Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

59th Annual Meeting of the American Academy of Neurology

Boston, Massachusetts / April 29-May 5, 2007

According to a three-year analysis of data from the BENEFIT (Betaseron in Newly Emerging Multiple Sclerosis for Initiation Treatment) trial, early initiation of treatment with interferon-beta 1b (IFNß-1b) was superior to delayed treatment in preventing patients with a first demyelinating event suggestive of multiple sclerosis (MS) from converting to a diagnosis of clinically-definite multiple sclerosis (CDMS). At three years, immediate initiation of IFNß-1b reduced the risk of permanent neurological disability by 40% compared with placebo, as measured by the Expanded Disability Status Score (EDSS).

As explained by Dr. Mark S. Freedman, Professor of Neurology, University of Ottawa, Ontario, and co-investigator of the study, “Some patients who present with first signs of MS already have significant neurological damage, which can lead to accumulated disability later in life. As demonstrated in the BENEFIT trial, immediate treatment with IFNß-1b after the first clinical event can significantly reduce that damage, which could translate into a greater delay in developing the debilitating consequences of MS.”

BENEFIT is the largest randomized, double-blind, prospective study to be conducted in MS patients with clinically isolated syndrome (CIS), recruiting patients at 98 sites in 20 countries. In the two-year follow-up presented at the 2006 AAN meeting, active treatment reduced the risk of converting to CDMS by 50% compared with placebo. Using McDonald diagnostic criteria, treated patients were twice as protected against developing MS compared with placebo.

Study Design

BENEFIT enrolled 468 patients with CIS and MRI evidence of two or more clinically silent lesions and randomized them in a 5:3 ratio to active treatment with IFNß-1b 250 µg q.d. (n=292) or placebo (n=176). The double-blind phase lasted up to 24 months or until diagnosis of CDMS was made. Patients who converted to CDMS were switched to active treatment during the two-year period. Patients were followed for up to two years; at the end of the second year, or if patients converted to CDMS, they could opt for active treatment for an additional 36 months in an open-label phase of the trial (results of the open-label phase will be available in 2008). Of the 468 patients who started treatment, 437 completed the study as planned.

Primary end points were time to CDMS according to Poser criteria and time to MS according to McDonald criteria, which are more recent and considered more sensitive than the former. Using the Poser criteria, the risk of conversion to CDMS was reduced by 50% in the active treatment group compared with placebo over the 24-month double-blind phase; the cumulative risk of converting to CDMS was 28% among actively treated patients compared with 45% in those on placebo. Using McDonald criteria, the risk reduction was 46%. EDSS remained the same in both groups, as would be expected in patients with early-stage MS. Dr. Freedman noted that more than 50% of patients in the placebo group of BENEFIT had progressed to MS within six months and 85% of them within two years.

Three-year Pre-planned Analysis

Here at the AAN meeting, Dr. Freedman presented results of the three-year analysis of BENEFIT. This analysis included 418 of the 437 eligible patients, including 261 patients previously treated with IFNß-1b and 157 originally treated with placebo but switched to active treatment when they converted to CDMS. This analysis showed that immediate treatment with IFNß-1b after the first clinically suggestive MS event reduced the risk of progression by 40% as measured by EDSS compared with delayed treatment; 24% of patients who received delayed treatment progressed on EDSS compared with 16% of those on early treatment. After three years, patients who took IFNß-1b immediately were 41% less likely to progress to CDMS vs. patients who had treatment delayed for up to 24 months (P=0.0218). After three years, 73% of the actively treated group remained on active treatment.

“The ability to prevent disease progression is an excellent reason to start therapy early,” Dr. Freedman told listeners. “Robust changes in EDSS favour early treatment. Differences in relapse [between the early and delayed treatment group] do not account for the divergence of the EDSS curves.”

Dr. Freedman noted that this is the first study in patients with CIS that was pre-defined to examine the longer-term impact of early vs. delayed treatment on disease progression. In that way, it differs from other studies showing the benefit of early vs. delayed treatment. “This study is even more meaningful because patients in the placebo group were on at least a year of placebo, so they never caught up. The extra protection added by starting the drug early continues to span three years,” he stated.

Characteristics of Patients with Benign Disease

An analysis of placebo-treated patients in the BENEFIT trial who did not convert to CDMS after two years found that older age, negative findings in the cerebrospinal fluid (CSF), and fewer than nine T2-weighted lesions at initial screening were predictive of inactive disease, reported Dr. Gilles Edan, Pontchaillou Hospital, Rennes, France, for the BENEFIT investigators.

He reminded delegates, “There is no clear way to identify patients with CIS who do not progress and have benign disease.”

Of the 166 analyzable placebo-treated BENEFIT patients, 154 progressed to CDMS and 12 (7.6%) fulfilled criteria for “inactive” disease following CIS: no relapse over two years following CIS; no progression on EDSS; no new gadolinium-enhancing or T2 lesions on MRI; and no clinical evidence of active disease.

All 12 patients agreed to further follow-up, four chose to remain untreated and eight opted to receive IFNß-1b. At three years, 11 of the 12 remain on study. None have developed CDMS and two developed MS according to McDonald criteria.

Regarding potential prognostic factors, age at baseline, negative CSF findings and fewer than nine T2 lesions were found to be predictive of inactive disease (Table 1). These factors also emerged as prognostic on univariate and multivariate analysis.

Table 1. BENEFIT: Prognostic Factors for Inactive Disease

A 0.85-fold decrease in risk of disease activity was seen for every year of increasing age at baseline. Patients with nine or more T2 lesions at baseline had a 3.5-times higher risk of active disease. Positive cerebrospinal fluid findings increased the probability of active disease tenfold, Dr. Edan reported.

These findings may be helpful in identifying patients who are less likely to progress from an isolated demyelinating episode to full-blown MS, he stated.