INTRODUCTION: Multiple Sclerosis (MS), a debilitating central nervous system (CNS) disorder, is characterized by inflammation, demyelination, and neuronal degeneration. Despite advancements in immunomodulatory treatments, neuroprotective or restorative strategies remain inadequate. Our research is focusing on the potential of the positive allosteric modulator of AMPA receptors (AMPA-PAM), PF4778574, in addressing MS symptoms. METHODS: We utilized the MOG35-55 induced experimental autoimmune encephalomyelitis (EAE) model in C57BL6J mice to examine PF4778574's therapeutic and prophylactic efficacy. Our comprehensive approach included clinical scoring, optical coherence tomography (OCT), optomotor response (OMR) and histological assessments. Additionally, we explored the effects of PF4778574 in comparison and in combination with the immunomodulatory agent fingolimod, and investigated the impact on Cuprizone induced toxic demyelination. RESULTS: Prophylactic administration of PF4778574 showed notable improvement in clinical EAE indices and reduction in neuronal loss. While it did not diminish microglial activity, it reduced demyelinated areas in optic nerves and in the corpus callosum. Both PF4778574 and fingolimod significantly enhanced clinical EAE scores and decreased demyelination. However, their combination did not yield additional benefits. In the cuprizone model, PF4778574 increased oligodendrocyte precursor and mature myelin-forming cells, suggesting a pro-remyelinating effect. DISCUSSION: PF4778574 demonstrates promise in mitigating EAE effects, especially in terms of clinical disability and demyelination. These results suggest AMPA-PAMs as potential targets of interest for MS treatment beyond immunomodulatory approaches.

• MeSH
• Allosteric Regulation MeSH
• Receptors, AMPA * metabolism   MeSH
• Demyelinating Diseases drug therapy   metabolism   MeSH
• Encephalomyelitis, Autoimmune, Experimental * drug therapy   metabolism   immunology   MeSH
• Fingolimod Hydrochloride pharmacology   therapeutic use   MeSH
• Disease Models, Animal MeSH
• Mice, Inbred C57BL * MeSH
• Mice MeSH
• Multiple Sclerosis * drug therapy   metabolism   immunology   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

AIM: To evaluate the real-world comparative effectiveness and the cost-effectiveness, from a UK National Health Service perspective, of natalizumab versus fingolimod in patients with rapidly evolving severe relapsing-remitting multiple sclerosis (RES-RRMS). METHODS: Real-world data from the MSBase Registry were obtained for patients with RES-RRMS who were previously either naive to disease-modifying therapies or had been treated with interferon-based therapies, glatiramer acetate, dimethyl fumarate, or teriflunomide (collectively known as BRACETD). Matched cohorts were selected by 3-way multinomial propensity score matching, and the annualized relapse rate (ARR) and 6-month-confirmed disability worsening (CDW6M) and improvement (CDI6M) were compared between treatment groups. Comparative effectiveness results were used in a cost-effectiveness model comparing natalizumab and fingolimod, using an established Markov structure over a lifetime horizon with health states based on the Expanded Disability Status Scale. Additional model data sources included the UK MS Survey 2015, published literature, and publicly available sources. RESULTS: In the comparative effectiveness analysis, we found a significantly lower ARR for patients starting natalizumab compared with fingolimod (rate ratio [RR] = 0.65; 95% confidence interval [CI], 0.57-0.73) or BRACETD (RR = 0.46; 95% CI, 0.42-0.53). Similarly, CDI6M was higher for patients starting natalizumab compared with fingolimod (hazard ratio [HR] = 1.25; 95% CI, 1.01-1.55) and BRACETD (HR = 1.46; 95% CI, 1.16-1.85). In patients starting fingolimod, we found a lower ARR (RR = 0.72; 95% CI, 0.65-0.80) compared with starting BRACETD, but no difference in CDI6M (HR = 1.17; 95% CI, 0.91-1.50). Differences in CDW6M were not found between the treatment groups. In the base-case cost-effectiveness analysis, natalizumab dominated fingolimod (0.302 higher quality-adjusted life-years [QALYs] and £17,141 lower predicted lifetime costs). Similar cost-effectiveness results were observed across sensitivity analyses. CONCLUSIONS: This MSBase Registry analysis suggests that natalizumab improves clinical outcomes when compared with fingolimod, which translates to higher QALYs and lower costs in UK patients with RES-RRMS.

• MeSH
• Cost-Effectiveness Analysis MeSH
• Cost-Benefit Analysis MeSH
• Fingolimod Hydrochloride therapeutic use   MeSH
• Immunosuppressive Agents therapeutic use   MeSH
• Humans MeSH
• Natalizumab therapeutic use   MeSH
• Multiple Sclerosis, Relapsing-Remitting * drug therapy   MeSH
• Multiple Sclerosis * drug therapy   MeSH
• State Medicine MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• United Kingdom MeSH

Huntington's disease (HD) is a debilitating neurodegenerative disorder characterized by severe motor deficits, cognitive decline and psychiatric disturbances. An early and significant morphological hallmark of HD is the activation of astrocytes triggered by mutant huntingtin, leading to the release of inflammatory mediators. Fingolimod (FTY), an FDA-approved sphingosine-1-phosphate (S1P) receptor agonist is used to treat multiple sclerosis (MS), a neuroinflammatory disease, and has shown therapeutic promise in other neurological conditions. Our study aimed to investigate the therapeutic potential of FTY for treating HD by utilizing a well-characterized mouse model of HD (zQ175dn) and wild-type littermates. The study design included a crossover, long-term oral treatment with 1 mg/kg to 2 mg/kg FTY from the age of 15-46 weeks (n = 128). Different motor behavior and physiological parameters were assessed throughout the study. The findings revealed that FTY rescued disease-related body weight loss in a sex-dependent manner, indicating its potential to regulate metabolic disturbances and to counteract neurodegenerative processes in HD. FTY intervention also rescued testicular atrophy, restored testis tissue structure in male mice suggesting a broader impact on peripheral tissues affected by huntingtin pathology. Histological analyses of the brain revealed delayed accumulation of activated astrocytes contributing to the preservation of the neural microenvironment by reducing neuroinflammation. The extent of FTY-related disease improvement was sex-dependent. Motor functions and body weight improved mostly in female mice with sustained estrogen levels, whereas males had to compensate for the ongoing, disease-related testis atrophy and the loss of androgen production. Our study underscores the beneficial therapeutic effects of FTY on HD involving endogenous steroid hormones and their important anabolic effects. It positions FTY as a promising candidate for therapeutic interventions targeting various aspects of HD pathology. Further studies are needed to fully evaluate its therapeutic potential in patients.

• MeSH
• Fingolimod Hydrochloride * therapeutic use   pharmacology   MeSH
• Huntington Disease * drug therapy   metabolism   MeSH
• Disease Models, Animal MeSH
• Sphingosine 1 Phosphate Receptor Modulators * pharmacology   therapeutic use   MeSH
• Mice, Inbred C57BL MeSH
• Mice MeSH
• Motor Activity drug effects   MeSH
• Sphingosine-1-Phosphate Receptors agonists   metabolism   MeSH
• Testis drug effects   pathology   metabolism   MeSH
• Animals MeSH
• Check Tag
• Male MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Fingolimod is a first-in-class, orally administered drug indicated for the treatment of relapsing-remitting multiple sclerosis. It acts as an immunomodulator, is classified as a "disease-modifying therapy", and its main mechanism of action is the modulation of sphingosine-1-phosphate receptors. In this prospective pilot study, whole blood concentrations of fingolimod and fingolimod phosphate obtained during routine health care were measured. In this study, we aimed to determine whether therapeutic monitoring of fingolimod and fingolimod phosphate concentrations can help personalise pharmacotherapy for patients with multiple sclerosis. METHOD: The study group consisted of 73 patients treated with oral fingolimod (0.5 mg) once daily. Blood samples were collected between July 2021 and January 2022. The whole blood concentrations of fingolimod and fingolimod phosphate were analysed using ultra-high-performance liquid chromatography-tandem mass spectrometry. The relationship between the measured concentrations and the absolute peripheral blood lymphocyte count was evaluated. RESULTS: Fingolimod concentrations ranged from 0.61 to 6.21 μg/L, and fingolimod phosphate concentrations from 0.48 to 4.28 μg/L. Significantly higher concentrations of the active metabolite, fingolimod phosphate, and a significantly higher fingolimod phosphate/fingolimod concentration ratio were observed in women. The sum of fingolimod and fingolimod phosphate concentrations was significantly higher in the subgroup of patients with a lower absolute peripheral blood lymphocyte count. CONCLUSION: Although all patients were treated with the same dose of fingolimod (0.5 mg orally daily), a 10-fold difference was observed in the achieved whole blood concentrations of fingolimod and fingolimod phosphate. This wide inter-individual variability may lead to potential toxicity or suboptimal concentrations, with the risk of further deterioration in the clinical condition of patients with multiple sclerosis. Therefore, fingolimod is a suitable candidate for therapeutic drug monitoring, including monitoring patient adherence to treatment.

• MeSH
• Adult MeSH
• Fingolimod Hydrochloride * blood   administration & dosage   pharmacology   MeSH
• Immunosuppressive Agents * blood   administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Drug Monitoring methods   MeSH
• Pilot Projects MeSH
• Prospective Studies MeSH
• Multiple Sclerosis, Relapsing-Remitting drug therapy   blood   MeSH
• Multiple Sclerosis drug therapy   blood   MeSH
• Tandem Mass Spectrometry MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Fingolimod is an oral drug for the escalation of treatment of relapsing-remitting multiple sclerosis in patients with persistent disease activity on first-line drugs or in patients with rapidly progressive severe relapsing-remitting multiple sclerosis. An ultra-high-performance liquid chromatography-tandem mass spectrometry method for determining the concentrations of fingolimod and its active metabolite fingolimod phosphate in whole blood has been developed and validated. The advantages of this method are the easy, fast and cheap sample preparation using protein precipitation from blood with a mixture of acetonitrile-methanol (40:60, v/v). Chromatographic separation was performed on a ultra-high performance liquid chromatography BEH C18 1.7 μm (100 × 2.1 mm) column. Two modes of ionization, electrospray ionization and atmospheric pressure chemical ionization, were tested and compared. For validation, the electrospray ionization mode was chosen. As internal standard, isotopically labeled fingolimod-D4 was used to quantify the analytes. The method was validated according to the rules of the European Medicines Agency. The coefficients of variation for fingolimod were in the range of 1.13-11.88%, and the recovery was 98.80-106.00%. The coefficients of variation for fingolimod phosphate were in the range of 2.73-9.31%, and the recovery was 90.08-107.00%. The method is quite easy and fast and can be used for routine analysis.

• MeSH
• Chromatography, Liquid methods   MeSH
• Adult MeSH
• Fingolimod Hydrochloride * blood   pharmacokinetics   therapeutic use   chemistry   MeSH
• Immunosuppressive Agents blood   pharmacokinetics   MeSH
• Humans MeSH
• Limit of Detection MeSH
• Linear Models MeSH
• Reproducibility of Results MeSH
• Multiple Sclerosis blood   drug therapy   MeSH
• Tandem Mass Spectrometry * methods   MeSH
• Chromatography, High Pressure Liquid methods   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: To mimic as closely as possible a randomised controlled trial (RCT) and calibrate the real-world evidence (RWE) studies against a known treatment effect would be helpful to understand if RWE can support causal conclusions in selected circumstances. The aim was to emulate the TRANSFORMS trial comparing Fingolimod (FTY) versus intramuscular interferon β-1a (IFN) using observational data. METHODS: We extracted from the MSBase registry all the patients with relapsing-remitting multiple sclerosis (RRMS) collected in the period 2011-2021 who received IFN or FTY (0.5 mg) and with the same inclusion and exclusion criteria of the TRANSFORMS RCT. The primary endpoint was the annualised relapse rate (ARR) over 12 months. Patients were 1:1 propensity-score (PS) matched. Relapse-rate ratio (RR) was calculated by mean of a negative binomial regression. RESULTS: A total of 4376 patients with RRMS (1140 in IFN and 3236 in FTY) were selected. After PS, 856 patients in each group were matched. The ARR was 0.45 in IFN and 0.25 in FTY with a significant difference between the two groups (RR: 0.55, 95% CI: 0.45 to 0.68; p<0.001). The result of the emulation was very similar and fell within the 95% CI of that observed in the RCT (RR: 0.49, 95% CI: 0.37 to 0.64; p<0.001) with a standardised difference of 0.66 (p=0.51). CONCLUSIONS: By applying the same inclusion and exclusion criteria used in the RCT and employing appropriate methodology, we successfully replicated the RCT results with only minor discrepancies. Also, even if the confounding bias cannot be fully eliminated, conducting a rigorous target trial emulation could still yield valuable insights for comparative effectiveness research.

• MeSH
• Adult MeSH
• Fingolimod Hydrochloride * therapeutic use   MeSH
• Immunosuppressive Agents therapeutic use   MeSH
• Interferon beta-1a * therapeutic use   MeSH
• Middle Aged MeSH
• Humans MeSH
• Randomized Controlled Trials as Topic * MeSH
• Registries * MeSH
• Multiple Sclerosis, Relapsing-Remitting * drug therapy   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing-remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis. METHODS: Longitudinal data were obtained from the international MSBase registry, containing data from people with multiple sclerosis from 151 centres across 41 countries, and the Italian Multiple Sclerosis and Related Disorders Register, containing data from people with multiple sclerosis from 178 Italian multiple sclerosis centres. People younger than 18 years at the onset of multiple sclerosis symptoms were included, provided they had a confirmed diagnosis of relapsing-remitting multiple sclerosis and at least four Expanded Disability Status Scale (EDSS) scores recorded within 12-month intervals. The primary outcome was the time to change in disability state: minimal disability (EDSS scores 0, 1·0, and 1·5), mild disability (EDSS scores 2·0 and 2·5), moderate disability (EDSS scores 3·0 and 3·5), gait impairment (EDSS scores ≥4·0), and clinician diagnosed secondary progressive multiple sclerosis. A multi-state model was constructed to simulate the natural course of multiple sclerosis, modelling the probabilities of both disability worsening and improvement simultaneously. The impact of high-efficacy disease-modifying therapies (alemtuzumab, cladribine, daclizumab, fingolimod, mitoxantrone, natalizumab, ocrelizumab, rituximab, or autologous haematopoietic stem cell transplantation) and low-efficacy disease-modifying therapies (dimethyl fumarate, glatiramer acetate, interferon beta, or teriflunomide), compared with no treatment, on the course of disability was assessed. Apart from recruitment, individuals with lived experience of multiple sclerosis were not involved in the design and conduct of this study. FINDINGS: A total of 5224 people (3686 [70·6%] female and 1538 [29·4%] male) with mean age at onset of multiple sclerosis 15·24 years (SD 2·52) were included. High-efficacy therapies reduced the hazard of disability worsening across the disability states. The largest reduction (hazard ratio 0·41 [95% CI 0·31-0·53]) was observed in participants who were treated with high-efficacy therapies while in the minimal disability state, compared with those remained untreated. The benefit of high-efficacy therapies declined with increasing disability. Young people with minimal disability who received low-efficacy therapy also experienced a reduced hazard (hazard ratio 0·65 [95% CI 0·54-0·77]) of transitioning to mild disability, in contrast to those who remained untreated. INTERPRETATION: Treatment of paediatric-onset relapsing-remitting multiple sclerosis with high-efficacy therapy substantially reduces the risk of reaching key disability milestones. This reduction in risk is most pronounced among young people with minimal or mild disability when treatment began. Children with relapsing-remitting multiple sclerosis should be treated early with high-efficacy therapy, before developing significant neurological impairments, to better preserve their neurological capacity. FUNDING: National Health and Medical Research Council, Australia; MSBase Foundation Fellowship; MS Australia Postdoctoral Fellowship.

• MeSH
• Multiple Sclerosis, Chronic Progressive * MeSH
• Child MeSH
• Adult MeSH
• Fingolimod Hydrochloride therapeutic use   MeSH
• Humans MeSH
• Adolescent MeSH
• Registries MeSH
• Multiple Sclerosis, Relapsing-Remitting * drug therapy   MeSH
• Multiple Sclerosis * complications   drug therapy   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND AND OBJECTIVES: Patients with pediatric-onset multiple sclerosis (POMS) typically experience higher levels of inflammation with more frequent relapses, and though patients with POMS usually recover from relapses better than adults, patients with POMS reach irreversible disability at a younger age than adult-onset patients. There have been few randomized, placebo-controlled clinical trials of multiple sclerosis (MS) disease-modifying therapies (DMTs) in patients with POMS, and most available data are based on observational studies of off-label use of DMTs approved for adults. We assessed the effectiveness of natalizumab compared with fingolimod using injectable platform therapies as a reference in pediatric patients in the global MSBase registry. METHODS: This retrospective study included patients with POMS who initiated treatment with an injectable DMT, natalizumab, or fingolimod between January 1, 2006, and May 3, 2021. Patients were matched using inverse probability treatment weighting. The primary outcome was time to first relapse from index therapy initiation. Secondary study outcomes included annualized relapse rate; proportions of relapse-free patients at 1, 2, and 5 years; time to treatment discontinuation; and times to 24-week confirmed disability worsening and confirmed disability improvement. RESULTS: A total of 1,218 patients with POMS were included in this analysis. Patients treated with fingolimod had a significantly lower risk of relapse than patients treated with injectable DMTs (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.29-0.83; p = 0.008). After adjustment for prior DMT experience in the unmatched sample, patients treated with natalizumab had a significantly lower risk of relapse than patients treated either with injectable DMTs (HR, 0.15; 95% CI 0.07-0.31; p < 0.001) or fingolimod (HR, 0.37; 95% CI 0.14-1.00; p = 0.049). The adjusted secondary study outcomes were generally consistent with the primary outcome or with previous observations. The findings in the inverse probability treatment weighting-adjusted patient populations were confirmed in multiple sensitivity analyses. DISCUSSION: Our analyses of relapse risk suggest that natalizumab is more effective than fingolimod in the control of relapses in this population with high rates of new inflammatory activity, consistent with previous studies of natalizumab and fingolimod in adult-onset patients and POMS. In addition, both fingolimod and natalizumab were more effective than first-line injectable therapies. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that patients with POMS treated with natalizumab had a lower risk of relapse than those with fingolimod.

• MeSH
• Child MeSH
• Adult MeSH
• Fingolimod Hydrochloride * therapeutic use   MeSH
• Humans MeSH
• Natalizumab therapeutic use   MeSH
• Recurrence MeSH
• Registries MeSH
• Retrospective Studies MeSH
• Multiple Sclerosis * drug therapy   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Patients with relapsing-remitting multiple sclerosis (RRMS) who experience relapses on a first-line therapy (interferon, glatiramer acetate, dimethyl fumarate, or teriflunomide; collectively, "BRACETD") often switch to another therapy, including natalizumab or fingolimod. Here we compare the effectiveness of switching from a first-line therapy to natalizumab or fingolimod after ≥1 relapse. METHODS: Data collected prospectively in the MSBase Registry, a global, longitudinal, observational registry, were extracted on February 6, 2018. Included patients were adults with RRMS with ≥1 relapse on BRACETD therapy in the year before switching to natalizumab or fingolimod. Included patients received natalizumab or fingolimod for ≥3 months after the switch. RESULTS: Following 1:1 propensity score matching, 1000 natalizumab patients were matched to 1000 fingolimod patients. Mean (standard deviation) follow-up time was 3.02 (2.06) years after switching to natalizumab and 2.58 (1.64) years after switching to fingolimod. Natalizumab recipients had significantly lower annualized relapse rate (relative risk=0.66; 95% confidence interval [CI], 0.59-0.74), lower risk of first relapse (hazard ratio [HR]=0.69; 95% CI, 0.60-0.80), and higher confirmed disability improvement (HR=1.27; 95% CI, 1.03-1.57) than fingolimod recipients. No difference in confirmed disability worsening was observed. CONCLUSIONS: Patients with RRMS switching from BRACETD demonstrated better outcomes with natalizumab than with fingolimod.

• MeSH
• Adult MeSH
• Fingolimod Hydrochloride MeSH
• Immunologic Factors MeSH
• Immunosuppressive Agents MeSH
• Humans MeSH
• Natalizumab MeSH
• Recurrence MeSH
• Multiple Sclerosis, Relapsing-Remitting * MeSH
• Multiple Sclerosis * MeSH
• Comparative Effectiveness Research MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Effectiveness of cladribine tablets, an oral disease-modifying treatment (DMT) for multiple sclerosis (MS), was established in clinical trials and confirmed with real-world experience. OBJECTIVES: Use real-world data to compare treatment patterns and clinical outcomes in people with MS (pwMS) treated with cladribine tablets versus other oral DMTs. METHODS: Retrospective treatment comparisons were based on data from the international MSBase registry. Eligible pwMS started treatment with cladribine, fingolimod, dimethyl fumarate, or teriflunomide tablets from 2018 to mid-2021 and were censored at treatment discontinuation/switch, death, loss to follow-up, pregnancy, or study period end. Treatment persistence was evaluated as time to discontinuation/switch; relapse outcomes included time to first relapse and annualized relapse rate (ARR). RESULTS: Cohorts included 633 pwMS receiving cladribine tablets, 1195 receiving fingolimod, 912 receiving dimethyl fumarate, and 735 receiving teriflunomide. Individuals treated with fingolimod, dimethyl fumarate, or teriflunomide switched treatment significantly more quickly than matched cladribine tablet cohorts (adjusted hazard ratio (95% confidence interval): 4.00 (2.54-6.32), 7.04 (4.16-11.93), and 6.52 (3.79-11.22), respectively). Cladribine tablet cohorts had significantly longer time-to-treatment discontinuation, time to first relapse, and lower ARR, compared with other oral DMT cohorts. CONCLUSION: Cladribine tablets were associated with a significantly greater real-world treatment persistence and more favorable relapse outcomes than all oral DMT comparators.

• MeSH
• Dimethyl Fumarate therapeutic use   MeSH
• Fingolimod Hydrochloride therapeutic use   MeSH
• Immunosuppressive Agents therapeutic use   MeSH
• Cladribine therapeutic use   MeSH
• Humans MeSH
• Recurrence MeSH
• Registries MeSH
• Multiple Sclerosis, Relapsing-Remitting * drug therapy   MeSH
• Retrospective Studies MeSH
• Multiple Sclerosis * drug therapy   MeSH
• Tablets therapeutic use   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH