Clinical Trial Results and Other Research News From ECTRIMS/ACTRIMS

The following brief reports summarize some of the findings presented at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). Additional coverage of the ECTRIMS/ACTRIMS meeting can be found online at www.neurologyreviews.com and in upcoming issues of Neurology Reviews.

BG-12: Data From the Phase 3 DEFINE Trials
AMSTERDAM—Results from a large phase 3 trial support the potential of BG-12 (dimethyl fumarate) as an effective oral treatment for patients with relapsing-remitting multiple sclerosis (MS). According to researchers, BG-12 may have dual anti-inflammatory and neuroprotective effects via the Nrf2 pathway.

DEFINE was a randomized, double-blind, placebo-controlled, multicenter trial that evaluated the efficacy and safety of BG-12 over two years in patients with relapsing-remitting MS. Patients ages 18 to 55 with relapsing-remitting MS and an Expanded Disability Status Scale (EDSS) score of 0 to 5 (inclusive) were randomly assigned to placebo, BG-12 240 mg BID, or BG-12 240 mg TID.

All patients underwent clinical assessments at screening, baseline, and every four weeks for up to two years. The primary end point was proportion of patients relapsing at two years. Secondary efficacy end points at two years were annualized relapse rate and disability progression as measured by EDSS score.

A total of 1,234 patients were randomized—408 received placebo, 410 received BG-12 BID, and 416 received BG-12 TID. All primary and secondary end points were met. BG-12 BID and TID reduced the risk of relapse by 49% and 50%, respectively, compared with placebo at two years. Annualized relapse rate was 0.36 with placebo, and 0.17 and 0.19 with BG-12 BID and TID, corresponding to reductions of 53% and 48% for BG-12 BID and TID. The risk of confirmed 12-week disability progression was reduced by 38% for the BID dosing and by approximately 34% with TID dosing.

The overall incidence of adverse and serious adverse events was similar among the three groups.

Alemtuzumab: Phase 3 CARE-MS I Data Released
Results of a head-to-head comparison of alemtuzumab and interferon beta-1a have shown that 78% of patients with relapsing-remitting MS treated with alemtuzumab remained relapse-free for two years, compared with 58% of patients taking interferon beta-1a.

The phase 3 CARE-MS I trial compared alemtuzumab (12 mg/d IV for five days with a second 3-day IV administration one year later) to treatment with interferon beta-1a (44 mcg SC injection 3 times per week) in 581 patients with relapsing-remitting MS who had had no previous MS treatment except steroids.

Additional findings include other secondary end points that suggest positive outcomes with alemtuzumab. Improvement in the Multiple Sclerosis Functional Composite (MSFC) score was observed in alemtuzumab-treated patients compared with interferon beta-1a–treated patients (0.12 vs 0.05, mean change from baseline at year 2). Reduction in T2-hyperintense lesion volume with alemtuzumab compared to interferon beta-1a was -9.3 versus -6.5 (median percent change at year 2). Statistically significant improvement was observed for alemtuzumab versus interferon beta-1a in the percentage of patients with new enlarging T2-hyperintense lesions (49% vs 58%), with new gadolinium-enhancing lesions (15% vs 27%), and with new T1-hypointense lesions (24% vs 31%). Alemtuzumab-treated patients also experienced less change in brain parenchymal fraction compared to interferon beta-1a (-0.87 vs -1.49, median change from baseline).

Common adverse events associated with alemtuzumab in the CARE-MS I trial were infusion-associated reactions that were mild to moderate. The incidence of infection was increased, with the most common infections involving the upper respiratory and urinary tract and oral herpes. Infections were mild to moderate, and none were life-threatening or fatal.

Serious adverse events were similar between both groups (18.4% for alemtuzumab and 14.4% for interferon beta-1a). Just over 18% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event, and 0.8% developed immune thrombocytopenia during the two-year study period. Cases of autoimmunity were detected and managed using conventional therapies.

Daclizumab: Phase 3 SELECT Trial Results Released
Monthly subcutaneous daclizumab monotherapy demonstrated a robust and clinically meaningful effect on MS activity, including evidence for early impact on disability progression, according to phase 3 data that were presented.

Researchers randomized 600 patients with relapsing-remitting MS and at least one MS relapse in the prior 12 months or one new gadolinium-enhancing lesion in the prior six weeks to receive low-dose daclizumab (150 mg), high-dose daclizumab (300 mg), or placebo as a subcutaneous injection once every four weeks for 52 weeks.

A total of 559 patients (93%) completed the treatment period. Annualized relapse rate, the study’s primary end point, was 0.21 for low-dose daclizumab, 0.23 for high-dose daclizumab, and 0.46 for placebo. The proportion of relapse-free patients was 81% in the low-dose group, 80% in the high-dose group, and 64% in the placebo group. There were significant reductions in the mean number of new or newly enlarging T2 lesions at one year (2.4 for low dose, 1.7 for high dose, and 8.1 for placebo). Among 309 patients in an MRI substudy, the mean number of new gadolinium-enhancing lesions between weeks 8 through 24 was 1.5 for low-dose daclizumab, 1.0 for the high-dose group, and 4.8 for placebo. The risk of three-month sustained disability progression at one year was reduced by 57% in the low-dose group and by 43% in the high-dose group.

Serious adverse events, excluding MS relapses, occurred in 5% of the placebo group, 6% of the low-dose group, and 8% of the high-dose group. One daclizumab-treated patient died due to a complication of a psoas abscess. Serious adverse events in the daclizumab-treated patients included an increase in serious infections (2%), serious cutaneous events (1%), and elevations in liver function tests (4%).

Clinical and MRI Outcomes in Patients With MS Treated With Fingolimod
Fingolimod at an oral dose of 0.5 mg consistently improved relapse rates, disability, and MRI outcomes compared with placebo or IM interferon beta-1a in all patient subgroups with active relapsing-remitting MS, investigators reported.

Eva Havrdová, PhD, from the Department of Neurology, First Faculty of Medicine, Charles University, Prague, and colleagues reported the results of post hoc analyses from FREEDOMS and TRANSFORMS in three patient subgroups: 1) patients who received interferon beta in the year before study entry and had equal or more relapses in the year immediately before the study than in the year two years before the study; 2) patients who received interferon beta in the year before study entry and had at least one relapse in the previous year plus at least one gadolinium-enhancing T1 lesion or nine T2 lesions at baseline; or 3) treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

In FREEDOMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with placebo in all three subgroups. In TRANSFORMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with IM interferon beta-1a in groups 1 and 2. Results in group 3 (n = 27) did not reach statistical significance. In both studies fingolimod reduced the risk of disability progression versus placebo and interferon beta-1a in all subgroups.

The researchers concluded that fingolimod (0.5 mg) improved clinical outcomes compared with placebo or IM interferon beta-1a in patients with relapsing-remitting MS with high disease activity despite previous treatment and in treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

Laquinimod: A Potential Novel Oral Agent for Relapsing-Remitting MS
Both preclinical and clinical data suggest that the oral immunomodulator laquinimod holds promise for patients with relapsing-remitting MS, according to investigators.

Giancarlo Comi, MD, Professor and Chairman of the Department of Neurology and Director of the Institute of Experimental Neurology at Vita-Salute San Raffaele University, Scientific Institute San Raffaele Milan, reported that a phase 2 study demonstrated reductions of MRI-active lesions, a trend for slowing the rate of MRI-measured brain volume loss, and a favorable safety and tolerability profile. Dr. Comi also summarized findings from the multicenter, randomized, double-blind, placebo-controlled Allegro trial. In the phase 3 trial, patients received a once-daily oral dose of 0.6 mg laquinimod or placebo for 24 months.

The study met the primary end point, with laquinimod achieving a decrease in relapse rate (23% reduction). The risk for EDSS disability progression was significantly reduced (36%) compared with placebo. Rate of brain atrophy progression was reduced by 33% at month 24.

Laquinimod was well-tolerated. Adverse events were similar in both groups, with the exception of transient, reversible elevations of liver enzymes without concomitant signs of liver dysfunction in the laquinimod group.

Dr. Comi also provided an advance glimpse of findings from the BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod) study. The profile of reduced annualized relapse rate, MRI-active lesions, brain-volume loss, and EDSS was similar to that seen in the Allegro study.

Teriflunomide: A Promising New Oral Therapy for Patients With Relapsing-Remitting MS
Data from TEMSO, the first pivotal phase 3 trial of teriflunomide, were reported by Paul O’Connor, FRCPC, MSc.

The two-year, double-blind study found a significant reduction in annualized relapse rates with both the 7-mg and 14-mg doses of teriflunomide compared with placebo, as well as a significant reduction in the risk of sustained disability progression in the higher dose group. Both doses showed good safety and tolerability in patients with relapsing-remitting MS. Both doses were superior to placebo on a range of MRI end points in a dose-dependent fashion.

A long-term extension of TEMSO showed that teriflunomide was well tolerated with a favorable safety profile up to six years following randomization, with no unexpected adverse events related to long-term treatment.

Dr. O’Connor, Professor of Medicine at the University of Toronto and Director of the MS Clinic at St. Michael’s Hospital in Toronto, also discussed results from an extension of the phase 2 study of teriflunomide, which has provided information on up to nine years of teriflunomide treatment. Clinical and MRI disease activity remained low during the course of this extension and treatment-related adverse events were similar to those in the initial 36-week double-blind trial.

Both the extension of the phase 2 trial and an extension of the TEMSO trial reported minimal clinical and MRI activity. A trend toward greater benefit on both clinical and MRI parameters was seen in patients who were continually treated with teriflunomide compared with placebo-treated patients who were switched to active treatment.

Natalizumab-Associated PML Survival Rates Exceed 80%
Early diagnosis through the enhanced clinical vigilance and optimal management of progressive multifocal leukoencephalopathy (PML) may improve outcomes, according to researchers.

Survival rates in excess of 80% were seen in the first 133 postmarketing natalizumab-associated PML cases, reported Ludwig Kappos, MD, from the Departments of Neurology and Biomedicine, University Hospital, Basel, Switzerland, and colleagues. Improved survival was associated with younger age (median, 43 vs 51.5) and less disability (median EDSS, 4.0 vs 5.5) at diagnosis, shorter time from symptom onset to diagnosis (mean, 40 vs 53 days), and more localized disease on brain MRI, as compared with fatal cases.

Of 159 PML cases identified in the postmarketing setting, 130 patients were still alive as of September 1, 2011 (82% survival rate). In survivors with more than six months of follow-up, 13% had mild disability, 47% had moderate disability, and 40% had severe disability.

Higher Vitamin D Levels Are Associated With Fewer Brain Lesions
Vitamin D levels are inversely associated with the risk of MS activity on brain MRI, according to researchers.

Begun in 2004, EPIC is a five-year longitudinal MS cohort study that sought to determine if vitamin D status is associated with the development of new T2 lesions or contrast-enhancing lesions on brain MRI in a cohort of patients with clinically isolated syndrome (CIS) or relapsing-remitting MS. Participants had clinical evaluations, brain MRI, and blood draws annually.

From the overall cohort, researchers evaluated patients who had a diagnosis of CIS or relapsing-remitting MS at baseline visit. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking status, and the use of MS treatments) models, annual 25-hydroxyvitamin D3 levels were evaluated for their association with the development of new T2-weighted lesions and gadolinium-enhancing T1-weighted lesions on brain MRI as well as with the occurrence of clinical relapses of MS.

A total of 469 subjects were studied and 2,362 3T brain MRI scans were acquired and analyzed. In multivariate analyses, each 10-ng/mL higher 25-hydroxyvitamin D3 level was associated with a 15% lower risk of developing a new T2 lesion and a 32% lower risk of a gadolinium-enhancing lesion. Higher vitamin D levels were associated with a lower relapse risk, although the association did not reach statistical significance.

The following brief reports summarize some of the findings presented at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). Additional coverage of the ECTRIMS/ACTRIMS meeting can be found online at www.neurologyreviews.com and in upcoming issues of Neurology Reviews.

BG-12: Data From the Phase 3 DEFINE Trials
AMSTERDAM—Results from a large phase 3 trial support the potential of BG-12 (dimethyl fumarate) as an effective oral treatment for patients with relapsing-remitting multiple sclerosis (MS). According to researchers, BG-12 may have dual anti-inflammatory and neuroprotective effects via the Nrf2 pathway.

DEFINE was a randomized, double-blind, placebo-controlled, multicenter trial that evaluated the efficacy and safety of BG-12 over two years in patients with relapsing-remitting MS. Patients ages 18 to 55 with relapsing-remitting MS and an Expanded Disability Status Scale (EDSS) score of 0 to 5 (inclusive) were randomly assigned to placebo, BG-12 240 mg BID, or BG-12 240 mg TID.

All patients underwent clinical assessments at screening, baseline, and every four weeks for up to two years. The primary end point was proportion of patients relapsing at two years. Secondary efficacy end points at two years were annualized relapse rate and disability progression as measured by EDSS score.

A total of 1,234 patients were randomized—408 received placebo, 410 received BG-12 BID, and 416 received BG-12 TID. All primary and secondary end points were met. BG-12 BID and TID reduced the risk of relapse by 49% and 50%, respectively, compared with placebo at two years. Annualized relapse rate was 0.36 with placebo, and 0.17 and 0.19 with BG-12 BID and TID, corresponding to reductions of 53% and 48% for BG-12 BID and TID. The risk of confirmed 12-week disability progression was reduced by 38% for the BID dosing and by approximately 34% with TID dosing.

The overall incidence of adverse and serious adverse events was similar among the three groups.

Alemtuzumab: Phase 3 CARE-MS I Data Released
Results of a head-to-head comparison of alemtuzumab and interferon beta-1a have shown that 78% of patients with relapsing-remitting MS treated with alemtuzumab remained relapse-free for two years, compared with 58% of patients taking interferon beta-1a.

The phase 3 CARE-MS I trial compared alemtuzumab (12 mg/d IV for five days with a second 3-day IV administration one year later) to treatment with interferon beta-1a (44 mcg SC injection 3 times per week) in 581 patients with relapsing-remitting MS who had had no previous MS treatment except steroids.

Additional findings include other secondary end points that suggest positive outcomes with alemtuzumab. Improvement in the Multiple Sclerosis Functional Composite (MSFC) score was observed in alemtuzumab-treated patients compared with interferon beta-1a–treated patients (0.12 vs 0.05, mean change from baseline at year 2). Reduction in T2-hyperintense lesion volume with alemtuzumab compared to interferon beta-1a was -9.3 versus -6.5 (median percent change at year 2). Statistically significant improvement was observed for alemtuzumab versus interferon beta-1a in the percentage of patients with new enlarging T2-hyperintense lesions (49% vs 58%), with new gadolinium-enhancing lesions (15% vs 27%), and with new T1-hypointense lesions (24% vs 31%). Alemtuzumab-treated patients also experienced less change in brain parenchymal fraction compared to interferon beta-1a (-0.87 vs -1.49, median change from baseline).

Common adverse events associated with alemtuzumab in the CARE-MS I trial were infusion-associated reactions that were mild to moderate. The incidence of infection was increased, with the most common infections involving the upper respiratory and urinary tract and oral herpes. Infections were mild to moderate, and none were life-threatening or fatal.

Serious adverse events were similar between both groups (18.4% for alemtuzumab and 14.4% for interferon beta-1a). Just over 18% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event, and 0.8% developed immune thrombocytopenia during the two-year study period. Cases of autoimmunity were detected and managed using conventional therapies.

Daclizumab: Phase 3 SELECT Trial Results Released
Monthly subcutaneous daclizumab monotherapy demonstrated a robust and clinically meaningful effect on MS activity, including evidence for early impact on disability progression, according to phase 3 data that were presented.

Researchers randomized 600 patients with relapsing-remitting MS and at least one MS relapse in the prior 12 months or one new gadolinium-enhancing lesion in the prior six weeks to receive low-dose daclizumab (150 mg), high-dose daclizumab (300 mg), or placebo as a subcutaneous injection once every four weeks for 52 weeks.

A total of 559 patients (93%) completed the treatment period. Annualized relapse rate, the study’s primary end point, was 0.21 for low-dose daclizumab, 0.23 for high-dose daclizumab, and 0.46 for placebo. The proportion of relapse-free patients was 81% in the low-dose group, 80% in the high-dose group, and 64% in the placebo group. There were significant reductions in the mean number of new or newly enlarging T2 lesions at one year (2.4 for low dose, 1.7 for high dose, and 8.1 for placebo). Among 309 patients in an MRI substudy, the mean number of new gadolinium-enhancing lesions between weeks 8 through 24 was 1.5 for low-dose daclizumab, 1.0 for the high-dose group, and 4.8 for placebo. The risk of three-month sustained disability progression at one year was reduced by 57% in the low-dose group and by 43% in the high-dose group.

Serious adverse events, excluding MS relapses, occurred in 5% of the placebo group, 6% of the low-dose group, and 8% of the high-dose group. One daclizumab-treated patient died due to a complication of a psoas abscess. Serious adverse events in the daclizumab-treated patients included an increase in serious infections (2%), serious cutaneous events (1%), and elevations in liver function tests (4%).

Clinical and MRI Outcomes in Patients With MS Treated With Fingolimod
Fingolimod at an oral dose of 0.5 mg consistently improved relapse rates, disability, and MRI outcomes compared with placebo or IM interferon beta-1a in all patient subgroups with active relapsing-remitting MS, investigators reported.

Eva Havrdová, PhD, from the Department of Neurology, First Faculty of Medicine, Charles University, Prague, and colleagues reported the results of post hoc analyses from FREEDOMS and TRANSFORMS in three patient subgroups: 1) patients who received interferon beta in the year before study entry and had equal or more relapses in the year immediately before the study than in the year two years before the study; 2) patients who received interferon beta in the year before study entry and had at least one relapse in the previous year plus at least one gadolinium-enhancing T1 lesion or nine T2 lesions at baseline; or 3) treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

In FREEDOMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with placebo in all three subgroups. In TRANSFORMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with IM interferon beta-1a in groups 1 and 2. Results in group 3 (n = 27) did not reach statistical significance. In both studies fingolimod reduced the risk of disability progression versus placebo and interferon beta-1a in all subgroups.

The researchers concluded that fingolimod (0.5 mg) improved clinical outcomes compared with placebo or IM interferon beta-1a in patients with relapsing-remitting MS with high disease activity despite previous treatment and in treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

Laquinimod: A Potential Novel Oral Agent for Relapsing-Remitting MS
Both preclinical and clinical data suggest that the oral immunomodulator laquinimod holds promise for patients with relapsing-remitting MS, according to investigators.

Giancarlo Comi, MD, Professor and Chairman of the Department of Neurology and Director of the Institute of Experimental Neurology at Vita-Salute San Raffaele University, Scientific Institute San Raffaele Milan, reported that a phase 2 study demonstrated reductions of MRI-active lesions, a trend for slowing the rate of MRI-measured brain volume loss, and a favorable safety and tolerability profile. Dr. Comi also summarized findings from the multicenter, randomized, double-blind, placebo-controlled Allegro trial. In the phase 3 trial, patients received a once-daily oral dose of 0.6 mg laquinimod or placebo for 24 months.

The study met the primary end point, with laquinimod achieving a decrease in relapse rate (23% reduction). The risk for EDSS disability progression was significantly reduced (36%) compared with placebo. Rate of brain atrophy progression was reduced by 33% at month 24.

Laquinimod was well-tolerated. Adverse events were similar in both groups, with the exception of transient, reversible elevations of liver enzymes without concomitant signs of liver dysfunction in the laquinimod group.

Dr. Comi also provided an advance glimpse of findings from the BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod) study. The profile of reduced annualized relapse rate, MRI-active lesions, brain-volume loss, and EDSS was similar to that seen in the Allegro study.

Teriflunomide: A Promising New Oral Therapy for Patients With Relapsing-Remitting MS
Data from TEMSO, the first pivotal phase 3 trial of teriflunomide, were reported by Paul O’Connor, FRCPC, MSc.

The two-year, double-blind study found a significant reduction in annualized relapse rates with both the 7-mg and 14-mg doses of teriflunomide compared with placebo, as well as a significant reduction in the risk of sustained disability progression in the higher dose group. Both doses showed good safety and tolerability in patients with relapsing-remitting MS. Both doses were superior to placebo on a range of MRI end points in a dose-dependent fashion.

A long-term extension of TEMSO showed that teriflunomide was well tolerated with a favorable safety profile up to six years following randomization, with no unexpected adverse events related to long-term treatment.

Dr. O’Connor, Professor of Medicine at the University of Toronto and Director of the MS Clinic at St. Michael’s Hospital in Toronto, also discussed results from an extension of the phase 2 study of teriflunomide, which has provided information on up to nine years of teriflunomide treatment. Clinical and MRI disease activity remained low during the course of this extension and treatment-related adverse events were similar to those in the initial 36-week double-blind trial.

Both the extension of the phase 2 trial and an extension of the TEMSO trial reported minimal clinical and MRI activity. A trend toward greater benefit on both clinical and MRI parameters was seen in patients who were continually treated with teriflunomide compared with placebo-treated patients who were switched to active treatment.

Natalizumab-Associated PML Survival Rates Exceed 80%
Early diagnosis through the enhanced clinical vigilance and optimal management of progressive multifocal leukoencephalopathy (PML) may improve outcomes, according to researchers.

Survival rates in excess of 80% were seen in the first 133 postmarketing natalizumab-associated PML cases, reported Ludwig Kappos, MD, from the Departments of Neurology and Biomedicine, University Hospital, Basel, Switzerland, and colleagues. Improved survival was associated with younger age (median, 43 vs 51.5) and less disability (median EDSS, 4.0 vs 5.5) at diagnosis, shorter time from symptom onset to diagnosis (mean, 40 vs 53 days), and more localized disease on brain MRI, as compared with fatal cases.

Of 159 PML cases identified in the postmarketing setting, 130 patients were still alive as of September 1, 2011 (82% survival rate). In survivors with more than six months of follow-up, 13% had mild disability, 47% had moderate disability, and 40% had severe disability.

Higher Vitamin D Levels Are Associated With Fewer Brain Lesions
Vitamin D levels are inversely associated with the risk of MS activity on brain MRI, according to researchers.

Begun in 2004, EPIC is a five-year longitudinal MS cohort study that sought to determine if vitamin D status is associated with the development of new T2 lesions or contrast-enhancing lesions on brain MRI in a cohort of patients with clinically isolated syndrome (CIS) or relapsing-remitting MS. Participants had clinical evaluations, brain MRI, and blood draws annually.

From the overall cohort, researchers evaluated patients who had a diagnosis of CIS or relapsing-remitting MS at baseline visit. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking status, and the use of MS treatments) models, annual 25-hydroxyvitamin D3 levels were evaluated for their association with the development of new T2-weighted lesions and gadolinium-enhancing T1-weighted lesions on brain MRI as well as with the occurrence of clinical relapses of MS.

A total of 469 subjects were studied and 2,362 3T brain MRI scans were acquired and analyzed. In multivariate analyses, each 10-ng/mL higher 25-hydroxyvitamin D3 level was associated with a 15% lower risk of developing a new T2 lesion and a 32% lower risk of a gadolinium-enhancing lesion. Higher vitamin D levels were associated with a lower relapse risk, although the association did not reach statistical significance.

The following brief reports summarize some of the findings presented at the 5th Joint Triennial Congress of the European Committee for Treatment and Research in Multiple Sclerosis/Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS). Additional coverage of the ECTRIMS/ACTRIMS meeting can be found online at www.neurologyreviews.com and in upcoming issues of Neurology Reviews.

BG-12: Data From the Phase 3 DEFINE Trials
AMSTERDAM—Results from a large phase 3 trial support the potential of BG-12 (dimethyl fumarate) as an effective oral treatment for patients with relapsing-remitting multiple sclerosis (MS). According to researchers, BG-12 may have dual anti-inflammatory and neuroprotective effects via the Nrf2 pathway.

DEFINE was a randomized, double-blind, placebo-controlled, multicenter trial that evaluated the efficacy and safety of BG-12 over two years in patients with relapsing-remitting MS. Patients ages 18 to 55 with relapsing-remitting MS and an Expanded Disability Status Scale (EDSS) score of 0 to 5 (inclusive) were randomly assigned to placebo, BG-12 240 mg BID, or BG-12 240 mg TID.

All patients underwent clinical assessments at screening, baseline, and every four weeks for up to two years. The primary end point was proportion of patients relapsing at two years. Secondary efficacy end points at two years were annualized relapse rate and disability progression as measured by EDSS score.

A total of 1,234 patients were randomized—408 received placebo, 410 received BG-12 BID, and 416 received BG-12 TID. All primary and secondary end points were met. BG-12 BID and TID reduced the risk of relapse by 49% and 50%, respectively, compared with placebo at two years. Annualized relapse rate was 0.36 with placebo, and 0.17 and 0.19 with BG-12 BID and TID, corresponding to reductions of 53% and 48% for BG-12 BID and TID. The risk of confirmed 12-week disability progression was reduced by 38% for the BID dosing and by approximately 34% with TID dosing.

The overall incidence of adverse and serious adverse events was similar among the three groups.

Alemtuzumab: Phase 3 CARE-MS I Data Released
Results of a head-to-head comparison of alemtuzumab and interferon beta-1a have shown that 78% of patients with relapsing-remitting MS treated with alemtuzumab remained relapse-free for two years, compared with 58% of patients taking interferon beta-1a.

The phase 3 CARE-MS I trial compared alemtuzumab (12 mg/d IV for five days with a second 3-day IV administration one year later) to treatment with interferon beta-1a (44 mcg SC injection 3 times per week) in 581 patients with relapsing-remitting MS who had had no previous MS treatment except steroids.

Additional findings include other secondary end points that suggest positive outcomes with alemtuzumab. Improvement in the Multiple Sclerosis Functional Composite (MSFC) score was observed in alemtuzumab-treated patients compared with interferon beta-1a–treated patients (0.12 vs 0.05, mean change from baseline at year 2). Reduction in T2-hyperintense lesion volume with alemtuzumab compared to interferon beta-1a was -9.3 versus -6.5 (median percent change at year 2). Statistically significant improvement was observed for alemtuzumab versus interferon beta-1a in the percentage of patients with new enlarging T2-hyperintense lesions (49% vs 58%), with new gadolinium-enhancing lesions (15% vs 27%), and with new T1-hypointense lesions (24% vs 31%). Alemtuzumab-treated patients also experienced less change in brain parenchymal fraction compared to interferon beta-1a (-0.87 vs -1.49, median change from baseline).

Common adverse events associated with alemtuzumab in the CARE-MS I trial were infusion-associated reactions that were mild to moderate. The incidence of infection was increased, with the most common infections involving the upper respiratory and urinary tract and oral herpes. Infections were mild to moderate, and none were life-threatening or fatal.

Serious adverse events were similar between both groups (18.4% for alemtuzumab and 14.4% for interferon beta-1a). Just over 18% of alemtuzumab-treated patients developed an autoimmune thyroid-related adverse event, and 0.8% developed immune thrombocytopenia during the two-year study period. Cases of autoimmunity were detected and managed using conventional therapies.

Daclizumab: Phase 3 SELECT Trial Results Released
Monthly subcutaneous daclizumab monotherapy demonstrated a robust and clinically meaningful effect on MS activity, including evidence for early impact on disability progression, according to phase 3 data that were presented.

Researchers randomized 600 patients with relapsing-remitting MS and at least one MS relapse in the prior 12 months or one new gadolinium-enhancing lesion in the prior six weeks to receive low-dose daclizumab (150 mg), high-dose daclizumab (300 mg), or placebo as a subcutaneous injection once every four weeks for 52 weeks.

A total of 559 patients (93%) completed the treatment period. Annualized relapse rate, the study’s primary end point, was 0.21 for low-dose daclizumab, 0.23 for high-dose daclizumab, and 0.46 for placebo. The proportion of relapse-free patients was 81% in the low-dose group, 80% in the high-dose group, and 64% in the placebo group. There were significant reductions in the mean number of new or newly enlarging T2 lesions at one year (2.4 for low dose, 1.7 for high dose, and 8.1 for placebo). Among 309 patients in an MRI substudy, the mean number of new gadolinium-enhancing lesions between weeks 8 through 24 was 1.5 for low-dose daclizumab, 1.0 for the high-dose group, and 4.8 for placebo. The risk of three-month sustained disability progression at one year was reduced by 57% in the low-dose group and by 43% in the high-dose group.

Serious adverse events, excluding MS relapses, occurred in 5% of the placebo group, 6% of the low-dose group, and 8% of the high-dose group. One daclizumab-treated patient died due to a complication of a psoas abscess. Serious adverse events in the daclizumab-treated patients included an increase in serious infections (2%), serious cutaneous events (1%), and elevations in liver function tests (4%).

Clinical and MRI Outcomes in Patients With MS Treated With Fingolimod
Fingolimod at an oral dose of 0.5 mg consistently improved relapse rates, disability, and MRI outcomes compared with placebo or IM interferon beta-1a in all patient subgroups with active relapsing-remitting MS, investigators reported.

Eva Havrdová, PhD, from the Department of Neurology, First Faculty of Medicine, Charles University, Prague, and colleagues reported the results of post hoc analyses from FREEDOMS and TRANSFORMS in three patient subgroups: 1) patients who received interferon beta in the year before study entry and had equal or more relapses in the year immediately before the study than in the year two years before the study; 2) patients who received interferon beta in the year before study entry and had at least one relapse in the previous year plus at least one gadolinium-enhancing T1 lesion or nine T2 lesions at baseline; or 3) treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

In FREEDOMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with placebo in all three subgroups. In TRANSFORMS, fingolimod 0.5 mg significantly reduced annualized relapse rates compared with IM interferon beta-1a in groups 1 and 2. Results in group 3 (n = 27) did not reach statistical significance. In both studies fingolimod reduced the risk of disability progression versus placebo and interferon beta-1a in all subgroups.

The researchers concluded that fingolimod (0.5 mg) improved clinical outcomes compared with placebo or IM interferon beta-1a in patients with relapsing-remitting MS with high disease activity despite previous treatment and in treatment-naïve patients with rapidly evolving severe relapsing-remitting MS.

Laquinimod: A Potential Novel Oral Agent for Relapsing-Remitting MS
Both preclinical and clinical data suggest that the oral immunomodulator laquinimod holds promise for patients with relapsing-remitting MS, according to investigators.

Giancarlo Comi, MD, Professor and Chairman of the Department of Neurology and Director of the Institute of Experimental Neurology at Vita-Salute San Raffaele University, Scientific Institute San Raffaele Milan, reported that a phase 2 study demonstrated reductions of MRI-active lesions, a trend for slowing the rate of MRI-measured brain volume loss, and a favorable safety and tolerability profile. Dr. Comi also summarized findings from the multicenter, randomized, double-blind, placebo-controlled Allegro trial. In the phase 3 trial, patients received a once-daily oral dose of 0.6 mg laquinimod or placebo for 24 months.

The study met the primary end point, with laquinimod achieving a decrease in relapse rate (23% reduction). The risk for EDSS disability progression was significantly reduced (36%) compared with placebo. Rate of brain atrophy progression was reduced by 33% at month 24.

Laquinimod was well-tolerated. Adverse events were similar in both groups, with the exception of transient, reversible elevations of liver enzymes without concomitant signs of liver dysfunction in the laquinimod group.

Dr. Comi also provided an advance glimpse of findings from the BRAVO (Benefit-Risk Assessment of Avonex and Laquinimod) study. The profile of reduced annualized relapse rate, MRI-active lesions, brain-volume loss, and EDSS was similar to that seen in the Allegro study.

Teriflunomide: A Promising New Oral Therapy for Patients With Relapsing-Remitting MS
Data from TEMSO, the first pivotal phase 3 trial of teriflunomide, were reported by Paul O’Connor, FRCPC, MSc.

The two-year, double-blind study found a significant reduction in annualized relapse rates with both the 7-mg and 14-mg doses of teriflunomide compared with placebo, as well as a significant reduction in the risk of sustained disability progression in the higher dose group. Both doses showed good safety and tolerability in patients with relapsing-remitting MS. Both doses were superior to placebo on a range of MRI end points in a dose-dependent fashion.

A long-term extension of TEMSO showed that teriflunomide was well tolerated with a favorable safety profile up to six years following randomization, with no unexpected adverse events related to long-term treatment.

Dr. O’Connor, Professor of Medicine at the University of Toronto and Director of the MS Clinic at St. Michael’s Hospital in Toronto, also discussed results from an extension of the phase 2 study of teriflunomide, which has provided information on up to nine years of teriflunomide treatment. Clinical and MRI disease activity remained low during the course of this extension and treatment-related adverse events were similar to those in the initial 36-week double-blind trial.

Both the extension of the phase 2 trial and an extension of the TEMSO trial reported minimal clinical and MRI activity. A trend toward greater benefit on both clinical and MRI parameters was seen in patients who were continually treated with teriflunomide compared with placebo-treated patients who were switched to active treatment.

Natalizumab-Associated PML Survival Rates Exceed 80%
Early diagnosis through the enhanced clinical vigilance and optimal management of progressive multifocal leukoencephalopathy (PML) may improve outcomes, according to researchers.

Survival rates in excess of 80% were seen in the first 133 postmarketing natalizumab-associated PML cases, reported Ludwig Kappos, MD, from the Departments of Neurology and Biomedicine, University Hospital, Basel, Switzerland, and colleagues. Improved survival was associated with younger age (median, 43 vs 51.5) and less disability (median EDSS, 4.0 vs 5.5) at diagnosis, shorter time from symptom onset to diagnosis (mean, 40 vs 53 days), and more localized disease on brain MRI, as compared with fatal cases.

Of 159 PML cases identified in the postmarketing setting, 130 patients were still alive as of September 1, 2011 (82% survival rate). In survivors with more than six months of follow-up, 13% had mild disability, 47% had moderate disability, and 40% had severe disability.

Higher Vitamin D Levels Are Associated With Fewer Brain Lesions
Vitamin D levels are inversely associated with the risk of MS activity on brain MRI, according to researchers.

Begun in 2004, EPIC is a five-year longitudinal MS cohort study that sought to determine if vitamin D status is associated with the development of new T2 lesions or contrast-enhancing lesions on brain MRI in a cohort of patients with clinically isolated syndrome (CIS) or relapsing-remitting MS. Participants had clinical evaluations, brain MRI, and blood draws annually.

From the overall cohort, researchers evaluated patients who had a diagnosis of CIS or relapsing-remitting MS at baseline visit. In univariate and multivariate (adjusted for age, sex, ethnicity, smoking status, and the use of MS treatments) models, annual 25-hydroxyvitamin D3 levels were evaluated for their association with the development of new T2-weighted lesions and gadolinium-enhancing T1-weighted lesions on brain MRI as well as with the occurrence of clinical relapses of MS.

A total of 469 subjects were studied and 2,362 3T brain MRI scans were acquired and analyzed. In multivariate analyses, each 10-ng/mL higher 25-hydroxyvitamin D3 level was associated with a 15% lower risk of developing a new T2 lesion and a 32% lower risk of a gadolinium-enhancing lesion. Higher vitamin D levels were associated with a lower relapse risk, although the association did not reach statistical significance.