siponimod and Multiple-Sclerosis

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.

Topics: COVID-19; Fingolimod Hydrochloride; Humans; Multiple Sclerosis; SARS-CoV-2; Sphingosine; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors

As a modulator of the sphingosine 1-phosphate receptor, siponimod is administered as a therapeutic intervention for multiple sclerosis. A previous phase 3 study first reported siponimod-associated macular edema. Since that report, there were only few relevant reports in clinical settings. Here, we report a case of secondary progressive multiple sclerosis developed macular edema after siponimod treatment. We also review the progress of sphingosine 1-phosphate receptor modulators, elaborate on accepted mechanisms in treating multiple sclerosis, and discuss the causation of siponimod-associated macular edema.. A 38-year-old Chinese female patient with secondary progressive multiple sclerosis, who had recurrent numbness of the limbs and right leg fatigue, developed mild macular edema following 4 months of siponimod treatment. The macular edema resolved after discontinuing the medication, and did not recur after resuming siponimod.. Although siponimod-associated macular edema may be rare, mild, transitory, and manageable, it cannot be ignored and requires ongoing vigilance.

Topics: Adult; Female; Humans; Macular Edema; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sphingosine-1-Phosphate Receptors

Multiple sclerosis (MS) is a chronic neurodegenerative disease that affects the central nervous system (CNS). Currently, MS treatment is limited to several Food and Drug Administration (FDA)- and European Medicines Agency (EMA)-approved medications that slow disease progression by immunomodulatory action. Fingolimod and siponimod have similar mechanisms of action, and consequently, their therapeutic effects may be comparable. However, while fingolimod is mainly used for relapsing-remitting MS (RRMS), siponimod, according to EMA label, is recommended for active secondary progressive MS (SPMS). Clinicians and scientists are analysing whether patients can switch from fingolimod to siponimod and identifying the advantages or disadvantages of such a switch from a therapeutic point of view. In this review, we aim to discuss the therapeutic effects of these two drugs and the advantages/disadvantages of switching treatment from fingolimod to siponimod in patients with the most common forms of MS, RRMS and SPMS.

Topics: Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Neurodegenerative Diseases; Recurrence; Risk Assessment

Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects mainly young adults (two to three times more frequently in women than in men) and causes significant disability after onset. Although it is accepted that immunotherapies for people with MS decrease disease activity, uncertainty regarding their relative safety remains.. To compare adverse effects of immunotherapies for people with MS or clinically isolated syndrome (CIS), and to rank these treatments according to their relative risks of adverse effects through network meta-analyses (NMAs).. We searched CENTRAL, PubMed, Embase, two other databases and trials registers up to March 2022, together with reference checking and citation searching to identify additional studies.. We included participants 18 years of age or older with a diagnosis of MS or CIS, according to any accepted diagnostic criteria, who were included in randomized controlled trials (RCTs) that examined one or more of the agents used in MS or CIS, and compared them versus placebo or another active agent. We excluded RCTs in which a drug regimen was compared with a different regimen of the same drug without another active agent or placebo as a control arm.. We used standard Cochrane methods for data extraction and pairwise meta-analyses. For NMAs, we used the netmeta suite of commands in R to fit random-effects NMAs assuming a common between-study variance. We used the CINeMA platform to GRADE the certainty of the body of evidence in NMAs. We considered a relative risk (RR) of 1.5 as a non-inferiority safety threshold compared to placebo. We assessed the certainty of evidence for primary outcomes within the NMA according to GRADE, as very low, low, moderate or high.. This NMA included 123 trials with 57,682 participants. We found mostly low and very low-certainty evidence that drugs used to treat MS may not increase SAEs, but may increase withdrawals compared with placebo. The results suggest that there is no important difference in the occurrence of SAEs between first- and second-line drugs and between oral, injectable, or infused drugs, compared with placebo. Our review, along with other work in the literature, confirms poor-quality reporting of adverse events from RCTs of interventions. At the least, future studies should follow the CONSORT recommendations about reporting harm-related issues. To address adverse effects, future systematic reviews should also include non-randomized studies.

Topics: Adolescent; Adult; Alemtuzumab; Azathioprine; Cladribine; Daclizumab; Dimethyl Fumarate; Female; Fingolimod Hydrochloride; Glatiramer Acetate; Humans; Immunosuppressive Agents; Immunotherapy; Interferon beta-1a; Interferon beta-1b; Male; Multiple Sclerosis; Natalizumab; Network Meta-Analysis; Rituximab; Young Adult

Ocrelizumab and siponimod are the two on-label drugs used for progressive forms of multiple sclerosis (PMS). However, many patients with PMS do not have access to these high-efficacy disease-modifying drugs (DMDs). Off-label prescription of other high-efficacy DMDs (fingolimod, rituximab and natalizumab) may be a strategy to improve access to immunotherapy for these patients. We aim to compare on-label and off-label high-efficacy drugs for their effect on disability progression in PMS. In December 2021, we searched MEDLINE (PubMed), Embase, Cochrane Central and Scopus databases for randomized clinical trials involving patients with PMS. High-efficacy drugs were considered as intervention and placebos as comparison. The outcome contemplated was risk of Expanded Disability Severity Scale (EDSS) progression at 2 years. A network meta-analysis was performed to compare the relative risk of EDSS progression at 2 years compared with placebo in on-label and off-label drugs. We included five studies with 4526 patients. The median EDSS progression at 2 years in patients that received any immunotherapy was 30%, compared with 35% in placebo groups. Overall, the risk of bias of individual studies was low. Network analysis revealed overlapping confidence intervals in off-label drugs (CI95% 0.51-2.16) versus ocrelizumab (reference) and off-label drugs (CI 95% 0.53-1.96) versus siponimod (reference), suggesting similar efficacy. The same result was found even after excluding studies with the risk of publication bias. Off-label high efficacy immunotherapy in PMS has biological plausibility and presented similar effectiveness to on-label DMDs in this network meta-analysis. The use of fingolimod, rituximab or natalizumab may be a strategy that reduces costs and improves access to immunotherapy for patients with PMS.

Topics: Azetidines; Benzyl Compounds; Fingolimod Hydrochloride; Humans; Immunologic Factors; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Natalizumab; Network Meta-Analysis; Off-Label Use; Rituximab

Siponimod is a selective modulator of sphingosine-1-phosphate (S1P) receptors of types 1 and 5, registered in the Russian Federation for the treatment of patients with secondary progressive multiple sclerosis (SPMS), regardless of the presence or absence of exacerbations. The effectiveness of the drug in comparison with placebo was demonstrated in patients with SPMS in the international clinical trial EXPAND (phase III). This review devotes actual problems in the treatment of patients with SPMS, discusses the pathophysiology of multiple sclerosis progression, describes the peripheral and central mechanisms of siponimod action and its differences from fingolimod. According to analysis of scientific literature experimental, clinical and neuroimaging data are presented, which could explain the reasons for the successful use of siponimod in patients with SPMS, taking into account the pathophysiological mechanisms of the development of progression and the mechanisms of drug action.. Сипонимод — селективный модулятор рецепторов сфингозин-1-фосфата (S1P) 1-го и 5-го типов, зарегистрированный в Российской Федерации для лечения пациентов с вторично-прогрессирующим рассеянным склерозом (ВПРС) независимо от наличия или отсутствия обострений. Эффективность препарата по сравнению с плацебо продемонстрирована у пациентов с ВПРС в международном клиническом исследовании EXPAND (III фаза). В настоящем обзоре представлены актуальные проблемы терапии пациентов с ВПРС, обсуждены вопросы патофизиологии прогрессирования РС, описаны периферические и центральные механизмы действия сипонимода, его отличия от финголимода. Представлены по результатам анализа научной литературы экспериментальные, клинические и нейровизуализационные данные, которые могли бы объяснить причины успешного применения сипонимода у пациентов с ВПРС с учетом патофизиологических механизмов развития прогрессирования и механизмов действия препарата.

Topics: Azetidines; Benzyl Compounds; Fingolimod Hydrochloride; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system, with an unpredictable course. Current MS therapies such as disease-modifying therapies focus on treating exacerbations, preventing new exacerbations and avoiding the progression of disability. Siponimod (BAF312) is an oral treatment, a selective sphingosine-1-phosphate (S1P) receptor modulator, for the treatment of adults with relapsing forms of MS including active, secondary progressive MS with relapses.. To assess the benefits and adverse effects of siponimod as monotherapy or combination therapy versus placebo or any active comparator for people diagnosed with MS.. On 18 June 2020, we searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Trials Register, which contains studies from CENTRAL, MEDLINE and Embase, and the trials registry databases ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP). We also handsearched relevant journals and screened the reference lists of published reviews and retrieved articles and searched reports (2004 to June 2020) from the MS societies in Europe and America.. We included randomised parallel controlled clinical trials (RCTs) that evaluated siponimod, as monotherapy or combination therapy, versus placebo or any active comparator in people with MS. There were no restrictions on dose or administration frequency.. We used standard methodological procedures expected by Cochrane. We discussed disagreements and resolved them by consensus among the review authors. Our primary outcomes wereworsening  disability , relapse and adverse events, and secondary outcomes were annualised relapse rate, gadolinium-enhancing lesions, new lesions or enlarged pre-existing lesions and mean change of brain volume. We independently evaluated the certainty of evidence using the GRADE approach. We contacted principal investigators of included studies for additional data or confirmation of data.. Two studies (1948 participants) met our selection criteria, 608 controls and 1334 treated with siponimod. The included studies compared siponimod with placebo. Overall, all studies had a high risk of bias due to selective reporting and attrition bias.  Comparing siponimod administered at a dose of 2 mg to placebo, we found that siponimod may reduce the number of participants with disability progression at six months (56 fewer people per 1000; risk ratio (RR) 0.78, 95% confidence interval (CI) 0.65 to 0.94; 1 study, 1641 participants; low-certainty evidence) and annualised relapse rate (RR 0.43, 95% CI 0.34 to 0.56; 2 studies, 1739 participants; low-certainty evidence). But it might lead to little reduction in the number of participants with new relapse (166 fewer people per 1000; RR 0.38, 95% CI 0.15 to 1.00; 1 study, 94 participants; very low-certainty evidence). We observed no evidence of a difference   due to adverse events for siponimod at 2 mg compared to placebo (14 more people per 1000; RR 1.52, 95% CI 0.85 to 2.71; 2 studies, 1739 participants, low-certainty evidence). In addition, due to the high risk of inaccurate magnetic resonance imaging (MRI) data in the two included studies, we could not combine data for active lesions on MRI scans. Both studies had high attrition bias resulting from the unbalanced reasons for dropouts among groups and high risk of bias due to conflicts of interest. Siponimod may reduce the number of gadolinium-enhancing T1-weighted lesions at two years of follow-up (RR 0.14, 95% CI 0.10 to 0.19; P < 0.0001; 1 study, 1641 participants; very low-certainty evidence). There may be no evidence of a difference between groups in the number of participants with at least one serious adverse event excluding relapses (113 more people per 1000; RR 1.80, 95% CI 0.37 to 8.77; 2 studies, 1739 participants; low-certainty evidence) at six months. No data were available regarding cardiac adverse events. In terms of safety profile, the most common adverse events associated with siponimod were headache, back pain, bradycardia, dizziness, fatigue, influenza, urinary tract infection, lymphopenia, nausea, alanine amino transferase increase and upper respiratory tract infection. These adverse events have dose-related effects and rarely led to discontinuation of treatment.. Based on the findings of the RCTs included in this review, we are uncertain whether siponimod interventions are beneficial for people with MS. There was low-certainty evidence to support that siponimod at a dose of 2 mg orally once daily as monotherapy compared with placebo may reduce the annualised relapse rate and the number of participants who experienced disability worsening, at 6 months. However, the certainty of the evidence to support the benefit in reducing the number of people with a relapse is very low.  The risk of withdrawals due to adverse events requires careful monitoring of participants over time. The duration of all studies was less than 24 months, so the efficacy and safety of siponimod over 24 months are still uncertain, and further exploration is needed in the future. There is no high-certainty data available to evaluate the benefit on MRI outcomes. We assessed the certainty of the body of evidence for all outcomes was low to very low, downgraded due to serious study limitations, imprecision and indirectness. We are uncertain whether siponimod is beneficial for people with MS. More new studies with robust methodology and longer follow-up are needed to evaluate the benefit of siponimod for the management of MS and to observe long-term adverse effects. Also, in addition to comparing with placebo, more new studies are needed to evaluate siponimod versus other therapeutic options.

Topics: Adult; Azetidines; Benzyl Compounds; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive

All agents engaging sphongosine-1-phospate receptors (S1PRs) will have some cardiovascular effect. This study aimed to elucidate the risk of cardiovascular adverse events (AEs) in patients with multiple sclerosis (MS) treated with S1PR modulators (S1PRMs).. We systematically searched the PubMed, EMBASE, and Cochrane Library databases for randomised controlled trials (RCTs) published through January 5, 2021. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated using the random-effects model. Sensitivity analyses and meta-regression were performed.. Seventeen RCTs (12 for fingolimod; 3 for ozanimod; 2 for siponimod) involving 13,295 patients were included. Compared with the control treatment, S1PRMs significantly increased the risk of cardiovascular AEs (RR, 2.21; 95% CI, 1.58-3.10; I. S1PRM use increased the risk of cardiovascular AEs by 1.21 times in patients with MS, and increased risks for bradyarrhythmia and hypertension were at 2.92- and 2.00-fold, respectively. These findings can help clinicians assess the risk of cardiovascular AEs in patients treated with S1PRMs.. The PROSPERO ID is CRD42020183215.

Topics: Azetidines; Benzyl Compounds; Bradycardia; Drug-Related Side Effects and Adverse Reactions; Fingolimod Hydrochloride; Humans; Hypertension; Indans; Multiple Sclerosis; Oxadiazoles; Randomized Controlled Trials as Topic; Risk; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors

Lysophospholipids are a class of bioactive lipid molecules that produce their effects through various G protein-coupled receptors (GPCRs). Sphingosine 1-phosphate (S1P) is perhaps the most studied lysophospholipid and has a role in a wide range of physiological and pathophysiological events, via signalling through five distinct GPCR subtypes, S1PR

Topics: Animals; Azetidines; Benzyl Compounds; Fingolimod Hydrochloride; Humans; Indans; Multiple Sclerosis; Oxadiazoles; Prodrugs; Signal Transduction; Sphingosine-1-Phosphate Receptors

The sphingosine 1-phosphate (S1P) signalling pathways have important and diverse functions. S1P receptors (S1PRs) have been proposed as a therapeutic target for various diseases due to their involvement in regulation of lymphocyte trafficking, brain and cardiac function, vascular permeability, and vascular and bronchial tone. S1PR modulators were first developed to prevent rejection by the immune system following renal transplantation, but the only currently approved indication is multiple sclerosis. The primary mechanism of action of S1PR modulators in multiple sclerosis is through binding S1PR subtype 1 on lymphocytes resulting in internalisation of the receptor and loss of responsiveness to the S1P gradient that drives lymphocyte egress from lymph nodes. The reduction in circulating lymphocytes presumably limits inflammatory cell migration into the CNS. Four S1PR modulators (fingolimod, siponimod, ozanimod, and ponesimod) have regulatory approval for multiple sclerosis. Preclinical evidence and ongoing and completed clinical trials support development of S1PR modulators for other therapeutic indications.

Topics: Animals; Azetidines; Benzyl Compounds; Clinical Trials as Topic; Fingolimod Hydrochloride; Humans; Immune System Diseases; Indans; Multiple Sclerosis; Nervous System Diseases; Oxadiazoles; Signal Transduction; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors; Thiazoles

Siponimod fumarate (BAF-312) is a synthetic sphingosine 1- phosphate (S1P) receptor modulator, which exerts immunomodulating effects mediated by B- and T-cell sequestration in secondary lymphoid organs. S1P receptor modulators have consistently shown a significant benefit on relapse rate and other measures of disease activity in patients with relapsing multiple sclerosis (MS), compared with both placebo and active comparator. However, most clinical trials of S1P receptor modulators--as well as other therapies for MS--lack evidence of a significant benefit on disability progression. A phase III trial of siponimod for secondary progressive MS showed a significant effect of the active drug compared with placebo on reduction of disability progression. Siponimod exhibits selective affinity for types 1 and 5 S1P receptors, indicating a possible lower risk of bradycardia and vasoconstriction compared with modulators with type 3 S1P receptor affinity. Current evidence supporting siponimod efficacy for secondary progressive MS is reviewed in the present article.

Topics: Azetidines; Benzyl Compounds; Clinical Trials, Phase III as Topic; Humans; Multiple Sclerosis; Randomized Controlled Trials as Topic; Recurrence; Sphingosine 1 Phosphate Receptor Modulators

The modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes in lymph nodes. Different sphingosine 1-phosphate receptor subtypes are expressed in the brain and spinal cord, and their pharmacological effects may improve disease development and neuropathology. Siponimod (BAF312) is a novel sphingosine 1-phosphate receptor modulator that has recently been approved for the treatment of active secondary progressive multiple sclerosis (MS). In this review article, we summarize recent evidence suggesting that the active role of siponimod in patients with progressive MS may be due to direct interaction with central nervous system cells. Additionally, we tried to summarize our current understanding of the function of siponimod and discuss the effects observed in the case of MS.

Topics: Animals; Azetidines; Benzyl Compounds; Central Nervous System; Disease Models, Animal; Humans; Mice; Multiple Sclerosis; Sphingosine 1 Phosphate Receptor Modulators

Topics: Animals; Azetidines; Benzyl Compounds; Dose-Response Relationship, Drug; Humans; Multiple Sclerosis; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors

Sphingolipids represent an essential class of lipids found in all eukaryotes, and strongly influence cellular signal transduction. Autoimmune diseases like asthma and multiple sclerosis (MS) are mediated by the sphingosine-1-phosphate receptor 1 (S1P

Topics: Autoimmune Diseases; Biological Availability; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis; Oxadiazoles; Receptors, Lysosphingolipid; Sphingolipids

Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. This disorder is a heterogeneous, multifactorial, immune-mediated disease that is influenced by both genetic and environmental factors. In most patients, reversible episodes of neurological dysfunction lasting several days or weeks characterize the initial stages of the disease (that is, clinically isolated syndrome and relapsing-remitting MS). Over time, irreversible clinical and cognitive deficits develop. A minority of patients have a progressive disease course from the onset. The pathological hallmark of MS is the formation of demyelinating lesions in the brain and spinal cord, which can be associated with neuro-axonal damage. Focal lesions are thought to be caused by the infiltration of immune cells, including T cells, B cells and myeloid cells, into the central nervous system parenchyma, with associated injury. MS is associated with a substantial burden on society owing to the high cost of the available treatments and poorer employment prospects and job retention for patients and their caregivers.

Topics: Azetidines; Benzyl Compounds; Demyelinating Diseases; Humans; Indans; Magnetic Resonance Imaging; Multiple Sclerosis; Oxadiazoles; Risk Factors; Thiazoles; Tomography, X-Ray Computed

Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor's function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing-remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability. Fingolimod can cause undesirable effects as a result of its interaction with other S1PR subtypes, which are expressed in diverse tissues, including cardiac myocytes. As such, agents that more selectively target subtype 1 of the S1PR are of interest and are at various stages of development. These include ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303. Data from phase II trials and early results from phase III studies have been promising and will be presented in this review. Of special interest are results from the EXPAND study of siponimod, which suggest a potential role for S1PR modulators in secondary progressive MS.

Topics: Animals; Azetidines; Benzyl Compounds; Clinical Trials as Topic; Fingolimod Hydrochloride; Humans; Immunologic Factors; Indans; Indoles; Multiple Sclerosis; Naphthalenes; Oxadiazoles; Propanolamines; Receptors, Lysosphingolipid; Thiazoles; Treatment Outcome

Siponimod (BAF312) is a synthetic molecule belonging to the sphingosine-1-phosphate (S1P) modulator family, which has putative neuroprotective properties and well-characterized immunomodulating effects mediated by sequestration of B and T cells in secondary lymphoid organs. Compared to fingolimod (ie, precursor of the S1P modulators commercially available for the treatment of relapsing-remitting [RR] multiple sclerosis [MS]), siponimod exhibits selective affinity for types 1 and 5 S1P receptor, leading to a lower risk of adverse events that are mainly induced by S1P3 receptor activation, such as bradycardia and vasoconstriction. In addition, S1P1 and S1P5 receptors are expressed by neurons and glia and could mediate a possible neuroprotective effect of the drug. A Phase II clinical trial of siponimod for RR MS showed a significant effect of the active drug compared to placebo on reducing gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) after 3 months of treatment. In a recently completed Phase III trial, treatment with siponimod was associated with a significant reduction in disability progression in secondary progressive (SP) MS patients compared to placebo. In this article, current evidence supporting siponimod efficacy for SP MS is reviewed.

Topics: Azetidines; Benzyl Compounds; Humans; Multiple Sclerosis

Older age and longer disease duration (DD) may impact the effectiveness of disease-modifying therapies in patients with multiple sclerosis (MS). Siponimod is a sphingosine 1-phosphate receptor modulator approved for the treatment of active secondary progressive MS (SPMS) in many countries. The pivotal phase 3 EXPAND study examined siponimod versus placebo in a broad SPMS population with both active and non-active disease. In this population, siponimod demonstrated significant efficacy, including a reduction in the risk of 3-month confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP). Benefits of siponimod were also observed across age and DD subgroups in the overall EXPAND population. Herein we sought to assess the clinical impact of siponimod across age and disease duration subgroups, specifically in participants with active SPMS.. This study is a post hoc analysis of a subgroup of EXPAND participants with active SPMS (≥ 1 relapse in the 2 years before the study and/or ≥ 1 T1 gadolinium-enhancing magnetic resonance imaging lesion at baseline) receiving oral siponimod (2 mg/day) or placebo during EXPAND. Data were analyzed for participant subgroups stratified by age at baseline (primary cut-off: < 45 year ≥ 45 years; and secondary cut-off: < 50 years or ≥ 50 years) and by DD at baseline (< 16 years or ≥ 16 years). Efficacy endpoints were 3mCDP and 6mCDP. Safety assessments included adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation.. Data from 779 participants with active SPMS were analyzed. All age and DD subgroups had 31-38% (3mCDP) and 27-43% (6mCDP) risk reductions with siponimod versus placebo. Compared with placebo, siponimod significantly reduced the risk of 3mCDP in participants aged ≥ 45 years (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.48-0.97), < 50 years (HR: 0.69; 95% CI: 0.49-0.98), ≥ 50 years (HR: 0.62; 95% CI: 0.40-0.96), and in participants with < 16 years DD (HR: 0.68; 95% CI: 0.47-0.98). The risk of 6mCDP was significantly reduced with siponimod versus placebo for participants aged < 45 years (HR: 0.60; 95% CI: 0.38-0.96), ≥ 45 years (HR: 0.67; 95% CI: 0.45-0.99), < 50 years (HR: 0.62; 95% CI: 0.43-0.90), and in participants with < 16 years DD (HR: 0.57; 95% CI: 0.38-0.87). Increasing age or longer MS duration did not appear to increase the risk of AEs, with an observed safety profile that remained consistent with the overall active SPMS and overall SPMS populations in EXPAND.. In participants with active SPMS, treatment with siponimod demonstrated a statistically significant reduction in the risk of 3mCDP and 6mCDP compared with placebo. Although not every outcome reached statistical significance in the subgroup analyses (possibly a consequence of small sample sizes), benefits of siponimod were seen across a spectrum of ages and DD. Siponimod was generally well tolerated by participants with active SPMS, regardless of baseline age and DD, and AE profiles were broadly similar to those observed in the overall EXPAND population.

Topics: Azetidines; Benzyl Compounds; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive

Magnetic resonance imaging (MRI) measurements of gray matter (GM) atrophy and magnetization transfer ratio (MTR; correlate of myelination) may provide better insights than conventional MRI regarding brain tissue integrity/myelination in multiple sclerosis (MS).. To examine the effect of siponimod in the EXPAND trial on whole-brain and GM atrophy, newly formed normalized magnetization transfer ratio (nMTR) lesions, and nMTR-assessed integrity of normal-appearing brain tissue (NABT), cortical GM (cGM), and normal-appearing white matter (NAWM).. Compared with placebo, siponimod significantly reduced progression of whole-brain and GM atrophy over 12/24 months, and was associated with improvements in brain tissue integrity/myelination within newly formed nMTR lesions and across NABT, cGM, and NAWM over 24 months. Effects were consistent across age, disease duration, inflammatory activity subgroups, and disease severity.. Siponimod reduced brain tissue damage in patients with SPMS as evidenced by objective measures of brain tissue integrity/myelination. This is consistent with central nervous system (CNS) effects observed in preclinical models. ClinicalTrials.gov number: NCT01665144.

Topics: Atrophy; Azetidines; Benzyl Compounds; Brain; Gray Matter; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive

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.. 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.. 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.. In aSPMS, siponimod reduced risk of disability progression and was associated with benefits on cognition and MRI outcomes vs placebo.. ClinicalTrials.gov number: NCT01665144.

Topics: Azetidines; Benzyl Compounds; Disease Progression; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting

The study aim was to evaluate the cost effectiveness and budget impact of siponimod compared to interferon beta-1a for adult patients with secondary progressive multiple sclerosis (SPMS) with active disease, from a Swiss health insurance perspective.. We conducted an analysis using a Markov cohort model with a cycle length of 1 year, life-long time horizon, and discount rate of 3% for cost and health outcomes. We used a matching-adjusted indirect comparison to estimate clinical outcomes using data from the EXPAND randomised controlled trial of siponimod vs placebo and the Nordic SPMS randomised controlled trial of interferon beta-1a vs placebo as the basis for estimates of disability progression and relapse outcomes. We used 6-month confirmed disability progression results to estimate disability progression in the base-case analysis. We calculated quality-adjusted life-years (QALYs) based on an external study that administered the EQ-5D-3L questionnaire to European patients with multiple sclerosis. We included costs (Swiss Franc (CHF), year 2020) of drug acquisition/administration, adverse events and disease management. We also performed a budget impact analysis to estimate the cost over the first 3 years of introducing siponimod.. For the base case, siponimod resulted in mean incremental costs of CHF 84,901 (siponimod: CHF 567,838, interferon beta-1a: CHF 482,937) and mean incremental QALYs of 1.591 (siponimod: 7.495, interferon beta-1a: 5.905), leading to an incremental cost-effectiveness ratio of CHF 53,364 per QALY gained. In the probabilistic sensitivity analysis, the probability of the cost effectiveness of siponimod assuming a willingness-to-pay threshold of CHF 100,000 per QALY gained was 90%. Siponimod was projected to result in drug administration costs for siponimod of CHF 23,817,856 in the first 3 years after introduction, accompanied by large cost offsets in drug acquisition of other multiple sclerosis drugs. Considering drug administration, monitoring and adverse event management costs, it was estimated to result in additional healthcare costs in Switzerland of CHF 2,177,021.. In the base-case analysis, we found that siponimod may be cost effective for treating Swiss adult patients with SPMS with active disease. The results of the cost-effectiveness analyses are valid under the assumption that the efficacy of siponimod and the comparators on disability progression for the overall SPMS population would be the same in the active SPMS population.. NCT01665144. This economic evaluation was based on the EXPAND trial.

Topics: Adult; Azetidines; Benzyl Compounds; Cost-Benefit Analysis; Humans; Interferon beta-1a; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Quality-Adjusted Life Years; Switzerland

Theranostic imaging methods could greatly enhance our understanding of the distribution of CNS-acting drugs in individual patients. Fluorine-19 magnetic resonance imaging (

Topics: Animals; Fluorine-19 Magnetic Resonance Imaging; Magnetic Resonance Imaging; Mice; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Pharmaceutical Preparations; Sphingosine-1-Phosphate Receptors

Sphingosine 1-phosphat receptor modulators (S1PRMs) have been linked to attenuated immune response to SARS-CoV-2 vaccines.. To characterize differences in the immune response to SARS-CoV-2 vaccines in patients on selective versus unselective S1PRMs.. Monocentric, longitudinal study on people with multiple sclerosis (pwMS) on fingolimod (FTY), siponimod (SIP), ozanimod (OZA), or without disease-modifying therapy (DMT) following primary and booster SARS-CoV-2 vaccination. Anti-SARS-CoV-2 antibodies and T-cell response was measured with electro-chemiluminescent immunoassay and interferon-γ release assay.. Primary vaccination induced a significant antibody response in pwMS without DMT while S1PRM patients exhibited reduced antibody titers. The lowest antibodies were found in patients on FTY, whereas patients on OZA and SIP presented significantly higher levels. Booster vaccinations induced increased antibody levels in untreated patients and comparable titers in patients on OZA and SIP, but no increase in FTY-treated patients. While untreated pwMS developed a T-cell response, patients on S1PRMs presented a diminished/absent response. Patients undergoing SARS-CoV-2 vaccination before onset of S1PRMs presented a preserved, although attenuated humoral response, while T-cellular response was blunted.. Our data confirm differential effects of selective versus unselective S1PRMs on T- and B-cell response to SARS-CoV-2 vaccination and suggest association with S1PRM selectivity rather than lymphocyte redistribution.

Topics: Antibodies, Viral; COVID-19; COVID-19 Vaccines; Humans; Longitudinal Studies; Multiple Sclerosis; SARS-CoV-2; Sphingosine 1 Phosphate Receptor Modulators; Sphingosine-1-Phosphate Receptors; Vaccination

To investigate whether the formation or retention of meningeal ectopic lymphoid tissue (mELT) can be inhibited by the sphingosine 1-phosphate receptor 1,5 modulator siponimod (BAF312) in a murine model of multiple sclerosis (MS).. A murine spontaneous chronic experimental autoimmune encephalomyelitis (EAE) model, featuring meningeal inflammatory infiltrates resembling those in MS, was used. To prevent or treat EAE, siponimod was administered daily starting either before EAE onset or at peak of disease. The extent and cellular composition of mELT, the spinal cord parenchyma, and the spleen was assessed by histology and immunohistochemistry.. Siponimod, when applied before disease onset, ameliorated EAE. This effect was also present, although less prominent, when treatment started at peak of disease. Treatment with siponimod resulted in a strong reduction of the extent of mELT in both treatment paradigms. Both B and T cells were diminished in the meningeal compartment.. Beneficial effects on the disease course correlated with a reduction in mELT, suggesting that inhibition of mELT may be an additional mechanism of action of siponimod in the treatment of EAE. Further studies are needed to establish causality and confirm this observation in MS.

Topics: Animals; Azetidines; Benzyl Compounds; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Meninges; Mice; Multiple Sclerosis; Sphingosine 1 Phosphate Receptor Modulators; Tertiary Lymphoid Structures

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).. In 13 pwSPMS taking siponimod and 11 HC, testing for SARS-CoV2 antibodies was performed after vaccination against COVID-19.. 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.. 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.

Topics: Antibodies, Viral; Azetidines; Benzyl Compounds; BNT162 Vaccine; COVID-19; COVID-19 Vaccines; Humans; Immunity, Humoral; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; RNA, Viral; SARS-CoV-2; Vaccination

Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The mechanisms of lysophospholipid recognition by an active GPCR, and the activations of lysophospholipid GPCR-G-protein complexes remain unclear. Here we report single-particle cryo-EM structures of human S1P receptor 1 (S1P

Topics: Animals; Azetidines; Benzyl Compounds; Cryoelectron Microscopy; GTP-Binding Protein alpha Subunits, Gi-Go; Humans; Lysophospholipids; Molecular Conformation; Molecular Docking Simulation; Multiple Sclerosis; Receptors, Lysophosphatidic Acid; Recombinant Proteins; Sf9 Cells; Single Molecule Imaging; Sphingosine; Sphingosine-1-Phosphate Receptors; Spodoptera

Siponimod is an effective treatment for patients with secondary progressive multiple sclerosis (SPMS), with active disease evidenced by relapses or imaging features characteristic of multiple sclerosis inflammatory activity, however there is a need to evaluate its economic value and sustainability compared to other disease modifying-therapies (DMTs).. To estimate the siponimod cost-effectiveness profile and its relative budget impact compared with other DMTs, by using the Italian National Healthcare System perspective.. We performed: 1) a cost-effectiveness analysis (CEA) vs interferon beta-1b using an analytical Markov model and a life time-horizon, and 2) a budget impact analysis by using 3-years time-horizon. The results were reported as incremental cost-effectiveness ratio (ICER) and net-monetary benefit (NMB) for CEA, using a willingness to pay threshold of €40,000 per QALY gained, and as difference in the overall budget (Euro) between the scenario with and without siponimod for budget impact.. In the base case scenario siponimod resulted cost-effective compared with interferon beta-1b 28,891€ per QALY. Overall, the market access of siponimod was associated to an increased budget of about 3€ millions (+0.9%) in the next 3 years simulated.. Compared to interferon beta-1b, siponimod seems to be cost-effective in SPMS patients and sustainable, with less than 1% overall budget increased in the next 3 years. Future studies need to confirm our results in the real word setting and in other countries.

Topics: Azetidines; Benzyl Compounds; Cost-Benefit Analysis; Humans; Interferon beta-1b; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Quality-Adjusted Life Years

Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study.. The aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years.. In the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group).. Continuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66-0.92). The sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation.. NCT01665144.

Topics: Atrophy; Azetidines; Benzyl Compounds; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Multiple Sclerosis, Relapsing-Remitting; Recurrence

The aim of this study was to investigate the short- and long-term effects of siponimod on autonomic nervous system (ANS) function, in people with secondary progressive multiple sclerosis (pwSPMS) METHODS: The following ANS tests were performed in 26 pwSPMS: a 10 min supine resting position, Valsalva maneuver, deep breathing test and a 10 min tilt-up table test. Heart rate variability (HRV) was performed for the 10 min in supine resting position (M0) and for a 3 h period after siponimod treatment initiation (M0. In all 6 intervals after siponimod ingestion (M0. This study has shown an inverse relationship in short- versus long-term effects of siponimod on ANS function. A shift towards parasympathetic predominance was observed during the first three hours after ingestion, while after 6 or more months of continuous treatment with siponimod, a shift towards sympathetic predominance was observed.

Topics: Autonomic Nervous System; Azetidines; Benzyl Compounds; Heart Rate; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive

Despite significant success in the treatment of multiple sclerosis achieved in the recent years, the issues of therapy for progressive forms of the disease are far from being resolved. The first medication with proven efficiency at SPMS is the oral selective sphingosine 1 phosphate (S1P) receptor modulator siponimod. Before the registration of siponimod in Russia, Novartis company organized a «Managed access program to enable siponimod in patients with secondary progressive multiple sclerosis without satisfactory alternative therapy». For the period from September 2020 to May 2021, 10 patients with SPMS with exacerbations were included in the programme by RAS. The results of the treatment of the patients under the programme were similar to the results of previously controlled studies. The medication was well tolerated and the expected side effects (mainly lymphopenia and Elevated transaminases) were not more severe than moderate and were stopped by temporary cancel of the current treatment or concomitant therapy. During 1 year of therapy, the stabilization of condition of all patients and positive dynamics was noticed, including a decrease in the EDSS score in 44% of patients. Despite the limited number of patients and time of observation, the safety and efficacy of siponimod in patients with SPMS are quite high. The use of the medication in routine clinical practice does not require extraordinary methods of observation and control, but nevertheless includes genetic examination before the prescription of therapy, regular monitoring of clinical blood and biochemical parameters.. Несмотря на значительные успехи в лечении рассеянного склероза (РС), достигнутые в последние годы, вопросы терапии прогрессирующих форм заболевания далеки от разрешения. Первым препаратом с доказанной эффективностью при вторично-прогрессирующем РС (ВПРС) является пероральный селективный модулятор рецептора сфингозин-1-фосфата сипонимод. До регистрации сипонимода в России компанией «Новартис» в рамках раннего доступа была организована Программа контролируемого доступа для предоставления возможности применения сипонимода пациентами со вторично-прогрессирующим рассеянным склерозом при отсутствии удовлетворительной альтернативной терапии. В ИМЧ РАН в период с сентября 2020 г. по май 2021 г. в Программу были включены 10 больных ВПРС с обострениями. Результаты лечения пациентов в рамках Программы были сходны с результатами проведенных ранее контролируемых исследований. Препарат хорошо переносился, ожидаемые побочные эффекты (в большинстве случаев — лимфопения и повышение трансаминаз) были не тяжелее умеренных и купировались временной отменой терапии или назначением сопутствующего лечения. На протяжении первого года терапии отмечалась стабилизация состояния всех пациентов, положительная динамика, в том числе уменьшение балла EDSS, отмечена у 44% пациентов. Несмотря на лимитированное количество и время наблюдений, можно говорить о достаточно высокой безопасности и эффективности сипонимода у пациентов с ВПРС. Применение препарата в рутинной клинической практике не требует экстраординарных методов наблюдения и контроля, но тем не менее включает генетическое обследование до назначения терапии, регулярный контроль показателей клинической крови и биохимических показателей.

Topics: Azetidines; Benzyl Compounds; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive

Siponimod, which is approved to treat active secondary progressive multiple sclerosis, acts as a functional antagonist of sphingosine-1-phosphate (S1P) receptor 1 (S1P

Topics: Animals; Anti-Inflammatory Agents; Astrocytes; Azetidines; Benzyl Compounds; Cytokines; Histone Deacetylases; Mice; Multiple Sclerosis; NF-kappa B

Microglia, together with astrocytes and pericytes, cooperate to ensure blood-brain barrier (BBB) stability, modulating endothelial responses to inflammatory insults. Agonists of the sphingosine 1 phosphate (S1P) receptors, such as siponimod (BAF-312), are important pharmacological tools in multiple sclerosis and other inflammatory diseases. Modulation of S1P receptors may result in a reduced inflammatory response and increased BBB stability. An in vitro BBB model was reproduced using human-derived endothelial cells, astrocytes and microglia. Co-cultures were exposed to inflammatory cytokines (TNFα, 10 UI and IFNγ, 5 UI) in the presence of BAF-312 (100 nM), and the BBB properties and microglia role were evaluated. The drug facilitated microglial migration towards endothelial/astrocyte co-cultures, involving the activity of the metalloprotease 2 (MMP2). Microglia actively cooperated with astrocytes in the maintenance of endothelial barrier stability: in the triple co-culture, selective treatment of microglial cells with BAF-312 significantly prevented cytokines' effects on the endothelial barrier. In conclusion, BAF-312, modulating S1P receptors in microglia, may contribute to the reinforcement of the endothelial barrier at the BBB, suggesting an additional effect of the drug in the treatment of multiple sclerosis.

Topics: Azetidines; Benzyl Compounds; Blood-Brain Barrier; Cytokines; Endothelial Cells; Humans; Matrix Metalloproteinase 2; Microglia; Multiple Sclerosis; Phosphates; Sphingosine; Tumor Necrosis Factor-alpha

Siponimod (Mayzent

Topics: Azetidines; Benzyl Compounds; Humans; Microglia; Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Although immune modulation and suppression are effective during relapsing-remitting MS, secondary progressive MS (SPMS) requires neuroregenerative therapeutic options that act on the CNS. The sphingosine-1-phosphate receptor modulator siponimod is the only approved drug for SPMS. In the pivotal trial, siponimod reduced disease progression and brain atrophy compared with placebo. The enteric nervous system (ENS) was recently identified as an additional autoimmune target in MS. We investigated the effects of siponimod on the ENS and CNS in the experimental autoimmune encephalomyelitis model of MS. Mice with late-stage disease were treated with siponimod, fingolimod, or sham. The clinical disease was monitored daily, and treatment success was verified using mass spectrometry and flow cytometry, which revealed peripheral lymphopenia in siponimod- and fingolimod-treated mice. We evaluated the mRNA expression, ultrastructure, and histopathology of the ENS and CNS. Single-cell RNA sequencing revealed an upregulation of proinflammatory genes in spinal cord astrocytes and ependymal cells in siponimod-treated mice. However, differences in CNS and ENS histopathology and ultrastructural pathology between the treatment groups were absent. Thus, our data suggest that siponimod and fingolimod act on the peripheral immune system and do not have pronounced direct neuroprotective effects.

Topics: Animals; Benzyl Compounds; Central Nervous System; Encephalomyelitis, Autoimmune, Experimental; Fingolimod Hydrochloride; Mice; Multiple Sclerosis

A descriptive analysis of COVID-19 infection in patients with multiple sclerosis (MS) receiving fingolimod or siponimod.. We reviewed the cases of COVID-19 from postmarketing or ongoing clinical trials reported to Novartis through December 27, 2020.. As of December 27, 2020, 283 cases had been reported in fingolimod-treated patients. The mean age was 44 years (from n = 224; range 11-69 years), and 190 were women. Of 161 cases with available information, 138 were asymptomatic (6), mild (100), or moderate (32); 50 cases required hospitalization. At the last follow-up, 140 patients were reported as recovered/recovering, condition was unchanged in 22, and deteriorated in 3 patients; 4 patients had a fatal outcome. Information was not available for 114 patients. Of the 54 cases of COVID-19 reported in siponimod-treated patients, 45 were from the postmarketing setting and 9 from an ongoing open-label clinical trial. The mean age was 54 years (from n = 45; range 31-70), and 30 were women. Of 28 cases with available information, 24 were asymptomatic (2), mild (17), or moderate (5); 9 cases required hospitalization. At the last follow-up, 27 patients were reported as recovered/recovering, condition remained unchanged for 1, and 3 patients had a fatal outcome. Information was not available for 23 patients.. Based on a review of available information, the risk of more severe COVID-19 in patients receiving fingolimod or siponimod seems to be similar to that reported in the general population and the MS population with COVID-19. However, limitations of spontaneous reporting, especially missing data, should be considered in the interpretation of these observations.

Topics: Adolescent; Adult; Aged; Azetidines; Benzyl Compounds; Child; Clinical Trials as Topic; Comorbidity; COVID-19; Female; Fingolimod Hydrochloride; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Sclerosis; Product Surveillance, Postmarketing; Retrospective Studies; Severity of Illness Index; Young Adult

Topics: Azetidines; Benzyl Compounds; Cognition; Humans; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive

Head-to-head trials comparing siponimod with fingolimod or ofatumumab in patients with multiple sclerosis (MS) are lacking. Instead, the comparative efficacy of siponimod can be derived from indirect treatment comparisons (ITCs). We assessed the suitability of ITCs leveraging individual patient data from relevant phase III trials across different MS phenotypes.. One siponimod trial in patients with secondary progressive MS (SPMS), four fingolimod trials (three in relapsing-remitting MS [RRMS], and one in primary progressive MS [PPMS]), and two ofatumumab trials in relapsing MS (RMS) were considered. The suitability of ITCs was evaluated based on trial design, patient eligibility criteria, baseline patient characteristics, placebo response, and outcome definitions for each trial. Analyses deemed feasible were conducted using one-to-one propensity score matching (PSM).. An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible because of insufficient overlap in key patient characteristics (e.g. disability level and relapse history) and differences in placebo response. However, a comparison between siponimod in SPMS and fingolimod in PPMS was feasible because of sufficient overlap in eligibility criteria and baseline characteristics. One-to-one PSM demonstrated siponimod was favored relative to fingolimod for time to 6- and 3-month confirmed disability progression though not significantly different (hazard ratio 0.76 [95% confidence interval 0.48-1.20;. For trials in MS, clinical phenotype is an important determinant of ITC feasibility. An ITC between siponimod in SPMS and either fingolimod in RRMS or ofatumumab in RMS was not feasible. The only feasible comparison was between siponimod in SPMS and fingolimod in PPMS.

Topics: Antibodies, Monoclonal, Humanized; Azetidines; Benzyl Compounds; Clinical Trials, Phase III as Topic; Disease Progression; Feasibility Studies; Fingolimod Hydrochloride; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Propensity Score

Topics: Adult; Alleles; Azetidines; Benzyl Compounds; Black or African American; Clinical Trials as Topic; Cytochrome P-450 CYP2C9; Genetic Predisposition to Disease; Genotype; Humans; Multiple Sclerosis; Prevalence; Sphingosine 1 Phosphate Receptor Modulators

Subpial demyelination is a specific hallmark of multiple sclerosis and a correlate of disease progression. Although the mechanism(s) that mediate pathogenesis in the subpial compartment remain unclear, it has been speculated that inflammation in the overlying meninges may be associated with subpial injury. Here we show that adoptive transfer of proteolipid protein-primed Th17 cells into SJL/J recipient mice induces subpial demyelination associated with microglial/macrophage activation, disruption of the glial limitans, and evidence of an oxidative stress response. This pathology was topologically associated with foci of immune cells in the meninges and occurred in the absence of measurable anti-myelin oligodendrocyte glycoprotein IgM or IgG antibodies. To test the role of brain-infiltrating leukocytes on subpial injury, we modulated sphingosine 1-phosphate (S1P) receptor1,5 activity with BAF312 (siponimod) treatment. Administration of BAF312, even after adoptively transferred T cells had entered the brain, significantly ameliorated clinical experimental autoimmune encephalomyelitis and diminished subpial pathology, concomitant with a selective reduction in the capacity of transferred T cells to make Th17 cytokines. We conclude that sustained subpial cortical injury is associated with the capacity for brain-resident T cells to produce Th17 cytokines, and this pathological process occurs in an S1P receptor1,5-dependent manner.

Topics: Adoptive Transfer; Animals; Azetidines; Benzyl Compounds; Brain; Cytidine Deaminase; Cytokines; Disease Progression; Encephalomyelitis, Autoimmune, Experimental; Female; Immunoglobulin G; Immunoglobulin M; Inflammation; Macrophages; Meninges; Mice; Mice, Inbred C57BL; Microglia; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Neuroglia; Th17 Cells

Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system (CNS) with heterogeneous pathophysiology. In its progressive course oligodendrocyte and neuroaxonal damage is sustained by compartmentalized inflammation due to glial dysregulation. Siponimod (BAF312), a modulator of two sphingosine-1-phosphate (S1P) receptors (S1P1 and S1P5) is the first oral treatment specifically approved for active secondary progressive MS. To address potential direct effects of BAF312 on glial function and glia-neuron interaction, we set up a series of

Topics: Astrocytes; Azetidines; Benzyl Compounds; Cell Differentiation; Cells, Cultured; Disease Resistance; Down-Regulation; Excitatory Amino Acid Transporter 2; Fibroblasts; Humans; Multiple Sclerosis; Neurodegenerative Diseases; NF-E2-Related Factor 2; NF-kappa B; Signal Transduction; Sphingosine 1 Phosphate Receptor Modulators

Multiple sclerosis disease modifying drugs (MS-DMD) currently used in Japan are interferon β-1a, interferon β-1b and gratiramer acetate, fingolimod, dimethyl furmarate, and natalizumab. Ofatumumab and siponimod will be approved probably in 2021. Ofatumumab is an ant-CD20 human monoclonal antibody. A clinical trial revealed that the efficacy of ofatumumab is clearly superior to teriflunomide that has comparable efficacy to dimethyl fumarate. Siponimod, a selective sphingosine-1-phosphate receptor modulator, exhibited mild, but significant efficacy for secondary progressive form of MS. OCH, a synthetic glycolipid agent, is being tested in phase II clinical trials in Japan. What DMD is to select is challenging since MS prognosis varies and is unexpected. Only very few have truly benign course without treatment. Silent progression should be considered especially in cases with those with interferon β-1a, interferon β-1b and gratiramer acetate. Escalation therapy is more widely accepted than initiation of high efficacy therapy in Japan because emphasizing safety. In such strategy three injectables and dimethyl fumarate are regarded as first line therapies. On the other hand, initiation of high efficacy drugs may be reasonable to prevent from disease progression. Even if either is acceptable, early induction of DMD with sufficient efficacy is mandatory for MS treatment.

Topics: Antibodies, Monoclonal, Humanized; Azetidines; Benzyl Compounds; Clinical Trials as Topic; Dimethyl Fumarate; Fingolimod Hydrochloride; Glatiramer Acetate; Humans; Interferons; Japan; Multiple Sclerosis; Natalizumab

The Siponimod (Mayzent) is a newly developed drug, similar to Fingolimod (FTY720) but with fewer side effects, approved by the Food and Drug Administration for the treatment of multiple sclerosis (MS). The therapeutic effect of siponimod and FTY720 in MS relies on their inhibitory effect on the sphingosine 1-phosphate (S1P) signaling. These drugs bind to the S1P receptors and block the CCL2 chemokine pathway that is responsible for the exit of the immune cells from the lymphoid organs, and circulation, thus preventing immune cell-dependent injury to the nervous system. We recently found that FTY720 beside its effect on the S1P pathway also blocks the RhoA pathway, which is involved in the actin cytoskeleton-related function of macrophages, such as expression/recycling of fractalkine (CX3CL1) receptors (CX3CR1), which direct macrophages to the transplanted organs during the development of the long-term (chronic) rejection. Here we tested the effects of siponimod on the RhoA pathway and the expression of the S1P1 and CX3CR1 receptors in mouse RAW 264.7 macrophages. We found that siponimod downregulates the expression of RhoA protein and decreases the cell surface expression of S1P1 and CX3CR1 receptors. This newly discovered crosstalk between S1P and RhoA/CX3CR1 pathways may help in the development of novel anti-chronic rejection therapies in clinical transplantation.

Topics: Actin Cytoskeleton; Animals; Azetidines; Benzyl Compounds; Cell Membrane; Chemokine CCL2; Down-Regulation; Fingolimod Hydrochloride; Graft Rejection; Humans; Lysophospholipids; Macrophages; Membrane Proteins; Mice; Multiple Sclerosis; Organ Transplantation; Phosphoric Monoester Hydrolases; RAW 264.7 Cells; Receptors, Interleukin-8A; rhoA GTP-Binding Protein; Signal Transduction; Sphingosine; United States; United States Food and Drug Administration

We encourage studies on the effectiveness of multiple sclerosis drugs for the treatment of ARDS in COVID-19 infection. These drugs, through the inhibition of the RhoA/actin-dependent expression of virus receptors in the macrophages and macrophage recruitment to the lungs, have the potential to inhibit cytokine storm of lung macrophages, reduce or eliminate ARDS and improve the outcome of COVID-19 infection.

Topics: Azetidines; Benzyl Compounds; Betacoronavirus; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Enzyme Inhibitors; Fingolimod Hydrochloride; Humans; Multiple Sclerosis; Pandemics; Pneumonia, Viral; Respiratory Distress Syndrome; rhoA GTP-Binding Protein; SARS-CoV-2

Multiple sclerosis is the most common demyelinating disease of the central nervous system with serious social and economic burden. Siponimod is a sphingosine-1-phosphate receptor agonist, and clinical trials in the past decade have shown good prospects for the treatment of multiple sclerosis. But there is a lack of comprehensive understanding of the dose-effect relationship and safety in different subtypes of multiple sclerosis at present.. We will perform a systematic review and meta-analysis of clinical randomized controlled trials to evaluate the efficacy and safety of siponimod in multiple sclerosis. We will search PubMed, EMBASE, Cochrane Library, Clinical Trials, Cochrane Central Register of Controlled Trials (CENTRAL) using a comprehensive strategy. The reference lists of the articles we select for inclusion will be checked to identify additional studies for potential inclusion. Two reviewers will review all literature independently. Upon inclusion of articles, another 2 reviewers will extract available data using a standardized form and assess the potential bias. Review Manager will be used to conduct data synthesis. There is no requirement of ethical approval and informed consent.. This is the first systematic assessment of siponimod for the treatment of multiple sclerosis. We predict it will provide high-quality synthesis of existing evidence for the efficacy and safety of siponimod for multiple sclerosis and a relatively comprehensive reference for clinical practice and clinical trials about siponimod to be conducted.. The results of the systematic review and meta-analysis will provide updated evidence for the use of siponimod for multiple sclerosis.. The systematic review and meta-analysis is registered in the PROSPERO international prospective register of systematic review (PROSPERO#CRD42018112721).

Topics: Azetidines; Benzyl Compounds; Dose-Response Relationship, Drug; Humans; Immunosuppressive Agents; Meta-Analysis as Topic; Multiple Sclerosis; Prospective Studies; Randomized Controlled Trials as Topic; Research Design; Systematic Review as Topic

Progressive multiple sclerosis (PMS) causes slow accumulation of neurologic disability and has been refractory to treatment with the immunomodulatory medications that effectively control relapsing MS. Siponimod modestly slowed the rate of disability progression among PMS patients who had inflammatory disease activity, evidenced by new or gadolinium-enhancing MRI lesions. To view this Bench to Bedside, open or download the PDF.

Topics: Azetidines; Benzyl Compounds; Clinical Trials as Topic; Humans; Multiple Sclerosis; United States; United States Food and Drug Administration

Siponimod (Mayzent

Topics: Administration, Oral; Adult; Azetidines; Benzyl Compounds; Drug Approval; European Union; Humans; Japan; Multiple Sclerosis; Sphingosine 1 Phosphate Receptor Modulators; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Azetidines; Benzyl Compounds; Humans; Immunosuppressive Agents; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Receptors, Lysosphingolipid

Topics: Azetidines; Benzyl Compounds; Cladribine; Humans; Immunosuppressive Agents; Multiple Sclerosis

Sphingosine 1-phosphate (S1P) is a signaling molecule that binds to five G protein-coupled receptors (Proc Natl Acad Sci USA 108:751-756, 2011). Modulation of these receptors has been associated with pleiotropic biological effects in the immune, cardiovascular, and central nervous systems (CNS). The functional S1P receptor antagonist fingolimod was the first member of this class of pharmacotherapeutics to be approved for treatment of relapsing multiple sclerosis (MS). Siponimod is currently in clinical trial in patients with secondary progressive (SP) MS, a clinical trial for which there is an unmet need for disease-modifying agents. 10 weeks into the trial, the patient awoke with blurry vision in his left eye, and was subsequently diagnosed with an acute optic neuritis. Despite discontinuation of siponimod and treatment with pulse corticosteroids, the patient did not regain visual function in the affected eye. This is the first report of disease reactivation shortly after initiating siponimod in a patient with SPMS. This case illustrates that the known changes in lymphocyte numbers and composition in the CNS associated with S1P receptor antagonism during the SPMS disease stage may have adverse outcomes in some patients during treatment initiation, and that close clinical and paraclinical monitoring is advised.

Topics: Adult; Azetidines; Benzyl Compounds; Humans; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Recurrence; Tomography, Optical Coherence; Vision Disorders

Topics: Azetidines; Benzyl Compounds; Humans; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting