Reports

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58th Annual Meeting of the American Academy of Neurology

San Diego, California / April 1-8, 2006

Long-term Treatment Results

The longest follow-up of any study of disease-modifying therapy in multiple sclerosis (MS) showed that treatment makes a difference. Sixteen years of follow-up of patients with relapsing-remitting MS originally enrolled in a pivotal randomized, prospective, placebo-controlled trial has shown that subcutaneous (s.c.) interferon beta 1b (IFNb-1b) delayed disease progression compared with no treatment. The median time to reach an Expanded Disability Status Scale (EDSS) score of 6.0 (reflecting needing a cane for walking) was 13 years for the actively treated group compared with seven years in the placebo group. For this analysis, long-term treatment was defined as use of the immunomodulator for more than 80% of the time (approximately 12 years or longer), whereas short-term treatment was defined as use for less than 10% of the time.

According to lead investigator Dr. George Ebers, Department of Clinical Neurology, Radcliffe Infirmary, University of Oxford, UK, “The most important issue is what happens with treatment over the long term. A tremendous number of people in the world are taking these drugs, and very little is known about long-term efficacy. The evidence is convincing for relapse rate reduction and long-term safety of IFNb-1b. We plan to analyze further the impact of treatment on disease progression.”

Dr. Ebers indicated that he and colleagues were able to identify 90% of the original 372 patients enrolled in the trial. “Some of the patients are still on the drug, some are off of it, and some have died,” he told delegates.

He reported that long-term findings are reassuring: active treatment was safe, and no unexpected side effects emerged over the 16-year period. He noted that neutralizing antibodies (NAbs) that were present in the first few years of treatment disappeared over time.

Dr. Ebers stated that treatment reduced relapse rates, although he informed the audience that the data have not yet been analyzed according to duration of treatment. “We are planning to analyze that and carefully evaluate long-term outcome according to treatment duration.” He added, “One question is whether there is a difference if you are on treatment or off it in terms of disability, and another question is if you remain on treatment, do you do better than if you had not been on treatment at all? That requires comparison with historical controls.”

Future plans include an intent-to-treat analysis to compare disability in patients who were advised to take the drug with disability outcomes in 1000 historical controls from London, Ontario, who have been followed for 30 years.

Clinically Isolated Syndrome

Betaferon/Betaseron in Newly Emerging MS for Initial Treatment (BENEFIT), the largest study ever conducted in MS patients with clinically isolated syndrome (CIS), supports the benefit of early treatment with disease-modifying therapy in patients with a first episode of MS. Treatment with the subcutaneously administered agent reduced the risk of converting to clinically definite MS (CDMS) by 50% compared with placebo. Moreover, according to McDonald diagnostic criteria, patients who received active treatment derived twice as much protection against developing MS as those treated with placebo.

According to Dr. Mark S. Freedman, Director, Multiple Sclerosis Clinic, and Professor of Medicine, University of Ottawa, Ontario, “Overall, the study showed that if therapy is initiated at the time of a first demyelinating event, it is effective. With MS, time is against you. You know that patients will progress, and CIS gives you the opportunity to intervene and make a difference for patients.” He also noted that treatment delayed the onset of MS for almost a year.

Dr. Freedman reported results of the first phase of BENEFIT, during which 487 patients with CIS and evidence of two or more clinically silent MRI lesions were randomized in a 5:3 ratio to receive treatment with either IFNb-1b every other day or placebo. Patients were followed for up to two years to see if a second attack occurred. At the end of the second year or a diagnosis of CDMS, patients could opt for the active treatment for another 36 months in an open-label extension phase of the trial. The primary outcome measure was time to a diagnosis of MS according to the modified Poser criteria and also by the McDonald criteria.

Four hundred and sixty-eight patients entered the study (292 on the active treatment and 176 on placebo). Both arms were well balanced for demographic and disease characteristics. About half the patients in both arms had monofocal onset (symptoms reflecting one MRI lesion in the CNS) and half had multifocal onset (reflecting disseminated disease spread of two or more lesions). About 40% had gadolinium-enhancing (Gd+) lesions on MRI, a measure of disease activity.

Dr. Freedman reported that 96% of patients chose to enter the follow-up extension phase of the study and results are expected in 2008. Among placebo patients, the risk of developing McDonald MS after six months was 51% and 85% after two years. At month 24, the cumulative probability of progression to CDMS was 28% with IFNb-1b compared to 45% with placebo; this highly significant difference in favour of early treatment represents about a 50% risk reduction. Treatment was of benefit in all patients, regardless of whether or not they had MRI evidence of increased disease activity (i.e., new T2 lesions, new Gd+ lesions), Dr. Freedman told delegates.

No change in EDSS was observed between the two groups, but Dr. Freedman noted, “It is still early at two years and that is not surprising.” NAbs developed in 15 to 25% of patients, but there was no significant impact of NAbs over 24 months. Injection-site reaction was the only frequent side effect with treatment, and the frequency and severity of these reactions decreased after one year. “We used slower titrations during the first three weeks of this study, concomitant ASA and ibuprofen, and an autoinjector, and had better results regarding injection-site reactions. This may have implications for clinical practice,” Dr. Freedman stressed. The agent was well tolerated, and more than 90% of patients in both arms completed the two-year phase.

Subgroup Analyses of BENEFIT

Some interesting findings emerged in subgroup analyses of BENEFIT, as presented by Dr. Chris Polman, Vrije University, Amsterdam, The Netherlands.

The effect of treatment was robust and compelling across all subgroups (age, gender, monofocal or multifocal disease presentation, disease activity as seen on MRI). The treatment effect was even greater in patients with less evidence of disseminated disease, lower lesion loads or no enhancing lesions on MRI, but these patients still had a substantial risk of developing CDMS. Factors associated with earlier conversion to MS were age, steroid treatment, positive spinal fluid, and MRI regarding only the monofocal patients.

In the monofocal patient group, the strongest treatment effect was observed in those patients with higher disease activity on MRI. In a post-session interview at the AAN, Dr.Freedman suggested that a treatment effect might emerge over the next 36 months in this patient group.