ZEPOSIA EFFICACY

Proven Control With ZEPOSIA—Rapid and Sustained Clinical Remission at Weeks 10 and 521

In the Subset of Patients in Clinical Remission at Week 52 and Had Continuous ZEPOSIA Exposure, 73% of Patients Were in Clinical Remission at Week 98 (Observed Cases)2

TRUE NORTH OLE is an ongoing trial that enrolled participants who were nonresponders at the end of induction, experienced disease relapse during maintenance, or completed maintenance treatment in the Phase 3 TRUE NORTH study or remained at study closure and received once-daily oral ZEPOSIA 0.92 mg in the Phase 2 TOUCHSTONE OLE. A total of 823 patients from TRUE NORTH entered the TRUE NORTH OLE as of the cut-off date (September 30, 2020). Mean ZEPOSIA exposure in the OLE was 1.5 years.3,4

Clinical remission, clinical response, endoscopic improvement, and corticosteroid (CS)-free remission were evaluated at Week 46 for all patients who entered the OLE from the TRUE NORTH parent study and in a subset of patients in clinical remission at Week 52 and had continuous ZEPOSIA exposure.2,3

Data were analyzed in the ITT population using OC and NRI. OC used the number of patients remaining in the study at the corresponding time point. NRI used the number of patients remaining in the study at the corresponding time point and those who withdrew before the time point but would have reached the time point if they had stayed.3

In the NRI analysis of a subset of patients in clinical remission at Week 52 and had continuous ZEPOSIA exposure, 53% (n=30/57) were in clinical remission at Week 98 (Week 46 of OLE).2

For all patients in OLE (N=823)3:

  • In the OC analysis, 45% of patients were in clinical remission at 46 weeks post-OLE entry
  • In the NRI analysis, 28% of patients were in clinical remission at 46 weeks post-OLE entry

aClinical remission is defined as: rectal bleeding subscore (RBS)=0, stool frequency subscore (SFS) 0 or 1 (and a decrease of ≥1 point from baseline SFS), and endoscopy subscore 0 or 1 without friability.1

bTreatment difference (adjusted for stratification factors of prior TNFi exposure and corticosteroid use at baseline).1

cTreatment difference (adjusted for stratification factors of clinical remission and concomitant corticosteroid use at Week 10).1

dData cutoff of September 30, 2020.3

eIn the NRI analysis of a subset of patients in clinical response at Week 52 and had continuous ZEPOSIA exposure, 53% (n=30/57) were in clinical remission at Week 98 (Week 46 of OLE).2

ITT=intent-to-treat; NRI=nonresponder imputation; OC=observed case; OLE=open-label extension; RBS=rectal bleeding subscore; SFS=stool frequency subscore; TNFi=tumor necrosis factor inhibitor; UC=ulcerative colitis.

Proven Control With ZEPOSIA—Rapid and Sustained Clinical Response at Weeks 10 and 521

In the Subset of Patients in Clinical Response at Week 52 and Had Continuous ZEPOSIA Exposure, 97% of Patients Were in Clinical Response at Week 98 (Observed Cases)2

TRUE NORTH OLE is an ongoing trial that enrolled participants who were nonresponders at the end of induction, experienced disease relapse during maintenance, or completed maintenance treatment in the Phase 3 TRUE NORTH study or remained at study closure and received once-daily oral ZEPOSIA 0.92 mg in the Phase 2 TOUCHSTONE OLE. A total of 823 patients from TRUE NORTH entered the TRUE NORTH OLE as of the cut-off date (September 30, 2020). Mean ZEPOSIA exposure in the OLE was 1.5 years.3,4

Clinical remission, clinical response, endoscopic improvement, and corticosteroid (CS)-free remission were evaluated at Week 46 for all patients who entered the OLE from the TRUE NORTH parent study and in a subset of patients in clinical response at Week 52 and had continuous ZEPOSIA exposure.2,3

Data were analyzed in the ITT population using OC and NRI. OC used the number of patients remaining in the study at the corresponding time point. NRI used the number of patients remaining in the study at the corresponding time point and those who withdrew before the time point but would have reached the time point if they had stayed.3

In the NRI analysis of a subset of patients in clinical response at Week 52 and had continuous ZEPOSIA exposure, 64% (n=61/95) were in clinical response at Week 98 (Week 46 of OLE).2

For all patients in OLE (N=823)3:

  • In the OC analysis, 80% of patients were in clinical response at 46 weeks post-OLE entry
  • In the NRI analysis, 48% of patients were in clinical response at 46 weeks post-OLE entry

aClinical response is defined as a reduction from baseline in the 3-component Mayo score of ≥2 points and ≥35%, and a reduction from baseline in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1.1

bTreatment difference (adjusted for stratification factors of prior TNFi exposure and corticosteroid use at baseline).1

cTreatment difference (adjusted for stratification factors of clinical remission and concomitant corticosteroid use at Week 10).1

dData cutoff of September 30, 2020.3

eIn the NRI analysis of a subset of patients in clinical response at Week 52 and had continuous ZEPOSIA exposure, 64% (n=61/95) were in clinical response at Week 98 (Week 46 of OLE).2

ITT=intent-to-treat; NRI=nonresponder imputation; OC=observed case; OLE=open-label extension; TNFi=tumor necrosis factor inhibitor.

Post-hoc Analysis: Symptomatic Response and Remission Observed in Patients Treated With ZEPOSIA Starting at Week 2a—1 Week After Completing the 7-Day Dose Titration5

In a post-hoc analysis, patients treated with ZEPOSIA observed a decrease in RBS and SFS as early as Week 2, 1 week after completing the 7-day dose titration.1,6

aITT population, observed cases.7

bSymptomatic response is defined as: a decrease from baseline of ≥1 point and ≥30% in the adapted partial Mayo score (sum of the RBS, SFS, and Physician Global Assessment subscore, ranging from 0-9 points) and a decrease of ≥1 point from baseline in RBS or an absolute RBS ≤1 point from baseline.5,8

cData are based on the nonresponder imputation.8

dSymptomatic remission is defined as: RBS=0 point and SFS ≤1 point (and a decrease of ≥1 from the baseline SFS).5,8

ITT=intention to treat; RBS=rectal bleeding subscore; SFS=stool frequency subscore.

Post-hoc Analysis: Symptomatic Clinical Responsea Observed Among Week 10 Nonrespondersb Treated With ZEPOSIA9

49% of Nonresponders Who Entered OLE at Week 10 After the Induction Period
Observed Symptomatic Clinical Response by Week 20 (OLE Week 10)

This analysis examined ZEPOSIA efficacy in patients from TRUE NORTH who were treated with double-blind ZEPOSIA but did not achieve clinical response at Week 10 and subsequently continued ZEPOSIA in the OLE (N=150) and observed extended treatment with ZEPOSIA for an additional 10 weeks. Efficacy analyses of symptomatic response were not prespecified.

aSymptomatic clinical response is defined as a reduction from baseline in the partial Mayo score of ≥1 point and ≥30% and a ≥1-point decrease in RBS or absolute RBS ≤1.9

bNonresponders were patients who did not achieve clinical response (defined as a reduction from baseline in the 3-component Mayo score of ≥2 points and ≥35%, and a reduction from baseline in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 1) on ZEPOSIA at Week 10 of induction and entered the OLE.9

cData are based on the nonresponder imputation.9

OLE=open-label extension; RBS=rectal bleeding subscore.

 

ZEPOSIA Demonstrated Mucosal Healing Defined by Significant Endoscopic-Histologic Mucosal Improvement1

Key Secondary Endpoints: Endoscopic Improvementa and Endoscopic-Histologic Mucosal Improvement (EHMI)b at Weeks 10 and 52 (% of Patients)1

ZEPOSIA for ulcerative colitis - endoscopic improvement and endoscopic improvement with histologic remission (mucosal healing) chart

The relationship of endoscopic-histologic mucosal improvement, as defined in UC Study 1 and UC Study 2 at Weeks 10 and 52, to disease progression and long-term outcomes, was not evaluated1

aEndoscopic improvement is defined as a Mayo endoscopy subscore of 0 or 1 without friability.1

bEndoscopic-histologic mucosal improvement is defined as both a Mayo endoscopy subscore of 0 or 1 without friability and histologic improvement of colonic tissue (defined as no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation tissue, ie, Geboes <2.0).1

cTreatment difference (adjusted for stratification factors of prior TNFi exposure and corticosteroid use at baseline).1

dTreatment difference (adjusted for stratification factors of clinical remission and concomitant corticosteroid use at Week 10).1

eThe relationship of EHMI, as defined in UC Study 1 and UC Study 2 at Weeks 10 and 52, to disease progression and long-term outcomes was not evaluated.1

 TNFi=tumor necrosis factor inhibitor.

ZEPOSIA: Control Is Possible Without the Use of Corticosteroids1

In the Subset of Patients in Clinical Remission at Week 52 and Had Continuous ZEPOSIA Exposure, 71% of Patients Were in CS-Free Remission at Week 98 (Observed Cases)2

ZEPOSIA for ulcerative colitis - corticosteroid-free clinical remission chart
  • Corticosteroid-free remission is defined as clinical remission while off corticosteroids for ≥12 weeks1
  • Clinical remission is defined as: rectal bleeding subscore (RBS)=0, stool frequency subscore (SFS) 0 or 1 (and a decrease of ≥1 point from baseline SFS), and endoscopy subscore 0 or 1 without friability1

In the NRI analysis of a subset of patients in clinical remission at Week 52 and had continuous ZEPOSIA exposure, 51% (n=29/57) were in CS-free remission at Week 98 (Week 46 of OLE).2

aTreatment difference (adjusted for stratification factors of clinical remission and concomitant corticosteroid use at Week 10).1

bData cutoff of September 30, 2020.3

cData were analyzed in the ITT population using OC and NRI. OC used the number of patients remaining in the study at the corresponding time point. NRI used the number of patients remaining in the study at the corresponding time point and those who withdrew before the time point but would have reached the time point if they had stayed.3

dFor all patients in OLE (n=823): In the OC analysis, 42% were in CS-free remission at 46 weeks post-OLE entry. In the NRI analysis, 26% were in CS-free remission at 46 weeks of post-OLE entry.3

CS=corticosteroid; ITT=intent-to-treat; NRI=nonresponder imputation; OC=observed case; OLE=open-label extension.

Efficacy Across TNFi Subgroups With Improved Disease Control Observed in TNFi-Naïve Patients at Weeks 10 and 521

Prespecified Subgroup Analysisa (% of Patients)

ZEPOSIA for ulcerative colitis subgroup analysis chart: TNFi-naïve patients vs TNFI-exposed patients at week 10
  • Clinical remission is defined as: rectal bleeding subscore=0, stool frequency subscore (SFS) 0 or 1 (and a decrease of ≥1 point from baseline SFS), and endoscopy subscore 0 or 1 without friability1
  • Clinical response is defined as: a reduction from baseline in the 3-component Mayo score of ≥2 points and ≥35%, and a reduction from baseline in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 11
  • Endoscopic improvement is defined as a Mayo endoscopy score=0 or 1 without friability1
  • Endoscopic-histologic mucosal improvement is defined as both a Mayo endoscopy subscore of 0 or 1 without friability and histologic improvement of colonic tissue (defined as no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation tissue, ie, Geboes <2.0)1
  • The relationship of endoscopic-histologic mucosal improvement, as defined in UC Study 1 and UC Study 2 at Weeks 10 and 52 to disease progression and long-term outcomes was not evaluated1

aEfficacy analysis by prior TNFi therapy was prespecified, but not powered to detect a difference in the treatment effect in these subgroups.6

EHMI=endoscopic-histologic mucosal improvement (mucosal healing); TNFi=tumor necrosis factor inhibitor.

Prespecified Subgroup Analysisa (% of Patients)

ZEPOSIA for ulcerative colitis subgroup analysis chart: TNFi-naïve patients vs TNFI-exposed patients at week 52
  • Clinical remission is defined as: rectal bleeding subscore=0, stool frequency subscore (SFS) 0 or 1 (and a decrease of ≥1 point from baseline SFS), and endoscopy subscore 0 or 1 without friability1
  • Clinical response is defined as: a reduction from baseline in the 3-component Mayo score of ≥2 points and ≥35%, and a reduction from baseline in the rectal bleeding subscore of ≥1 point or an absolute rectal bleeding subscore of 0 or 11
  • Endoscopic improvement is defined as a Mayo endoscopy score=0 or 1 without friability1
  • Endoscopic-histologic mucosal improvement is defined as both a Mayo endoscopy subscore of 0 or 1 without friability and histologic improvement of colonic tissue (defined as no neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation tissue, ie, Geboes <2.0)1
  • The relationship of endoscopic-histologic mucosal improvement, as defined in UC Study 1 and UC Study 2 at Weeks 10 and 52 to disease progression and long-term outcomes was not evaluated1

aEfficacy analysis by prior TNFi therapy was prespecified, but not powered to detect a difference in the treatment effect in these subgroups.6

EHMI=endoscopic-histologic mucosal improvement (mucosal healing); TNFi=tumor necrosis factor inhibitor.

See the demonstrated safety profile for
ZEPOSIA in clinical trials

References: 1. ZEPOSIA. Prescribing Information. Celgene Corporation, a Bristol Myers Squibb company. 2. Data on file. BMS-REF-OZA-022. Princeton, NJ; Bristol-Myers Squibb Company; 2021. 3. Danese S, Colombel JF, Ponich T, et al. Long-term use of ozanimod in patients with moderately to severely active ulcerative colitis. Oral Presentation at: ECCO 2022; February 16-19. 2022. Presentation DOP44. 4. Sandborn WJ, Feagan BG, Hanauer S. et al, Long-term efficacy and safety of ozanimod in moderately to severely active ulcerative colitis: results from the open-label extension of the randomized, phase 2 TOUCHSTONE study. J Crohns Colitis. 2021;15:1120-1129. 5. Siegmund B, Axelrad J, Pondel M, et al. Rapidity of ozanimod-induced symptomatic response and remission in patients with moderately to severely active ulcerative colitis: results from the induction period of True North. Poster presented at: ECCO 2022; February 16-19, 2022. 6. Sandborn WJ, Feagan BG, D’Haens G, et al. Ozanimod as induction and maintenance therapy for ulcerative colitis [supplementary appendix]. N Engl J Med. 2021;385(14):1280-1291. 7. Osterman MT, Longman R, Sninsky C, et al. Rapid induction effects of ozanimod on clinical symptoms and inflammatory biomarkers in patients with moderately to severely active ulcerative colitis: results from the induction phase of True North. Oral presentation at: DDW 2021 Virtual Disease Week; May 21-23, 2021. 8. Siegmund B, Axelrad J, Pondel M, et al. Rapidity of ozanimod-induced symptomatic response and remission in patients with moderately to severely active ulcerative colitis: results from the induction period of True North. Oral Presentation at: ECCO 2022; February 16-19, 2022. 9. Panaccione R, Afzali A, Hudesman D, et al. Extended therapy with ozanimod for delayed responders to ozanimod in moderately to severely active ulcerative colitis: data from the True North open-label extension study. Poster presented at: DDW 2022; May 21-24, 2022.

IMPORTANT SAFETY INFORMATION

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.

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 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.
  • 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. If PML is suspected, withhold ZEPOSIA and perform an appropriate diagnostic evaluation.

If confirmed, treatment with ZEPOSIA should be discontinued.

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 sino-atrial 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. 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. 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 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.

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 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: Use is not recommended.

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

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Indications:

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