Skip to main content

Study Design

SDMT

Secondary Endpoints

Adverse Events

Data in Early RMS: ENLIGHTEN Study

ZEPOSIA was evaluated in 2 pivotal trials, SUNBEAM (1 year; N=1346) and RADIANCE (2 years; N=1313) that were multicenter, randomized, double-blind, double-dummy, active treatment-controlled studies of daily oral ozanimod 0.46 mg (not approved for maintenance dose) or 0.92 mg oral daily dose vs weekly Avonex (interferon beta-1a), 30-μg intramuscular injection. Please see study results below.1-3

ENLIGHTEN: A Post-Marketing Study Focused on Patients With Early RMS4

An open-label, single-arm, phase 3b study that evaluated treatment with ZEPOSIA 0.92 mg in participants with early RMS over 3 years4a

ENLIGHTEN study trial timeline with ZEPOSIA (ozanimod) 0.92-mg oral daily dose

Primary endpoint4

  • Clinically meaningful increase in SDMT scoreb

Key secondary endpoints4

  • ARR
  • MRI lesions
  • Brain volume loss
  • Adverse events

Key baseline
characteristics (N=188)4

  • 71% DMT naïve​
  • 1.0 year post-diagnosis
    (mean)
  • 2.0 median EDSS​
  • 79% female​
  • Mean age 39.5 years​​

Mia was not a participant in the ENLIGHTEN study. She is a real ZEPOSIA patient who was compensated for her time. Individual results may vary.

Endpoints were analyzed descriptively.4

Trial inclusion criteria4a

  • Aged 18-65 years at screening
  • Diagnosis of MS per the 2010 or 2017 revised McDonald criteria within the last 5 years
  • ≤1 MS disease-modifying therapy (none within 1 month of enrollment)
  • EDSS score of ≤3.5 at screening
  • No relapses within 30 days before screening
  • ≤10 GdE lesions on baseline brain MRI scan
  • No history of developmental disorders or motor or sensory defects that could interfere with cognitive test performance

a

The database lock was June 20, 2025. SDMT, relapse evaluation, MRI, physical examination, ECG, and lab analyses were evaluated at 12 months, 24 months, and 36 months. Bristol Myers Squibb closed the ENLIGHTEN study early for strategic business-related reasons unrelated to safety and efficacy, which resulted in a smaller sample size at Year 3 than initially planned.4

b

The proportion of participants with an increase in SDMT score of ≥4 points or ≥10% from baseline to Year 3. The SDMT pairs a series of symbols with digits, and participants must match the appropriate symbol to the paired numerical digit using a key; the SDMT was administered verbally in ENLIGHTEN. Scoring is based on the correct number of responses given in 90 seconds, with higher scores indicating faster cognitive processing speed.4

ZEPOSIA pivotal trials SUNBEAM (1 year; N=1346) and RADIANCE (2 years; N=1313). Primary endpoint: ZEPOSIA reduced ARR vs Avonex by 48% at 1 year (0.181 vs 0.350, respectively) and by 38% at 2 years (0.172 vs 0.276, respectively). Secondary endpoints: ZEPOSIA reduced the number of new or enlarging T2 lesions by 48% at 1 year and by 42% at 2 years, and reduced the number of GdE lesions vs Avonex by 63% at 1 year and 53% at 2 years. 9 of 10 patients showed no confirmed 3-month disability progression. There was no significant difference in 3-month confirmed disability between ZEPOSIA and Avonex.1-3,5

ARR=annualized relapse rate; DMT=disease-modifying therapy; ECG=electrocardiogram; EDSS=Expanded Disability Status Scale; GdE=gadolinium enhancing; MRI=magnetic resonance imaging; MS=multiple sclerosis; RMS=relapsing multiple sclerosis; SDMT=Symbol Digit Modalities Test.

Cognitive Processing Speed (SDMT) at 3 Years4

Banner for Primary Endpoint of SDMT Scores

Categorical Analysis of Clinically Meaningful Change in SDMT Relative to Baseline From the ENLIGHTEN Trial

Graph of categorical analysis of clinically meaningful change in SDMT scores from the ENLIGHTEN trial over 3 years

88%

Improved or Remained Stable in SDMT Scores at 3 Yearsa

The Symbol Digit Modalities Test (SDMT) assesses cognitive processing speed.4

In ENLIGHTEN, an SDMT score change of ≥ 4points, or ≥ 10% from baseline, was consideredclinically meaningful.4

Endpoints were analyzed descriptively.4c

Total population who received ZEPOSIA 0.92 mg: Year 1 (n=168), Year 2 (n=149), Year 3 (n=104).4

c

This SDMT category represents unadjusted data. Improved: at least a 4-point or 10% increase in SDMT relative to baseline; stable: change from baseline SDMT between -4 and 4 points and percentage change between -10% and 10%; worsened: at least a 4-point or 10% decrease in SDMT relative to baseline.4

Secondary Endpoints: ARR, Lesions, and WBV at 3 Years4

Banner for Secondary Endpoint of ZEPOSIA 0.92 mg
Graph of adjusted annualized relapse rate after 3 years on ZEPOSIA

GdE Lesions

Patients who were lesion-free

98%f

Change in GdE lesion count from baselined

-0.6g

T2 Lesions

Adjusted mean number of new/enlarging lesions per scan

0.32g

WBV

Mean change in WBV from prior year

-0.31h

Mean change in WBV remained consistent
(-0.31%) at Years 1, 2, and 3i

Endpoints were analyzed descriptively.4

Patients who were GdE lesion-free: 93% at Year 1 (n=151) and 95% at Year 2 (n=131); GdE lesion count change from baseline: -0.5 at Year 1 (n=161) and -0.6 at Year 2 (n=137). Adjusted mean number of new/enlarging T2 lesions per scan: 0.57 at Year 1 (n=161) and 0.45 at Year 2 (n=137).4

d

Based on a negative binomial model that adjusted for age at baseline, the number of relapses in the previous 2 years prior to enrollment, and baseline number of GdE lesions; the natural log transformation of treatment duration was included as an offset term to account for participants’ varying durations of time in the treatment period.4

e

n=188.4

f

n=84.4

g

n=85.4

h

n=68.4

i

Year 1 to Year 2 (n=127); Year 2 to Year 3 (n=68).4

ARR=annualized relapse rate; GdE=gadolinium enhancing; WBV=whole brain volume.

Adverse Events Reported at 3 Years4

Banner for Secondary Endpoint of Incidence of Adverse Events at 3 Years

Summary of Treatment-Emergent Adverse Events (TEAEs)

ZEPOSIA
(N=188)

Any TEAE

84%

Serious TEAEsj

9%

TEAEs in ≥5% of Patients

ZEPOSIA

COVID-19k

27%

Fatigue

12%

Headache

12%

Nasopharyngitis

12%

Urinary tract infection

12%

Upper respiratory tract infection

11%

Muscle spasms

9%

Sinusitis

9%

Arthralgia

7%

Hypoesthesia

7%

Paresthesia

7%

Hypertension

7%

Insomnia

7%

Pain in extremity

6%

The safety profile for patients with early RMS is generally similar to that observed in pivotal trials1-4

3.7%

Discontinuation rate due to AEs4

j

The following serious TEAE-preferred terms were reported in 1 participant (0.5%) each: COVID-19, pneumonia, and sepsis (all reported in the same participant), appendicitis, diverticulitis, urinary tract infection, papillary thyroid cancer, squamous cell carcinoma, goiter, hyponatremia, suicidal ideation, angina pectoris, pneumothorax, abdominal pain, abdominal pain lower, small intestinal obstruction, bile duct stone, ecchymosis, back pain, ectopic pregnancy, breast hyperplasia, and hemorrhagic ovarian cyst.4

k

The COVID-19 pandemic began at the start of the trial.4

ZEPOSIA pivotal trials SUNBEAM (1 year; N=1346) and RADIANCE (2 years; N=1313) adverse reactions:

Overall incidence of adverse reactions for ZEPOSIA vs Avonex at 1 year was 59.8% and 75.5%, respectively, and at 2 years was 74.7% and 83.0%, respectively. Across 2 head-to-head trials, the most common adverse reactions with an incidence of at least 2% in patients treated with ZEPOSIA and at least 1% greater than Avonex, respectively, were as follows: upper respiratory infection, 26% (vs 23%); hepatic transaminase elevation, 10% (vs 5%); orthostatic hypotension, 4% (vs 3%); urinary tract infection, 4% (vs 3%); back pain, 4% (vs 3%); hypertension, 4% (vs 2%); and upper abdominal pain, 2% (vs 1%). Data are not an adequate basis for comparison of rates between ZEPOSIA and the active control. Upper respiratory infection includes nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, viral respiratory tract infection, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis. Hepatic transaminase elevation includes alanine aminotransferase increased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, and transaminase increased. Hypertension includes hypertension, essential hypertension, and orthostatic hypertension. Severe adverse reactions: the rate of severe adverse reactions at 1 year for ZEPOSIA was 1.6% vs 2.2% for Avonex, and the rate at 2 years for ZEPOSIA was 3.5% vs 4.3% for Avonex. Serious adverse reactions: the rate of serious adverse reactions at 1 year for ZEPOSIA was 2.9% vs 2.5% for Avonex, and the rate at 2 years for ZEPOSIA was 6.5% vs 6.4% for Avonex. Please see the full Prescribing Information for additional SUNBEAM and RADIANCE data.1-3

AE=adverse event; TEAE=treatment-emergent adverse event.

Explore the efficacy data

Explore the safety profile

References:

  1. Zeposia. Prescribing Information. Bristol-Myers Squibb Company; 2024.
  2. Comi G, Kappos L, Selmaj KW, et al; SUNBEAM Study Investigators. 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 and Suppl 1-26.
  3. Cohen JA, Comi G, Selmaj KW, et al; RADIANCE Trial Investigators. 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 and Suppl 1-31.
  4. Naismith RT, Zivadinov R, Morrow SA, et al. Safety and efficacy of ozanimod over 1 year in patients with early relapsing multiple sclerosis: an interim analysis of the ENLIGHTEN study. Presented at the 9th Joint ECTRIMS-ACTRIMS Meeting; October 11–13, 2023; Milan, Italy. Poster P690.
  5. Data on file. BMS-REF-OZA-0098. Princeton, NJ: Bristol-Myers Squibb Company; 2025.
References
IMPORTANT SAFETY
INFORMATION

Contraindications:

  • Patients who in the last 6 months, experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA), decompensated heart failure requiring hospitalization, or Class III/IV heart failure or have a presence of Mobitz type II second-degree or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial block, unless the patient has a functioning pacemaker
  • Patients with severe untreated sleep apnea
  • Patients taking a monoamine oxidase (MAO) inhibitor

Infections: ZEPOSIA may increase the susceptibility to infections. Life-threatening and rare fatal infections have occurred in patients receiving ZEPOSIA. Obtain a recent (i.e., within 6 months or after discontinuation of prior MS or UC therapy) complete blood count (CBC) including lymphocyte count before initiation of ZEPOSIA. Delay initiation of ZEPOSIA in patients with an active infection until the infection is resolved. Consider interruption of treatment with ZEPOSIA if a patient develops a serious infection. Continue monitoring for infections up to 3 months after discontinuing ZEPOSIA.

  • Herpes zoster and herpes simplex were seen in clinical trials of ZEPOSIA. Herpes simplex encephalitis and varicella zoster meningitis have been reported with sphingosine 1-phosphate (S1P) receptor modulators. Patients without a healthcare professional-confirmed history of varicella (chickenpox), or without documentation of a full course of vaccination against varicella zoster virus (VZV), should be tested for antibodies to VZV before initiating ZEPOSIA.
  • Cases of fatal cryptococcal meningitis (CM) and disseminated cryptococcal infections have been reported with S1P receptor modulators. If CM is suspected, ZEPOSIA should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
  • In the MS and UC clinical studies, patients who received ZEPOSIA were not to receive concomitant treatment with antineoplastic, non-corticosteroid immunosuppressive, or immune-modulating therapies used for treatment of MS and UC. Concomitant use of ZEPOSIA with any of these therapies would be expected to increase the risk of immunosuppression. When switching to ZEPOSIA from immunosuppressive medications, consider the duration of their effects and their mode of action to avoid unintended additive immunosuppressive effects.
  • Use of live attenuated vaccines should be avoided during and for 3 months after treatment with ZEPOSIA. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of ZEPOSIA.

Progressive Multifocal Leukoencephalopathy (PML): PML is an opportunistic viral infection of the brain that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability.

PML has been reported in patients treated with S1P receptor modulators, including ZEPOSIA, and other MS and UC therapies and has been associated with some risk factors (e.g., immunocompromised patients, polytherapy with immunosuppressants, duration of use). Based on data from patients with MS, longer treatment duration increases the risk of PML in patients treated with S1P receptor modulators, and the majority of PML cases have occurred in patients treated with S1P receptor modulators for at least 18 months. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation. If confirmed, treatment with ZEPOSIA should be discontinued.

Immune reconstitution inflammatory syndrome (IRIS) has been reported in MS patients treated with S1P receptor modulators who developed PML and subsequently discontinued treatment. IRIS presents as a clinical decline in the patient’s condition that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes on MRI. The time to onset of IRIS in patients with PML was generally within a few months after S1P receptor modulator discontinuation. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

Bradyarrhythmia and Atrioventricular Conduction Delays: Since initiation of ZEPOSIA may result in a transient decrease in heart rate and atrioventricular conduction delays, dose titration is recommended to help reduce cardiac effects. If treatment with ZEPOSIA is considered, advice from a cardiologist should be sought for those individuals:

  • with significant QT prolongation
  • with arrhythmias requiring treatment with Class 1a or III anti-arrhythmic drugs
  • with ischemic heart disease, heart failure, history of cardiac arrest or myocardial infarction, cerebrovascular disease, and uncontrolled hypertension
  • with a history of Mobitz type II second-degree or higher AV block, sick sinus syndrome, or sino-atrial heart block

Liver Injury: Clinically significant liver injury, including acute liver failure requiring transplant, has occurred in patients treated with ZEPOSIA in the postmarketing setting. Signs of liver injury, including elevated serum hepatic enzymes and elevated total bilirubin, have occurred as early as ten days after the first dose. Obtain transaminase and bilirubin levels, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Obtain transaminase levels and total bilirubin levels periodically during treatment and until two months after ZEPOSIA discontinuation. Patients should be monitored for signs and symptoms of any hepatic injury. Patients who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes promptly checked, and ZEPOSIA should be interrupted. Treatment should not be resumed if a plausible alternative etiology for the signs and symptoms cannot be established, because these patients are at risk for severe drug-induced liver injury.

Fetal Risk: There are no adequate and well-controlled studies in pregnant women. Based on animal studies, ZEPOSIA may cause fetal harm. Women of childbearing potential should use effective contraception to avoid pregnancy during treatment and for 3 months after stopping ZEPOSIA. Women who become pregnant while taking ZEPOSIA for MS may enroll in the ZEPOSIA pregnancy registry by calling 1-877-301-9314 or visiting www.zeposiapregnancyregistry.com.

Increased Blood Pressure: Increase in systolic pressure was observed after about 3 months of treatment and persisted throughout treatment. Blood pressure should be monitored during treatment and managed appropriately.

Respiratory Effects: ZEPOSIA may cause a decline in pulmonary function. Spirometric evaluation of respiratory function should be performed during therapy, if clinically indicated.

Macular Edema: S1P modulators have been associated with an increased risk of macular edema. Obtain a baseline evaluation of the fundus, including a macula, near the start of treatment with ZEPOSIA. Perform an examination of the fundus, including the macula, periodically while on therapy and any time there is a change in vision. Continuation of ZEPOSIA therapy in patients with macular edema has not been evaluated. Macular edema over an extended period of time (i.e. 6 months) can lead to permanent visual loss. Consider discontinuing ZEPOSIA if macular edema develops. The risk of recurrence after rechallenge has not been evaluated.

Patients with a history of uveitis and patients with a history of diabetes mellitus are at increased risk of macular edema during ZEPOSIA therapy.

Cutaneous Malignancies: The risk of cutaneous malignancies (including basal cell carcinoma, squamous cell carcinoma, and melanoma) is increased in patients treated with S1P receptor modulators. Skin examinations are recommended prior to or shortly after the start of treatment and periodically thereafter for all patients, particularly those with risk factors for skin cancer. Providers and patients are advised to monitor for suspicious skin lesions. If a suspicious skin lesion is observed, it should be promptly evaluated. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using sunscreen with a high protection factor. Concomitant phototherapy with UV-B radiation or PUV-A photochemotherapy is not recommended in patients taking ZEPOSIA.

Posterior Reversible Encephalopathy Syndrome (PRES): Rare cases of PRES have been reported in patients receiving a S1P receptor modulator. If a ZEPOSIA-treated patient develops unexpected neurological or psychiatric symptoms or any symptom/sign suggestive of an increase in intracranial pressure, a complete physical and neurological examination should be conducted. Symptoms of PRES are usually reversible but may evolve into ischemic stroke or cerebral hemorrhage. Delay in diagnosis and treatment may lead to permanent neurological sequelae. If PRES is suspected, treatment with ZEPOSIA should be discontinued.

Unintended Additive Immunosuppressive Effects From Prior Immunosuppressive or Immune-Modulating Drugs: When switching from drugs with prolonged immune effects, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation.

Severe Increase in Multiple Sclerosis (MS) Disability After Stopping ZEPOSIA: In MS, severe exacerbation of disease, including disease rebound, has been rarely reported after discontinuation of a S1P receptor modulator. The possibility of severe exacerbation of disease should be considered after stopping ZEPOSIA treatment so patients should be monitored upon discontinuation. After stopping ZEPOSIA in the setting of PML, monitor for development of immune reconstitution inflammatory syndrome (PML-IRIS).

Immune System Effects After Stopping ZEPOSIA: After discontinuing ZEPOSIA, the median time for lymphocyte counts to return to the normal range was 30 days, with approximately 80% to 90% of patients in the normal range within 3 months. Use of immunosuppressants within this period may lead to an additive effect on the immune system, therefore caution should be applied when initiating other drugs 4 weeks after the last dose of ZEPOSIA.

Most Common Adverse Reactions that occurred in the MS clinical trials of ZEPOSIA-treated patients (≥4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

In the UC clinical trials, the most common adverse reactions that occurred in ≥4% of ZEPOSIA-treated patients and greater than in patients who received placebo were upper respiratory infection, liver test increased, and headache.

Use in Specific Populations: Hepatic Impairment: Dosage adjustment in patients with mild or moderate hepatic impairment (Child-Pugh class A or B) is required, and use of ZEPOSIA in patients with severe hepatic impairment (Child-Pugh class C) is not recommended.

For additional safety information, please see the full Prescribing Information and Medication Guide.

INDICATIONS

ZEPOSIA® (ozanimod) is indicated for the treatment of:

  1. Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.
  2. Moderately to severely active ulcerative colitis (UC) in adults.

 

Bristol Myers Squibb logo   

Contact Us  |  Privacy Policy  |  Your Privacy Choices  |  Legal-Notice  |  Bristol Myers Squibb  |  Site Map

ZEPOSIA, ZEPOSIA 360 Support and ZEPOSIA logo are trademarks of Celgene Corporation, a Bristol Myers Squibb company.
All other trademarks are the property of their respective owners.
© 2026 Bristol-Myers Squibb Company.
2084-US-2600083   09/26
2084-US-2600029   06/26