More Than 45 Novel MS Susceptibility Variants Are Identified

BOSTON—More than 45 new multiple sclerosis (MS) susceptibility variants were reported by researchers.

“We now present a comprehensive view of MS genetic susceptibility and provide a detailed map of proximal biologic effects that identify new molecular pathways involved in the transition from health to MS,” said Philip Laurence De Jager, MD, PhD, Assistant Professor, Harvard Medical School in Boston, on behalf of the International MS Genetics Consortium.

To identify MS susceptibility associations outside the validated MS susceptibility loci and uncover new biologic processes that drive the onset of MS, the researchers conducted a genomewide discovery study of approximately eight million single-nucleotide polymorphisms (SNPs) in each of 14,802 MS cases and 26,703 controls. This step was followed by a deep replication study of more than 80,000 SNPs in more than 19,217 MS cases and 17,842 controls. The 4,716 SNPs with a P value of less than 0.05 in the discovery study were included in the present study. Functional evaluations of the results were conducted using DEPICT for pathway analysis, as well as analyses of immune cell RNA expression data from ImmVar and reference epigenomic maps from the Epigenome Roadmap and ENCODE projects.

At the end of the replication study, more than 45 new susceptibility variants were identified, with 10 major histocompatibility complex (MHC) and more than 150 non-MHC SNPs meeting a threshold of genomewide significance. The depth of the replication effort identified multiple independent effects in many regions that were previously unresolvable. For example, the EVI5 region has as many as four independent susceptibility variants.

“Uncovering this multiplicity of associations in certain regions is critical to our efforts to model the biologic consequences of MS susceptibility variants and to develop predictive algorithms,” Dr. De Jager said. “With more than 150 independent susceptibility effects and a high resolution analysis of each locus in hand, we have created a reference map of MS susceptibility and now turn to the task of understanding the biology of MS susceptibility.

“With the new MS map and multiple approaches to epigenomic annotation and functional evaluations, it is clear that non-TH1/Th17/Treg processes are important in the onset of MS,” he continued. “Myeloid, NK, and CD8 cells are now implicated, and B and dendritic cell functions are suggested to be altered by MS variants.”

Leveraging RNA data from 405 subjects with purified CD4 T and monocytes, 29% of MS variants with RNA effects are unique to monocytes, which is now the same proportion as for T cells (29%). Pathway analyses highlighted an enrichment of NK and B cell activation molecular networks in addition to T cell effects.

—Glenn S. Williams

Investigational Oral Drug Reduces Disease Activity in Relapsing-Remitting MS
An oral, selective sphingosine 1-phosphate 1 receptor modulator appears to reduce MRI measures of disease activity in patients with relapsing-remitting multiple sclerosis (MS), according to data presented. The drug, RPC1063, may be safe and tolerable for these patients.

Data are from the international, combined phase II/III RADIANCE trial. Jeffrey Cohen, MD, Director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research in Cleveland, and colleagues randomized 258 patients with relapsing-remitting MS. A total of 87 participants received a low dose (0.5 mg) of RPC1063, 83 participants received a high dose (1.0 mg) of RPC1063, and 88 participants received placebo for 24 weeks.

The trial’s primary end point was the cumulative number of total gadolinium-enhancing lesions on MRI at weeks 12, 16, 20, and 24. Key secondary end points included the number of gadolinium-enhancing lesions at week 24, the cumulative number of new or enlarging T2 lesions from weeks 12 to 24, and annualized relapse rate.

The researchers assessed safety using vital signs, laboratory tests, ECG, Holter monitoring, pulmonary function test, optical coherence tomography, and adverse events. Patients were titrated to their assigned doses during one week to mitigate the first doses’ effects on heart rate.

Approximately 98% of patients completed the trial. The cumulative number of gadolinium-enhancing lesions from weeks 12 to 24 was reduced by 86% in both treatment arms, compared with placebo. The numbers of gadolinium-enhancing lesions at week 24 were significantly reduced by 91% in the low-dose group and by 94% in the high-dose group, compared with placebo. The cumulative number of new or enlarging T2 lesions from weeks 12 to 24 was reduced by 84% in the low-dose group and by 91% in the high-dose group. The researchers observed a favorable trend toward a reduction in annualized relapse rate among treated patients, compared with controls.

The adverse event profiles were similar between groups. The most common adverse events in the treated groups, compared with placebo, were nasopharyngitis (9.4% vs 13.6%), headache (4.7% vs 9.1%), and urinary tract infection (4.7% vs 2.3%). During the first six hours after the first dose of RPC1063, maximum reductions in mean hourly heart rate were < 2 bpm from baseline, and no patient had a minimum hourly heart rate < 45 bpm. The investigators did not observe any notable cardiac, pulmonary, ophthalmologic, or malignancy adverse events.

“Both doses of RPC1063 demonstrated large, significant, and consistent reductions of all MRI measures of MS disease activity,” said Dr. Cohen. “The tolerability and safety results suggest a favorable risk–benefit profile of RPC1063 in the treatment of relapsing-remitting MS. These results support the ongoing phase III portion of the RADIANCE trial of RPC1063 vs interferon beta-1a in relapsing-remitting MS,” he concluded.

—Erik Greb

Improved Adherence to Disease-Modifying Therapy Reduces Health Care Resource Use and Medical Costs
Improved adherence to disease-modifying therapy (DMT) is associated with lower medical and indirect costs, reduced work-loss days, and decreased inpatient stays and emergency visits for patients with multiple sclerosis (MS), investigators reported.

According to published estimates, real-world adherence to DMTs in MS ranges from 41% to 88%, and higher adherence is associated with lower rates of relapse and lower costs. Sander Yermakov, from the Analysis Group in Boston, and researchers from Biogen Idec in Cambridge, Massachusetts, sought to estimate the effect of adherence to DMTs in health care resource use and cost outcomes in patients with MS and to model the impact of improving adherence on these outcomes.

A retrospective analysis was conducted using the OptumHealth Reporting & Insights employer claims database, which contains information on medical and pharmacy claims for more than 18 million beneficiaries in the US, as well as disability claims and salary information in a subset of approximately 4.2 million employees. Employed patients with two or more MS diagnoses (ICD-9-CM 340) initiating DMT from January 2, 2002, through March 31, 2012, were included in the analysis.

Direct medical costs (paid amounts to providers for services or drugs, excluding payments for DMTs), indirect costs (disability payments to employees and work-loss costs to employers), and resource use were analyzed in the six months prior to initiation of any DMT (baseline period) and for three years after initiation (follow-up period). Adherence to any DMT was defined as the proportion of days covered (PDC) and measured using the percentage of days in each follow-up period during which the patient had one or more MS DMT available.

Multivariate regression analyses were used to estimate the effect of PDC on follow-up period outcomes, controlling for baseline characteristics. The estimated model was used to predict the change in use and costs associated with a 10% improvement in PDC.

A total of 1,538 patients met the selection criteria (baseline age, 43.6; 63% female). PDC had a statistically significant effect on direct medical and indirect work productivity costs, work-loss days, and likelihood of an inpatient stay or emergency visit at one-, two-, and three-year follow-up. A 10% improvement in PDC was estimated to reduce direct costs by 4%, indirect costs by 3% to 4%, work-loss days by 3% to 7%, likelihood of an inpatient stay by 13% to 19%, and likelihood of an emergency visit by 8% to 19%, depending on the follow-up period.

The impact on the likelihood of an inpatient stay or emergency visit increased with the length of the follow-up period. In the first year, the decrease in direct costs associated with a 10% improvement in adherence was greater for patients with PDC of 0.8 or higher (10%), men (6%), and patients not on disability in the baseline period.

—Glenn S. Williams

Equivalence Demonstrated by a Generic Version of Glatiramer Acetate
Results of the randomized, double-blind GATE trial indicate that generic glatiramer acetate is equivalent to branded Copaxone in reducing the number of gadolinium-enhancing lesions, a clinically relevant end point in relapsing-remitting multiple sclerosis (RRMS). Other efficacy outcomes, safety, and tolerability also were comparable.

“This is the first generic glatiramer acetate with an efficacy and safety profile demonstrated to be equivalent to the currently marketed product,” said Jeffrey A. Cohen, MD, Director of the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, on behalf of the GATE Study Group.

“Generic alternatives to the currently approved therapies for RRMS are needed,” Dr. Cohen said. But because glatiramer acetate is a complex polypeptide mixture that precludes pharmacokinetic comparison, a generic version needs to demonstrate equivalence in efficacy and safety. The GATE trial aimed to show that generic glatiramer acetate was equivalent to Copaxone (Teva Pharmaceuticals; North Wales, Pennsylvania), as measured by MRI and clinical end points, safety, and tolerability in RRMS.

Patients with ambulatory RRMS (ages 18 to 55) with one or more relapse in the year prior to screening and one to 15 gadolinium-enhancing brain lesions were randomized in a 4.3:4.3:1 fashion in a multicenter, double-blind, placebo-controlled trial to receive 20 mg of generic glatiramer acetate, 20 mg of Copaxone, or placebo by daily subcutaneous injection for nine months. The primary end point was combined number of gadolinium-enhancing lesions over months seven, eight, and nine. Additional efficacy end points included other MRI parameters, annualized relapse rate, Expanded Disability Status Scale (EDSS) score, and freedom from disease activity. Safety and tolerability were assessed through monitoring of adverse events, injection site reactions, and routine blood laboratory tests.

A total of 794 patients were randomized and treated with generic glatiramer acetate (n = 353), Copaxone (n = 357), or placebo (n = 84). Of these, 735 patients (92.5%) completed the nine-month double-blind treatment period. The estimated geometric mean numbers of gadolinium-enhancing lesions were 0.42 for generic glatiramer acetate and 0.39 for Copaxone, resulting in an estimated generic/brand lesion ratio of 1.097 with a 95% confidence interval of 0.884 to 1.362, which is within the predefined equivalence margin.

The estimated geometric mean number of gadolinium-enhancing lesions for both the generic and brand drug groups was lower than for the placebo group, confirming assay sensitivity. Annualized relapse rates were 0.31 for generic glatiramer acetate, 0.41 for Copaxone, and 0.39 for placebo. Comparable proportions of patients treated with the generic and branded drug were free from disease activity. EDSS was stable in all three groups. The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the two treatment groups.

The generic version of glatiramer acetate is being developed by Synthon Biopharmaceuticals BV (Nijmegen, the Netherlands).

—Glenn S. Williams

Does Brain Reserve Protect Against Physical Disability in MS?
Patients with multiple sclerosis (MS) who have larger maximal lifetime brain growth may have less physical disability, according to researchers. Larger maximal lifetime brain growth may help preserve patients’ ambulation and fine motor function.

“Clinical consideration of maximal lifetime brain growth … may help identify patients with MS at highest risk for future physical disability,” said James F. Sumowski, PhD, Senior Research Scientist of Neuropsychology and Neuroscience Research at the Kessler Foundation Research Center in West Orange, New Jersey. “At-risk patients can be enrolled in early intervention treatments or research on such treatments.”

Dr. Sumowski and colleagues studied 352 patients with MS, including 255 people with relapsing-remitting MS and 97 people with secondary progressive MS. The researchers assessed participants’ disease burden using high-resolution, 3-D, T1 fast field echo. They used software to normalize patients’ total brain, gray matter, white matter, deep gray matter, and thalamus volumes. The researchers also used dual-echo turbo spin echo to quantify T2 lesion volume. Dr. Sumowski’s group estimated maximal lifetime brain growth with SIENAX v-scaling factor (adjusted for gender), a proxy for intracranial volume.

In addition, the investigators assessed 168 participants’ ambulation with the 25-Foot Walk. Participants who used assistive devices for walking were excluded. Fine motor function was assessed with the Nine-Hole Peg Test (in 323 patients) and Finger Tapping Test (in 330 patients). Cognitive status was assessed in 333 patients with the Paced Auditory Serial Addition Test-3 (PASAT-3).

Dr. Sumowski and colleagues found that maximal lifetime brain growth significantly predicted pyramidal and cerebellar function. Maximal lifetime brain growth accounted for the variance between patients in physical disability, as measured by the Finger Tapping Test. People with larger maximal lifetime brain growth performed better on that test. Disability was worse in people with smaller maximal lifetime brain growth, and the relationship did not change when the researchers controlled for demographics and deep gray matter atrophy.

The investigators found a similar relationship for cerebellar function. Participants with larger maximal lifetime brain growth had less disability and cerebellar dysfunction, even when the researchers controlled for demographics and disease burden. Patients with larger maximal lifetime brain growth completed the 25-Foot Walk more quickly, which indicated that they had less disability.

The researchers did not find a relationship between maximal lifetime brain growth and other functional systems, such as brainstem, visual, motor sensory, and bladder function.

—Erik Greb

BOSTON—More than 45 new multiple sclerosis (MS) susceptibility variants were reported by researchers.

“We now present a comprehensive view of MS genetic susceptibility and provide a detailed map of proximal biologic effects that identify new molecular pathways involved in the transition from health to MS,” said Philip Laurence De Jager, MD, PhD, Assistant Professor, Harvard Medical School in Boston, on behalf of the International MS Genetics Consortium.

To identify MS susceptibility associations outside the validated MS susceptibility loci and uncover new biologic processes that drive the onset of MS, the researchers conducted a genomewide discovery study of approximately eight million single-nucleotide polymorphisms (SNPs) in each of 14,802 MS cases and 26,703 controls. This step was followed by a deep replication study of more than 80,000 SNPs in more than 19,217 MS cases and 17,842 controls. The 4,716 SNPs with a P value of less than 0.05 in the discovery study were included in the present study. Functional evaluations of the results were conducted using DEPICT for pathway analysis, as well as analyses of immune cell RNA expression data from ImmVar and reference epigenomic maps from the Epigenome Roadmap and ENCODE projects.

At the end of the replication study, more than 45 new susceptibility variants were identified, with 10 major histocompatibility complex (MHC) and more than 150 non-MHC SNPs meeting a threshold of genomewide significance. The depth of the replication effort identified multiple independent effects in many regions that were previously unresolvable. For example, the EVI5 region has as many as four independent susceptibility variants.

“Uncovering this multiplicity of associations in certain regions is critical to our efforts to model the biologic consequences of MS susceptibility variants and to develop predictive algorithms,” Dr. De Jager said. “With more than 150 independent susceptibility effects and a high resolution analysis of each locus in hand, we have created a reference map of MS susceptibility and now turn to the task of understanding the biology of MS susceptibility.

“With the new MS map and multiple approaches to epigenomic annotation and functional evaluations, it is clear that non-TH1/Th17/Treg processes are important in the onset of MS,” he continued. “Myeloid, NK, and CD8 cells are now implicated, and B and dendritic cell functions are suggested to be altered by MS variants.”

Leveraging RNA data from 405 subjects with purified CD4 T and monocytes, 29% of MS variants with RNA effects are unique to monocytes, which is now the same proportion as for T cells (29%). Pathway analyses highlighted an enrichment of NK and B cell activation molecular networks in addition to T cell effects.

—Glenn S. Williams

Investigational Oral Drug Reduces Disease Activity in Relapsing-Remitting MS
An oral, selective sphingosine 1-phosphate 1 receptor modulator appears to reduce MRI measures of disease activity in patients with relapsing-remitting multiple sclerosis (MS), according to data presented. The drug, RPC1063, may be safe and tolerable for these patients.

Data are from the international, combined phase II/III RADIANCE trial. Jeffrey Cohen, MD, Director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research in Cleveland, and colleagues randomized 258 patients with relapsing-remitting MS. A total of 87 participants received a low dose (0.5 mg) of RPC1063, 83 participants received a high dose (1.0 mg) of RPC1063, and 88 participants received placebo for 24 weeks.

The trial’s primary end point was the cumulative number of total gadolinium-enhancing lesions on MRI at weeks 12, 16, 20, and 24. Key secondary end points included the number of gadolinium-enhancing lesions at week 24, the cumulative number of new or enlarging T2 lesions from weeks 12 to 24, and annualized relapse rate.

The researchers assessed safety using vital signs, laboratory tests, ECG, Holter monitoring, pulmonary function test, optical coherence tomography, and adverse events. Patients were titrated to their assigned doses during one week to mitigate the first doses’ effects on heart rate.

Approximately 98% of patients completed the trial. The cumulative number of gadolinium-enhancing lesions from weeks 12 to 24 was reduced by 86% in both treatment arms, compared with placebo. The numbers of gadolinium-enhancing lesions at week 24 were significantly reduced by 91% in the low-dose group and by 94% in the high-dose group, compared with placebo. The cumulative number of new or enlarging T2 lesions from weeks 12 to 24 was reduced by 84% in the low-dose group and by 91% in the high-dose group. The researchers observed a favorable trend toward a reduction in annualized relapse rate among treated patients, compared with controls.

The adverse event profiles were similar between groups. The most common adverse events in the treated groups, compared with placebo, were nasopharyngitis (9.4% vs 13.6%), headache (4.7% vs 9.1%), and urinary tract infection (4.7% vs 2.3%). During the first six hours after the first dose of RPC1063, maximum reductions in mean hourly heart rate were < 2 bpm from baseline, and no patient had a minimum hourly heart rate < 45 bpm. The investigators did not observe any notable cardiac, pulmonary, ophthalmologic, or malignancy adverse events.

“Both doses of RPC1063 demonstrated large, significant, and consistent reductions of all MRI measures of MS disease activity,” said Dr. Cohen. “The tolerability and safety results suggest a favorable risk–benefit profile of RPC1063 in the treatment of relapsing-remitting MS. These results support the ongoing phase III portion of the RADIANCE trial of RPC1063 vs interferon beta-1a in relapsing-remitting MS,” he concluded.

—Erik Greb

Improved Adherence to Disease-Modifying Therapy Reduces Health Care Resource Use and Medical Costs
Improved adherence to disease-modifying therapy (DMT) is associated with lower medical and indirect costs, reduced work-loss days, and decreased inpatient stays and emergency visits for patients with multiple sclerosis (MS), investigators reported.

According to published estimates, real-world adherence to DMTs in MS ranges from 41% to 88%, and higher adherence is associated with lower rates of relapse and lower costs. Sander Yermakov, from the Analysis Group in Boston, and researchers from Biogen Idec in Cambridge, Massachusetts, sought to estimate the effect of adherence to DMTs in health care resource use and cost outcomes in patients with MS and to model the impact of improving adherence on these outcomes.

A retrospective analysis was conducted using the OptumHealth Reporting & Insights employer claims database, which contains information on medical and pharmacy claims for more than 18 million beneficiaries in the US, as well as disability claims and salary information in a subset of approximately 4.2 million employees. Employed patients with two or more MS diagnoses (ICD-9-CM 340) initiating DMT from January 2, 2002, through March 31, 2012, were included in the analysis.

Direct medical costs (paid amounts to providers for services or drugs, excluding payments for DMTs), indirect costs (disability payments to employees and work-loss costs to employers), and resource use were analyzed in the six months prior to initiation of any DMT (baseline period) and for three years after initiation (follow-up period). Adherence to any DMT was defined as the proportion of days covered (PDC) and measured using the percentage of days in each follow-up period during which the patient had one or more MS DMT available.

Multivariate regression analyses were used to estimate the effect of PDC on follow-up period outcomes, controlling for baseline characteristics. The estimated model was used to predict the change in use and costs associated with a 10% improvement in PDC.

A total of 1,538 patients met the selection criteria (baseline age, 43.6; 63% female). PDC had a statistically significant effect on direct medical and indirect work productivity costs, work-loss days, and likelihood of an inpatient stay or emergency visit at one-, two-, and three-year follow-up. A 10% improvement in PDC was estimated to reduce direct costs by 4%, indirect costs by 3% to 4%, work-loss days by 3% to 7%, likelihood of an inpatient stay by 13% to 19%, and likelihood of an emergency visit by 8% to 19%, depending on the follow-up period.

The impact on the likelihood of an inpatient stay or emergency visit increased with the length of the follow-up period. In the first year, the decrease in direct costs associated with a 10% improvement in adherence was greater for patients with PDC of 0.8 or higher (10%), men (6%), and patients not on disability in the baseline period.

—Glenn S. Williams

Equivalence Demonstrated by a Generic Version of Glatiramer Acetate
Results of the randomized, double-blind GATE trial indicate that generic glatiramer acetate is equivalent to branded Copaxone in reducing the number of gadolinium-enhancing lesions, a clinically relevant end point in relapsing-remitting multiple sclerosis (RRMS). Other efficacy outcomes, safety, and tolerability also were comparable.

“This is the first generic glatiramer acetate with an efficacy and safety profile demonstrated to be equivalent to the currently marketed product,” said Jeffrey A. Cohen, MD, Director of the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, on behalf of the GATE Study Group.

“Generic alternatives to the currently approved therapies for RRMS are needed,” Dr. Cohen said. But because glatiramer acetate is a complex polypeptide mixture that precludes pharmacokinetic comparison, a generic version needs to demonstrate equivalence in efficacy and safety. The GATE trial aimed to show that generic glatiramer acetate was equivalent to Copaxone (Teva Pharmaceuticals; North Wales, Pennsylvania), as measured by MRI and clinical end points, safety, and tolerability in RRMS.

Patients with ambulatory RRMS (ages 18 to 55) with one or more relapse in the year prior to screening and one to 15 gadolinium-enhancing brain lesions were randomized in a 4.3:4.3:1 fashion in a multicenter, double-blind, placebo-controlled trial to receive 20 mg of generic glatiramer acetate, 20 mg of Copaxone, or placebo by daily subcutaneous injection for nine months. The primary end point was combined number of gadolinium-enhancing lesions over months seven, eight, and nine. Additional efficacy end points included other MRI parameters, annualized relapse rate, Expanded Disability Status Scale (EDSS) score, and freedom from disease activity. Safety and tolerability were assessed through monitoring of adverse events, injection site reactions, and routine blood laboratory tests.

A total of 794 patients were randomized and treated with generic glatiramer acetate (n = 353), Copaxone (n = 357), or placebo (n = 84). Of these, 735 patients (92.5%) completed the nine-month double-blind treatment period. The estimated geometric mean numbers of gadolinium-enhancing lesions were 0.42 for generic glatiramer acetate and 0.39 for Copaxone, resulting in an estimated generic/brand lesion ratio of 1.097 with a 95% confidence interval of 0.884 to 1.362, which is within the predefined equivalence margin.

The estimated geometric mean number of gadolinium-enhancing lesions for both the generic and brand drug groups was lower than for the placebo group, confirming assay sensitivity. Annualized relapse rates were 0.31 for generic glatiramer acetate, 0.41 for Copaxone, and 0.39 for placebo. Comparable proportions of patients treated with the generic and branded drug were free from disease activity. EDSS was stable in all three groups. The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the two treatment groups.

The generic version of glatiramer acetate is being developed by Synthon Biopharmaceuticals BV (Nijmegen, the Netherlands).

—Glenn S. Williams

Does Brain Reserve Protect Against Physical Disability in MS?
Patients with multiple sclerosis (MS) who have larger maximal lifetime brain growth may have less physical disability, according to researchers. Larger maximal lifetime brain growth may help preserve patients’ ambulation and fine motor function.

“Clinical consideration of maximal lifetime brain growth … may help identify patients with MS at highest risk for future physical disability,” said James F. Sumowski, PhD, Senior Research Scientist of Neuropsychology and Neuroscience Research at the Kessler Foundation Research Center in West Orange, New Jersey. “At-risk patients can be enrolled in early intervention treatments or research on such treatments.”

Dr. Sumowski and colleagues studied 352 patients with MS, including 255 people with relapsing-remitting MS and 97 people with secondary progressive MS. The researchers assessed participants’ disease burden using high-resolution, 3-D, T1 fast field echo. They used software to normalize patients’ total brain, gray matter, white matter, deep gray matter, and thalamus volumes. The researchers also used dual-echo turbo spin echo to quantify T2 lesion volume. Dr. Sumowski’s group estimated maximal lifetime brain growth with SIENAX v-scaling factor (adjusted for gender), a proxy for intracranial volume.

In addition, the investigators assessed 168 participants’ ambulation with the 25-Foot Walk. Participants who used assistive devices for walking were excluded. Fine motor function was assessed with the Nine-Hole Peg Test (in 323 patients) and Finger Tapping Test (in 330 patients). Cognitive status was assessed in 333 patients with the Paced Auditory Serial Addition Test-3 (PASAT-3).

Dr. Sumowski and colleagues found that maximal lifetime brain growth significantly predicted pyramidal and cerebellar function. Maximal lifetime brain growth accounted for the variance between patients in physical disability, as measured by the Finger Tapping Test. People with larger maximal lifetime brain growth performed better on that test. Disability was worse in people with smaller maximal lifetime brain growth, and the relationship did not change when the researchers controlled for demographics and deep gray matter atrophy.

The investigators found a similar relationship for cerebellar function. Participants with larger maximal lifetime brain growth had less disability and cerebellar dysfunction, even when the researchers controlled for demographics and disease burden. Patients with larger maximal lifetime brain growth completed the 25-Foot Walk more quickly, which indicated that they had less disability.

The researchers did not find a relationship between maximal lifetime brain growth and other functional systems, such as brainstem, visual, motor sensory, and bladder function.

—Erik Greb

BOSTON—More than 45 new multiple sclerosis (MS) susceptibility variants were reported by researchers.

“We now present a comprehensive view of MS genetic susceptibility and provide a detailed map of proximal biologic effects that identify new molecular pathways involved in the transition from health to MS,” said Philip Laurence De Jager, MD, PhD, Assistant Professor, Harvard Medical School in Boston, on behalf of the International MS Genetics Consortium.

To identify MS susceptibility associations outside the validated MS susceptibility loci and uncover new biologic processes that drive the onset of MS, the researchers conducted a genomewide discovery study of approximately eight million single-nucleotide polymorphisms (SNPs) in each of 14,802 MS cases and 26,703 controls. This step was followed by a deep replication study of more than 80,000 SNPs in more than 19,217 MS cases and 17,842 controls. The 4,716 SNPs with a P value of less than 0.05 in the discovery study were included in the present study. Functional evaluations of the results were conducted using DEPICT for pathway analysis, as well as analyses of immune cell RNA expression data from ImmVar and reference epigenomic maps from the Epigenome Roadmap and ENCODE projects.

At the end of the replication study, more than 45 new susceptibility variants were identified, with 10 major histocompatibility complex (MHC) and more than 150 non-MHC SNPs meeting a threshold of genomewide significance. The depth of the replication effort identified multiple independent effects in many regions that were previously unresolvable. For example, the EVI5 region has as many as four independent susceptibility variants.

“Uncovering this multiplicity of associations in certain regions is critical to our efforts to model the biologic consequences of MS susceptibility variants and to develop predictive algorithms,” Dr. De Jager said. “With more than 150 independent susceptibility effects and a high resolution analysis of each locus in hand, we have created a reference map of MS susceptibility and now turn to the task of understanding the biology of MS susceptibility.

“With the new MS map and multiple approaches to epigenomic annotation and functional evaluations, it is clear that non-TH1/Th17/Treg processes are important in the onset of MS,” he continued. “Myeloid, NK, and CD8 cells are now implicated, and B and dendritic cell functions are suggested to be altered by MS variants.”

Leveraging RNA data from 405 subjects with purified CD4 T and monocytes, 29% of MS variants with RNA effects are unique to monocytes, which is now the same proportion as for T cells (29%). Pathway analyses highlighted an enrichment of NK and B cell activation molecular networks in addition to T cell effects.

—Glenn S. Williams

Investigational Oral Drug Reduces Disease Activity in Relapsing-Remitting MS
An oral, selective sphingosine 1-phosphate 1 receptor modulator appears to reduce MRI measures of disease activity in patients with relapsing-remitting multiple sclerosis (MS), according to data presented. The drug, RPC1063, may be safe and tolerable for these patients.

Data are from the international, combined phase II/III RADIANCE trial. Jeffrey Cohen, MD, Director of the Cleveland Clinic’s Mellen Center for MS Treatment and Research in Cleveland, and colleagues randomized 258 patients with relapsing-remitting MS. A total of 87 participants received a low dose (0.5 mg) of RPC1063, 83 participants received a high dose (1.0 mg) of RPC1063, and 88 participants received placebo for 24 weeks.

The trial’s primary end point was the cumulative number of total gadolinium-enhancing lesions on MRI at weeks 12, 16, 20, and 24. Key secondary end points included the number of gadolinium-enhancing lesions at week 24, the cumulative number of new or enlarging T2 lesions from weeks 12 to 24, and annualized relapse rate.

The researchers assessed safety using vital signs, laboratory tests, ECG, Holter monitoring, pulmonary function test, optical coherence tomography, and adverse events. Patients were titrated to their assigned doses during one week to mitigate the first doses’ effects on heart rate.

Approximately 98% of patients completed the trial. The cumulative number of gadolinium-enhancing lesions from weeks 12 to 24 was reduced by 86% in both treatment arms, compared with placebo. The numbers of gadolinium-enhancing lesions at week 24 were significantly reduced by 91% in the low-dose group and by 94% in the high-dose group, compared with placebo. The cumulative number of new or enlarging T2 lesions from weeks 12 to 24 was reduced by 84% in the low-dose group and by 91% in the high-dose group. The researchers observed a favorable trend toward a reduction in annualized relapse rate among treated patients, compared with controls.

The adverse event profiles were similar between groups. The most common adverse events in the treated groups, compared with placebo, were nasopharyngitis (9.4% vs 13.6%), headache (4.7% vs 9.1%), and urinary tract infection (4.7% vs 2.3%). During the first six hours after the first dose of RPC1063, maximum reductions in mean hourly heart rate were < 2 bpm from baseline, and no patient had a minimum hourly heart rate < 45 bpm. The investigators did not observe any notable cardiac, pulmonary, ophthalmologic, or malignancy adverse events.

“Both doses of RPC1063 demonstrated large, significant, and consistent reductions of all MRI measures of MS disease activity,” said Dr. Cohen. “The tolerability and safety results suggest a favorable risk–benefit profile of RPC1063 in the treatment of relapsing-remitting MS. These results support the ongoing phase III portion of the RADIANCE trial of RPC1063 vs interferon beta-1a in relapsing-remitting MS,” he concluded.

—Erik Greb

Improved Adherence to Disease-Modifying Therapy Reduces Health Care Resource Use and Medical Costs
Improved adherence to disease-modifying therapy (DMT) is associated with lower medical and indirect costs, reduced work-loss days, and decreased inpatient stays and emergency visits for patients with multiple sclerosis (MS), investigators reported.

According to published estimates, real-world adherence to DMTs in MS ranges from 41% to 88%, and higher adherence is associated with lower rates of relapse and lower costs. Sander Yermakov, from the Analysis Group in Boston, and researchers from Biogen Idec in Cambridge, Massachusetts, sought to estimate the effect of adherence to DMTs in health care resource use and cost outcomes in patients with MS and to model the impact of improving adherence on these outcomes.

A retrospective analysis was conducted using the OptumHealth Reporting & Insights employer claims database, which contains information on medical and pharmacy claims for more than 18 million beneficiaries in the US, as well as disability claims and salary information in a subset of approximately 4.2 million employees. Employed patients with two or more MS diagnoses (ICD-9-CM 340) initiating DMT from January 2, 2002, through March 31, 2012, were included in the analysis.

Direct medical costs (paid amounts to providers for services or drugs, excluding payments for DMTs), indirect costs (disability payments to employees and work-loss costs to employers), and resource use were analyzed in the six months prior to initiation of any DMT (baseline period) and for three years after initiation (follow-up period). Adherence to any DMT was defined as the proportion of days covered (PDC) and measured using the percentage of days in each follow-up period during which the patient had one or more MS DMT available.

Multivariate regression analyses were used to estimate the effect of PDC on follow-up period outcomes, controlling for baseline characteristics. The estimated model was used to predict the change in use and costs associated with a 10% improvement in PDC.

A total of 1,538 patients met the selection criteria (baseline age, 43.6; 63% female). PDC had a statistically significant effect on direct medical and indirect work productivity costs, work-loss days, and likelihood of an inpatient stay or emergency visit at one-, two-, and three-year follow-up. A 10% improvement in PDC was estimated to reduce direct costs by 4%, indirect costs by 3% to 4%, work-loss days by 3% to 7%, likelihood of an inpatient stay by 13% to 19%, and likelihood of an emergency visit by 8% to 19%, depending on the follow-up period.

The impact on the likelihood of an inpatient stay or emergency visit increased with the length of the follow-up period. In the first year, the decrease in direct costs associated with a 10% improvement in adherence was greater for patients with PDC of 0.8 or higher (10%), men (6%), and patients not on disability in the baseline period.

—Glenn S. Williams

Equivalence Demonstrated by a Generic Version of Glatiramer Acetate
Results of the randomized, double-blind GATE trial indicate that generic glatiramer acetate is equivalent to branded Copaxone in reducing the number of gadolinium-enhancing lesions, a clinically relevant end point in relapsing-remitting multiple sclerosis (RRMS). Other efficacy outcomes, safety, and tolerability also were comparable.

“This is the first generic glatiramer acetate with an efficacy and safety profile demonstrated to be equivalent to the currently marketed product,” said Jeffrey A. Cohen, MD, Director of the Cleveland Clinic Mellen Center for Multiple Sclerosis Treatment and Research, on behalf of the GATE Study Group.

“Generic alternatives to the currently approved therapies for RRMS are needed,” Dr. Cohen said. But because glatiramer acetate is a complex polypeptide mixture that precludes pharmacokinetic comparison, a generic version needs to demonstrate equivalence in efficacy and safety. The GATE trial aimed to show that generic glatiramer acetate was equivalent to Copaxone (Teva Pharmaceuticals; North Wales, Pennsylvania), as measured by MRI and clinical end points, safety, and tolerability in RRMS.

Patients with ambulatory RRMS (ages 18 to 55) with one or more relapse in the year prior to screening and one to 15 gadolinium-enhancing brain lesions were randomized in a 4.3:4.3:1 fashion in a multicenter, double-blind, placebo-controlled trial to receive 20 mg of generic glatiramer acetate, 20 mg of Copaxone, or placebo by daily subcutaneous injection for nine months. The primary end point was combined number of gadolinium-enhancing lesions over months seven, eight, and nine. Additional efficacy end points included other MRI parameters, annualized relapse rate, Expanded Disability Status Scale (EDSS) score, and freedom from disease activity. Safety and tolerability were assessed through monitoring of adverse events, injection site reactions, and routine blood laboratory tests.

A total of 794 patients were randomized and treated with generic glatiramer acetate (n = 353), Copaxone (n = 357), or placebo (n = 84). Of these, 735 patients (92.5%) completed the nine-month double-blind treatment period. The estimated geometric mean numbers of gadolinium-enhancing lesions were 0.42 for generic glatiramer acetate and 0.39 for Copaxone, resulting in an estimated generic/brand lesion ratio of 1.097 with a 95% confidence interval of 0.884 to 1.362, which is within the predefined equivalence margin.

The estimated geometric mean number of gadolinium-enhancing lesions for both the generic and brand drug groups was lower than for the placebo group, confirming assay sensitivity. Annualized relapse rates were 0.31 for generic glatiramer acetate, 0.41 for Copaxone, and 0.39 for placebo. Comparable proportions of patients treated with the generic and branded drug were free from disease activity. EDSS was stable in all three groups. The incidence, spectrum, and severity of reported adverse events, including injection site reactions, were similar in the two treatment groups.

The generic version of glatiramer acetate is being developed by Synthon Biopharmaceuticals BV (Nijmegen, the Netherlands).

—Glenn S. Williams

Does Brain Reserve Protect Against Physical Disability in MS?
Patients with multiple sclerosis (MS) who have larger maximal lifetime brain growth may have less physical disability, according to researchers. Larger maximal lifetime brain growth may help preserve patients’ ambulation and fine motor function.

“Clinical consideration of maximal lifetime brain growth … may help identify patients with MS at highest risk for future physical disability,” said James F. Sumowski, PhD, Senior Research Scientist of Neuropsychology and Neuroscience Research at the Kessler Foundation Research Center in West Orange, New Jersey. “At-risk patients can be enrolled in early intervention treatments or research on such treatments.”

Dr. Sumowski and colleagues studied 352 patients with MS, including 255 people with relapsing-remitting MS and 97 people with secondary progressive MS. The researchers assessed participants’ disease burden using high-resolution, 3-D, T1 fast field echo. They used software to normalize patients’ total brain, gray matter, white matter, deep gray matter, and thalamus volumes. The researchers also used dual-echo turbo spin echo to quantify T2 lesion volume. Dr. Sumowski’s group estimated maximal lifetime brain growth with SIENAX v-scaling factor (adjusted for gender), a proxy for intracranial volume.

In addition, the investigators assessed 168 participants’ ambulation with the 25-Foot Walk. Participants who used assistive devices for walking were excluded. Fine motor function was assessed with the Nine-Hole Peg Test (in 323 patients) and Finger Tapping Test (in 330 patients). Cognitive status was assessed in 333 patients with the Paced Auditory Serial Addition Test-3 (PASAT-3).

Dr. Sumowski and colleagues found that maximal lifetime brain growth significantly predicted pyramidal and cerebellar function. Maximal lifetime brain growth accounted for the variance between patients in physical disability, as measured by the Finger Tapping Test. People with larger maximal lifetime brain growth performed better on that test. Disability was worse in people with smaller maximal lifetime brain growth, and the relationship did not change when the researchers controlled for demographics and deep gray matter atrophy.

The investigators found a similar relationship for cerebellar function. Participants with larger maximal lifetime brain growth had less disability and cerebellar dysfunction, even when the researchers controlled for demographics and disease burden. Patients with larger maximal lifetime brain growth completed the 25-Foot Walk more quickly, which indicated that they had less disability.

The researchers did not find a relationship between maximal lifetime brain growth and other functional systems, such as brainstem, visual, motor sensory, and bladder function.

—Erik Greb