The initiation of Avonex® (interferon beta-1a, Biogen) after a first demyelinating event can significantly delay the development of clinically definite multiple sclerosis (CDMS), according to the Controlled High Risk Subjects Avonex® Multiple Sclerosis Prevention Study (CHAMPS). This news was reported at the 52nd Annual Meeting of the American Academy of Neurology, held in San Diego, California. Patients who received Avonex® very early in their disease course were 43% less likely to convert to CDMS compared to a placebo-treated group. This is a statistically significant result reaching a p value of 0.002.

At the pre-planned interim analysis on January 31, 2000, and based on pre-determined criteria, an independent data and safety monitoring committee concluded that active treatment achieved a statistically significant delay of onset of CDMS. MRI measures also showed significant reductions in the development of new brain lesions, consistent with the clinical result. The committee determined that withholding Avonex® from the placebo-treated group would be unethical. At this point, the majority of patients have completed at least two years in the study.

The results of the study were communicated by Lawrence D. Jacobs, MD, Professor of Neurology at the University of Buffalo, and Jack H. Simon, MD, Professor of Radiology and Neurology and MRI Chief at the University of Colorado.

The findings lend further support to the concept of earlier treatment with Avonex® for patients who are at high risk of developing CDMS. Avonex® is currently indicated for the treatment of relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations.

Dr. Jacobs commented, "Avonex® has shown a global efficacy by delaying disability progression, decreasing the relapse rate, and reducing MRI disease activity, brain atrophy, and cognitive dysfunction for patients with relapsing MS."

Previous studies showed that 50-60% of patients have clinically silent lesions on MRI when diagnosed, and over 80% of these patients will progress to CDMS. CHAMPS was designed to determine if Avonex® treatment after only one demyelinating event, such as optic neuritis, a spinal cord syndrome, or brainstem/cerebellar syndrome could (1) reduce the rate of developing CDMS and (2) reduce the rate of developing subclinical abnormalities on brain MRI.

The study began in 1996 and involved 383 patients ages 18-50 from 50 sites in the US and Canada. Subjects were included if they had experienced a first occurrence of an isolated, well-defined neurologic event suggesting demyelination.

Subjects in both study arms received intravenous steroids and were then randomized to either 30 micrograms of Avonex® or placebo injected once a week for up to three years. The two study arms were well balanced with the exception of a slightly higher, but not significant, T2 lesion volume on brain MRI in the Avonex®-treated group. Dr. Jacobs and Dr. Simon noted in their presentation that if anything, this higher volume might bias against a treatment effect.

Patients underwent neurologic examinations at least every six months during the study; MRI scans were done at 6, 12, and 18 months of treatment. The onset and timing of any new neurologic demyelinating events were tracked, as were adverse events and side effects. An investigating neurologist treated patients and a second examining neurologist evaluated their EDSS scores at scheduled and unscheduled visits; both physicians were blinded as to the patient's treatment.

IMPRESSIVE RESULTS WITH AVONEX®-TREATED GROUP

At the end of the study, the Kaplan-Meier analysis indicated that about 38% of placebo patients progressed to CDMS compared to about 21% of patients treated with Avonex®, Dr. Jacobs reported.

"There are more placebo patients progressing and doing it at a faster rate than in the Avonex® arm, where there are fewer patients progressing and doing so at a slower rate. The discrepancy by Cox proportional hazards was 0.57, meaning the treatment reduced the conversion to CDMS by 43% (p = 0.002)," Dr. Jacobs observed. He also said, "This is the first time such an effect has been shown in a group at high risk for definite disease. The 43% is clearly an Avonex® effect, and the p value of 0.002 is an order of magnitude beyond the preplanned stopping point of 0.02."

He added that during the study, Avonex® was well tolerated and had a 1% incidence of neutralizing antibodies indicating a low immunogenicity.

Relative Risk of Clinically Definite MS (CDMS)

AVONEX ® Placebo Relative Month n %CDMS n %CDMS Risk 6 164 8% 146 17% 0.48 12 143 15% 131 23% 0.65 18 109 19% 94 32% 0.60 24 69 21% 56 38% 0.56

POSITIVE RESULTS ON ALL MRI PARAMETERS

Early treatment with Avonex® not only reduced the rate of developing CDMS, but also reduced the rate of developing subclinical abnormalities on brain MRI. In fact, all predetermined MRI measures at all the time points were positive and significant in favor of early Avonex® treatment, Dr. Simon reported.

MRI measures were taken at baseline, 6, 12, and 18 months. At all time intervals and compared to the placebo group, treatment with Avonex® reduced the accumulation of T2 hyperintense lesion volumes, decreased the accumulation of individual new and enlarging T2 lesions, and reduced the number and volume of gadolinium-enhancing lesions.

The following comparisons demonstrate the magnitude of the treatment effects at 18 months between placebo and Avonex®:

Magnitude of Treatment Effects at 18 Months on Brain MRI

MRI Lesions Avonex® Placebo % Reduction p value Group Group Comparing Avonex® (n=135) (n=119) to Placebo Group

Mean number of 2.1 5.0 57% p<0.0001 new or enlarging T2 lesions

Change in T2 lesion 28 313 91% p<0.0001 volume [median mm3 ] Mean number of 0.5 1.4 67% p<0.0001 enhancing lesions

Volume of 37 108 66% p<0.0001 enhancing lesions [median mm3]

Furthermore, he reported that at 18 months 47% of interferon recipients had no new or enlarging T2 hyperintense lesions, compared with only 18% of placebo recipients. He added that twice as many placebo recipients had four or more lesions at all time points.

"Some patients in the placebo group at 18 months had no CDMS events, but [did have] up to 63 new or enlarging lesions," Dr. Simon noted.

"In addition to demonstrating a treatment effect on brain lesions, these data suggest that MRI studies can be used to monitor the course and response to treatment of early disease," Dr. Simon added. "From years of experience, we've known that you can identify patients on the basis of their MRIs, and the trials now show this is reliable data."

R. Philip Kinkel, MD, Medical Director at the Mellen Center at the Cleveland Clinic and one of the study investigators, commented on the findings, "Our recommendation has always been to treat early. But earlier is better than just 'early'," he said. "The major message from this study is that the disease is active right from the first symptoms and should be treated right from the first symptoms."

(c) 2000 Millennium Medical Communications, Inc.

Multiple Sclerosis Alert is a product of Millennium Medical Communications, Inc. ("MMC, Inc."), an independent, third-party organization providing educational information concerning current medical data and opinions presented at worldwide medical meetings. The Multiple Sclerosis Alert is published in accordance with the Guidance for Industry: Industry Supported Scientific and Educational Activities, 62 Fed. Reg. 64,093, 64,096-99 (1997) adopted by the U.S. Department of Health and Human Services Food and Drug Administration. Pursuant to the foregoing standards, MMC, Inc. is solely responsible for selecting the topics discussed herein. This Multiple Sclerosis Alert may contain data on products, product uses, indications, and dosages which are not approved for use in the USA, Canada, and the European Union and no endorsement is hereby made or intended by coverage of any unapproved use. The content of this report is intended for educational purposes only, and merely conveys scientific data presented at medical meetings. Approved product labeling should always be consulted for prescribing information. The Multiple Sclerosis Alert is an independent and non-promotional report intended to provide accurate scientific and medical information for educational purposes. MMC, Inc. is not responsible for errors or omissions in reports. The production of this report was supported by a wholly unrestricted educational grant from Biogen, Inc. Biogen, Inc. maintains no control, direct or indirect, over the content, substance, or distribution of this report.