February 1, 2000

Summary: Biogen, Inc. (Cambridge, MA) has announced the early termination of its clinical trial of interferon beta-1a (Avonex®) for individuals with first signs of demyelinating disease who are at risk for developing clinically definite MS (the "CHAMPS" study).

• The study was designed to test the effect of Avonex on delaying the development of additional clinical signs and symptoms that would result in a diagnosis of clinically definite MS.
• A pre-planned interim analysis of efficacy and safety conducted by an independent data safety monitoring committee determined that, well in advance of expectation, a statistically significant outcome had been reached: when used at the standard dose of 30 micrograms in once-weekly intramuscular injections, Avonex delayed development of clinically definite MS, in comparison with treatment with placebo.
• Individuals who have participated in the trial will be informed of the trial results and, if they have been receiving placebo, offered the opportunity to receive Avonex.
• These results, which will be presented to the U.S. Food and Drug Administration and other regulatory agencies, may result in extending the current licensing of Avonex to include initial demyelinating disease.

Details: In April 1996, Biogen, Inc. (Cambridge, MA) initiated a large clinical trial of Avonex® (interferon beta-1a) for individuals who have experienced a single, isolated neurological event suggesting demyelination (loss of nerve-fiber insulation) and who are at high risk for developing clinically definite multiple sclerosis (MS). The study was designed to take place over five years (including subject identification and enrollment and three years of treatment) and to include some 380 individuals at about 50 clinical centers in the United States and Canada. The aim of the study was to determine if using Avonex very early in demyelinating disease could delay the development of a second objective sign of demyelinating disease that would signal clinically definite MS. This has been called by Biogen the CHAMPS study.

Men and women between 18-50 years of age were included. To be eligible, an individual must have had a first and recent occurrence of an isolated, well-defined demyelinating neurological sign or symptom, such as optic neuritis, spinal cord syndrome (for instance, sensory problems, urinary or fecal incontinence or retention, dystonia), or a brainstem/cerebellar syndrome (for instance, vertigo, trigeminal neuralgia, nystagmus, ataxia, tremor). While such signs and symptoms are consistent with a possible MS diagnosis, each alone is insufficient to make an MS diagnosis as a first, isolated event.

In addition, eligible individuals must have had multiple MRI-detected brain lesions at the time of their first clinical attack, indicating that they were at high risk for progressing to clinically definite MS. (Previous studies have shown that individuals with first occurrence of a sign or symptoms of demyelination and clinically "silent" MRI-detected brain lesions are at high risk for developing clinically definite MS within several years after the isolated clinical event. Individuals with similar neurologic problems but with no evidence of MRI-detected lesions are at relatively low risk for developing MS over the same time period.)

Upon enrollment in the study, all participants received a course of intravenous and oral steroid treatment, which is standard therapy for treatment of isolated demyelinating clinical events. Then, subjects began either weekly 30 microgram intramuscular injections of Avonex or an inactive placebo substance. Participants underwent neurologic exams at least every six months during the study; MRI brain scans were done every six months for the first 18 months of treatment. The onset and timing of any new neurologic demyelinating events were tracked, as were adverse events and side effects.

At a pre-planned interim analysis on January 31, 2000, an independent data and safety monitoring committee determined that Avonex caused a statistically significant delay of onset of clinically definite MS, compared with the placebo-treated group. MRI measures showed significant decrease in the development of new brain lesions, consistent with the clinical result. Finally, the data and safety monitoring committee determined that there were no unexpected safety or tolerability problems.

Individuals who participated in this trial will be informed of its outcomes and termination. Those who had been receiving placebo will be offered Avonex.

The earliest stages of MS are often characterized by relatively minor sensory or motor signs and symptoms and can often be successfully treated. With development of subsequent neurological problems over time, increasing disability may result. Therefore, if the disease can be treated at its earliest stages - at the initial development of a first demyelinating event with MRI evidence of other, clinically "silent" lesions - it may be possible to delay the development of full-blown disease and reduce accumulation of long-term disability.