Mechanism of action of s1p receptor modulators in multiple sclerosis: The double requirement

The introduction of oral disease modifying therapies has transformed the treatment landscape for patients with multiple sclerosis (MS). Fingolimod (Gilenya®, Novartis, Basel, Switzerland), the first oral therapy to be approved, has demonstrated clinical efficacy as a result of modulation of subtype 1 sphingosine-1-phosphate (S1P1) receptors. This leads to retention of lymphocytes in the lymph nodes, preventing their entry into the central nervous system. However, fingolimod can cause adverse effects as a result of its interaction with other S1P receptor subtypes, which are expressed in numerous tissues, including cardiac myocytes. More selective S1P receptor agents are currently in phase II and III clinical development. Siponimod, ozanimod, ponesimod and amiselimod have demonstrated efficacy with improved safety profiles compared with fingolimod. While more long-term data are needed, these selective S1P receptor modulators appear to be promising options for the treatment of MS and other disorders associated with autoimmunity and inflammation.

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Central Modulation of Selective Sphingosine-1-Phosphate Receptor 1 Ameliorates Experimental Multiple Sclerosis

Cells ◽

10.3390/cells9051290 ◽

2020 ◽

Vol 9 (5) ◽

pp. 1290 ◽

Cited By ~ 4

Author(s):

Alessandra Musella ◽

Antonietta Gentile ◽

Livia Guadalupi ◽

Francesca Romana Rizzo ◽

Francesca De Vito ◽

...

Keyword(s):

Multiple Sclerosis ◽

Ex Vivo ◽

The United States ◽

Neuroprotective Effects ◽

Local Inflammatory Response ◽

Electrophysiological Studies ◽

Sphingosine 1 Phosphate ◽

S1p Receptor ◽

Receptor Modulators

Future treatments of multiple sclerosis (MS), a chronic autoimmune neurodegenerative disease of the central nervous system (CNS), aim for simultaneous early targeting of peripheral immune function and neuroinflammation. Sphingosine-1-phosphate (S1P) receptor modulators are among the most promising drugs with both “immunological” and “non-immunological” actions. Selective S1P receptor modulators have been recently approved for MS and shown clinical efficacy in its mouse model, the experimental autoimmune encephalomyelitis (EAE). Here, we investigated the anti-inflammatory/neuroprotective effects of ozanimod (RPC1063), a S1P1/5 modulator recently approved in the United States for the treatment of MS, by performing ex vivo studies in EAE brain. Electrophysiological experiments, supported by molecular and immunofluorescence analysis, revealed that ozanimod was able to dampen the EAE glutamatergic synaptic alterations, through attenuation of local inflammatory response driven by activated microglia and infiltrating T cells, the main CNS-cellular players of EAE synaptopathy. Electrophysiological studies with selective S1P1 (AUY954) and S1P5 (A971432) agonists suggested that S1P1 modulation is the main driver of the anti-excitotoxic activity mediated by ozanimod. Accordingly, in vivo intra-cerebroventricular treatment of EAE mice with AUY954 ameliorated clinical disability. Altogether these results strengthened the relevance of S1P1 agonists as immunomodulatory and neuroprotective drugs for MS therapy.

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Abuse and dependence potential of sphingosine-1-phosphate (S1P) receptor modulators used in the treatment of multiple sclerosis: a review of literature and public data

Psychopharmacology ◽

10.1007/s00213-021-06011-6 ◽

2021 ◽

Author(s):

Kerri A. Schoedel ◽

Carine Kolly ◽

Anne Gardin ◽

Srikanth Neelakantham ◽

Kasra Shakeri-Nejad

Keyword(s):

Multiple Sclerosis ◽

Prescription Drugs ◽

Subjective Effects ◽

Review Of Literature ◽

Dependence Potential ◽

Public Data ◽

Sphingosine 1 Phosphate ◽

The Usa ◽

S1p Receptor ◽

Receptor Modulators

AbstractAbuse and misuse of prescription drugs remains an ongoing concern in the USA and worldwide; thus, all centrally active new drugs must be assessed for abuse and dependence potential. Sphingosine-1-phosphate (S1P) receptor modulators are used primarily in the treatment of multiple sclerosis. Among the new S1P receptor modulators, siponimod, ozanimod, and ponesimod have recently been approved in the USA, European Union (EU), and other countries. This review of literature and other public data has been undertaken to assess the potential for abuse of S1P receptor modulators, including ozanimod, siponimod, ponesimod, and fingolimod, as well as several similar compounds in development. The S1P receptor modulators have not shown chemical or pharmacological similarity to known drugs of abuse; have not shown abuse or dependence potential in animal models for subjective effects, reinforcement, or physical dependence; and do not have adverse event profiles demonstrating effects of interest to individuals who abuse drugs (such as sedative, stimulant, mood-elevating, or hallucinogenic effects). In addition, no reports of actual abuse, misuse, or dependence were identified in the scientific literature for fingolimod, which has been on the market since 2010 (USA) and 2011 (EU). Overall, the data suggest that S1P receptor modulators are not associated with significant potential for abuse or dependence, consistent with their unscheduled status in the USA and internationally.

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Novel Multiple Sclerosis Agents-Induced Cardiotoxicity

10.1101/2021.12.11.21267656 ◽

2021 ◽

Author(s):

Zaki Al-Yafeai ◽

Hamzah Abduljabbar ◽

Alexander Carvajal-Gonzalez ◽

Muhammed Arvas ◽

Shaun Patel ◽

...

Keyword(s):

Multiple Sclerosis ◽

Adverse Events ◽

Signal Analysis ◽

Cardiovascular Complications ◽

Reporting Odds Ratio ◽

New Agents ◽

Sphingosine 1 Phosphate ◽

S1p Receptor ◽

Artery Disease ◽

Receptor Modulators

Background: Emerging novel therapeutics have been developed to hamper the progression of multiple sclerosis. However, the adverse events related to these new agents remain largely unknown. Therefore, we sought to investigate the cardiovascular complications of these drugs. Methods: Utilizing data from the U.S. Food and Drug Administration Adverse Events Reporting System, we comprehensively evaluated the cardiovascular complications of the newly FDA approved anti-multiple sclerosis agents. Disproportionality signal analysis was conducted by measuring reporting odds ratio (ROR) with 95% confidence interval of all the cardiovascular adverse events adverse events since approval till 2021. Results: After vetting the newly approved agents for multiple sclerosis, CD20 and CD25 inhibitors and sphingosine-1-phosphate receptors agonists were the latest approved medications for multiple sclerosis since 2015. Two CD20 (ocrelizumab, ofatumumab) and one CD25 inhibitors (daclizumab) were significantly associated with multiple cardiovascular adverse events. Among all the cardiotoxic events; coronary artery disease, cardiac failure and atrial fibrillation were the most predominant among CD20 or CD25 blockers. Interestingly, Sphingosine-1-phosphate receptors agonists showed much fewer reported cardiac adverse events. However, fingolimod and siponimod were associated with significant bradycardia. Conclusions: Our data revealed the new agents prescribed for multiple sclerosis have cardiotoxic effects, including not only the known adverse effects observed effects for S1P receptor modulators but also undefined cardiovascular complications associated with CD20 and CD25 inhibitors. These findings potentially instigate further studies to personalize prescribing these agents for multiple sclerosis based on patient cardiovascular profile.

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Alemtuzumab in the long-term treatment of relapsing-remitting multiple sclerosis: an update on the clinical trial evidence and data from the real world

Therapeutic Advances in Neurological Disorders ◽

10.1177/1756285617722706 ◽

2017 ◽

Vol 10 (10) ◽

pp. 343-359 ◽

Cited By ~ 58

Author(s):

Tjalf Ziemssen ◽

Katja Thomas

Keyword(s):

Multiple Sclerosis ◽

Adverse Events ◽

Mechanism Of Action ◽

Real World ◽

Continuous Treatment ◽

The Real ◽

Relapsing Remitting ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

Alemtuzumab is a humanized monoclonal antibody approved for the treatment of relapsing-remitting multiple sclerosis (RRMS), given as two annual courses on five consecutive days at baseline and on three consecutive days 12 months later. Here we provide an update on the long-term efficacy and safety of alemtuzumab in RRMS, including real-world experience, and advances in our understanding of its mechanism of action. Recent data from the phase II/III extension study have demonstrated that alemtuzumab reduces relapse rates, disability worsening, and the rate of brain volume loss over the long term, with many patients achieving no evidence of disease activity. In high proportions of patients, preexisting disability remained stable or improved. Alemtuzumab is associated with a consistent safety profile over the long term, with no new safety signals emerging and the overall annual incidence of reported adverse events decreasing after the first year on treatment. Acyclovir prophylaxis reduces herpetic infections, and monitoring has been shown to mitigate the risk of autoimmune adverse events, allowing early detection and overall effective management. Data from clinical practice and ongoing observational studies are providing additional information on the real-world use of alemtuzumab. Recent evidence on the mechanism of action of alemtuzumab indicates that in addition to its previously known effects of inducing depletion and repopulation of T and B lymphocytes, it also results in a relative increase of cells with memory and regulatory phenotypes and a decrease in cells with a proinflammatory signature, and may further promote an immunoregulatory environment through an impact on other innate immune cells (e.g. dendritic cells) that play a role in MS. These effects may allow preservation of innate immunity and immunosurveillance. Together, these lines of evidence help explain the durable clinical efficacy of alemtuzumab, in the absence of continuous treatment, in patients with RRMS.

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Therapeutic Value of Single Nucleotide Polymorphisms on the Efficacy of New Therapies in Patients with Multiple Sclerosis

Journal of Personalized Medicine ◽

10.3390/jpm11050335 ◽

2021 ◽

Vol 11 (5) ◽

pp. 335

Author(s):

María José Zarzuelo Romero ◽

Cristina Pérez Ramírez ◽

María Isabel Carrasco Campos ◽

Almudena Sánchez Martín ◽

Miguel Ángel Calleja Hernández ◽

...

Keyword(s):

Multiple Sclerosis ◽

Mechanism Of Action ◽

Dimethyl Fumarate ◽

Response To Treatment ◽

Nucleotide Polymorphisms ◽

New Therapies ◽

Therapeutic Value ◽

The Impact

The introduction of new therapies for the treatment of multiple sclerosis (MS) is a very recent phenomenon and little is known of their mechanism of action. Moreover, the response is subject to interindividual variability and may be affected by genetic factors, such as polymorphisms in the genes implicated in the pathologic environment, pharmacodynamics, and metabolism of the disease or in the mechanism of action of the medications, influencing the effectiveness of these therapies. This review evaluates the impact of pharmacogenetics on the response to treatment with new therapies in patients diagnosed with MS. The results suggest that polymorphisms detected in the GSTP1, ITGA4, NQO1, AKT1, and GP6 genes, for treatment with natalizumab, ZMIZ1, for fingolimod and dimethyl fumarate, ADA, for cladribine, and NOX3, for dimethyl fumarate, may be used in the future as predictive markers of treatment response to new therapies in MS patients. However, there are few existing studies and their samples are small, making it difficult to generalize the role of these genes in treatment with new therapies. Studies with larger sample sizes and longer follow-up are therefore needed to confirm the results of these studies.

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Are sigma receptor modulators a weapon against multiple sclerosis disease?

Future Medicinal Chemistry ◽

10.4155/fmc-2017-0122 ◽

2017 ◽

Vol 9 (17) ◽

pp. 2029-2051 ◽

Cited By ~ 8

Author(s):

Simona Collina ◽

Marta Rui ◽

Silvia Stotani ◽

Emanuele Bignardi ◽

Daniela Rossi ◽

...

Keyword(s):

Multiple Sclerosis ◽

Sigma Receptor ◽

Multiple Sclerosis Disease ◽

Receptor Modulators

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Vaccination opportunities in multiple sclerosis patients treated with cladribine tablets

Current Neuropharmacology ◽

10.2174/1570159x20666211217160451 ◽

2021 ◽

Vol 20 ◽

Author(s):

Lucia Moiola ◽

Agostino Riva ◽

Ferdinando Nicoletti ◽

Antonio Uccelli ◽

Marco Salvetti ◽

...

Keyword(s):

Multiple Sclerosis ◽

Immune System ◽

Mechanism Of Action ◽

Vaccination Campaign ◽

Humoral Response ◽

Focused Attention ◽

Vulnerable Patients ◽

Mass Vaccination Campaign ◽

Multiple Sclerosis Patients ◽

Vaccination Campaigns

: The COVID-19 pandemic and the mass vaccination campaign highlighted the situation of the most vulnerable patients. In this work, we focused attention on patients who have Multiple Sclerosis (MS), particularly in treatment with cladribine tablets, trying to understand if and when it is possible to administer the vaccine successfully. Considering the innovative topic, we reviewed the existing literature with an analysis of the experiences also related to other vaccinations, including influenza and VZV, and very recent data from countries with vaccination campaigns already advanced. Overall, we have taken into account the mechanism of action, the pharmacokinetic/pharmacodynamic of cladribine and the changes in the immune system after its administration, together with the preliminary data about the humoral response to influenza, VZV and SARS-CoV-2 vaccinations in cladribine treated patients. In conclusion, data showed that the use of cladribine tablets seems to permit flexibility regarding vaccination timing and we suggest that vaccination in those patients should be safe and effective.

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