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60th Annual Meeting of the American Academy of Neurology

Chicago, Illinois / April 12-19, 2008

As clinical trials show that early therapy can delay progression of disease and potentially reduce disability, a movement toward initiating treatment even earlier, before multiple sclerosis (MS) develops, is gaining momentum. A new study in clinically isolated syndrome (CIS) revealed an effective new choice for preventing progression to clinically definite MS (CDMS).

PreCISe: Preventing Conversion to CDMS

Glatiramer acetate (GA) represents a new option for preventing MS before it develops, as reported by Prof. Giancarlo Comi, Department of Neurology, Universita Vita-Salute San Raffaele, San Raffaele Scientific Institute, Milan, Italy, and principal investigator of the PreCISe study. PreCISe was a randomized comparison of GA and placebo initiated shortly after the first clinical event suggestive of MS. The study was terminated earlier than originally planned because of an advantage of GA in preventing conversion to CDMS, a decision was based on the data obtained at the interim analysis. Some interferon beta (IFNß) preparations were previously shown to delay the development of CDMS. With the favorable finding with GA in PreCISe, “we now have a second potential treatment for early MS,” Prof. Comi stated.

The first presentation of an unpredictable, self-limited attack of neurologic dysfunction caused by focal or multifocal inflammatory demyelination within the central nervous system (CNS) is termed a CIS. It implies risk for future CNS attacks and development of relapsing-remitting MS (RRMS). The evidence that patients with CIS and white matter lesions on magnetic resonance imaging (MRI) are at high risk of MS is strong. The conversion rate of CIS to CDMS over two years in the placebo groups in therapeutic trials was 43% to 85%, depending on the outcome used.

PreCISe was a multinational, prospective, randomized trial of 481 patients presenting with a single clinical episode and an MRI scan suggestive of MS. Eligible patients had a single unifocal clinical attack in the 90 days prior to enrolment and a positive brain MRI (two or more T2-weighted lesions with a size <u>></u>6 mm) at screening.

The double-blind phase was scheduled for 36 months, during which patients were randomly assigned to subcutaneous (s.c.) GA 20 mg/day or placebo, unless a second attack was experienced and they were diagnosed with CDMS. During the double-blind phase, patients underwent brain MRI every three months. Patients who converted to CDMS continued the trial on active treatment for an additional two years. The primary efficacy endpoint was time to CDMS, based on a second clinical attack.

A pre-planned interim analysis was performed on data accumulated from approximately 80% of the three-year placebo-controlled study exposure. At the time of the interim analysis, the Data Safety and Monitoring Board recommended that the trial be stopped and that patients randomized to placebo be given the opportunity to receive GA. At the time the trial was stopped, the risk of conversion to CDMS was 24.7% in patients assigned to GA compared with 42.9% in those assigned to placebo, a relative risk reduction of 45% (P<0.0001) in the GA group. GA prolonged the quartile time to conversion to CDMS from 336 days for the placebo arm to 722 days (+115%, hazard ratio 0.56; P=0.0005) (Figure 1).

Figure 1. PreCISe Primary End Point: Risk Reduction to CDMS

“The effect [of GA] is significant and independent from the subtype of clinical presentations, T2 lesion load, and the presence of MRI active lesions,” Prof. Comi told delegates. GA was significantly superior to placebo in the total number of T2 lesions (P<0.001), the total number of T2 lesions at one year (P<0.001), the total number of T2 lesions at year 2 (P=0.021), and the number of new gadolinium (Gd)-enhancing lesions (P=0.001). The safety profile of GA in PreCISe was similar to the excellent tolerability observed in studies of RRMS. The overall withdrawal rate up to the interim analysis was 13%.

Results from BEYOND: The Largest Comparative Study in RRMS

A clinical trial in patients with early RRMS showed no advantage when comparing the investigational 500-µg dose of IFNß-1b and the approved 250-µg dose of IFNß-1b or GA 20 mg in reducing relapse risk. The purpose of the BEYOND (Betaferon/Betaseron Efficacy Yielding Outcomes of a New Dose) study was to determine whether treatment with IFNß-1b 500 µg was safe, tolerable, and more effective than treatment with IFNß-1b 250 µg, and whether treatment with IFNß-1b was more tolerable and effective than treatment with GA 20 mg.

BEYOND recruited 2244 treatment-naïve patients with an Expanded Disability Status Scale (EDSS) score of 0 to 5 and one or more relapses in the year prior to enrolment. The trial was unique in that the primary endpoint was the risk for recurrent relapses, and not annualized relapse rate. “We found no significant differences between any treatment group on the primary outcome measure,” reported BEYOND lead investigator Dr. O’Connor. Likewise, there were no differences between groups in the annualized relapse rates. Compared with the year before entry into the study, the annualized relapse rate in each treatment arm decreased by almost 80%. “Sixty per cent of patients in each group were relapse-free during the course of the study,” he added. Adherence was not significantly different between the three groups: dropout rates ranged from 13% (IFNß-1b 250 µg) to 19% (IFNß-1b 500 µg). Flu-like symptoms were more common in the IFNß-1b groups. Systemic reactions were more common in patients assigned to GA “but they reflect the host injection reaction that is known to occur with GA,” he noted. “BEYOND shows unequivocally the irreplaceable value of doing head-to-head studies vs. cross-comparing studies, which invariably involves looking at a slightly different population of patients using slightly different protocols, making it impossible to do an apples-to-apples comparison.”

The BEYOND study parallels the results of REGARD (Rebif vs. Glatiramer Acetate in Relapsing MS Disease), an earlier study in which IFNß-1a (44 µg s.c. three times weekly) and GA (20 mg once daily) were compared in 764 patients with RRMS. As reported previously, no difference was observed between the treatments in time to first relapse and relapse rates over two years. IFNß-1a had a greater effect on Gd-enhancing lesions but no difference was detected between the two treatments on new and enlarging T2 lesions.

“Choosing a therapy always involves a dialogue with the patient,” said Dr. O’Connor. “It may boil down to choosing different patterns of side effects. For some patients, avoidance of particular side effects is of paramount importance when efficacy is the same.” Some patients may prefer a treatment that requires injections three times a week over one that requires daily injection, he said. Others may want to avoid the flu-like symptoms that occur more often with IFNß preparations, he added.

REGARD: Results on Safety and Immunogenicity

Results were presented from a new safety analysis of the REGARD study. Findings indicated that tolerability was comparable, with similar frequencies of adverse events, serious adverse events, and discontinuations between the treatment groups. Treatment-emergent adverse events that were “probably” related to the study drug occurred in 33.6% and 32.2% of the patients receiving IFNß-1a and GA, respectively, noted Dr. Patricia Coyle, Stony Brook University Medical Center, New York, US. “Ninety-five percent of adverse events were mild to moderate in nature, and less than 0.5% in either arm were considered to be very serious.” Flu-like reactions, headache, myalgia, and an increase in ALT were significantly more common with IFNß-1a, whereas dyspnea and immediate post-injection reactions were significantly more common with GA. Adverse events leading to discontinuation were few: 6% in the IFNß-1a arm and 5.1% in the GA arm.

Of the patients with known antibody status, 33.7% in the IFNß-1a arm were neutralizing antibody (Nab)-positive at any time; of these, 19.0% seroconverted, leaving 27.3% of patients persistent Nab-positive at the last assessment. There was no effect of Nab-positivity on most outcomes.

In an attempt to put the comparative trials into perspective, Dr. Steven R. Schwid, University of Rochester, New York, remarked that the established first-line treatments for MS have more similarities than differences in their effects on MS disease activity. “They also show that side effects are comparable, even though each medication has its own unique issues,” he told delegates.

Effect of Neutralizing Antibodies

A small study suggests that among patients who develop Nabs to IFNß, switching to GA reduces relapse rates and increases the time to first relapse, reported Dr. Marco Capobianco, Centro di Riferimento Regionale Sclerosi Multipla and Neurobiologia Clinica, Orbassano, Turin, Italy. Nineteen patients with persistent Nab-positivity, abolition of IFNß biological activity, and low clinical disease activity (one relapse or fewer during the last year of IFNß treatment) were switched to GA and followed for at least 12 months. All of the patients were still IFNß Nab-positive during GA treatment.

Although not significant, the mean annualized relapse rate decreased slightly from 0.32 during the Nab-positive period on IFNß to 0.21 during GA treatment. Further, the percentage of patients who were relapse-free was greater during GA treatment (57.9% during 32.5 months of follow-up) than during the Nab-positive period during IFNß treatment (52.6% at 18.2 months of follow-up). A significant increase in the time to first relapse was observed in patients during GA treatment than during the Nab-positive period while on IFNß (50th percentile: 37.9 months vs. 17.8 months, respectively; P=0.0389).

Dr. Capobianco concluded that GA reduces disease activity in Nab-positive patients, and must be considered as alternative treatment in Nab-positive patients who show low disease activity.

Disease-modifying Therapies Reduce Brain Atrophy

A five-year imaging study in patients with early and mildly affected RRMS was carried out by Dr. Omar Khan, Department of Neurology, Detroit Medical Center, and colleagues. The study showed that disease-modifying therapies reduced brain atrophy compared with no treatment, but that GA was more efficacious than high-dose s.c. IFNß and low-dose intramuscular (i.m.) IFNß in reducing brain atrophy.

Treatment-naïve patients (n=275) with RRMS of less than five years duration who were started and remained on the same therapy had brain MRI scans at onset of therapy and again five years later.

The mean annualized rate of brain atrophy was -0.46% in the GA group, which was significantly less than the -0.52% in the low-dose IFN group (P=0.00336) and the -0.64% in the high-dose IFN group (P<0.0001). All three treatment groups had a significantly lower annualized rate of brain atrophy than the untreated controls (P<0.0001).

“Long-term assessment of brain atrophy in early RRMS patients shows that all disease-modifying therapies are effective in reducing the rate of brain atrophy compared to no treatment; however, brain atrophy continued to accumulate despite five years of continuous therapy in all three treatment groups, indicating a partially therapeutic effect of currently available disease-modifying therapies and the need to develop improved therapeutic strategies, ” researchers reported. “Among the three therapies compared in our study, GA had the best effect in reducing the rate of brain atrophy over five years, which was significantly better than IFNß i.m. or s.c. These observations were sustained even after adjusting for brain volume changes in the first year [pseudo atrophy],” they concluded.

Altering Therapy After Disease Progression

In patients with progressive-relapsing MS despite IFNß treatment, induction therapy with mitoxantrone followed by GA monotherapy offers an effective alternative to avoid relapse and reduce disability progression, according to investigators from Hospital Británico de Buenos Aires, Argentina.

The investigators compared the effect of continuing treatment only with IFNß-1b (controls; n=70) to switching to one of two protocols in which induction with mitoxantrone (monthly or every three months) and methylprednisolone was followed by GA monotherapy (n=14) in patients who had disability progression while on IFNß-1b.

After a mean follow-up of 7.3 years, the annual relapse rates were not significantly different between the two treatment groups but mean EDSS scores were significantly better (P<0.001) in the induction group compared with the controls. EDSS scores worsened in 36.2% of the control group compared with 14.2% of the induction group. Stable or improved EDSS scores were observed in 63.8% of the controls and 85.6% of the induction group, with slightly better results with the monthly mitoxantrone induction regimen.

AFFIRM and SENTINEL: Reducing Disease Severity on the MS Severity Scale

Natalizumab was able to reduce disease severity on the MS Severity Scale (MSSS) in RRMS patients enrolled in the AFFIRM (Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis) and SENTINEL (Safety and Efficacy of Natalizumab in Combination with IFNß-1a in Patients with Relapsing Remitting Multiple Sclerosis) studies, according to data provided by Dr. Joseph Herbert, MS Comprehensive Center, New York University Hospital for Joint Diseases, New York.

Because the MSSS relates disability to duration of disease, it may be a more sensitive measure of disease progression than traditional outcomes, he explained, and thus may be a useful outcome to include in MS clinical studies. “We often talk about change in EDSS scores but we forget to take into account how long the patient has had the disease,” remarked Dr. Herbert. “We have a much more certain reflection of disease severity by taking into account duration of disease.”

In both AFFIRM and SENTINEL, investigators found that the change from baseline in median MSSS scores was greater in natalizumab-treated patients compared with placebo. In AFFIRM, the natalizumab group experienced an improvement of 0.68 points on the MSSS compared with a 0.38 improvement in the placebo recipients (P<0.001), and in SENTINEL, the improvements were 0.56 and 0.34 in the natulizumab and placebo groups (P<0.001), respectively. In the analysis, patients were assigned to one of six severity groups based on their MSSS scores at baseline. In both studies, more patients treated with natalizumab shifted to a lower severity group than the placebo groups (AFFIRM: 46% vs. 37%; SENTINEL: 41% vs. 34%), and fewer shifted to a higher disease severity group (AFFIRM: 10% vs. 20%; SENTINEL: 15% vs. 19%).

Other Monoclonal Treatment Strategies

A phase II study of alemtuzumab showed that it significantly reduced the rate of relapse over three years compared with IFNß-1a 44 µg s.c. three times weekly in patients with treatment-naïve RRMS, but may induce immune thrombocytopenic purpura (ITP). Alemtuzumab is a humanized monoclonal antibody targeting the CD52 antigen on lymphocytes and monocytes. In the multicenter CAMMS223 trial, 334 RRMS patients within the first three years of disease onset and with one or more Gd-enhancing lesions on MRI screening were randomized to IFNß-1a or a high (24 mg/day) or low (12 mg/day) dose of alemtuzumab.

The annual relapse rate at three years was 0.10 for the pooled alemtuzumab group compared with 0.36 for the IFNß-1a group, corresponding to a 73% reduction in risk (P<0.0001) with alemtuzumab. “The difference emerged early and was maintained, if not amplified, during the course of the study,” reported lead investigator Dr. Alasdair Coles, Senior Lecturer, Neurology Unit, University of Cambridge, UK. Further, the time to sustained accumulation of disability was reduced by 71% with alemtuzumab vs. IFNß-1a (P<0.0001). The EDSS scores worsened by 0.39 points from baseline in patients assigned to IFNß-1a whereas it improved by 0.38 points in those assigned to alemtuzumab (P<0.0001 between groups). “The improvement seen in disability is unprecedented” in a clinical trial in RRMS, noted Dr. Coles.

Six of 216 patients on alemtuzumab developed ITP, one of which was fatal, compared with one of 107 patients treated with IFNß-1a. Also, 16% of patients treated with alemtuzumab developed autoimmune thyroid disease. Infections were also significantly more common in the alemtuzumab recipients.