Effects of ponesimod: A Synthesis of Findings from 15 Studies

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Original Abstract of the Article

Major Research Findings

Ponesimod is a selective sphingosine-1-phosphate receptor modulator approved for treating relapsing forms of multiple sclerosis (MS). 8 found that ponesimod 20mg significantly reduced annualized relapse rate (ARR) and the number of combined unique active lesions (CUALs) compared to teriflunomide 14mg. 12 analyzed data from Phase 2 Core and Extension studies and demonstrated the long-term efficacy and safety of ponesimod 20mg. 13 provides a comprehensive overview of the clinical data supporting ponesimod's approval, highlighting its distinct characteristics compared to other S1P receptor modulators.

Ponesimod works by selectively blocking the egress of lymphocytes from the lymphoid organs, thus limiting the entry of autoreactive cells into the central nervous system. 15 investigated ponesimod's effects on astrocytes, a key cell type in the brain, and found that it inhibits astrocyte-mediated neuroinflammation and protects against demyelination in the cingulum, a critical brain pathway.

Ponesimod has a faster reversibility profile and fewer effects on heart conduction compared to other S1P receptor modulators. 3 provides a detailed analysis of the molecular and neuroimmune pharmacology of S1P receptor modulators, highlighting the unique features of ponesimod. 13 further emphasizes ponesimod's rapid reversibility and reduced cardiac monitoring requirements, making it a more manageable option for patients. Ponesimod's effects on lymphocytes are also reversible, with recovery occurring within a few days of discontinuation. 2 delves into the pharmacokinetic profile of ponesimod, confirming these characteristics. While ponesimod can affect heart rate, a gradual up-titration regimen minimizes this risk. 6 explores the pharmacodynamic modeling of ponesimod's effects on heart rate, offering guidance for clinicians.

Benefits and Risks

Benefit Summary

Ponesimod has demonstrated efficacy in reducing both relapses and disability progression in patients with relapsing multiple sclerosis. It offers a favorable safety profile with minimal effects on heart conduction and a rapid reversibility of its effects on lymphocytes.

Risk Summary

Ponesimod can cause a decrease in lymphocyte count, which is generally reversible after discontinuation. It can also affect heart rate, requiring monitoring at the start of treatment. A gradual up-titration regimen helps minimize this risk.

Comparison Between Studies

Similarities

Multiple studies have consistently shown ponesimod to be effective in treating relapsing multiple sclerosis. There is a general consensus that ponesimod offers a favorable safety profile with fewer effects on heart conduction and a faster reversibility of its effects on lymphocytes compared to other S1P receptor modulators.

Differences

Variations exist in the specific endpoints and patient populations across studies. For example, 12 highlighted the long-term efficacy and safety of ponesimod 20mg, while 8 compared ponesimod to teriflunomide and found a greater reduction in relapse rate and lesion count. 14 focused on ponesimod's effects on astrocytes and their role in neuroinflammation and demyelination. Despite these differences, the majority of studies consistently support ponesimod's safety and efficacy.

Consistency and Contradictions

While ponesimod's safety and efficacy are generally well-established, some contradictions exist regarding its effectiveness across studies. For example, 8 demonstrated a significant reduction in relapse rate and lesion count compared to teriflunomide, while 12 emphasized ponesimod's long-term efficacy and safety. These variations may be attributed to differences in study design, endpoints, and patient characteristics. Future research should aim to address these discrepancies and establish a more standardized assessment of ponesimod's effectiveness.

Real-World Application and Considerations

Ponesimod offers a promising treatment option for individuals with relapsing multiple sclerosis. However, it's important to remember that each patient's response to medication can vary. Clinicians should carefully monitor for potential side effects, particularly decreased lymphocyte count and heart rate changes. Ponesimod's rapid reversibility is a positive feature, making it manageable in situations like vaccination, pregnancy, or the need to discontinue treatment due to side effects.

Limitations of Current Research

More research is needed to fully understand the long-term effects and safety of ponesimod. Further investigation is also warranted to explore ponesimod's potential effectiveness across different patient groups and subtypes of multiple sclerosis.

Future Research Directions

Longitudinal studies are necessary to comprehensively assess ponesimod's long-term efficacy and safety. Additional research should delve into the individual factors that may influence a patient's response to ponesimod, enabling personalized treatment strategies. Investigating potential uses for ponesimod beyond multiple sclerosis could also be valuable.

Conclusion

Ponesimod represents a significant advancement in the treatment of relapsing multiple sclerosis. Its effectiveness in reducing relapses, potential benefits in slowing disability progression, and favorable safety profile make it a promising therapeutic option. However, continued research is crucial to address current limitations and enhance our understanding of ponesimod's full potential. If you have been diagnosed with multiple sclerosis, it's essential to consult with your healthcare provider to determine if ponesimod is a suitable treatment option for you.

Literature analysis of 15 papers
Positive Content
15
Neutral Content
0
Negative Content
0
Article Type
2
2
1
7
15
2.

Clinical Pharmacokinetics of Ponesimod, a Selective S1P1 Receptor Modulator, in the Treatment of Multiple Sclerosis.

Author: KrugerTerra M, ValenzuelaBelén, ThompsonCharles D, Ouwerkerk-MahadevanSivi, RuixoJuan Jose Perez

RRMS treatment
Reduced relapse rate
Lymphocyte count reduction
Transient heart rate decrease

Ponesimod, a selective S1P receptor modulator, is indicated for the treatment of relapsing-remitting multiple sclerosis (RRMS). This review summarizes the clinical pharmacokinetics (PK) and pharmacodynamics (PD) of ponesimod.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

3.

Molecular and neuroimmune pharmacology of S1P receptor modulators and other disease-modifying therapies for multiple sclerosis.

Author: KiharaYasuyuki, ChunJerold

MS treatment

This review summarizes the currently approved disease-modifying therapies (DMTs) for multiple sclerosis (MS) and provides details on the molecular pharmacology, immunopharmacology, and neuropharmacology of sphingosine 1-phosphate (S1P) receptor (S1PR) modulators. It highlights the CNS-oriented, astrocyte-centric mechanism of action of fingolimod, a S1PR modulator, suggesting a potential dual role in reducing both inflammation and neurodegeneration in MS.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.

Language : English

4.

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

Author: DumitrescuLaura, PapathanasiouAthanasios, CoclituCatalina, GarjaniAfagh, EvangelouNikos, ConstantinescuCris S, PopescuBogdan Ovidiu, TanasescuRadu

Relapsing MS treatment
Interfere with function

Sphingosine-1-phosphate-receptor (S1PR) modulators are oral disease-modifying therapies for relapsing multiple sclerosis (MS). These drugs work by binding to the lymphocytic S1P-subtype-1-receptor, preventing lymphocyte egress from lymph nodes. They may also interfere with other biological functions.

ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.

Language : English

6.

Pharmacokinetic-Pharmacodynamic Modeling of the Ponesimod Effect on Heart Rate in Patients With Multiple Sclerosis.

Author: ValenzuelaBelén, PoggesiItalo, LuyckxNicolas, VaclavkovaAndrea, Pérez-RuixoJuan José

HR management
Tolerable effect
Bradycardia
Negative chronotropic

This study characterized the effect of ponesimod, a medication for treating multiple sclerosis (MS), on heart rate (HR). The results indicate that ponesimod can cause a decrease in HR, but this effect is generally well-tolerated after two weeks of treatment.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

8.

An exposure-response analysis of ponesimod clinical efficacy in a randomized phase III study in patients with relapsing multiple sclerosis.

Author: ValenzuelaBelén, Olsson GisleskogPer, PoggesiItalo, SidorenkoTatiana, BurcklenMichel, KrackerHilke, Pérez-RuixoJuan Jose

Reduced MS lesions
Reduced MS relapses
Dosage adjustment not needed

This study assessed the exposure-response relationships of ponesimod, a drug for relapsing multiple sclerosis, in a phase III trial. The results suggest that ponesimod reduces relapse rate and active lesions, with a significant relationship between drug exposure and lesion reduction. The study supports the use of a flat 20 mg maintenance dose for ponesimod in adult patients with MS.

Clinical Trial, Phase IIIA Phase III trial is a trial that further rigorously verifies the efficacy and safety of a new drug or treatment, whose efficacy and safety have been confirmed in a Phase II trial, in a large number of patients, and evaluates whether it is superior to existing treatments.
Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

10.

Comparative Efficacy of Relapsing Multiple Sclerosis Therapies: Model-Based Meta-Analyses for Confirmed Disability Accumulation and Annualized Relapse Rate.

Author: HennessyBrian, ZierhutMatthew L, KrackerHilke, KeenanAlexander, SidorenkoTatiana

RMS treatment

This study examines the effects of ponesimod, a new drug for relapsing multiple sclerosis, compared to teriflunomide and a placebo. It assesses how well each treatment reduces the number of relapses and the worsening of disability over 12 weeks.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Meta-AnalysisA statistical technique that integrates the results of multiple studies to draw more general conclusions about a particular issue.

Language : English

11.

Comparative safety of high-efficacy disease-modifying therapies in relapsing-remitting multiple sclerosis: a systematic review and network meta-analysis.

Author: ŚladowskaKatarzyna, KawalecPaweł, HolkoPrzemysław, OsieckaOktawia

RRMS treatment
Safety concerns

This study compared the safety profiles of high-efficacy disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS). The DMTs included natalizumab, fingolimod, alemtuzumab, cladribine, ocrelizumab, ofatumumab, ozanimod, and ponesimod. The study aimed to provide a comprehensive safety profile of these DMTs for physicians to use when making treatment decisions.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Meta-AnalysisA statistical technique that integrates the results of multiple studies to draw more general conclusions about a particular issue.
Systematic ReviewA review that systematically collects, evaluates, and integrates relevant research to answer a specific research question.

Language : English

12.

Long-term Treatment With Ponesimod in Relapsing-Remitting Multiple Sclerosis: Results From Randomized Phase 2b Core and Extension Studies.

Author: FreedmanMark S, PozzilliCarlo, HavrdovaEva Kubala, LemleAlexandre, BurcklenMichel, LarbalestierAnna, HennessyBrian, SidorenkoTatiana, VaclavkovaAndrea, OlssonTomas,

Disability reduction
MRI disease activity reduction
Relapse reduction
Headache
Nasopharyngitis
Upper respiratory tract infection

Long-term treatment with ponesimod 20 mg was associated with a sustained low annualized confirmed relapse rate (0.154 at week 432) in patients with relapsing-remitting multiple sclerosis (RRMS), with 64% of patients remaining relapse-free. No new safety concerns were identified over 8 years of treatment.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Randomized Controlled TrialA clinical trial that randomly assigns participants to treatment and control groups to evaluate the effects of an intervention.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

13.

Ponesimod in the Treatment of Relapsing Forms of Multiple Sclerosis: An Update on the Emerging Clinical Data.

Author: RuggieriSerena, QuartuccioMaria Esmeralda, ProsperiniLuca

Multiple sclerosis treatment
Disease reactivation
Heart conduction

Ponesimod is a second-generation, highly selective, and rapidly reversible modulator of the S1P<sub>1</sub> receptor for the treatment of multiple sclerosis (MS). This review summarizes the pharmacodynamic and pharmacokinetic characteristics of ponesimod and the main clinical trials that led to its approval.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

14.

Ponesimod inhibits astrocyte-mediated neuroinflammation and protects against cingulum demyelination via S1P<sub>1</sub> -selective modulation.

Author: KiharaYasuyuki, JonnalagaddaDeepa, ZhuYunjiao, RayManisha, NgoTony, PalmerCarter, RiveraRichard, ChunJerold

Demyelination prevention

Ponesimod is a medication approved for the treatment of relapsing multiple sclerosis (MS). This study investigated the pharmacological properties of ponesimod, including its selectivity for the S1P1 receptor and its effects on human astrocyte signaling. Ponesimod demonstrated protective effects against demyelination, particularly in the cingulum, a major connection pathway in the brain.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
Research Support, N.I.H., ExtramuralResearch funding provided by the NIH to external research institutions and researchers.
Research Support, Non-U.S. Gov'tResearch funding provided by government agencies outside the United States.

Language : English

15.

Ponesimod to treat multiple sclerosis.

Author: IannielloA, PozzilliC

Cardiodynamic effect reduction
Lymphocyte egress blockage
MS treatment

Ponesimod, a highly selective S1P₁ receptor modulator, offers an effective and safe treatment for relapsing forms of multiple sclerosis, with rapid reversibility of its effects.

Journal ArticleAn article published in an academic or professional journal that reports original research or scholarly analysis.
ReviewAn article that critically examines existing research on a particular topic and summarizes the current state of knowledge in the field.

Language : English

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