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.

17th Annual Meeting of the European Neurological Society

Rhodes, Greece / June 16-20, 2007

The “inexorable” axonal loss in multiple sclerosis (MS) starts not when clinicians can first detect it but much earlier, at the very beginning of the disease, stated Dr. Mark S. Freedman, Professor of Neurology, University of Ottawa, Ontario, co-investigator of the BENEFIT (Betaseron in Newly Emergent Multiple Sclerosis for Initiation Treatment) trial. “The disease starts well before that patient’s first visit. Moreover, inflammation comes and goes so it makes absolute sense to introduce an anti-inflammatory such as interferon beta-1b (IFNß-1b), when inflammation is peaking. As in stroke, time is prime in MS and starting treatment early may make all the difference in the world.”

BENEFIT Three-year Analysis

The three-year analysis was the largest randomized, double-blind, prospective study conducted in MS patients with clinically isolated syndrome (CIS) and the first in which a high-dose, high-frequency IFN was used at the first event. Inclusion criteria included an expanded disability status scale EDSS) score of 0 to 5 seen at least once during screening or at baseline, and at least two clinically silent ovoid lesions on T2-weighted MRI of at least 3 mm in size, located either periventricularly or infratentorially. These lesions could be either monofocal (indicative of a single lesion) or multifocal.

In this study, 468 patients received either subcutaneous IFNß-1b 250 µg (n=292) or placebo (n=176) every other day for two years or until diagnosis of clinically definite MS (CDMS). Of these 468 patients, 418 were enrolled in a follow-up study offering active treatment for up to three further years. This showed that its immediate initiation reduced the risk of permanent neurological disability by 40% compared with placebo as measured by the EDSS. Using McDonald criteria, the risk of converting to CDMS was reduced by 41% over three years. By contrast, more than half of placebo recipients progressed to MS within six months and 85% did so within two years.

Signs of MS to Watch For

Dr. Freedman told delegates that these findings required clinicians to consider the scenarios typically associated with demyelination. He suggested that they should note that the first event consistent with demyelination was not the same as the first neurological symptom.

As Dr. Freedman related, when there was “no better explanation,” differential diagnosis and multifocal presentation, the patient likely had MS, regardless of the cerebrospinal fluid (CSF), which, in his opinion, indicated reason enough to begin treatment. Likewise, in a patient who had had a typical first event, with “no better explanation” and a monofocal presentation, and if significant dissemination in space could be demonstrated with typical appearance of lesions and nine or more T2 lesions or at least one gadolinium-enhancing lesion, again there was no reason to delay treatment, regardless of the CSF, because it was very likely that the patient had MS and would benefit from early therapy.

“The window of therapeutic opportunity opens early,” explained Dr. Freedman. “If you want to maximize this opportunity, that would mean starting a medication that all previous studies show is only partially effective, and that was because they started too late. The three-year BENEFIT analysis shows us how early that window does open so that we can jump in and do something about managing the disease. The findings strongly support the conclusion that IFNß-1b, at least in the early stages, will have its maximal benefit and therefore it should be considered one of the first treatments for MS.”

Timing of MS Therapy

Dr. Ludwig Kappos, Professor of Clinical Neuroimmunology, University of Basel, Switzerland, reinforced the consensus in favour of the earliest possible treatment. All the BENEFIT data, he mentioned, demonstrated the value of intervention in patients after the very first clinical presentation of the disease.

Dr. Kappos noted that BENEFIT was the first study to show a statistically significant effect on delaying disability progression in patients presenting with a first demyelinating event. It was also the first study pre-determined to examine the longer-term effect of treatment on disease progression in the earliest phase vs. delayed treatment. “BENEFIT showed that early is late in MS,” he emphasized. “When first symptoms develop, patients may already have had MS for some time.”

As Dr. Kappos pointed out, BENEFIT’s findings were particularly robust. The study had carefully avoided the shortcomings of previous trials by making “huge efforts” to retain patients and ensure their adherence to the study protocol. Bias due to dropouts was thus minimized, allowing a high retention rate and a true intention-to-treat analysis. Patients were blinded to treatment until they reached two years or had a second clinical attack.

Recognizing Benign Disease

Dr. Kappos and co-investigators also reported in a poster presentation on the characteristics of patients with potentially benign MS, an inactive course of the disease after a CIS suggestive of MS. In a cohort of 176 untreated patients with two or more clinically silent T2 lesions, only 12 (6.8%) had a complete remission for two years. Predictive factors influencing inactivity were older age, negative CSF findings and fewer than nine T2 lesions at screening.

As echoed by Dr. Xavier Montalban, Director, Neurology Research and Clinical Neuroimmunology Multiple Sclerosis Unit, Val d’Hebron University Hospital, Barcelona, Spain, “Beware of the concept of benign MS. It does exist but the percentage is almost certainly not high.”

Summarizing evidence supporting early treatment, Dr. Montalban commented that the “conservative” approach taken by many physicians to starting treatment at the time of diagnosing MS has been based on the view that disease-modifying therapies have failed to show a long-term effect on preventing disability or impairment. “That is no longer true,” he insisted. Many recent findings, notably in BENEFIT, clearly indicate that treatment should start as early as possible. The axonal injury which occurs early in MS is irreversible, he explained, and the inflammation which is likely responsible for some of that injury also occurs early: patients with earlier inflammatory events show earlier progression. Moreover, as inflammatory changes diminish with time, the window of therapeutic opportunity closes sooner.

Evidence reinforcing the value of early immunomodulatory therapy for MS was presented by a team led by Dr. Octavia-Claudia Chebut, Targu Mures, Romania. A total of 67 patients with relapsing-remitting MS who began treatment with IFNß-1b in the first year after diagnosis had a lower EDSS than patients who began therapy after a mean of 9.5 years. They had fewer and less severe relapses and fewer black holes in T1-weighted images after five years of treatment, as well as improved quality of life.

Other Evidence

A research team headed by Prof. Mefkure Eraksoy, Istanbul University, Turkey, reported they had found IFNß-1b to be safe and tolerable in children with MS in both the short term and after five years.

Dr. Marinella Clerico, San Luigi Gonzaga University Hospital, Orbassano, Italy, led a multinational team of researchers who used Cochrane methodology to observe results from BENEFIT and two earlier studies, CHAMPS and ETOMS. The efficacy of multiple-weekly, high-dose treatment in reducing the risk of conversion from CIS to CDMS was confirmed in all sensitivity analyses at two years. That compared with only modest efficacy at one year when low-dose, once-weekly IFNß-1b was administered.