Encephalitis, Herpes Simplex

PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced an update following the initial analysis of results from the first of two induction studies in the Phase 3 YELLOWSTONE clinical trial program evaluating Zeposia (ozanimod) in adult patients with moderate to severe active Crohn’s disease. The study did not meet its primary endpoint of clinical remission at Week 12. The safety pro Zeposia in this study was consistent with that observed in previously reported trials. The company will complete a full evaluation of the YELLOWSTONE trial data and work with investigators to share the results with the scientific community in the future. “To date, no S1P modulator has shown an effect in a Phase 3 trial in Crohn’s disease, where a high unmet medical need remains for new therapies that offer more patients relief from symptoms and the potential for remission,” said Roland Chen, MD, senior vice president and head, Immunology, Cardiovascular and Neuroscience development, Bristol Myers Squibb. “While we are disappointed that the primary endpoint was not reached in this first induction trial, we are committed to driving transformative science on behalf of individuals with immune-mediated diseases and would like to thank the investigators and patients who are participating in the YELLOWSTONE clinical trial program.” About the YELLOWSTONE Clinical Trial Program YELLOWSTONE is a Phase 3, multicenter clinical trial program consisting of two 12-week induction studies, a 52-week maintenance study and a 264-week open-label extension study. YELLOWSTONE is designed to evaluate the safety and efficacy of Zeposia (ozanimod) administered orally to patients with Crohn’s disease versus placebo. The induction studies include approximately 600 patients each, with responders moving on to participate in the maintenance study. Nonresponders, those with disease relapse during maintenance, and completers of the maintenance study have the option to enroll in the open-label extension trial. Patients in the trial program are receiving Zeposia 0.92 mg (equivalent to 1 mg). The primary endpoint of the induction studies is the proportion of patients with a Crohn’s Disease Activity Index (CDAI) score of less than 150. The co-primary endpoints of the maintenance study are the proportion of patients with a CDAI score of less than 150 and the proportion of patients with a Simple Endoscopic Score for Crohn’s disease (SES-CD) score decrease from baseline of at least 50%. About Crohn’s disease Crohn's disease is a chronic inflammatory bowel disease (IBD) affecting the digestive tract. IBD results in the swelling or inflammation of the intestines, which may result in permanent damage and impact everyday life during disease flares. It is estimated that approximately 12.6 million people worldwide have IBD. For many patients, Crohn’s disease occurs in the colon or the third segment of the small intestine, the ileum, but may occur in any part of the intestinal tract. Signs and symptoms of Crohn’s disease can range from mild to severe. Most often, symptoms appear gradually but can sometimes develop suddenly or without warning. Patients with Crohn’s disease may experience ongoing disease symptoms, or have episodes of symptom-free remission, which can be followed by relapse or flares. Patients with Crohn's disease are also at an increased risk of developing colorectal cancer. Living with Crohn’s disease may severely affect quality of life both physically and psychologically, particularly during disease flares and relapses. Bristol Myers Squibb: Pioneering Paths Forward in Immunology to Transform Patients’ Lives Bristol Myers Squibb is inspired by a single vision – transforming patients’ lives through science. For people living with immune-mediated diseases, the debilitating reality of enduring chronic symptoms and disease progression can take a toll on their physical, emotional and social well-being, making simple tasks and daily life a challenge. Driven by our deep understanding of the immune system that spans over 20 years of experience, and our passion to help patients, the company continues to pursue pathbreaking science with the goal of delivering meaningful solutions that address unmet needs in rheumatology, gastroenterology, dermatology and pulmonology. We follow the science, aiming to tailor therapies to individual needs, improve outcomes and expand treatment options by working to identify mechanisms with the potential to achieve long-term remission – and perhaps even cures – in the future. By building partnerships with researchers, patients and caregivers to deliver innovative treatments, Bristol Myers Squibb strives to elevate patient care to new standards and deliver what matters most – the promise of living a better life. About Zeposia (ozanimod) Zeposia (ozanimod) is an oral, sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5. Zeposia blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which Zeposia exerts therapeutic effects in Crohn’s disease is unknown but may involve the reduction of lymphocyte migration into the gut. Zeposia is approved in numerous countries around the world for the treatment of adults with relapsing forms of MS and adults with moderately to severely active ulcerative colitis. U.S. FDA APPROVED INDICATIONS ZEPOSIA® (ozanimod) 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. 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. 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. 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. 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 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. 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 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. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on historical performance and current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, the possibility of unfavorable results from further clinical trials involving Zeposia (ozanimod) and whether Zeposia for the additional indication described in this release will be successfully developed and commercialized. No forward-looking statement can be guaranteed. Forward-looking statements in this press release should be evaluated together with the many risks and uncertainties that affect Bristol Myers Squibb’s business and market, particularly those identified in the cautionary statement and risk factors discussion in Bristol Myers Squibb’s Annual Report on Form 10-K for the year ended December 31, 2023, as updated by our subsequent Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and other filings with the Securities and Exchange Commission. The forward-looking statements included in this document are made only as of the date of this document and except as otherwise required by applicable law, Bristol Myers Squibb undertakes no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events, changed circumstances or otherwise. corporatefinancial-news

Sustained efficacy was confirmed with an annualized relapse rate of 0.098 and 67% of patients were relapse-free at six years Safety was consistent with prior findings and the established safety pro Zeposia with nearly 10 years of clinical experience In a separate DAYBREAK analysis, nearly 97% of followed patients were relapse-free at 90 days post Zeposia discontinuation; patients that did relapse showed no evidence of rebound effect PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb Company (NYSE: BMY) today announced new results from the Phase 3 DAYBREAK open-label extension trial, demonstrating the long-term efficacy and safety pro Zeposia (ozanimod) in patients with relapsing forms of multiple sclerosis (MS). These data (Poster #P090) and nine additional abstracts will be presented at the 9th annual Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2024 in West Palm Beach, Florida taking place February 29 to March 2. In the DAYBREAK long-term extension study, treatment with Zeposia demonstrated a low annualized relapse rate of 0.098. Three- and six-month confirmed disability progression was absent in 82.8% and 84.8% of participants in the trial respectively. At Month 60, the adjusted mean number of new/enlarging T2 lesions per scan (range: 0.79–0.93) and the adjusted mean number of gadolinium-enhancing lesions (0.06–0.08) were similar across patient cohorts. “These DAYBREAK data continue to validate the role of Zeposia in the long-term management of relapsing forms of multiple sclerosis, with two-thirds of patients relapse-free at six years of treatment,” said Bruce Cree, MD, PhD, MAS, study investigator and professor of Clinical Neurology, University of California San Francisco (UCSF) Weill Institute for Neurosciences and Clinical Research Director, UCSF MS Center. “These findings add to our confidence in Zeposia as an important treatment option for people living with the disease, highlighting its efficacy and safety over time.” In the DAYBREAK trial, 2,494 participants were exposed to Zeposia for an average of 60.9 months (12,664.7 person-years); 2,219 participants (89.0%) had any treatment-emergent adverse event (TEAE), 381 (15.3%) had a serious TEAE and 98 (3.9%) discontinued the study due to a TEAE. The most common TEAEs were nasopharyngitis (21.3%), headache (17.1%), COVID-19 infection (16.5%) and upper respiratory tract infection (12.4%). No new safety signals emerged; data from this long-term observational study of patients treated for up to 81.5 months were consistent with the established safety pro Zeposia. Additionally, a separate analysis (Poster #P097) was conducted to assess the risk of rebound after Zeposia discontinuation in the DAYBREAK trial. Five hundred forty-four participants (21.8%) discontinued the study early, while 1,950 participants (78.2%) remained on treatment until the end of the trial. Approximately 2.2% were known to have relapsed after permanently discontinuing Zeposia, with 87.3% of relapses occurring between 29 and 90 days (median time to onset: 61 days) after discontinuation. Nearly all patients were not taking any disease modifying therapy for MS at the time of relapse. Most relapses were mild (n=20 [36.4%]) or moderate (n=34 [61.8%]) and most patients made a complete recovery. No post-treatment relapse was associated with rebound effect, characterized by severe exacerbation of disease or severe persistent increase in disability. “Currently no cure exists for multiple sclerosis, but effective strategies and treatments can help slow disease progression and alleviate symptoms,” said Jonathan Sadeh, MD, MSc, senior vice president and head of global program leaders, Immunology, Cardiovascular and Neuroscience development, Bristol Myers Squibb. “These DAYBREAK efficacy, safety and rebound data underscore a consistent and sustained safety and efficacy pro add to the body of evidence supporting Zeposia’s role in the treatment armamentarium. We remain focused on advancing care and delivering meaningful innovations in neuroscience, including for the millions of people impacted by relapsing forms of multiple sclerosis.” At the ACTRIMS Forum 2024, Bristol Myers Squibb and collaborators will present multiple abstracts that reinforce the company’s growing body of research on Zeposia as a treatment for relapsing forms of MS and unwavering commitment to people living with the disease. Summary of Presentations: Bristol Myers Squibb presentations featured at the ACTRIMS Forum 2024 include: Zeposia clinical abstracts Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis: Final analysis of the DAYBREAK open-label extension study Author: Krzysztof Selmaj Presentation Number: P090 Session Number: Poster session 1 Absence of rebound effect following ozanimod discontinuation among participants in the DAYBREAK open-label extension study Author: Ralf Gold Presentation Number: P097 Session: Poster session 1 Patient-reported outcomes after 1 year of ozanimod use for early relapsing multiple sclerosis: An interim analysis of the ENLIGHTEN study Author: Sarah Morrow Presentation Number: P433 Session: Poster session 2 Baseline predictors of long-term disability progression in ozanimod-treated participants with relapsing multiple sclerosis from the SUNBEAM, RADIANCE, and DAYBREAK trials Author: Hans-Peter Hartung Presentation Number: P096 Session: Poster session 1 Changes in cognitive functioning over 1 year in ozanimod-treated patients with early relapsing multiple sclerosis: An interim analysis of the ENLIGHTEN study Author: John DeLuca Presentation Number: P354 Session: Poster session 2 Long-term efficacy of ozanimod in disease-modifying treatment–naive vs experienced patients with relapsing multiple sclerosis Author: Diego Centonze Presentation Number: P092 Session: Poster session 1 Long-term efficacy of the sphingosine 1-phosphate receptor modulator ozanimod by age category in patients with relapsing multiple sclerosis: Final results from two Phase 3 trials and an open-label extension trial Author: Bruce Cree Presentation Number: P091 Session: Poster session 1 Effects of ozanimod on cognitive processing speed: Updated findings from the Phase 3 SUNBEAM and DAYBREAK extension trials Author: John DeLuca Presentation Number: P353 Session: Poster session 2 Zeposia MS health economics outcomes research abstracts Real-world clinical outcomes for disease-modifying therapy–naïve and experienced patients with multiple sclerosis treated with ozanimod: A U.S. retrospective medical chart review Author: Damemarie Paul Presentation Number: P477 Session: Poster session 2 Ozanimod use in patients with multiple sclerosis treated in a large U.S. healthcare system: A retrospective case series Author: Jennifer Hadlock Presentation Number: P478 Session: Poster session 2 Bristol Myers Squibb thanks the patients and investigators who have participated in Zeposia clinical trials. About DAYBREAK DAYBREAK was a Phase 3, multi-center, long-term open-label extension study to evaluate the safety and efficacy of Zeposia (ozanimod) administered orally to patients with relapsing forms of multiple sclerosis (RMS). Eligible patients from the RADIANCE, SUNBEAM and RPC01-1001 trials diagnosed with RMS were enrolled to receive treatment until the end of the DAYBREAK. Patients in the trial received Zeposia 0.92 mg (equivalent to 1 mg). About Multiple Sclerosis Multiple sclerosis (MS) is a disabling, unpredictable disease in which the immune system attacks the protective myelin sheath that covers the nerves. The myelin damage disrupts communication between the brain and the rest of the body. Ultimately, the nerves themselves may deteriorate—a process that's currently irreversible. MS affects 700,000 people in Europe and approximately 2.9 million people worldwide. Relapsing forms of MS (RMS), including clinically isolated syndrome, relapsing remitting disease and active secondary progressive disease, is characterized by clearly defined attacks of worsening neurologic function. These attacks—often called relapses, flare-ups or exacerbations—are followed by partial or complete recovery periods. During these recovery periods, also called remissions, symptoms improve partially or completely with no apparent progression of disease. However, smoldering neuroinflammation can be present from the earliest stages of MS, which is underlying and continuous disease activity occurring simultaneously in different areas of the brain that contributes to disability accumulation. Since MS relapses are unpredictable, patients can feel frustrated, stressed or scared when they occur. RMS is the most common disease course at the time of diagnosis. Approximately 85% of patients are initially diagnosed with RMS, compared with 10%-15% diagnosed with progressive forms of the disease. Bristol Myers Squibb: Delivering Breakthrough Science for Meaningful Interventions in Neuroscience Neurological conditions represent some of the greatest challenges of our time because of their impact on society, including patients, caregivers, families and healthcare systems. At Bristol Myers Squibb, we are committed to advancing our robust pipeline of potential medicines for neurological disorders with the goal of modifying disease and improving quality of life. Leveraging genetics, biomarkers and predictive sciences, we target key pathways involved in the initiation and progression of neurological diseases to develop therapies with the potential to optimize patient outcomes. About Zeposia (ozanimod) Zeposia (ozanimod) is an oral, sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5. Zeposia blocks the capacity of lymphocytes to egress from lymph nodes, reducing the number of lymphocytes in peripheral blood. The mechanism by which Zeposia exerts therapeutic effects in multiple sclerosis (MS) is unknown but may involve the reduction of lymphocyte migration into the central nervous system. Zeposia is approved in numerous countries around the world for the treatment of adults with relapsing forms of MS and adults with moderately to severely active ulcerative colitis. U.S. FDA APPROVED INDICATIONS ZEPOSIA® (ozanimod) 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. 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. 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. 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. 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 . 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. 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 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. About Bristol Myers Squibb Bristol Myers Squibb is a global biopharmaceutical company whose mission is to discover, develop and deliver innovative medicines that help patients prevail over serious diseases. For more information about Bristol Myers Squibb, visit us at BMS.com or follow us on LinkedIn, Twitter, YouTube, Facebook and Instagram. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 regarding, among other things, the research, development and commercialization of pharmaceutical products. All statements that are not statements of historical facts are, or may be deemed to be, forward-looking statements. Such forward-looking statements are based on current expectations and projections about our future financial results, goals, plans and objectives and involve inherent risks, assumptions and uncertainties, including internal or external factors that could delay, divert or change any of them in the next several years, that are difficult to predict, may be beyond our control and could cause our future financial results, goals, plans and objectives to differ materially from those expressed in, or implied by, the statements. These risks, assumptions, uncertainties and other factors include, among others, that results of future post-marketing studies will be consistent with the results of this study, that Zeposia (ozanimod) for the additional indication described in this release may not be commercially successful, any marketing approvals, if granted, may have significant limitations on their use, and that continued approval of such treatment for such additional indication may be contingent upon verification and description of clinical benefit in additional confirmatory trials. No forward-looking statement can be guaranteed. 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Systemic lupus erythematosus (SLE) is an autoimmune disease, in which the immune system that normally protects the body from invading microbes turns against the body's own cells. Researchers studied four patients from two families who developed symptoms of SLE in the first years of life. As familial occurrence of SLE in young children is highly unusual, the team searched for a primary genetic cause and found a mutation in the UNC93B1 gene in all affected family members. Systemic lupus erythematosus (SLE) is an autoimmune disease, in which the immune system that normally protects the body from invading microbes, turns against the body´s own cells. This autoimmune attack can affect any organ and patients commonly develop skin rashes, joint inflammation, blood clots, kidney failure, heart disease, fatigue and psychiatric problems. Until to date, there is no cure for SLE and patients are treated with immunosuppressing drugs with considerable side effects. A group of researchers lead by Min Ae Lee-Kirsch from the Department of Pediatrics, Medical Faculty, TUD Dresden University of Technology (Germany), studied four patients from two families who developed symptoms of SLE in the first years of life. As familial occurrence of SLE in young children is highly unusual, her team searched for a primary genetic cause and found a mutation in the UNC93B1 gene in all affected family members. UNC93B1 is a membrane-spanning structural protein required for maturation and trafficking of a group of receptors that play an important role in the defense against viral infections. These receptors recognize the nucleic acid component of the virus and activate type I interferons, which instruct cells to fight a viral infection. However, nucleic acids, such as DNA and RNA, are not only found in viruses, but are also present in every cell of the human body. This means that the immune system must be capable of discriminating foreign from self nucleic acids. The identified UNC93B1 mutations lead to selective overactivation of TLR7, one of the UNC93B1-regulated receptors that specifically recognizes RNA, leading to erroneous recognition of self RNA with uncontrolled overproduction of type I interferon. This results in an immune attack on normal cells which then triggers inflammation. Moreover, this also stimulates the survival of self-reactive B cells that produce autoantibodies directed against the body´s own cells, fueling the autoimmune attack. These findings demonstrate that UNC93B1 controls the activity of specific nucleic acid receptors, such as TLR7, thereby preventing autoimmunity. Remarkably, people lacking functional UNC93B1 are prone to viral infections with a severe course, such as herpes simplex virus encephalitis and severe COVID-19, highlighting the essential role of UNC93B1 for a healthy immune system. The findings of this study are also of clinical relevance regarding the development of novel targeted therapies for patients with common forms of SLE, who often show signs of overactivation of the TLR7 pathway. Professor Lee-Kirsch says: "Our study demonstrates a direct causal link between an overactive UNC93B1/TLR7 axis and lupus pathogenesis and indicates that blocking overactive TLR7 might be therapeutically effective. As such, our findings are expected to accelerate further development of TLR7 inhibitors for patients with SLE and related autoimmune diseases." The study was funded in part by the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG) and the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung; BMBF). Results were published in Science Immunology as early release on January 11, 2024.