|
BENEFITS OF EARLY AND LONG-TERM MS THERAPY
SAN DIEGO—Early treatment with interferon beta-1b (Betaseron®) in patients who have experienced a single clinical episode suggestive of multiple sclerosis (MS) thwarts progression to clinically definite MS, investigators announced at the 58th Annual Meeting of the American Academy of Neurology.
In a separate study, researchers reported that early efficacy and safety improvements with interferon beta-1b in patients with relapsing forms of MS were maintained with ongoing treatment over a 16-year follow-up period.
IMPETUS FOR EARLY TREATMENT
"With the existing approaches to treatment, the horses are all out of the barn, and it’s difficult to close the door, because the damage has been done by the time treatment is started," said Mark S. Freedman, MD, Director of the Multiple Sclerosis Research Unit at the University of Ottawa. "We know, for example, that axonal damage occurs very early in the course of the disease process of MS and even before the disease is diagnosed. So the thought is that maybe if we limit the amount of axonal damage by introducing early and effective therapy, we can postpone patients’ disability. And, in fact, our patients’ main concern is that they will become disabled in the next 10 to 20 years, so the prospect of disability is particularly worrisome in those individuals whose symptoms first present when they are in their 20s or 30s."
Dr. Freedman and coinvestigators in the Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment (BENEFIT) trial randomized 468 patients to treatment in a 5:3 ratio with either 250 mg interferon beta-1b or placebo administered subcutaneously every other day. Participants had experienced their first clinical event suggestive of MS within the last 60 days and presented with either monofocal or multifocal symptoms and an MRI screening scan suggestive of MS.
Patients were treated until clinically definite MS was diagnosed or 24 months. The primary end points were time to clinically definite MS—based on relapse or an Expanded Disability Status Scale (EDSS) progression of 1.5 points or more—and time to MS according to McDonald criteria established in 2001. The mean age of the study population was 30.7, and about 70% were women.
Using the conventional criteria for diagnosing MS, 28% of the interferon beta-1b group had developed clinically definite MS at two years compared with 45% of placebo-treated patients. When the diagnosis was established by McDonald criteria, 69% of the interferon beta-1b group had MS versus 85% of the placebo cohort. Also, interferon beta-1b prolonged the time to a diagnosis of clinically definite MS by one year.
"Overall, we found that interferon beta-1b treatment significantly reduced the progression to McDonald MS by 46%, and the risk of progression to clinically definite MS by 50%," Dr. Freedman said. "This is important because the question of how early treatment should be started has been widely debated. And we have now been able to demonstrate that if we introduce therapy at a time even before patients satisfy the criteria for a definition of true MS, we can prevent further activity."
Compliance was high, with more than 93% of patients in each group adhering to the study protocol and 84% in each group adhering to their assigned therapy, Dr. Freedman added. The high compliance rate can probably be explained by the use of a four-step dose titration scheme during the initial three weeks of treatment, the use of an autoinjector to decrease injection-site reactions, and prophylactic treatment with anti-inflammatory agents like ibuprofen or acetaminophen to reduce flu-like symptoms, he said.
Notably, 10 of 11 placebo-treated patients who had not experienced additional demyelinating events during the two-year follow-up period opted to enter a five-year prospective, open-label, follow-up arm of the trial.
"It is important to note that the study provides a number of firsts," Dr. Freedman pointed out. "For example, it is the first to test the use of high-dose, high-frequency interferon," he said. "Also, it is the first time we have used the newest criteria for an outcome measure—the so-called revised McDonald outcome criteria—which allow us to make a specific diagnosis."
LONG-TERM EFFICACY
George Ebers, MD, Professor of Neurology at Oxford University, United Kingdom, presented the results of the Betaseron 16-Year Long-Term Follow-Up Study. The trial is the longest follow-up study to date of an immunomodulatory therapy in MS.
"A lot of patients worldwide are being treated with interferon for their MS, yet there is very little information about the long-term outcome with this treatment," Dr. Ebers explained. "MS is a disease that runs for 30 to 40 years, so information about long-term outcomes is critical. Most of the information thus far has been based on short-term studies or surrogate markers."
The research group examined the long-term safety and efficacy of interferon beta-1b in patients with relapsing-remitting MS, using data from patients who had been enrolled in the original pivotal trial. Long-term treatment was defined as use of interferon beta-1b for more than 80% of the time since the start of the pivotal trial (about 12 years or longer), while short-term treatment referred to the use of interferon beta-1b for less than 10% of the time (about 1.6 years or less).
Two-year results showed that relapses and MS-related hospitalizations were less likely in patients randomized to subcutaneous interferon beta-1b, 50 or 250 mg every other day, than in the placebo group. Improvements were maintained at five years.
Despite the lengthy interval from the last follow-up period, the investigators were able to locate 328 (88.2%) of subjects from the original 392-patient trial. The overall survival rate at 16-year follow-up was 89%, and the median length of treatment was 10 years. Patients receiving long-term treatment had a slower disease progression compared with patients who did not continue on long-term treatment, Dr. Ebers reported.
Among patients who reached EDSS level 6, he continued, those on long-term interferon beta-1b treatment reached this outcome after a median of 13 years versus seven years for patients on short-term treatment.
The efficacy in relapse rate reduction was demonstrated beyond the treatment duration of five years, Dr. Ebers said. "In fact, patients who have been on long-term treatment had a relapse reduction of up to 40%, which is in the same range as that observed early on," he noted. Also, neutralizing antibody titers decreased over time, and only 11% were positive at 16-year follow-up.
Dr. Ebers allowed that the whole cohort may be a selected group, as compared to natural history cohorts, and that this might represent a potential study limitation. However, he was quick to emphasize that further analyses will compare these results to expected outcomes using different natural history databases. "Overall, the findings suggest a possible advantage of early and continuous long-term treatment with interferon beta-1b," he concluded.
NR
—Jill Stein
Suggested Reading
Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. The IFNB Multiple Sclerosis Study Group. Neurology. 1993;43:655-661.
Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group. Neurology. 1995;45: 1277-1285.
Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald criteria." Ann Neurol. 2005;58:840-846.
Return to table of contents
|
|
