Multiple Sclerosis Express Report
12th Meeting of the European Neurological Society (ENS)
Berlin, Germany

Sustained Effects in Relapsing-Remitting Multiple Sclerosis with Long-Term Interferon Beta-1a (Avonex) Treatment

Results of the European Dose-Comparison Study presented at ENS 2002 demonstrate the sustained, long-term safety of interferon beta-1a (Avonex, Biogen, Inc.)1, as well as support a sustained treatment effect of Avonex on slowing the loss of brain tissue in relapsing-remitting multiple sclerosis (MS). 2 The European Dose-Comparison Study was the largest long-term study that has been conducted in relapsing-remitting MS without patient re-randomization3 and investigated the question of whether a higher dose of weekly Avonex (60 mcg) provides greater efficacy than the conventional 30 mcg once-weekly dose.

The European Dose-Comparison Study

Earlier this year, results of an extension analysis of the European Dose-Comparison study showed that the efficacy of both low- and high-dose Avonex achieved sustained efficacy through at least four years in patients with relapsing-remitting MS.4 The original 3-year study was undertaken to define the optimal dose of Avonex and to determine whether a higher dose (60 mcg) would increase efficacy versus the standard approved dose (30 mcg). The study showed that increasing the dose of Avonex from 30 mcg once weekly to 60 mcg once weekly resulted in no significant clinical differences or magnetic resonance imaging (MRI) outcomes and therefore provided no additional clinical benefit to the patient. Further, the levels of neutralizing antibodies, which are thought to impact treatment effects, remained low during long-term use of Avonex.

The double blind, parallel group European Dose-Comparison Study included patients from 38 European centers. Previous analysis of 608 evaluable patients showed sustained efficacy in delaying disease progression during 3 years of treatment with a weekly dose of Avonex 30 mcg as well as a higher weekly dose of Avonex 60 mcg.5 The extension analysis included 491 patients who continued double blind treatment for an additional year.4

The efficacy of Avonex at both doses was observed for multiple outcomes, including cumulative rate of sustained disability progression, magnitude of change in the Expanded Disability Status Score (EDSS), percentage of relapse-free patients, and need for intravenous steroids. Further, no significant differences were found between the 30 mcg and 60 mcg doses for effects on clinical and MRI, including the number and volume of new gadolinium-enhancing lesions and number of new or enlarging T2 lesions.6

The reduction in relapse rate from baseline was 43% with the 30 mcg dose and 42% with the 60 mcg dose. Mean relapse rate was reduced from 1.3 at baseline to 0.74 with 30 mcg and from 1.3 at baseline to 0.75 with 60 mcg. Percentage of relapse-free patients was 18% with 30 mcg and 19% with 60 mcg (p = 0.850). Median time to first relapse was 402 days with 30 mcg and 347 days with 60 mcg (p = 0.83). At the end of the 4-year treatment period, 52% of patients receiving 30 mcg and 57% of patients receiving 60 mcg were free of disease progression.

Clinical Study at ENS 2002: Four-Year Safety Results of Avonex

Four-year results of the European Dose-Comparison Study confirmed efficacy and safety of long-term treatment with Avonex in more disabled patients with relapsing-remitting MS.1

"This is the largest long-term study conducted in multiple sclerosis patients and [the study] confirmed the sustained effects of Avonex," stated Michel Clanet, MD, Federation of Neurology, CHU Purpan Hospital, Toulouse, France.

Throughout the 4-year treatment period, the incidence of neutralizing antibodies remained low. With both the 30 mcg and the 60 mcg doses, the percentage of patients with neutralizing antibodies was below 6% at the end of the four years. The percentage of patients with neutralizing antibody titers ≥20 NU/mL at any point during the 4-year study was 2.3% with the 30 mcg dose compared to 5.8% with the 60 mcg dose (p = 0.011). The overall incidence of neutralizing antibodies demonstrates the low immunogenicity of Avonex compared to other interferon beta products (interferon beta-1b [Betaseron] and interferon beta-1a [Rebif]). It may further indicate that using the once-weekly dose of 30 mcg of Avonex, can possibly lead to a lower incidence of neutralizing antibodies. It has been shown that neutralizing antibodies negatively impact the long-term efficacy of beta interferons on both clinical and MRI outcomes.

Thirty-one patients (13%) in the 30 mcg dose group and 16 patients (6%) in the 60 mcg dose group discontinued treatment over the four-year study. Treatment related depression in MS was observed in 27 patients (11%) in the 30 mcg dose group and 22 patients (9%) in the 60 mcg dose group. The incidence and severity of adverse events known to be associated with the administration of interferon beta agents were similar between the two doses. Flu-like symptoms were observed more frequently with the 60 mcg dose than the 30 mcg dose (96% vs. 90%), whereas headache occurred more frequently with the 30 mcg dose than the 60 mcg dose (37% vs. 33%). MS exacerbations were observed in 76% and 77% of patients, respectively. Asthenia was found in 46% and 45% of patients, respectively.

Serious adverse events reported in > 5% of patients were as follows: flu-like symptoms in 16% of the low-dose group and 21% of the high-dose group; MS exacerbations in 11% and 17%, respectively; asthenia in 7% and 4%, respectively, and headache in 5% and 3%, respectively.

Adverse events that were associated with a > 5% difference between treatment groups, which received the 30 mcg or 60 mcg dose, were flu-like symptoms (90% and 96%, respectively); arthralgia (23% and 17%, respectively); hypertonia (28% and 23%, respectively), and infection (17% and 12%, respectively).

"The four-year safety and efficacy results of the European Dose-Comparison Study show that weekly 30 mcg is the optimal dose for Avonex," Dr. Clanet told the audience. "Raising the dose to 60 mcg once weekly doesn't add any benefit. The efficacy of Avonex was sustained for four years, with a good safety and efficacy profile and low immunogenicity."

The need for higher and more frequent doses of interferon beta is debatable, since some studies of interferon beta formulations other than Avonex have suggested that increasing the dose might be beneficial. The European Dose-Comparison Study showed that a higher dose of Avonex was not superior to the standard dose. According to Frederick E. Munschauer III, MD, Professor of Clinical Neurology and Internal Medicine at the State University of New York at Buffalo, Buffalo, New York and the Jacobs Neurological Institute, the focus on dosing is misguided, and other more important issues deserve attention. Dr. Munschauer commented that there may be a ceiling effect where giving more interferon beta-1a may not be able to bind to additional receptors. Once receptors are triggered, they are refractory to further stimulation for several days.

"From a 35,000-foot vantage point, the magnitude of the treatment effect of these agents [interferon beta] is remarkably similar, even though the different drugs have different routes of administration and different pharmacokinetics. The dose level is less important than moving on to identify neuroprotection strategies that will increase treatment efficacy," Dr. Munschauer said.

Substudy at ENS 2002: Avonex Effect on Brain Atrophy

A substudy of the European Dose-Comparison Study in relapsing-remitting MS suggests that the effect of Avonex on brain atrophy becomes evident over time and is sustained at year 2 and 3 following initiation of treatment.2 The study used brain parenchymal fraction (BPF) as a measure of brain atrophy. BPF is a very sensitive and reproducible tool for determination of brain atrophy. The greatest decrease in BPF occurred in the pre-treatment period and the first four months of treatment. Avonex slowed the atrophy significantly after four months, which was sustained in years 2 and 3. The study showed a higher rate of brain volume loss [reduction in brain volume] in the first 4 months of treatment followed by a significantly slower rate in the subsequent phases, explained Martin Hardmeier, MD, Department of Neurology, University Hospitals, Basel, Switzerland.

Dr. Hardmeier attributed the dramatic reduction in brain volume during the first four months of treatment to the anti-inflammatory and anti-edematous properties of Avonex. He said that early monitoring might not give a true picture of the effects of Avonex on slowing brain atrophy.

"The implication of our study is that the effects of immunomodulatory treatment on atrophy should not be assessed before the second half of the first year of treatment. In the first few months after treatment initiation, the possible beneficial treatment effects on the rate of atrophy progression might be masked by suppression of edema and inflammation," he said.

Brain volume, as measured by BPF, was significantly reduced at all intervals in the study, with the most significant difference from baseline observed in the first year of therapy. A lower, but still significant, rate of reduction in brain volume was observed at year 2 and year 3 compared with year 1.

Changes in Brain Volume

MRI scans were performed 3 and 2 months before treatment (Phase 0), and at 4, 5, 6, 10, 11, 12 (Phase 1) months; at 24 months (Phase 2); and at 36 months (Phase 3) after initiation of treatment. BPF was determined according to the method used by Rudick et al7, who reported that change in BPF was significantly slowed by 55% in year 2 of treatment with interferon beta-1a when compared to patients on placebo.

Patients had relapsing-remitting MS, a median EDSS of 3.51 (range, 2.0-5.5), a mean age of 38.5 years, and median disease duration of 7.5 years. One hundred-sixteen patients completed the study.

The decrease in BPF after treatment initiation was paralleled by a decrease in T2 lesion load and the number of T1 gadolinium-enhanced, Dr. Hardmeier added. BPF changes at year 1, 2, and 3 were significantly correlated with T2 lesion load and volume of gadolinium-enhanced lesions (p < 0.05).

During a question and answer session, Dr. Hardmeier told the audience that the first scan after initiation of treatment was done at month 4, so no conclusions could be drawn about brain volume changes during month 1, month 2, or month 3. "If our hypothesis is true, brain volume changes may occur earlier than month 4," he added.

Dr. Hardmeier also pointed out that the BPF results were analyzed for the entire group of study patients with no differentiation between the currently approved 30 mcg dose and the 60 mcg dose of Avonex.


1. Clanet M, Kappos L and the European Interferon Beta-1a Dose-Comparison Study Group. Sustained Safety of Interferon Beta-1a in Relapsing Multiple Sclerosis: Results from the European Dose-Comparison Study. 12th Meeting of the European Neurological Society, June 22-26, 2002, Berlin, Germany.
2. Hardmeier M, Freitag P, Wagenfeil S, et al. Short and Long Term Brain Volume Changes after Initiation of Treatment with Interferon Beta-1a in Multiple Sclerosis. 12th Meeting of the European Neurological Society, June 22-26, 2002, Berlin, Germany.
3. [no authors listed] Double Blind, Randomized Multicenter Dose Comparison Study of Interferon Beta-1a (Avonex): Rationale, Design and Baseline Data. Mult Scler 2001; 7(3):179-183.
4. Kappos L, Clanet M, for the European Interferon Beta-1a (Avonex) Dose-Comparison Study Group: Sustained Efficacy of Interferon Beta-1a in Relapsing Multiple Sclerosis: 4-Year Results from the European Dose-Comparison Study. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver, Colorado. Poster #P06.085.
5. Clanet M, Radue EW, Kappos L, et al. A Randomized, Double Blind, Dose Comparison Study of Interferon Beta-1a (Avonex) in Relapsing MS. Neurology (Submitted).
6. Radue EW, Kappos L, Simonian N, et al. MRI Results of the European Interferon Beta-1a Dose-Comparison Study. 54th Annual Meeting of the American Academy of Neurology, April 13-20, 2002, Denver, Colorado. Poster #P03.069.
7. Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L. Use of the Brain Parenchymal Fraction to Measure Whole Brain Atrophy in Relapsing-Remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology 1999;53(8):1698-1704.