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CHMP recommendation based on positive results from the Phase 3 True North study, in which Zeposia demonstrated clinically meaningful improvements in key clinical, endoscopic and mucosal healing endpoints
If approved by the European Commission, Zeposia will become the first and only oral sphingosine 1-phosphate (S1P) receptor modulator approved for ulcerative colitis in the European Union
Bristol Myers Squibb (NYSE:BMY) today announced the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of Zeposia (ozanimod) for the treatment of adults with moderately to severely active ulcerative colitis (UC) who have had an inadequate response, lost response, or were intolerant to either conventional therapy or a biologic agent. Zeposia , an oral medication taken once daily, is a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity selectively to S1P subtypes 1 (S1P 1 ) and 5 (S1P 5 ). The CHMP recommendation will now be reviewed by the European Commission (EC), which has the authority to approve medicines for the European Union (EU).
"Despite available therapies, many people living with ulcerative colitis struggle to effectively manage this often relentless and unpredictable disease, making the availability of different treatment options extremely important," said Jonathan Sadeh, M.D., MSc., senior vice president of Immunology and Fibrosis Development, Bristol Myers Squibb. "With this positive recommendation from the CHMP, we are one step closer to bringing Z eposia, which has the potential to be a truly transformative medicine, and the first and only oral S1P receptor modulator for ulcerative colitis, to appropriate patients in the EU living with the disease."
The CHMP adopted this positive opinion based on data from True North, a pivotal Phase 3 trial evaluating Zeposia as an induction and maintenance therapy versus placebo in adult patients with moderately to severely active UC. The trial demonstrated significant improvements across all primary and secondary efficacy endpoints including clinical remission, clinical response, endoscopic improvement and endoscopic histologic mucosal improvement versus placebo at Week 10 and Week 52. The overall safety observed in True North was consistent with the known safety profile for Zeposia in approved labeling. The clinical findings from True North, entitled "Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis," were published in the September 30 th issue of The New England Journal of Medicine .
The U.S. Food and Drug Administration approved Zeposia for the treatment of adults with moderately to severely active UC on May 27, 2021.
Bristol Myers Squibb thanks the patients and investigators involved in the True North clinical trial.
About True North
True North is a Phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of Zeposia 0.92 mg in patients with moderately to severely active UC who had an inadequate response or were intolerant to any of the following: oral aminosalicylates, corticosteroids, immunomodulators or a biologic. Patients were to be receiving treatment with oral aminosalicylates and/or corticosteroids prior to and during the induction period. A total of 30% of patients had previously failed or were intolerant to TNF blockers. Of these patients, 63% received at least two biologics including TNF blockers. At study entry, mean age was 42 years, 60% were male and mean disease duration was 7 years; patient characteristics were well-balanced across treatment groups. In the 10-week induction study (UC Study 1), a total of 645 patients were randomized 2:1 to receive Zeposia (n=429) or placebo (n=216), of whom 94% and 89%, respectively, completed the induction study. No new safety signals were observed in the induction phase.
In maintenance, UC Study 2, a total of 457 patients who received Zeposia in either UC Study 1 or in an open-label arm and achieved clinical response at Week 10 were re-randomized 1:1 and were treated with either Zeposia 0.92 mg (n=230) or placebo (n=227) for 42 weeks (UC Study 2), for a total of 52 weeks of treatment. Concomitant aminosalicylates were required to remain stable through week 52. Patients on concomitant corticosteroids were to taper their dose upon entering the maintenance study. Of these, 80% and 54.6% of patients who received Zeposia and placebo, respectively, completed the study. In the maintenance phase, the overall safety profile was consistent with the known safety profile for Zeposia and patients with moderate-to-severe UC.
All eligible patients were rolled into an open-label extension trial, which is ongoing and designed to assess the longer-term profile of Zeposia for the treatment of moderately to severely active UC. More information can be found on www.clinicaltrials.gov , NCT02435992.
About Ulcerative Colitis
Ulcerative colitis, a chronic inflammatory bowel disease (IBD), is characterized by an irregular, chronic immune response that creates inflammation and ulcers (sores) in the mucosa (lining) of the large intestine (colon) or rectum. Symptoms include bloody stools, severe diarrhea and frequent abdominal pain. Ulcerative colitis has a major impact on patients' health-related quality of life, including physical functioning, social and emotional well-being and ability to go to work/school. Many patients have an inadequate response or do not respond at all to currently available therapies. It is estimated that approximately 12.6 million people worldwide are living with IBD.
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 reduces the capacity of lymphocytes to migrate from lymphoid tissue, reducing the number of circulating lymphocytes in peripheral blood. The mechanism by which Zeposia exerts therapeutic effects in ulcerative colitis is unknown but may involve the reduction of lymphocyte migration into the intestines.
Bristol Myers Squibb is continuing to evaluate Zeposia in an open-label extension trial, which is ongoing and designed to assess the longer-term profile of Zeposia for the treatment of moderately to severely active ulcerative colitis. The company is also investigating Zeposia for the treatment of moderately to severely active Crohn's disease in the ongoing Phase 3 YELLOWSTONE clinical trial program.
The U.S. Food and Drug Administration (FDA) approved Zeposia for the treatment of adults with moderately to severely active UC on May 27, 2021. Zeposia was approved by the FDA for the treatment of adults with relapsing forms of multiple sclerosis (RMS) in March 2020. The European Commission approved Zeposia for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS) with active disease as defined by clinical or imaging features in May 2020.
FDA APPROVED 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 the 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
- 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. PML has been reported in patients treated with S1P receptor modulators 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
- 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
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
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 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
For additional safety information, please see the full Prescribing Information and Medication Guide .
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 multiple sclerosis. 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 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 .
Celgene and Juno Therapeutics are wholly owned subsidiaries of Bristol-Myers Squibb Company. In certain countries outside the U.S., due to local laws, Celgene and Juno Therapeutics are referred to as, Celgene, a Bristol Myers Squibb company and Juno Therapeutics, a Bristol Myers Squibb company.
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, that the CHMP opinion is not binding on the EC and that Zeposia (ozanimod) may not receive regulatory approval for the additional indication described in this release in the currently anticipated timeline or at all, any marketing approvals, if granted, may have significant limitations on their use, and, if approved, whether such product candidate for such additional indication described in this release will be commercially successful. 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, 2020, 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.
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