THIS ARTICLE IS INTENDED FOR U.S. HEALTH CARE PROFESSIONALS ONLY.

Bringing a new option to the ulcerative colitis community

Bristol Myers Squibb’s oral treatment is now approved by the U.S. Food and Drug Administration

June 01, 2021

With symptoms such as frequent abdominal pain and severe diarrhea, ulcerative colitis (UC), a chronic inflammatory bowel disease (IBD), can be debilitating.1,2,3,4  Despite the availability of approved therapies, many patients are still seeking additional treatment options to manage their disease.5 Appropriate patients with UC now have an additional treatment option following the U.S. Food and Drug Administration’s approval of Bristol Myers Squibb’s Zeposia® (ozanimod) 0.92 mg for the treatment of adults with moderately to severely active UC on May 27, 2021.6

“As of 2015, approximately 3 million people in the United States have inflammatory bowel disease, which includes ulcerative colitis and Crohn’s disease.7 The needs of the ulcerative colitis patient community were squarely at the center of our pursuit of transformative science in this condition,” said Tina Deignan, vice president and U.S. head of Immunology, Bristol Myers Squibb. 

Zeposia is the first and only sphingosine 1-phosphate (S1P) receptor modulator approved for UC and works differently than available therapies.6 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.6,8,9

“This approval marks the first time Bristol Myers Squibb Immunology has offered a gastrointestinal disease treatment. We’re thrilled to introduce Zeposia, a new option for UC that combines disease control through lasting remission and demonstrated safety in a once-daily pill,6” said Deignan.

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.6

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 remissiona (18% versus 6%, p<0.0001) as well as key secondary endpoints, including clinical responseb (48% versus 26%, p<0.0001), endoscopic improvementc (27% versus 12%, p<0.0001) and endoscopic-histologic mucosal improvementd (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 remissiona (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 remissione (32% versus 17%, p<0.001) and endoscopic-histologic mucosal improvement (30% versus 14%, p<0.001) for Zeposia versus placebo, respectively. Additionally, 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.6

Deignan adds, “We are committed to making this therapy accessible to the patients who need it.” 

She explains that eligible patients can take part in the Zeposia 360 Support program, which 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. 

For more information on Zeposia and the Zeposia 360 SupportTM program, visit Zeposia.com.

INDICATION 

 

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

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.

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).

Corticosteroid-free remission is defined as clinical remission at Week 52 while off corticosteroids for ≥ 12 weeks.

References :

1. Crohn’s & Colitis Foundation. What is Ulcerative Colitis? https://www.crohnscolitisfoundation.org/what-is-ulcerative-colitis. Accessed May 26, 2021.
2. 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
3. Crohn’s & Colitis Foundation. Signs and Symptoms of Ulcerative Colitis. https://www.crohnscolitisfoundation.org/what-is-ulcerative-colitis/symptoms. Accessed May 26, 2021.
4. 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.
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. Zeposia Prescribing Information. Zeposia U.S. Product Information. Last updated: May 2021. Princeton, N.J.: Bristol-Myers Squibb Company.
7. 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.
8. 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
9. 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

2084-US-2100288  05/21