Sphingosine 1-phosphate Receptor Modulator Research Articles

Efficacy and Safety of S1P1 Receptor Modulator Drugs for Patients with Moderate-to-Severe Ulcerative Colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that negatively impacts patients' quality of life. In the last decades, the therapeutic options available for the management of patients with moderate to severe UC have increased significantly, including not only biological drugs but also small molecules. However, there is a persistent need to develop new drugs that act on new targets while minimizing the risk of adverse events. Sphingosine-1-phosphate (S1P) is a membrane-derived lysophospholipid. The S1P gradient between tissues and the circulatory system has a key role in regulating the trafficking of immune cells as autoreactive B and T lymphocytes. S1P receptor modulators could be a safe and efficacious alternative mechanism for reducing inflammation in immune-mediated disorders, including UC, by reducing lymphocyte egress from the lymph nodes to the bloodstream. Several S1P receptor modulators have been developed and tested in UC. Ozanimod is already approved by Food and Drug Administration (FDA) and European Medical Agency (EMA), while etrasimod and VTX002 are still under approval. Oral administration route, rapidity and reliable safety profile are the main advantages of this class of drugs. The aim of this review is to summarize the available evidence for the efficacy, safety, and pharmacokinetics of ozanimod, etrasimod, and VTX002 in UC.

Blocking sphingosine 1-phosphate receptor 1 with modulators reduces immune cells infiltration and alleviates endometriosis in mice

Research questionDo sphingosine 1-phosphate (S1P) modulators have therapeutic effects on endometriosis in mice and, if they do, which receptor is responsible for these effects? DesignA surgically induced endometriosis mouse model was established. In the pilot experiment, lesions were harvested to assess fibrosis and inflammation and determine the optimal concentration of a broad-spectrum S1P modulator, FTY720. Subsequently, FTY720 was compared with a selective S1P receptor 1 modulator, SEW2871 to evaluate their effects on endometriotic lesion growth, fibrosis, inflammation and immune cell infiltration. ResultsThe results demonstrated that both FTY720 and SEW2871, two S1P receptor modulators, effectively inhibited the growth and fibrosis of endometriotic lesions. SEW2871 inhibited inflammation-related cytokine expression, including PTGS-2, IL-1β, TNF-α and TGF-β1, more effectively compared with FTY720. Lymphopaenia was mainly caused by FTY720, whereas SEW2871 had a lesser effect. Both FTY720 and SEW2871 significantly reduced CD45+ cells (P = 0.002 and P = 0.032, respectively) and F4/80+ cells (P < 0.001 and P = 0.004, respectively) infiltration into the lesions, with FTY720 exerting a strong regulatory effect on CD4+ T cells. ConclusionsThis study suggests that S1P receptor 1 could be investigated as a potential novel therapeutic target for endometriosis in the future.

NVX-CoV2373-induced T- and B-cellular immunity in immunosuppressed people with multiple sclerosis that failed to respond to mRNA and viral vector SARS-CoV-2 vaccines.

Immunological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is important, especially in people with multiple sclerosis (pwMS) on immunosuppressive therapies. This study aims to determine whether adjuvanted protein-based vaccine NVX-CoV2373 is able to induce an immune response to SARS-CoV-2 in pwMS with inadequate responses to prior triple mRNA/viral vector vaccination. We conducted a single-center, prospective longitudinal cohort study at the MS Center in Dresden, Germany. In total, 65 participants were included in the study in accordance with the following eligibility criteria: age > 18 years, immunomodulatory treatment, and insufficient T-cellular and humoral response to prior vaccination with at least two doses of SARS-CoV-2 mRNA (BNT162b2, mRNA-1273) or viral vector vaccines (AZD1222, Ad26.COV2.S). Intramuscular vaccination with two doses of NVX-CoV2373 at baseline and 3 weeks of follow-up. The development of SARS-CoV-2-specific antibodies and T-cell responses was evaluated. For the final analysis, data from 47 patients on stable treatment with sphingosine-1-phosphate receptor (S1PR) modulators and 17 on ocrelizumab were available. The tolerability of the NVX-CoV2373 vaccination was overall good and comparable to the one reported for the general population. After the second NVX-CoV2373 vaccination, 59% of S1PR-modulated patients developed antispike IgG antibodies above the predefined cutoff of 200 binding antibody units (BAU)/ml (mean, 1,204.37 [95% CI, 693.15, 2,092.65] BAU/ml), whereas no clinically significant T-cell response was found. In the subgroup of the patients on ocrelizumab treatment, 23.5% developed antispike IgG > 200 BAU/ml (mean, 116.3 [95% CI, 47.04, 287.51] BAU/ml) and 53% showed positive spike-specific T-cellular responses (IFN-gamma release to antigen 1: mean, 0.2 [95% CI, 0.11, 0.31] IU/ml; antigen 2: mean, 0.24 [95% CI, 0.14, 0.37]) after the second vaccination. Vaccination with two doses of NVX-CoV2373 was able to elicit a SARS-CoV-2-specific immune response in pwMS lacking adequate immune responses to previous mRNA/viral vector vaccination. For patients receiving S1PR modulators, an increase in anti-SARS-CoV-2 IgG antibodies was detected after NVX-CoV2373 vaccination, whereas in ocrelizumab-treated patients, the increase of antiviral T-cell responses was more pronounced. Our data may impact clinical decision-making by influencing the preference for NVX-CoV2373 vaccination in pwMS receiving treatment with S1PR modulation or anti-CD20 treatment.

Clinician's Guide to Using Ozanimod for the Treatment of Ulcerative Colitis.

The emergence of advanced therapies [eg, biologics, Janus kinase inhibitors] over the past few decades has revolutionised the treatment of ulcerative colitis. However, the limitations of these therapies leave an unmet need for safer and more effective or convenient treatment options. There is growing interest in the development of novel oral small molecule therapies for the treatment of ulcerative colitis. Ozanimod is an oral small molecule therapy that is approved in the USA, the European Union, and other countries as the first sphingosine 1-phosphate receptor modulator for the treatment of moderately to severely active ulcerative colitis in adults. This review provides guidance for ozanimod use for the treatment of ulcerative colitis, based on the prescribing information, clinical trial and real-world data, and the authors' clinical experiences. This guidance outlines patient characteristics to consider when deciding if ozanimod treatment is suitable and describes how to educate patients on risks and best practices. It also details the nature and frequency of monitoring during treatment, which should be adapted to the individual patient based on pre-existing risk factors and events that possibly occur during treatment. This review also provides insights into the patient characteristics and clinical scenarios best suited for ozanimod treatment, based on its efficacy, safety profile, and risks compared with other therapies.

Effects of baseline age and disease duration on the efficacy and safety of siponimod in patients with active SPMS: Post hoc analyses from the EXPAND study.

Older age and longer disease duration (DD) may impact the effectiveness of disease-modifying therapies in patients with multiple sclerosis (MS). Siponimod is a sphingosine 1-phosphate receptor modulator approved for the treatment of active secondary progressive MS (SPMS) in many countries. The pivotal phase 3 EXPAND study examined siponimod versus placebo in a broad SPMS population with both active and non-active disease. In this population, siponimod demonstrated significant efficacy, including a reduction in the risk of 3-month confirmed disability progression (3mCDP) and 6-month confirmed disability progression (6mCDP). Benefits of siponimod were also observed across age and DD subgroups in the overall EXPAND population. Herein we sought to assess the clinical impact of siponimod across age and disease duration subgroups, specifically in participants with active SPMS. This study is a post hoc analysis of a subgroup of EXPAND participants with active SPMS (≥1 relapse in the 2 years before the study and/or ≥1 T1 gadolinium-enhancing magnetic resonance imaging lesion at baseline) receiving oral siponimod (2mg/day) or placebo during EXPAND. Data were analyzed for participant subgroups stratified by age at baseline (primary cut-off: <45 year ≥45 years; and secondary cut-off: <50 years or ≥50 years) and by DD at baseline (<16 years or ≥16 years). Efficacy endpoints were 3mCDP and 6mCDP. Safety assessments included adverse events (AEs), serious AEs, and AEs leading to treatment discontinuation. Data from 779 participants with active SPMS were analyzed. All age and DD subgroups had 31-38% (3mCDP) and 27-43% (6mCDP) risk reductions with siponimod versus placebo. Compared with placebo, siponimod significantly reduced the risk of 3mCDP in participants aged ≥45 years (hazard ratio [HR]: 0.68; 95% confidence interval [CI]: 0.48-0.97), <50 years (HR: 0.69; 95% CI: 0.49-0.98), ≥50 years (HR: 0.62; 95% CI: 0.40-0.96), and in participants with <16 years DD (HR: 0.68; 95% CI: 0.47-0.98). The risk of 6mCDP was significantly reduced with siponimod versus placebo for participants aged <45 years (HR: 0.60; 95% CI: 0.38-0.96), ≥45 years (HR: 0.67; 95% CI: 0.45-0.99), <50 years (HR: 0.62; 95% CI: 0.43-0.90), and in participants with <16 years DD (HR: 0.57; 95% CI: 0.38-0.87). Increasing age or longer MS duration did not appear to increase the risk of AEs, with an observed safety profile that remained consistent with the overall active SPMS and overall SPMS populations in EXPAND. In participants with active SPMS, treatment with siponimod demonstrated a statistically significant reduction in the risk of 3mCDP and 6mCDP compared with placebo. Although not every outcome reached statistical significance in the subgroup analyses (possibly a consequence of small sample sizes), benefits of siponimod were seen across a spectrum of ages and DD. Siponimod was generally well tolerated by participants with active SPMS, regardless of baseline age and DD, and AE profiles were broadly similar to those observed in the overall EXPAND population.

Efficacy and Safety of Advanced Oral Small Molecules for Inflammatory Bowel Disease: Systematic Review and Meta-Analysis.

Oral small-molecule drugs [SMDs] are expanding the therapeutic landscape for inflammatory bowel disease [IBD]. This systematic review and meta-analysis summarizes the efficacy and safety of JAK inhibitor [JAKi] and sphingosine-1-phosphate [S1P] receptor modulator treatments for ulcerative colitis [UC] and Crohn's disease [CD]. MEDLINE, Embase, and CENTRAL were searched from inception to May 30, 2022. Randomized controlled trials [RCTs] of JAKi and S1P receptor modulators in adults with UC or CD were eligible. Clinical, endoscopic, histological, and safety data were pooled and analysed using a random-effects model. Thirty-five RCTs [26 UC, nine CD] were included. In UC, JAKi therapy was associated with induction of clinical (risk ratio [RR] 3.16, 95% confidence interval [CI] 2.03-4.92; I2 = 65%) and endoscopic [RR 3.99, 95% CI 2.36-6.75; I2 = 36%] remission compared to placebo. Upadacitinib was associated with histological response [RR 2.63, 95% CI 1.97-3.53]. S1P modulator therapy was associated with induction of clinical [RR 2.52, 95% CI 1.88-3.39; I2 = 1%] and endoscopic [RR 2.39, 95% CI 1.07-5.33; I2 = 0%] remission relative to placebo. Ozanimod was superior to placebo for inducing histological remission in UC [RR 2.20, 95% CI 1.43-3.37; I2 = 0%], while etrasimod was not [RR 2.36, 95% CI 0.71-7.88; I2 = 0%]. In CD, JAKi therapy was superior to placebo for induction of clinical remission [RR 1.53, 95% CI 1.19-1.98; I2 = 31%], and endoscopic remission [RR 4.78, 95% CI 1.63-14.06; I2 = 43%] compared to placebo. The risk of serious infections was similar for oral SMDs and placebo. JAKi and S1P receptor modulator therapies are effective in IBD for inducing clinical and endoscopic remission and, in some circumstances, histological response.

Siponimod as a novel inhibitor of retinal angiogenesis: in vitro and in vivo evidence of therapeutic efficacy.

S1P receptors control endothelial cell proliferation, migration, and survival. Evidence of the ability of S1P receptor modulators to influence multiple endothelial cell functions suggests their potential use for antiangiogenic effect. The main purpose of our study was to investigate the potential of siponimod for the inhibition of ocular angiogenesis in vitro and in vivo We investigated the effects of siponimod on the metabolic activity (MTT assay), cell toxicity (LDH release), basal proliferation and growth factor induced proliferation (BrdU assay), and migration (transwell migration assay) of human umbilical vein endothelial cells (HUVEC) and retinal microvascular endothelial cells (HRMEC). The effects of siponimod on HRMEC monolayer integrity, and barrier function under basal conditions and TNF-a induced disruption were assessed using the trans-endothelial electrical resistance (TEER) and FITC-dextran permeability assays. Siponimod's effect on TNF-α induced distribution of barrier proteins in HRMEC was investigated using immunofluorescence. Finally, the effect of siponimod on ocular neovascularization in vivo was assessed using suture-induced corneal neovascularization in albino rabbits. Our results show that siponimod did not affect endothelial cell proliferation or metabolic activity, but significantly inhibited endothelial cell migration, increased HRMEC barrier integrity, and reduced TNF-a induced barrier disruption. Siponimod also protected against TNF-a induced disruption of claudin-5, ZO-1, and VE-cadherin in HRMEC. These actions are mainly mediated by S1PR1 modulation. Finally, siponimod prevented the progression of suture-induced corneal neovascularization in albino rabbits. In conclusion, the effects of siponimod on various processes known to be involved in angiogenesis support its therapeutic potential in disorders associated with ocular neovascularization. Significance Statement Siponimod is an extensively characterized S1P receptor modulator already approved for the treatment of multiple sclerosis. It inhibits retinal endothelial cell migration, potentiates endothelial barrier function, protects against TNF-a induced barrier disruption, and also inhibits suture-induced corneal neovascularization in rabbits. These results support its use for a novel therapeutic indication in the management of ocular neovascular diseases.

The investigation of selective sphingosine-1 phosphate receptor 1&amp;4 modulator to treat alopecia areata mouse model

Abstract Alopecia areata (AA) is a T cell mediated autoimmune disease characterized phenotypically by hair loss. NKG2D +CD8 +T cells is involved in the pathogenesis of AA. Sphingosine-1 phosphate (S1P) is a biologically active metabolite of cell membrane sphingolipids, which is essential for immune cell transport, and is known to be mainly involved in immune and inflammatory reactions. Due to involvement of S1P receptor (S1PR) in the immune system, S1PR modulator is being investigated for application in multiple sclerosis and other conditions. Among the five S1PRs, S1PRs 1&amp;4 modulator (NXC736, Nextgen Bioscience, South Korea) was used to confirm its efficacy in the treatment of AA. AA lesion size measurement, disease-free ratio, immunohistochemistry and flow cytometry were used for analysis method. After oral administration of NXC736 for 84 days to AA mice, it was confirmed that the AA lesion area and disease-free ratio were significantly decreased compared to control group, and the infiltration of CD8 +T cells in the lesion skin was also significantly decreased. In addition, NKG2D level was decreased in effector CD8 +T cells. According to this result, we speculate that S1PR 1&amp;4 modulator can be used as a promising treatment for AA. Supported by Nextgen Bioscience

Lysophospholipid (S1P) receptors in GtoPdb v.2023.1

Sphingosine 1-phosphate (S1P) receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Lysophospholipid receptors [96]) are activated by the endogenous lipid sphingosine 1-phosphate (S1P). Originally cloned as orphan members of the endothelial differentiation gene (edg) family [16, 123], the receptors are currently designated as S1P1R through S1P5R [73, 16, 123]. Their gene nomenclature has been codified as human S1PR1, S1PR2, etc. (HUGO Gene Nomenclature Committee, HGNC) and S1pr1, S1pr2, etc. for mice (Mouse Genome Informatics Database, MGI) to reflect species and receptor function. All S1P receptors (S1PRs) have been knocked-out in mice constitutively and in some cases, conditionally. S1PRs, particularly S1P1, are expressed throughout all mammalian organ systems. Ligand delivery occurs via two known carriers (or "chaperones"): albumin and HDL-bound apolipoprotein M (ApoM), the latter of which elicits biased agonist signaling by S1P1 in multiple cell types [18, 53]. The five S1PRs, two chaperones, and active cellular metabolism have complicated analyses of receptor ligand binding in native systems. Signaling pathways and physiological roles have been characterized through radioligand binding in heterologous expression systems, targeted deletion of the different S1PRs, and most recently, mouse models that report in vivo S1P1R activation [101, 103]. The structures of S1P1 [180, 69, 108, 184], S1P2 [32], S1P3[116, 187], and S1P5 [110, 185] are solved, and confirmed aspects of ligand binding, specificity, and receptor activation, determined previously through biochemical and genetic studies [69, 17]. fingolimod (FTY720), the first FDA-approved drug to target any of the lysophospholipid receptors, binds as a phosphorylated metabolite to four of the five S1PRs, and was the first oral therapy for multiple sclerosis (MS) [35]. Second-generation S1PR modulators siponimod, ozanimod, and ponesimod that target S1P1 and S1P5 are also FDA approved for the treatment of various MS forms [16, 123]. In 2021, ozanimod became the first S1PR modulator to be FDA approved for the treatment of ulcerative colitis [145]. The mechanisms of action of fingolimod and other S1PR-modulating drugs now in development include binding S1PRs in multiple organ systems, e.g., immune and nervous systems, although the precise nature of their receptor interactions requires clarification [141, 37, 63, 64].

Mocravimod, a S1P receptor modulator, increases T cell counts in bone marrow biopsies from patients undergoing allogeneic hematopoietic stem cell transplantation

Graft-versus-leukemia (GvL) effects are critical to prevent relapses after allogeneic hematopoietic cell transplantation (allo-HCT). However, the success of allo-HCT is limited by graft-versus-host disease (GvHD). Both, CD4+ and CD8+ T cells contribute to GvHD and GvL. The sphingosine-1-phosphate receptor (S1PR) signaling plays a crucial role in lymphocyte trafficking. Mocravimod is an S1PR modulator and its administration leads to blocking lymphocyte egress from lymphoid organs. We hypothesized that this applies to the bone marrow (BM) too, and analyzed BM biopsies from the clinical study with mocravimod (phase I trial in allo-HCT patients; NCT01830010) by immunohistochemical staining for CD3, CD4, CD8, TIA1, FoxP3, PD1, T-Bet, GATA3, and ROR-γt to identify and quantify T cell subsets in situ. Allo-HCT patients without receiving mocravimod were used as controls. BM from 9 patients in the mocravimod group and 10 patients in the control group were examined. CD3+ T cells were found to accumulate in the BM of mocravimod-treated patients compared to controls, both on day 30 and 90 post-transplant. The effect was stronger for CD4+ T cells, than CD8+ T cells, which is in line with data from murine studies showing that CD4+ T cells are more sensitive to mocravimod treatment than CD8+ T cells. Clinically-relevant acute GvHD events (grade II-IV) were slightly lower, but comparable to controls when mocravimod was administered. Taken together, data are supportive of mocravimod’s mode of action and bring additional evidence of fewer relapses for allo-HCT patients treated with S1PR modulators.

Herpes Simplex Virus (HSV), Varicella-Zoster Virus (VZV), and Cryptococcal Infections Associated With Sphingosine-1-Phosphate Receptor (S1PR) Modulators: A Review (P12-10.005)

<h3>Objective:</h3> To summarize the existing data on the incidence of herpes simplex virus (HSV), varicella-zoster virus (VZV), and Cryptococcus sp. infections with sphingosine-1-phosphate receptor (S1PR) modulators. <h3>Background:</h3> S1PR modulators are a novel class of disease-modifying therapies for multiple sclerosis (MS) that produce immunosuppression and potential lymphopenia. Herpesvirus and cryptococcal diseases were the most common opportunistic infections in clinical trials. Several post-hoc analyses have subsequently been published with revised incidence rates (IRs) for these conditions. <h3>Design/Methods:</h3> A literature review and descriptive analysis of phase-3 trials (n=6), post-marketing studies (n=8), and case reports (n=17) were conducted using PubMed and Google Scholar. Further data was accessed through Novartis AG, Bristol-Myers Squibb, and Janssen Pharmaceuticals. <h3>Results:</h3> <h3>FINGOLIMOD:</h3> Herpesvirus infection rates were similar between placebo (2.8%) and 0.5 mg (2.1%) but increased with 1.25 mg (5.5%) in the TRANSFORMS study. VZV rates were higher with fingolimod 0.5 mg (3.0%; 11 per 1000 patient-years [PY]) than with placebo (1.0%; 6 per 1000 PY), but comparable post-marketing. Cryptococcal infections (n=74) had an IR of 9 per 100,000 PY, and 13 cases were individually reported. <h3>SIPONIMOD:</h3> VZV reactivation occurred more frequently with siponimod (2%) than with placebo (1%); EXPAND extension analyses calculated an IR of 0.9 for HSV and 1.8 for VZV infections. One case of cryptococcal meningitis (from 7236 PY of exposure) was documented. <h3>OZANIMOD:</h3> An integrated safety analysis reported oral herpes at 1.5%, VZV at 1.4%, and HSV at 0.5% from all clinical trials versus 0.7%, 0.6%, and 0.1% from the phase-3 trials. The IR of herpes zoster was 5.3/1000 PY. <h3>PONESIMOD:</h3> The incidence of herpetic infections was equal between both groups (4.8%) in the OPTIMUM trial. Cryptococcal infections have not yet been reported with ozanimod or ponesimod. <h3>Conclusions:</h3> Overall, the incidence of these opportunistic infections associated with S1PR modulators in MS was low, with favorable outcomes and limited fatalities. <b>Disclosure:</b> Dr. Sharma has nothing to disclose. Mr. JHA has nothing to disclose. Dr. Khanal has nothing to disclose. Dr. Sriwastava has nothing to disclose.

Long-term Safety of Ozanimod in Relapsing Multiple Sclerosis and Moderately to Severely Active Ulcerative Colitis (P7-3.007)

Long-term Safety of Ozanimod in Relapsing Multiple Sclerosis and Moderately to Severely Active Ulcerative Colitis (P7-3.007)

Serologic Response and Clinical Outcomes of SARS-CoV-2 Infection and Vaccination in Ozanimod-Treated Participants With Relapsing Multiple Sclerosis (P2-3.018)

Serologic Response and Clinical Outcomes of SARS-CoV-2 Infection and Vaccination in Ozanimod-Treated Participants With Relapsing Multiple Sclerosis (P2-3.018)

Relationship Between Infections and Absolute Lymphocyte Count During Phase 3 and Open-label Extension Trials of Ozanimod in Patients With Relapsing Multiple Sclerosis (P7-3.002)

Relationship Between Infections and Absolute Lymphocyte Count During Phase 3 and Open-label Extension Trials of Ozanimod in Patients With Relapsing Multiple Sclerosis (P7-3.002)

Review article: Risk of cardiovascular events in patients with inflammatory bowel disease receiving small molecule drugs.

In the context of an ageing inflammatory bowel disease (IBD) population, cardiovascular comorbidities become particularly relevant. Novel small molecule drugs (SMDs) for the treatment of moderate-to-severe IBD have been recently approved, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor (S1P) modulators. Data from rheumatoid arthritis population have raised concerns about the risk of cardiovascular events with the use of tofacitinib, which was extrapolated to other immune-mediated diseases and other JAK inhibitors. S1P receptor modulation has been associated with potential cardiovascular events, especially bradycardia and cardiac conduction abnormalities. To review the incidence of cardiovascular events with the use of SMDs in patients with IBD and to provide practical recommendations on mitigation strategies. Published literature was reviewed; recommendations were synthesised by experts in both cardiovascular diseases and IBD. Evidence from the IBD population does not indicate a higher risk of cardiovascular events with tofacitinib and other JAK inhibitors. The risk is higher in patients with intermediate to high cardiovascular risk. S1P modulators may be associated with a dose-dependent, first-dose effect, transient risk of conduction abnormalities (bradycardia and AV block). Screening and monitoring of cardiovascular risk factors should be done in all patients with IBD. Risk stratification for cardiovascular disease should be performed before starting treatment with SMDs. Available evidence of both JAK inhibitors and S1P modulators indicates a reassuring safety profile of SMDs from the cardiovascular perspective in the overall IBD population. Efforts should be made to identify patients with IBD at a higher risk of cardiovascular events.

Repurposing drugs against Alzheimer's disease: can the anti-multiple sclerosis drug fingolimod (FTY720) effectively tackle inflammation processes in AD?

Therapeutic approaches providing effective medication for Alzheimer's disease (AD) patients after disease onset are urgently needed. Previous studies in AD mouse models and in humans suggested that physical exercise or changed lifestyle can delay AD-related synaptic and memory dysfunctions when treatment started in juvenile animals or in elderly humans before onset of disease symptoms. However, a pharmacological treatment that can reverse memory deficits in AD patients was thus far not identified. Importantly, AD disease-related dysfunctions have increasingly been associated with neuro-inflammatory mechanisms and searching for anti-inflammatory medication to treat AD seems promising. Like for other diseases, repurposing of FDA-approved drugs for treatment of AD is an ideally suited strategy to reduce the time to bring such medication into clinical practice. Of note, the sphingosine-1-phosphate analogue fingolimod (FTY720) was FDA-approved in 2010 for treatment of multiple sclerosis patients. It binds to the five different isoforms of Sphingosine-1-phosphate receptors (S1PRs) that are widely distributed across human organs. Interestingly, recent studies in five different mouse models of AD suggest that FTY720 treatment, even when starting after onset of AD symptoms, can reverse synaptic deficits and memory dysfunction in these AD mouse models. Furthermore, a very recent multi-omics study identified mutations in the sphingosine/ceramide pathway as a risk factor for sporadic AD, suggesting S1PRs as promising drug target in AD patients. Therefore, progressing with FDA-approved S1PR modulators into human clinical trials might pave the way for these potential disease modifying anti-AD drugs.

PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSIS OF AMISELIMOD, A SELECTIVE SPHINGOSINE 1-PHOSPHATE RECEPTOR MODULATOR, IN HEALTHY SUBJECTS: RESULTS FROM A PHASE 1 STUDY

Amiselimod is a selective sphingosine 1-phosphate receptor modulator in development for inflammatory bowel disease. It is converted to its active metabolite, amiselimod phosphate (amiselimod-P), and has a long half-life and slow accumulation to steady state. We evaluated a multiple-dose titration regimen to determine the plasma pharmacokinetic (PK) profile of amiselimod and amiselimod-P at steady state for the 0.4 mg QD therapeutic dose on day 13 and for the 0.8 mg QD supratherapeutic dose on day 26. We also investigated the pharmacodynamic (PD) effect of amiselimod on absolute lymphocyte counts (ALCs).

Fingolimod Administration Following Hypoxia Induced Neonatal Seizure Can Restore Impaired Long-term Potentiation and Memory Performance in Adult Rats

Neonatal seizures commonly caused by hypoxia can lead to long-term neurological outcomes. Early inflammation plays an important role in the pathology of these outcomes. Therefore, in the current study, we explored the long-term effects of Fingolimod (FTY720), an analog of sphingosine and potent sphingosine 1-phosphate (S1P) receptors modulator, as an anti-inflammatory and neuroprotective agent in attenuating anxiety, memory impairment, and possible alterations in gene expression of hippocampal inhibitory and excitatory receptors following hypoxia-induced neonatal seizure (HINS). Seizure was induced in 24 male and female pups (6 in each experimental group) at postnatal day 10 (P10) by premixed gas (5% oxygen/ 95% nitrogen) in a hypoxic chamber for 15 minutes. Sixty minutes after the onset of hypoxia, FTY720 (0.3 mg/kg) or saline (100 µl) was administered for 12 days (from P10 up to P21). Anxiety-like behavior and hippocampal memory function were assessed at P90 by elevated plus maze (EPM) and novel object recognition (NOR), respectively. Long-term potentiation (LTP) was recorded from hippocampal dentate gyrus region (DG) following stimulation of perforant pathway (PP). In addition, the hippocampal concentration of superoxide dismutase activity (SOD), malondialdehyde (MDA), and thiol as indices of oxidative stress were evaluated. Finally, the gene expression of NR2A subunit of N-Methyl-D-aspartic acid (NMDA) receptor, GluR2 subunit of (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) AMPA receptor and γ2 subunit of γ-Aminobutyric acid (GABAA) receptor were assessed at P90 by the quantitative real-time PCR. FTY720 significantly reduced later-life anxiety-like behavior, ameliorated object recognition memory and increased the amplitude and slope of the field excitatory postsynaptic potential (fEPSP) in the rats following HINS. These effects were associated with restoration of the hippocampal thiol content to the normal values and the regulatory role of FTY720 in the expression of hippocampal GABA and glutamate receptors subunits. In conclusion, FTY720 could restore the dysregulated gene expression of excitatory and inhibitory receptors. It also increased the reduced hippocampal thiol content, which was accompanied with attenuation of HINS-induced anxiety, reduced the impaired hippocampal related memory, and prevented hippocampal LTP deficits in later life following HINS.

Targeted Small Molecules for Systemic Lupus Erythematosus: Drugs in the Pipeline.

Despite the uncertainty of the pathogenesis of systemic lupus erythematosus, novel small molecules targeting specific intracellular mechanisms of immune cells are being developed to reverse the pathophysiological processes. These targeted molecules have the advantages of convenient administration, lower production costs, and the lack of immunogenicity. The Janus kinases, Bruton's tyrosine kinases, and spleen tyrosine kinases are important enzymes for activating downstream signals from various receptors on immune cells that include cytokines, growth factor, hormones, Fc, CD40, and B-cell receptors. Suppression of these kinases impairs cellular activation, differentiation, and survival, leading to diminished cytokine actions and autoantibody secretion. Intracellular protein degradation by immunoproteasomes, levered by the cereblon E3 ubiquitin ligase complex, is an essential process for the regulation of cellular functions and survival. Modulation of the immunoproteasomes and cereblon leads to depletion of long-lived plasma cells, reduced plasmablast differentiation, and production of autoantibodies and interferon-α. The sphingosine 1-phosphate/sphingosine 1-phosphate receptor-1 pathway is responsible for lymphocyte trafficking, regulatory T-cell/Th17 cell homeostasis, and vascular permeability. Sphingosine 1-phosphate receptor-1 modulators limit the trafficking of autoreactive lymphocytes across the blood-brain barrier, increase regulatory T-cell function, and decrease production of autoantibodies and type I interferons. This article summarizes the development of these targeted small molecules in the treatment of systemic lupus erythematosus, and the future prospect for precision medicine.

Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies

Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. Arena Pharmaceuticals.