Current and Future Trends in MS Management: Near East Perspective

Objective(s): The objectives were to provide an overview of the current practices of Near East (NE) healthcare practitioners (HCPs) by probing their prescribing decisions, to report the COVID-19 impacts on neurologists' prescribing habits, and to explore the future relevance of current medication used in MS management among other newcomers Material(s) and Method(s): A cross-sectional study was carried out using an online survey from April 27, 2022, to July 5, 2022. The questionnaire was designed with the input of five neurologists representing five NE countries (Iran, Iraq, Lebanon, Jordan & Palestine). They identified several factors that play a crucial role in the optimal care of MS patients. The link was shared among neurologists using snowball sampling Result(s): The survey included 98 neurologists from the included NE countries, the majority of whom had more than 15 years of experience in the field, and 39% were seeing more than 40 MS patients a month. Effectiveness and safety balance was the most important factor considered when selecting the MS treatment. In the treatment of mild to moderate RRMS in men, Interferon beta 1a SC, Fingolimod, and Glatiramer acetate were the most commonly recommended treatments. Dimethyl fumarate substituted fingolimod in female patients. According to 80.7% of participants, interferon beta 1a SC was the safest treatment for mild to moderate RRMS. Interferon beta 1a SC was preferred over other treatments for patients with mild to moderate MS and planning for pregnancy (56.6%) or breastfeeding (60.2%). Fingolimod was not a choice for these patients. Neurologists seemed to discuss the top three treatments of Natalizumab, Ocrelizumab, and Cladribine with patients with highly active MS. Conclusion(s): Most neurologists in the NE region followed MENACTRIMS recommendations for prescribing treatment. The treatment choice also depended on the availability of DMTs in the region. Regarding the use of upcoming DMTs such as Ofatumumab, Siponimod, Ozanimod, and BTK inhibitors, there is a clear need for real-world data, long-term extension studies, and comparative studies to support their efficacy and safety profiles in treating patients with MSCopyright © 2022

34th Annual Meeting of the Japanese Society for Neuroimmunology (JSNI)

The proceedings contain 14 papers. The topics discussed include: MOG-positive anti-NMDA receptor encephalitis with no demyelinating lesions: two case reports;safety and tolerability of rozanolixizumab in the randomized phase 3 MycarinG study;Outcomes from RAISE: A randomized, phase 3 trial of zilucoplan in generalized myasthenia gravis;efficacy and safety of zilucoplan in myasthenia gravis: responder analysis from the randomized Phase 3 RAISE trial;distinct effects among calcium-binding proteins for microglia to produce chemokines associated with the clinical severity of ALS;astroglial connexin 43 is a novel therapeutic target for a chronic multiple sclerosis model;targeting lymphocytes in SPMS: Th cell populations as a biomarker to predict the efficacy of Siponimod;CSF lysophospholipids as a novel biomarker in relapsing-remitting multiple sclerosis;the immune response to SARS-COV-2 MRNA vaccines in siponimod-treated patients with secondary progressive multiple sclerosis;patient characteristics of siponimod-treated SPMS patients in Japan: interim results from post-marketing surveillance;and efficacy of ravulizumab across sex and age subgroups of patients with generalized myasthenia gravis: a post hoc analysis of the CHAMPION MG study.

The immune response to SARS-COV-2 MRNA vaccines in siponimod-treated patients with secondary progressive multiple sclerosis

Objective: We aimed to understand the longitudinal cellular and humoral immune responses to SARS-CoV-2 mRNA vaccines depending on the timing of vaccination and SPMS treatment. Background(s): SARS-CoV-2 mRNA vaccines are a key factor in fighting the COVID-19 pandemic. However, data are lacking on the efficacy of vaccination in patients with secondary progressive multiple sclerosis (SPMS) on disease-modifying therapies (DMTs), both over time and after a booster vaccination. Design/Methods: AMA-VACC is an open-label, three-cohort, prospective study in Germany with 41 multiple sclerosis patients currently treated with siponimod, any first-line DMT or without treatment in clinical routine. Cohort 1 received SARS-CoV-2 mRNA vaccination while continuing current siponimod treatment, cohort 2 interrupted siponimod treatment for the purpose of a full vaccination cycle, and cohort 3 received vaccination during continuous treatment with first-line DMTs (glatirameracetate, interferons, teriflunomide) or no current treatment in clinical routine. The primary endpoint was the rate of patients achieving seroconversion assessed by detection of serum neutralizing antibodies 1 week after SARS-CoV-2 mRNA vaccination. Furthermore, development and maintenance of SARS-CoV-2 specific T-cells was evaluated in all patients. Both parameters were analyzed in week one and months one and six after the initial vaccination cycle and 1 month after a potential booster vaccination. Result(s): After a positive first interim analysis showing both SARSCoV- 2 neutralizing antibodies and T-cell responses 1 week after complete vaccination in siponimod patients, data will be available in early 2022 for all patients at week one and later timepoints, including first booster vaccinations. Conclusion(s): This analysis will provide the first longitudinal data on the immune response after SARS-CoV-2 mRNA vaccination in siponimodtreated SPMS patients and enable physicians and patients to make an informed decision on the coordination of SARS-CoV-2 mRNA vaccination and SPMS treatment.

An update on the use of sphingosine 1-phosphate receptor modulators for the treatment of relapsing multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is an immune-mediated disorder of the CNS manifested by recurrent attacks of neurological symptoms (related to focal inflammation) and gradual disability accrual (related to progressive neurodegeneration and neuroinflammation). Sphingosine-1-phosphate-receptor (S1PR) modulators are a class of oral disease-modifying therapies (DMTs) for relapsing MS. The first S1PR modulator developed and approved for MS was fingolimod, followed by siponimod, ozanimod, and ponesimod. All are S1P analogues with different S1PR-subtype selectivity. They restrain the S1P-dependent lymphocyte egress from lymph nodes by binding the lymphocytic S1P-subtype-1-receptor. Depending on their pharmacodynamics and pharmacokinetics, they can also interfere with other biological functions. AREAS COVERED: Our narrative review covers the PubMed English literature on S1PR modulators in MS until August 2022. We discuss their pharmacology, efficacy, safety profile, and risk management recommendations based on the results of phase II and III clinical trials. We briefly address their impact on the risk of infections and vaccines efficacy. EXPERT OPINION: S1PR modulators decrease relapse rate and may modestly delay disease progression in people with relapsing MS. Aside their established benefit, their place and timing within the long-term DMT strategy in MS, as well as their immunological effects in the new and evolving context of the post-COVID-19 pandemic and vaccination campaigns warrant further study.

The impact of sphinogosine-1-phosphate receptor modulators on COVID-19 and SARS-CoV-2 vaccination.

BACKGROUND: Sphingosine-one phosphate receptor (S1PR) modulation inhibits S1PR1-mediated lymphocyte migration, lesion formation and positively-impacts on active multiple sclerosis (MS). These S1PR modulatory drugs have different: European Union use restrictions, pharmacokinetics, metabolic profiles and S1PR receptor affinities that may impact MS-management. Importantly, these confer useful properties in dealing with COVID-19, anti-viral drug responses and generating SARS-CoV-2 vaccine responses. OBJECTIVE: To examine the biology and emerging data that potentially underpins immunity to the SARS-CoV-2 virus following natural infection and vaccination and determine how this impinges on the use of current sphingosine-one-phosphate modulators used in the treatment of MS. METHODS: A literature review was performed, and data on infection, vaccination responses; S1PR distribution and functional activity was extracted from regulatory and academic information within the public domain. OBSERVATIONS: Most COVID-19 related information relates to the use of fingolimod. This indicates that continuous S1PR1, S1PR3, S1PR4 and S1PR5 modulation is not associated with a worse prognosis following SARS-CoV-2 infection. Whilst fingolimod use is associated with blunted seroconversion and reduced peripheral T-cell vaccine responses, it appears that people on siponimod, ozanimod and ponesimod exhibit stronger vaccine-responses, which could be related notably to a limited impact on S1PR4 activity. Whilst it is thought that S1PR3 controls B cell function in addition to actions by S1PR1 and S1PR2, this may be species-related effect in rodents that is not yet substantiated in humans, as seen with bradycardia issues. Blunted antibody responses can be related to actions on B and T-cell subsets, germinal centre function and innate-immune biology. Although S1P1R-related functions are seeming central to control of MS and the generation of a fully functional vaccination response; the relative lack of influence on S1PR4-mediated actions on dendritic cells may increase the rate of vaccine-induced seroconversion with the newer generation of S1PR modulators and improve the risk-benefit balance IMPLICATIONS: Although fingolimod is a useful asset in controlling MS, recently-approved S1PR modulators may have beneficial biology related to pharmacokinetics, metabolism and more-restricted targeting that make it easier to generate infection-control and effective anti-viral responses to SARS-COV-2 and other pathogens. Further studies are warranted.

Group counselling consultations: the way forward?

Introduction: Virtual patient consultations have become increasingly common following the COVID-19 pandemic. In our region, we have utilised virtual group meetings of up to 30 patients to deliver education sessions regarding drug therapy for multiple sclerosis. Counselling sessions using Microsoft Teams provided information for either Siponimod, Fampridine, or Ocrelizumab and Ofatumumab, with opportunity following the presentation for questions. Patients were subsequently offered an individual Consultant review for a personalised discussion. Objective(s): All individuals who attend a virtual session during February 2021 - March 2022 will be sent an online questionnaire to complete. Aim(s): To determine the effectiveness of online group counselling consultations in providing information on medication. Method(s): Patients attending a virtual session during February 2021 - March 2022 were contacted to complete an online questionnaire. Result(s): More than half (42/80) of patients who responded had no previous experience of using MS Teams. Sessions were considered easy to access (average rating 8.8/10) and technical issues with sound or connection were only reported by 9/80. Average knowledge of the drug prior to the session was 3.8/10 and following the session this improved to 7.9/10. A virtual group session allowed the opportunity to hear the questions of other patients and this was felt to be beneficial (average rating 8.9/10). The vast majority (78/80) had no concerns regarding their confidentiality. Preference for this session to be delivered virtually rather than in person, favoured virtual delivery (7.6/10). Final comments highlighted the time and travel savings, with no significant concerns raised. Conclusion(s): Virtual group counselling sessions provide clear advantages to both patients and clinicians, saving time for the clinicians, but also giving patients group support around medication decisions. This review confirms that the majority of patients report group sessions are an effective, convenient and safe method of discussing medication. As treatment options for patients with MS expand and demand on services increases, this group counselling platform will allow greater flexibility to deliver information to patients.

Rationale for Use of Sphingosine-1-Phosphate Receptor Modulators in COVID-19 Patients: Overview of Scientific Evidence.

Maladjusted immune responses to the coronavirus disease 2019 (COVID-19), for example, cytokine release syndrome, may result in immunopathology and acute respiratory distress syndrome. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, and its S1P receptor (S1PR) are crucial in maintaining endothelial cell chemotaxis and barrier integrity. Apart from the S1P1 receptor-mediated mechanisms of sequestration of cytotoxic lymphocytes, including Th-17 and S1P1/2/3-mediated endothelial barrier functions, S1PR modulators may also attenuate cytokine release via activation of serine/threonine protein phosphatase 2A and enhance the pulmonary endothelial barrier via the c-Abl tyrosine kinase pathway. Chronic treatment with fingolimod (S1PR1,3,4,5 modulator) and siponimod (S1PR1,5 modulator) has demonstrated efficacy in reducing inflammatory disease activity and slowing down disease progression in multiple sclerosis. The decision to selectively suppress the immunity of a critically ill patient with COVID-19 remains a difficult choice. It has been suggested that treatment with fingolimod or siponimod may be appropriate to attenuate severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced hyperinflammation in patients with COVID-19 since these patients are already monitored in an intensive care setting. Here, we review the use of S1PR modulators, fingolimod and siponimod, in regulating the inflammatory response to SARS-CoV-2 with the aim of understanding their potential rationale use in patients with COVID-19.

Assessing the immune response to SARSCoV- 2 mRNA vaccines in SPMS patients treated with siponimod (clinical trial)

Background and aims: SARS-CoV-2 mRNA vaccines are a key factor for fighting the COVID-19 pandemic across the globe. However, data are lacking on the efficacy of these vaccines to induce cellular and humoral immune responses in patients with secondary progressive multiple sclerosis (SPMS) on disease-modifying therapies (DMTs) both over time and after a booster vaccination. Methods: AMA-VACC is prospective, open-label, threecohort study including 41 multiple sclerosis patients at ten sites in Germany. Cohort 1 receives SARS-CoV-2 mRNA vaccination during continuous siponimod treatment, cohort 2 interrupts siponimod treatment for the purpose of a full vaccination cycle and cohort 3 is vaccinated during continuous treatment with first-line DMTs (dimethylfumarate, glatirameracetate, interferons, teriflunomide) or no current treatment in clinical routine. Development of neutralizing antibodies (primary endpoint) as well as detection of SARS-CoV-2 specific T-cells (secondary endpoint) are assessed after initial and booster vaccination and monitored for up to 6 months. Results: Results of previous interim analysis showed that the majority of patients treated with siponimod can mount an immune response after SARS-CoV-2 mRNA vaccination. Here, longitudinal data will be presented describing for the first time the level of cellular and humoral immune response for up to 6 months after vaccination and the effect of booster vaccines in siponimod treated patients. Conclusion: This analysis will provide data on the maintenance of humoral and cellular immune response after SARS-CoV-2 vaccination in siponimod treated patients and enable physicians and patients to make an informed decision on the coordination of SARS-CoV-2 mRNA (booster) vaccination and SPMS treatment.

AMA-VACC: Clinical trial assessing the immune response to SARS-CoV-2 mRNA vaccinesin siponimod treated patients with secondary progressive multiple sclerosis

Objective: We are aiming to understand the longitudinal cellular and humoral immune responses to SARS-CoV-2 mRNA vaccines depending on the timing of vaccination and SPMS treatment. Background: SARS-CoV-2 mRNA vaccines are a key factor fighting the COVID-19 pandemic across the globe. However, data are lacking on efficacy of vaccination in patients with secondary progressive multiple sclerosis (SPMS) on disease-modifying therapies (DMTs) both over time and after a booster vaccination. Design/Methods: AMA-VACC is an open-label, three-cohort, prospective study in Germany with 41 multiple sclerosis patients currently treated with siponimod, first-line DMT or without treatment in clinical routine. Cohort 1 receives SARS-CoV-2 mRNA vaccination while continuing their current siponimod treatment, cohort 2 interrupts siponimod treatment for the purpose of a full vaccination cycle and cohort 3 receives vaccination during continuous treatment with first-line DMTs (glatirameracetate, interferons, teriflunomide) or no current treatment in clinical routine. Primary endpoint is the rate of patients achieving seroconversion assessed by detection of serum neutralizing antibodies one week after SARS-CoV-2 mRNA vaccination. Furthermore, development and maintenance of SARS-CoV-2 specific T-cells is evaluated in all patients. Both parameters are analyzed in week one and month one and six after initial vaccination cycle and one month after a potential booster vaccination. Results: After a positive first interim analysis showing both SARS-CoV-2 neutralizing antibodies and T-cell responses one week after complete vaccination in siponimod patients data will be available in early 2022 for all patients at week one and later time points including first booster vaccinations. If possible, AMA-VACC results will be compared to findings from other clinical SARS-CoV-2 vaccination studies in patients with MS. Conclusions: This analysis will provide first longitudinal data on the immune response after SARS-CoV-2 mRNA vaccination in siponimod treated SPMS patients and enable physicians and patients to make an informed decision on the coordination of SARS-CoV-2 mRNA vaccination and SPMS treatment.

Lowered COVID-19 mRNA vaccine antibody response in MS patientstreated with B-cell depleting and S1P-receptor-targeting therapies compared to controls: interim analysis

Objective: Assess the SARS-CoV2 Spike antibody response in multiple sclerosis (MS) patients on high efficacy immunotherapies. Background: There is limited knowledge about SARS-CoV2 mRNA vaccine response in MS patients on immunotherapy. Design/Methods: Patients with MS, aged 18-65, on fingolimod, siponimod, ofatumumab, or ocrelizumab for at least 3 months prior to first mRNA SARS-CoV2 vaccine (Pfizer or Moderna) were offered enrollment. A cohort of healthy controls who received the mRNA vaccines were also enrolled. Blood samples for the SARS-CoV2 Spike antibody (Anti-SARS-CoV2 S, RocheElecsys) were collected 2-3 months after the second mRNA vaccine. The proportion who seroconverted (antibody>0.4 U/ml), and SARS-CoV2 Spike antibody levels were assessed. Results: A total of 39 MS patients (6 fingolimod, 33 ocrelizumab) and 31 controls were included in this interim analysis. 33%(13/39) of MS patients seroconverted, compared to 100%(31/31) in the control group, with an estimated risk difference of -0.67,(95% confidence interval: -0.81, -0.52;Fisher's exact test, p=9.0∗10-10 ). There was no difference in seroconversion rates between MS patients who received the Pfizer (34%, 10/29) versus the Moderna vaccine (30%, 3/10) (95% confidence interval -0.38, 0.29;Fisher's exact test=1). Seroconversion was found in 100% (31/31) of controls, 66.7% (4/6) of fingolimod-treated patients, and 27.3% (9/33) of ocrelizumab-treated patients (three group comparison, Fisher's exact test p-value =2.7∗10 -10). The median Spike antibody level was <0.4 U/ml in MS patients, and 1,663 U/ml in controls (Wilcoxon rank sum test, p-value= 1.0∗10-12 ). The median Spike antibody level in the ocrelizumab group was <0.4 U/ml, 3.45 U/ml in the fingolimod group, and 1,663 U/ml in the control group (Kruskal Wallis test, p-value=5.9∗10-12 ). Total IgG correlated with Spike antibody levels in the ocrelizumab-treated group only (Spearman correlation, p=0.025). Conclusions: MS patients on ocrelizumab and fingolimod have significantly lower rates of seroconversion, and lower median Spike antibody levels in response to the mRNA SARS-CoV2 vaccines compared to controls.

Prescrire's ratings of new drugs in 2021: A brief review

Three new drugs, all based on messenger RNA or small interfering RNA technology, represented a major therapeutic advance in 2021. But the bigger picture is that most of the new authorisations that advanced patient care were adaptations of existing drugs. And that more than half of this year's new authorisations were not advances, and in fact about one-tenth represented a step backwards compared to existing options.

Humoral immune response to COVID-19 vaccines in people with secondary progressive multiple sclerosis treated with siponimod.

OBJECTIVE: The aim of this study is to determine a development of humoral response after COVID-19 vaccination in persons with secondary progressive multiple sclerosis (pwSPMS) on siponimod, compared to healthy controls (HC). METHODS: In 13 pwSPMS taking siponimod and 11 HC, testing for SARS-CoV2 antibodies was performed after vaccination against COVID-19. RESULTS: pwSPMS taking siponimod had a significantly lower titer of SARS-CoV2 antibodies compared to healthy controls (19.4 (0-250) vs. 250 (250), p>0.001). Two (15.4%) pwSPMS on siponimod had unmeasurable titers of SARS-CoV2-2 antibodies, while all HC had positive titers. CONCLUSION: Although the results of this study are limited by a small sample size, results have consistently shown low titers of SARS-CoV-2 IgG after COVID-19 vaccinations in pwSPMS on siponimod.