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.

World Congress on Treatment and Research in Multiple Sclerosis (ACTRIMS-ECTRIMS-LACTRIMS)

Montreal, Quebec / September 17-20, 2008

Immune-modulating therapies for multiple sclerosis (MS), available for over a decade, have been shown to decrease relapse rate, progression to disability and burden of disease on magnetic resonance imaging (MRI). Evidence presented here supports the practice of employing treatment early—soon after a first demyelinating event or clinically isolated syndrome (CIS)—and for sustaining it over the long term. There has been debate about the need for aggressive intervention in patients who feel well after the CIS has resolved and in whom the disease course might appear slow or benign. Yet an increasing body of evidence indicates treatment can help address both clinical and “silent” disease, as well as insidious, potentially devastating cognitive deterioration. Delaying treatment might allow irreparable damage, speakers here suggested.

The BENEFIT (Betaseron in Newly Emerging Multiple Sclerosis for Initial Treatment) study showed that treatment with subcutaneous interferon beta (IFNß)-1b in patients who had experienced a CIS and had two clinically silent lesions on MRI nearly halved the risk of a second clinical event or a diagnosis of MS according to the McDonald criteria (Kappos et al. Neurology 2006;67:1242-9). In this trial, patients in the placebo group were offered treatment upon experiencing a second clinical event or at the end of the two-year placebo-controlled study. As such, the difference in duration of treatment between the two arms was one year and four months, rather than the two-year study period, explained Dr. Mark Freedman, Professor of Medicine, University of Ottawa, and Director, MS Research Unit, Ottawa Hospital, Ontario.

The subsequent prospective open-label study confirmed that after three years, early vs. delayed treatment continued to reduce risk of clinically definite MS (CDMS) by a significant 40% (P=0.0011). It also produced the unique finding that early treatment decreased the likelihood of disability—progression on the Expanded Disability Status Scale (EDSS)—by 40% (P=0.022) (Kappos et al. Lancet 2007;370(9585):389-97). In patients who were initially in the placebo group, Dr. Freedman stressed, “The delay did irreversible damage which showed itself in terms of disability progression at year 3. So everything is being driven by what happens in the first year.”

BENEFIT Five-year Results

Dr. Freedman presented the results of the five-year follow-up of BENEFIT participants here (abstract P901). The authors concluded that early initiation of treatment led to a 37% lower risk of conversion to CDMS (P=0.003) and a 45% lower risk of McDonald MS (P<0.0001). These reductions translated into a difference of more than two years before conversion to CDMS. Early initiation of therapy also led to a significantly lower annualized relapse rate (0.214 vs.0.270, P=0.0141) and significantly reduced new or enlarging T2 and gadolinium-enhancing lesions on brain MRI. The likelihood of EDSS progression in the early- vs. late-treatment groups, 25% vs. 29%, was not significantly different. This finding was expected, Dr. Freedman stated, given that the study was not powered to assess disability and that by the five-year point, the majority of patients had been receiving treatment for MS for three to five years. “I would have been very discouraged if that had not happened, because the entire placebo group are now on treatment, albeit delayed.”

The BENEFIT five-year follow-up also determined that therapy had no negative impact on the treated patients’ quality of life, commented Dr. Freedman. Using two quality-of-life questionnaires, he noted, the investigators determined “there wasn’t a trade-off from starting the treatment early.”

Additional data presented here point to the advantages of early initiation of therapy in MS. A study of 231 patients receiving intramuscular (i.m.) INFß-1a determined that those who received therapy after a single clinical demyelinating event had a significantly lower rate of relapse over one year than those who started treatment later, and two-thirds of this group had no relapses. Those who started treatment after two events tended to have a greater number of relapses (Haas et al. poster 56).

Cognition a Relevant End Point

Cognitive decline occurs in up to two out of three patients with MS. Its effects are underappreciated, principally because MS does not typically affect language or attention. “MS patients are much more likely to be impaired on measures of information processing speed and episodic or recent memory, and there is an intermediate degree of impairment on measures of visuospatial skills and conceptual reasoning or problem solving,” remarked Dr. Stephen Rao, Director, Schey Center for Cognitive Neuroimaging, Cleveland Clinic, Ohio.

Dr. Rao indicated cognitive function should be more widely assessed in clinical trials of MS therapies, noting that physical disability does not correlate well with cognitive disability. On the other hand, observed Dr. Tony Traboulsee, Assistant Professor of Medicine and Assistant Director, MS/MRI Research Group, University of British Columbia, Vancouver, more active disease on MRI during the early stages of disease does correlate with eventual cognitive deterioration. Furthermore, cognition is a powerful predictor of outcome in MS. “Cognition is the greatest anticipator of disability. People who have early cognitive change are the ones who are most likely to suffer with MS,” Dr. Freedman added. Cognitive symptoms influence daily functioning and can eventually contribute to such devastating events as job loss and automobile accidents. “This takes us back to the concept of treating the disease as early as possible to prevent such deterioration,” Dr. Traboulsee commented.

An important finding in the BENEFIT follow-up is that early treatment had a substantial positive impact on cognition, as measured by the Paced Auditory Serial Addition Test (PASAT). While it does not replace comprehensive neuropsychological testing, this test is a key tool for measuring intellectual function, Dr. Freedman stated.

Another study documented that treatment with s.c. IFNß-1a may help prevent cognitive decline in patients with relapsing-remitting MS. In this analysis, the proportion of patients with impaired cognitive function remained stable over three years of treatment (Patti et al. poster 85).

Long-Term Considerations

Ensuring the safety and tolerability of MS treatment over the long term is vital, given that clinicians may now be contemplating chronic interferon therapy in young adults with a CIS, noted Dr. Traboulsee. In a presentation here (Goodin et al. poster 52), researchers determined that early initiation and sustained exposure to IFNß-1b are strongly associated with a reduced risk of disability (EDSS >6.0, use of a wheelchair, conversion to secondary progressive disease, or death) over 16 years. A low degree of disability at treatment outset was also associated with a more optimal outcome at 16 years, Dr. Traboulsee remarked. In another presentation describing the follow-up of patients receiving i.m. IFNß-1a for up to 15 years, the authors determined that long-term/current users were less disabled and had a better quality of life and sense of independence than those who had not received or had discontinued the treatment (Bermel et al. poster 14).

In the BEST (Betaseron/Betaferon in Early Relapsing-Remitting Multiple Sclerosis Surveillance) trial, Dr. Urs Pohlmann, Department of Neurology, University Hospital, Basel, Switzerland, and co-investigators sought to ascertain whether long-term outcomes in clinical settings are similar to those achieved in randomized clinical trials. Their observations to date of 3566 patients treated with IFNß-1b (poster 86) showed that as might be expected, treatment drop-out is more common outside the randomized control trial setting. However, noted Dr. Pohlmann, the efficacy results are similar. Over two years, annualized relapse rates were approximately halved with treatment vs. pretreatment status (0.43 vs. 0.97) and 66% of patients remained free of relapse and disability progression.

Nonadherence to or discontinuation of MS therapies is a recognized problem. The reasons are numerous: for instance, suggested Dr. Bernd Kieseier, Professor of Neurology, and Head, MS Outpatient Clinic, Heinrich Heine University, Düsseldorf, Germany, some people feel “confronted by the disease” when they must inject themselves multiple times per week. A perceived lack of efficacy is also a common reason for discontinuing treatment. One study found that 50% of patients often forget to take their medication, which supports further consideration of cognitive issues in the disease, Dr. Kieseier suggested. Improvements in administration such as auto-injectors and thinner and sharper needles have been shown to be helpful in promoting adherence. Further improvements may be anticipated with new developments such as medications with lower dosing frequency due to PEGylation and new delivery methods such as inhaled or oral therapies.

Improvements Observed Over Time

Over the last few years, MS treatment trials have produced better results than first occurred with the advent of disease-modifying therapies, observed Dr. Freedman. “Maybe we are finally using these medications the way they were supposed to be used. We are getting to our patients earlier, within the first year or two. And as a result of that, we are getting better responses, better reductions in relapse rates, more improvement overall.”