized to one of two doses of subcutaneous interferon beta-1b every other day or to placebo. The primary endpoint was the annual relapse rate, pre-specified before unblinding. Secondary endpoints included MRI lesion burden, which was a relatively novel outcome measure for MS trials at the time; few prior trials had treated imaging findings as a co-primary or corroborating endpoint.
Interferon beta-1b at the higher dose reduced relapse rate by about one-third compared to placebo. MRI scans showed reduced new lesion activity in the treated groups, providing biological evidence that the drug was doing something beyond merely suppressing clinical events. The effect on disability progression was less clear in the trial's follow-up period, a limitation that would be debated in the years after publication. Injection-site reactions were common and a meaningful proportion of patients developed neutralizing antibodies to the drug.
The FDA approved interferon beta-1b, marketed as Betaseron, in July 1993, the first drug cleared in the United States for any form of multiple sclerosis. The approval process was expedited given the absence of any alternative, and the agency accepted MRI activity as supportive evidence. Kenneth Johnson of the University of Maryland was among the key principal investigators; his center had been involved in earlier interferon research that informed the phase 3 design.
Subsequent years brought a series of additional approvals that gradually widened the treatment options available to patients. Interferon beta-1a preparations under the brand names Avonex and Rebif followed, offering different dosing intervals and routes. Glatiramer acetate received approval in 1996. Later came natalizumab, fingolimod, and a series of high-efficacy agents that reduced relapses by 50 to 70% or more. The interferon beta-1b trial did not establish large absolute benefit by current standards, but it provided evidence that immune modulation could change the clinical course of MS, and it gave the field a regulatory pathway that subsequent drugs could follow.
Key People
- Interferon Beta MS Study Group — Multicenter group that ran the pivotal phase 3 trial
- Kenneth Johnson — University of Maryland neurologist, key principal investigator
- Lawrence Jacobs — Buffalo neurologist whose earlier interferon work contributed to the phase 3 rationale
Neurology, 1993
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