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.

Sixteenth Meeting of the European Neurological Society

Lausanne, Switzerland / May 27-31, 2006

On the strength of findings from a double-blind, placebo-controlled study performed in North America between 1988 and 1993, interferon beta-1b (IFNß-1b) was approved for relapsing-remitting multiple sclerosis (MS) (Neurology 1993;43:655-61). According to investigators under lead author Dr. George Ebers, Department of Clinical Neurology, Radcliffe Infirmary, University of Oxford, UK, the patients who participated in this pivotal trial were tracked down to provide “a snapshot today of what happened in these patients.” Follow-up in this study therefore lasted 16 years—the longest follow-up for any disease-modifying treatment (DMT), partly because IFNß-1b was the first MS therapy to be approved. Long-term follow-up is important because even relatively modest treatment effects can accumulate over the prolonged natural history of MS.

Of the original 372 patients, investigators were able to identify 328 (88.2%); of these, 293 were still alive. The percentage of patients not found was similar according to initial dosage group (placebo, IFNß-1b 50 µg or IFNß-1b 250 µg). What did vary was the percentage of deceased patients, which was higher (16.2%) for those originally on placebo compared to those on active treatment (7.2% for IFNß-1b 50 µg, 4.8% for IFNß-1b 250 µg). Researchers are still investigating the reasons for this, and that for the moment, this finding should not be overinterpreted.

Patients were grouped according to overall length of exposure to IFNß-1b, expressed as a percentage of time since the start of the pivotal trial (£10%, 10-80%, >80%). The demographics and baseline characteristics of the different exposure groups were similar.

The number of adverse events reported by patients still on IFNß-1b was reassuringly low. What was striking was the six-year difference in median time from diagnosis until confirmed expanded disability status scale (EDSS) score of 6.0 between patients with highest and lowest exposures. These data suggest that good adherence to treatment can substantially delay disease progression. As researchers concluded, “The study has limitations and analysis is still ongoing, but the data seem to tie together.”

Early Treatment

The pivotal clinical trials with IFNs were performed in patients with clinically definite MS (CDMS). Dr. Ludwig Kappos, University Hospital, Basel, Switzerland, presented results from the Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) study, which sought to determine if there were any advantages to early MS treatment, i.e. after the first clinical event.

Briefly, in a double-blind phase, patients with a first clinically demyelinating event and at least two clinically silent brain MRI lesions were randomized 5:3 to receive either 250 µg IFNß-1b subcutaneously or placebo. The double-blind phase lasted up to 24 months or until diagnosis of CDMS was made. Overall, 468 patients started treatment (292 with IFNß-1b and 176 with placebo), and 437 completed the study as planned. The primary end points were time to CDMS according to Poser criteria and time to MS according to McDonald criteria (the more recent McDonald criteria considered more sensitive). Patients were stratified according to a number of baseline characteristics, including age, sex, monofocal (episode consistent with single lesion) or multifocal (episode consistent with multiple lesions) disease, cerebrospinal fluid (CSF) findings and MRI activity or dissemination at onset.

For the Poser criteria, the risk of conversion to CDMS was reduced by 50% in the active-treatment group compared to the placebo group over the 24 months of the study. The risk reduction was slightly smaller (46%) according to the McDonald criteria. EDSS score remained unchanged in both groups, as expected in patients with MS in its early stages. Dr. Kappos told delegates that a 36-month, open-label follow-up would provide information on the effect of early intervention over a longer term, which is essential in a chronic disease such as MS.

According to Dr. Chris Polman, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands, who presented findings from the subgroup analyses of this same study, “The risk of conversion to CDMS was lower in the active-treatment arm of all subgroups. The results are robust and suggest that early treatment with IFNß-1b is beneficial.” The subgroup analysis also revealed that younger patients and those with positive CSF findings were at a higher risk of conversion.

Interestingly, the treatment effect was more pronounced for monofocal disease than for multifocal disease, although there was still a significant effect in multifocal disease. For monofocal disease, the treatment effect was even higher among those with a higher level of MRI dissemination, unlike multifocal disease, in which no such difference was found. Dr. Polman concluded that these results were “similar to the CHAMPS [Controlled High Risk Avonex Multiple Sclerosis] study [carried out in patients at risk of developing CDMS treated with intramuscular IFNß-1a], but the present study included patients with multifocal disease, and so went beyond the CHAMPS study.”

The Role of Neutralizing Antibodies

Neutralizing antibodies (NAbs) have been associated with all DMTs currently used for MS. However, the repercussions on the patient’s response to DMT are still unclear. Dr. Joel Oger, Neuroimmunology Laboratories and Multiple Sclerosis Clinic, University of British Columbia, Vancouver, presented a poster analyzing the incidence of NAbs over time during IFNß-1b treatment.

During the North American pivotal study in relapsing-remitting MS, samples were initially collected every three months for up to five years. Initial analyses of NAb status were inconclusive, due in part to assay unreliability at the time. Recent advances have made possible a re-analysis of these frozen samples. The best assay for determining NAb titres is still subject to discussion, although the myxovirus protein A (MxA) assay (J Interferon Cytokine Res 1998;18:1019-24) used in the present analysis has become the assay accepted by European regulatory authorities.

For this analysis, NAb titres ³20 were positive and titres ³400 were considered high. Patients with two consecutive NAb-positive titres were classified as “eventually NAb-positive.” High titres were not detected until month 6, and the proportion of patients with high titres remained low throughout the study (1.9-14.6% of those who eventually became NAb-positive). Unlike patients receiving treatment with IFNß-1a, in whom high NAb titres tend to remain high, those receiving IFNß-1b showed a peak NAb titre at around 1.5 years after starting treatment that tended to decrease after further treatment. According to Dr. Oger, “It is an open question why NAb response is different for IFNß-1b, which is a large protein, and that might partly explain the difference.”

When asked about the correlation between NAb titre and clinical outcome, Dr. Oger explained, “In the first year of treatment, NAb patients actually seem to do better; it is something that we don’t understand.” For the time being, treatment decisions should be based on clinical considerations, not NAb status.