Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Dumitrescu L

PROVIDER: S-EPMC10069376 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Publications

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

Dumitrescu Laura L Papathanasiou Athanasios A Coclitu Catalina C Garjani Afagh A Evangelou Nikos N Constantinescu Cris S CS Popescu Bogdan Ovidiu BO Tanasescu Radu R

Expert opinion on pharmacotherapy 20230322 4

<h4>Introduction</h4>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, ...[more]

PMID: 36946625

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Project description:Since the approval of fingolimod, several selective sphingosine-1-phosphate receptor modulators have entered clinical development for multiple sclerosis. However, side effects can occur with sphingosine-1-phosphate receptor modulators. By considering short-term data across the drug class and longer term fingolimod data, we aim to highlight the potential of sphingosine-1-phosphate receptor modulators in multiple sclerosis, while offering reassurance that their benefit-risk profiles are suitable for long-term therapy. Short-term fingolimod studies demonstrated the efficacy of this drug class, showed that cardiac events upon first-dose administration are transient and manageable, and showed that serious adverse events are rare. Early-phase studies of selective sphingosine-1-phosphate receptor modulators also show efficacy with a similar or improved safety profile, and treatment initiation effects were reduced with dose titration. Longer term fingolimod studies demonstrated sustained efficacy and raised no new safety concerns, with no increases in macular edema, infection, or malignancy rates. Switch studies identified no safety concerns and greater patient satisfaction and persistence with fingolimod when switching from injectable therapies with no washout period. Better outcomes were seen with short than with long washouts when switching from natalizumab. The specific immunomodulatory effects of sphingosine-1-phosphate receptor modulators are consistent with the low observed rates of long-term, drug-related adverse effects with fingolimod. Short-term data for selective sphingosine-1-phosphate receptor modulators support their potential effectiveness in multiple sclerosis, and improved side-effect profiles may widen patient access to this drug class. The long-term safety, tolerability, and persistence profiles of fingolimod should reassure clinicians that sphingosine-1-phosphate receptor modulators are likely to be suitable for the long-term treatment of multiple sclerosis.

Project description:BackgroundFour sphingosine-1-phosphate receptor (S1PR) modulators are currently available in the USA for treating relapsing forms of multiple sclerosis (MS). These S1PR modulators have similar efficacy. Clinicians may therefore consider other factors, such as clinical management considerations, when distinguishing among treatments. This study estimated which S1PR modulator clinicians would choose on the basis of a treatment's clinical management and quantified how individual aspects of clinical management might drive this choice.MethodsA multi-criteria decision analysis (MCDA) was conducted on the basis of clinical management preferences elicited in a discrete choice experiment (DCE) and real-world clinical management profiles of the S1PR modulators currently available to treat relapsing forms of MS (fingolimod, ozanimod, ponesimod, siponimod). The DCE was completed by neurologists in the USA experienced in treating MS and included eight clinical management attributes: first-dose observations, genotyping, liver function tests, eye exams, drug-drug interactions, interactions with antidepressants, interactions with foods high in tyramine, and immune system recovery time. Attribute levels were selected on the basis of S1PR modulator product labels. In the MCDA, partial MCDA scores were created for each attribute and summed to produce an overall MCDA score for each S1PR modulator.ResultsThe DCE was completed by 200 neurologists. The overall MCDA score was highest for ponesimod (4.78 points), followed by siponimod (4.10 points), fingolimod (3.61 points), and ozanimod (2.38 points). Having fewer drug-drug interactions contributed most to the overall scores (up to 1.56 points), followed by having no first-dose observations (0.95 points), the shortest immune system recovery time (0.94 points), and not interacting with foods high in tyramine (0.86 points).ConclusionWhen considering clinical management convenience, the average US-based neurologist treating MS is likely to choose ponesimod over siponimod, fingolimod, or ozanimod. The strongest driver of preferences was the number of drug-drug interactions. This information can help inform recommendations for the treatment of MS and facilitate shared decision-making between clinicians and patients.

Dataset Information

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

Introduction

Areas covered

Expert opinion

Publications

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

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