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

Montreal, Quebec / September 17-20, 2008

The availability of disease-modifying therapies (DMTs) for multiple sclerosis (MS) over the past decade has led to advances in the management of this disorder. Specifically, DMTs have reduced the frequency of relapses and slowed disease progression.

The newest thinking is that identifying patients after a first neurological episode, called a clinically isolated syndrome (CIS), provides an opportunity to intervene in MS at an earlier stage in appropriate (high-risk) patients. Of note, the effect of first-line therapies is greatest when they are used at disease onset rather than waiting for a more advanced disease stage. Clinical, radiological and histological evidence support the early treatment of MS with DMTs.

Cumulative Data to 15 Years: Maintenance of Benefit on Disability

Continuous, long-term use of GA in patients with relapsing-remitting MS (RRMS) remains effective in preventing relapses, slowing disease progression, and preserving ambulation, according to multiple long-term studies. One such study—the US Prospective Open-label Study of Glatiramer Acetate—has followed a group of patients on continuous GA for as long as 15 years. One hundred of 232 patients who were ever exposed to GA at least once since the beginning of this study represented the focus of the investigation. In this ongoing cohort, the mean duration of GA exposure was 13.6 years.

“Pivotal trial data usually goes out to two years in a disease that can last 50 years. So how do we know where the future lies for these people unless we try to follow them over the long term? This is an attempt to do that in a prospectively designed way,” stated lead investigator Dr. Corey Ford, Department of Neurology, University of New Mexico School of Medicine, Albuquerque. “This is the longest prospectively-designed, long-term follow-up study that we currently have. These patients have been followed since they were entered into the original trial in 1991, and followed every six months at the same center. They are only on GA; if they change drugs or drop out for other reasons, they are no longer counted in this ongoing group.”

The mean Expanded Disability Status Score (EDSS) was 2.5 at the start of GA and 3.1 at the last observation. While on GA, the proportion of patients reaching a mean EDSS of 4, 6, and 8 was 38%, 18%, and 3%, respectively. Fifty-seven percent of the ongoing cohort had improved or stable EDSS scores. The estimated time for one quartile of patients to reach an EDSS of 4 was 6.8 years.

“Patients who stay on the drug and tolerate it—and obviously they do tolerate it if they can stay on it for 15 years—do quite well,” Dr. Ford told delegates. “Not everybody responds over that length of time but a large percentage of the group does. As a group, their accumulation of disability and progression is slower than we see from studies of the natural history of the disease. For example, only about half as many as the natural history would predict reach an EDSS of 6, which means needing a cane to walk. Their disability scores on average are staying pretty much the same and two-thirds have not made a transition to secondary progressive [SP] MS.”

High Adherence, Reduction in Relapses Over Eight Years

In her examination of four immunomodulatory therapies in patients with early RRMS, Dr. Judith Haas, Department of Neurology, Jewish Hospital, Berlin, Germany, found the long-term efficacy and adherence to GA remained favorable at eight years. She assessed a database of 285 patients treated in daily clinical practices with either intramuscular (i.m.) interferon beta (IFNß)-1a , IFNß-1b s.c., IFNß-1a s.c. or GA. “The longer the observation period is, the more important becomes another parameter: adherence to the treatment,” she observed. “In long-term treatment, not side effects but lack of efficacy is the most frequent reason for discontinuing, switching, or escalating a therapy.”

After eight years, 29.1% of the patients treated with GA were still adhering to their initial treatment, compared with 13.8% of those initially treated with IFNß-1a i.m. (P=0.02), 18.2% of those initially treated with IFNß-1b s.c. (P=NS), and 18.4% of those initially treated with IFNß-1a s.c. (P=NS). A switch of therapy was the most frequent reason for dropping out in patients treated with IFNßs (range: 61.4% to 71.4%), whereas it was loss to follow-up in patients treated with GA. The frequency of escalation therapy was not significantly different between the four groups.

Each therapy was associated with a significant reduction in mean annual relapse rates after eight years of continuous treatment compared with the two years prior to beginning therapy. Patients treated with GA experienced the lowest annual relapse rate of the four therapies at any time point, and these patients had a significantly lower relapse rate than those treated with IFNß-1a s.c. at four and eight years.

There were no significant differences between treatments in change of EDSS scores out to eight years. “Freedom from progression was declining slightly within the course of time in all four treatment groups. However, in patients treated with GA, the percentage of patients without progression was greater than 84% after 96 months, whereas it amounted to approximately 75% in the IFN treatment groups, although not significantly different,” she reported.

Due to a positive selection of patients remaining longer on the initial treatment, differences between treatment groups are becoming smaller with time, according to Dr. Haas. “However, GA was still significantly superior to IFNß-1a s.c. regarding the relapse rate after 48 and 96 months of treatment,” she said.

The findings from this long-term study “may give useful hints for the selection of the initial immunomodulation therapy,” according to Dr. Haas.

Stabilizing MS

Long-term treatment with GA after mitoxantrone induction in patients with rapidly progressive MS maintains disease stability, said Dr. Yasmin Handouk, Department of Neuroscience, Clinica Neurologica, Ospedali Riuniti, Ancona, Italy. Dr. Handouk and colleagues compared annualized relapse rates, EDSS scores, and brain MRI scans in 12 patients with either progressive-relapsing MS or worsening RRMS who were treated with mitoxantrone every three months up to a maximum cumulative dose of 140 mg/m² (mean treatment period of 17.4 months); six of the patients then received maintenance treatment with GA and the other six patients received no further treatment.

After two years, the GA-treated patients had a mean annualized relapse rate of 0.2, compared with 2.8 during the two years before mitoxantrone therapy (P=0.009). The mean EDSS score declined from 5.4 pre-treatment to 4.4 after two years of GA (P=0.34), and lesion load was similar on brain MRI before and two years after treatment. In contrast, patients who did not receive GA had no significant reduction in their annualized relapse rate (pretreatment mean of 1.1 vs. 0.25 after two years; P=0.1), and their mean EDSS score was unchanged (P=0.1) compared with pre-treatment. Further, two of the untreated patients had gadolinium (Gd)-enhancing lesions identified on brain MRI.

Standardized Protocol Suppresses Disease Activity

In active RRMS, a protocol of mitoxantrone induction followed by overlapping GA, and then GA alone, suppressed clinical disease activity and minimized the dose-related effects of immunosuppression, reported Dr. Jason Ramtahal, The Walton Center for Neurology and Neurosurgery NHS Trust, Liverpool, UK. Enthusiasm for the use of mitoxantrone in the treatment of RRMS has been tempered by the potential for significant dose-related toxicity, cautioned Dr. Ramtahal.

His protocol in RRMS patients is mitoxantrone induction therapy alone for three months at a dosage of 12 mg/m² followed by initiation of GA. The fourth and fifth doses of mitoxantrone are given at 6 mg/m² at month 5 and month 8, after which the patient is treated with GA alone.

Dr. Ramtahal discussed his center’s experience in treating 77 patients with RRMS who were treated with mitoxantrone/GA with more than one year of follow-up. Fifty-eight of the patients were treated with the protocol described above. “The remainder, largely the earlier treated patients, received somewhat higher total doses before we standardized the treatment protocol,” he said.

The mean follow-up from initiation of mitoxantrone was 44 months (range: 20 to 90 months); 33 months on GA monotherapy. The annualized relapse rate declined from 1.85 to 0.16 or less, which was sustained up to six years of follow-up. The mean EDSS score was improved or stable in 91%. Three patients developed SPMS. Regarding safety, one patient developed therapy-related leukemia.

Sustained Benefits on MRI Endpoints

A brief immunosuppression with mitoxantrone prior to starting GA resulted in sustained benefits at 36 months on MRI markers of focal white matter inflammation and injury, reported Dr. Douglas L. Arnold, Montreal Neurological Institute, Quebec, Canada.

MRI outcomes were measured in 29 patients with RRMS who received either induction therapy with open-label i.v. mitoxantrone for two months (cumulative dose: 36 mg/m2) followed by daily GA for 12.5 months or GA alone. The patients were followed for an additional 21 months in an open-label observational extension.

The cumulative number of Gd-enhancing lesions from months 6 to 36 was 1.33 in the mitoxantrone/GA group, compared to 11.47 in the GA-alone group (P=0.02). The cumulative volume of Gd-enhancing lesions was also lower in the GA/mitoxantrone group compared to the GA-alone group (0.06 mL vs. 1.20 mL; P=0.02).

The percent change in the volume of T2 lesions was significantly lower in the mitoxantrone/GA group vs. the GA-alone group (-9.17% vs. 10.16%; P=0.01).

The proportion of Gd-enhancing lesions at baseline that evolved into chronic black holes was lower in the mitoxantrone/GA group compared to the GA-alone group (31% vs. 45%). The proportion of Gd-enhancing lesions that evolved on treatment was also lower in the mitoxantrone/GA group vs. the GA-alone group (27% vs. 9%; P=0.06).

MRS, MRI Data Support Clinical Benefit

Early treatment with GA reduced axonal injury in patients with CIS, said Dr. Arnold, who presented data from a subgroup of patients in the PreCISe trial who underwent magnetic resonance spectroscopy (MRS).

PreCISe was a multinational, prospective randomized trial of 481 patients presenting with a single clinical episode and a MRI scan suggestive of MS. Eligible patients had a single unifocal clinical attack in the 90 days prior to enrollment and a positive brain MRI (³2 T2-weighted lesions with a size ³6 mm) at screening.

The double-blind phase was scheduled for 36 months, during which patients were randomly assigned to s.c. GA 20 mg/day or placebo, unless a second attack was experienced and they were diagnosed with CDMS. An interim analysis was specified in the protocol, planned for when approximately 80% of the 3-year placebo-controlled study exposure was accumulated. At the time of this pre-planned interim analysis, which occurred at 2.4 years, the double-blind portion of the trial was halted due to a significantly favorable effect of GA on reducing conversion to CDMS.

At the time the double-blind portion of the trial was stopped (after which all patients were offered to continue on active treatment for future follow-up), the risk of conversion to CDMS was 24.7% in the patients assigned to GA compared with 42.9% in those assigned to placebo, a relative risk reduction of 45% (P<0.0001) in the group randomized to GA.

The MRS substudy included 34 patients, with the purpose of examining the neuroprotective effect of GA based on N-acetylspartate (NAA) density, which is a measure of neuro-axonal integrity. NAA is synthesized exclusively by neuronal mitochondria. The MRS protocol consisted of acquiring spectra at 12 and 24 months from a single voxel centered on the corpus callosum.

At 12 months, the placebo arm experienced a reduction of 0.33 in paired changes in NAA relative to creatine, whereas this measure increased by 0.14 in the GA arm (P=0.03). At 24 months, these changes were maintained but the difference between the two groups lost statistical significance (P=0.15). There was no significant difference between the two groups in brain atrophy at either time point.

The MRS substudy suggests that “GA reduced axonal injury and helped to preserve neurons even at the earliest stage of MS [after a single attack],” said Dr. Arnold. “MRS was more sensitive than atrophy in detecting neuronal integrity,” presumably because neuro-axonal injury was still largely sublethal at this early stage of disease.

Secondary endpoints in PreCISe revealed a favorable effect of early treatment with GA when examined by MRI metrics. Patients assigned to active therapy experienced a significant reduction in the cumulative number of T2-weighted lesions compared with placebo at the last observed value of the placebo-controlled phase (P<0.0001). Further, GA was associated with significant reductions in the number of T1 Gd-enhancing lesions (P<0.0001) and the number of new T1 hypointense lesions (P<0.0001) when assessed annually.

PreCISe Subgroup Analysis

Subgroup data from PreCISe demonstrated significant reductions in the primary endpoint (conversion to CDMS) across subpopulations based on gender, age, corticosteroid use and MRI disease activity at baseline, according to Prof. Giancarlo Comi, Department of Neurology, Universita Vita-Salute San Raffaele, San Raffaele Scientific Institute, Milan, Italy.

The risk of achieving the primary endpoint with GA treatment (compared with placebo) was reduced by 48% in women (P=0.0037) and by 53% in patients younger than 30 years (P=0.006). GA treatment had a significant effect in reducing the risk of conversion to CDMS in patients whether or not they took corticosteroid treatment for the initial attack.

MRI disease activity was also suppressed by GA: patients with one or more T1 Gd-enhancing lesions at baseline had a 71% reduction in risk of conversion to CDMS if treated with GA (P<0.0001) and patients with nine or more T2 lesions at baseline had a 58% relative risk reduction with GA treatment (P<0.0001).

This subgroup analysis indicates a robust effect of GA across the entire study population, including those with and without MRI-active disease, less clinical or MRI disease dissemination at baseline, and patients not receiving steroids for CIS.

Anti-inflammatory Mechanism

New research demonstrates the presence and functionality of GA Th2 cells in the central nervous system (CNS) of humans with MS. Previously, the presence of GA Th2 cells was documented only in an animal model of MS, the experimental autoimmune encephalomyelitis mouse, and this finding has finally been extended to patients with MS, supporting an anti-inflammatory mechanism of GA in the CNS, according to Dr. Trygve Holmoy, Institute of Immunology, University of Oslo, Norway.

The data he presented showed that GA treatment for three to six months induced Th2 polarization in both cerebrospinal fluid (CSF) and blood, compatible with the notion that a Th2 shift is induced in the periphery and that a subpopulation of GA-reactive T cells subsequently gains access to the CNS.

Of note, GA-reactive T cells from CSF were more Th2 biased than were GA-reactive T cells from blood, possibly reflecting that GA induces Th2 skewing earlier in the CSF than in blood, or a preferential migration of strongly Th2-biased T cells to the CSF.

Dose Efficacy in RRMS

In patients with definite MS (RRMS), a study comparing a higher dose of GA (40 mg) than the currently approved dose (20 mg) showed that the two doses were equally effective in reducing the rate of clinical relapse and the number of T1 Gd-enhancing lesions, stated Prof. Comi in presenting the results of the FORTE study. “Both doses demonstrated remarkable reduction compared to baseline in clinical and MRI activity,” he told delegates.

The study, conducted at 136 centers worldwide, included 1155 patients with definite MS who had at least one documented relapse in the 12 months prior to screening or two documented relapses in the 24 months prior to screening. They were randomized to 20 mg or 40 mg of GA and followed for 12 months.

The mean annualized rate of confirmed relapses on an intent-to-treat basis was 0.33 in the group randomized to 20 mg and 0.35 in those randomized to 40 mg (P=0.4859). In assessing only study completers (534 in the 20-mg group and 490 in the 40-mg group), the mean annualized relapse rate was identical in each group (0.27). The proportion of relapse-free individuals was 77.6% in the 20-mg arm and 77.0% in the 40-mg arm.

Both doses reduced the mean number of T1 Gd-enhancing lesions and new T2 lesions over time, with a trend toward a faster reduction in the group assigned to 40 mg. Brain atrophy was reduced by 0.58% and 0.53% in the 20-mg and 40-mg dose groups, respectively.

Both doses were well tolerated. The safety profile was similar to that observed in previous studies of GA 20 mg; treatment discontinuation was higher with the higher dose due to more frequent injection-site reactions.

Symptomatic Improvements

Spasticity in MS is often worsened by treatment with IFNß; data from a pilot study suggest that GA can reduce the frequency of spasms in patients previously treated with IFNßs, revealed Dr. Jose Mecca-Lallana, Unidad de Esclerosis Multiple, Hospital Universitario Virgen de la Arrixaca, Murcia, Spain.

The percentage of patients treated with IFNß who report increased spasticity ranges from 13% to 18%, with no clear difference between the IFNs, noted Dr. Mecca-Lallana. He evaluated spasticity evolution in 11 patients with MS who switched from IFNß to GA due to lack of efficacy or adverse effects. Total follow-up was 18 months.

The frequency of spasms was reduced from 2.0 before the switch to 0.27 after switching to GA (P=0.002). The rating of the Ashworth Scale on the right side was reduced from 1.85 to 1.18 (P=0.002) and on the left side from 1.86 to 1.27 (P=0.0449). The Global Pain Rating Scale also declined from 47.69 to 24.09 (P=0.002).

Fatigue is a common symptom in MS, and GA appears to exert a beneficial effect in some patients with RRMS and fatigue, according to findings from an open-label trial conducted by Dr. Oliver Neuhaus, Department of Neurology, Kliniken Landkreis-Sigmaringen, Sigmaringen, Germany.

Thirty patients with RRMS and fatigue were treated with GA for 12 months; 25 of the patients completed fatigue self-assessments before and after 12 months of treatment. On the Visual Analog Scale (VAS) of pain (0=no fatigue, 10=maximum fatigue), the mean score decreased from 6.17 at baseline to 4.69 after 12 months of GA. There was a trend toward improvement on the Fatigue Severity Scale (FSS) and no significant effect found on the MS-FSS.

The Modified Fatigue Impact Scale showed significant improvement in the social subscore and a trend toward improvement on the total score and physical subscore, with no effect on the cognitive subscore. The quality-of-life score on the VAS improved from 57.7 at baseline to 67.7 (P=0.0223) at the last follow-up visit (0=worst; 100=best imaginable health state).