Fingolimod

Immunological Mechanisms of Action

The primary immunological effect of fingolimod-phosphate is its interaction with S1P1 receptors on lymphocytes, which is crucial for their egress from lymphoid organs. aimspress.comscripps.edudiva-portal.orgresearchgate.netfrontiersin.org

This compound-phosphate's binding to S1P1 receptors on lymphocytes leads to the internalization and degradation of these receptors. aimspress.comfrontiersin.orgneurology.orgjsir.gr.jp This functional antagonism prevents lymphocytes from responding to the S1P gradient, which normally facilitates their exit from lymphoid tissues. aimspress.comfrontiersin.orgjsir.gr.jp

The core mechanism of this compound involves the reversible retention of T and B cells within secondary lymphoid organs, such as lymph nodes and the spleen. frontiersin.orgaimspress.comnih.govnih.govscripps.edudiva-portal.orgresearchgate.netfrontiersin.orgneurology.org This sequestration prevents these cells from re-entering the peripheral circulation. aimspress.comnih.govscripps.edudiva-portal.orgresearchgate.netfrontiersin.orgneurology.org

By trapping lymphocytes in lymphoid organs, this compound significantly reduces the number of autoreactive lymphocytes, including T and B cells, that can recirculate and infiltrate the central nervous system (CNS). aimspress.comnih.govnih.govscripps.edudiva-portal.orgfrontiersin.orgneurology.orgjsir.gr.jpplos.orgfrontiersin.orgiomcworld.orgnih.gov This reduction in CNS infiltration is a key aspect of its therapeutic benefit in autoimmune diseases like MS, where immune cells contribute to inflammation and tissue damage within the CNS. nih.govnih.govscripps.edudiva-portal.orgresearchgate.netfrontiersin.orgneurology.orgiomcworld.org

This compound exhibits a selective effect on different T-cell subpopulations. It primarily prevents the egress of C-C chemokine receptor type 7 (CCR7)-positive naïve T cells and central memory T cells (TCM) from lymph nodes. diva-portal.orgresearchgate.netfrontiersin.orgplos.orgiomcworld.orgnih.govmdpi.com In contrast, effector memory T cells (TEM), which are generally CCR7-negative, are largely unaffected and retain their ability to circulate, thereby preserving a significant portion of immune surveillance and defense against pathogens. diva-portal.orgresearchgate.netfrontiersin.orgplos.orgiomcworld.orgnih.govmdpi.com Studies have shown a pronounced reduction in naïve and central memory T cells, while effector memory cells show a less pronounced reduction. plos.org

Table 1: Differential Impact of this compound on T-cell Subpopulations

This compound's active form, this compound-phosphate, acts as a functional antagonist by binding to S1P1 receptors on the surface of lymphocytes. aimspress.comscripps.eduresearchgate.netneurology.orgplos.orgfrontiersin.org This binding leads to the internalization and subsequent degradation of the S1P1 receptor, effectively reducing the number of available receptors on the cell surface. aimspress.comfrontiersin.orgneurology.orgjsir.gr.jp This process, known as receptor down-modulation, renders the lymphocytes unresponsive to the natural S1P gradient, which is essential for their migration out of lymphoid tissues. aimspress.comfrontiersin.orgjsir.gr.jp

The sequestration of lymphocytes in lymphoid organs results in a notable and dose-dependent reduction in absolute lymphocyte counts in the peripheral blood. diva-portal.orgplos.orgfrontiersin.orgnih.govfrontiersin.orgmims.comneurology.org This lymphopenia is a well-known pharmacodynamic effect of this compound. frontiersin.orgfrontiersin.orgneurology.org Studies have shown a significant decrease in total lymphocyte count, with the most pronounced reductions observed in CD4+ T helper cells and B cell populations. plos.orgfrontiersin.orgfrontiersin.org While CD8+ cytotoxic T cells are also reduced, natural killer (NK) cells are only moderately affected. plos.orgfrontiersin.orgfrontiersin.org This reduction in circulating lymphocytes is a redistribution to lymphoid tissues rather than a destruction of the cells, and it is reversible upon discontinuation of the drug. diva-portal.orgneurology.org Early immunological changes, including a decrease in absolute lymphocyte count, CD3+, CD3+CD4+, and CD19+ cells, can be detected as early as 6 hours after the first administration of this compound. frontiersin.org

Table 2: Changes in Peripheral Blood Lymphocyte Subsets Following this compound Treatment

Studies in Experimental Autoimmune Encephalomyelitis (EAE) Models

Experimental autoimmune encephalomyelitis (EAE) serves as a widely accepted animal model for multiple sclerosis (MS), and preclinical studies using this model have been crucial in understanding fingolimod's efficacy and mechanisms ufrgs.brtranspharmation.com.

Investigations in Other Neurodegenerative Disease Models

The observed direct CNS effects of this compound in EAE models have prompted investigations into its potential therapeutic utility in other neurodegenerative diseases, where neuroinflammation and neuronal damage are key pathological features nih.govd-nb.info.

Efficacy in Relapsing-Remitting Multiple Sclerosis (RRMS)

Long-Term Efficacy Studies

Efficacy in Pediatric MS Patients

This compound holds a unique position as the only FDA-approved disease-modifying therapy for pediatric MS patients, specifically for those aged 10 to 17 years dovepress.comneurologylive.commdpi.com. The pivotal Phase 3 PARADIGMS study demonstrated its robust efficacy in this population. The study showed a significant and clinically meaningful reduction in the annualized relapse rate (ARR) in children and adolescents with MS over a period of up to two years, compared to interferon beta-1a intramuscular injections dovepress.comnovartis.com. The adjusted ARR was 0.12 in the this compound-treated group, meaning these patients experienced a relapse less than every 8 years, a dramatic difference compared to the interferon beta-1a group where the relapse rate was significantly higher neurologylive.com. This compound was also superior in reducing the number of new and enhancing or enlarging lesions on MRI, as well as in reducing brain volume loss or atrophy neurologylive.com. Beyond clinical and radiological outcomes, this compound also improved health-related quality of life (HRQoL) in pediatric patients with MS, as evidenced by both self-reported and parent-reported Pediatric Quality of Life (PedsQL) scores bmj.com.

Biomarkers of Efficacy (e.g., Neurofilaments in CSF)

Biomarkers play an increasingly important role in assessing disease activity and treatment efficacy in multiple sclerosis. Neurofilament light chain (NfL), a neuronal structural protein, has emerged as a promising biomarker for axonal injury in MS bmj.comnih.goveasp.esfrontiersin.org. Elevated levels of NfL in cerebrospinal fluid (CSF) correlate with MS activity and reflect axonal damage bmj.comfrontiersin.org. Studies have shown that this compound treatment can lead to a reduction in CSF NfL levels, indicating a beneficial effect on axonal injury nih.govucl.ac.uk. For instance, in a subset of patients from the FREEDOMS study, median changes from baseline in CSF NfL levels after 12 months of this compound treatment (0.5 mg and 1.25 mg) were significantly lower than zero, unlike the placebo group nih.gov. This reduction in NfL levels correlated with improvements in relapse and MRI outcomes nih.gov. Beyond NfL, other CSF biomarkers such as C-X-C motif chemokine 13 (CXCL13), a marker of B-cell activity, and chitinase-3-like protein 1 (CHI3L1) and chitotriosidase (CHIT1), markers of glial activation, have also been observed to decrease after this compound treatment, particularly in patients switching from first-line DMTs ucl.ac.uk. These findings suggest that CSF biomarkers can provide an additional measure of treatment efficacy by reflecting the influence of DMTs on different aspects of MS immunopathogenesis ucl.ac.uk.

Table 5: Effect of this compound on CSF Biomarkers nih.govucl.ac.uk

Cardiac Adverse Event Mechanisms

Ocular Adverse Event Mechanisms

Ocular adverse events, particularly macular edema, are a recognized complication of this compound therapy. nih.goveyewiki.org

Dermatological Adverse Event Mechanisms

Other Systemic Adverse Event Mechanisms (e.g., Liver Enzyme Elevation)

Elevated liver enzyme levels, particularly alanine transaminase (ALT) and aspartate transaminase (AST), are commonly observed adverse events associated with this compound treatment. nih.gove-century.us In large clinical trials, serum ALT elevations above 3 times the upper limit of normal (ULN) were reported more frequently in this compound recipients compared to placebo recipients. nih.goveuropa.eu While the exact mechanism by which this compound causes liver injury is not fully known, it is extensively metabolized by the liver, primarily via the cytochrome P450 system, and liver injury may potentially be caused by a toxic or immunogenic intermediate of its metabolism. nih.gov In vitro studies using human hepatocellular carcinoma cell lines (HepG2) suggest that the active form, this compound (S)-phosphate, can induce time- and dose-dependent decreases in cell viability, mitochondrial membrane potential, and ATP levels, along with the induction of oxidative stress. oup.comlarvol.com It is hypothesized that this toxic profile may originate from the interaction of this compound (S)-phosphate with sirtuin proteins, specifically SIRT3 and SIRT5. oup.comlarvol.com

Management of liver enzyme elevation involves monitoring liver function tests. Routine liver tests are recommended before initiating treatment and at specified intervals thereafter, and periodically until two months after discontinuation. nih.goveuropa.eu More frequent monitoring is advised if serum enzyme levels exceed 3 times the ULN. nih.gov If there are symptoms or signs of liver injury or if aminotransferase levels rise above 5 times ULN, discontinuation of therapy is recommended. nih.goveuropa.eu Liver enzyme levels typically return to normal within approximately two months after discontinuing this compound. nih.gov In cases of confirmed significant liver injury, treatment should be discontinued and generally not resumed unless an alternative cause can be established. europa.euwww.gov.uk Screening for hepatitis B virus (HBV) infection is also recommended before starting therapy, as this compound can cause reactivation of hepatitis B in susceptible patients. nih.gov

Other systemic adverse events with known or hypothesized mechanisms include:

Bradycardia and Atrioventricular Block: this compound phosphate binds to S1P receptors in cardiac tissue, including the sinoatrial and atrioventricular nodes and atrial myocytes. This binding can induce inward potassium flow, leading to a negative chronotropic effect on the heart, resulting in transient bradycardia and AV conduction delays, typically observed upon treatment initiation. nih.govmedcentral.com

Macular Edema: A dose-dependent increase in the risk of macular edema has been observed with this compound. medcentral.com While the precise mechanism is not fully understood, S1P receptors are present in the retina, and modulation of these receptors by this compound may affect vascular permeability and fluid balance, contributing to macular edema. scripps.edu Ophthalmologic evaluations are recommended at baseline and after treatment initiation, with more frequent checks for patients with risk factors like diabetes mellitus or a history of uveitis. europa.eu

Infections: The immunosuppressive properties of this compound, primarily due to lymphocyte sequestration in lymph nodes, increase the risk of various infections, including viral, bacterial, and fungal opportunistic infections. nih.gov This is a direct consequence of its intended mechanism of reducing circulating lymphocytes. bmj.comdrugbank.com Management involves monitoring for signs and symptoms of infection and considering therapy interruption in case of serious infections. sfda.gov.sa

Refining Understanding of Precise Mechanisms of Action

While Fingolimod's main pharmacological effect is immunomodulation through lymphocyte homing, its full spectrum of action is still being elucidated. nih.gov

Beyond its well-known S1P receptor modulation, emerging evidence suggests that this compound may exert effects through mechanisms independent of S1P receptors. larvol.complos.org These non-S1P receptor mediated effects could contribute to its diverse biological functions, including potential anti-tumor activities, angiogenesis inhibition, calcium mobilization, and apoptosis. plos.org Candidate cellular targets for these effects include cPLA2, 14-3-3, PKC, and PP2A. plos.org Furthermore, this compound has been shown to inhibit S1P lyase activity, an enzyme responsible for the irreversible degradation of S1P, which could alter S1P chemotactic gradients and influence various cellular functions like survival, migration, and inflammation. nih.gov A deeper understanding of these non-S1P receptor mediated pathways could uncover additional therapeutic avenues and explain some of its broader pharmacological effects.

Exploring Novel Therapeutic Applications Beyond MS

The multifaceted actions of this compound, including its neuroprotective and anti-inflammatory properties, have generated significant interest in exploring its therapeutic potential beyond MS. nih.govlarvol.comfrontiersin.org Preclinical studies have shown promising results in various neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy. nih.govfrontiersin.orgresearchgate.net this compound has demonstrated neuroprotective effects in animal models, correlating with increased brain-derived neurotrophic factor (BDNF) levels and improved cognitive and/or motor abilities. nih.govfrontiersin.orgresearchgate.net It has also been shown to reduce neuroinflammatory markers by inhibiting lymphocytes and directly affecting astrocytes and microglia. nih.govresearchgate.net Specific effects observed include the reduction of amyloid-beta production in AD models and antiepileptogenic properties. nih.govresearchgate.net Beyond neurodegenerative conditions, this compound is being investigated for other autoimmune and inflammatory disorders, including plaque psoriasis, dermatomyositis, Crohn's disease, ulcerative colitis, polymyositis, liver failure, renal failure, acute stroke, graft-versus-host disease (GVHD), and transplant rejection. biomolther.org Its potential in organ transplantation, oncological conditions, viral infections, and hypersensitivity diseases is also under review. larvol.com

Development of More Selective S1P Receptor Modulators

This compound is a non-selective S1P receptor modulator, binding with high affinity to S1P1, S1P3, S1P4, and S1P5 receptors. tandfonline.comnih.govresearchgate.net While this broad activity contributes to its efficacy, it is also associated with certain adverse effects, particularly cardiac-related side effects like bradycardia, which necessitate first-dose monitoring. nih.govnih.govresearchgate.net Consequently, a significant area of research focuses on developing more selective S1P receptor modulators, primarily targeting S1P1, to minimize off-target effects and improve safety profiles. biomolther.orgnih.govresearchgate.netnih.gov Second-generation S1PR modulators, such as Siponimod, Ozanimod, and Ponesimod, have been developed with greater selectivity for S1P1 and improved pharmacokinetic profiles, including shorter half-lives and no requirement for phosphorylation for activation, potentially leading to a faster onset of action and quicker reversal of pharmacological effects if needed. biomolther.orgnih.govnih.govresearchgate.net These newer agents aim to retain efficacy while reducing safety concerns associated with broader S1PR modulation. nih.govresearchgate.net

Long-Term Safety and Efficacy in Diverse Patient Populations

While clinical trials have demonstrated this compound's efficacy and safety in the short to medium term, ongoing research is crucial to assess its long-term safety and effectiveness in diverse patient populations. tandfonline.comneurology.orgnih.gov Real-world data studies and long-term extensions of pivotal trials continue to provide valuable insights into the sustained benefits of this compound in reducing relapse rates, disability progression, and brain volume loss. neurology.orgnih.govfrontiersin.orgd-nb.info These studies also monitor for late-onset safety events and assess the drug's profile in specific subgroups, such as young adults and pediatric patients. neurology.orgfrontiersin.org Understanding the impact of comorbidities and prior treatments on this compound outcomes in varied patient demographics remains an important area of investigation. frontiersin.org

Patient-Reported Outcomes and Quality of Life Studies

Patient-reported outcomes (PROs) and quality of life (QoL) are increasingly recognized as crucial measures of treatment success, reflecting the patient's perspective on their health status and the impact of therapy. Studies investigating this compound have consistently demonstrated positive effects on these parameters.

In the phase 3 PARADIGMS Study, which evaluated this compound in pediatric patients with multiple sclerosis (PoMS), treatment with this compound showed improvements compared to interferon β-1a on the 23-item Pediatric Quality of Life (PedsQL) scale bmj.com. Specifically, self-reported Total Scale Scores improved by 4.66 with this compound versus -1.16 with interferon β-1a (p≤0.001). Parent-reported Total Scale Scores also favored this compound (2.71 vs -1.02, p≤0.05) bmj.com. The proportion of patients achieving a clinically meaningful improvement in the PedsQL Total Scale Score was notably higher with this compound (47.5%) compared to interferon β-1a (24.2%) based on self-reported scores (p=0.001) bmj.com.

Table 1: PedsQL Total Scale Score Changes in PARADIGMS Study

Real-world evidence further supports these findings. A prospective observational study in Greece indicated that this compound treatment contributed to high patient-reported treatment satisfaction and improvements in the QoL of MS patients nih.gov. Significant increases were observed in patients' global satisfaction and effectiveness domain scores from enrollment to 24 months nih.gov. Similarly, a survey found that the majority of patients treated with this compound reported an improvement in their QoL and an enhanced capacity to plan for the future dovepress.com. These perceptions were more frequent among patients satisfied with their treatment, aligning with findings from other interventional and observational studies dovepress.com. The EPOC (Evaluate Patient OutComes) study, a phase 4, open-label, multi-center study, also aimed to assess patient-reported treatment satisfaction, perceived effectiveness, activities of daily living, fatigue, and depression in patients switching to this compound tandfonline.com.

Combined Clinical Outcomes and Overall Treatment Effectiveness

This compound has demonstrated robust effectiveness across various clinical outcomes, both in controlled trials and real-world settings. Pivotal clinical trials have shown this compound's superior efficacy in reducing the annualized relapse rate (ARR) and improving brain magnetic resonance imaging (MRI) outcomes compared to placebo or intramuscular interferon nsj.org.sa.

Real-world studies consistently confirm these benefits. In a study of 60 patients with relapsing-remitting multiple sclerosis (RRMS) in Western Iran, a significant 85% reduction in the annualized relapse rate was observed, decreasing from 1.8±1.35 at baseline to 0.27±0.58 after 12 months of treatment (p=0.001) nsj.org.sa. Furthermore, 76.66% of these patients were relapse-free after the 12-month intervention nsj.org.sa. Another multivariate pooled analysis of two observational studies in Spain, involving 988 RRMS patients, reported a decrease in mean ARR by 76.5% after 1 year, 82.4% after 2 years, and 86.3% after 3 years, compared to the year prior to this compound initiation (all p<0.0001) neurology.org. This analysis also showed that at 12 months, 89.6% of patients had stable or improved Expanded Disability Status Scale (EDSS) scores, which was maintained in 84.4% of patients at 24 months neurology.org.

Table 2: Annualized Relapse Rate (ARR) Reduction with this compound

A systematic review of real-world data for this compound highlighted that treatment improved outcomes compared to the period before treatment initiation and was more effective than interferons or glatiramer acetate researchgate.netnih.gov. Long-term extension studies of the FREEDOMS trial also demonstrated sustained effectiveness, with the ARR remaining low and a high proportion of patients remaining free of relapse and confirmed disease progression over several years dovepress.com. MRI outcomes were also favorable, with a high percentage of patients free of gadolinium-enhancing lesions (GELs) and new or enlarging T2 lesions dovepress.com.

Neurofilament Light Chain as a Biomarker for Neurodegeneration

Neurofilament light chain (NfL) is a neuronal structural protein that has emerged as a promising biomarker for axonal injury and neurodegeneration in multiple sclerosis frontiersin.orgnih.govmdpi.com. Elevated levels of NfL in cerebrospinal fluid (CSF) and blood are associated with MS activity, relapses, disability progression, and MRI lesions, reflecting ongoing neuronal damage mdpi.com.

Studies have investigated the impact of this compound on NfL levels. In a subset of patients from the phase 3 FREEDOMS study, CSF NfL levels were assessed at baseline and after 12 months of treatment nih.govneurology.org. Median NfL levels did not significantly differ between treatment groups at baseline. However, following 12 months of treatment, median changes from baseline in NfL levels were significantly reduced in the this compound groups compared to placebo nih.govneurology.org. For the pooled 0.5/1.25 mg this compound group, the median change was -326 pg/mL (83.3% with reduction, p=0.002), whereas the placebo group showed a reduction of -214 pg/mL (66.7% with reduction, p=0.388) nih.govneurology.org. Importantly, these reductions in NfL levels at month 12 correlated with an improvement in relapse and MRI outcomes, suggesting a beneficial effect of this compound on axonal integrity and supporting NfL's utility as a quantitative biomarker in MS nih.govneurology.org.

Table 3: Median Neurofilament Light Chain (NfL) Levels and Changes in FREEDOMS Study (12 Months)

While NfL is a non-specific marker of neurodegeneration, its consistent elevation in MS activity and its reduction with effective therapies like this compound underscore its potential as a prognostic biomarker for identifying early biochemical signs of disease progression and treatment response mdpi.compracticalneurology.com.

Q. What experimental models are commonly used to investigate Fingolimod’s mechanism of action in multiple sclerosis (MS)?

this compound’s mechanism is studied using in vitro lymphocyte migration assays and in vivo models like experimental autoimmune encephalomyelitis (EAE). These models assess immune modulation via sphingosine-1-phosphate receptor (S1PR) internalization, which traps lymphocytes in lymph nodes . CNS effects are evaluated using brain tissue analysis to measure direct S1PR modulation on astrocytes and oligodendrocytes .

Q. How are clinical trial endpoints (e.g., relapse rate, MRI activity) standardized in this compound studies?

Phase III trials (e.g., FREEDOMS, TRANSFORMS) use annualized relapse rate (ARR), gadolinium-enhancing MRI lesions, and disability progression (EDSS) as primary endpoints. Standardized protocols include double-blinded designs, placebo or active comparators (e.g., interferon-β), and 24-month follow-ups to assess sustained efficacy .

Q. What methodologies are employed to validate this compound’s pharmacokinetics and hepatic metabolism?

Pharmacokinetic studies use liquid chromatography-mass spectrometry (LC-MS) to measure plasma concentrations, with a focus on CYP4F2-mediated metabolism. Severe hepatic impairment cohorts are monitored for altered exposure using terminal half-life calculations (6–9 days) and dose adjustments .

Advanced Research Questions

Q. How can researchers resolve contradictory findings on this compound’s infection risk in meta-analyses?

Systematic reviews (e.g., Zhao et al., 2021) address heterogeneity by stratifying trials based on patient demographics, prior DMT use, and infection definitions. Sensitivity analyses exclude studies with high bias risk, while subgroup analyses differentiate between herpesviruses (e.g., VZV) and bacterial infections. Pooled odds ratios are adjusted for confounders like lymphocyte count thresholds .

Q. What advanced bioinformatics tools identify this compound’s oncological targets, such as PLK1 in head and neck squamous cell carcinoma (HNSC)?

TCGA data mining combined with Bayesian differential expression analysis (limma R package) identifies PLK1 as a key target. Validation includes in vitro lentiviral PLK1 overexpression in SCC9 cells, CCK-8 proliferation assays, and survival analysis via Kaplan-Meier curves. GSEA confirms enrichment in cell cycle pathways (NES=1.53, P<0.05) .

Q. What methodologies mitigate bias in real-world this compound studies comparing clinical trial vs. practice populations?

Real-world studies (e.g., PANGAEA) use propensity score matching to balance cohorts for disease severity and prior DMT exposure. Sensitivity analyses restrict populations to EU label criteria (highly active MS). Missing data are handled via multiple imputation or observed-case frameworks .

Q. How is this compound’s neuroprotective potential evaluated in Alzheimer’s disease models?

The 3xTg-AD mouse model undergoes Novel Object Location (NOL) tests to assess spatial memory. This compound’s efficacy is quantified by discrimination index improvements (e.g., from 0.2 to 0.5 at 12 months) and Western blot validation of amyloid-β reduction. CNS penetration is confirmed via LC-MS of brain tissue .

Q. What strategies address rebound syndrome after this compound discontinuation in MS patients?

Rebound risk is managed by overlapping this compound cessation with B-cell depleting therapies (e.g., rituximab) or corticosteroids. MRI monitoring at 4-week intervals tracks gadolinium lesion surges (median >30 new lesions). Washout periods are minimized (<2 weeks) to reduce relapse severity .

Methodological Considerations

Q. How are Bayesian statistical frameworks applied in TCGA-based studies of this compound’s anticancer effects?

Bayesian analysis with the limma package identifies differentially expressed genes (|log2FC|≥1, P<0.05). Heatmaps and volcano plots visualize tumor vs. paracancerous tissue differences. Survival significance is validated via log-rank tests (HR=1.34 for PLK1) .

Q. What experimental designs validate this compound’s biomarker-driven efficacy, such as serum Sema4A levels?

Retrospective cohorts stratify MS patients by baseline Sema4A (ELISA-measured). Efficacy endpoints (ARR, EDSS) are compared between high/low Sema4A subgroups. Preclinical validation uses EAE mice injected with recombinant Sema4A-Fc, with this compound response assessed via clinical score reductions .