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22nd Congress of the European Committee for Treatment and Research in Multiple Sclerosis

Madrid, Spain / September 27-30, 2006

According to Dr. Giancarlo Comi, Professor of Neurology, Vita-Salute San Raffaele University, Milan, Italy, “Patients with clinically isolated syndrome (CIS) have a high risk of developing multiple sclerosis [MS.]” He cited findings from a natural history study conducted by Dr. Christian Confavreux, Hôpital neurologique Pierre-Wertheimer, Lyon, France, which showed that approximately 75% of patients had developed clinically definite MS (CDMS) within five years of the CIS diagnosis. Thirty-eight per cent of patients in CHAMPS (Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study), and 45% of those in both ETOMS (Early Treatment of MS) and BENEFIT (Betaferon in Newly Emerging Multiple Sclerosis for Initial Treatment) had reached a CDMS diagnosis after two years.

BENEFIT, a randomized, multicentre, double-blind, placebo-controlled trial, is the first study in CIS patients to examine the effects of high-dose, high-frequency interferon beta (IFNb) according to the 2001 McDonald criteria and is also the largest CIS clinical trial to date. Dr. Mark Freedman, Director, Multiple Sclerosis Research Unit, Ottawa Hospital, and Professor of Neurology, University of Ottawa, Ontario, indicated more than 50% of patients in the placebo group of the BENEFIT trial had progressed to MS within six months and 85% of them within two years. Furthermore, subgroup analyses of this study have shown a higher risk of CDMS in younger patients (<30 years: 60% vs. 33%). Patients with monofocal disease and with more than nine lesions on MRI or the presence of gadolinium-enhancing lesions had a higher risk of converting to MS than those without these MRI findings (55% vs. 31% and 63% vs. 36%, respectively). However, MRI parameters provided no additional information on risk of MS in patients with multifocal onset.

Rationale for Early Treatment

As explained by Dr. Comi, the rationale for early treatment is based on the severity of the disease together with the ability to diagnose it in its earliest, biological phase. Moreover, irreversible axonal damage starts very early in the course of the disease and is probably due to inflammation. Immunomodulating treatments, which suppress inflammation, are more effective early on since inflammatory evolution diminishes with time. Furthermore, CNS plasticity is greater in early disease, allowing for more functional recovery. Another consideration is that the early course of the disease predicts its long-term evolution. Finally, the positive results from CHAMPS, ETOMS and BENEFIT with IFNb therapy “clearly demonstrate that these agents are effective and, what is even more important, the same type of drug is more effective if given very early compared to delayed treatment. I personally believe there is quite a strong rationale for an early treatment for MS,” Dr. Comi declared.

Nevertheless, despite the proven therapeutic benefits of these agents and the well known overall prognosis of MS, clinicians would like to be able to predict the long-term outcome in a given individual to help them decide when to start treatment. Fortunately, long-term data, going back over 40 years, is available from several epidemiological studies. Dr. Comi summarised the relevant findings, explaining that multifocal presentation, an early high relapse rate, an abnormal MRI with a large lesion load, and disability progression within the first five years were all adverse prognostic factors for CIS patients.

Dr. Freedman emphazised that both CHAMPS and ETOMS trials had used once weekly IFNb-1a. However, in patients with established relapsing-remitting MS (RRMS), once weekly s.c. IFNb-1a had had no effect on relapse rate in the Once Weekly Interferon for MS (OWIMS) trial whereas three times weekly dosing of s.c IFNb-1a had produced a clear, statistically significant (P=0.0003) reduction in relapse rate in patients in PRISMS (Prevention of Relapses and Disability by Inteferon beta-1a Subcutaneously in Multiple Sclerosis).

The main objective of BENEFIT were to demonstrate the efficacy, safety and tolerability of IFNb-1b in patients with CIS with at least two clinically silent MRI lesions. Patients received IFNb-1b 250 mcg s.c. or placebo every other day until CDMS was diagnosed or they had been followed for 24 months. After two years, 45% of placebo patients had converted to CDMS and 85% fulfilled the McDonald criteria, the primary outcome measures. Treatment with IFNb-1b delayed the overall risk of developing CDMS (P<0.0001) and McDonald MS (P<0.00001). Hazard ratios (95% confidence intervals) were 0.50 (0.36, 0.70) for CDMS and 0.54 (0.43, 0.67) for McDonald MS. “This translated to almost a year’s delay [in developing MS] just in the two-year study,” Dr. Freedman reported.

The MS Functional Composite (MSFC) from baseline to the end of the study, a secondary, exploratory end point, improved by a median of 0.06 in the placebo group and by 0.199 in the IFNb-1b group (P=0.0386). This improvement was driven primarily by the Paced Auditory Serial Addition Test (PASAT) score which showed no change in the placebo arm but increased by a median of 0.124 in the patients receiving active therapy (P=0.0007). “This is telling us something we really need to pay attention to in the CIS group: that we’ve really underrated the importance of cognitive impairment. We know that a lot of perfectly walking, normal, physically minimally disabled patients complain very early on of cognitive disturbance and we’re seeing that starting the medication even at CIS might make a difference in that regard.”

The Decision to Treat

Findings from CHAMPS, ETOMS and now BENEFIT trials are sufficient to support a strategy for treating CIS patients, stated Dr. Comi. If a patient has first demyelinating attack, typical brain MRI and one or more negative prognostic factors (i.e. nine or more brain lesions on MRI, one or more enhancing lesion, multifocal presentation, or a severe attack) “you must immediately start therapy.” In the absence of negative prognostic factors, therapy can be withheld for the time being and the brain MRI should be repeated after three months. However, therapy is indicated in patients with evidence of temporal dissemination. Otherwise, MRI should be repeated after six to 12 months. “If we are not so sure about the diagnosis or if we have very little in the way of MRI findings, or if we have no evidence of lesions in the brain, then we know that these patients are at low risk to evolve [to CDMS],” explained Dr. Comi. “It is much better to clarify the position, to wait to repeat the MRI after six months or a year.”

Dr. Xavier Montalbán, Vall D’Hebrón University Hospital, Barcelona, Spain, who chaired this session on early treatment, expressed some concerns about treating MS at the CIS stage. The diagnosis might still be in question and/or some patients might be destined to have a benign disease course. When considering 15–20 years of therapy using a partially effective agent with known side effects, why not wait to ensure the disease is active? Furthermore, how might physicians ensure long-term compliance with regular injections? Finally, Dr. Montalbán indicated that disease-modifying therapies (DMTs) have not demonstrated a long-term effect in preventing disability or impairment.

According to Dr. Comi , the diagnosis was not generally in doubt. “The results of these three trials have clearly indicated that when we classify a patient with CIS as a high-risk MS patient we are seeing this type of definition in probably 95% of the cases, at least.” Benign MS is “very, very rare” affecting 7% to 8% of all patients. In any event, benign MS can only be diagnosed in retrospect, at the end of a patient’s life. In addition, even patients without severe physical disabilities usually have cognitive impairment. He also questioned the claim that DMTs had no long-term effects on disability: “The PRISMS study showed that patients who received the treatment in the first two years compared with patients who had the delayed treatment still, after two years, had a better condition…What we lose will never be recovered.”

Dr. Freedman added some reassuring information about long-term compliance with high-dose, high-frequency IFNb therapy. In both EVIDENCE (European North American Comparative Efficacy) and INCOMIN (Independent Comparison of Interferon) studies, “adherence was very high,” he said. Moreover, 96% of eligible patients reaching the end of BENEFIT chose to enter the follow-up study. Regarding long-term benefit, the results of the 16-year follow-up of the pivotal IFNb-1b study, presented elsewhere during the congress, demonstrate that lower EDSS scores at the start of therapy correlate with lower scores at follow-up and that more patients in the initial placebo group than in the treatment groups had died: 20 patients vs. nine and six, respectively, of those receiving 50 mcg and 250 mcg IFNb-1b. These findings suggest that early initiation of IFNb-1b therapy may indeed have a long-lasting impact on disease course in MS.