Search

Background: Multiple sclerosis (MS) slowly expanding lesions (SELs) are defined on magnetic resonance imaging (MRI) as contiguous regions of pre-existing focal non-contrast-enhancing T2 lesions with constant and concentric local expansion on conventional T1-weighted and T2-weighted images. SELs are associated with an increased risk of disability progression., Methods: Myelin-related changes detected using myelin water fraction (MWF) and magnetisation transfer ratio (MTR) in SELs and T2 lesions were measured over 192 weeks in participants with relapsing MS., Results: In participants with SELs (SEL+), SELs (MWF: 0.12 ± 0.03, MTR: 33.1 ± 3.6 pu) showed reduced myelin measures at baseline compared to T2 lesions (MWF: 0.13 ± 0.02, MTR: 35.1 ± 2.4 pu). In participants without SELs (SEL-), T2 lesions had higher myelin measures (MWF: 0.15 ± 0.02, MTR: 36.2 ± 2.0 pu) compared to T2 lesions in SEL+. Over 4 years, only SELs showed decreases in MWF (-11.4%). The percentage of abnormal voxels within normal-appearing white matter was higher in SEL+ and increased over time (SEL+ MWF Week 0: 0.56%, Week 192: 0.98%; SEL- MWF Week 0: 0.13%, Week 192: 0.25%)., Conclusion: Our results indicate progressive focal and global demyelination in SEL+ participants and that the presence of SELs might be a biomarker for participants with ongoing diffuse or smouldering inflammation within the whole brain., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: I Vavasour has nothing to disclose. C Elliott is an employee of NeuroRx Research. DL Arnold has received consulting fees from Alkermes, Biogen, Celgene, Genentech/Roche, Frequency Therapeutics, Immunotec, Immune Tolerance Network, MedDay, Merck-Serono, Novartis, Pfizer, and Sanofi-Aventis. He has carried out contracted research for Novartis and Biogen. L Gaetano is an employee of Novartis AG. D Clayton is an employee and shareholder of F. Hoffmann-La Roche Ltd. S Magon is an employee and shareholder of F. Hoffmann-La Roche Ltd. U Bonati is an employee and shareholder of F. Hoffmann-La Roche Ltd. C Bernasconi is an employee of Limites Medical Research. A Traboulsee has received research support from Sanofi Genzyme and Roche; has received consulting fees from Sanofi Genzyme, Roche, Teva Neuroscience, Novartis, Biogen and EMD Serono; and has received honoraria for his involvement in speaker bureau activities for Sanofi Genzyme and Roche. S Kolind has received research support from Biogen, Roche and Sanofi Genzyme and consulting fees from Novartis and Roche.

Background: Limited licensed medications are available for multiple sclerosis (MS) in pediatric patients., Objective: To evaluate the efficacy, safety, and tolerability of alemtuzumab in pediatric patients with relapsing-remitting multiple sclerosis (RRMS) and disease activity on prior disease-modifying therapies (DMTs)., Methods: LemKids was a multicenter, multinational, single-arm, open-label, switch (from ongoing DMT to alemtuzumab treatment) study in pediatric RRMS patients (aged 10-<18 years), with disease activity on DMT. The primary endpoint was a comparison of the number of new/enlarging T2 lesions on the magnetic resonance imaging of the brain between the prior-DMT period and alemtuzumab treatment., Results: This study was prematurely terminated due to low enrollment and an European Medicines Agency Article-20 pharmacovigilance review of alemtuzumab in adult RRMS. Of 46 screened patients, 16 were enrolled; 12 completed prior-DMT treatment period; 11 received alemtuzumab of whom 7 completed treatment. Patients on alemtuzumab developed fewer new/enlarging T2 lesions compared with prior-DMT (7 vs 178, relative risk (95% confidence interval): 0.04 (0.01-0.14)). No significant pharmacodynamic changes or safety concerns were noted in this limited dataset., Conclusion: Alemtuzumab treatment was associated with a low number of new/enlarging T2 lesions in pediatric patients with RRMS and was safe and well tolerated in seven patients during infusion and the initial 4 months., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: T.C. received consulting fees from Genentech-Roche and Novartis; is member of advisory boards of Novartis, Roche-Genentech, and Sanofi; received research support from Novartis, Sanofi, Serono, and Verily; and received speaking fees from Medscape. D.L.A. received personal compensation for serving as a consultant for Alexion, Biogen, Celgene, Eli Lilly, EMD Serono, Frequency Therapeutics, Genentech, Merck, Novartis, Roche, Sanofi, and Shionogi; and holds an equity interest in NeuroRx. P.Q. received consultancy or speaking fees from AbbVie, Amgen, Bristol-Myers Squibb, Chugai-Roche, Eli Lilly, Novartis, Novimmune, Pfizer, and Swedish Orphan Biovitrum; and participated in two data safety monitoring boards for Sanofi. M.C., W.H., and S.J. are employees of Sanofi; may hold shares and/or stock options in the company. E.K.H. received honoraria and grant support from Actelion, Biogen, Merck Serono, Janssen, Novartis, Receptos, Roche, Sanofi, and Teva; and support from the Ministry of Education of Czech Republic project (Cooperation LF1, research area Neuroscience) and the National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107—funded by the European Union-Next Generation EU).

Slowly expanding lesions (SELs) in adults with multiple sclerosis (MS) indicate a progressive pathological process. Whether SELs are present in pediatric-onset MS (POMS) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is unknown. We studied 19 children with POMS and 14 with MOGAD (median age 14.3 and 9.4 years, respectively) recruited to the Canadian Pediatric Demyelinating Disease Study with: (1) ≥3 research scans 12 months apart; and (2) ≥1 T2-lesions on the earliest scan. A total of 70 SELs from 16 POMS participants and 1 SEL in the MOGAD group were detected. SELs are an early feature of POMS and essentially not a feature of MOGAD. ANN NEUROL 2024;96:1086-1091., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Evobrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, has shown preliminary efficacy in people with relapsing multiple sclerosis in a phase 2 trial. Here, we aimed to compare the safety and efficacy of evobrutinib with the active comparator teriflunomide in people with relapsing multiple sclerosis., Methods: EvolutionRMS1 and evolutionRMS2 were two multicentre, randomised, double-blind, double-dummy, active-controlled, phase 3 trials conducted at 701 multiple sclerosis centres and neurology clinics in 52 countries. Adults aged 18-55 years with relapsing multiple sclerosis (Expanded Disability Status Scale [EDSS] score of 0·0-5·5) were included. Participants were randomly assigned (1:1) using a central interactive web response system to receive either evobrutinib (45 mg twice per day with placebo once per day) or teriflunomide (14 mg once per day with placebo twice per day), all taken orally and in an unfasted state, with randomisation stratified by geographical region and baseline EDSS. All study staff and participants were masked to the study interventions. The primary endpoint for each study was annualised relapse rate based on adjudicated qualified relapses up to 156 weeks, assessed in the full analysis set (defined as all randomly assigned participants) with a negative binomial model. These studies are registered with ClinicalTrials.gov (NCT04338022 for evolutionRMS1 and NCT04338061 for evolutionRMS2, both are terminated)., Findings: The primary analysis was done using data for 2290 randomly assigned participants collected from June 12, 2020, to Oct 2, 2023. 1124 participants were included in the full analysis set in evolutionRMS1 (560 in the evobrutinib group and 564 in the teriflunomide group) and 1166 in evolutionRMS2 (583 in each group). 751 (66·8%) participants were female and 373 (33·1%) were male in evolutionRMS1, whereas 783 (67·2%) were female and 383 (32·8%) were male in evolutionRMS2. Annualised relapse rate was 0·15 (95% CI 0·12-0·18 with evobrutinib vs 0·14 [0·11-0·18] with teriflunomide (adjusted RR 1·02 [0·75-1·39]; p=0·55) in evolutionRMS1 and 0·11 (0·09-0·13 vs 0·11 [0·09-0·13]; adjusted RR 1·00 [0·74-1·35]; p=0·51) in evolutionRMS2. The pooled proportion of participants with any treatment-emergent adverse event (TEAE) was similar between treatment groups (976 [85·6%] of 1140 with evobrutinib vs 999 [87·2%] of 1146 with teriflunomide). The most frequently reported TEAEs were COVID-19 (223 [19·6%] with evobrutinib vs 223 [19·5%] with teriflunomide), alanine aminotransferase increased (173 [15·2%] vs 204 [17·8%]), aspartate aminotransferase increased (110 [9·6%] vs 131 [11·4%]), and headache (175 [15·4%] vs 176 [15·4%]). Serious TEAE incidence rates were higher with evobrutinib than teriflunomide (86 [7·5%] vs 64 [5·6%]). Liver enzyme elevations at least 5 × upper limit of normal were more common with evobrutinib than with teriflunomide, particularly in the first 12 weeks (55 [5·0%] vs nine [<1%]). Three people who received evobrutinib and one who received teriflunomide met the biochemical definition of Hy's law; all cases resolved after discontinuation of treatment. There were two deaths (one in each group), neither related to study treatment., Interpretation: The efficacy of evobrutinib was not superior to that of teriflunomide. Together, efficacy and liver-related safety findings do not support the use of evobrutinib in people with relapsing multiple sclerosis., Funding: Merck., Competing Interests: Declaration of interests XM received speaking honoraria or travel expenses, or both, for participation in scientific meetings; and has been a steering committee member of clinical trials and participated in advisory boards with AbbVie, Actelion (Janssen [Johnson & Johnson]), Alexion (AstraZeneca), Bayer, Biogen, Celgene (Bristol Myers Squibb), EMD Serono, Immunic, Janssen (Johnson & Johnson), MedDay, Merck, Mylan, Nervgen, Novartis, Roche, Sandoz, Sanofi, Teva, TG Therapeutics, Excemed, Multiple Sclerosis International Federation, and National Multiple Sclerosis Society. PV received honoraria and consulting fees from AB Science, Ad Scientiam, Biogen, Celgene (Bristol Myers Squibb), Imcyse, Janssen (Johnson & Johnson), Merck, Novartis, Roche, and Sanofi; and received research support from Novartis, Roche, and Sanofi. DLA received personal compensation for serving as a consultant for Alexion (AstraZeneca), Biogen, Celgene, Eli Lilly, Frequency Therapeutics, Merck, Novartis, Roche, Sanofi, and Shionogi; and holds an equity interest in NeuroRx Research. AB-O holds the Melissa and Paul Anderson Chair; received research funding from the Canadian Institutes of Health Research, Juvenile Diabetes Research Foundation, Multiple Sclerosis Society of Canada, Multiple Sclerosis Scientific Foundation, National Institutes of Health, and National Multiple Sclerosis Society; was a speaker in sponsored meetings and received consulting fees from Accure, Actelion (Janssen [Johnson & Johnson]), Atara Biotherapeutics, Biogen, Celgene (Receptos [Bristol Myers Squibb]), EMD Serono, Gossamer Bio, GSK, Medimmune, Merck, Novartis, Roche, and Sanofi; and received grant support to the University of Pennsylvania from Biogen, EMD Serono, Merck, Billerica, Novartis, and Roche. BACC received personal compensation for consulting from Alexion, Atara, Autobahn, Avotres, Biogen, Boston Pharma, EMD Serono, Gossamer Bio, Hexal (Sandoz), Horizon, Immunic AG, Kyverna, Neuron23, Novartis, Sanofi, Siemens, and TG Therapeutics; and received research support from Genentech. AHC received funding for this study from the Hope Center for Neurological Disorders (Washington University, St Louis, MO, USA); a salary from the Manny and Rosalyn Rosenthal Dr John L Trotter Multiple Sclerosis Center Chair in Neuroimmunology of the Barnes-Jewish Hospital Foundation; grant support from the National Institutes of Health, US Department of Defense, and National Multiple Sclerosis Society USA; consulting fees from Genentech (Roche), TG Therapeutics, Bristol Myers Squibb, Janssen (Johnson & Johnson), and Novartis; payment or honoraria for lectures from the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024, University of Arizona, University of Maryland, University of South Alabama, University of Miami, Mayo Foundation, Consortium of Multiple Sclerosis Centers, and Biogen; payment or honoraria for writing chapters of the American Academy of Neurology; payment or honoraria for construction of continuing medical education talks and written documents from Catamount, Projects in Knowledge, Vindico Medical Education, and WebMD; payment or honoraria for preparation of educational materials from Indy Airone; financial support for attending scientific or medical meetings from EMD Serono, Novartis, Genentech, and Hoffmann-La Roche; financial support for attending advisory boards from Novartis, Genentech, Biogen, Bristol Myers Squibb, Janssen (Johnson & Johnson), TG Therapeutics, Octave, and Horizon; holds a patent (US patent 15060–630 [015875); participated on a data safety monitoring board or advisory board for Novartis for the ASCLEPIOS trials on ofatumumab, EMD Serono for the evolutionRMS trials on evobrutinib, and Genentech for the OBOE study on ocrelizumab; is the president of the board of governors for the Consortium of Multiple Sclerosis Centers; is on the programme nominating committee for ACTRIMS; was a member and chair of the Research Programs Advisory Committee for the National Multiple Sclerosis Society; is a member representing the National Multiple Sclerosis Society and a member of the nominating committee for the International Progressive Multiple Sclerosis Alliance; and received medical writing support from Genentech, EMD Serono, and Novartis. EKH received personal compensation for consulting, for serving on a scientific advisory board or data safety monitoring board, and for serving as an expert witness from Actelion (Janssen [Johnson & Johnson]), Biogen, Celgene, Merck, Novartis, Roche, and Sanofi. LK received research support to the institution (University Hospital Basel, Basel, Switzerland) including steering committee, advisory board, and consultancy fees from Actelion (Janssen [Johnson & Johnson]), Bayer, Biogen, Bristol Myers Squibb, GSK, Janssen (Johnson & Johnson), Japan Tobacco, Merck, Novartis, Roche, Sanofi, Santhera, and Shionogi, and TG Therapeutics; speaker fees from Bayer, Biogen, Merck, Novartis, Roche, and Sanofi; support of educational activities from Allergan, Bayer, Biogen, CSL Behring, Desitin, Merck, Novartis, Pfizer, Roche, Sanofi, Shire, and Teva; license fees for Neurostatus platform access; and grants from Bayer, Biogen, EU, InnoSwiss, Merck, Novartis, Roche, Swiss Multiple Sclerosis Society, and Swiss National Research Foundation. OS received personal compensation for consulting from EMD Serono, Novartis, and Octave Bioscience; grants from EMD Serono; and for serving as an editorial board member of Therapeutic Advances in Neurological Disorders. HW received personal compensation for consulting, for serving on a scientific advisory board, speaking and traveling or attending meetings from AbbVie, Actelion (Janssen [Johnson & Johnson]), Alexion (AstraZeneca), Argenx, Beckton Dickinson, Biogen, Bristol Myers Squibb (Celgene), EMD Serono, Fondazione Cariplo, Gossamer Bio, Idorsia, Immunic, Immunovant, Janssen (Johnson & Johnson), Lundbeck, Merck, Neurodiem, NexGen, Novartis, Ology, Roche, Sandoz, Sanofi, Teva, WebMD, and Worldwide Clinical Trials; contracted research with Alexion (AstraZeneca), Amicus Therapeutics, Argenx, Biogen, CSL Behring, Merck, Novartis, Roche, and Sanofi. JSW received personal compensation for consulting, serving on a scientific advisory board, speaking or other activities from Cleveland Clinic Foundation, EMD Serono, Inmagene, Novartis, Roche, Sandoz, and Zenas BioPharma; and royalties for out-licensing monoclonal antibodies through UTHealth from Millipore Corporation. FD provides consultancy to Merck through Impulze. CLB is an employee of Merck Santé. YH, HG, and SG are employees of Merck and own stock or stock options. AJ and DT are employees of Ares Trading. DT received stock or an ownership interest from Novartis. NT and LSL are employees of EMD Serono., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Magnetic resonance imaging (MRI) is increasingly being used to delineate morphological changes underlying neurological disorders. Successfully detecting these changes depends on the MRI data quality. Unfortunately, image artifacts frequently compromise the MRI utility, making it critical to screen the data. Currently, quality assessment requires visual inspection, a time-consuming process that suffers from inter-rater variability. Automated methods to detect MRI artifacts could improve the efficiency of the process. Such automated methods have achieved high accuracy using small datasets, with balanced proportions of MRI data with and without artifacts. With the current trend towards big data in neuroimaging, there is a need for automated methods that achieve accurate detection in large and imbalanced datasets. Deep learning (DL) is the ideal MRI artifact detection algorithm for large neuroimaging databases. However, the inference generated by DL does not commonly include a measure of uncertainty. Here, we present the first stochastic DL algorithm to generate automated, high-performing MRI artifact detection implemented on a large and imbalanced neuroimaging database. We implemented Monte Carlo dropout in a 3D AlexNet to generate probabilities and epistemic uncertainties. We then developed a method to handle class imbalance, namely data-ramping to transfer the learning by extending the dataset size and the proportion of the artifact-free data instances. We used a 34,800 scans (98% clean) dataset. At baseline, we obtained 89.3% testing accuracy (F1 = 0.230). Following the transfer learning (with data-ramping), we obtained 94.9% testing accuracy (F1 = 0.357) outperforming focal cross-entropy (92.9% testing accuracy, F1 = 0.304) incorporated for comparison at handling class imbalance. By implementing epistemic uncertainties, we improved the testing accuracy to 99.5% (F1 = 0.834), outperforming the results obtained in previous comparable studies. In addition, we estimated aleatoric uncertainties by incorporating random flips to the MRI volumes, and demonstrated that aleatoric uncertainty can be implemented as part of the pipeline. The methods we introduce enhance the efficiency of managing large databases and the exclusion of artifact images from big data analyses., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ricardo Pizarro reports financial support was provided by McGill University. Haz-Edine Assemlal reports financial support was provided by NeuroRx, Inc. Thomas Jubault reports financial support was provided by NeuroRx, Inc. Samson Antel reports financial support was provided by NeuroRx, Inc. Douglas Arnold reports financial support was provided by NeuroRx, Inc. Sethu K. Boopathy Jegathambal reports financial support was provided by McGill University. Amir Shmuel reports financial support was provided by McGill University., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Paramagnetic rim lesions (PRLs) and slowly expanding lesions (SELs) have been posited as markers of chronic active lesions (CALs)., Objective: To assess the lesion-level concordance of PRLs and SELs in MS and to characterize changes in brain tissue integrity in CALs over time., Methods: MRIs were analyzed from a substudy of AFFINITY [NCT03222973], a phase 2 trial of opicinumab in relapsing MS. Assessments included (1) identification of SELs based on longitudinal MRIs over 72 weeks, and identification of PRLs on susceptibility-weighted imaging (SWI) filtered phase images at week 72; (2) evaluation of subject-level correlation of SEL and PRL counts, volumes, and degree of lesion-level overlap between SELs and PRLs; and (3) characterization of tissue integrity over time in overlapping and non-overlapping SELs and PRLs., Results: In 41 subjects, 119 chronic PRLs and 267 SELs were detected. Of 119 (39.5%) chronic PRLs, 47 co-localized with a SEL; 46/267 (17.2%) SELs co-localized with a PRL. PRLs co-localized with SELs showed expansion and worsening microstructural damage over time. SELs with and without co-localization with PRLs showed ongoing tissue damage., Conclusions: Chronic MS lesions identified as both PRL and SEL were associated with the most severe accumulation of tissue damage., Trial Registration: AFFINITY [NCT03222973].

Background: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by two major and interconnected hallmarks: inflammation and progressive neurodegeneration., Objective: The aim of this work was to compare neurodegenerative processes, in the form of global and regional brain volume loss rates, in healthy controls (HCs) and in patients with relapsing MS (RMS) treated with ocrelizumab, which suppresses acute inflammation., Methods: Whole brain, white matter, cortical gray matter, thalamic, and cerebellar volume loss rates were assessed in 44 HCs that were part of a substudy in the OPERA II randomized controlled trial (NCT01412333) and 59 patients with RMS enrolled in the same substudy as well as age- and sex-matched patients in OPERA I (NCT01247324) and II. Volume loss rates were computed using random coefficients models over a period of 2 years., Results: Ocrelizumab-treated patients showed global and regional brain volume loss rates that were approaching that of HCs., Conclusion: These findings are consistent with an important role of inflammation on overall tissue loss and the role of ocrelizumab in reducing this phenomenon.

In recent years, the use of magnetic resonance imaging (MRI) for the diagnostic work-up of multiple sclerosis (MS) has evolved considerably. The 2017 McDonald criteria show high sensitivity and accuracy in predicting a second clinical attack in patients with a typical clinically isolated syndrome and allow an earlier diagnosis of MS. They have been validated, are evidence-based, simplify the clinical use of MRI criteria and improve MS patients' management. However, to limit the risk of misdiagnosis, they should be applied by expert clinicians only after the careful exclusion of alternative diagnoses. Recently, new MRI markers have been proposed to improve diagnostic specificity for MS and reduce the risk of misdiagnosis. The central vein sign and chronic active lesions (i.e., paramagnetic rim lesions) may increase the specificity of MS diagnostic criteria, but further effort is necessary to validate and standardize their assessment before implementing them in the clinical setting. The feasibility of subpial demyelination assessment and the clinical relevance of leptomeningeal enhancement evaluation in the diagnostic work-up of MS appear more limited. Artificial intelligence tools may capture MRI attributes that are beyond the human perception, and, in the future, artificial intelligence may complement human assessment to further ameliorate the diagnostic work-up and patients' classification. However, guidelines that ensure reliability, interpretability, and validity of findings obtained from artificial intelligence approaches are still needed to implement them in the clinical scenario. This review provides a summary of the most recent updates regarding the application of MRI for the diagnosis of MS., (© 2022. The Author(s).)

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease characterized by the appearance of focal lesions across the central nervous system. The discrimination of acute from chronic MS lesions may yield novel biomarkers of inflammatory disease activity which may support patient management in the clinical setting and provide endpoints in clinical trials. On a single timepoint and in the absence of a prior reference scan, existing methods for acute lesion detection rely on the segmentation of hyperintense foci on post-gadolinium T1-weighted magnetic resonance imaging (MRI), which may underestimate recent acute lesion activity. In this paper, we aim to improve the sensitivity of acute MS lesion detection in the single-timepoint setting, by developing a novel machine learning approach for the automatic detection of acute MS lesions, using single-timepoint conventional non-contrast T1- and T2-weighted brain MRI. The MRI input data are supplemented via the use of a convolutional neural network generating "lesion-free" reconstructions from original "lesion-present" scans using image inpainting. A multi-objective statistical ranking module evaluates the relevance of textural radiomic features from the core and periphery of lesion sites, compared within "lesion-free" versus "lesion-present" image pairs. Then, an ensemble classifier is optimized through a recursive loop seeking consensus both in the feature space (via a greedy feature-pruning approach) and in the classifier space (via model selection repeated after each pruning operation). This leads to the identification of a compact textural signature characterizing lesion phenotype. On the patch-level task of acute versus chronic MS lesion classification, our method achieves a balanced accuracy in the range of 74.3-74.6% on fully external validation cohorts., Competing Interests: Disclosures of Competing Interest Caba, Liu, Jiang, Gafson, Fisher and Belachew are employees and shareholders of Biogen. Cafaro and Lombard are employees and shareholders of Therapanacea. Elliott is an employee of NeuroRx Research. Arnold receives consulting fees from Biogen, Celgene, Frequency Therapeutics, Genentech, Merck, Novartis, Race to Erase MS, Roche, and Sanofi-Aventis, Shionogi, Xfacto Communications, grants from Immunotec and Novartis, and an equity interest in NeuroRx Research. Paragios is an employee of Therapanacea, employee of CentraleSupélec, Université Paris-Saclay, French Ministry of Higher Education and Research; holds stock options in Arterdrone and TheraPanacea; and receives compensation for editorial services from Elsevier., (Copyright © 2022. Published by Elsevier Inc.)

Background: In multiple sclerosis (MS), thalamic integrity is affected directly by demyelination and neuronal loss, and indirectly by gray/white matter lesions outside the thalamus, altering thalamic neuronal projections., Objective: To assess the efficacy of ocrelizumab compared with interferon beta-1a (IFNβ1a)/placebo on thalamic volume loss and the effect of switching to ocrelizumab on volume change in the Phase III trials in relapsing MS (RMS, OPERA I/II; NCT01247324/NCT01412333) and in primary progressive MS (PPMS, ORATORIO; NCT01194570)., Methods: Thalamic volume change was computed using paired Jacobian integration and analyzed using an adjusted mixed-effects repeated measurement model., Results: Over the double-blind period, ocrelizumab treatment significantly reduced thalamic volume loss with the largest effect size (Cohen's d : RMS: 0.561 at week 96; PPMS: 0.427 at week 120) compared with whole brain, cortical gray matter, and white matter volume loss. At the end of up to 7 years of follow-up, patients initially randomized to ocrelizumab still showed less thalamic volume loss than those switching from IFNβ1a ( p  < 0.001) or placebo ( p  < 0.001)., Conclusion: Ocrelizumab effectively reduced thalamic volume loss compared with IFNβ1a/placebo. Early treatment effects on thalamic tissue preservation persisted over time. Thalamic volume loss could be a potential sensitive marker of persisting tissue damage.

Disability progression in multiple sclerosis remains resistant to treatment. The absence of a suitable biomarker to allow for phase 2 clinical trials presents a high barrier for drug development. We propose to enable short proof-of-concept trials by increasing statistical power using a deep-learning predictive enrichment strategy. Specifically, a multi-headed multilayer perceptron is used to estimate the conditional average treatment effect (CATE) using baseline clinical and imaging features, and patients predicted to be most responsive are preferentially randomized into a trial. Leveraging data from six randomized clinical trials (n = 3,830), we first pre-trained the model on the subset of relapsing-remitting MS patients (n = 2,520), then fine-tuned it on a subset of primary progressive MS (PPMS) patients (n = 695). In a separate held-out test set of PPMS patients randomized to anti-CD20 antibodies or placebo (n = 297), the average treatment effect was larger for the 50% (HR, 0.492; 95% CI, 0.266-0.912; p = 0.0218) and 30% (HR, 0.361; 95% CI, 0.165-0.79; p = 0.008) predicted to be most responsive, compared to 0.743 (95% CI, 0.482-1.15; p = 0.179) for the entire group. The same model could also identify responders to laquinimod in another held-out test set of PPMS patients (n = 318). Finally, we show that using this model for predictive enrichment results in important increases in power., (© 2022. The Author(s).)

Background: Siponimod is a sphingosine 1-phosphate receptor modulator approved for active secondary progressive multiple sclerosis (aSPMS) in most countries; however, phase 3 EXPAND study data are from an SPMS population with/without disease activity. A need exists to characterize efficacy/safety of siponimod in aSPMS., Methods: Post hoc analysis of participants with aSPMS (≥ 1 relapse in 2 years before study and/or ≥ 1 T1 gadolinium-enhancing [Gd +] magnetic resonance imaging [MRI] lesions at baseline) receiving oral siponimod (2 mg/day) or placebo for up to 3 years in EXPAND., Endpoints: 3-month/6-month confirmed disability progression (3mCDP/6mCDP); 3-month confirmed ≥ 20% worsening in Timed 25-Foot Walk (T25FW); 6-month confirmed improvement/worsening in Symbol Digit Modalities Test (SDMT) scores (≥ 4-point change); T2 lesion volume (T2LV) change from baseline; number of T1 Gd + lesions baseline-month 24; number of new/enlarging (N/E) T2 lesions over all visits., Results: Data from 779 participants with aSPMS were analysed. Siponimod reduced risk of 3mCDP/6mCDP vs placebo (by 31%/37%, respectively; p < 0.01); there was no significant effect on T25FW. Siponimod increased likelihood of 6-month confirmed SDMT improvement vs placebo (by 62%; p = 0.007) and reduced risk of 6-month confirmed SDMT worsening (by 27%; p = 0.060). Siponimod was associated with less increase in T2LV (1316.3 vs 13.3 mm 3 ; p < 0.0001), and fewer T1 Gd + and N/E T2 lesions than placebo (85% and 80% reductions, respectively; p < 0.0001)., Conclusions: In aSPMS, siponimod reduced risk of disability progression and was associated with benefits on cognition and MRI outcomes vs placebo., Trial Registration: ClinicalTrials.gov number: NCT01665144., (© 2022. The Author(s).)

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS caused by the JC virus, which infects white and grey matter cells and leads to irreversible demyelination and neuroaxonal damage. Brain MRI, in addition to the clinical presentation and demonstration of JC virus DNA either in the CSF or by histopathology, is an important tool in the detection of PML. In clinical practice, standard MRI pulse sequences are utilized for screening, diagnosis and monitoring of PML, but validated imaging-based outcome measures for use in prospective, interventional clinical trials for PML have yet to be established. We review the existing literature regarding the use of MRI and PET in PML and discuss the implications of PML histopathology for neuroradiology. MRI not only demonstrates the localization and extent of PML lesions, but also mirrors the tissue destruction, ongoing viral spread, and resulting inflammation. Finally, we explore the potential for imaging measures to serve as an outcome in PML clinical trials and provide recommendations for current and future imaging outcome measure development in this area., (Published by Oxford University Press on behalf of the Guarantors of Brain 2021. This work is written by a US Government employee and is in the public domain in the US.)

Background: Dimethyl fumarate (DMF) demonstrated favorable benefit-risk in relapsing-remitting multiple sclerosis (RRMS) patients in phase-III DEFINE and CONFIRM trials, and ENDORSE extension., Objective: The main aim of this study is assessing DMF safety/efficacy up to 13 years in ENDORSE., Methods: Randomized patients received DMF 240 mg twice daily or placebo (PBO; Years 0-2), then DMF (Years 3-10; continuous DMF/DMF or PBO/DMF); maximum follow-up (combined studies), 13 years., Results: By January 2020, 1736 patients enrolled/dosed in ENDORSE (median follow-up 8.76 years (ENDORSE range: 0.04-10.98) in DEFINE/CONFIRM and ENDORSE); 52% treated in ENDORSE for ⩾6 years. Overall, 551 (32%) patients experienced serious adverse events (mostly multiple sclerosis (MS) relapse or fall; one progressive multifocal leukoencephalopathy); 243 (14%) discontinued treatment due to adverse events (4% gastrointestinal (GI) disorders). Rare opportunistic infections, malignancies, and serious herpes zoster occurred, irrespective of lymphocyte count. For DMF/DMF ( n = 501), overall annualized relapse rate (ARR) remained low (0.143 (95% confidence interval (CI), 0.120-0.169)), while for PBO/DMF ( n = 249), ARR decreased after initiating DMF and remained low throughout (ARR 0-2 years, 0.330 (95% CI, 0.266-0.408); overall ARR (ENDORSE, 0.151 (95% CI, 0.118-0.194)). Over 10 years, 72% DMF/DMF and 73% PBO/DMF had no 24-week confirmed disability worsening., Conclusion: Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF's positive benefit/risk profile for long-term RRMS treatment.

Background: Early intervention with well-tolerated disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) is recommended in order to delay disease progression, reduce neurologic damage, preserve brain volume, and optimize long-term patient outcomes. Lack of conversion of new/newly enlarging T2 (NET2) or gadolinium-enhancing (Gd+) lesions to chronic hypointensities (black hole conversion) and achievement of no evidence of disease activity (NEDA) early in the course of treatment are considered potential indicators of treatment effect and predictors of longer-term clinical outcomes., Methods: Patients with RRMS who were treated with peginterferon beta-1a in the 2-year ADVANCE phase 3 clinical trial (NCT0090639) and its 2-year open-label extension study, ATTAIN (NCT01332019), were grouped as newly diagnosed (diagnosed ≤1 year prior to enrollment and DMT naive) or non-newly diagnosed. For analyses of the impact of early treatment and disease activity control, the newly diagnosed and non-newly diagnosed subgroups were further divided based on whether they initiated peginterferon beta-1a every 2 weeks (Q2W) starting in study year 1 (continuously treated) or peginterferon beta-1a Q2W or every 4 weeks in study year 2 (delayed treatment). Patient subgroups were evaluated for conversion of NET2 or Gd+ lesions to persistent black holes (PBHs), brain atrophy (percentage change in whole brain volume [WBV]), achievement of NEDA composite outcomes, and the association of these disease activity measures with longer-term clinical outcomes (annualized relapse rate [ARR] and confirmed disability worsening [CDW])., Results: At 2 years, significantly fewer PBHs developed from NET2 lesions or Gd+ lesions in newly diagnosed and non-newly diagnosed patients continuously treated with peginterferon beta-1a than in the corresponding delayed-treatment groups (all p<0.0001). Percentage decrease in WBV from 6 months (rebaselined) to 2 years was significantly lower for newly diagnosed and non-newly diagnosed patients who received continuous peginterferon beta-1a treatment than for patients who received delayed treatment (both p ≤ 0.0442). In study year 1, a higher proportion of newly diagnosed and non-newly diagnosed patients treated with peginterferon beta-1a than those treated with placebo achieved NEDA (newly diagnosed: 28.3% vs 13.5% [p = 0.0010]; non-newly diagnosed: 40.8% vs 15.8% [p<0.0001]). NEDA rates remained stable over study years 2-4 for the newly diagnosed (range: 50.0%-53.9%) and non-newly diagnosed (range: 54.4%-57.0%) subgroups. Patients without PBH conversion had significantly lower ARR at 2 years (newly diagnosed: p = 0.0109; non-newly diagnosed: p = 0.0044) and a lower proportion of patients with 12-week CDW at 2 years (newly diagnosed: p = 0.2787; non-newly diagnosed: p = 0.0045) than the corresponding patient subgroups with PBH conversion. Patients who achieved NEDA in ADVANCE (study years 1-2) had a significantly lower ARR in ATTAIN (study years 3-4) than patients who did not achieve NEDA (newly diagnosed, p = 0.0003; non-newly diagnosed, p = 0.0001). Over 4 years, safety outcomes did not differ for the newly diagnosed and non-newly diagnosed patient subgroups., Conclusions: These results indicate that newly diagnosed and non-newly diagnosed patients treated continuously with peginterferon beta-1a Q2W experienced better disease control over time than those who received delayed treatment. Patients with NEDA or evidence of less radiological disease activity in the first 2 years of treatment had better longer-term clinical outcomes than those with evidence of greater disease activity., (Copyright © 2021. Published by Elsevier B.V.)

Normal-appearing white matter is far from normal in multiple sclerosis; little is known about the precise pathology or spatial pattern of this alteration and its relation to subsequent lesion formation. This study was undertaken to evaluate normal-appearing white matter abnormalities in brain areas where multiple sclerosis lesions subsequently form, and to investigate the spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis. Brain MRIs of pre-lesion normal-appearing white matter were analysed in participants with new T2 lesions, pooled from three clinical trials: SYNERGY (NCT01864148; n = 85 with relapsing multiple sclerosis) was the test data set; ASCEND (NCT01416181; n = 154 with secondary progressive multiple sclerosis) and ADVANCE (NCT00906399; n = 261 with relapsing-remitting multiple sclerosis) were used as validation data sets. Focal normal-appearing white matter tissue state was analysed prior to lesion formation in areas where new T2 lesions later formed (pre-lesion normal-appearing white matter) using normalized magnetization transfer ratio and T2-weighted (nT2) intensities, and compared with overall normal-appearing white matter and spatially matched contralateral normal-appearing white matter. Each outcome was analysed using linear mixed-effects models. Follow-up time (as a categorical variable), patient-level characteristics (including treatment group) and other baseline variables were treated as fixed effects. In SYNERGY, nT2 intensity was significantly higher, and normalized magnetization transfer ratio was lower in pre-lesion normal-appearing white matter versus overall and contralateral normal-appearing white matter at all time points up to 24 weeks before new T2 lesion onset. In ASCEND and ADVANCE (for which normalized magnetization transfer ratio was not available), nT2 intensity in pre-lesion normal-appearing white matter was significantly higher compared to both overall and contralateral normal-appearing white matter at all pre-lesion time points extending up to 2 years prior to lesion formation. In all trials, nT2 intensity in the contralateral normal-appearing white matter was also significantly higher at all pre-lesion time points compared to overall normal-appearing white matter. Brain atlases of normal-appearing white matter abnormalities were generated using measures of voxel-wise differences in normalized magnetization transfer ratio of normal-appearing white matter in persons with multiple sclerosis compared to scanner-matched healthy controls. We observed that overall spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis largely recapitulated the anatomical distribution of probabilities of T2 hyperintense lesions. Overall, these findings suggest that intrinsic spatial properties and/or longstanding precursory abnormalities of normal-appearing white matter tissue may contribute to the risk of autoimmune acute demyelination in multiple sclerosis., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Reduction in absolute lymphocyte count (ALC) is expected with fingolimod treatment., Objective: To evaluate the effect of fingolimod 0.5 mg versus intramuscular interferon β-1a (30 μg) on ALC and its relationship with infections in paediatric-onset multiple sclerosis (POMS) up to 4 years., Methods: We assessed ALC at baseline, monthly till 3 months, and every 3 months (core phase) and with variable periodicity (extension phase) of Phase 3 PARADIG MS study ( N  = 215). Incidence rates (IRs) of infection-related adverse events ( inf AEs)/100 patient-years were analysed by on-study nadir ALC., Results: With fingolimod, ALC rapidly reduced to 29.9%-34.4% of baseline values within 2 weeks and remained stable thereafter; no relevant changes observed with interferon. IRs of inf AEs were 67.6 with fingolimod and 61.8 with interferon; IR ratios with respect to interferon, overall: 1.09, by nadir ALC 0.2-0.4 × 10 9 /L: 1.13 and >0.4 × 10 9 /L: 0.91. Three patients had a single episode of ALC <0.2 × 10 9 /L (core phase). No opportunistic infections were observed and infection risk did not increase during the extension phase., Conclusion: In paediatric patients, the overall incidence of infections was comparable between fingolimod and interferon. No association was observed between nadir ALC and infections in POMS, although sample size may have been too small to rule an association.

Background: EXTEND (NCT01797965), an open-label extension study, evaluated the safety and efficacy of daclizumab beta in participants with relapsing multiple sclerosis (MS) who had completed the randomized DECIDE study., Methods: Eligible participants who received either daclizumab beta or interferon beta-1a in DECIDE received daclizumab beta 150 mg subcutaneously every 4 weeks for up to 5 years in EXTEND, followed by 24 weeks of post-dosing follow-up. Safety and tolerability were evaluated, as were clinical efficacy and magnetic resonance imaging (MRI). EXTEND was terminated ahead of schedule by the sponsors., Results: The total safety population ( N  = 1203) received at least one dose of daclizumab beta in EXTEND. In the DECIDE and EXTEND combined periods, the median number of doses of daclizumab beta was 53; median time on treatment was 196 weeks. By 24 September 2018, the end of the study, 110/1203 (9%) participants had completed the protocol-specified treatment period and 1101/1203 (92%) had experienced an adverse event (AE). The most commonly reported AEs were MS relapse, nasopharyngitis, and upper respiratory tract infection. Hepatic events (18%), cutaneous events (45%), and infections (62%) were common treatment-related AEs. The incidence of serious AEs was 29%, most commonly MS relapse and infections. The incidence of immune-mediated disorders was 2%; three of seven were encephalitis. Two of six deaths were considered treatment related. In participants who received continuous daclizumab beta throughout DECIDE and EXTEND, the treatment effects on clinical and MRI outcomes were maintained for up to 6 years., Conclusion: Results from the combined DECIDE-EXTEND study elucidate outcomes of longer-term treatment with daclizumab beta in the clinical trial setting and underscore the importance of pharmacovigilance with immunomodulatory therapies in the real-world setting., Competing Interests: Conflict of interest: LK reports funding to his institution (University Hospital Basel) in the last 3 years used exclusively for research support; steering committee, advisory board, and consultancy fees from Actelion, Addex, Bayer, Biogen, Celgene, Genzyme, Merck, Mitsubishi, Novartis, Pfizer, Sanofi, and Santhera; speaker fees from Biogen, Merck, Novartis, Sanofi, and Teva; support of educational activities from Bayer, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva; license fees for Neurostatus products; and grants from Bayer, Biogen, European Union, Innosuisse, Merck, Novartis, Roche Research Foundation, Swiss MS Society, and Swiss National Research Foundation. SC reports speaking honoraria from and/or advisory boards for Biogen, Bristol Myers Squibb, EMD Serono, Novartis, Pear Therapeutics, Roche Genentech, and Sanofi Genzyme; and research support from AbbVie, Acorda, Actelion, Biogen, MedDay, Novartis, Roche Genentech, and Sanofi Genzyme. DLA reports consultant fees and/or grants from Acorda, Adelphi, Alkermes, Biogen, Canadian Institutes of Health Research, Celgene, Frequency Therapeutics, Genentech, Genzyme, Immune Tolerance Network, Immunotec, International Progressive MS Alliance, MedDay, Merck Serono, MS Society of Canada, Novartis, Pfizer, Receptos, Roche, and Sanofi and an equity interest in NeuroRx Research. RRR is an employee of and holds stock/stock options in AbbVie. JH was a former employee of and holds stock/stock options in AbbVie. BP was a former employee of and holds stock/stock options in Biogen. SF, SX and WC-B are employees of and hold stock/stock options in Biogen. The EXTEND study and these analyses were funded by Biogen (Cambridge, MA, USA) and AbbVie (Redwood City, CA, USA)., (© The Author(s), 2021.)

Background: The safety and efficacy of ocrelizumab in primary progressive multiple sclerosis were shown in the phase 3 ORATORIO trial. In this study, we assessed the effects of maintaining or switching to ocrelizumab therapy on measures of disease progression and safety in the open-label extension phase of ORATORIO., Methods: ORATORIO was an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 trial done at 182 study locations including academic centres, hospitals, and community speciality centres within 29 countries across the Americas, Australia, Europe, Israel, New Zealand, and Russia. Patients with primary progressive multiple sclerosis aged 18-55 years who had an Expanded Disability Status Scale (EDSS) score of 3·0-6·5 were eligible for enrolment. Those who had previous treatment with B-cell-targeted therapies or other immunosuppressive medications were excluded. Eligible participants were randomly assigned (2:1) to receive either intravenous infusion of 600 mg of ocrelizumab (two 300 mg infusions 14 days apart) or placebo every 24 weeks for at least 120 weeks until a prespecified number (n=253) of disability events occurred. After the double-blind phase, patients entered an extended controlled period of variable duration, during which they and investigators became aware of treatment allocation. Following this period, patients could enter an optional open-label extension, during which they continued ocrelizumab or switched from placebo to ocrelizumab. Time to onset of disability progression was confirmed at 24 weeks with four measures (ie, increase in EDSS score, ≥20% increase in time to complete the 9-Hole Peg Test [9HPT], ≥20% increase in time to perform the Timed 25-Foot Walk [T25FW], and composite progression defined as the first confirmed occurrence of any of these three individual measures), as was time to requiring a wheelchair (EDSS ≥7). Conventional MRI measures were also analysed. The intention-to-treat population was used for the safety and efficacy analyses; all analyses, and their timings, were done post hoc. ORATORIO is registered with ClinicalTrials.gov, NCT01194570, and is ongoing., Findings: From March 3, 2011, to Dec 27, 2012, 488 patients were randomly assigned to the ocrelizumab group and 244 to the placebo group. The extended controlled period started on July 24, 2015, and ended on April 27, 2016, when the last patient entered the open-label extension. Overall, 544 (74%) of 732 participants completed the double-blind period to week 144; 527 (97%) of 544 entered the open-label extension phase, of whom 451 (86%) are ongoing in the open-label extension. After at least 6·5 study years (48 weeks per study year) of follow-up, the proportion of patients with progression on disability measures was lower in those who initiated ocrelizumab early than in those initially receiving placebo for most of the measures of 24-week confirmed disability progression: EDSS, 51·7% vs 64·8% (difference 13·1% [95% CI 4·9-21·3]; p=0·0018); 9HPT, 30·6% vs 43·1% (12·5% [4·1-20·9]); p=0·0035); T25FW, 63·2% vs 70·7% (7·5% [-0·3 to 15·2]; p=0·058); composite progression, 73·2% vs 83·3% (10·1% [3·6-16·6]; p=0·0023); and confirmed time to requiring a wheelchair, 11·5% vs 18·9% (7·4% [0·8-13·9]; p=0·0274). At study end, the percentage change from baseline was lower in those who initiated ocrelizumab early than in those initially receiving placebo for T2 lesion volume (0·45% vs 13·00%, p<0·0001) and T1 hypointense lesion volume (36·68% vs 60·93%, p<0·0001). Over the entire period, in the ORATORIO all ocrelizumab exposure population, the rate of adverse events was 238·09 (95% CI 232·71-243·57) per 100 patient-years and serious adverse events was 12·63 (95% CI 11·41-13·94) per 100 patient-years; the most common serious adverse events were infections at 4·13 (95% CI 3·45-4·91) per 100 patient-years. No new safety signals emerged compared with the double-blind phase of ORATORIO., Interpretation: Compared with patients switching from placebo, earlier and continuous ocrelizumab treatment provided sustained benefits on measures of disease progression over the 6·5 study years of follow-up. Although this study shows the benefit of earlier intervention with ocrelizumab in primary progressive disease, progression remains an important unmet need in multiple sclerosis. Further research should focus on how the potential benefits described in this study might be improved upon, particularly over longer time periods., Funding: F Hoffmann-La Roche., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: We report safety and efficacy in patients treated with dimethyl fumarate (DMF) for ~9 years in ENDORSE. Lymphocyte analysis data are also reported., Methods: Incidence of serious adverse events (SAEs), discontinuations due to adverse events (AEs), annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) score were assessed. Patients were treated with DMF 240 mg twice daily (BID): placebo (PBO)/DMF (PBO for years 0-2 /DMF for years 3-9) or continuous (DMF/DMF) treatment; newly diagnosed patients were included. Annual magnetic resonance imaging (MRI) was evaluated in patients from the MRI cohort of DEFINE/CONFIRM. For the lymphocyte analysis, data from first DMF exposure were analyzed., Results: Of 2079 DEFINE/CONFIRM completers, 1736 enrolled and received ⩾1 dose of DMF. The MRI cohort included 530 patients. In the overall population, 527 (30%) patients experienced SAEs; most were fall and urinary tract infection. Over 9 years on DMF treatment, adjusted ARR remained low (⩽0.20). In patients treated with PBO in years 0-2, decreased ARR was apparent as early as year 3. Of DMF/DMF and PBO/DMF patients, 73% and 74%, respectively, had no 24-week confirmed disability progression. Most patients (~70%) had no new T1 or new/newly enlarging T2 lesions compared with previous MRI scans after 7 years treatment with DMF; the annual number of new T1 hypointense lesions and new/newly enlarging T2 hyperintense lesions were 0.6-0.8 and 0.9-2.0, respectively. Mean percentage brain volume change from ENDORSE baseline (6 years treatment in ENDORSE) was -1.32% (range -1.60% to -1.05%). Of the 2513 patients with lymphocyte assessments, 2470 had ⩾1 post-baseline measurement, 53 developed severe prolonged lymphopenia and were followed for up to 11 years; incidence of serious infection was not higher than in patients with absolute lymphocyte count (ALC) always ⩾ lower limit of normal (LLN). In patients with lymphopenia while on DMF and ALC < 0.91 × 10 9 /L at discontinuation ( n  = 138), median time to ALC ⩾ LLN was 7 weeks post-discontinuation., Conclusions: Sustained safety and efficacy of DMF was observed in patients continuing on treatment for up to 11 years, supporting DMF as a long-term treatment option for patients with RRMS., Trial Registration: ClinicalTrials.gov identifiers, NCT00835770 (ENDORSE); NCT00420212 (DEFINE); NCT00451451 (CONFIRM)., Competing Interests: Conflict of interest statement: RG reports honoraria/research support from Bayer, Biogen, Merck Serono, Novartis, and Teva Neuroscience; and compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders. DLA reports consultant fees and/or grants from Acorda, Adelphi, Alkermes, Biogen, Celgene, Genentech, Genzyme, Hoffman-La Roche, Immune Tolerance Network, Immunotec, MedDay, Novartis, Pfizer, Receptos, Roche, Sanofi-Aventis, Canadian Institutes of Health Research, MS Society of Canada, and International Progressive MS Alliance; and equity interest in NeuroRx Research. AB-O reports speaker/consulting fees/grant support from Atara Biotherapeutics, Biogen, Celgene/Receptos, Genentech/Roche, GlaxoSmithKline, MedImmune, Merck/EMD Serono, Novartis, and Sanofi-Genzyme. RJF reports consulting fees from Biogen, MedDay, Novartis, Questcor, Teva, and XenoPort; advisory committees for Biogen and Novartis; and research grant funding from Novartis. LK reports the following, which were payed to his institution in the past 3 years and used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Alkermes, Almirall, Bayer, Biogen, Celgene/Receptos, df-mp, EXCEMED, GeNeuro SA, Genzyme, Japan Tobacco, Merck, Minoryx, Mitsubishi Pharma, Novartis, Roche, Sanofi-Aventis, Santhera, Teva and Vianex; and license fees for Neurostatus-UHB products; research performed at his institution has been supported by grants from Bayer, Biogen, Novartis, the European Union, Innoswiss, Roche Research Foundations, the Swiss MS Society and the Swiss National Research Foundation. CC, BP, and CM are employees of, and hold stock/stock options in, Biogen., (© The Author(s), 2020.)

Background: Chronic lesion activity driven by smoldering inflammation is a pathological hallmark of progressive forms of multiple sclerosis (MS)., Objective: To develop a method for automatic detection of slowly expanding/evolving lesions (SELs) on conventional brain magnetic resonance imaging (MRI) and characterize such SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations., Methods: We defined SELs as contiguous regions of existing T2 lesions showing local expansion assessed by the Jacobian determinant of the deformation between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change in T2- and T1-weighted MRIs. SELs were examined in 1334 RMS patients and 555 PPMS patients., Results: Compared with RMS patients, PPMS patients had higher numbers of SELs ( p  = 0.002) and higher T2 volumes of SELs ( p  < 0.001). SELs were devoid of gadolinium enhancement. Compared with areas of T2 lesions not classified as SEL, SELs had significantly lower T1 intensity at baseline and larger decrease in T1 intensity over time., Conclusion: We suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. SELs may represent a conventional brain MRI correlate of chronic active MS lesions and a candidate biomarker for smoldering inflammation in MS.

Background: Opicinumab is a human monoclonal antibody against LINGO-1, an inhibitor of oligodendrocyte differentiation and axonal regeneration. Previous findings suggested that opicinumab treatment might enhance remyelination in patients with CNS demyelinating diseases. We aimed to assess the safety and efficacy of opicinumab in patients with relapsing multiple sclerosis., Methods: We did a randomised, double-blind, placebo-controlled, dose-ranging, phase 2 study (SYNERGY) at 72 sites in 12 countries. Participants (aged 18-58 years) with relapsing multiple sclerosis (relapsing-remitting multiple sclerosis and secondary progressive multiple sclerosis with relapses) were randomised in a 1:2:2:2:2 ratio by an interactive voice and web response system to opicinumab 3 mg/kg, 10 mg/kg, 30 mg/kg, or 100 mg/kg, or placebo. An identical volume of study drug was administered intravenously once every 4 weeks. All participants self-administered intramuscular interferon beta-1a as background anti-inflammatory treatment once a week. The primary endpoint was the percentage of participants achieving confirmed disability improvement over 72 weeks, which was a multicomponent endpoint measured by the Expanded Disability Status Scale, the Timed 25-Foot Walk, the Nine-Hole Peg Test, and the 3 s Paced Auditory Serial Addition Test. The primary endpoint was analysed under intention-to-treat principles. This study is registered at ClinicalTrials.gov, number NCT01864148., Findings: Between Aug 13, 2013, and July 31, 2014, 419 patients were enrolled and randomly assigned either placebo (n=93) or opicinumab 3 mg/kg (n=45), 10 mg/kg (n=95), 30 mg/kg (n=94; one patient did not receive the assigned treatment), or 100 mg/kg (n=92). The last patient visit was on March 29, 2016. Confirmed disability improvement over 72 weeks was seen in 45 (49%) of 91 patients assigned to placebo, 21 (47%) of 45 assigned to opicinumab 3 mg/kg, 59 (63%) of 94 assigned to opicinumab 10 mg/kg, 59 (65%) of 91 assigned to opicinumab 30 mg/kg, and 36 (40%) of 91 assigned to opicinumab 100 mg/kg. A linear dose-response in the probability of confirmed disability improvement was not seen (linear trend test p=0·89). Adverse events occurred in 79 (85%) patients assigned placebo and in 275 (85%) assigned any dose of opicinumab. The most common adverse events of any grade in patients assigned any dose of opicinumab included influenza-like illness (140 [43%] with any dose of opicinumab vs 37 [40%] with placebo), multiple sclerosis relapses (117 [36%] vs 30 [32%]), and headache (51 [16%] vs 23 [25%]). Serious adverse events reported as related to treatment were urinary tract infection in one (1%) participant in the the placebo group, suicidal ideation and intentional overdose in one (1%) participant in the 30 mg/kg opicinumab group, bipolar disorder in one (1%) participant in the 100 mg/kg opicinumab group, and hypersensitivity in four (4%) participants in the 100 mg/kg opicinumab group. One patient in the opicinumab 30 mg/kg group died during the study due to a traffic accident, which was not considered related to study treatment., Interpretation: Our findings did not show a significant dose-linear improvement in disability compared with placebo in patients with relapsing multiple sclerosis. Further studies are needed to investigate whether some subpopulations identified in the study might benefit from opicinumab treatment at an optimum dose., Funding: Biogen., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Chronic active and slowly expanding lesions with smouldering inflammation are neuropathological correlates of progressive multiple sclerosis pathology. T1 hypointense volume and signal intensity on T1-weighted MRI reflect brain tissue damage that may develop within newly formed acute focal inflammatory lesions or in chronic pre-existing lesions without signs of acute inflammation. Using a recently developed method to identify slowly expanding/evolving lesions in vivo from longitudinal conventional T2- and T1-weighted brain MRI scans, we measured the relative amount of chronic lesion activity as measured by change in T1 volume and intensity within slowly expanding/evolving lesions and non-slowly expanding/evolving lesion areas of baseline pre-existing T2 lesions, and assessed the effect of ocrelizumab on this outcome in patients with primary progressive multiple sclerosis participating in the phase III, randomized, placebo-controlled, double-blind ORATORIO study (n = 732, NCT01194570). We also assessed the predictive value of T1-weighted measures of chronic lesion activity for clinical multiple sclerosis progression as reflected by a composite disability measure including the Expanded Disability Status Scale, Timed 25-Foot Walk and 9-Hole Peg Test. We observed in this clinical trial population that most of total brain non-enhancing T1 hypointense lesion volume accumulation was derived from chronic lesion activity within pre-existing T2 lesions rather than new T2 lesion formation. There was a larger decrease in mean normalized T1 signal intensity and greater relative accumulation of T1 hypointense volume in slowly expanding/evolving lesions compared with non-slowly expanding/evolving lesions. Chronic white matter lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in slowly expanding/evolving lesions and in non-slowly expanding/evolving lesion areas of pre-existing lesions predicted subsequent composite disability progression with consistent trends on all components of the composite. In contrast, whole brain volume loss and acute lesion activity measured by longitudinal T1 hypointense lesion volume accumulation in new focal T2 lesions did not predict subsequent composite disability progression in this trial at the population level. Ocrelizumab reduced longitudinal measures of chronic lesion activity such as T1 hypointense lesion volume accumulation and mean normalized T1 signal intensity decrease both within regions of pre-existing T2 lesions identified as slowly expanding/evolving and in non-slowly expanding/evolving lesions. Using conventional brain MRI, T1-weighted intensity-based measures of chronic white matter lesion activity predict clinical progression in primary progressive multiple sclerosis and may qualify as a longitudinal in vivo neuroimaging correlate of smouldering demyelination and axonal loss in chronic active lesions due to CNS-resident inflammation and/or secondary neurodegeneration across the multiple sclerosis disease continuum., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Neuroimaging science has seen a recent explosion in dataset size driving the need to develop database management with efficient processing pipelines. Multi-center neuroimaging databases consistently receive magnetic resonance imaging (MRI) data with unlabeled or incorrectly labeled contrast. There is a need to automatically identify the contrast of MRI scans to save database-managing facilities valuable resources spent by trained technicians required for visual inspection. We developed a deep learning (DL) algorithm with convolution neural network architecture to automatically infer the contrast of MRI scans based on the image intensity of multiple slices. For comparison, we developed a random forest (RF) algorithm to automatically infer the contrast of MRI scans based on acquisition parameters. The DL algorithm was able to automatically identify the MRI contrast of an unseen dataset with <0.2% error rate. The RF algorithm was able to identify the MRI contrast of the same dataset with 1.74% error rate. Our analysis showed that reduced dataset sizes caused the DL algorithm to lose generalizability. Finally, we developed a confidence measure, which made it possible to detect, with 100% specificity, all MRI volumes that were misclassified by the DL algorithm. This confidence measure can be used to alert the user on the need to inspect the small fraction of MRI volumes that are prone to misclassification. Our study introduces a practical solution for automatically identifying the MRI contrast. Furthermore, it demonstrates the powerful combination of convolution neural networks and DL for analyzing large MRI datasets.

Background: ADVANCE was a phase III trial of the efficacy and safety of subcutaneous peginterferon beta-1a 125 µg every 2 or 4 weeks in patients with relapsing-remitting multiple sclerosis (RRMS). ATTAIN was a 2-year extension study of ADVANCE. The aim was to evaluate the long-term safety, tolerability, and efficacy of peginterferon beta-1a 125 µg every 2 or 4 weeks in ATTAIN., Methods: ADVANCE dosing schedules were maintained in ATTAIN, except that every-4-weeks dosing patients were switched to every-2-weeks dosing after conversion of the study to an open-label protocol. ATTAIN was considered complete when the last patient completed the 96-week extension study. Primary endpoints included adverse event (AE) and serious AE (SAE) incidence. Secondary endpoints included relapse, magnetic resonance imaging, and disability outcomes., Results: Of the 1512 patients randomized in ADVANCE, 1076 (71%) continued treatment in ATTAIN; of these, 842 (78%) completed the open-label extension study. During ATTAIN, 478 patients (87%) in the every-2-weeks group and 471 patients (89%) in the every-4-weeks group experienced an AE; SAEs were reported in 90 patients (16%) in the every-2-weeks group and 113 patients (21%) in the every-4-weeks group. The most frequent AEs reported were injection site reactions and flu-like symptoms, both of which numerically decreased over time. Peginterferon beta-1a every 2 weeks versus every 4 weeks significantly reduced the adjusted annualized relapse rate over 6 years (0.188 versus 0.263, p = 0.0052) and the risk of relapse over 5 years (36% versus 49%, p = 0.0018). Fewer new T1, new/newly enlarging T2, and gadolinium-enhancing magnetic resonance imaging lesions were observed with every-2-weeks dosing than every-4-weeks dosing over 4 years., Conclusions: Results from the ADVANCE extension study, ATTAIN, confirm the favorable long-term safety and tolerability profile of peginterferon beta-1a in patients with RRMS and provide additional evidence for the clinical and radiological benefits associated with this therapy., Competing Interests: Conflict of interest statement: SDN has received research support (paid directly to institution) from Biogen, Genentech, the National MS Society, and Novartis, and has participated in scientific advisory boards for Biogen and Genentech. TFS has received research support from Biogen and Novartis and has received honoraria for participation in scientific advisory boards and speaking from Acorda Therapeutics, Biogen, Genentech, Genzyme, Novartis, and Teva Neurosciences. DLA reports an equity interest in NeuroRx during the conduct of the study and personal fees from Acorda, Biogen, EMD Serono, Genentech, Genzyme, Hoffman-La Roche, Innate Immunotherapy, MedImmune, Mitsubishi, Novartis, Receptos, Sanofi-Aventis, and Teva outside the submitted work, as well as grants from Biogen and Novartis. GN has participated in scientific advisory boards for Bayer HealthCare, Biogen, Genzyme, and Merck, and received personal compensation for speaking activities from Bayer HealthCare, Biogen, Genzyme, Merck, Novartis, and Teva. SH, YC, and SS were full-time employees of Biogen and holders of Biogen stock and/or stock options at the time of the analysis. MLN is a full-time employee of Biogen and holder of Biogen stock and/or stock options. MK has received research grants, research support, and personal compensation for consulting or speaking activities from Biogen, the Canadian Institute of Health Research, Genzyme, the MS Society of Canada, Novartis, Sanofi, Teva, and Wellesley Therapeutics. MK’s institution has received research grants from Biogen and the Canadian Institute of Health Research and research support from the Chapman Chair in MS Clinical Research at London Health Sciences Centre.

Background: No evidence of disease activity (NEDA) is a composite measurement, incorporating clinical and magnetic resonance imaging (MRI) elements of disease activity to sensitively evaluate the therapeutic efficacy of treatments for relapsing-remitting multiple sclerosis (RRMS)., Objective: To assess the NEDA status of patients treated with peginterferon β-1a in the ADVANCE and ATTAIN studies and explore its predictive value on longer-term clinical outcomes., Methods: ATTAIN was a 2-year extension of the pivotal 2-year ADVANCE study of peginterferon β-1a for RRMS. Achievement of clinical NEDA, MRI NEDA, or overall NEDA was calculated cumulatively and by year over 4 years. Clinical outcomes during ATTAIN were analyzed based on NEDA status at the end of ADVANCE., Results: Significantly more patients treated with peginterferon β-1a every 2 weeks than every 4 weeks achieved clinical NEDA (60.6% versus 50.6%, p  = 0.0063) and MRI NEDA (28.3% versus 15.8%, p  = 0.0005) through year 4 and overall NEDA through year 3 (20.9% versus 13.9%, p  = 0.0160). Over 4 years, 15.8% of patients in the every 2 weeks group and 10.7% of patients in the every 4 weeks group maintained overall NEDA ( p  = 0.0584). Achievement of clinical NEDA, MRI NEDA, or overall NEDA in ADVANCE was predictive of annualized relapse rate in ATTAIN; achievement of clinical NEDA in ADVANCE was also predictive of NEDA achievement and confirmed disability worsening in ATTAIN., Conclusions: Peginterferon β-1a every 2 weeks is associated with higher levels of NEDA compared with placebo in year 1 or peginterferon β-1a every 4 weeks in years 2-4. Overall NEDA within the first 2 years of treatment may be prognostic of long-term clinical outcomes. Clinicaltrials.gov : NCT01332019., Competing Interests: Conflict of interest statement: DA: had an equity interest in NeuroRx during the conduct of the study and has received personal fees from Acorda, Biogen, EMD Serono, Genentech, Genzyme, Hoffman–La Roche, Innate Immunotherapy, MedImmune, Mitsubishi, Novartis, Receptos, Sanofi, and Teva, and grants from Biogen and Novartis. SS, QD: full-time employees and stockholders of Biogen at the time of the analysis. MM, MLN: full-time employees and stockholders of Biogen.

Objective: The objective of this paper is to assess, in individuals with clinically stable multiple sclerosis (MS), the safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics of the monoclonal recombinant human antibody IgM22 (rHIgM22)., Methods: Seventy-two adults with stable MS were enrolled in a double-blind, randomized, placebo-controlled, single ascending-dose, Phase 1 trial examining rHIgM22 from 0.025 to 2.0 mg/kg. Assessments included MRI, MR spectroscopy, plasma PK, and changes in clinical status, laboratory values and adverse events for three months. The final cohort had additional clinical, ophthalmologic, CSF collection and exploratory biomarker evaluations. Participants were monitored for six months., Results: rHIgM22 was well tolerated with no clinically significant safety signals. Noncompartmental PK modeling demonstrated linear dose-proportionality both of C max and AUC 0-Last . The steady-state apparent volume of distribution of approximately 58 ml/kg suggested primarily vascular compartmentalization. CSF:plasma rHIgM22 concentration increased from 0.003% on Day 2 for both 1.0 and 2.0 mg/kg to 0.056% and 0.586% for 1.0 and 2.0 mg/kg, respectively, on Day 29. No statistically significant treatment-related changes were observed in exploratory pharmacodynamic outcome measures included for the 21 participants of the extension cohort., Conclusions: Single doses of rHIgM22 were well tolerated and exhibited linear PK, and antibody was detected in the CSF.

The presence of chronic black holes, i.e., chronic lesions that are hypointense on T1-weighted images and are indicative of more severe tissue injury, has been increasingly utilized as a surrogate marker of therapeutic outcome in multiple sclerosis. The ADVANCE study was a 2-year, double-blind, pivotal trial evaluating the safety and efficacy of subcutaneous peginterferon beta-1a 125 mcg in 1512 patients with relapsing-remitting multiple sclerosis (RRMS). This report describes the correlation of clinical outcomes with the evolution of acute lesions into chronic black holes in ADVANCE, and the efficacy of peginterferon beta-1a in reducing this evolution. Treatment with peginterferon beta-1a significantly reduced the mean number of new/enlarging T2-weighted (NET2) lesions (0.76 vs. 1.03 from week 24, p = 0.0037; 0.44 vs. 0.99 from week 48, p < 0.0001) and new gadolinium-enhancing (Gd+) lesions (0.15 vs. 0.32 from week 24, p < 0.0001; 0.09 vs. 0.19 from week 48) that evolved into chronic black holes by 2 years. Patients with NET2 or Gd+ lesions at 24 weeks that evolved into chronic black holes showed significantly worse clinical outcomes, including a greater proportion with 12-week (14.9 vs. 8.4%; p = 0.0167) and 24-week (12.3 vs. 7.0%; p = 0.0333) confirmed disability worsening and higher mean annualized relapse rate (0.62 vs. 0.43; p = 0.0118), compared with patients with lesions that did not evolve into black holes. The correlation was independent of treatment. Reduced risk of evolution of new lesions into chronic black holes with peginterferon beta-1a treatment suggests potential to reduce long-term disability in RRMS by preventing irreversible tissue damage.

Background: Subcutaneous peginterferon beta-1a has previously been shown to reduce the number of T2-hyperintense and gadolinium-enhancing (Gd+) lesions over 2 years in patients with relapsing-remitting multiple sclerosis (RRMS), and to reduce T1-hypointense lesion formation and the proportion of patients showing evidence of disease activity, based on both clinical and radiological measures, compared with placebo over 1 year of treatment. The objectives of the current analyses were to evaluate T1 lesions and other magnetic resonance imaging (MRI) measures, including whole brain volume and magnetization transfer ratio (MTR) of normal appearing brain tissue (NABT), and the proportions of patients with no evidence of disease activity (NEDA), over 2 years., Methods: Patients enrolled in the ADVANCE study received continuous peginterferon beta-1a every 2 or 4 weeks for 2 years, or delayed treatment (placebo in Year 1; peginterferon beta-1a every 2 or 4 weeks in Year 2). MRI scans were performed at baseline and Weeks 24, 48, and 96. Proportions of patients with NEDA were calculated based on radiological criteria (absence of Gd + and new/newly-enlarging T2 lesions) and clinical criteria (no relapse or confirmed disability progression) separately and overall., Results: Peginterferon beta-1a every 2 weeks significantly reduced the number and volume of T1-hypointense lesions compared with delayed treatment over 2 years. Changes in whole brain volume and MTR of NABT were suggestive of pseudoatrophy during the first 6 months of peginterferon beta-1a treatment, which subsequently began to resolve. Significantly more patients in the peginterferon beta-1a every 2 weeks group compared with the delayed treatment group met MRI-NEDA criteria (41% vs 21%; odds ratio [OR] 2.56; p < 0.0001), clinical-NEDA criteria (71% vs 57%; OR 1.90; p < 0.0001) and achieved overall-NEDA (37% vs 16%; OR 3.09; p < 0.0001)., Conclusion: Peginterferon beta-1a provides significant improvements in MRI measures and offers patients a good chance of remaining free from evidence of MRI, clinical and overall disease activity over a sustained 2-year period., Trial Registration: ClinicalTrials.gov: NCT00906399 ; Registered on: May 20, 2009.

Histamine H 3 receptor blockade may enhance lesion remyelination in multiple sclerosis (MS). The efficacy (using a magnetic resonance imaging marker of myelination, magnetisation transfer ratio [MTR]), safety and pharmacokinetics of GSK239512, a potent and brain penetrant H 3 receptor antagonist/inverse agonist on lesion remyelination in relapsing-remitting MS (RRMS) were assessed. This was a phase II, randomised, parallel-group, placebo-controlled, double-blind (sponsor-unblinded), international, multicentre study (NCT01772199). Patients aged 18-50 with RRMS, receiving intramuscular interferon-β1a or glatiramer acetate, were randomised 1:1 to once-daily oral GSK239512 or placebo, up-titrated over 4-5 weeks to a maximum tolerable dose up to 80 µg and maintained until Week 48. The co-primary endpoints were mean changes in post-lesion MTR in gadolinium-enhanced (GdE) or Delta-MTR defined lesions from pre-lesion values. Adverse events (AE) and withdrawals were monitored. Of the 131 patients randomised, 114 patients completed the study (GSK239512, n = 51; placebo, n = 63) and 27 (GSK239512) and 28 (placebo) patients contributed lesions to the primary analysis. GSK239512 was associated with positive effect sizes of 0.344 [90% confidence interval (CI) 0.018, 0.671] and 0.243 (90% CI -0.112, 0.598) for adjusted mean changes in the normalised MTR for GdE and Delta-MTR lesions, respectively. The overall incidence of AEs was similar between GSK239512 and placebo during the treatment phase although some AEs including insomnia were more common with GSK239512, particularly during the titration period. A small but positive effect of GSK239512 on remyelination was observed. MTR assessment represents a promising method for detecting lesion remyelination in RRMS., Competing Interests: Compliance with ethical standards Conflicts of interest CJS is a former employee of GSK and holds stocks/shares in GSK. RAG and DT are employees of GSK and hold stocks/shares in GSK; RB has received personal compensation from NeuroRx Research for consulting services. FTB has received an honorarium from GSK for speaking at an investigators´ meeting for the trial reported here; his institution received compensation from GSK for the treatment and documentation of those patients included at his site; he has received personal compensation for speaking or serving on advisory boards from Bayer-Schering, Biogen, Genzyme, Novartis and Teva; through his institution, he received grants from Actelion, Bayer, Novartis and Teva. DLA has an equity interest in NeuroRx Research, has received personal fees from Biogen, EMD Serono, Genentech, Genzyme, Hoffman LaRoche, Innate Immunotherapy, MedImmune, Mitsubishi, Novartis, Receptos, Acorda, Sanofi-Aventis, and Teva, and Grants from Biogen and Novartis. Ethical standards The study was conducted in accordance with the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Good Clinical Practice (ICH-GCP) and the ethical principles outlined in the Declaration of Helsinki 2008 [17]. Ethics approval was obtained from respective countries’ Ethics Committees (Online resource 1). The study protocol is available online at http://www.gsk-clinicalstudyregister.com/files2/gsk-116477-protocol-redact.pdf.

Background: Delayed-release dimethyl fumarate (DMF) demonstrated strong efficacy and a favorable benefit-risk profile for patients with relapsing-remitting multiple sclerosis (RRMS) in phase 3 DEFINE/CONFIRM studies. ENDORSE is an ongoing long-term extension of DEFINE/CONFIRM., Objective: We report efficacy and safety results of a 5-year interim analysis of ENDORSE (2 years DEFINE/CONFIRM; minimum 3 years ENDORSE)., Methods: In ENDORSE, patients randomized to DMF 240 mg twice (BID) or thrice daily (TID) in DEFINE/CONFIRM continued this dosage, and those initially randomized to placebo (PBO) or glatiramer acetate (GA) were re-randomized to DMF 240 mg BID or TID., Results: For patients continuing DMF BID (BID/BID), annualized relapse rates were 0.202, 0.163, 0.139, 0.143, and 0.138 (years 1-5, respectively) and 63%, 73%, and 88% were free of new or enlarging T2 hyperintense lesions, new T1 hypointense lesions, and gadolinium-enhanced lesions, respectively, at year 5. Adverse events (AEs; serious adverse events (SAEs)) were reported in 91% (22%; BID/BID), 95% (24%; PBO/BID), and 88% (16%; GA/BID) of the patients. One case of progressive multifocal leukoencephalopathy was reported in the setting of severe, prolonged lymphopenia., Conclusion: Treatment with DMF was associated with continuously low clinical and magnetic resonance imaging (MRI) disease activity in patients with RRMS. These interim data demonstrate a sustained treatment benefit and an acceptable safety profile with DMF.

ADVANCE was a 2-year, double-blind, placebo-controlled, Phase 3 study in 1512 patients aged 18-65 years with relapsing-remitting multiple sclerosis, which demonstrated that peginterferon beta-1a 125 mcg administered subcutaneously every 2 or 4 weeks led to significant reductions in annualized relapse rate (ARR) compared with placebo. This analysis examined ARR over 2 years in ADVANCE across subgroups. Patients were treated with peginterferon beta-1a every 2 weeks or every 4 weeks, or placebo during Year 1. Thereafter, patients on placebo were re-randomized to peginterferon beta-1a every 2 weeks or every 4 weeks (delayed treatment). Subgroup analyses were conducted by demographics and baseline disease characteristics. The following results compared ARR in these subgroups for patients in continuous 2-week treatment versus continuous 4-week treatment. ARR was similar in most demographic and baseline disease characteristic subgroups evaluated within the peginterferon beta-1a every-2-week arm or every-4-week arm over 2 years. Although for both doses some differences in the point estimates for ARR were noted among the subgroups, considerable overlap in the confidence intervals suggested that the efficacy of peginterferon beta-1a is similar in all patients irrespective of gender, age, body weight, geographical region, and disease activity at initiation of treatment. Within each peginterferon beta-1a dosing group, ARR was generally similar across most subgroups., Competing Interests: Compliance with ethical standards The study protocol was approved by the institutional review board at each site and the study was carried out according to the International Conference on Harmonization Guidelines for Good Clinical Practice and the Declaration of Helsinki. Every patient provided written informed consent before entering the study. Conflicts of interest The ADVANCE study was funded by Biogen (Cambridge, MA, USA). Scott D. Newsome has received research support from Biogen and Novartis, and has participated in scientific advisory boards for Biogen, Genzyme, and Novartis. Bernd C. Kieseier has received personal compensation for activities with Bayer Schering, Biogen, Merck Serono, Novartis, Roche, Sanofi-Aventis, and Teva Neurosciences as a lecturer, and research support from Bayer Schering, Biogen, Merck Serono, and Teva Neurosciences; he is now an employee of Biogen. Douglas L. Arnold reports an equity interest in NeuroRx during the conduct of the study and personal fees from Biogen, EMD Serono, Genentech, Genzyme, Hoffman-La Roche, Innate Immunotherapy, MedImmune, Mitsubishi, Novartis, Receptos, Acorda, Sanofi-Aventis, and Teva outside the submitted work, as well as grants from Biogen and Novartis. Shulian Shang, Shifang Liu, Serena Hung, and Guido Sabatella are full-time employees and stockholders of Biogen.

Background: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis., Methods: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930., Findings: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score., Interpretation: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature., Funding: Multiple Sclerosis Scientific Research Foundation., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

We measured changes in brain magnetization transfer ratio (MTR) as a potential indicator of myelin density in brain tissue of patients with relapsing-remitting multiple sclerosis (RRMS) treated with delayed-release dimethyl fumarate (DMF) in the Phase 3 DEFINE study. DEFINE was a randomized, double-blind, placebo-controlled study in which patients with RRMS were randomized 1:1:1 to 2 years of treatment with delayed-release DMF 240 mg twice daily (BID) or three times daily (TID) or placebo. MTR was analyzed in whole brain and normal-appearing brain tissue (NABT) at baseline, week 24, 1 year, and 2 years in a subset of patients. MTR data from 392 patients were analyzed. Mean percentage reduction from baseline to 2 years in median whole brain MTR was -0.386% in the placebo group vs increases of 0.129% (p = 0.0027) and 0.096% (p = 0.0051) in the delayed-release DMF BID and TID groups, respectively. Similarly, mean percentage reduction from baseline in median NABT MTR was -0.392% with placebo vs increases of 0.190% (p = 0.0006) and 0.115% (p = 0.0029) with delayed-release DMF BID and TID, respectively. Post hoc analysis of data from patients with no new or enlarging T2 lesions (n = 147), or who experienced no relapses (n = 238), yielded similar results. In this analysis, increases in MTR in brain tissue most likely reflect increases in myelin density in response to delayed-release DMF. These data in patients with RRMS are consistent with preclinical studies that indicate a potential for cytoprotection and remyelination with delayed-release DMF treatment.

In the Phase 3 DEFINE study, delayed-release dimethyl fumarate (DMF) 240 mg twice (BID) and three times daily (TID) significantly reduced the mean number of new or enlarging T2-hyperintense lesions and gadolinium-enhancing (Gd+) lesion activity at 2 years in patients (MRI cohort; n = 540) with relapsing-remitting MS. The analyses described here expand on these results by considering additional MRI measures (number of T1-hypointense lesions; volume of T2-hyperintense, Gd+, and T1-hypointense lesions; brain atrophy), delineating the time course of the effects, and examining the generality of the effects across a diverse patient population. Reductions in lesion counts with delayed-release DMF BID and TID, respectively, vs. placebo were apparent by the first MRI assessment at 6 months [T2-hyperintense: 80 and 69 % reduction (both P < 0.0001); Gd+, 94 and 81 % reduction (both P < 0.0001); T1-hypointense: 58 % (P < 0.0001) and 48 % (P = 0.0005) reduction] and maintained at 1 and 2 years. Reductions in lesion volume were statistically significant beginning at 6 months for T2-hyperintense [P = 0.0002 (BID) and P = 0.0035 (TID)] and Gd+ lesions [P = 0.0059 (BID) and P = 0.0176 (TID)] and beginning at 1 year [P = 0.0126 (BID)] to 2 years [P = 0.0063 (TID)] for T1-hypointense lesions. Relative reductions in brain atrophy from baseline to 2 years (21 % reduction; P = 0.0449) and 6 months to 2 years (30 % reduction; P = 0.0214) were statistically significant for delayed-release DMF BID. The effect of delayed-release DMF on mean number of new or enlarging T2-hyperintense lesions and Gd+ lesion activity was consistent across pre-specified patient subpopulations. Collectively, these results suggest that delayed-release DMF favorably affects multiple aspects of MS pathophysiology.

Background: Subcutaneous pegylated interferon (peginterferon) beta-1a is being developed for treatment of relapsing multiple sclerosis, with less frequent dosing than currently available first-line injectable treatments. We assessed the safety and efficacy of peginterferon beta-1a after 48 weeks of treatment in the placebo-controlled phase of the ADVANCE trial, a study of patients with relapsing-remitting multiple sclerosis., Methods: We did this 2-year, double-blind, parallel group, phase 3 study, with a placebo-controlled design for the first 48 weeks, at 183 sites in 26 countries. Patients with relapsing-remitting multiple sclerosis (age 18-65 years, with Expanded Disability Status Scale score ≤5) were randomly assigned (1:1:1) via an interactive voice response or web system, and stratified by site, to placebo or subcutaneous peginterferon beta-1a 125 μg once every 2 weeks or every 4 weeks. The primary endpoint was annualised relapse rate at 48 weeks. This trial is registered with ClinicalTrials.gov, number NCT00906399., Findings: We screened 1936 patients and enrolled 1516, of whom 1512 were randomly assigned (500 to placebo, 512 to peginterferon every 2 weeks, 500 to peginterferon every 4 weeks); 1332 (88%) patients completed 48 weeks of treatment. Adjusted annualised relapse rates were 0·397 (95% CI 0·328-0·481) in the placebo group versus 0·256 (0·206-0·318) in the every 2 weeks group and 0·288 (0·234-0·355) in the every 4 weeks group (rate ratio for every 2 weeks group 0·644, 95% CI 0·500-0·831, p=0·0007; rate ratio for the every 4 weeks group 0·725, 95% CI 0·565-0·930, p=0·0114). 417 (83%) patients taking placebo, 481 (94%) patients taking peginterferon every 2 weeks, and 472 (94%) patients taking peginterferon every 4 weeks reported adverse events including relapses. The most common adverse events associated with peginterferon beta-1a were injection site reactions, influenza-like symptoms, pyrexia, and headache. 76 (15%) patients taking placebo, 55 (11%) patients taking study drug every 2 weeks, and 71 (14%) patients taking study drug every 4 weeks reported serious adverse events; relapse, pneumonia, and urinary tract infection were the most common., Interpretation: After 48 weeks, peginterferon beta-1a significantly reduced relapse rate compared with placebo. The drug might be an effective treatment for relapsing-remitting multiple sclerosis with less frequent administration than available treatments., Funding: Biogen Idec., (Copyright © 2014 Elsevier Ltd. All rights reserved.)