Reversible oxidation/reduction steps in the metabolic degradation of the glycerol side chain of the S1P1 modulator ponesimod.

1. Ponesimod is a selective modulator of the sphingosine 1-phosphate receptor 1 (S1P1) approved for the treatment of active relapsing forms of multiple sclerosis. The chemical structure of ponesimod contains a glycerol side chain which is the major target of drug metabolism in humans.2. The two major metabolic pathways give the acids M12 (-OCH2CH(OH)COOH) and M13 (-OCH2COOH). While the former results from oxidation of the terminal alcohol, the mechanism yielding the chain-shortened acid M13 is less obvious. A detailed mechanistic study with human liver microsomes and hepatocytes using ponesimod, M12 and some of the suspected intermediates revealed an unexpectedly complex pattern of enzyme-mediated and chemical reactions.3. Metabolic pathways for both acids were not independent and several of the transformations were reversible, depending on reaction conditions. Formation of M13 occurred either via initial oxidation of the secondary alcohol, or as a downstream process starting from M12.4. The phenol metabolite M32 was produced as part of several pathways. Control experiments at various pH values and in the absence of metabolising enzymes support the conclusion that its formation resulted from chemical degradation rather than from metabolic processes.

Ponesimod protects against neuronal death by suppressing the activation of A1 astrocytes in early brain injury after experimental subarachnoid hemorrhage.

As an important initiator and responder of brain inflammation in the central nervous system (CNS), astrocytes transform into two new reactive phenotypes with changed morphology, altered gene expression and secretion profiles, termed detrimental A1 and beneficial A2. Inflammatory events have been shown to occur during the phase of early brain injury (EBI) after subarachnoid hemorrhage (SAH). However, the phenotype transformation of astrocytes as well as its potential contribution to inflammatory status in the EBI of SAH has yet to be determined. In the present study, both in vivo and in vitro models of SAH were established, and the polarization of astrocytes after SAH was analyzed by RNA-seq, western blotting, and immunofluorescence staining. The effect of astrocytic phenotype transformation on neuroinflammation was examined by real-time quantitative PCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA). We demonstrated that astrocytes were transformed into A1 astrocytes and caused neuronal death through the release of pro-inflammatory factors in EBI after SAH. Importantly, Ponesimod, an S1PR1 specific modulator, exerted neuroprotective effects through the prevention of astrocytic polarization to the A1 phenotype as proved by immunofluorescence, neurological tests, and TUNEL study. We also revealed the role of Ponesimod in modulating astrocytic response was mediated by the signal transducer and activator of transcription 3 (STAT3) signaling. Our study suggested that Ponesimod may be a promising therapeutic target for the treatment of brain injury following SAH.

Emerging systemic drugs in the treatment of plaque psoriasis.

INTRODUCTION: Psoriasis is a common, chronic inflammatory skin condition that affects 2-3% of the US population and represents a large psychosocial burden for patients. Over the last decade, highly effective targeted therapies for psoriasis have been developed - namely, those targeting interleukin (IL)-17 and IL-23. The success of biologic agents targeting IL-17 and IL-23 underscores the importance of the IL-23/T helper (Th)17 cell axis in psoriasis pathogenesis. Oral small molecule drugs - such as Janus kinase (JAK) inhibitors, tyrosine kinase 2 (TYK2) inhibitors, and fumaric acid esters (FAEs) - are also being investigated for the treatment of psoriasis. AREAS COVERED: This article reviews systemic biologic and oral small molecule drugs currently undergoing clinical trials for the treatment of plaque psoriasis. EXPERT OPINION: Many patients with psoriasis have mild disease, and many with mild disease do not seek medical care for their condition. Many patients with mild disease could be adequately treated with topical treatments and phototherapy; however, adherence and feasibility have often been an issue with these treatment types. There seems to be limited room for development of novel biologics, as the existing ones are extraordinarily safe, effective, and convenient with few injections. Patients would prefer a safe, effective oral treatment; however, JAK inhibitors seem unlikely to fill this role completely.

Ponesimod, a selective sphingosine 1-phosphate (S1P1) receptor modulator for autoimmune diseases: review of clinical pharmacokinetics and drug disposition.

1. Ponesimod, a selective sphingosine 1-phosphate (S1P1) receptor modulator, is undergoing clinical development for the treatment of autoimmune diseases (multiple sclerosis/psoriasis). 2. Published literature data describing pharmacokinetic disposition of ponesimod were collected, reviewed and tabulated. 3. Across various clinical phase-I studies, ponesimod displayed consistent pharmacokinetics - relatively faster absorption peak time (approximately 2.5 h), elimination half-life of approximately 30 h and modest accumulation (2- to 2.6-fold). Ponesimod was extensively metabolized and two major metabolites were ACT-204426 and ACT-338375. 4. Extensive population pharmacokinetic-pharmacodynamic modeling has confirmed the therapeutic dose(s) for ponesimod to achieve the balance between safety (primarily heart rate) and efficacy using the maximum inhibition of the total lymphocytes as the pharmacodynamic marker. 5. None of the covariates (ethnicity, body weight, sex, diseased state including multiple sclerosis and psoriasis, food intake, formulation, etc.) examined in population pharmacokinetic model influenced the pharmacokinetics of ponesimod from a clinical relevance perspective. However, hepatic impairment (moderate/severe but not mild), profoundly influenced its disposition; and therefore, would necessitate dosage adjustment of ponesimod in clinical therapy. 6. Ponesimod has a favorable safety profile and pharmacokinetics, which will allow maximizing its ability to inhibit circulating lymphocytes in a given dosing regimen for treating autoimmune diseases.

Mass balance, pharmacokinetics and metabolism of the selective S1P1 receptor modulator ponesimod in humans.

1. Ponesimod [(R)-5-[3-chloro-4-(-2,3-dihydroxy-propoxy)-benzylidene]-2-propylimino-3-o-tolyl-thiazolidin-4-one] is an orally administered, selective S1P1 receptor modulator that blocks the egress of lymphocytes from lymphoid organs and reduces the availability of circulating effector T/B-cells. 2. The mass balance, pharmacokinetics and metabolism of 40 mg (14)C-ponesimod were investigated in six healthy male subjects. The total radioactivity in whole blood, plasma, urine, faeces and expired CO2 was determined by liquid scintillation counting. Metabolite profiling was performed by high-performance liquid chromatography and detection by mass spectrometry. 3. The majority of the radioactivity (% of administered dose) was recovered in faeces (57.3-79.6%), followed by urine (10.3-18.4%) and a small proportion in CO2 from expired air (0.6-1.9%). The average cumulative recovery (mass balance) of (14)C-associated radioactivity in faeces and urine was 77.9% of the administered dose. Unchanged ponesimod made up 25.9% of total radioactivity in faeces; none was detected in urine. Ponesimod was extensively metabolised and two pharmacologically inactive metabolites, M12 (ACT-204426) and M13 (ACT-338375), were detected in the circulation. M12 corresponded to 8.1% and M13 to 25.7% of the total drug-related radioactive exposure (AUC0-∞) in plasma. M12 was highly abundant in faeces (22.3% of total radioactivity) and to a smaller extent in urine (2.5% of total radioactivity).

Efficacy and Safety of Ponesimod Compared with Teriflunomide in Female Patients with Relapsing Multiple Sclerosis: Findings from the Pivotal OPTIMUM Study.

Background: Multiple sclerosis (MS) is threefold more prevalent in women than men. However, sex-specific efficacy analysis for MS disease-modifying therapies is not typically performed. Methods: Post hoc analyses of data from female patients enrolled in the phase 3, double-blind OPTIMUM study of relapsing MS were carried out. Eligible adults were randomized to ponesimod 20 mg or teriflunomide 14 mg once daily for up to 108 weeks. The primary endpoint was annualized relapse rate (ARR); secondary endpoints included change in symptom domain of Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) at week 108, number of combined unique active lesions (CUALs) per year on magnetic resonance imaging, and time to 12- and 24-week confirmed disability accumulation (CDA). Results: A total of 735 female patients (581 of childbearing potential) were randomized to ponesimod (n = 363, 49.4%) or teriflunomide (n = 372, 50.6%). Relative risk reduction in the ARR for ponesimod versus teriflunomide was 33.1% (mean, 0.192 vs. 0.286, respectively; p < 0.002). Mean difference in FSIQ-RMS for ponesimod versus teriflunomide was -4.34 (0.12 vs. 4.46; p = 0.002); rate ratio in CUALs per year, 0.601 (1.45 vs. 2.41; p < 0.0001), and hazard ratio for time to 12- and 24-week CDA risk estimates, 0.83 (10.7% vs. 12.9%; p = 0.38) and 0.91 (8.8% vs. 9.7%; p = 0.69), respectively. Incidence of treatment-emergent adverse events was similar between treatment groups (89.0% and 90.1%). Conclusions: Analyses demonstrate the efficacy and safety of ponesimod, versus active comparator, for women with relapsing MS, supporting data-informed decision-making for women with MS. Clinical Trial Registration Number: NCT02425644.

Comparative effectiveness and safety of ozanimod versus other oral DMTs in relapsing-remitting multiple sclerosis: a synthesis of matching-adjusted indirect comparisons.

Background: Several oral disease-modifying therapies (DMTs) have been approved by the Food and Drug Administration for the treatment of relapsing-remitting multiple sclerosis (RRMS). In the absence of head-to-head randomized data, matching-adjusted indirect comparisons (MAICs) can evaluate the comparative effectiveness and safety of ozanimod versus other oral DMTs in RRMS. Objectives: To synthesize results from the published MAICs of ozanimod and other oral DMTs for 2-year outcomes in RRMS. Methods: Published MAICs involving ozanimod for the treatment of RRMS were identified. Extracted data elements included efficacy [annualized relapse rate (ARR), confirmed disability progression (CDP), and brain volume loss] and safety [adverse events (AEs), serious AEs (SAEs), AEs leading to discontinuation, and infection] outcomes. Results: The four MAIC studies identified compared ozanimod with fingolimod, teriflunomide, dimethyl fumarate (DMF), and ponesimod. All comparisons were adjusted for differences in age, sex, relapses within the previous year, Expanded Disability Status Scale score, and percentage of patients with prior DMTs. Outcomes at 2 years were analyzed based on comparisons that lacked a common comparator arm. Ozanimod was associated with significantly lower ARR versus teriflunomide [ARR ratio (95% CI) 0.73 (0.62, 0.84) and DMF 0.80 (0.67, 0.97)], with no significant difference versus fingolimod or ponesimod. The proportions of patients treated with ozanimod or fingolimod had similar 3- and 6-month CDP. Compared with teriflunomide and DMF, ozanimod was associated with a significantly lower risk of 3-month CDP; 6-month CDP was comparable. Ozanimod was associated with significantly lower rates of any AE and AEs leading to discontinuation compared with the other oral DMTs evaluated. Ozanimod also had significantly lower rates of SAEs versus teriflunomide and DMF and lower rates of reported infection outcomes versus fingolimod and ponesimod. Conclusion: Compared with the other oral DMTs evaluated in MAICs, ozanimod was associated with a favorable safety profile and improved or comparable efficacy outcomes.

An indirect comparison of ozanimod vs other oral treatments in relapsing-remitting multiple sclerosis The many treatment options available for relapsing-remitting multiple sclerosis (RRMS) make treatment decisions difficult. While direct head-to-head treatment comparisons provide useful information, these studies are not available for every pair of treatments. Indirect comparisons of published study results can help fill that evidence gap. A technique called matching-adjusted indirect comparison (MAIC) offers a statistically robust way to compare safety/efficacy outcomes from different studies by accounting for important differences across the studies. We collected data from four MAIC studies that compared 2-year treatment outcomes in patients treated with ozanimod versus those treated with fingolimod, teriflunomide, dimethyl fumarate (DMF), or ponesimod. Each study accounted for differences in age, sex, relapses within the previous year, disability status, and previous therapy use. We found ozanimod was either better than or similar to other treatments based on the outcomes measured. The annual rate of RRMS relapse was lower for patients treated with ozanimod than for patients treated with teriflunomide or DMF and similar for patients treated with ponesimod or fingolimod. Ozanimod-treated patients saw their RRMS progress at rates similar to those treated with fingolimod at 3 and 6 months and teriflunomide and DMF at 6 months; RRMS was more likely to progress at 3 months in patients treated with teriflunomide and DMF versus those treated with ozanimod. Our analyses also found that patients treated with ozanimod had lower rates of side effects, including those serious enough to cause treatment discontinuation, compared with patients receiving other treatments. By comparing findings from existing MAIC studies, we found that patients with RRMS treated with ozanimod had fewer side effects and better or similar efficacy outcomes compared with patients who received other treatments for RRMS. These findings can potentially inform treatment decisions for patients with RRMS.

Ponesimod-Associated Macular Edema: Onset and Resolution.

Purpose: To present a patient with cystoid macular edema (CME) associated with ponesimod use and offer suggestions for the management of this condition. Methods: A case report is presented. Results: A 75-year-old woman with relapsing-remitting multiple sclerosis had an unremarkable baseline ophthalmic examination prior to starting ponesimod. At her 9-month follow-up, an examination showed the development of CME in the left eye. The patient's macular edema fully resolved after transitioning off ponesimod to an alternative systemic medication and starting treatment with a topical corticosteroid and nonsteroidal anti-inflammatory drug. Conclusions: To our knowledge, this is the first case report discussing the entity and management of ponesimod-associated macular edema. Ponesimod cessation and concomitant topical therapy can result in successful resolution of macular edema.

Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study.

AIMS: This study investigated the tolerability, safety, pharmacokinetics and pharmacodynamics of ponesimod, a novel oral selective sphingosine-1-phosphate (S1P1) receptor modulator in development for the treatment of auto-immune diseases. METHODS: This was a double-blind, placebo-controlled, ascending, single-dose study. Healthy male subjects received doses of 1-75 mg or placebo control. RESULTS: Ponesimod was well tolerated. Starting with a dose of 8 mg, transient asymptomatic reductions in heart rate were observed. Ponesimod pharmacokinetics were dose proportional. The median time to maximal concentration ranged from 2.0 to 4.0 h, and ponesimod was eliminated with a mean half-life varying between 21.7 and 33.4 h. Food had a minimal effect on ponesimod pharmacokinetics. Doses of ≥8 mg reduced total lymphocyte count in a dose-dependent manner. Lymphocyte counts returned to normal ranges within 96 h. A pharmacokinetic/pharmacodynamic model was developed that adequately described the observed effects of ponesimod on total lymphocyte counts. CONCLUSIONS: Single doses of ponesimod up to and including 75 mg were well tolerated. The results of this ascending single-dose study indicate an immunomodulator potential for ponesimod and a pharmacokinetic/pharmacodynamic profile consistent with once-a-day dosing.

Comparative efficacy and safety of ozanimod and ponesimod for relapsing multiple sclerosis: A matching-adjusted indirect comparison.

BACKGROUND: Ozanimod and ponesimod are sphingosine 1-phosphate receptor modulators approved by the U.S. Food and Drug Administration for treatment of relapsing forms of multiple sclerosis (MS). Given that no head-to-head trials have assessed these two treatments, we performed a matching-adjusted indirect comparison (MAIC) to compare efficacy and safety outcomes between ozanimod and ponesimod for MS. METHODS: A MAIC compared efficacy and safety of ozanimod and ponesimod at 2 years. Outcomes included annualized relapse rate (ARR) and percentage change from baseline in brain volume loss (BVL) as well as rates of any treatment-emergent adverse events (TEAEs), serious adverse events (AEs), AEs leading to discontinuation, and other safety outcomes. Individual patient-level data were obtained for ozanimod from the RADIANCE-B trial, while aggregate-level patient data were obtained for ponesimod from the OPTIMUM trial. The MAIC was not anchored owing to lack of a common comparator across the two trials. The following characteristics were matched between the trials' populations: age, sex, time since MS symptom onset, relapses in prior year, Expanded Disability Status Scale score, disease-modifying therapies received in the prior 2 years, absence of gadolinium-enhancing T1 lesions, and percentage of patients from Eastern Europe. RESULTS: After matching, key baseline characteristics were balanced between patients receiving ozanimod and ponesimod. Compared with ponesimod, ozanimod had a numerically lower ARR (rate ratio: 0.80 [95% CI: 0.57, 1.10]) and was associated with a significant reduction in BVL (% change difference: 0.20 [95% CI: 0.05, 0.36]). Additionally, ozanimod was associated with a significantly lower risk of TEAEs (risk difference: -11.9% [95% CI: -16.8%, -7.0%]), AEs leading to discontinuation (-6.1% [95% CI: -8.9%, -3.4%]), and lymphocyte count <0.2 K/µL (-2.3% [95% CI: -4.2%, -0.5%]). There were no statistically significant differences in the other safety outcomes. CONCLUSION: The MAIC results suggest that, compared with ponesimod, ozanimod is more effective in preserving brain volume, is comparable in terms of reducing relapse rates, and has a favorable safety profile.

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

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.

The S1P receptor 1 antagonist Ponesimod reduces TLR4-induced neuroinflammation and increases Aß clearance in 5XFAD mice.

BACKGROUND: Previously, we showed that the sphingosine-1-phosphate (S1P) transporter spinster 2 (Spns2) mediates activation of microglia in response to amyloid ß peptide (Aß). Here, we investigated if Ponesimod, a functional S1P receptor 1 (S1PR1) antagonist, prevents Aß-induced activation of glial cells and Alzheimer's disease (AD) pathology. METHODS: We used primary cultures of glial cells and the 5XFAD mouse model to determine the effect of Aß and Ponesimod on glial activation, Aß phagocytosis, cytokine levels and pro-inflammatory signaling pathways, AD pathology, and cognitive performance. FINDINGS: Aß42 increased the levels of TLR4 and S1PR1, leading to their complex formation. Ponesimod prevented the increase in TLR4 and S1PR1 levels, as well as the formation of their complex. It also reduced the activation of the pro-inflammatory Stat1 and p38 MAPK signaling pathways, while activating the anti-inflammatory Stat6 pathway. This was consistent with increased phagocytosis of Aß42 in primary cultured microglia. In 5XFAD mice, Ponesimod decreased the levels of TNF-α and CXCL10, which activate TLR4 and Stat1. It also increased the level of IL-33, an anti-inflammatory cytokine that promotes Aß42 phagocytosis by microglia. As a result of these changes, Ponesimod decreased the number of Iba-1+ microglia and GFAP+ astrocytes, and the size and number of amyloid plaques, while improving spatial memory as measured in a Y-maze test. INTERPRETATION: Ponesimod targeting S1PR1 is a promising therapeutic approach to reprogram microglia, reduce neuroinflammation, and increase Aß clearance in AD. FUNDING: NIHR01AG064234, RF1AG078338, R21AG078601, VAI01BX003643.

The impact of sphingosine-1-phosphate receptor modulators on COVID-19 and SARS-CoV-2 vaccination.

BACKGROUND: Sphingosine-one phosphate receptor (S1PR) modulation inhibits S1PR1-mediated lymphocyte migration, lesion formation and positively-impacts on active multiple sclerosis (MS). These S1PR modulatory drugs have different: European Union use restrictions, pharmacokinetics, metabolic profiles and S1PR receptor affinities that may impact MS-management. Importantly, these confer useful properties in dealing with COVID-19, anti-viral drug responses and generating SARS-CoV-2 vaccine responses. OBJECTIVE: To examine the biology and emerging data that potentially underpins immunity to the SARS-CoV-2 virus following natural infection and vaccination and determine how this impinges on the use of current sphingosine-one-phosphate modulators used in the treatment of MS. METHODS: A literature review was performed, and data on infection, vaccination responses; S1PR distribution and functional activity was extracted from regulatory and academic information within the public domain. OBSERVATIONS: Most COVID-19 related information relates to the use of fingolimod. This indicates that continuous S1PR1, S1PR3, S1PR4 and S1PR5 modulation is not associated with a worse prognosis following SARS-CoV-2 infection. Whilst fingolimod use is associated with blunted seroconversion and reduced peripheral T-cell vaccine responses, it appears that people on siponimod, ozanimod and ponesimod exhibit stronger vaccine-responses, which could be related notably to a limited impact on S1PR4 activity. Whilst it is thought that S1PR3 controls B cell function in addition to actions by S1PR1 and S1PR2, this may be species-related effect in rodents that is not yet substantiated in humans, as seen with bradycardia issues. Blunted antibody responses can be related to actions on B and T-cell subsets, germinal centre function and innate-immune biology. Although S1P1R-related functions are seeming central to control of MS and the generation of a fully functional vaccination response; the relative lack of influence on S1PR4-mediated actions on dendritic cells may increase the rate of vaccine-induced seroconversion with the newer generation of S1PR modulators and improve the risk-benefit balance IMPLICATIONS: Although fingolimod is a useful asset in controlling MS, recently-approved S1PR modulators may have beneficial biology related to pharmacokinetics, metabolism and more-restricted targeting that make it easier to generate infection-control and effective anti-viral responses to SARS-COV-2 and other pathogens. Further studies are warranted.

Sphingosine-1 Phosphate Receptor Modulators Increase In Vitro Melanoma Cell Line Proliferation at Therapeutic Doses Used in Patients with Multiple Sclerosis.

INTRODUCTION: S1P1 receptor modulators (S1P1-RM) are oral disease-modifying therapies (DMTs) for multiple sclerosis (MS). Several authorities have raised doubts that S1P1-RM are responsible for an increased risk of melanoma in patients with MS. We studied the in vitro effects of S1P1-RM on different melanoma cell lines to compare the effect of available S1P1-RM on the proliferation of human melanoma cells. METHODS: Four S1P1-RM were studied which are currently approved for managing MS, namely fingolimod (Gilenya®), siponimod (Mayzent®), ozanimod (Zeposia®), and ponesimod (Ponvory®). We tested these four drugs at different concentrations, including therapeutic doses (0.5, 1.6, 5.5, 18, and 60 µM), on human melanoma cell lines (501Mel cells, 1205LU cells, and M249R cells) to analyze in vitro cell proliferation monitored with the IncuCyte ZOOM live cell microscope (Essen Bioscience). RESULTS: At therapeutic doses, median confluence increased overall for all lineages: + 122% for ozanimod (p < 0.001), + 71% for ponesimod (p < 0.001), + 67% for siponimod (NS), and + 41% for fingolimod (p = 0.094). Ozanimod- and ponesimod-treated cells increased confluency in 501Mel, 1205LU, and M249R cell lines (p < 0.001). CONCLUSION: These data suggest an increased proliferation of various melanoma cell lines with S1P1-RM treatments used at therapeutic concentrations for patients with MS and should raise the question of increased dermatologic surveillance.

FTY720 requires vitamin B12-TCN2-CD320 signaling in astrocytes to reduce disease in an animal model of multiple sclerosis.

Vitamin B12 (B12) deficiency causes neurological manifestations resembling multiple sclerosis (MS); however, a molecular explanation for the similarity is unknown. FTY720 (fingolimod) is a sphingosine 1-phosphate (S1P) receptor modulator and sphingosine analog approved for MS therapy that can functionally antagonize S1P1. Here, we report that FTY720 suppresses neuroinflammation by functionally and physically regulating the B12 pathways. Genetic and pharmacological S1P1 inhibition upregulates a transcobalamin 2 (TCN2)-B12 receptor, CD320, in immediate-early astrocytes (ieAstrocytes; a c-Fos-activated astrocyte subset that tracks with experimental autoimmune encephalomyelitis [EAE] severity). CD320 is also reduced in MS plaques. Deficiency of CD320 or dietary B12 restriction worsens EAE and eliminates FTY720's efficacy while concomitantly downregulating type I interferon signaling. TCN2 functions as a chaperone for FTY720 and sphingosine, whose complex induces astrocytic CD320 internalization, suggesting a delivery mechanism of FTY720/sphingosine via the TCN2-CD320 pathway. Taken together, the B12-TCN2-CD320 pathway is essential for the mechanism of action of FTY720.

Bioavailable central nervous system disease-modifying therapies for multiple sclerosis.

Disease-modifying therapies for relapsing multiple sclerosis reduce relapse rates by suppressing peripheral immune cells but have limited efficacy in progressive forms of the disease where cells in the central nervous system play a critical role. To our knowledge, alemtuzumab, fumarates (dimethyl, diroximel, and monomethyl), glatiramer acetates, interferons, mitoxantrone, natalizumab, ocrelizumab, ofatumumab, and teriflunomide are either limited to the periphery or insufficiently studied to confirm direct central nervous system effects in participants with multiple sclerosis. In contrast, cladribine and sphingosine 1-phosphate receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are central nervous system-penetrant and could have beneficial direct central nervous system properties.

Pivotal Trials in Multiple Sclerosis: Similarities Prove Not to Be Useful.

We present a commentary on the inclusion criteria and outcome measures of the major randomized trials on multiple sclerosis. A qualitative comparison of the characteristics of the enrolled patients is done. The objective is to stimulate a discussion about the need to improve research strategies. The discovery of new drugs studied without personalized criteria does not allow for useful advances in knowledge.

Single-Nucleus RNA-seq of Normal-Appearing Brain Regions in Relapsing-Remitting vs. Secondary Progressive Multiple Sclerosis: Implications for the Efficacy of Fingolimod.

Multiple sclerosis (MS) is an immune-mediated demyelinating disease that alters central nervous system (CNS) functions. Relapsing-remitting MS (RRMS) is the most common form, which can transform into secondary-progressive MS (SPMS) that is associated with progressive neurodegeneration. Single-nucleus RNA sequencing (snRNA-seq) of MS lesions identified disease-related transcriptomic alterations; however, their relationship to non-lesioned MS brain regions has not been reported and which could identify prodromal or other disease susceptibility signatures. Here, snRNA-seq was used to generate high-quality RRMS vs. SPMS datasets of 33,197 nuclei from 8 normal-appearing MS brains, which revealed divergent cell type-specific changes. Notably, SPMS brains downregulated astrocytic sphingosine kinases (SPHK1/2) - the enzymes required to phosphorylate and activate the MS drug, fingolimod. This reduction was modeled with astrocyte-specific Sphk1/2 null mice in which fingolimod lost activity, supporting functionality of observed transcriptomic changes. These data provide an initial resource for studies of single cells from non-lesioned RRMS and SPMS brains.

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

Sphingosine 1-phosphate (S1P) receptors are bioactive lipid metabolites that bind five different types of receptors expressed ubiquitously in human body and mediate a broad range of biological functions. Targeting S1P receptors is nowadays a well-established pharmacological strategy to treat multiple sclerosis (MS). However, the adverse events associated with the ancestor (fingolimod), especially in terms of heart conduction and slow reversibility of its pharmacodynamics effect on lymphocytes, have stimulated a search for a S1P modulator with greater selectivity for S1P1 (the most important immune mechanism to prevent MS-related neuroinflammation). Ponesimod is a second-generation, orally active, directly bioavailable, highly selective, and rapidly reversible modulator of the S1P1 receptor. Gradual 14-day up-titration of ponesimod mitigates its first-dose effects on heart rate and facilitates its use over fingolimod, as it does not require first-dose cardiac monitoring. Ponesimod is rapidly eliminated within 1 week of discontinuation, thereby representing a more manageable approach in case of vaccination, pregnancy, or adverse events. However, the fast reversibility of ponesimod may also raise concerns about the possibility of a rapid reactivation of disease activity following its discontinuation. Ponesimod was recently approved for the treatment of relapsing MS forms on the basis of a Phase III, double-blind, double-dummy, randomized clinical trial (OPTIMUM) that demonstrated the superiority of ponesimod over teriflunomide on disease activity markers, without unexpected safety concerns. This review summarizes the pharmacodynamic and pharmacokinetic characteristics of ponesimod, and the main Phase II and III studies that led to its approval. Comparisons of ponesimod with other S1P receptor modulators currently available for MS (fingolimod, ozanimod, siponimod) are also provided.

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

BACKGROUND: Multiple sclerosis (MS) is an inflammatory autoimmune disorder and the most common cause of non-traumatic disability in young adults. The Phase 3 OPTIMUM study evaluated the efficacy and safety of oral ponesimod, a selective sphingosine-1-phosphate (S1P) receptor 1 modulator, vs. teriflunomide in patients with relapsing multiple sclerosis (RMS). The aim of this analysis was to assess the effect of ponesimod and other disease modifying treatments (DMTs) compared to placebo, as measured by 12-week confirmed disability accumulation (CDA) and annualized relapse rate (ARR) in RMS patients. METHODS: A database was developed by Certara Inc. (USA) based on relevant clinical trials identified from searching the following sources: PubMed, clinicaltrials.gov, FDA and EMEA documents, and conference abstracts. This database consisted of 203 unique randomized controlled trials (RCTs) with 74 MS treatments and was subsequently filtered to include RCTs with more than 25 patients receiving monotherapy to treat RMS for at least 48 weeks. A model-based meta-analysis (MBMA) was performed on the filtered database to assess treatment effects measured by CDA and ARR. Analyzed data for CDA were digitized from published Kaplan-Meier plots. A Weibull distribution was assumed to adequately capture the relationship of CDA probability over time, and hazard ratios (HRs) between treatments were assumed constant over time (proportional hazards). HRs were estimated for 12-week CDA for 17 DMTs vs. placebo. Additionally, mean ARR for each treatment arm was modelled, where relative effect versus placebo was estimated as a fixed effect parameter for each unique drug. A dose-response relationship was included if data for multiple doses were available. Relative treatment effect covariates explored for CDA and ARR included: percent of patients with relapsing-remitting MS (RRMS), trial start year, mean duration of disease, percent of patients who received DMTs within the prior 2 years (pDMT), mean number of relapses in the prior year, mean age, mean baseline EDSS score, and mean treatment duration (for ARR). RESULTS: The 12-week CDA model utilized longitudinal data from 26 RCTs (18 unique treatments [including placebo]), 69 treatment arms, 31,160 patients). The ARR model utilized data from 40 RCTs (18 unique treatments [including placebo], 100 treatment arms, 33,686 patients). Compared to placebo, ponesimod significantly reduced 12-week CDA by 39% (HR: 0.61; 95% CI: 0.45-0.82) and reduced ARR by 53% (rate ratio [RR]: 0.47; 95% CI: 0.39-0.58). Except for three DMTs (interferon ß-1b, glatiramer acetate, ozanimod), HR of 12-week CDA vs. placebo was significantly lower for the DMTs included in this analysis (HR range: 0.41 to 0.79). The ARR was significantly reduced for all DMTs compared to placebo (RR range: 0.29 to 0.82). A dose-response relationship indicated a potential dose-dependent effect (12-week CDA: 6 treatments; ARR: 8 treatments). Relative treatment effect was found to be significantly smaller in trials including more patients with prior DMT usage. Cross-trial heterogeneity in relative effects was assessed and found to be negligible; however, there is a possibility that confounders remain which may impact estimated relative treatment effects. CONCLUSIONS: Compared to placebo, ponesimod 20 mg significantly reduced both the risk of 12-week CDA and mean ARR, suggesting it has robust efficacy in the treatment of RMS. The study was funded by Janssen Research & Development, LLC.