Interferon beta-1b for relapsing-remitting MS

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 IFNB Multiple Sclerosis Study Group enrolled 372 ambulatory patients with relapsing-remitting disease, an EDSS score of 0 to 5.5 and at least two attacks in the previous two years. A third received placebo, a third 1.6 million international units and a third 8 million units of interferon beta-1b, self-injected under the skin every other day. The primary endpoints were the attack rate and the proportion of patients who stayed free of attacks. 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.

After two years the annual attack rate was 1.27 on placebo, 1.17 on the low dose and 0.84 on the high dose, a reduction of about a third, and 36 high-dose patients were attack-free against 18 on placebo. Serial MRI scans showed significantly less disease activity in the high-dose group, and moderate and severe attacks were half as frequent. 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. EDSS disability scores changed little in either arm.

The FDA approved interferon beta-1b, marketed as Betaseron, on July 23, 1993, as an orphan drug, the first drug approved in the United States for any form of multiple sclerosis. Kenneth Johnson of the University of Maryland was among the trial's investigators.

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 other agents with larger effects on relapses. The interferon beta-1b trial did not show a large benefit by current standards or a clear effect on disability, but it was the first evidence that a drug could reduce attacks of MS.