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PRIORITY PRESS - 2nd World Congress on Controversies in Neurology

Athens, Greece / October 23-26, 2008

Rationale for Early MS Treatment

Multiple sclerosis (MS) is the major neurologic disease of young adults, the group most likely to benefit from the prevention of early onset of progressive disease and long-term disability. “One very important rationale for early MS treatment is that permanent neuro-axonal damage and loss is known to begin early in the course of MS,” Dr. Douglas Goodin, Medical Director, University of California, San Francisco, Multiple Sclerosis Center, told delegates. “These axonal transections in acute, early inflammatory lesions presumably underlie the disability that occurs in MS.”

The number of damaged axons is greatest in active early lesions. They are more abundant in the early phase of the disease, and less so over the course of the next 10 years or so. Presumably, this is accounted for by the fact that the axonal transections occur in the inflammatory phase, and the inflammatory phase of the disease is the early phase. According to Dr. Goodin, the beneficial effect of interferon (IFN)-based agents is based on their anti-inflammatory properties.

“So we have very good rationales for treating MS early,” Dr. Goodin noted. “We know that permanent neuro-axonal loss begins early in the course of the disease and is followed by disability and deterioration of cognitive function. Recent trials suggest that our therapies are more effective in the early form of the disease, and that long-term efficacy is better when treatment is initiated early and when patients are adherent. Since the goal of therapy is to help maintain function for as long as possible, and because current disease-modifying therapies probably do not reverse existing functional deficits, what is lost by delaying treatment is probably permanently lost and cannot be regained, so treatment must begin early.”

A Review of BENEFIT

Speakers at this congress agreed that there was benefit to early, long-term MS treatment with IFN beta or glatiramer acetate, which are first-line agents with manageable adverse effects that patients with early disease can tolerate well. Dr. Xavier Montalban, Director, MS Centre of Catalonia, Barcelona, Spain, specifically discussed the BENEFIT (Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) trial at a dedicated symposium. He remarked that it is the first and only prospectively planned randomized trial to show a long-lasting benefit from IFN beta-1b treatment on time to clinically definite MS (CDMS) and McDonald MS, when initiated after the first clinical event.

“The benefit of an early start with IFN beta-1b compared to a delayed start was sustained at five years despite a relatively short time period before IFN beta-1b was initiated in the placebo control delayed group,” Dr. Montalban told delegates. “The mean time on placebo in the delayed treatment group was 1.33 years, meaning that you have to take this into account when assessing five-year results because most of the patients were treated with IFN beta-1b most of the time.”

BENEFIT randomized 468 clinically isolated syndrome (CIS) patients with at least two silent MRI lesions to conventional subcutaneous (s.c.) doses of IFN beta-1b 250 µg every other day or placebo for 24 months or until the patient converted to CDMS. All patients were then invited to participate in a follow-up study with IFN beta-1b to prospectively assess the impact of immediate vs. delayed treatment with IFN beta-1b on the long-term course of the disease for five years.

Dr. Montalban reported that, compared to delayed treatment, five-year integrated analysis showed that early treatment with IFN beta-1b initiated after the first event suggestive of MS delayed the onset of CDMS by 37% (P=0.003), and McDonald MS by 45% (P<0.0001). It postponed conversion to CDMS by more than two years (750 days) in the 40th percentile and prolonged the onset of confirmed disability progression by 1.5 years (549 days) in the 20th percentile (P=0.177). It also led to greater improvement in cognitive function measured by the Paced Auditory Serial Addition Test (PASAT) score, an effect that became more pronounced over time.

Disability was low and stable over five years in both study arms and quality of life remained high, with no difference between the groups. The vast majority of serious side effects bore no relationship to the study medication. IFN beta-1b was well tolerated and accepted by the patient group with the earliest signs of MS.

The study also demonstrated a decrease in confirmed disability on the Expanded Disability Status Scale (EDSS) in favour of early treatment with IFN beta-1b. This effect first appeared at year 3, with a significant risk reduction of 40% (P=0.022). Over five years, a nominal disability risk reduction of 24% was observed for early treatment over delayed treatment, a difference which did not reach statistical significance. In another statistically significant benefit, early treatment reduced the development of new or enlarging T2 lesions and gadolinium-enhancing lesions compared to delayed treatment (P=0.0062). There were no differences between treatment groups for other MRI parameters, including changes in T2 lesion volume, black hole lesion volume or brain volume.

Dr. Montalban concluded, “The findings of the BENEFIT study, and the established safety profile of IFN beta-1b, make it an appropriate choice for starting treatment at the time of the first event suggesting MS.”

Reduction of Relapses

Dr. Trevor Kilpatrick, Director, Centre for Neuroscience, University of Melbourne, Australia, characterized BENEFIT as a well-conducted study in which patients treated early with IFN beta-1b had a greater relapse rate reduction over five years than patients given delayed treatment, despite the latter receiving at least three years of IFN beta-1b after the second attack or after two years (P=0.014; Poisson model). This difference in effect was driven mainly by the differences between the groups over the first two years.

“Most trials deal with relapses as the primary outcome measure. But the severity of relapses is also important,” Dr. Kilpatrick noted. “For example, IFN beta-1b has been shown to reduce relapses by about a third, but the reduction in severe relapses is in the order of 50%. Many studies in MS have also included MRI outcome measures. In the pivotal [IFN beta-1b] study, MRI activity in terms of T2 lesion load and enhancing lesions was reduced by about 80%. Obviously, there is a disconnect in relation to that 80% vs. the reduction of relapse rate by about 33%. If one had a choice between normalizing MRI activity and maintaining MRI activity for the same clinical benefit, one would want to choose the former.”

Patient Management Implications

Regarding the implications of the BENEFIT study for patient management, Dr. Mark Freedman, Professor of Medicine, University of Ottawa, and Director, MS Research Unit, Ottawa Hospital, Ontario, remarked, “It gives us an advantage in MS that we do not have in any of the neurodegenerative conditions that present fairly late. We know this irreversible disease starts with axonal loss or inflammation but if we wait for that aspect of the disease to present, it could be into the secondary progressive phase, in which our medications are only partially effective at best. When the patients present after their first attack, you have the opportunity to assess where they are within the window of opportunity for treatment. If they are very early in their treatment window, there is the option of starting treatment at a time when the neurodegenerative phase has not yet surfaced.”

He stated, “If you start with a disease-modifying therapy, the BENEFIT study would suggest that IFN beta-1b provides long-lasting benefits in reducing lesion load, conversion to CDMS, and now slowing of disability and cognitive decline. It reduces the risk and postpones second attacks, reduces the risk of new MRI lesions and delays the onset of disability and cognitive dysfunction.”