Cost Per Relapse Avoided for Ozanimod Versus Other Selected Disease-Modifying Therapies for Relapsing-Remitting Multiple Sclerosis in the United States.

INTRODUCTION: This study assessed the cost-effectiveness of ozanimod compared with commonly used disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS). METHODS: Annualized relapse rate (ARR) and safety data were obtained from a network meta-analysis (NMA) of clinical trials of RRMS treatments including ozanimod, fingolimod, dimethyl fumarate, teriflunomide, interferon beta-1a, interferon beta-1b, and glatiramer acetate. ARR-related number needed to treat (NNT) relative to placebo and annual total MS-related healthcare costs was used to estimate the incremental annual cost per relapse avoided with ozanimod vs each DMT. ARR and adverse event (AE) data were combined with drug costs and healthcare costs to manage relapses and AEs in order to estimate annual cost savings with ozanimod vs other DMTs, assuming a 1 million USD fixed treatment budget. RESULTS: Treatment with ozanimod was associated with lower incremental annual healthcare costs to avoid a relapse, ranging from $843,684 vs interferon beta-1a (30 µg; 95% confidence interval [CI] - $1,431,619, - $255,749) to $72,847 (95% CI - $153,444, $7750) vs fingolimod. Compared with all other DMTs, ozanimod was associated with overall healthcare cost savings ranging from $8257 vs interferon beta-1a (30 µg) to $2178 vs fingolimod. Compared with oral DMTs, ozanimod was associated with annual cost savings of $6199 with teriflunomide 7 mg, $4737 with teriflunomide 14 mg, $2178 with fingolimod, and $2793 with dimethyl fumarate. CONCLUSION: Treatment with ozanimod was associated with substantial reductions in annual drug costs and total MS-related healthcare costs to avoid relapses compared with other DMTs. In the fixed-budget analysis, ozanimod demonstrated a favorable cost-effective profile relative to other DMTs.

Arbaclofen extended-release tablets for spasticity in multiple sclerosis: open-label extension study.

Baclofen, a racemic γ-aminobutyric acid B receptor agonist, is commonly used for the management of multiple sclerosis-related spasticity but is associated with frequent dosing and poor tolerability. Arbaclofen, the active R-enantiomer of baclofen, exhibits 100- to 1000-fold greater specificity for the γ-aminobutyric acid B receptor compared with the S-enantiomer and ∼5-fold greater potency compared with racemic baclofen. Arbaclofen extended-release tablets allow a dosing interval of 12 h and have shown a favourable safety and efficacy profile in early clinical development. A 12-week, randomized, placebo-controlled Phase 3 trial in adults with multiple sclerosis-related spasticity demonstrated that arbaclofen extended-release 40 mg/day significantly reduced spasticity symptoms compared with placebo and was safe and well tolerated. The current study is an open-label extension of the Phase 3 trial designed to evaluate the long-term safety and efficacy of arbaclofen extended-release. In a 52-week, open-label, multicentre study, adults with a Total Numeric-transformed Modified Ashworth Scale score ≥2 in the most affected limb received oral arbaclofen extended-release titrated over 9 days up to 80 mg/day based on tolerability. The primary objective was assessment of arbaclofen extended-release safety and tolerability. Secondary objectives included an assessment of efficacy using the Total Numeric-transformed Modified Ashworth Scale-most affected limb, the Patient Global Impression of Change and Expanded Disability Status Scale. Of 323 patients enrolled, 218 (67.5%) completed 1 year of treatment. Most patients (74.0%) achieved an arbaclofen extended-release maintenance dose of 80 mg/day. At least one treatment-emergent adverse event was reported by 278 patients (86.1%). The most common adverse events were [n patients (%)]: urinary tract disorder [112 (34.7)], muscle weakness [77 (23.8)], asthenia [61 (18.9)], nausea [70 (21.7)], dizziness [52 (16.1)], somnolence [41 (12.7)], vomiting [29 (9.0)], headache [24 (7.4)] and gait disturbance [20 (6.2)]. Most adverse events were of mild-moderate severity. Twenty-eight serious adverse events were reported. One death occurred during the study, a myocardial infarction that was considered by investigators as unlikely to be related to treatment. Overall, 14.9% of patients discontinued due to adverse events, primarily muscle weakness, multiple sclerosis relapse, asthenia and nausea. Evidence of improvement in multiple sclerosis-related spasticity was observed across arbaclofen extended-release dosages. Arbaclofen extended-release treatment (up to 80 mg/day) was well tolerated and reduced symptoms of spasticity in adult patients with multiple sclerosis for 1 year. Clinical Trial Identifier: ClinicalTrials.gov, NCT03319732.

Arbaclofen extended-release tablets for spasticity in multiple sclerosis: randomized, controlled clinical trial.

Baclofen, a racemic GABA-B (GABAB) receptor agonist, is commonly used for the management of multiple sclerosis-related spasticity but is associated with frequent dosing and poor tolerability. Arbaclofen, the active R-enantiomer of baclofen, exhibits 100- to 1000-fold greater specificity for the GABAB receptor compared with the S-enantiomer and ∼5-fold greater potency compared with racemic baclofen. Arbaclofen extended-release tablets have a dosing interval of 12 hours and have shown a favourable safety and efficacy profile in early-phase clinical development. The current Phase 3 study was designed to evaluate the efficacy and safety of arbaclofen extended-release tablets in patients with multiple sclerosis-related spasticity. In this multicentre, double-blind, placebo-controlled study, adults with multiple sclerosis-related spasticity were randomized to arbaclofen extended-release 40 mg/day, arbaclofen extended-release 80 mg/day or placebo for 12 weeks. The co-primary end-points were the change from baseline to Week 12 in the Total Numeric-transformed Modified Ashworth Scale in the Most Affected Limb score and the Clinical Global Impression of Change score. A hierarchical testing procedure was used to evaluate the co-primary end-points; analyses for the 80 mg/day group were considered inferential only if the arbaclofen extended-release 40 mg/day and placebo groups demonstrated a statistically significant difference (P ≤ 0.05) for both end-points. Five hundred thirty-six patients were included in the study. At Week 12, the least squares mean change from baseline in Total Numeric-transformed Modified Ashworth Scale in the Most Affected Limb score was -1.67 (95% confidence interval: -1.97 to -1.36) and -1.28 (95% confidence interval: -1.57 to -0.99) in the arbaclofen extended-release 40 mg/day and placebo groups, respectively (least squares mean difference: -0.39; P < 0.048). Improvements were seen in the mean Clinical Global Impression of Change scores for both the arbaclofen extended-release 40 mg/day and placebo groups; however, no statistically significant difference was observed between them (least squares mean difference: -0.10; P = 0.43). Most adverse events were of mild-moderate severity. Arbaclofen extended-release 40 mg/day for 12 weeks significantly reduced multiple sclerosis-related spasticity compared with placebo and was safe and well tolerated over the 12-week treatment period. Although arbaclofen extended-release 40 mg/day improved Clinical Global Impression of Change scores, a significant difference from placebo was not observed.

Digital Scientific Platform for Independent Content in Neurology: Rigorous Quality Guideline Development and Implementation.

BACKGROUND: Digital communication has emerged as a major source of scientific and medical information for health care professionals. There is a need to set up an effective and reliable methodology to assess and monitor the quality of content that is published on the internet. OBJECTIVE: The aim of this project was to develop content quality guidelines for Neurodiem, an independent scientific information platform dedicated to neurology for health care professionals and neuroscientists. These content quality guidelines are intended to be used by (1) content providers as a framework to meet content quality standards and (2) reviewers as a tool for analyzing and scoring quality of content. METHODS: Specific scientific criteria were designed using a 5-point scale to measure the quality of curated and original content published on the website: for Summaries, (1) source reliability and topic relevance for neurologists, (2) structure, and (3) scientific and didactic value; for Congress highlights, (1) relevance of congress selection, (2) congress coverage based on the original program, and (3) scientific and didactic value of individual abstracts; for Expert points of view and talks, (1) credibility (authorship) and topic relevance for neurologists, (2) scientific and didactic value, and (3) reliability (references) and format. The criteria were utilized on a monthly basis and endorsed by an independent scientific committee of widely recognized medical experts in neurology. RESULTS: Summary content quality for the 3 domains (reliability and relevance, structure, and scientific and didactic value) increased in the second month after the implementation of the guidelines. The domain scientific and didactic value had a mean score of 8.20/10. Scores for the domains reliability and relevance (8-9/10) and structure (45-55/60) showed that the maintenance of these 2 quality items over time was more challenging. Talks (either in the format of interviews or slide deck-supported scientific presentations) and expert point of view demonstrated high quality after the implementation of the content quality guidelines that was maintained over time (15-25/25). CONCLUSIONS: Our findings support that content quality guidelines provide both (1) a reliable framework for generating independent high-quality content that addresses the educational needs of neurologists and (2) are an objective evaluation tool for improving and maintaining scientific quality level. The use of these criteria and this scoring system could serve as a standard and reference to build an editorial strategy and review process for any medical news or platforms.

Confirmed 6-Month Disability Improvement and Worsening Correlate with Long-term Disability Outcomes in Alemtuzumab-Treated Patients with Multiple Sclerosis: Post Hoc Analysis of the CARE-MS Studies.

INTRODUCTION: In the 2-year CARE-MS trials (NCT00530348; NCT00548405) in patients with relapsing-remitting multiple sclerosis, alemtuzumab showed superior efficacy versus subcutaneous interferon beta-1a. Efficacy was maintained in two consecutive extensions (NCT00930553; NCT02255656). This post hoc analysis compared disability outcomes over 9 years among alemtuzumab-treated patients according to whether they experienced confirmed disability improvement (CDI) or worsening (CDW) or neither CDI nor CDW. METHODS: CARE-MS patients were randomized to receive two alemtuzumab courses (12 mg/day; 5 days at baseline; 3 days at 12 months), with additional as-needed 3-day courses in the extensions. CDI or CDW were defined as ≥ 1.0-point decrease or increase, respectively, in Expanded Disability Status Scale (EDSS) score from core study baseline confirmed over 6 months, assessed in patients with baseline EDSS score ≥ 2.0. Improved or stable EDSS scores were defined as ≥ 1-point decrease or ≤ 0.5-point change (either direction), respectively, from core study baseline. Functional systems (FS) scores were also assessed. RESULTS: Of 511 eligible patients, 43% experienced CDI and 34% experienced CDW at any time through year 9 (patients experiencing both CDI and CDW were counted in each individual group); 29% experienced neither CDI nor CDW. At year 9, patients with CDI had a -0.58-point mean EDSS score change from baseline; 88% had stable or improved EDSS scores. Improvements occurred across all FS, primarily in sensory, pyramidal, and cerebellar domains. Patients with CDW had a +1.71-point mean EDSS score change; 16% had stable or improved EDSS scores. Patients with neither CDI nor CDW had a -0.10-point mean EDSS score change; 98% had stable or improved EDSS scores. CONCLUSION: CDI achievement at any point during the CARE-MS studies was associated with improved disability at year 9, highlighting the potential of alemtuzumab to change the multiple sclerosis course. Conversely, CDW at any point was associated with worsened disability at year 9.

Treatment Patterns and Relapses Among Newly Treated Multiple Sclerosis Patients From a Retrospective Claims Analysis.

PURPOSE: Although all disease-modifying therapies (DMTs) reduce risk of relapse in multiple sclerosis (MS), many factors, including route of administration, influence selection of first-line DMT. Knowledge of real-world treatment patterns and effectiveness in reducing relapses across DMTs is important to understanding factors influencing this choice. This study sought to describe treatment patterns and relapses among newly treated adults with MS and by DMT route of administration (oral, injectable, and infusion). METHODS: IBM MarketScan research databases were used to identify MS adults newly initiating DMTs (index event) from January 1, 2011-April 1, 2016, who had 12 months of continuous preindex and postindex medical and pharmacy benefits. Newly treated patients were those with ≥2 nondiagnostic claims with an International Classification of Diseases, Ninth Revision, Clinical Modification (340) or Tenth Revision, Clinical Modification (G35) code and no DMT prescription claims in the 12 months' preindex. Persistence and adherence were measured from index until the earliest of ≥60 days without DMT, switching DMTs, or end of follow-up. Relapses were defined using a validated claims-based algorithm and measured in the 12-month preindex and postindex periods. Regression analysis adjusting for patient characteristics and prior relapses was used to determine the association between DMT route of administration and odds of 12-month persistence, odds of postindex relapse, and number of postindex relapses. FINDINGS: Of 9378 newly treated MS patients meeting inclusion criteria; average age was 46.7 years, and 73.3% were female. Most patients initiated an injectable (65.5%) or oral (26.1%) DMT. Relapses decreased markedly from preindex to postindex (32.9%-24.0%), which was highest among oral users (35.8%-21.6%). Patients with no (vs ≥3) relapses preindex were more likely to be relapse free postindex (81.6% vs 31.4%). Nonpersistence (39.1% overall) was lowest among oral users (33.4%) and higher among those with versus without a postindex relapse (50.6% vs 35.5%). Patients initiating oral versus injectable agents were more likely to be persistent at 12 months (odds ratio [OR], 1.45; p < 0.0001) and less likely to relapse (OR, 0.75; p < 0.0001) postindex. Switches were uncommon (~10%) across cohorts. Preindex relapses were associated with increased odds of postindex relapses (OR, 1.73; p < 0.0001) but not with odds of persistence at 12 months. IMPLICATIONS: The 12-month nonpersistence rate was high among all MS patients but lower among oral users. Oral users were also less likely to relapse postindex. Despite the effectiveness of DMTs in reducing relapses, the low persistence, lack of switching to a new DMT, and continued relapses highlight an unmet need in the MS treatment landscape.

Multiple sclerosis relapse rates and healthcare costs of two versions of glatiramer acetate.

Objective: To compare relapse rates and healthcare costs in MS patients treated with Glatopa 20 mg (generic glatiramer acetate) versus Copaxone 20 mg in a US managed care population.Methods: A retrospective claims study was conducted using the HealthCore Integrated Research Database. Patients with ≥1 Glatopa or Copaxone claim between 01 April 2015 (Glatopa) or 01 January 2013 (Copaxone) and 30 April 2018 were included. Patients with prior Copaxone 40 mg use or <1 year continuous health plan enrollment were excluded. Patients who switched from Glatopa to Copaxone were censored. Glatopa users were matched to Copaxone users, and outcomes measured at 6-12 months follow-up.Results: A total of 357 Glatopa and 2291 Copaxone patients qualified for inclusion; 158 per cohort were retained after matching. Baseline characteristics were well-balanced (mean age 49.9 years, 75% female, mean 3.8 Copaxone fills). At baseline, 8% of patients had ≥1 relapse with mean annualized relapse rates (ARR) of 0.18; at follow-up, the relapse rates were 8% versus 15% (Glatopa versus Copaxone; p = .05), and ARRs were 0.12 versus 0.30 (p = .05). 45% of Glatopa patients switched (back) to Copaxone 20/40 mg and were censored at that point. Mean (SD) all-cause medical and pharmacy costs were $51,507 ($28,494) versus $55,085 ($37,061; p = .50). Mean MS-related costs were $45,379 ($24,732) versus $47,949 ($32,615; p = .67), of which mean disease modifying therapy costs were $42,926 ($23,196) versus $44,932 ($28,554; p = .59). Results were similar in sensitivity analyses.Conclusions: In this real-world study, MS patients treated with Glatopa experienced similar health outcomes and costs compared to those treated with Copaxone, with a trend towards lower relapse rates (borderline statistically significant) and cost savings (not statistically significant).

Two Sides to Every Story: Perspectives from Four Patients and a Healthcare Professional on Multiple Sclerosis Disease Progression.

Multiple sclerosis (MS) is a chronic progressive disease and many patients transition from an initial relapsing-remitting course to a secondary progressive pattern. Accurate classification of disease status is critical to ensure that patients are treated appropriately and kept informed of their prognosis. Consensus terms defining the different forms of MS are available but were developed primarily for healthcare professionals (HCPs) and may be of limited value to patients. This article provides direct insights from four patients with MS, at different points in their disease trajectory, regarding their understanding of, and attitudes toward, MS progression. We also examine the utility of the current classification systems from the perspectives of patients and HCPs. Responses collected during in-depth, structured interviews and questionnaires portrayed the difficulties patients face accepting their MS diagnosis and treatment, revealed how understanding of the term "disease progression" varies considerably, and highlighted the challenges surrounding the period of transition to secondary progressive MS (SPMS). The terms describing different MS types were considered confusing and can make patients feel "compartmentalized" or "labeled". Patients also struggled to relate these terms to their reality of living with MS, were reluctant to discuss progression with their HCPs, and feared being diagnosed with SPMS owing to concerns about treatment access. These insights highlight the need to develop patient-friendly language to describe MS progression; it may also be preferable for HCPs to describe MS as a disease spectrum in discussions with their patients. FUNDING: Novartis Pharmaceuticals Corporation. Plain language summary available for this article.

Effectiveness of alternative dose fingolimod for multiple sclerosis.

BACKGROUND: Fingolimod is a daily oral medication used to treat relapsing multiple sclerosis (MS). Clinicians often adopt less frequent dosing for patients with profound drug-induced lymphopenia or other adverse events. Data on the effectiveness of alternate dose fingolimod are limited. METHODS: We conducted a multicenter, retrospective, observational study at 14 sites and identified 170 patients with MS taking alternate doses of fingolimod for ≥1 month. Clinical and radiologic outcomes were collected and compared during daily and alternate fingolimod dosing. RESULTS: Profound lymphopenia (77%), liver function abnormalities (9%), and infections (7%) were the most common reasons for patients to switch to alternate fingolimod dosing. The median follow-up was 12 months on daily dose and 14 months on alternate dose. Most patients (64%) took fingolimod every other day during alternate dosing. Disease activity was similar on alternate dose compared to daily dose: annualized relapse rate was 0.1 on daily dose vs 0.2 on alternate dose (p = 0.25); proportion of patients with contrast-enhancing MRI lesions was 7.6% on daily vs 9.4% on alternate (p = 0.55); proportion of patients with cumulative MS activity (clinical and radiologic disease) was 13.5% on daily vs 18.2% on alternate (p = 0.337). Patients who developed contrast-enhancing lesions while on daily dose were at higher risk for breakthrough disease while on alternate dose fingolimod (odds ratio 11.4, p < 0.001). CONCLUSIONS: These data support the clinical strategy of alternate dosing of fingolimod in patients with good disease control but profound lymphopenia or other adverse events while on daily dose. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with MS on daily dose fingolimod with adverse events, alternate dose fingolimod is associated with disease activity similar to daily dose fingolimod.

Real-world persistence with fingolimod for the treatment of multiple sclerosis: A systematic review and meta-analysis.

OBJECTIVE: To systematically review reports of fingolimod persistence in the treatment of relapsing-remitting multiple sclerosis (RRMS) across data sources and practice settings, and to develop a consensus estimate of the 1-year real-world persistence rate. METHODS: A systematic literature review was conducted (MEDLINE, EMBASE, and abstracts from selected conferences [2013-2015]) to identify observational studies reporting 1-year fingolimod persistence among adult patients with RRMS (sample size ≥50). A random-effects meta-analysis was performed to estimate a synthesized 1-year persistence rate and to assess heterogeneity across studies. RESULTS: Of 527 publications identified, 25 real-world studies reporting 1-year fingolimod persistence rates were included. The studies included patients from different data sources (e.g., administrative claims, electronic medical records, or registries), used different definitions of persistence (e.g., based on prescriptions refills, patient report, or prescription orders), and spanned multiple geographic regions. Reported 1-year persistence rates ranged from 72%-100%, and exhibited statistical evidence of heterogeneity (I2 = 93% of the variability due to heterogeneity across studies). The consensus estimate of the 1-year persistence rate was 82% (95% confidence interval: 79%-85%). CONCLUSIONS: Across heterogeneous study designs and patient populations found in real-world studies, the consensus 1-year fingolimod persistence rate exceeded 80%, consistent with persistence rates identified in the recently-completed trial, PREFERMS.

Development of Glatopa® (Glatiramer Acetate): The First FDA-Approved Generic Disease-Modifying Therapy for Relapsing Forms of Multiple Sclerosis.

The multiple sclerosis (MS) treatment landscape in the United States has changed dramatically over the past decade. While many disease-modifying therapies (DMTs) have been approved by the US Food and Drug Administration (FDA) for the treatment of relapsing forms of MS, DMT costs continue to rise. The availability of generics and biosimilars in the MS-treatment landscape is unlikely to have a major impact on clinical benefit. However, their availability will provide alternative treatment options and potentially lower costs through competition, thus increasing the affordability of and access to these drugs. In April 2015, the first generic version of the complex drug glatiramer acetate (Glatopa® 20 mg/mL) injection was approved in the United States as a fully substitutable generic for all approved indications of the 20 mg/mL branded glatiramer acetate (Copaxone®) dosage form. Despite glatiramer acetate's complex nature-being a chemically synthesized (ie, nonbiologic) mixture of peptides-the approval occurred without conducting any clinical trials. Rather, extensive structural and functional characterization was performed to demonstrate therapeutic equivalence to the innovator drug. The approval of Glatopa signifies an important milestone in the US MS-treatment landscape, with the hope that the introduction of generic DMTs and eventually biosimilar DMTs will lead to future improvements in the affordability and access of these much-needed treatments for MS.

Perspectives from the Patient and the Healthcare Professional in Multiple Sclerosis: Social Media and Participatory Medicine.

When faced with a diagnosis of multiple sclerosis (MS), patients often turn to the Internet and social media to find support groups, read about the experiences of other people affected by MS and seek their advice, and research their condition and treatment options to discuss with their healthcare professionals (HCPs). Here, we examine the use of social media and the Internet among patients with MS, considering its impact on patient empowerment and patient participation in treatment decision-making and MS research. These themes are exemplified with first-hand experiences of the patient author. We also explore the impact of the Internet and social media on the management of patients from the perspective of HCPs, including new opportunities for HCPs to engage in participatory medicine and to improve communication with and among patients. We consider both the benefits afforded to and the potential pitfalls faced by HCPs when interacting with their patients via these routes, and discuss potential concerns around privacy and confidentiality in the use of the Internet and social media in the clinical context. Communication online is driving the evolution of the patient-HCP relationship, and is empowering patients to participate more actively in the decision-making process relating to the provision of their health care. Funding Novartis Pharmaceuticals Corporation.

Perspectives from the Patient and the Healthcare Professional in Multiple Sclerosis: Social Media and Patient Education.

A diagnosis of multiple sclerosis (MS) is life-altering. Because the course of MS is heterogeneous, patients may face uncertainty in terms of long-term physical and cognitive challenges, potential loss of employment, and the risk of social isolation. Patients often turn to the Internet and social media for information about MS and its management, and to seek out fellow patients and support groups. Here, we examine the use of social media and the Internet among patients with MS, considering its impact on patient education. We consider the access that these conduits provide not only to other patients with MS but also to a wealth of disease-related information online. These themes are further illustrated with first-hand experiences of the patient author and her physician. We also explore the impact of the Internet and social media on the education and support of patients with MS from the healthcare professional's (HCP's) perspective, including opportunities for HCPs to promote disease education among their patients, and the advantages that arise from patients being better informed about their disease. The rise of the Internet and social media has changed the patient experience, helping patients to support each other, to educate themselves proactively about their condition, and to participate more actively in decisions relating to disease management than perhaps was the case historically. Funding Novartis Pharmaceuticals Corporation.

Safety and efficacy of dual-lead thalamic deep brain stimulation for patients with treatment-refractory multiple sclerosis tremor: a single-centre, randomised, single-blind, pilot trial.

BACKGROUND: Efficacy in previous studies of surgical treatments of refractory multiple sclerosis tremor using lesioning or deep brain stimulation (DBS) has been variable. The aim of this study was to investigate the safety and efficacy of dual-lead thalamic DBS (one targeting the ventralis intermedius-ventralis oralis posterior nucleus border [the VIM lead] and one targeting the ventralis oralis anterior-ventralis oralis posterior border [the VO lead]) for the treatment of multiple sclerosis tremor. METHODS: We did a single centre, single-blind, prospective, randomised pilot trial at the University of Florida Center for Movement Disorders and Neurorestoration clinic (Gainesville, FL, USA). We recruited adult patients with a clinical diagnosis of multiple sclerosis tremor refractory to previous medical therapy. Before surgery to implant both leads, we randomly assigned patients (1:1) to receive 3 months of optimised single-lead DBS-either VIM or VO. We did the randomisation with a computer-generated sequence, using three blocks of four patients, and independent members of the Center did the assignment. Patients and all clinicians other than the DBS programming nurse were masked to the choice of lead. Patients underwent surgery 1 month after their baseline visit for implantation of the dual lead DBS system. A pulse generator and two extension cables were implanted in a second surgery 3-4 weeks later. Patients then received an initial 3-month period of continuous stimulation of either the VIM or VO lead followed by blinded safety assessment of their tremor with the Tolosa-Fahn-Marin Tremor Rating Scale (TRS) during optimised VIM or VO lead stimulation at the end of the 3 months. After this visit, both leads were activated in all patients for an additional 3 months, and optimally programmed during serial visits as dictated by a prespecified programming algorithm. At the 6-month follow-up visit, TRS score was measured, and mood and psychological batteries were administered under four stimulation conditions: VIM on, VO on, both on, and both off (the order of testing was chosen by a computer-generated random sequence, assigned by independent members of the centre, and enacted by an unmasked DBS programming nurse). Each of four stimulation settings were tested over 4 consecutive days, with stimulation settings held constant for at least 12 h before testing. The primary outcome was change in mean total TRS score at the 6-month postoperative assessment with both leads activated, compared with the preoperative baseline mean TRS score. Analysis was by intention to treat. Safety was analysed in all patients who received the surgical implantation except in one patient who discontinued before the safety assessment. This trial is registered with ClinicalTrials.gov, number NCT00954421. FINDINGS: Between Jan 16, 2007, and Dec 17, 2013, we enrolled 12 patients who were randomly assigned either to 3 initial months of VIM-only or VO-only stimulation. One patient from the VO-only group developed an infection necessitating DBS explantation, and was excluded from the assessment of the primary outcome. Compared with the mean baseline TRS score of 57·0 (SD 10·2), the mean score at 6 months decreased to 40·1 (17·6), -29·6% reduction; t=-0·28, p=0·03. Three of 11 patients did not respond to surgical intervention. One patient died suddenly 2 years after surgery, but this was judged to be unrelated to DBS implantation. Serious adverse events included a superficial wound infection in one patient that resolved with antibiotic therapy, and transient altered mental status and late multiple sclerosis exacerbation in another patient. The most common non-serious adverse events were headache and fatigue. INTERPRETATION: Dual lead thalamic DBS might be a safe and effective option for improving severe, refractory multiple sclerosis tremor. Larger studies are necessary to show whether this technique is widely applicable, safe in the long-term, and effective in treating multiple sclerosis tremor or other severe tremor disorders. FUNDING: US National Institutes of Health, the Cathy Donnellan, Albert E Einstein, and Birdie W Einstein Fund, and the William Merz Professorship.

Two decades of glatiramer acetate: From initial discovery to the current development of generics.

Multiple sclerosis (MS) is a chronic, incurable, inflammatory disease of the central nervous system (CNS). In the United States, several US Food and Drug Administration (FDA)-approved disease-modifying treatments (DMTs) are available, including glatiramer acetate (GA; Copaxone®), one of the most longstanding treatments. GA was discovered serendipitously in the late 1960s/early 1970s while attempting to produce a synthetic antigen capable of inducing experimental autoimmune encephalomyelitis (EAE), an animal model of autoimmune inflammatory CNS disorders, including MS. Instead, GA was found to be protective in EAE models. Subsequent clinical evaluations resulted in GA's FDA approval for relapsing-remitting MS in 1996, followed by a change to the current indication of relapsing forms of MS along with approval of a higher dose and less frequently administered version in 2014. The cost of DMTs including GA remains high, highlighting the potential value of generic therapies for MS. A rigorous scientific approach may be undertaken to demonstrate equivalence between the generic and innovator drug. The introduction of generic versions of GA into the MS treatment landscape has the potential to reduce treatment costs, improving access to these much-needed treatments.

Demonstration of Biological and Immunological Equivalence of a Generic Glatiramer Acetate.

BACKGROUND: In April 2015, the US Food and Drug Administration approved the first generic glatiramer acetate, Glatopa® (M356), as fully substitutable for Copaxone® 20 mg/mL for relapsing forms of multiple sclerosis (MS). This approval was accomplished through an Abbreviated New Drug Application that demonstrated equivalence to Copaxone. METHOD: This article will provide an overview of the methods used to establish the biological and immunological equivalence of the two glatiramer acetate products, including methods evaluating antigenpresenting cell (APC) biology, T-cell biology, and other immunomodulatory effects. RESULTS: In vitro and in vivo experiments from multiple redundant orthogonal assays within four biological processes (aggregate biology, APC biology, T-cell biology, and B-cell biology) modulated by glatiramer acetate in MS established the biological and immunological equivalence of Glatopa and Copaxone and are described. The following were observed when comparing Glatopa and Copaxone in these experiments: equivalent delays in symptom onset and reductions in "disease" intensity in experimental autoimmune encephalomyelitis; equivalent dose-dependent increases in Glatopa- and Copaxone- induced monokine-induced interferon-gamma release from THP-1 cells; a shift to a T helper 2 phenotype resulting in the secretion of interleukin (IL)-4 and downregulation of IL-17 release; no differences in immunogenicity and the presence of equivalent "immunofingerprints" between both versions of glatiramer acetate; and no stimulation of histamine release with either glatiramer acetate in basophilic leukemia 2H3 cell lines. CONCLUSION: In summary, this comprehensive approach across different biological and immunological pathways modulated by glatiramer acetate consistently supported the biological and immunological equivalence of Glatopa and Copaxone.

Demonstration of equivalence of a generic glatiramer acetate (Glatopa™).

Glatiramer acetate (GA) has been available under the brand name Copaxone® for nearly two decades. Recently, the US Food and Drug Administration (FDA) approved the first generic GA, Glatopa™, as fully substitutable for all indications for which Copaxone 20mg is approved; Glatopa also represents the first FDA-approved "AP-rated," substitutable generic for treating patients with MS. Glatiramer acetate is a complex mixture of polypeptides and, consequently, its characterization presented challenges not generally encountered in drug development. Despite its complexity, and without requiring any clinical data, approval was accomplished through an Abbreviated New Drug Application in which equivalence to Copaxone was evaluated across four criteria: starting materials and basic chemistry; structural signatures for polymerization, depolymerization, and purification; physicochemical properties; and biological and immunological properties. This article describes the rigorous overall scientific approach used to successfully establish equivalence between Glatopa and Copaxone, and presents key representative data from several of the comprehensive sets of physicochemical (structural) and biological (functional) assays that were conducted.

Equivalent Gene Expression Profiles between Glatopa™ and Copaxone®.

Glatopa™ is a generic glatiramer acetate recently approved for the treatment of patients with relapsing forms of multiple sclerosis. Gene expression profiling was performed as a means to evaluate equivalence of Glatopa and Copaxone®. Microarray analysis containing 39,429 unique probes across the entire genome was performed in murine glatiramer acetate--responsive Th2-polarized T cells, a test system highly relevant to the biology of glatiramer acetate. A closely related but nonequivalent glatiramoid molecule was used as a control to establish assay sensitivity. Multiple probe-level (Student's t-test) and sample-level (principal component analysis, multidimensional scaling, and hierarchical clustering) statistical analyses were utilized to look for differences in gene expression induced by the test articles. The analyses were conducted across all genes measured, as well as across a subset of genes that were shown to be modulated by Copaxone. The following observations were made across multiple statistical analyses: the expression of numerous genes was significantly changed by treatment with Copaxone when compared against media-only control; gene expression profiles induced by Copaxone and Glatopa were not significantly different; and gene expression profiles induced by Copaxone and the nonequivalent glatiramoid were significantly different, underscoring the sensitivity of the test system and the multiple analysis methods. Comparative analysis was also performed on sets of transcripts relevant to T-cell biology and antigen presentation, among others that are known to be modulated by glatiramer acetate. No statistically significant differences were observed between Copaxone and Glatopa in the expression levels (magnitude and direction) of these glatiramer acetate-regulated genes. In conclusion, multiple methods consistently supported equivalent gene expression profiles between Copaxone and Glatopa.