Ozanimod in Patients With Moderate to Severe Ulcerative Colitis Naive to Advanced Therapies.

BACKGROUND & AIMS: The pivotal phase 3 True North (TN) study demonstrated the efficacy and safety of ozanimod in patients with moderately to severely active ulcerative colitis. This analysis assessed ozanimod during TN and the ongoing open-label extension (OLE) in patients with active disease who were naive to advanced therapies (ATs). METHODS: TN was a randomized, double-blind, placebo-controlled trial consisting of 10-week induction period and 42-week maintenance period. Eligible patients could enter the OLE. Symptomatic efficacy was evaluated from induction through the OLE. Clinical, endoscopic, and mucosal outcomes were evaluated at the end of induction (Week [W] 10) and maintenance (W52) and at predefined OLE timepoints (OLE W46 and W94). Safety during TN was reported. RESULTS: This analysis included 616 AT-naive patients. Numerically greater proportions of patients receiving ozanimod than placebo achieved symptomatic response (39% vs 29%, 95% confidence interval, -0.1 to 18.8) by W2, with significant differences (56% vs 39%, 95% confidence interval, 6.3-26.3) achieved by W4. Patients receiving ozanimod showed significant improvements across efficacy outcomes versus placebo at W10 and W52 (P < .05, all endpoints). In patients on continuous ozanimod who entered the OLE in clinical response at W52, 91% maintained clinical response through OLE W94, and 74% achieved endoscopic improvement and 57% achieved mucosal healing at OLE W94. In ozanimod-treated patients without clinical response by W10 who received extended induction in the OLE, 62% achieved symptomatic response by OLE W10. Safety outcomes in AT-naive patients were consistent with the total TN population. CONCLUSIONS: Ozanimod is an effective, durable, and well-tolerated oral therapy for AT-naive ulcerative colitis patients. CLINICALTRIALS: gov, numbers NCT02435992 and NCT02531126.

Real World Clinical Effectiveness and Safety of Ozanimod in the Treatment of Ulcerative Colitis: 1-Year Follow-Up from a Tertiary Center.

BACKGROUND: Ozanimod is a first-in-class Sphingosine-1-phosphate (S1P) receptor modulator approved for the treatment of moderately to severely active ulcerative colitis (UC). Real world data describing use of ozanimod are limited. AIM: To provide 1-year follow-up results of our UC patient cohort treated with ozanimod. METHODS: This prospective, observational cohort study includes consecutive patients who initiated ozanimod at the University of Chicago IBD Center between 5/2021 and 12/2022. We collected demographic, clinical, and laboratory data. Clinical disease activity was prospectively assessed using the Simple Clinical Colitis Activity Index. RESULTS: Forty-five patients with UC initiated ozanimod therapy and were included in the effectiveness analysis. The median age was 35 years (interquartile range (IQR) 28-52), median disease duration of 6 years (IQR 3-13), 26 (58%) were male, 23 (51%) had extensive colitis, 34 (76%) had previous advanced therapy exposure. Thirty-four patients had clinically active UC at the time of ozanimod initiation; week 10 clinical response and remission rates were 58% and 53%, respectively. By week 52, the rates were 25% for both clinical response and remission. In the 12 (39%) patients with a > 75% reduction in absolute lymphocyte count, numerically greater induction clinical response and remission rates were observed (80% vs 54%, p = 0.4 and 75% vs 53%, p = 0.4, respectively). There were no episodes of symptomatic bradycardia and no other new safety signals. CONCLUSION: Ozanimod effectively induced clinical response and remission patients with largely treatment refractory UC, however, had modest long-term effectiveness. The safety profile was favorable with no new signals.

Therapeutic Drug Monitoring for Biologic and Small-Molecule Therapies for Inflammatory Bowel Disease.

Background: Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, necessitates long-term medical therapy to manage symptoms and prevent complications. Therapeutic drug monitoring (TDM) has emerged as a strategy to optimize treatment efficacy, particularly with anti-tumour necrosis factor (anti-TNF) alpha drugs. This review explores the role of TDM for non-anti-TNF advanced therapies in IBD, focusing on vedolizumab, ustekinumab, tofacitinib, upadacitinib, risankizumab and ozanimod. Methods: The literature search, conducted through OVID (Medline) and PubMed, delves into proactive versus reactive TDM, timing of monitoring and methods for measuring drug levels and anti-drug antibodies. Results: While ustekinumab and vedolizumab exhibit exposure-response relationships, consensus on target levels and the role of TDM adjustments remains elusive. Limited data on risankizumab suggest a dose-dependent response, while for small molecule therapies (janus kinase inhibitors and ozanimod), the absence of real-world data and commercially available TDM tools pose challenges. Conclusion: At present, with the available data, there is a limited role for TDM in non-anti-TNF biologic and small-molecule therapies. This review underscores the need for further research to delineate the utility of TDM in guiding treatment decisions for these agents.

Ozanimod differentially preserves human cerebrovascular endothelial barrier proteins and attenuates matrix metalloproteinase-9 activity following in vitro acute ischemic injury.

Endothelial integrity is critical in mitigating a vicious cascade of secondary injuries following acute ischemic stroke (AIS). Matrix metalloproteinase-9 (MMP-9), a contributor to endothelial integrity loss, is elevated during stroke and is associated with worsened stroke outcome. We investigated the FDA-approved selective sphingosine-1-phosphate receptor 1 (S1PR1) ligand, ozanimod, on the regulation/activity of MMP-9 as well as endothelial barrier components [platelet endothelial cell adhesion molecule 1 (PECAM-1), claudin-5, and zonula occludens 1 (ZO-1)] in human brain microvascular endothelial cells (HBMECs) following hypoxia plus glucose deprivation (HGD). We previously reported that S1PR1 activation improves HBMEC integrity; however, mechanisms underlying S1PR1 involvement in endothelial cell barrier integrity have not been clearly elucidated. We hypothesized that ozanimod would attenuate an HGD-induced increase in MMP-9 activity that would concomitantly attenuate the loss of integral barrier components. Male HBMECs were treated with ozanimod or vehicle and exposed to 3 h of normoxia (21% O2) or HGD (1% O2). Immunoblotting, zymography, qRT-PCR, and immunocytochemical labeling techniques assessed processes related to MMP-9 and barrier markers. We observed that HGD acutely increased MMP-9 activity and reduced claudin-5 and PECAM-1 levels, and ozanimod attenuated these responses. In situ analysis, via PROSPER, suggested that attenuation of MMP-9 activity may be a primary factor in maintaining these integral barrier proteins. We also observed that HGD increased intracellular mechanisms associated with augmented MMP-9 activation; however, ozanimod had no effect on these select factors. Thus, we conclude that ozanimod has the potential to attenuate HGD-mediated decreases in HBMEC integrity in part by decreasing MMP-9 activity as well as preserving barrier properties.NEW & NOTEWORTHY We have identified a potential novel mechanism by which ozanimod, a selective sphingosine-1-phosphate receptor 1 (S1PR1) agonist, attenuates hypoxia plus glucose deprivation (HGD)-induced matrix metalloproteinase-9 (MMP-9) activity and disruptions in integral human brain endothelial cell barrier proteins. Our results suggest that ischemic-like injury elicits increased MMP-9 activity and alterations of barrier integrity proteins in human brain microvascular endothelial cells (HBMECs) and that ozanimod via S1PR1 attenuates these HGD-induced responses, adding to its therapeutic potential in cerebrovascular protection during the acute phase of ischemic stroke.

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.

Oral small molecule agents in management of ulcerative colitis: fact or fancy?

Ulcerative colitis is a chronic, immune-mediated disease characterized by recurring episodes of mucosal inflammation in the colon and rectum. The primary pathogenic mechanism of ulcerative colitis is the dysregulation of the mucosal immune response. The disease follows a relapsing-remitting course, and the goal of management is to successfully induce and then maintain remission. Effectively managing this chronic disease requires addressing all aspects of it. Currently, we have various antitumor necrosis factor agents and novel biologics available for treating ulcerative colitis patients with moderate-to-severe disease. However, none of the existing treatments are considered entirely satisfactory or ideal in these cases. After extensive progressive research, oral small molecule therapies targeting mediators of ongoing inflammation represent an exciting and revolutionary change in the treatment of ulcerative colitis, especially for patients with moderate-to-severe disease. In this review, we aimed to summarize the available experience and ongoing research on oral small molecule agents in the management of ulcerative colitis. The available experience and ongoing research with promising outcomes provide convincing evidence that the value of oral small molecule agents is fact not fancy.

Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Up to 5 years of follow-up in the DAYBREAK open-label extension trial.

BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor 1 and 5 modulator, is approved in multiple countries for treatment of relapsing forms of MS. OBJECTIVE: To characterize long-term safety and efficacy of ozanimod. METHODS: Patients with relapsing MS who completed a phase 1‒3 ozanimod trial were eligible for an open-label extension study (DAYBREAK) of ozanimod 0.92 mg/d. DAYBREAK began 16 October 2015; cutoff for this interim analysis was 2 February 2021. RESULTS: This analysis included 2494 participants with mean 46.8 (SD 11.9; range 0.033‒62.7) months of ozanimod exposure in DAYBREAK. During DAYBREAK, 2143 patients (85.9%) had treatment-emergent adverse events (TEAEs; similar in nature to those in the parent trials), 298 (11.9%) had a serious TEAE, and 75 (3.0%) discontinued treatment due to TEAEs. Serious infections (2.8%), herpes zoster infections (1.7%), confirmed macular edema cases (0.2%), and cardiac TEAEs (2.8%) were infrequent. Adjusted annualized relapse rate was 0.103 (95% confidence interval, 0.086‒0.123). Over 48 months, 71% of patients remained relapse free. Adjusted mean numbers of new/enlarging T2 lesions/scan and gadolinium-enhancing lesions were low and similar across parent trial treatment subgroups. CONCLUSIONS: This long-term extension of ozanimod trials confirmed a favorable safety/tolerability profile and sustained benefit on clinical and magnetic resonance imaging measures of disease activity.

Ozanimod: A First-in-Class Sphingosine 1-Phosphate Receptor Modulator for the Treatment of Ulcerative Colitis.

OBJECTIVE: To review the pharmacological and clinical profile of ozanimod in the treatment of ulcerative colitis (UC). DATA SOURCES: A PubMed search was conducted from inception to July 2021 using the keywords ozanimod, ulcerative colitis, and sphingosine 1-phosphate receptor modulator. Information was also extracted from published abstracts and the package insert. STUDY SELECTION AND DATA EXTRACTION: Phase 2 and 3 studies and relevant literature on ozanimod pharmacological and clinical profiles were reviewed. DATA SYNTHESIS: Ozanimod approval was based on True North, a phase 3 trial evaluating ozanimod's efficacy and safety in the treatment of moderate to severe UC. Compared with placebo, ozanimod led to clinical remission in a significantly higher proportion of patients in both the induction and maintenance phase. Additionally, for secondary end points of clinical response, endoscopic improvement, corticosteroid-free remission, and mucosal healing, ozanimod performed significantly better than placebo. Common adverse events included infections, headaches, hypertension, bradycardia, and liver enzyme elevations. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Ozanimod is the first sphingosine 1-phosphate modulator to be approved for UC and is administered orally. Its efficacy profile is comparable with other UC medications. However, its safety profile is unique, requiring extensive assessments prior to initiation of and during treatment. Thus, it is unclear how ozanimod will be positioned in UC treatment. CONCLUSION: Ozanimod is another option in the growing arsenal of UC treatment. Although it offers a novel mechanism of action and is administered orally, there are important safety, dosing, and pharmacokinetic factors to consider prior to initiation and use.

Ozanimod, an S1PR1 ligand, attenuates hypoxia plus glucose deprivation-induced autophagic flux and phenotypic switching in human brain VSM cells.

Vascular smooth muscle (VSM) cell phenotypic expression and autophagic state are dynamic responses to stress. Vascular pathologies, such as hypoxemia and ischemic injury, induce a synthetic VSM phenotype and autophagic flux resulting in a loss of vascular integrity and VSM cell death respectfully. Both clinical pilot and experimental stroke studies demonstrate that sphingosine-1-phosphate receptor (S1PR) modulation improves stroke outcome; however, specific mechanisms associated with a beneficial outcome at the level of the cerebrovasculature have not been clearly elucidated. We hypothesized that ozanimod, a selective S1PR type 1 ligand, will attenuate VSM synthetic phenotypic expression and autophagic flux in primary human brain VSM cells following acute hypoxia plus glucose deprivation (HGD; in vitro ischemic-like injury) exposure. Cells were treated with ozanimod and exposed to normoxia or HGD. Crystal violet staining, standard immunoblotting, and immunocytochemical labeling techniques assessed cellular morphology, vacuolization, phenotype, and autophagic state. We observed that HGD temporally decreased VSM cell viability and concomitantly increased vacuolization, both of which ozanimod reversed. HGD induced a simultaneous elevation and reduction in levels of pro- and antiautophagic proteins respectfully, and ozanimod attenuated this response. Protein levels of VSM phenotypic biomarkers, smoothelin and SM22, were decreased following HGD. Furthermore, we observed an HGD-induced epithelioid and synthetic morphological appearance accompanied by disorganized cytoskeletal filaments, which was rescued by ozanimod. Thus, we conclude that ozanimod, a selective S1PR1 ligand, protects against acute HGD-induced phenotypic switching and promotes cell survival, in part, by attenuating HGD-induced autophagic flux thus improving vascular patency in response to acute ischemia-like injury.

S1P1 Contributes to Endotoxin-enhanced B-Cell Functions Involved in Hypersensitivity Pneumonitis.

In a proportion of patients with hypersensitivity pneumonitis, the biological and environmental factors that sustain inflammation are ill defined, resulting in no effective treatment option. Bioaerosols found in occupational settings are complex and often include Toll-like receptor ligands, such as endotoxins. How Toll-like receptor ligands contribute to the persistence of hypersensitivity pneumonitis, however, remains poorly understood. In a previous study, we found that an S1P1 (sphingosine-1-phosphate receptor 1) agonist prevented the reactivation of antigen-driven B-cell responses in the lung. Here, we assessed the impact of endotoxins on B-cell activation in preexisting hypersensitivity pneumonitis and the role of S1P1 in this phenomenon. The impact of endotoxins on pre-established hypersensitivity pneumonitis was studied in vivo. S1P1 levels were tracked on B cells in the course of the disease using S1P1-eGFP knockin mice, and the role of S1P1 on B-cell functions was assessed using pharmacological tools. S1P1 was found on B cells in experimental hypersensitivity pneumonitis. Endotoxin exposure enhanced neutrophil accumulation in the BAL of mice with experimental hypersensitivity pneumonitis. This was associated with enhanced CD69 cell-surface expression on lymphocytes in the BAL. In isolated B cells, endotoxins increased cell-surface levels of costimulatory molecules and CD69, which was prevented by an S1P1 agonist. S1P1 modulators also reduced TNF production by B cells and their capacity to trigger T-cell cooperation ex vivo. An S1P1 ligand directly inhibited endotoxin-induced B-cell activation.

Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities.

Intensive research in the field of sphingolipids has revealed diverse roles in cell biological responses and human health and disease. This immense molecular family is primarily represented by the bioactive molecules ceramide, sphingosine, and sphingosine 1-phosphate (S1P). The flux of sphingolipid metabolism at both the subcellular and extracellular levels provides multiple opportunities for pharmacological intervention. The caveat is that perturbation of any single node of this highly regulated flux may have effects that propagate throughout the metabolic network in a dramatic and sometimes unexpected manner. Beginning with S1P, the receptors for which have thus far been the most clinically tractable pharmacological targets, this review will describe recent advances in therapeutic modulators targeting sphingolipids, their chaperones, transporters, and metabolic enzymes.

Comparative Effectiveness of Ozanimod and Vedolizumab as First-Line Advanced Therapies in Ulcerative Colitis: A Propensity-Matched Cohort Analysis.

INTRODUCTION: There is limited real-world evidence comparing the effectiveness of ozanimod to vedolizumab as first-line advanced therapies in patients with ulcerative colitis (UC). METHODS: We conducted a retrospective cohort study using TriNetX, a multi-institutional US database in adults with UC who were initiated on ozanimod compared to vedolizumab between January 1, 2021 and 22 June, 2024. The primary outcome was to compare the risk of a composite outcome of corticosteroid use, colectomy, or change to another advanced therapy between the 2 cohorts within 12 months. 1:1 propensity score matching (PSM) was performed for demographics, comorbid conditions, disease extent, laboratory parameters, and previous corticosteroid use. The risk was expressed as an adjusted odds ratio (aOR) with 95% CIs. RESULTS: We identified 222 patients in the ozanimod cohort (mean age 41.2 ±â€…15.7, 46.3% male sex, 68% White, and 22.5% ulcerative proctitis), and 4145 patients in the vedolizumab cohort (mean age 47.4 ±â€…18.3, 45.2% male sex, 69.7% White, and 17.2% ulcerative proctitis). After PSM, there was no significant difference in the risk of the composite outcome (aOR 0.92, 95% CI, 0.63-1.36) and corticosteroid use (aOR 0.80, 95% CI, 0.53-1.18) between the 2 cohorts within 12 months. There was a higher risk of change in therapy in the ozanimod cohort (aOR 1.95, 95% CI, 1.09-3.49) compared to the vedolizumab cohort. Colectomy rates were low in both cohorts (<0.04%). CONCLUSIONS: Our real-world study showed that ozanimod use is associated with similar corticosteroid use but higher odds of a change in therapy compared to vedolizumab when used as first-line therapy in patients with UC. Further prospective studies are needed to understand long-term outcomes.

Ozanimod use is associated with similar outcomes compared to vedolizumab when used as first-line therapy in patients with ulcerative colitis.

Efficacy and Safety of Approximately 3 Years of Continuous Ozanimod in Moderately to Severely Active Ulcerative Colitis: Interim Analysis of the True North Open-label Extension.

BACKGROUNDS AND AIMS: This interim analysis from the True North open-label extension [OLE] study examines efficacy and safety of approximately 3 years of continuous ozanimod treatment in patients with moderately to severely active ulcerative colitis. METHODS: Clinical responders after 52 weeks of ozanimod during the phase 3 True North study, who continued treatment in the OLE, were evaluated. Efficacy, including endoscopic and histological endpoints, was assessed during the OLE for approximately 2 additional years through OLE Week 94, using observed case [OC] and nonresponder imputation [NRI] analyses. Adverse events were monitored from True North baseline through OLE data cutoff and expressed as exposure-adjusted incidence rates. RESULTS: This analysis included 131 patients; 54% had achieved corticosteroid-free remission at True North Week 52. In OC analyses, clinical response, clinical remission, and corticosteroid-free remission were achieved by 91.4%, 69.1%, and 67.9% of patients, respectively, at OLE Week 94 [146 weeks of total treatment]. Similarly, endoscopic improvement, histological remission, and mucosal healing were achieved by 73.3%, 67.3%, and 56.3% of patients, respectively, at OLE Week 94. Efficacy rates were lower using NRI analyses, but maintenance of efficacy was demonstrated through OLE Week 94. No new safety signals emerged from this analysis. Serious infections, malignancy, cardiovascular events, and hepatic events occurred infrequently. CONCLUSIONS: Among patients who achieved clinical response after 1 year of ozanimod treatment during True North, a high percentage sustained clinical and mucosal efficacy over 2 additional years in the OLE. No new safety signals were observed with long-term ozanimod use.

Switching to ozanimod as a strategy to adjust fingolimod-related lymphopenia.

INTRODUCTION: Fingolimod is a disease-modifying therapy for multiple sclerosis (MS) that modulates sphingosine 1-phospate receptors, impeding the egress of lymphocytes from lymphnodes and thus causing lymphopenia. Severe lymphopenia should lead to fingolimod discontinuation. We aim to evaluate whether switching from fingolimod to ozanimod can adjust fingolimod-related lymphopenia while maintaining clinical efficacy. METHODS: In this real-world observational study, we included 18 people with MS (47.7 ± 7.6 years of age, 77.8 % of women, 13.9 ± 6.9 years of disease duration, median EDSS 3.0) at the time of fingolimod discontinuation due to lymphopenia. We collected laboratory (lymphocyte absolute count on the same hematological counter) and clinical variables at fingolimod discontinuation, at ozanimod prescription, and 6 months after ozanimod prescription. RESULTS: From 13 cases of grade 3 and 4 lymphopenia at the time of fingolimod discontinuation, we observed only 2 cases of grade 3 and no cases of grade 4 lymphopenia after 6 months of ozanimod treatment. On paired t-tests, absolute lymphocyte count at fingolimod discontinuation were lower than ozanimod prescription (p<0.001), and after 6 months (p<0.001). We observed no clinical changes. DISCUSSION: People with MS who have severe fingolimod-related lymphopenia and are clinically stable, can exhibit increased absolute lymphocyte counts when switched to ozanimod, while preserving clinical stability.

A Gastroenterologist's guide to drug interactions of small molecules for inflammatory bowel disease.

Small molecule drugs are becoming increasingly used in the treatment of inflammatory bowel diseases (IBD). However, unlike monoclonal antibody drugs, which have few interactions with other medications, the pharmacokinetics of small molecule drugs are complex and may be influenced by a myriad of drug-drug interactions (DDI) as well as by patient characteristics and food intake. This review aims to provide a concise practical guide to small molecule drug interactions for the use of IBD physicians. It starts with a brief overview of the main metabolizing enzymes and transporters involved in drug interactions and the Food and Drug Administration's (FDA) approach to determining drug-interaction hazard thresholds. It is then followed by a more detailed review of the pharmacokinetics of five novel small molecules approved in IBD: Tofacitinib, Upadacitinib, Filgotinib, Ozanimod, and Etrasimod, including their known interactions and specific warnings. This review will also inform readers on challenges in determining the actual magnitude of interactions and their clinical relevance, including the arbitrary nature of some hazard thresholds, the inference of the impact on metabolizing enzymes and transporters from single-drug assays which may not reflect poly-pharmaceutical regimens, and other challenges in this field which the IBD physician needs to be cognizant of. In practice, before administering a small molecule drug, it is advisable to evaluate any potential interactions with other medications the patient is receiving. An increased awareness by health care professionals and patients, may reduce the possible risks associated with DDI of small molecule IBD drugs.

Concomitant Administration of Ozanimod and Serotonergic Antidepressants in Patients With Ulcerative Colitis or Relapsing Multiple Sclerosis.

BACKGROUND: Ozanimod, approved for the treatment of moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (RMS), is a weak in vitro monoamine oxidase B (MAO-B) inhibitor. MAO-B inhibitors can cause serotonin accumulation with concomitant use of selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs). We evaluated the incidence of treatment-emergent adverse events (TEAEs) potentially associated with serotonin accumulation during ozanimod and concomitant SSRI/SNRI use in this post hoc analysis of pooled UC studies and the open-label extension RMS DAYBREAK. METHODS: Data for ozanimod 0.92 mg from pooled UC studies (n = 1158; cutoff: January 10, 2022) and RMS DAYBREAK (n = 2257; cutoff: February 1, 2022) were analyzed. Concomitant SSRI/SNRI use was allowed in the UC (n = 67) and RMS (n = 274) studies. A narrow Medical Dictionary for Regulatory Activities search ("serotonin syndrome," "neuroleptic malignant syndrome," and "malignant hyperthermia") and a broad search including terms potentially associated with serotonin accumulation were conducted. The percentages of patients with TEAEs in both searches were analyzed by concomitant SSRI/SNRI use when the TEAE occurred. RESULTS: No patients had TEAEs matching the narrow search criteria. No differences were observed in the percentages of patients with ≥1 TEAE matching the broad search regardless of SSRI/SNRI use in UC (with: 25.4% [n = 17 of 67]; without: 15.0% [n = 164 of 1091]) and RMS (with: 12.4% [n = 34 of 274]; without: 15.6% [n = 310 of 1982]) studies. CONCLUSIONS: No evidence of increased TEAEs potentially associated with serotonin accumulation was observed with concurrent use of ozanimod and SSRIs/SNRIs. CLINICAL TRIAL REGISTRATION: NCT01647516, NCT02531126, NCT02435992, NCT02576717.

No evidence of increased treatment-emergent adverse effects potentially associated with serotonin accumulation was observed with concurrent use of ozanimod and serotonergic antidepressants. Our findings support the absence of clinically meaningful ozanimod monoamine oxidase B inhibition in vivo.

Pharmacokinetics of S1P receptor modulators in the treatment of ulcerative colitis.

INTRODUCTION: Ulcerative colitis is a chronic inflammatory bowel disease, affecting the colorectal mucosae, with a relapsing-remitting course, characterized by the trafficking and gathering of lymphocytes in the inflammatory intestinal mucosa. Sphingosine-1-phosphate (S1P) receptor modulators preventing lymphocytes egress from lymphoid tissues to the active inflammation site is an alternative therapeutic option in this condition. AREA COVERED: We carried out a comprehensive review of the literature available on Medline, Scopus and Embase regarding the pharmacokinetics of S1P receptor modulators. For each compound, we reviewed the mechanism of action, pharmacokinetic data and efficacy and safety data from phase 3 studies and real-life studies when available. EXPERT OPINION: S1P receptor modulators, including ozanimod and etrasimod (both currently on the market) as well as VTX002 (under development), are a new class of drugs for the treatment of moderate to severe ulcerative colitis, inducing and maintaining the remission. Due to its pharmacokinetic features, this class of drugs has certain advantages such as an oral administration, a short half-life, a high volume of distribution, and no immunogenicity. On the other hand, there are risks of cardiological and ophthalmological side-effects, as well as drug-drug interactions risk, that require special attention from the healthcare providers.

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.

Comparative efficacy of diroximel fumarate, ozanimod and interferon beta-1a for relapsing multiple sclerosis using matching-adjusted indirect comparisons.

Aim: Diroximel fumarate (DRF), ozanimod (OZA) and interferon beta-1a (IFN) are disease-modifying therapies approved for the treatment of relapsing multiple sclerosis. No randomized trials have compared DRF versus OZA and IFN. We compared DRF versus OZA and DRF versus IFN using matching-adjusted indirect comparisons for efficacy outcomes, including annualized relapse rate (ARR), 12- and 24-week confirmed disability progression (CDP) and absence of gadolinium-enhancing (Gd+) T1 lesions and new/newly enlarging T2 lesions. Patients & methods: We used individual patient data from EVOLVE-MS-1 (NCT02634307), a 2-year, open-label, single-arm, phase III study of DRF (n = 1057) and aggregate data from RADIANCE (NCT02047734), a 2-year, double-blind, phase III study that compared OZA 1 mg once daily (n = 433) and intramuscular IFN 30 µg once weekly (n = 441). To account for cross-trial differences, the EVOLVE-MS-1 population was restricted to those who met the inclusion/exclusion criteria for RADIANCE, then weighted to match the average baseline characteristics of RADIANCE. Results: After weighting, DRF and OZA had similar ARRs (0.18 and 0.17, respectively), with a rate difference (DRF vs OZA) of 0.01 (95% confidence interval [CI]: -0.04 to 0.06). DRF had a lower ARR than IFN (0.18 and 0.28, respectively), with a rate difference (DRF vs IFN) of -0.10 (95% CI: -0.16 to -0.04) after weighting. Outcomes for 12- and 24-week CDP favored DRF versus OZA; 12-week CDP favored DRF versus IFN, but there was not strong evidence favoring DRF over IFN for 24-week CDP. Compared with OZA and IFN, DRF had higher proportions of patients without Gd+ T1 lesions and patients without new/newly enlarging T2 lesions. Conclusion: Disability progression and radiological outcomes were favorable for DRF versus OZA, although no differences were observed in ARR. Clinical and radiological outcomes generally favored DRF versus IFN. These findings may be informative for patients and clinicians considering different treatment options for MS.

Judicious Use of Ozanimod for Ulcerative Colitis and Multiple Sclerosis.

Clinical trials have demonstrated the efficacy of ozanimod, an oral sphingosine-1-phosphate receptor modulator, for the treatment of moderate-to-severe ulcerative colitis. Infrequently does an opportunity present itself to use one drug for two simultaneous disease states, proving especially beneficial in the case of this patient intolerant of numerous established therapies for ulcerative colitis. This case report describes the successful use of ozanimod for both ulcerative colitis and multiple sclerosis, achieving clinical remission in both diseases.