Elevated liver aminotransferase levels were more common with ozanimod. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. Mucosal healing was defined as endoscopic improvement plus histologic remission (i.e., a Geboes score of <2.0 [on a scale from 0 to 5.4, with higher scores indicating more severe inflammation] and an absence of neutrophils in the epithelial crypts or lamina propria and no increase in eosinophils, no crypt destruction, and no erosions, ulcerations, or granulation tissue). 15. Lancet Gastroenterol Hepatol. Randomization and Follow-up of the Patients in the Induction and Maintenance Periods. Colitis, Ulcerative, Colitis, Ulcer, Golimumab . Patients were randomly assigned, in a 1:1:1 ratio, to receive oral ozanimod at a dose of 0.5 mg or 1 mg (the choice of these doses was based on modeling of preclinical and phase 1 data) or placebo, once daily. Background: Only one head-to-head comparison of advanced treatments in moderately to severely active ulcerative colitis (UC) has been published; therefore, there remains a need for further comparisons. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. Once the percentage of patients with previous exposure to a tumor necrosis factor (TNF) antagonist reached 30% in cohort 1, the IxRS assigned patients with TNF antagonist exposure to cohort 2, in which patients received open-label ozanimod at the same daily dose. Assessment of vital signs, pulmonary-function testing, ophthalmologic examination (including optical coherence tomography), and electrocardiography (before and 6 hours after the first dose) were also performed. USA: A recent study in the New England Journal of Medicine reported ozanimod to be more effective than placebo for the treatment of patients with moderately to severely active ulcerative colitis. N1 - Funding Information: All the authors had full access to the data. S2 in the Supplementary Appendix). 2022 May;56(5):592-599. doi: 10.1177/10600280211041907. Endoscopic and histologic end points were determined by one central reader who used blinded videos of endoscopic procedures and preserved biopsy samples, respectively. The time to disease relapse was examined as an exploratory end point. In cohort 1, patients were randomly assigned to receive ozanimod or placebo; once the percentage of patients with previous exposure to a tumor necrosis factor (TNF) antagonist reached 30%, subsequent patients with TNF antagonist exposure were assigned to cohort 2, in which they received open-label ozanimod. METHODS We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. At the end of the 10-week induction period, ozanimod outperformed placebo on every measure of clinical effectiveness: clinical remission (23.4% vs. 8.9%), clinical response (53.7% vs. 30.7%), endoscopic improvement (35.6% vs. 14.9%) and mucosal healing (18% vs. 5%). The site is secure. Gastroenterology. The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). Am J Gastroenterol 2019;114:384-413. Li M, Zhang R, Xin M, Xu Y, Liu S, Yu B, Zhang B, Liu J. Metabolites. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. BACKGROUND: Ozanimod, an oral sphingosine 1-phosphate receptor modulator currently approved for the treatment of moderately to severely active ulcerative colitis and relapsing multiple sclerosis, showed clinical, endoscopic, and histological benefit in the phase 2 STEPSTONE trial for Crohn's disease (CD). 24. First, the time point of week 8 that was chosen for the evaluation of efficacy during induction may not be long enough for drugs that target lymphocyte trafficking, a possibility that is supported by the enhanced benefits seen in maintenance with antitrafficking agents.2 Second, as noted above, given the relatively brief duration of observation and the small number of patients evaluated, we cannot assess the safety of ozanimod. METHODS We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Mayo Clinic scores range from 0 to 12, with higher values indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. Demographic and Clinical Characteristics of the Patients at Baseline in the Induction Period (Modified Intention-to-Treat Population).*. Cancer was diagnosed in 1 patient who received ozanimod during the induction period (basal-cell carcinoma). Science 2002;296:346-349, 6. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. The key secondary efficacy end points were assessed in a closed, prespecified hierarchical testing procedure. 10. Editorial assistance was funded by Bristol Myers Squibb. After a screening period of up to 5 weeks, patients entered a 10-week induction period. A documented presence of varicellazoster virus IgG antibody or complete varicellazoster vaccination at least 30 days before randomization was also required. [5] Editorial assistance was funded by Bristol Myers Squibb. Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. 18. IMPORTANT SAFETY INFORMATION Contraindications: Aliment Pharmacol Ther 2016;44:1018-1029. Elevated liver aminotransferase levels were more common with ozanimod therapy than with placebo. ZEPOSIA is a sphingosine 1-phosphate receptor modulator 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. Fingolimod-associated macular edema: incidence, detection, and management. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Rosen H, Gonzalez-Cabrera PJ, Sanna MG, Brown S. Sphingosine 1-phosphate receptor signaling. The most advanced way to teach, practice, and assess clinical reasoning skills. Lancet Gastroenterol Hepatol. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. Four patients who received ozanimod (one patient who received 0.5 mg and three who received 1 mg) had an increase in the alanine aminotransferase level of more than 3 times the upper limit of the normal range during treatment. (%), Adverse event leading to discontinuation of the regimen no. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. Aim: The relative treatment effects of filgotinib and adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab were estimated using a network meta-analysis (NMA). Studies of other agents, notably monoclonal antibodies directed toward adhesion molecules, have previously shown that interference with lymphocyte trafficking is an effective therapeutic approach for patients with ulcerative colitis. N Engl J Med 2005;353:2462-2476, 20. Cohen JA, Comi G, Selmaj KW, et al. One patient in the 0.5-mg ozanimod group who had evidence of preexisting bradycardia (heart rate of 50 beats per minute and a PR interval of 198 msec before ozanimod treatment was initiated) had first-degree atrioventricular block and sinus bradycardia on day 8 (heart rate, 46 beats per minute; PR interval, 201 msec [upper limit of the normal range, 200 msec]); this event was asymptomatic and transient and resolved without intervention. Cohort 2 was included to increase the number of patients with a response who would be available for randomization in the maintenance phase of the trial. Ozanimod appears to be an effective treatment for moderate to severe ulcerative colitis (UC), according to research presented at the Advances in Inflammatory Bowel Diseases (AIBD) 2021 Annual Meeting, held from December 9 to 11, 2021, in Orlando, Florida and virtually. NEW! Neurology 2008;71:1261-1267, 11. A Phase 2b Randomized, Double-blind, Active-and Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Efficacy and Safety of Induction and Maintenance Combination Therapy With Guselkumab and Golimumab in Participants With Moderately to Severely Active Ulcerative Colitis. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. Rieder F, Wolf DC, Charles L, Kollengode K, Patel A, Ghosh S. Incidence of infections in patients with moderately to severely active ulcerative colitis treated with ozanimod and relationship to significant lymphopenia: results from a pooled . Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. Safety was also assessed. For end points that were not included in the hierarchies, point estimates and 95% confidence intervals are reported, without P values. Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Ozanimod-treated patients who had a clinical response (defined as a reduction in the total Mayo score of 3 points and 30% from baseline or in the three-component Mayo score of 2 points and 35% from baseline, as well as a reduction in the rectal-bleeding subscore of 1 point or an absolute rectal-bleeding subscore of 1 point) at week 10 were eligible to undergo randomization again, in a 1:1 ratio, to receive either ozanimod or placebo in a double-blind manner through week 52 (maintenance period). Scores were assessed by a central reader. 2022 Jun;162(7):2104-2106. doi: 10.1053/j.gastro.2022.01.033. In the maintenance phase, we typically rely on the drug to maintain the remission that was induced in the initial induction phase. All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. Long-Term Efficacy and Safety of Ozanimod in Moderately to Severely Active Ulcerative Colitis: Results From the Open-Label Extension of the Randomized, Phase 2 TOUCHSTONE Study. PDF | On Dec 5, 2022, Benjamin Misselwitz and others published Sphingosin-1-Phosphat-Rezeptor-Modulatoren bei Colitis ulcerosa - Game Changer oder einer unter vielen?Modulateurs du rcepteur de . The .gov means its official. Nat Rev Gastroenterol Hepatol 2020;17:1-2. Treatment-effect sizes in patients with TNF antagonist exposure were similar to those in patients without such exposure. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. Randomization was performed centrally with the use of a computerized system and was stratified according to previous exposure to a tumor necrosis factor (TNF) antagonist (yes or no). We have sent a message to the email address you have provided, .If this email is not correct, please update your settings with your correct address. Blood samples were obtained at each visit for clinical chemical and hematologic studies and for the measurement of the C-reactive protein concentration. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.5 mg or 1 mg or placebo daily for up to 32 weeks. An official website of the United States government. N2 - BACKGROUND Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. Zeposia reduces the capacity of lymphocytes to exit from lymph nodes, reducing the number of circulating lymphocytes in peripheral blood. Elevated liver aminotransferase levels were more common with ozanimod. Cohort 2 (with a planned sample of 300 patients) was used to ensure that the trial would have an enrollment of 400 patients in the maintenance period, with the trial having 90% power for the primary end point. METHODS We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Demographic and Clinical Characteristics of the Patients at Baseline in the Induction Period (Modified Intention-to-Treat Population). The eighth and ninth authors, both employees of the sponsor, vouch for the completeness and accuracy of the data, and the eighth author vouches for the adherence of the trial to the protocol. (%), Had a secondary nonresponse no./total no. Overall, our results were consistent with safety findings that have previously been reported regarding ozanimod therapy in phase 3 trials involving patients with multiple sclerosis.12,14,15, Our trial design was informed by the increasing use of rigorous therapeutic targets beyond symptom control and endoscopic improvement in patients with ulcerative colitis, such as mucosal healing (requiring both endoscopic and histologic improvement) and reduced use of glucocorticoids.27-30 For example, we required that the definition of mucosal healing include the absence of mucosal neutrophils, which has been associated with a reduced incidence of colectomy, hospitalization, and glucocorticoid use.30,31 We also defined glucocorticoid-free remission as clinical remission at week 52 without glucocorticoid use for at least 12 weeks because relapse within 12 weeks after the discontinuation of glucocorticoid therapy is a defining characteristic of patients with ulcerative colitis in whom the glucocorticoid dose cannot be reduced beyond a certain threshold without relapse occurring.32. Adverse events and use of concomitant medications were recorded through 32 weeks. Ozanimod previously demonstrated efficacy and tolerable safety in patients with moderate to severe UC for up to 32 weeks in the phase II TOUCHSTONE study. *The final safety follow-up visit was scheduled to occur 90 days (within a window of 10 days) after the final dose of ozanimod or placebo. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. The primary efficacy end point was the percentage of patients with clinical remission at week 10 (for the induction period) and at week 52 (for the maintenance period), assessed on the basis of the three-component Mayo score. During the maintenance period, serious adverse events of hypertensive crisis occurred in 1 patient each in the ozanimod group and the placebo group; neither event resulted in discontinuation of the trial regimen. The modified intention-to-treat population included all patients who underwent randomization and received at least one dose of ozanimod or placebo. FormalPara Hintergrund. The time to disease relapse (an exploratory end point) during the maintenance period is shown in Figure S4. Disclaimer, National Library of Medicine The most common adverse events overall were anemia and headache. Zeposia. All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. Ozanimod, sold under the brand name Zeposia, is an immunomodulatory medication for the treatment of relapsing multiple sclerosis and ulcerative colitis. PDF Ozanimod for the treatment of relapsing remitting multiple sclerosis Ludwig Rasche, F. Paul Biology, Psychology Ozanimod induction and maintenance treatment for ulcerative colitis. The patient discontinued treatment after these events. The incidences of elevated alanine aminotransferase levels were higher among patients who received ozanimod than among those who received placebo. PMC Ozanimod induction therapy for patients with moderate to severe Crohn's disease: a single-arm, phase 2, prospective observer-blinded endpoint study. Grler MH, Goetzl EJ. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. A total of 184 patients (80.0%) who had been assigned to receive ozanimod and 124 (54.6%) who had been assigned to receive placebo completed the maintenance period. Biometrika 1976;63:581-592. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. The three-component Mayo score is defined as the sum of the rectal-bleeding subscore, the stool-frequency subscore, and the endoscopy subscore; overall scores range from 0 to 9 (with each subscore ranging from 0 to 3), with higher scores indicating greater activity. Br J Clin Pharmacol 2013;76:888-896. Editorial assistance was funded by Bristol Myers Squibb. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis N Engl J Med. 11. Given the nonsignificant findings for the comparison of the remission rate at week 8 in the group that received 0.5 mg of ozanimod with that in the placebo group, all subsequent analyses were considered to be exploratory and the results not significant (nominal P values are provided). note = "Funding Information: The members of the steering committee designed the trial in collaboration with the sponsor (Bristol Myers Squibb). Prespecified subgroup analyses for the primary end point of clinical remission during the induction period are shown in Figure S3. Bradycardia, cardiac conduction abnormalities (second-degree and higher atrioventricular block), macular edema, cancer, serious or opportunistic infection, pulmonary effects, and hepatic effects were examined as adverse events of special interest on the basis of previous associations with S1P receptor modulation.21,22 Clinical laboratory measurements were performed at a central laboratory. 2022 Sep 8;18:913-927. doi: 10.2147/TCRM.S336139. government site. 2022 Aug;18(8):453-465. Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Lfberg R. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. No patients met Hys law criteria suggestive of drug-induced liver injury or had severe liver injury. and Subrata Ghosh and Petersen, {Ann Katrin} and Hua, {Steven Y.} 18. With respect to the advantages, the convenience of oral administration is attractive to patients and providers. Data were compiled by the sponsor; Pharmaceutical Product Development provided assistance with statistical programming. Blinded central reading of endoscopic videos and histologic findings was performed. Ozanimod is a recently approved drug for treatment of multiple sclerosis (U.S. Food and Drug Administration [FDA], 2020) and ulcerative colitis (FDA, 2021) [12]. Panel C shows the percentage of patients with mucosal healing (endoscopy subscore of 1 point) at week 8. Patients were excluded from the trial if they had macular edema at baseline or if they did not have immunity to varicellazoster virus or had not received vaccination against varicellazoster virus. (%), Adverse events of special interest no. The frequency of serious infections was less than 2% in each group. 2021 Sep 30;385(14):1280-1291. doi: 10.1056/NEJMoa2033617. At week 10, the percentage of patients with clinical remission was significantly higher in the ozanimod group than in the placebo group (18.4% vs. 6.0%, P<0.001) (, Among the 457 patients who had a response to ozanimod during the induction period and underwent subsequent randomization in the maintenance period, 37.0% in the ozanimod group and 18.5% in the placebo group had clinical remission at week 52 (P<0.001) (, Treatment-effect sizes in patients with TNF antagonist exposure were similar to those in patients without such exposure. East Hanover, NJ: Novartis Pharmaceuticals, 2015. Analyses of outcomes at week 32 were prespecified as other secondary outcomes and were considered to be exploratory. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). Nat Immunol 2007;8:1295-1301, 7. The order of testing was the primary-outcome comparison of remission rates at week 8 in the group that received 1 mg of ozanimod with the placebo group, followed by the comparison of remission rates at week 8 in the group that received 0.5 mg of ozanimod with the placebo group if the result of the primary analysis was significant (two-sided P<0.05), followed by each major secondary outcome in order (clinical response, change in Mayo Clinic score from baseline, and mucosal healing), with comparisons for the 1-mg dose preceding those for the 0.5-mg dose. At week 8, clinical remission occurred in 11 of 67 patients (16%) who received 1 mg of ozanimod and in 9 of 65 patients (14%) who received 0.5 mg of ozanimod, as compared with 4 of 65 (6%) who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo) (Figure 1A). Drugs. Demographic Characteristics and Disease Characteristics at Baseline, According to Trial Group. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). Along with the rising prevalence of inflammatory bowel disease (IBD) [Crohn's disease (CD) and ulcerative colitis (UC)], biological therapies need an update/insight.This review included randomized . Croft NM, Faubion WA Jr, Kugathasan S, Kierkus J, Ruemmele FM, Shimizu T, Mostafa NM, Venetucci M, Finney-Hayward T, Sanchez Gonzalez Y, Bereswill M, Lazar A, Turner D. Lancet Gastroenterol Hepatol. ZEPOSIA (ozanimod) is indicated for the treatment of: 1. Disclaimer, National Library of Medicine Curr Gastroenterol Rep. 2022 Dec;24(12):157-170. doi: 10.1007/s11894-022-00853-6. Comi G, Kappos L, Selmaj KW, et al. 2020 Sep;5(9):819-828. doi: 10.1016/S2468-1253(20)30188-6. Lewis JD, Chuai S, Nessel L, Lichtenstein GR, Aberra FN, Ellenberg JH. 26. AB - BACKGROUND Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. Analysis in the induction period was based on the two-sided CochranMantelHaenszel test and stratified according to glucocorticoid use at screening and previous use of a TNF antagonist. The incidence. Before Oral azacitidine for maintenance treatment of acute myeloid leukaemia after induction therapy (TA827) . 2022 Jan;7(1):28-37. doi: 10.1016/S2468-1253(21)00295-8. Curr Opin Pharmacol 2006;6:244-250, 14. Patients were excluded from the trial if they had not had a response to induction therapy with at least two biologic agents approved for the treatment of ulcerative colitis, had a clinically relevant cardiac condition, or had a history of uveitis or macular edema. A total of 645 patients entered cohort 1 and were randomly assigned to receive either ozanimod (429 patients) or placebo (216 patients) in a double-blind manner; 367 patients received open-label ozanimod in cohort 2 (Figure 1). eCollection 2022. Epub 2022 Nov 3. Mehling M, Lindberg R, Raulf F, et al. 2021;385:1280-1291. (HealthDay)For patients with moderately to severely active ulcerative colitis, ozanimod is more effective than placebo as induction and maintenance therapy, according to a study published in . We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Talquetamab, a T-CellRedirecting GPRC5D Bispecific Antibody for Multiple Myeloma, A Covid-19 Milestone Attained A Correlate of Protection for Vaccines, A Step toward Interoperability of Health IT, Breakthrough Infections after Postexposure Vaccination against Mpox, Tumor-Infiltrating Lymphocyte Therapy or Ipilimumab in Advanced Melanoma, Case 37-2022: A 55-Year-Old Man with Fatigue, Weight Loss, and Pulmonary Nodules, Brief Report: In Utero Enzyme-Replacement Therapy for Infantile-Onset Pompes Disease, NEJM Catalyst Innovations in Care Delivery. The incidence of clinical remission was significantly higher among patients who received ozanimod than among those who received placebo during both induction (18.4% vs. 6.0%, P<0.001) and maintenance (37.0% vs. 18.5% [among patients with a response at week 10], P<0.001). DOI: 10.1056/NEJMoa1513248, Tap into groundbreaking research and clinically relevant insights. This trial was not large enough or of sufficiently long duration to assess safety. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1R) and receptor-5 (S1P5R) agonist with autoimmune disease-modifying activity. Finally, the trial was limited to patients receiving ozanimod as monotherapy or in combination with glucocorticoids or aminosalicylates. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. 2022 Oct 20;12(10):997. doi: 10.3390/metabo12100997. Significant improvements with ozanimod as compared with placebo were also observed with regard to the three ranked key secondary end points of clinical response, endoscopic improvement, and mucosal healing (P<0.001 for all comparisons). Clipboard, Search History, and several other advanced features are temporarily unavailable. A Literature Review of Ozanimod Therapy in Inflammatory Bowel Disease: From Concept to Practical Application. Mehling M, Brinkmann V, Antel J, et al. This binding results in internalization of the sphingosine-1-phosphate receptors in lymph nodes to prevent the movement of lymphocytes to sites of inflammation (Br J Pharmacol 2016;173:1778-1792). 8600 Rockville Pike EP. The most common reasons for ineligibility were disease criteria not met (in 18.1% of the patients who underwent screening), a lack of documentation of varicellazoster virus IgG antibodies or vaccination (in 5.7%), inability to provide informed consent or to comply with protocol assessments (in 4.6%), and presence of Clostridium difficile or other stool pathogens (in 3.7%). Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, J Clin Pharmacol 2017;57:988-996. Methods: FASEB J 2004;18:551-553, 8. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. Selmaj KW, Steinman L, Comi G, et al. NEW! Ozanimod effective as induction, maintenance therapy for ulcerative colitis A once-daily oral formulation of ozanimod, a selective sphingosine-1-phosphate (S1P) receptor modulator, outdid placebo as induction and maintenance t. The first two authors wrote the first draft of the manuscript, and all the authors contributed to subsequent drafts, made a collective decision to submit the manuscript for publication, and vouch for the completeness and veracity of the data and analyses reported and for the adherence of the trial to the protocol. The content of this site is intended for health care professionals. No important differences were observed among the groups in the most commonly reported adverse events during the trial (Table 2). ); the Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (J.-F.C. In this trial that required patients to have a documented presence of varicellazoster virus IgG antibody or complete varicellazoster vaccination, herpes zoster infection occurred in 3 of 796 ozanimod-treated patients (0.4%) during the induction period and in 5 of 230 (2.2%) during the maintenance period (these events did not lead to hospitalization). The authorized source of trusted medical research and education for the Chinese-language medical community. We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. The total Mayo score is defined as the sum of the rectal-bleeding subscore, the stool-frequency subscore, the physicians global assessment subscore, and the endoscopy subscore; overall scores range from 0 to 12 (with each subscore on a scale from 0 to 3), with higher scores indicating greater activity. Therap Adv Gastroenterol. Abnormal liver-function tests led to the discontinuation of ozanimod therapy in 3 of 796 patients (0.4%) in the induction period and in 1 of 230 patients (0.4%) in the maintenance period. At the completion of the induction period, 233 patients (54.3%) in cohort 1 and 224 (61.0%) in cohort 2 had a clinical response to ozanimod therapy and underwent randomization again to receive either ozanimod (230 patients) or placebo (227 patients) in the maintenance period. 2022 May;18(5):265-271. Infliximab for induction and maintenance therapy for ulcerative colitis. Background: Ozanimod (RPC1063) is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract. 8. If the primary end point in each period was significant, key secondary end points were analyzed in sequence until a 5% significance level was not reached, after which all the subsequent ranked secondary end points were to be considered exploratory. Lancet Neurol 2016;15:373-381. The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). We calculated that a sample of 600 patients (randomly assigned in a 2:1 ratio in cohort 1 in the induction period) would provide the trial with at least 90% power to detect a between-group difference of 10 percentage points in the incidence of clinical remission during the induction period. Gastroenterol Hepatol (N Y). Missing data were handled with the use of a nonresponse imputation. The investigator decided whether the laboratory value qualified as an adverse event. Lancet Neurol 2019;18:1021-1033. Ozanimod is a small molecule drug that selectively targets S1P receptors 1 and 5 which play a crucial role in lymphocyte trafficking and has been shown to induce a reversible lymphopenia which correlates with response to therapy. Several adverse events of special interest that are known to be associated with S1P receptor modulation (e.g., bradycardia, serious or opportunistic infections, macular edema, and elevated liver-enzyme levels) were monitored in the clinical trials.10-15 We report here the results of True North, a 52-week, phase 3 trial to evaluate ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Epub 2022 Feb 2. Ozanimod is a sphingosine-1-phosphate (S1P) receptor modulator that binds with high affinity to S1P subtypes 1 and 5 (S1P1 and S1P5), leading to internalization of S1P1 receptors in lymphocytes and the prevention of lymphocyte mobilization to inflammatory sites.7-9 In a phase 2 trial, treatment with ozanimod showed significant improvements over placebo with regard to endoscopic, histologic, and clinical end points in patients with moderate-to-severe ulcerative colitis.10 A separate phase 2 trial showed benefits with ozanimod therapy in patients with Crohns disease.11 To date, the safety profile of ozanimod, as characterized on the basis of studies involving more than 4000 patients with ulcerative colitis, Crohns disease, or relapsing multiple sclerosis and healthy volunteers, is consistent across populations. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Sensitivity analyses were conducted for the primary and first key secondary end points with the use of an observed-cases analysis (assumption of data missing completely at random) and with the use of multiple imputation (assumption of data missing at random).23. The P values reported for these analyses are considered to be nominal and not significant. publisher = "Massachussetts Medical Society", Ozanimod as induction and maintenance therapy for ulcerative colitis. We anticipated that 10% of the patients in the placebo group would have clinical remission after induction therapy. Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. The group names indicate whether the patients received ozanimod or placebo during the maintenance period only; all the patients in the maintenance period had received ozanimod during the induction period. Scott FL, Clemons B, Brooks J, et al. Results were similar between the treatment/placebo and open-label arms. Keywords. We aim to describe the trial design of the YELLOWSTONE phase 3 program evaluating the . Panel A shows the primary end point (shaded area) and key secondary end points from the induction period (cohort 1) at week 10, and Panel B the primary end point (shaded area) and key secondary end points from the maintenance period at week 52. Gastroenterol Hepatol (N Y). Glucocorticoid doses were maintained unchanged through week 8, after which time the doses could be tapered at the discretion of the investigator. Discovery and Validation of Potential Serum Biomarkers with Pro-Inflammatory and DNA Damage Activities in Ulcerative Colitis: A Comprehensive Untargeted Metabolomic Study. Article Topic: Positioning Ulcerative Colitis Therapies in 2022 and Beyond. Patients receiving biologic agents or azathioprine, mercaptopurine, or methotrexate were required to discontinue these agents 5 half-lives before starting the trial regimen and 4 weeks before their screening endoscopy, respectively. Epub 2021 Aug 22. Efficacy analyses were performed according to the intention-to-treat principle. 23. A review of the therapeutic management of ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.). Cohen JA, Arnold DL, Comi G, et al. In this phase 2 trial involving patients with moderately or severely active ulcerative colitis, treatment with ozanimod at a once-daily oral dose of 1 mg resulted in slightly higher rates of clinical remission at week 8 than those with placebo (16% vs. 6%, P=0.048). Future studies are needed to assess the risk of infections associated with ozanimod. Finding a way out: lymphocyte egress from lymphoid organs. Conclusions: Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. 25. The Mayo Score is a composite index of four items (stool frequency, rectal bleeding, rectosigmoidoscopy findings, and physician's global assessment) with each item graded semi-quantitatively on a scale of 0 to 3 where 0 represents normal and higher score represents more severe disease status. Feagan BG, Sandborn WJ, Danese S, Wolf DC, Liu WJ, Hua SY, Minton N, Olson A, D'Haens G. Lancet Gastroenterol Hepatol. Roughly 33% of patients were on concomitant systemic corticosteroids at baseline. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg . The site is secure. Scores were assessed by a central reader. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. author = "{True North Study Group} and Sandborn, {William J.} Wolf DC, Colombel J-F, Ponich T, et al. Valuable tools for building a rewarding career in health care. Intest Res 2018;16:26-42. Patients with clinical response at week 8 continued their blinded regimen during the maintenance period. 17. doi: 10.1056/NEJMc1607287. 29. Feagan BG, Rutgeerts P, Sands BE, et al. 2022 Jan 13;386(2):194. doi: 10.1056/NEJMc2117224. This trial was not large enough or of sufficiently long duration to assess the safety of ozanimod. (%), Serious adverse event related to ozanimod or placebo no. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. All patients included had to have failed prior treatment for ulcerative colitis, and were generally not allowed to be on other ulcerative colitis treatments during the trial. @article{65919f183c004061ac6949cedcbae8f5. At week 8, a total of 103 patients who were considered by the investigators to have had clinical improvement (of whom 95 met the criteria for clinical response) continued in the blinded maintenance phase. Demographic characteristics and disease characteristics at baseline were compared with the use of descriptive statistics. DOI: 10.1056/NEJMoa2033617, Tap into groundbreaking research and clinically relevant insights. The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. 2021 Jul 5;15(7):1120-1129. doi: 10.1093/ecco-jcc/jjab012. Before Epub 2021 Nov 17. 2022 Sep 6;11(18):2780. doi: 10.3390/cells11182780. Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. Epub 2021 Dec 8. 1. 1. Other prespecified end points included histologic remission and clinical remission in subgroups defined according to demographic and disease-based characteristics. Elevated liver aminotransferase levels were more common with ozanimod. 2022 Feb;7(2):128-140. doi: 10.1016/S2468-1253(21)00298-3. and Feagan, {Brian G.} and Geert D'Haens and Wolf, {Douglas C.} and Igor Jovanovic and Hanauer, {Stephen B.} All the patients had documented presence of varicellazoster virus IgG antibody or complete varicellazoster vaccination at screening. Safety was also assessed. The primary outcome occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo). Abnormal liver-function tests led to the discontinuation of ozanimod therapy in 3 of 796 patients (0.4%) in the induction period and in 1 of 230 patients (0.4%) in the maintenance period. UR - http://www.scopus.com/inward/record.url?scp=85116386829&partnerID=8YFLogxK, UR - http://www.scopus.com/inward/citedby.url?scp=85116386829&partnerID=8YFLogxK, Powered by Pure, Scopus & Elsevier Fingerprint Engine 2022 Elsevier B.V, We use cookies to help provide and enhance our service and tailor content. IMPORTANT SAFETY INFORMATION Contraindications: The .gov means its official. Copyright 2021 Massachusetts Medical Society. and Lee, {Ji Hwan} and Lorna Charles and Denesh Chitkara and Keith Usiskin and Colombel, {Jean Frederic} and Loren Laine and Silvio Danese". RESULTS In the induction period, 645 patients were included in cohort 1 and 367 in cohort 2; a total of 457 patients were included in the maintenance period. The purpose of this study is to evaluate the efficacy and safety of ozanimod compared with placebo in participants with ulcerative colitis (UC) in mainland China and Taiwan. FOIA In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg (equivalent to 0.92 mg of ozanimod) or placebo once daily in a double-blind manner, and patients in cohort 2 received open-label ozanimod at the same daily dose. Schroeder KW, Tremaine WJ, Ilstrup DM. 16. Sandborn WJ1, Feagan BG1, Wolf DC1, D'Haens G1, Vermeire S1, Hanauer SB1, Ghosh S1, Smith H1, Cravets M1, Frohna PA1, Aranda R1, Gujrathi S1, Olson A1, TOUCHSTONE Study Group Collaborators (101) Sparrow M, Vermeire S, Churchev J, Kotzev I, Takov D, Dragomirov B, Vladimirov B, Epub 2022 Aug 22. Additional eligibility criteria and the exclusion criteria are provided in the Supplementary Appendix. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. Jain N, Bhatti MT. Leukocyte counts, including lymphocyte subsets, were not provided to investigators. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. In cohort 1, a total of 401 patients (93.5%) who had been assigned to receive ozanimod and 192 (88.9%) who had been assigned to receive placebo completed the induction period. 2,3 zeposia reduces the capacity of lymphocytes to migrate from lymphoid tissue, reducing the number of circulating lymphocytes in peripheral blood and lymphocyte migration into the intestines. Schroeder KW, Tremaine WJ, Ilstrup DM. Mult Scler 2014;20:471-480, 13. The induction phase is targeted to get as much of the drug into the patient as possible to rapidly eliminate the symptoms of inflammation and the severity of the disease. Am J Gastroenterol 2015;110:802-819, May 5, 2016N Engl J Med 2016; 374:1754-1762 Danese S, Roda G, Peyrin-Biroulet L. Evolving therapeutic goals in ulcerative colitis: towards disease clearance. S1 in the Supplementary Appendix). HHS Vulnerability Disclosure, Help The incidence of infection (of any severity) with ozanimod was similar to that with placebo during induction and higher than that with placebo during maintenance. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Together they form a unique fingerprint. Ther Clin Risk Manag. Absolute lymphocyte counts in blood decreased by a mean of 32% from baseline to week 8 in patients who received 0.5 mg of ozanimod and by 49% in patients who received 1 mg of ozanimod. Long-term . Safety Findings through the Final Safety Visit in the Induction and Maintenance Periods.*. In this phase 3 trial, we found that ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Vermeire S, Lakatos PL, Ritter T, Hanauer S, Bressler B, Khanna R, Isaacs K, Shah S, Kadva A, Tyrrell H, Oh YS, Tole S, Chai A, Pulley J, Eden C, Zhang W, Feagan BG; LAUREL Study Group. All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. The changes in the Mayo Clinic score from baseline to week 8 and to week 32 were analyzed with the use of analysis of covariance models with treatment group, status with respect to previous TNF-antagonist therapy, and baseline value of the corresponding outcome included as covariates. Bianchi Porro G, Cassinotti A, Ferrara E, Maconi G, Ardizzone S. The management of steroid dependency in ulcerative colitis. Benefits of High Versus Low Dose Upadacitinib as Maintenance Treatment in Ulcerative Colitis Patients Who Were Responders to 8-week Induction With Upadacitinib: Results From the U . The primary outcome was clinical remission (Mayo Clinic score 2, with no subscore >1) at 8 weeks. Ozanimod as induction and main-tenance therapy for ulcerative colitis. C-reactive protein, fecal calprotectin, and stool lactoferrin for detection of endoscopic activity in symptomatic inflammatory bowel disease patients: a systematic review and meta-analysis. The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Patients who had a clinical response while they were receiving placebo at the end of the induction period continued to receive double-blind placebo during the maintenance period. ozanimod (rpc1063) is a new oral s1p1-receptor and s1p5-receptor modulator with no activity on s1p2, s1p3, and s1p4. sharing sensitive information, make sure youre on a federal ACG clinical guideline: ulcerative colitis in adults. This article was updated on October 8, 2021, at NEJM.org. The protocol, available with the full text of this article at NEJM.org, was approved by the institutional review board at each center. / True North Study Group. Histologic remission, defined as a Geboes score of less than 2, at week 8 occurred in 7 of 65 patients (11%) in the placebo group, as compared with 9 of 65 (14%) in the group that received 0.5 mg of ozanimod (P=0.63) and 15 of 67 (22%) in the group that received 1 mg of ozanimod (P=0.07) (Figure 1D). Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. ); and IRCCS Humanitas Research Hospital and University Vita-Salute San Raffaele, Milan (S.D.). ); the Division of Gastroenterology, University Hospital Medical Center Beanijska Kosa, Belgrade, Serbia (I.J. Efficacy requires further assessment in larger trials. Ulcerative colitis is a chronic immune-mediated disease of the colon that is currently treated with mesalamine, glucocorticoids, thiopurines, and biologic agents.1,2 A lack of universal response, the risks of infection and neoplasia, a requirement for parenteral administration, and the development of antidrug antibodies have created a need for safe and effective oral therapies. The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. Clinical remission was defined as follows: a rectal-bleeding subscore of 0; a stool-frequency subscore of 1 or less, with a decrease of at least 1 point from baseline; and an endoscopy subscore of 1 or less (all on scales from 0 [none] to 3 [most severe]).19. Five patients who had a clinical response did not enter the maintenance phase (Table S7 in the Supplementary Appendix). J Crohns Colitis 2008;2:1-23. ), and the University of Calgary, Calgary, AB (S. Ghosh) all in Canada; Atlanta Gastroenterology Associates, Atlanta (D.C.W. Patients who did not have a response at week 8 were allowed to cross over to optional open-label treatment. The trial was conducted from May 2015 through June 2020. Ozanimod-Dependent Activation of SIRT3/NF-B/AIM2 Pathway Attenuates Secondary Injury After Intracerebral Hemorrhage. Herpes zoster infection did not occur in any patient who did not receive ozanimod. Positive topline results were announced from the phase 3 True North trial evaluating the efficacy of ozanimod as an induction. The results of this phase 3 trial showed that a once-daily oral formulation of ozanimod, an S1P receptor modulator, provided clinical efficacy in patients with moderately to severely active ulcerative colitis. N Engl J Med . Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist with autoimmune disease-modifying activity. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Data were collected by a contract research organization (Pharmaceutical Product Development) and analyzed by the sponsor. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. Proportions of patients with clinical remission at week 8 were compared with the use of the CochranMantelHaenszel chi-square test, stratified according to status with respect to previous receipt of TNF-antagonist therapy. First, in cohort 1, patients were randomly assigned in a 2:1 ratio to receive ozanimod hydrochloride at a dose of 1 mg per day (equivalent to 0.92 mg of ozanimod; referred to hereafter as ozanimod) or matched placebo once daily in a double-blind manner. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. Cohen JA, Barkhof F, Comi G, et al. METHODS We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial of ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Xeljanz. Clin Gastroenterol Hepatol 2020;18(11):2510.e5-2517.e5. A potential limitation of this trial is that the trial population may not be representative of the broader patient population in a routine clinical setting. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. The incidence of clinical response was also significantly higher with ozanimod than with placebo during induction (47.8% vs. 25.9%, P<0.001) and maintenance (60.0% vs. 41.0%, P<0.001). In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg . Rates of clinical remission at week 32 and clinical response and mucosal healing at weeks 8 and 32 were analyzed similarly. ); the Inflammatory Bowel Disease Center, Academic Medical Center, Amsterdam (G.D.); the Center for Crohns Disease and Ulcerative Colitis, Atlanta Gastroenterology Associates, Atlanta (D.C.W. Ozanimod Treatment for Ulcerative Colitis. We conducted this randomized, double-blind, placebo-controlled trial at 285 sites in 30 countries. 12. Endoscopic improvement was defined as a mucosal endoscopy subscore of 1 or less, without friability. From the University of California, San Diego, La Jolla (W.J.S. 9. DHaens G. Systematic review: second-generation vs. conventional corticosteroids for induction of remission in ulcerative colitis. 7. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.5 mg or 1 mg or placebo daily for up to 32 weeks. Panel B shows the percentage of patients who had a clinical response (defined as a reduction from baseline in the Mayo Clinic score of 3 points and 30%, and a decrease from baseline in the rectal-bleeding subscore of 1 point or an absolute rectal-bleeding subscore of 1 point) at week 8. If approved, Zeposia would be the first oral sphingosine-1-phosphate (S1P) receptor modulator for the treatment . Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. DHaens G, Sandborn WJ, Feagan BG, et al. Would you like email updates of new search results? Brossard P, Derendorf H, Xu J, Maatouk H, Halabi A, Dingemanse J. Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptor modulator, in the first-in-human study. 2. Initial Real-World Experience From a . Zeposia. 19. WEDNESDAY, Sept. 29, 2021 (HealthDay News) -- For patients with moderately to severely active ulcerative colitis, ozanimod is more effective than placebo as induction and maintenance therapy, according to a study published in the Sept. 30 issue of the New England Journal of Medicine.. William J. Sandborn, M.D., from the University of California San Diego in La Jolla, and colleagues conducted a . Background: Moderately to severely active ulcerative colitis (UC) in adults. During the maintenance phase response rate was better with ustekinumab, but remission and mucosal healing were better with vedolizumab. Alternatively, small molecules can be less selective than monoclonal antibodies, and off-target binding may result in adverse effects. 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