U.S. Food and Drug Administration Approves Bristol Myers Squibb’s Zeposia® (ozanimod), an Oral Treatment for Adults with Moderately to Severely Active Ulcerative Colitis1

Rhea-AI Summary

Bristol Myers Squibb (NYSE:BMY) announced FDA approval for Zeposia® (ozanimod) 0.92 mg to treat moderately to severely active ulcerative colitis (UC). This marks Zeposia as the first oral S1P receptor modulator approved for this condition. The approval is based on the True North Phase 3 trial, demonstrating significant improvements in clinical remission and other key endpoints. The company aims to enhance patient accessibility through the Zeposia 360 Support™ program, which includes financial assistance. A decision from the EMA regarding Zeposia's European approval is anticipated in late 2021.

Positive

• FDA approval of Zeposia for ulcerative colitis expands treatment options.
• Positive results from the True North Phase 3 trial, meeting primary and secondary endpoints.
• Zeposia 360 Support™ program to facilitate patient access and financial support.

Negative

• None.

Bristol Myers Squibb (NYSE:BMY) today announced that the U.S. Food and Drug Administration (FDA) approved Zeposia^® (ozanimod) 0.92 mg for the treatment of adults with moderately to severely active ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD).¹ Zeposia, an oral medication taken once daily, is the first and only sphingosine 1-phosphate (S1P) receptor modulator approved for patients with moderately to severely active UC. The mechanism by which Zeposia exerts therapeutic effects in UC is unknown but may involve the reduction of lymphocyte migration into the intestines. It is thought that by targeting S1P receptors on lymphocytes, a type of immune system cell, Zeposia reduces the number of lymphocytes in peripheral blood.^1,3,4

“Despite the availability of approved therapies, there is still unmet need and an opportunity to deliver additional treatment options to help patients better manage their disease,” said Adam Lenkowsky, general manager and head, U.S., Cardiovascular, Immunology and Oncology, Bristol Myers Squibb.⁵ “We’re thrilled that our pursuit of transformative science in immunology may benefit patients in their ulcerative colitis treatment by introducing a new option that has a different mechanism of action than available therapies. Zeposia combines disease control through lasting remission and demonstrated safety in a once-daily pill.”¹

The approval is 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. During induction at Week 10 (Zeposia N=429 versus placebo N=216) the trial met its primary endpoint of clinical remission^a (18% versus 6%, p<0.0001) as well as key secondary endpoints, including clinical response^b (48% versus 26%, p<0.0001), endoscopic improvement^c (27% versus 12%, p<0.0001) and endoscopic-histologic mucosal improvement^d (13% versus 4%, p<0.001) for Zeposia versus placebo, respectively. During maintenance at Week 52 (Zeposia N=230 versus placebo N=227) the trial met its primary endpoint of clinical remission^a (37% versus 19%, p<0.0001) as well as key secondary endpoints, including clinical response (60% versus 41%, p<0.0001), endoscopic improvement (46% versus 26%, p<0.001), corticosteroid-free clinical remission^e (32% versus 17%, p<0.001) and endoscopic-histologic mucosal improvement (30% versus 14%, p<0.001) for Zeposia versus placebo, respectively. Decreases in rectal bleeding and stool frequency subscores were observed as early as Week 2 (i.e.,1 week after completing the required 7-day dosage titration) in patients treated with Zeposia.

Zeposia is contraindicated in patients who in the last six 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; and patients taking a monoamine oxidase (MAO) inhibitor. Zeposia is associated with the following Warnings and Precautions: increased risk of infections, bradyarrhythmia and atrioventricular conduction delays, liver injury, fetal risk, increased blood pressure, respiratory effects, macular edema, posterior reversible encephalopathy syndrome (PRES), unintended additive immunosuppressive effects from prior immunosuppressive or immune-modulating drugs, and severe increase in disability and immune system effects after stopping Zeposia. Please see Important Safety Information for additional details. The most common adverse reactions (incidence ≥ 4%) were liver test increased, upper respiratory infection, and headache.¹

“In True North, Zeposia demonstrated efficacy for endpoints such as clinical remission, endoscopic and histological mucosal improvement and safety. All are very relevant considerations for patients with ulcerative colitis,” said Michael Chiorean, M.D., AGAF, FASGE, co-director of IBD Center, Swedish Medical Center, Seattle, Washington.⁶ “Zeposia has the potential to be an important new treatment option for adult patients with moderate to severe ulcerative colitis.”¹

“Ulcerative colitis can be debilitating and unpredictable for the people living with this chronic inflammatory bowel disease,” said Michael Osso, President & CEO of the Crohn’s & Colitis Foundation.^2,7,8 “The approval of this new oral treatment is welcome news for our community and provides hope to many patients who are looking for new options to achieve symptom relief and remission.”¹

Bristol Myers Squibb is committed to making Zeposia accessible to the patients who need it. The Zeposia 360 Support™ program will facilitate access to Zeposia for appropriate patients with UC. This includes a co-pay program for eligible appropriate patients to pay as little as $0 for their Zeposia prescription, assistance with financial support and a program that may help eligible patients with commercial insurance to receive free medication while they are experiencing delays or issues with insurance coverage. Support for eligible patients is also available for the routine initiation assessments, such as lab work. Through the program, health care professionals can opt to have eligible patients receive these tests in their own homes. These costs, whether incurred at home or in office, may be reimbursed. Terms, conditions, and eligibility criteria apply. More information is available at Zeposia.com.

A Marketing Authorization Application for Zeposia for the treatment of adults with moderately to severely active UC in the European Union is currently under review with the European Medicines Agency (EMA). A regulatory decision from the EMA is expected the second half of 2021.

About True North
True North is a Phase 3, multicenter, randomized, double-blind, placebo-controlled clinical trial assessing the efficacy and safety of Zeposia^® (ozanimod) 0.92 mg in patients with moderately to severely active ulcerative colitis 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.¹ 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.⁹ 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.⁹

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, for a total of 52 weeks of treatment.¹ Concomitant aminosalicylates were required to remain stable through Week 52. Patients on concomitant corticosteroids were to taper their dose upon entering the maintenance study.¹ Of these, 80% and 54.6% of patients who received Zeposia and placebo, respectively, completed the study.¹⁰

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 ulcerative colitis.¹⁰ More information can be found on www.clinicaltrials.gov, NCT02435992.

About Ulcerative Colitis
Ulcerative colitis (UC), 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.⁶ Symptoms include bloody stools, severe diarrhea and frequent abdominal pain.¹¹ 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.⁶ Many patients have an inadequate response or do not respond at all to currently available therapies.⁵ As of 2015, it was estimated that approximately 3 million adults in the United States have IBD, which includes UC and Crohn's disease.¹²

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.^1,4 Zeposia reduces the capacity of lymphocytes to migrate from lymphoid tissue, reducing the number of circulating lymphocytes in peripheral blood.⁴ 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.

Zeposia was approved by the U.S. Food and Drug Administration (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. The European Medicines Agency (EMA) validated Bristol Myers Squibb’s Marketing Authorization Application for Zeposia for the treatment of adults with moderately to severely active ulcerative colitis in December 2020. A regulatory decision from the EMA is expected in the second half of 2021.

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. 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 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.

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, whether Zeposia (ozanimod) for the additional indication described in this release will be commercially successful and that continued approval of such treatment for such additional indication described in this release may be contingent upon verification and description of clinical benefit in confirmatory trials. 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.

a	Clinical remission is defined as: rectal bleeding subscore = 0, stool frequency subscore = 0 or 1 (and a decrease from baseline in the stool frequency subscore of ≥ 1 point), and endoscopy subscore = 0 or 1 without friability.
b	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 1.
c	Endoscopic improvement is defined as a Mayo endoscopy subscore of 0 or 1 without friability.
d	Endoscopic-histologic mucosal improvement is defined as both Mayo endoscopic 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, i.e., Geboes <2.0).
e	Corticosteroid-free remission is defined as clinical remission at Week 52 while off corticosteroids for ≥ 12 weeks.

References

1. Zeposia Prescribing Information. Zeposia U.S. Product Information. Last updated: May 2021. Princeton, N.J.: Bristol-Myers Squibb Company.
2. Crohn’s & Colitis Foundation. What is Ulcerative Colitis? https://www.crohnscolitisfoundation.org/what-is-ulcerative-colitis. Accessed May 26, 2021.
3. Aoki M, Aoki H, Ramanathan R, Hait NC, Takabe K. Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential [published correction appears in Mediators Inflamm. 2016;2016:2856829]. Mediators Inflamm. 2016;2016:8606878. doi:10.1155/2016/8606878
4. Scott FL, Clemons B, Brooks J, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1 ) and receptor-5 (S1P5 ) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016;173(11):1778-1792. doi:10.1111/bph.13476
5. Danese S, Allez M, van Bodegraven AA, et al. Unmet Medical Needs in Ulcerative Colitis: An Expert Group Consensus. Dig Dis. 2019;37(4):266-283. doi:10.1159/000496739
6. Rubin D, Ananthakrishnan A, Siegel C, Sauer B, Long M. ACG Clinical Guideline: Ulcerative Colitis in Adults. American Journal of Gastroenterology. 2019;114:384–413. doi:10.14309
7. McMullan C, Pinkney TD, Jones LL, et al. Adapting to ulcerative colitis to try to live a ‘normal’ life: a qualitative study of patients’ experiences in the Midlands region of England BMJ Open 2017;7:e017544. doi: 10.1136/bmjopen-2017-017544
8. Crohn’s & Colitis Foundation. Signs and Symptoms of Ulcerative Colitis. https://www.crohnscolitisfoundation.org/what-is-ulcerative-colitis/symptoms.
Accessed May 26, 2021.
9. Sandborn W, D’Haens G, Wolf S, Hanauer S, Jovanovic I, Ghosh S, Petersen A, Hua S, Lee J, Charles L, Usiskin K, Danese S, Feagan B. Ozanimod As Induction Therapy in Moderate-To-Severe Ulcerative Colitis: Results from The Phase 3, Randomized, Double-Blind, Placebo-Controlled True North Study.
10. Danese, S, Feagan B, Wolf S, Hanauer S, Jovanovic I, Ghosh S, Petersen A, Hua S, Lee J, Charles L, Usiskin K, Sandborn W, D’Haens G, Ozanimod as Maintenance Therapy in Moderate-To-Severe Ulcerative Colitis: Results from The Phase 3, Randomized, Double-Blind, Placebo-Controlled True North Study.
11. National Institute of Diabetes and Digestive and Kidney Diseases. Ulcerative Colitis. https://www.niddk.nih.gov/health-information/digestive-diseases/ulcerative-colitis. Accessed May 26, 2021.
12. Centers for Disease Control and Prevention. Inflammatory Bowel Disease Prevalence (IBD) in the United States. https://www.cdc.gov/ibd/data-statistics.htm#1. Accessed May 26, 2021.

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FAQ

What did Bristol Myers Squibb announce regarding Zeposia on October 2023?

Bristol Myers Squibb announced the FDA approval of Zeposia® (ozanimod) for adults with moderately to severely active ulcerative colitis.

What is the significance of the True North trial for Zeposia?

The True North trial demonstrated Zeposia's effectiveness in achieving clinical remission and other significant health improvements for ulcerative colitis patients.

What support does Bristol Myers Squibb provide for Zeposia patients?

Bristol Myers Squibb offers the Zeposia 360 Support™ program, which includes financial assistance and access support for eligible patients.

When is the EMA expected to make a decision on Zeposia?

The European Medicines Agency (EMA) is expected to make a decision regarding Zeposia in the second half of 2021.

What type of medication is Zeposia?

Zeposia is an oral sphingosine 1-phosphate (S1P) receptor modulator approved for treating ulcerative colitis.