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Mode of Action & Selectivity
Clinical Study Data
Disease Background

Mode of Action & Selectivity

Mode of Action

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aInnate immune cells, which are responsible for antigen presentation and immunosurveillance, include macrophages, monocytes, and natural killer cells, among others. The effects of ozanimod on innate immune cells have been studied only in monocytes, natural killer cells, and natural killer T cells. For conceptual purposes, cells that are retained in lymphoid organs are not depicted in the bloodstream to the right; however, it should be noted that ozanimod  reduces circulating levels of these cells without eliminating them entirely. The mechanism by which ozanimod exerts therapeutic effects in multiple sclerosis is unknown but may involve the reduction of lymphocyte migration into, or direct effects on, the central nervous system. CNS, central nervous system; MHC, major histocompatibility complex; S1P, sphingosine-1 phosphate; S1P1, S1P receptor subtype 1; S1P5, S1P receptor subtype 5; TCR, T cell receptor. Figure adapted from Dendrou C et al. Nat Rev Immunol. 2015;15(9):545–558. Adapted from 1. Scott FL et al. Br J Pharmacol. 2016;173(11):1778–1792. 2. Surapaneni S, et al. Drug Metab Dispos. 2021 May;49(5):405-419. 3. Selkirk JV, et al., J Pharmacol Exp Ther. 2021 Dec;379(3):386-399. 4. Harris S et al. Neurol Neuroimmunol Neuroinflamm. 2020;7(5):e839. 5. Sallusto F et al. Nature. 1999;401(6754):708-712. 6. Jaillard C et al. J Neurosci. 2005;25(6):1459–1469. 7. Noda H et al. J Neuroimmunol. 2013;256:13–18. 8. Di Menna L et al. Pharmacol Res. 2013;67(1):1–9.


Selectivity

Ozanimod and its major metabolites are highly selective for S1P1 and S1P5

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aDerived from GTPγS binding in Chinese hamster ovary cells expressing the human recombinant receptors. EC50, half maximal effective concentration; GTPγS, [35S]methionine-labeled guanosine 5'-O-[gamma-thio]triphosphate; S1P, sphingosine 1-phosphate; S1P1–5, sphingosine 1-phosphate receptor subtypes 1 through 5; t1/2, half-life. Adapted from: 1. Tran JQ et al., Multiple-Dose Pharmacokinetics of Ozanimod and its Major Active Metabolites and the Pharmacodynamic and Pharmacokinetic Interactions with Pseudoephedrine, a Sympathomimetic Agent, in Healthy Subjects, Adv Ther. 2020 Dec;37(12):4944-4958. 2. Surapaneni S et al., Absorption, Metabolism, and Excretion, In Vitro Pharmacology, and Clinical Pharmacokinetics of Ozanimod, a Novel Sphingosine 1-Phosphate Receptor Modulator, Drug Metab Dispos. 2021 May;49(5):405-419. 3. SmPC Zeposia® https://www.ema.europa.eu/en/medicines/human/EPAR/zeposia#product-information-section Status december 2021 and Product Information for professionals Zeposia® (ozanimod), www.swissmedicinfo.ch, status may 2022..


Clinical Study Data

Introduction: Study Design & Endpoints

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aIn SUNBEAM, all participants continued on treatment until the last participant completed 12 months; the treatment period in RADIANCE was 24 months. At the end of the trial all participants had the opportunity to enter DAYBREAK. bAll MRI analyses were performed by a blinded central imaging facility. ARR, annualized relapse rate; GdE, gadolinium-enhancing; IFN, interferon; IM, intramuscular; MRI, magnetic resonance imaging; QD, once daily. Adapted with permission from: 1. Comi G et al.,Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial, Lancet Neurol 2019;18:1009-1020. 2. Cohen JA et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial, Lancet Neurol 2019;18:1021-1033.


Baseline Demographics and Disease Characteristics

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DMT, Disease Modifying Treatment; EDSS, Expanded Disability Status Scale; IFN β-1a, Interferon Beta-1a; SD, Standard Deviation. Adapted with permission from: 1. Comi G et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial, Lancet Neurol. 2019;18(11):1009-1020. 2. Cohen JA et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial, Lancet Neurol. 2019;18(11):1021-1033.

 


MRI Baseline Characteristics

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GdE, gadolinium-enhancing; IFN β-1a, Interferon Beta-1a; MRI, magnetic resonance imaging; SD, Standard Deviation. Adapted with permission from: 1. Comi G et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial, Lancet Neurol. 2019;18(11):1009-1020. 2. Cohen JA et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial, Lancet Neurol. 2019;18(11):1021-1033.


Efficacy (primary endpoint): annualized relapse rate (ARR)

aARR was analyzed using a Poisson regression model adjusted for region (Eastern Europe vs Rest of World), baseline age, and baseline number of GdE lesions, with natural log transformation of time on study as an offset term. IFNβ-1a, interferon beta-1a. Adapted with permission from: 1. Comi G et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial , Lancet Neurol. 2019;18(11):1009-1020. 2. Cohen JA et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial, Lancet Neurol. 2019;18(11):1021-1033.


Efficacy (secondary endpoint): CDP at 3 months in pooled phase 3 studies

CDP, confirmed disability progression; IFN, interferon. Analyzed using a Cox proportional hazards model adjusted for study, region (eastern Europe vs rest of world), baseline age, and baseline Expanded Disability Status Scale score. Adapted with permission from supplement to: Cohen JA et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial, Lancet Neurol. 2019;18(11):1021-1033.


Efficacy (secondary endpoint): gadolinium enhancing (GdE) lesions

aAnalysis based on a negative binominal regression model using observed data adjusted for region (Eastern Europe vs Rest of World), baseline age, and baseline number of GdE lesions, with natural log transformation of number of available scans over 12 and 24 months as an offset term. GdE, gadolinium enhancing lesions; IFN, interferon. Adapted with permission from: 1. Comi G et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial, Lancet Neurol. 2019;18(11):1009-1020. 2. Cohen JA et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial, Lancet Neurol. 2019;18(11):1021-1033.


Efficacy (secondary endpoint): new/enlarging T2 Lesions

aAnalysis based on a negative binominal regression model using observed data adjusted for region (Eastern Europe vs Rest of World), baseline age, and baseline number of GdE lesions, with natural log transformation of number of available scans over 12 and 24 months as an offset term. Adapted with permission from: 1. Comi G et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial, Lancet Neurol. 2019;18(11):1009-1020. 2. Cohen JA et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial, Lancet Neurol. 2019;18(11):1021-1033.


Efficacy (secondary and exploratory endpoints): brain volume change

P-value for comparison between the ozanimod and IFN β-1a 30 μg treatment groups are nominal and are based on rank analysis of covariance model, adjusted for region (Eastern Europe vs Rest of the World), and EDSS category per Interactive Voice Response System, with the residual of the rank at baseline as the dependent variable regressed on rank of percent change from baseline. IFN, interferon. Adapted with permission from supplement to: 1. Comi G et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial, Lancet Neurol. 2019;18(11):1009-1020. 2. Cohen JA et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial, Lancet Neurol. 2019;18(11):1021-1033.

 


Efficacy (exploratory, post hoc analyses): clinically meaningful improvement in cognitive processing speed

SDMT was a component of a secondary endpoint in SUNBEAM. a≥ 4-point increase relative to baseline at months 6 and 12 were analyzed based on a generalized estimating equation model adjusted by baseline SDMT score, stratification factors, age at baseline, brain volume at baseline, and treatment. Cohen’s d effect size was calculated based on odds ratios; interpretation: 0.2 = small effect, 0.5 = medium effect, 0.8 = large effect. IFN, interferon; SDMT, Symbol Digit Modalities Test. Adapted with permission from DeLuca J et al., Effect of Ozanimod on Symbol Digit Modalities Test Performance in Relapsing MS, Mult Scler Relat Disord. 2021;48.

 

Safety: overall adverse events

AE, adverse event; ALT, alanine aminotransferase; GGT, gamma-glutamyl transferase; IFN, interferon; TEAE, treatment-emergent adverse event.aDid not meet stated criteria for inclusion in the table. 1. Comi G. et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial, Lancet Neurol. 2019;18(11):1009-1020; 2. Cohen JA et al., Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial, Lancet Neurol. 2019;18(11):1021-1033. Table adapted with permission from Lancet Neurol.


Disease Background

Multiple Sclerosis

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