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.

23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis

Prague, Czech Republic / October 11-14, 2007

The treatment paradigm for multiple sclerosis (MS) has shifted markedly in the last few years toward increasingly earlier intervention. According to researchers, advances in the early diagnosis of the disease, its generally inexorable progress when untreated and the growing evidence that irreversible axonal damage begins before the first clinical symptoms appear necessitate early therapy.

BENEFIT: Three-year Results

The three-year results of the BENEFIT (Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) study were presented here by Dr. Mark S. Freedman, Professor of Neurology, University of Ottawa and Director, MS Research Unit, Ottawa Hospital, Ontario. The findings confirm those obtained from the same study at two years: that early treatment with interferon (IFN) beta-1b reduces the risk of developing clinically definite MS (CDMS) compared with delayed treatment.

During the placebo-controlled phase, patients in the early treatment group were randomized to either IFN beta-1b or placebo within 60 days after the first clinically isolated syndrome for up to two years. The other cohort, the delayed treatment group, did not start active treatment until either they had been diagnosed with CDMS, according to Poser criteria, or had been on placebo for 24 months. To optimize tolerability, dosage was escalated during both the placebo-controlled and follow-up phases, with the full dose of IFN beta-1b 250 µg s.c. every other day from day 19 onwards. Patients completing the randomized phase were eligible to enter the pre-planned follow-up phase. All patients were offered IFN beta-1b for a maximum of seven years, including the randomized phase, plus an additional two-year extension.

Quality of life, as measured by the European QoL 5-dimensional questionnaire (EQ-5D), showed a positive effect of early treatment. EQ-5D scores improved at three years in the early treatment group but decreased in the delayed treatment group.

The BENEFIT study has several important strengths, explained co-investigator Dr. Xavier Montalbán, Director, Neurology Research and Clinical Neuroimmunology MS Unit, Vall d’Hebron University Hospital, Barcelona, Spain. The dropout rate was low, with 343 (73.3%) of the 468 patients randomized to active treatment still on treatment at year 3. Moreover, investigators and patients (apart from 12 patients who received placebo and showed no further disease activity) remained blinded from initial randomization throughout the first two years of the trial. The pre-planned statistical analysis is another asset of the trial design.

Early treatment with IFN beta-1b reduced the risk of developing CDMS by 41% over three years (hazard ratio [HR]: 0.59, 95% CI: 0.44, 0.80; log-rank test P=0.001) compared with delayed treatment. Early vs. delayed treatment also reduced the risk of confirmed EDSS progression by 40% at three years (HR: 0.60, 95% CI 0.39, 0.92; log-rank test P=0.022).

“It was totally unexpected,” Dr. Freedman remarked. “When you took a truly early population of first-event MS and followed them for three years, none of us expected to see a significant EDSS progression. But nearly a quarter of the patients on placebo, despite the fact they got IFN for at least a year and some for almost two years, continued to progress. All of this was being driven by year one of that study.” This means, he added, that delaying treatment by as little as a year, until a diagnosis of CDMS, might result in irreversible axonal damage that manifests as EDSS progression only three years after the first clinical episode.

Dr. Freeman told delegates, “There has been this feeling that we are going to reserve this powerful drug for patients once they have developed more progressive disease. That was our notion 20 years ago. That changed when we discovered that irreversible disease occurs very early in the course of the disease.” Adherence was “very high,” he pointed out, even in patients who had experienced only a single attack after which they had remained asymptomatic. The dosage escalation scheme, use of an autoinjector and concomitant medication to reduce flu-like symptoms all contributed to better patient acceptance, Dr. Freeman suggested.

For the first time, there is evidence that early vs. delayed treatment also reduces the risk of confirmed progression on EDSS. Furthermore, the early treatment group experienced an improved quality of life. Tolerability and treatment adherence were excellent, supporting the use of this medication in a population of patients who may be asymptomatic for a considerable time after their first episode.

Long-term Therapy

Adherence is crucial if patients are to sustain long-term efficacy. While even three years’ treatment in BENEFIT significantly slowed EDSS progression, the 16-year follow-up from the pivotal North American IFN beta-1b trial shows a correlation between long exposure to treatment and delay in the time to reach EDSS 6 and to develop secondary progressive MS, Dr. Freedman explained. “It was clear that the patients who remained for most of those 16 years on [IFN beta-1b] took an average of about five years longer to reach this all-important stage of now becoming dependent on a cane for ambulation.”

Other data from the long-term follow-up study of patients in the pivotal trial reveal that both EDSS and MRI T2 burden of disease (BOD) strongly correlate with the patients’ cognitive status. Even more importantly, when tested in a regression model, these two parameters also significantly predict cognitive function at 16 years. Their predictive power applies not only to baseline values (P=0.0001 and P<0.0001 for EDSS and T2 BOD, respectively) but also to EDSS change from baseline and T2 BOD assessed two years into the trial (P=0.0526 and 0.0098, respectively).

Dr. Dawn Langdon, Senior Lecturer, Neuropsychology Department, Royal Holloway College, London, UK, who presented the findings on behalf of the study group, concluded: “It seems that disease activity and progression in the early stages of the disease clearly determine cognitive status 16 years later.” She added that these prospective cognitive data came from a total of 179 patients and did not distinguish between IFN beta-1b-treated partial and placebo groups. However, the slowed EDSS progression seen in patients originally given active treatment in both this study and BENEFIT, together with the previously reported correlation between T2 BOD and worsening EDSS score in the former, further support the current trend towards early treatment and are of added relevance in light of these latest cognitive findings.

Program to Examine Higher Doses

Dr. Freedman also discussed growing evidence from several other clinical trials that higher doses given more frequently offer the greatest therapeutic benefits. This evidence provided the rationale for the BEYOND (Betaseron Efficacy Yielding Outcomes of a New Dose) program, set up to assess the safety, tolerability and efficacy of IFN beta-1b 500 µg s.c. every other day.

In the first phase, a multicentre, randomized, parallel-group pilot study compared 250 µg and 500 µg s.c. every other day for 12 to 28 weeks. In an extension study, patients continued the treatment they had received for a further 10 weeks. The treatment was then unblinded and patients could choose whether to continue on their current dose or, as appropriate, to increase the 250-µg dose to 500 µg or decrease the 500-µg dose to 250 µg. A total of 71 patients completed the pilot phase, of whom 63 entered the extension study, with 61 continuing after week 10. Of these, 22 chose the lower dose and 39 the higher dose.

After three years of follow-up, 42 patients remained in the study. In general, both doses were well tolerated and there were no unexpected or new adverse events. Although flu-like syndrome was more common in patients treated with the higher vs. lower dose (62% vs. 23%), injection-site reactions were markedly more frequent in the group switching from the higher to the lower dose (50%). However, these reactions were similar among the other groups and lowest in the patients remaining on the low dose (13%). No relevant changes were seen from baseline in alanine aminotransferase or aspartate aminotransferase levels in any dose group.

The main phase of the BEYOND study will compare the efficacy of IFN beta-1b 250 µg and 500 µg and glatiramer acetate20 mg in 2244 patients with relapsing-remitting MS. Preliminary results are expected to be available at the end of November 2007.