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Background: In 1996, the clinical course of multiple sclerosis (MS) was characterized as relapsing-remitting, primary progressive, secondary progressive or progressive relapsing. Since then, an increased understanding of MS and its pathology prompted a re-examination of these clinical phenotypes. Main recommendations of the 2013 revisions are provided herein. Summary: Clinically isolated syndrome has been added, and progressive relapsing MS has been eliminated, from the clinical course descriptions. All forms of MS should be further subcategorized as either active or non-active. Active MS is defined as the occurrence of clinical relapse or the presence of new T2 or gadolinium-enhancing lesions over a specified period of time, preferably at least one year. An additional subcategory for patients with progressive MS differentiates between those who have shown signs of disability progression over a given time period and those who have remained stable. The term ‘worsening' is recommended to describe patients whose disease is advancing for any reason, whereas ‘disease progression' should be reserved for those with progressive disease who are truly progressing (as opposed to worsening from a relapse). The term ‘benign' should be used with caution as the course of MS can worsen at any time, even after many years of apparent stability. Key Messages: Newer characterizations of MS phenotypes include a consideration of disease activity (based on the clinical relapse rate and imaging findings) and disease progression. Accurate clinical course descriptions are useful for communication, prognostication, clinical trial design and to guide everyday clinical decision-making. © 2014 S. Karger AG, Basel

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

Fingolimod has shown reductions in clinical and MRI disease activity in patients with relapsing-remitting multiple sclerosis. We further assessed the efficacy and safety of fingolimod in such patients. We did this placebo-controlled, double-blind phase 3 study predominantly in the USA (101 of 117 centres). Using a computer-generated sequence, we randomly allocated eligible patients—those aged 18–55 years with relapsing-remitting multiple sclerosis—to receive fingolimod 0·5 mg, fingolimod 1·25 mg, or placebo orally once daily (1:1:1; stratified by study centre). On Nov 12, 2009, all patients assigned to fingolimod 1·25 mg were switched to the 0·5 mg dose in a blinded manner after a review of data from other phase 3 trials and recommendation from the data and safety monitoring board, but were analysed as being in the 1·25 mg group in the primary outcome analysis. Our primary endpoint was annualised relapse rate at month 24, analysed by intention to treat. Secondary endpoints included percentage brain volume change (PBVC) from baseline and time-to-disability-progression confirmed at 3 months. This trial is registered with ClinicalTrilals.gov, number NCT00355134. Between June 30, 2006, and March 4, 2009, we enrolled and randomly allocated 1083 patients: 370 to fingolimod 1·25 mg, 358 to fingolimod 0·5 mg, and 355 to placebo. Mean annualised relapse rate was 0·40 (95% CI 0·34–0·48) in patients given placebo and 0·21 (0·17–0·25) in patients given fingolimod 0·5 mg: rate ratio 0·52 (95% CI 0·40–0·66; p<0·0001), corresponding to a reduction of 48% with fingolimod 0·5 mg versus placebo. Mean PBVC was −0·86 (SD 1·22) for fingolimod 0·5 mg versus −1·28 (1·50) for placebo (treatment difference −0·41, 95% CI −0·62 to −0·20; p=0·0002). We recorded no statistically significant between-group difference in confirmed disability progression (hazard rate 0·83 with fingolimod 0·5 mg vs placebo; 95% CI 0·61–1·12; p=0·227). Fingolimod 0·5 mg caused more of the following adverse events versus placebo: lymphopenia (27 [8%] patients vs 0 patients), increased alanine aminotransferase (29 [8%] vs six [2%]), herpes zoster infection (nine [3%] vs three [1%]), hypertension (32 [9%] vs 11 [3%]), first-dose bradycardia (five [1%] vs one [<0·5%]), and first-degree atrioventricular block (17 [5%] vs seven [2%]). 53 (15%) of 358 patients given fingolimod 0·5 mg and 45 (13%) of 355 patients given placebo had serious adverse events over 24 months, which included basal-cell carcinoma (ten [3%] patients vs two [1%] patients), macular oedema (three [1%] vs two [1%]), infections (11 [3%] vs four [1%]), and neoplasms (13 [4%] vs eight [2%]). Our findings expand knowledge of the safety profile of fingolimod and strengthen evidence for its beneficial effects on relapse rates in patients with relapsing-remitting multiple sclerosis. We saw no effect of fingolimod on disability progression. Our findings substantiate the beneficial profile of fingolimod as a disease-modifying agent in the management of patients with relapsing-remitting multiple sclerosis. Novartis Pharma AG.

No approved therapies exist for neuromyelitis optica spectrum disorder (NMOSD), a rare, relapsing, autoimmune, inflammatory disease of the CNS that causes blindness and paralysis. We aimed to assess the efficacy and safety of inebilizumab, an anti-CD19, B cell-depleting antibody, in reducing the risk of attacks and disability in NMOSD. We did a multicentre, double-blind, randomised placebo-controlled phase 2/3 study at 99 outpatient specialty clinics or hospitals in 25 countries. Eligible participants were adults (≥18 years old) with a diagnosis of NMOSD, an Expanded Disability Status Scale score of 8·0 or less, and a history of at least one attack requiring rescue therapy in the year before screening or at least two attacks requiring rescue therapy in the 2 years before screening. Participants were randomly allocated (3:1) to 300 mg intravenous inebilizumab or placebo with a central interactive voice response system or interactive web response system and permuted block randomisation. Inebilizumab or placebo was administered on days 1 and 15. Participants, investigators, and all clinical staff were masked to the treatments, and inebilizumab and placebo were indistinguishable in appearance. The primary endpoint was time to onset of an NMOSD attack, as determined by the adjudication committee. Efficacy endpoints were assessed in all randomly allocated patients who received at least one dose of study intervention, and safety endpoints were assessed in the as-treated population. The study is registered with ClinicalTrials.gov, number NCT02200770. Between Jan 6, 2015, and Sept 24, 2018, 230 participants were randomly assigned to treatment and dosed, with 174 participants receiving inebilizumab and 56 receiving placebo. The randomised controlled period was stopped before complete enrolment, as recommended by the independent data-monitoring committee, because of a clear demonstration of efficacy. 21 (12%) of 174 participants receiving inebilizumab had an attack versus 22 (39%) of 56 participants receiving placebo (hazard ratio 0·272 [95% CI 0·150–0·496]; p<0·0001). Adverse events occurred in 125 (72%) of 174 participants receiving inebilizumab and 41 (73%) of 56 participants receiving placebo. Serious adverse events occurred in eight (5%) of 174 participants receiving inebilizumab and five (9%) of 56 participants receiving placebo. Compared with placebo, inebilizumab reduced the risk of an NMOSD attack. Inebilizumab has potential application as an evidence-based treatment for patients with NMOSD. MedImmune and Viela Bio.

The efficacy of natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has prompted the investigation of whether natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity. Post-hoc analyses of data from the AFFIRM study were done to determine the effects of natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two. 383 (64%) of 596 patients taking natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25·4%, 95% CI 18·7–32·1%, p<0·0001); 342 (58%) of 593 and 42 (14%) of 296 were free of radiological disease activity (43·5%, 37·9–49·1%, p<0·0001); and 220 (37%) of 600 and 22 (7%) of 304 were free of combined activity (29·5%, 24·7–34·3%, p<0·0001) over 2 years. The effect of natalizumab versus placebo was consistent across subgroups of patients with highly active or non-highly active disease at baseline. Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies. Biogen Idec.

This placebo-controlled, randomized trial of patients with relapsing multiple sclerosis demonstrated benefits of natalizumab (an α 4 integrin antagonist) in all the primary and secondary outcome measures. After two years, the probability of sustained progression of disability was 17 percent with natalizumab and 29 percent with placebo. Fatigue and allergic reaction were more common among patients receiving natalizumab. This trial of patients with relapsing multiple sclerosis demonstrated benefits of natalizumab in all the primary and secondary outcome measures. In this trial, natalizumab in combination with interferon was more effective than interferon alone. Progressive multifocal leukoencephalopathy developed in two patients. In this systematic evaluation for PML in patients who received natalizumab in clinical trials, no additional cases were identified. Relapsing multiple sclerosis is characterized by the intermittent development of inflammatory lesions in the brain and spinal cord, resulting in plaques of demyelination and axonal loss. Lymphocyte migration across the blood–brain barrier is thought to be an important early step in the formation of lesions. 1 The interaction of α 4 β 1 integrin, a protein on the surface of lymphocytes, with vascular-cell adhesion molecule 1 (VCAM-1), which is expressed on the surface of vascular endothelial cells in brain and spinal cord blood vessels, mediates the adhesion and migration of lymphocytes in areas of inflammation. 2 – 6 Furthermore, the interaction of α . . .

No treatments have been approved for primary progressive multiple sclerosis. Fingolimod, an oral sphingosine 1-phosphate receptor modulator, is effective in relapse-onset multiple sclerosis, but has not been assessed in primary progressive multiple sclerosis. We assessed the safety and efficacy of fingolimod in patients with primary progressive multiple sclerosis. In INFORMS, a multicentre, double-blind, placebo-controlled parallel-group study, patients with primary progressive multiple sclerosis recruited across 148 centres in 18 countries were randomly allocated (1:1) with computer-generated blocks to receive oral fingolimod or placebo for at least 36 months and a maximum of 5 years. Patients were initially assigned to fingolimod 1·25 mg per day or placebo (cohort 1); however, after a protocol amendment on Nov 19, 2009, patients were switched in a masked manner to fingolimod 0·5 mg, whereas those on placebo continued on matching placebo. From then onwards, patients were assigned to receive fingolimod 0·5 mg/day or placebo (cohort 2). Key inclusion criteria were age 25–65 years, clinical diagnosis of primary progressive multiple sclerosis, 1 year or more of disease progression, and two of the following criteria: positive brain MRI; positive spinal cord MRI; or positive cerebrospinal fluid. Additional eligibility criteria included disease duration of 2–10 years and objective evidence of disability progression in the previous 2 years. Patients and study investigators were masked to group assignment. We used a novel primary composite endpoint based on change from baseline in Expanded Disability Status Scale (EDSS), 25' Timed-Walk Test, or Nine-Hole Peg Test to assess time to 3-month confirmed disability progression in study participants treated for at least 3 years. All randomised patients took at least one dose of study drug. The primary efficacy analysis included all patients in cohort 2 and those assigned to placebo in cohort 1. The safety analysis included all patients in cohorts 1 and 2. This study is registered with ClinicalTrials.gov, number NCT00731692. The study is now closed. 970 patients were randomly assigned between Sept 3, 2008, and Aug 30, 2011 (147 to fingolimod 1·25 mg and 133 to placebo in cohort 1; 336 to fingolimod 0·5 mg and 354 to placebo in cohort 2). The efficacy analysis set (n=823) consisted of 336 patients randomly allocated to fingolimod 0·5 mg and 487 to placebo. Baseline characteristics were similar across groups and representative of a primary progressive multiple sclerosis population (48% women, mean age 48·5 years [SD 8·4], mean EDSS 4·67 [SD 1·03], 87% free of gadolinium-enhancing lesions). By end of study, 3-month confirmed disability progression had occurred in 232 and 338 patients in the fingolimod and placebo groups, respectively, resulting in Kaplan-Meier estimates of 77·2% (95% CI 71·87–82·51) of patients in the fingolimod group versus 80·3% (73·31–87·25) of patients in the placebo group (risk reduction 5·05%; hazard ratio 0·95, 95% CI 0·80–1·12; p=0·544). Safety results were generally consistent with those of studies of fingolimod in patients with relapse-onset multiple sclerosis. Lymphopenia occurred in 19 (6%) patients in the fingolimod group versus none in the placebo group, bradycardia in five (1%) versus one (<1%), and first-degree atrioventricular block in three (1%) versus six (1%). Serious adverse events occurred in 84 (25%) patients in the fingolimod group and 117 (24%) in the placebo group, including macular oedema in six (2%) versus six (1%), and basal-cell carcinoma in 14 (4%) versus nine (2%). The anti-inflammatory effects of fingolimod did not slow disease progression in primary progressive multiple sclerosis. Therapeutic strategies for primary progressive multiple sclerosis might need different approaches to those used for relapse-onset multiple sclerosis. Novartis Pharma AG.

There is an unmet need to develop therapeutic interventions directed at the neurodegeneration that underlies progression in multiple sclerosis. High-dose, pharmaceutical-grade biotin (MD1003) might enhance neuronal and oligodendrocyte energetics, resulting in improved cell function, repair, or survival. The MS-SPI randomised, double-blind, placebo-controlled study found that MD1003 improved disability outcomes over 12 months in patients with progressive multiple sclerosis. The SPI2 study was designed to assess the safety and efficacy of MD1003 in progressive forms of multiple sclerosis in a larger, more representative patient cohort. SPI2 was a randomised, double-blind, parallel-group, placebo-controlled trial done at 90 academic and community multiple sclerosis clinics across 13 countries. Patients were aged 18–65 years, had a diagnosis of primary or secondary progressive multiple sclerosis fulfilling the revised International Panel criteria and Lublin criteria, a Kurtzke pyramidal functional subscore of at least 2 (defined as minimal disability), an expanded disability status scale (EDSS) score of 3·5–6·5, a timed 25-foot walk (TW25) of less than 40 s, evidence of clinical disability progression, and no relapses in the 2 years before enrolment. Concomitant disease-modifying therapies were allowed. Patients were randomly assigned (1:1) by an independent statistician using an interactive web response system, with stratification by study site and disease history, to receive MD1003 (oral biotin 100 mg three times daily) or placebo. Participants, investigators, and assessors were masked to treatment assignment. The primary endpoint was a composite of the proportion of participants with confirmed improvement in EDSS or TW25 at month 12, confirmed at month 15, versus baseline. The primary endpoint was assessed in the intention-to-treat analysis set, after all participants completed the month 15 visit. Safety analyses included all participants who received at least one dose of MD1003. This trial is registered with ClinicalTrials.gov (NCT02936037) and the EudraCT database (2016-000700-29). From Feb 22, 2017, to June 8, 2018, 642 participants were randomly assigned MD1003 (n=326) or placebo (n=316). The double-blind, placebo-controlled phase of the study ended when the primary endpoint for the last-entered participant was assessed on Nov 15, 2019. The mean time in the placebo-controlled phase was 20·1 months (SD 5·3; range 15–27). For the primary outcome, 39 (12%) of 326 patients in the MD1003 group compared with 29 (9%) of 316 in the placebo group improved at month 12, with confirmation at month 15 (odds ratio 1·35 [95% CI 0·81–2·26]). Treatment-emergent adverse events occurred in 277 (84%) of 331 participants in the MD1003 group and in 264 (85%) of 311 in the placebo group. 87 (26%) of 331 participants in the MD1003 group and 82 (26%) of 311 participants in the placebo group had at least one serious treatment-emergent adverse event. One (<1%) person died in the MD1003 group and there were no deaths in the placebo group. Despite use of mitigation strategies, MD1003 led to inaccurate laboratory results for tests using biotinylated antibodies. This study showed that MD1003 did not significantly improve disability or walking speed in patients with progressive multiple sclerosis and thus, in addition to the potential of MD1003 for deleterious health consequences from interference of laboratory tests, MD1003 cannot be recommended for treatment of progressive multiple sclerosis. MedDay Pharmaceuticals.

IntroductionCurrent multiple-sclerosis(MS) disease-modifying treatments(DMTs) alter patients’ immune-sys- tem with varying degrees and speed of reversibility. Certain clinical situations require fast drug-elimination and a fully-functioning immune-system. For ponesimod, lymphocyte-counts return to normal-range in>90% of patients-within 1week of stopping.ObjectivesTo assess clinical and MRI-outcomes in RMS patients at 48weeks of follow-up after short-term interruption and re-initiation of ponesimod.MethodsPatients who completed 108weeks of ponesimod or teriflunomide in Phase3 OPTIMUM study and underwent an accelerated-elimination procedure were eligible to enrol in OLE(open-label exten- sion)-where they received ponesimod20 mg. Of the 567ponesimod-patients, 439(77.4%) entered OLE and 239(42.2%) had at least 48 weeks follow-up in OLE. Annualized-relapse-rate (ARR) and cumulative number ofcombined-unique-active-lesions (CUALs) followingshort-termtreatment-interruption (betweencore-study and OLE) and re-initiation (at start of OLE) were examined in the239 ponesimod-patients.ResultsThe mean duration of ponesimod treatment-interruption was 17.6 days (range 13–45days). The ARR at OLE-week48, and considering treatment-interruption and re-initiation, was 0.191 (95% CI: 0.140, 0.261). This was numerically lower than the 2-year ARR of 0.234 (95% CI: 0.186, 0.296) with a relative rate-reduction (RRR) of 18.4% (RRR: 0.816, 95% CI: 0.595, 1.120). At OLE-week 48, patients had 1.73CUALs/year (95% CI: 1.30, 2.31) which was not statistically significantly different from 1.48CUALs/year (95% CI: 1.19, 1.82) in OPTIMUM.ConclusionsIn this study, based on clinical and imaging outcomes, disease-activity at OLE-48weeks following short-term interruption and re-initiation of ponesimod treatment remained consistent with dis- ease-activity prior to interruption.

Interferon beta and glatiramer acetate have been mainstays of treatment in relapsingremitting multiple sclerosis for two decades. Remarkable advances in our understanding of immune function and dysfunction as well as increasingly sophisticated clinical trial design have stemmed from efforts to better understand these drugs. In this chapter, we review the history of their development and elaborate on known and theorized mechanisms of action. We describe the pivotal clinical trials that have led to their widespread use. We evaluate the clinical use of the drugs including tolerability, side effects, and efficacy measures. Finally, we look to the future of interferon beta and glatiramer acetate in the context of an ever growing armamentarium of treatments for relapsing remitting multiple sclerosis.