DAYBREAK (OLE)

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DAYBREAK INTERIM SAFETY DATA WITH LONG‑TERM USE OF ZEPOSIA

Safety Findings Up to 3 Yearsa Were Generally Similar With Previous Studies of ZEPOSIA1

PRIMARY ENDPOINT

Summary of TEAEs in DAYBREAK in
Patients Treated With ZEPOSIA

  
ZEPOSIA
n=846
Any TEAE80.6%
Severe TEAEs4.6%
Serious TEAEs9.5%
TEAEs leading to permanent
treatment discontinuation
1.7%


TEAEs in ≥4% of patients treated
with ZEPOSIA
Nasopharyngitis17.1%
Headache14.1%
Upper respiratory tract infection9.5%
Lymphopenia8.2%
ALC decreased8.2%
Back pain6.6%
Urinary tract infection5.0%
GGT increased4.7%
Hypertension4.3%

Study Design1

  • DAYBREAK is an ongoing open-label extension (OLE) trial that enrolled participants from multiple randomized phase 1 to 3 studies including SUNBEAM and RADIANCE, and is presented as an interim analysis with a data cutoff of December 20, 2019
  • The patient population evaluated in this analysis included those receiving ZEPOSIA 0.92 mg (n=846) who completed the randomized phase 1 to 3 trials
  • The primary objective was to evaluate long-term safety of ZEPOSIA. Secondary objectives included ARR, new/enlarging T2 lesions, and GdE lesions. Endpoints were analyzed descriptively

TEAEs are sorted by decreasing incidence in patients treated with ZEPOSIA.

aStudy period includes DAYBREAK Day 1 through last treatment date for the data-cutoff date.

GGT=gamma-glutamyl transferase; TEAE=treatment-emergent adverse event.

ARRa Up to 3 yearsb for patients treated with zeposia1,2
Chart showing ARR up to 3 years in patients treated with Zeposia®
Absolute ARR for ZEPOSIA1,2
  • SUNBEAM 0.18
  • RADIANCE 0.17
  • DAYBREAK 0.11

DAYBREAK is an ongoing OLE trial that enrolled participants from multiple randomized phase 1 to 3 studies, including SUNBEAM and RADIANCE, and is presented as an interim analysis with a data cutoff of December 20, 2019. Endpoints were analyzed descriptively.

aA relapse was defined as the occurrence of new or worsening neurological symptoms persisting for more than 24 hours attributable to MS and immediately preceded by a relatively stable or improving neurological state of at least 30 days.3,4

bStudy period includes DAYBREAK Day 1 through last treatment date for the data-cutoff date.

GdE lesions Up to 3 yearsa IN patients treated with zeposia1
Chart showing GdE Lesions up to 3 years in patients treated with Zeposia®

Includes patients from SUNBEAM and RADIANCE clinical trials. Endpoints were analyzed descriptively.

aStudy period includes DAYBREAK Day 1 through last treatment date for the data-cutoff date.
NEW/enlarging T2 lesions Up to 3 yearsa IN patients treated with zeposia1
Chart showing new/Enlarging T2 lesions up to 3 years in patients treated with Zeposia®

Includes patients from SUNBEAM and RADIANCE clinical trials. Endpoints were analyzed descriptively.

aStudy period includes DAYBREAK Day 1 through last treatment date for the data-cutoff date.

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References: 1. Selmaj KW, Steinman L, Comi G, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1-3 trials. Presented at: 8th Joint Actrims-Ectrims Meeting; September 11-13, 2020; MSVirtual2020. Presentation P0217. 2. ZEPOSIA. Prescribing information. Bristol Myers Squibb; 2020. 3. 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. doi:10.1016/S1474-4422(19)30239-X 4. 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. doi:10.1016/S1474-4422(19)30238-8

IMPORTANT SAFETY INFORMATION

Indication

ZEPOSIA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

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 or third-degree atrioventricular (AV) block, sick sinus syndrome, or sino-atrial, 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 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 was reported as an adverse reaction in ZEPOSIA-treated patients. 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. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to commencing treatment with ZEPOSIA
  • Cases of fatal cryptococcal meningitis (CM) were reported in patients treated with another S1P receptor modulator. If CM is suspected, ZEPOSIA should be suspended until cryptococcal infection has been excluded. If CM is diagnosed, appropriate treatment should be initiated.
  • Progressive Multifocal Leukoencephalopathy (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. No cases of PML were identified in active-controlled MS clinical trials with ZEPOSIA. PML has been reported in patients treated with S1P receptor modulators and other MS therapies and has been associated with some risk factors. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation. If confirmed, treatment with ZEPOSIA should be discontinued
  • In 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. 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

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. Initiation of ZEPOSIA without dose escalation may result in greater decreases in heart rate. 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 sinoatrial heart block

Liver Injury: Elevations of aminotransferases may occur in patients receiving ZEPOSIA. Obtain liver function tests, if not recently available (i.e., within 6 months), before initiation of ZEPOSIA. Patients who develop symptoms suggestive of hepatic dysfunction should have hepatic enzymes checked and ZEPOSIA should be discontinued if significant liver injury is confirmed. Caution should be exercised when using ZEPOSIA in patients with history of significant liver disease

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

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. Certain foods that may contain very high amounts of tyramine could cause severe hypertension in patients taking ZEPOSIA. Patients should be advised to avoid foods containing a very large amount of tyramine while taking ZEPOSIA

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. Patients with a history of uveitis or diabetes mellitus are at increased risk. Patients with a history of these conditions should have an ophthalmic evaluation of the fundus, including the macula, prior to treatment initiation and regular follow-up examinations. An ophthalmic evaluation is recommended in all patients at any time if there is a change in vision. Continued use of ZEPOSIA in patients with macular edema has not been evaluated; potential benefits and risks for the individual patient should be considered if deciding whether ZEPOSIA should be discontinued

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. Initiating treatment with ZEPOSIA after treatment with alemtuzumab is not recommended

Severe Increase in Disability After Stopping ZEPOSIA: 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

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 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 (≥ 4%): upper respiratory infection, hepatic transaminase elevation, orthostatic hypotension, urinary tract infection, back pain, and hypertension.

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

ZEPOSIA Delivers
Powerful Efficacy vs Avonex

Proven Superior vs Avonex in Reducing ARR1ab

Chart showing absolute ARR (annualized relapse rate) for Zeposia® and Avonex, proven in 2 clinical trials (1-year and 2-year study)
Absolute ARR for ZEPOSIA
  • SUNBEAM 0.18
  • RADIANCE 0.17
ZEPOSIA—Proven Superior to Avonex in Reducing Lesions Across All Secondary Measures of MRI Activity

Significant Reductions vs Avonex Across All Secondary Measures of MRI Activity1

Up to 63% Fewer GdE Lesions vs Avonex1

Chart showing reduction of GdE Lesions in 2 Zeposia® clinical trials with up to 63% fewer GdE Lesions for 1-year and up to 53% reduction for 2-year study vs Avonex
GdE Lesions at Baseline
The mean number of GdE lesions observed in patients at baseline for both ZEPOSIA and Avonex was 1.8 in SUNBEAM and 1.7 in RADIANCE2,3

In the 1-year SUNBEAM study, brain MRIs were performed at baseline, Month 6, and Month 12.2

In the 2-year RADIANCE study, brain MRIs were performed at baseline, Month 12, and Month 24.3

Up to 48% Fewer New or Enlarging T2 Lesions vs Avonex1

Chart showing a reduction in new or enlarging T2 Lesions in Zeposia® clinical trials with up to 48% fewer new or enlarging T2 lesions in 1-year and up to 42% in 2-year study vs Avonex
T2 Lesions at Baseline
The mean number of T2 lesions observed in patients at baseline for both ZEPOSIA and Avonex was 54 in SUNBEAM and 48 in RADIANCE2,3

In the 1-year SUNBEAM study, brain MRIs were performed at baseline, Month 6, and Month 12.2

In the 2-year RADIANCE study, brain MRIs were performed at baseline, Month 12, and Month 24.3

9 of 10 Patients Showed No Confirmed 3-Month Disability Progression

CDP Results From Clinical Trials1


Disability progression results: 92.4% for Zeposia vs 92.2% for Avonex showed no confirmed 3-month disability progression

92.4% vs 92.2% for Avonex Showed No Confirmed 3-Month Disability Progression

Patients Classified as Having No Disability Progression Did Not Show Sustained Worsening for 3 Consecutive Months1c

7.6% of patients treated with ZEPOSIA (n=67/880) experienced 3‑month CDP, as measured by EDSS, similar to Avonex (7.8%; n=69/889) (P=NS)1,3

Statistical significance was not reached for the pooled confirmed disability progression.3

ZEPOSIA—A safety profile comparable to avonex in overall incidence of adverse reactions

Overall incidence of adverse reactions was similar across 2 pivotal head-to-head trials (N=2659)2,3

Overall Incidence of Adverse Reactions

  • SUNBEAM: Avonex 75.5% | ZEPOSIA 59.8%
  • RADIANCE: Avonex 83.0% | ZEPOSIA 74.7%

Adverse Reactions With an Incidence of at Least 2% in Patients Treated With ZEPOSIA and at Least 1% Greater Than Avonex1d

SUNBEAM and RADIANCE: POOLED DATA   
Adverse ReactionsAvonex
n=885
ZEPOSIA
n=822
Upper respiratory infectione23%26%
Hepatic transaminase elevationf
5%10%
Orthostatic hypotension3%4%
Urinary tract infection
3%4%
Back pain3%4%
Hypertensiong2%4%
Abdominal pain upper1%2%

Adverse reactions are sorted by decreasing incidence in patients treated with ZEPOSIA.

For adverse reactions pertaining to liver function tests, increases were transient and generally resolved without discontinuation.1

Elevations of 3-fold the ULN or greater occurred in 5.5% of patients taking ZEPOSIA and in 3.1% of patients taking Avonex. The majority (79%) continued treatment with ZEPOSIA with values returning to less than 3 times the ULN within approximately 2 to 4 weeks.1

1.6%

(n=448)

vs 2.2% for
Avonex (n=445)

3.5%

(n=434)

vs 4.3% for
Avonex (n=440)

2.9%

(n=448)

vs 2.5% for
Avonex (n=445)

6.5%

(n=434)

vs 6.4% for
Avonex (n=440)

Daybreak interim safety data with long-term use of zeposia

Safety Findings Up to 3 Yearsh Were Generally Similar With Previous Studies of ZEPOSIA4

PRIMARY ENDPOINT

Summary of TEAEs in DAYBREAK in
Patients Treated With ZEPOSIA

  
ZEPOSIA
n=846
Any TEAE80.6%
Severe TEAEs4.6%
Serious TEAEs9.5%
TEAEs leading to permanent
treatment discontinuation
1.7%

TEAEs in ≥4% of patients treated
with ZEPOSIA
Nasopharyngitis17.1%
Headache14.1%
Upper respiratory tract infection9.5%
Lymphopenia8.2%
ALC decreased8.2%
Back pain6.6%
Urinary tract infection5.0%
GGT increased4.7%
Hypertension4.3%

Study Design4

  • DAYBREAK is an ongoing open-label extension (OLE) trial that enrolled participants from multiple randomized phase 1 to 3 studies including SUNBEAM and RADIANCE, and is presented as an interim analysis with a data cutoff of December 20, 2019
  • The patient population evaluated in this analysis included those receiving ZEPOSIA 0.92 mg (n=846) who completed the randomized phase 1 to 3 trials
  • The primary objective was to evaluate long-term safety of ZEPOSIA. Secondary objectives included ARR, new/enlarging T2 lesions, and GdE lesions. Endpoints were analyzed descriptively

TEAEs are sorted by decreasing incidence in patients treated with ZEPOSIA.

aStudy designs: SUNBEAM (1 year; N=1346) and RADIANCE (2 years; N=1313) 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 vs weekly Avonex (interferon beta-1a), 30-μg intramuscular injection. Primary endpoint: ARR was assessed for ZEPOSIA and Avonex at 1 year and 2 years. Secondary endpoints: The number of new or enlarging T2 lesions and the number of GdE lesions were assessed for ZEPOSIA and Avonex at 1 year and 2 years. In addition, confirmed disability progression was prospectively evaluated for ZEPOSIA and Avonex in a pooled analysis from the 1-year and 2-year studies. There was no significant difference in 3-month confirmed disability between ZEPOSIA and Avonex.1-3
bA relapse was defined as the occurrence of new or worsening neurological symptoms persisting for more than 24 hours attributable to MS and immediately preceded by a relatively stable or improving neurological state of at least 30 days.2,3
cCDP was defined as at least a 1-point increase from baseline EDSS confirmed after 3 months and after 6 months. CDP was prospectively evaluated in a pooled analysis from SUNBEAM (1 year) and RADIANCE (2 years) studies.1
dData are not an adequate basis for comparison of rates between ZEPOSIA and the active control.
eIncludes the following terms: nasopharyngitis, upper respiratory tract infection, pharyngitis, respiratory tract infection, bronchitis, rhinitis, respiratory tract infection viral, viral upper respiratory tract infection, rhinorrhea, tracheitis, and laryngitis.
fIncludes the following terms: alanine aminotransferase increased, gamma-glutamyl transferase increased, aspartate aminotransferase increased, hepatic enzyme increased, liver function test abnormal, and transaminases increased.
gIncludes hypertension, essential hypertension, and orthostatic hypertension.
hStudy period includes DAYBREAK Day 1 through last treatment date for the data-cutoff date.

ARR=annualized relapse rate; CDP=confirmed disability progression; EDSS=Expanded Disability Status Scale; GdE=gadolinium enhancing; GGT=gamma-glutamyl transferase; MS=multiple sclerosis; NS=nonsignificant; TEAE=treatment-emergent adverse event; ULN=upper limit of normal.

References: 1. ZEPOSIA. Prescribing information. Bristol Myers Squibb; 2020. 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. doi:10.1016/S1474-4422(19)30239‑X 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. doi:10.1016/S1474-4422(19)30238-8 4. Selmaj KW, Steinman L, Comi G, et al. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 1-3 trials. Presented at: 8th Joint Actrims-Ectrims Meeting; September 11-13, 2020; MSVirtual2020. Presentation P0217.

ZEPOSIA® is a registered trademark of Celgene Corporation, a Bristol-Myers Squibb Company.

Avonex® is a registered trademark of Biogen.

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