Clinical response was defined as a reduction in the three-component Mayo score of at least 2 points and at least 35% from baseline, as well as a reduction in the rectal-bleeding subscore of at least 1 point or an absolute rectal-bleeding subscore of 1 or less. Mehling M, Lindberg R, Raulf F, et al. Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE): a randomised, placebo-controlled, phase 2 trial. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. In the 10-week induction period, patients in cohort 1 were assigned to receive oral ozanimod hydrochloride at a dose of 1 mg . N Engl J Med. With respect to the advantages, the convenience of oral administration is attractive to patients and providers. No patient with a serious or opportunistic infection had an absolute lymphocyte count of less than 200 cells per cubic millimeter. 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. 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. 16. We thank the staff of the participating sites and the staff of Robarts Clinical Trials for trial management, data management and analysis, and editorial assistance with an earlier version of the manuscript (funded by Receptos). Ozanimod is an oral sphingosine 1-phosphate receptor modulator. EP. Data were compiled by the sponsor; Pharmaceutical Product Development provided assistance with statistical programming. Gastrointest Endosc 2018;88:887-898. We anticipated that 10% of the patients in the placebo group would have clinical remission after induction therapy. 7. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). Sandborn WJ, Feagan BG, D'Haens G et al (2022) Ozanimod as induction and maintenance therapy for ulcerative colitis. We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. (%), Adverse event leading to discontinuation of the regimen no. ZEPOSIA (ozanimod) is indicated for the treatment of: 1. 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. The modified intention-to-treat population included all the patients who underwent randomization and received at least one dose of ozanimod or placebo. Early mucosal healing with infliximab is associated with improved long-term clinical outcomes in ulcerative colitis. Figueroa, Gabriela; Forster, Erin . The incidences of elevated alanine aminotransferase levels were higher among patients who received ozanimod than among those who received placebo. Cells. The mechanism by which Zeposia exerts therapeutic effects in ulcerative . A post hoc analysis showed decreases in the rectal-bleeding and stool-frequency subscores by week 2 (i.e., 1 week after the completion of dose adjustment during the induction period) in patients receiving ozanimod (Figs. 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 first two trials (OCTAVE 1 and 2) randomly assigned patients to treatment groups of 10 mg tofacitinib twice a day (n = 476 and 439, respectively) or a placebo (n = 122 . Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. 2022 Aug;18(8):453-465. The modified intention-to-treat population included all patients who underwent randomization and received at least one dose of ozanimod or placebo. Publisher Copyright: Pai RK, Jairath V, Vande Casteele N, Rieder F, Parker CE, Lauwers GY. 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 comparison of 1 mg of ozanimod with placebo was hierarchically ranked before the comparison of 0.5 mg of ozanimod with placebo. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). We thank the patients and trial site personnel for their involvement; and Traci Stuve, M.A., of Peloton Advantage, an OPEN Health company, for providing writing assistance with an earlier version of the manuscript, with funding from Bristol Myers Squibb. Positioning Ozanimod in Ulcerative Colitis: Restoring Leukocyte Traffic Under Control. Demographic Characteristics and Disease Characteristics at Baseline, According to Trial Group. All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992. All the patients had documented presence of varicellazoster virus IgG antibody or complete varicellazoster vaccination at screening. 22. N Engl J Med 2010;362:387-401, 9. ); Western University, London, ON, Canada (B.G.F. A complete list of the members of the True North Study Group is provided in the Supplementary Appendix, available at NEJM.org. Efficacy requires further assessment in larger trials. 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. Ulcerative colitis has an incidence of 9 to 20 cases per 100,000 persons per year. 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. 30. Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Lfberg R. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. 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. Careers. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Table 1. Absolute lymphocyte counts of less than 200 cells per cubic millimeter occurred in 1.1% of the patients who received ozanimod (in cohort 1 or 2) and in no patients who received placebo during the induction period. Panel C shows the percentage of patients with mucosal healing (endoscopy subscore of 1 point) at week 8. Elevated liver aminotransferase levels were more common with ozanimod. Elevated liver aminotransferase levels were more common with ozanimod. Patients with clinical response at week 8 continued their blinded regimen during the maintenance period. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. Rubin DT, Ananthakrishnan AN, Siegel CA, Sauer BG, Long MD. Sandborn et al. Jain N, Bhatti MT. The current study consisted of a 10-week. 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. ), VISUAL ABSTRACTOzanimod Therapy for Ulcerative Colitis, Ulcerative colitis is a chronic disease that is characterized by a dysregulated immune response and chronic inflammation in the colonic mucosa.1 Conventional therapies such as aminosalicylates are modestly effective in patients with moderate, but not severe, disease.2 Glucocorticoids have been associated with adverse events and long-term adverse health consequences and are not recommended as maintenance therapy.2-4 Newer agents, including biologic drugs and Janus kinase inhibitors, are not effective in all patients or can lose efficacy with long-term use, and they have been associated with infections, infusion reactions, and cancers.5,6 Thus, the need remains for new oral treatments for ulcerative colitis that are safe and glucocorticoid-sparing and that have durable efficacy.2. 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. Lancet Neurol 2019;18:1021-1033. Cohen JA, Arnold DL, Comi G, et al. Neurology 2008;71:1261-1267, 11. S37 Efficacy and Safety of Upadacitinib Maintenance Therapy in Patients With Moderately to Severely Active Crohn's Disease: U-ENDURE Phase 3 Results . 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. Multiple sclerosis treatment with fingolimod: profile of non-cardiologic adverse events. The three-component Mayo score is defined as the sum of the rectal-bleeding subscore, the stool-frequency subscore, and the endoscopy subscore. Safety was also assessed. 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. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Glucocorticoid-free remission was defined as clinical remission at 52 weeks without receipt of glucocorticoids for at least 12 weeks. 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. 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 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. The Memory T Cell "Communication Web" in Context with Gastrointestinal Disorders-How Memory T Cells Affect Their Surroundings and How They Are Influenced by It. 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. Clinical remission was significantly higher in the ozanimod group than placebo in both induction (18.4% versus 6.0%; P < 0.001) and maintenance (37.0% versus 18.5%; P < 0.001). 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). Knauss A, Gabel M, Neurath MF, Weigmann B. 15. Clinical response at week 8 occurred in 24 of 65 patients (37%) in the placebo group, as compared with 35 of 65 (54%) who received 0.5 mg of ozanimod (P=0.06) and 38 of 67 (57%) who received 1 mg of ozanimod (P=0.02) (Figure 1B). Etrolizumab as induction and maintenance therapy for ulcerative colitis in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial. N Engl J Med 2021; 385 (14) 1280-1291 Clinical response was defined as a reduction of at least 3 points and of at least 30% from baseline in the total Mayo score or a reduction of at least 2 points and of at least 35% from baseline in the three-component Mayo score, plus a reduction of at least 1 point in the rectal-bleeding score or an absolute rectal-bleeding score of no more than 1 point. We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. The most advanced way to teach, practice, and assess clinical reasoning skills. Feagan BG, Rutgeerts P, Sands BE, et al. At week 8, absolute lymphocyte counts declined 49% from baseline in the group that received 1 mg of ozanimod and 32% from baseline in the group that received 0.5 mg. The authorized source of trusted medical research and education for the Chinese-language medical community. 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. 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. Lancet 2012;380:1606-1619, 2. All the patients provided written informed consent. Analyses of outcomes at week 32 were prespecified as other secondary outcomes and were considered to be exploratory. 2016 May 5;374(18):1754-62. doi: 10.1056/NEJMoa1513248. 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. Glucocorticoid doses were maintained unchanged through week 8, after which time the doses could be tapered at the discretion of the investigator. *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. Clipboard, Search History, and several other advanced features are temporarily unavailable. Zeposia reduces the capacity of lymphocytes to exit from lymph nodes, reducing the number of circulating lymphocytes in peripheral blood. Vedolizumab as induction and maintenance therapy for ulcerative colitis. All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. FOIA Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. Valuable tools for building a rewarding career in health care. Keywords. S2 in the Supplementary Appendix). 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. CONCLUSIONS Ozanimod was more effective than placebo as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. 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. J Crohns Colitis 2008;2:1-23. Methods We conducted a phase 3, multicenter,. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE): a multicentre, randomised, 24-month, phase 3 trial. 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. P values reported for analyses other than the primary outcome of clinical remission at week 8 are considered to be nominal and not significant. 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. Continued ozanimod treatment for the induction of non-responders in the phase 3 True North trial, induced symptomatic clinical response in nearly half of the patients with ulcerative colitis (UC) after 10 weeks in an open-label extension trial (OLE). 2022 May;18(5):265-271. Bethesda, MD 20894, Web Policies Results were similar between the treatment/placebo and open-label arms. The most common reason for discontinuation in the maintenance period was disease relapse (in 31 patients [13.5%] in the ozanimod group and in 77 [33.9%] in the placebo group). The authorized source of trusted medical research and education for the Chinese-language medical community. Rates of clinical remission at week 32 and clinical response and mucosal healing at weeks 8 and 32 were analyzed similarly. Furthermore, clinical remission was reached by 19.3% at this timepoint. The protocol, available with the full text of this article at NEJM.org, was approved by the institutional review board at each center. 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. Aim: The relative treatment effects of filgotinib and adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab were estimated using a network meta-analysis (NMA). and Lee, {Ji Hwan} and Lorna Charles and Denesh Chitkara and Keith Usiskin and Colombel, {Jean Frederic} and Loren Laine and Silvio Danese". *Plusminus values are means SD. Methods: We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Adverse events and use of concomitant medications were recorded through 32 weeks. METHODS: We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. A total of 199 patients were randomly assigned to the trial groups, of whom 197 received placebo or ozanimod (Fig. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. 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%). ); the Feinberg School of Medicine, Chicago (S.B.H. doi: 10.1056/NEJMc1607287. Acta Neurol Belg 2017;117:821-827. Zeposia (ozanimod) is an oral, sphingosine-1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis: a randomized study. Neurology 2012;78:672-680. 2021 Sep 30;385 (14):1280-1291. doi: 10.1056/NEJMoa2033617. 13. Safety was also assessed. conducted a 52-week, phase 3 trial to evaluate ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). We conducted this randomized, double-blind, placebo-controlled trial at 285 sites in 30 countries. The site is secure. 11. Predictors and outcomes of histological remission in ulcerative colitis treated to endoscopic healing. Each subscore category is rated on a scale from 0 to 3, which was summed to give a total Mayo score between 0 and 12; higher scores indicate greater activity.16. The overall incidence of nonserious infection with ozanimod therapy was similar to that with placebo during the induction period but was higher than that with placebo during the maintenance period (Table 2). The https:// ensures that you are connecting to the N Engl J Med. Long-term safety and efficacy of ozanimod in relapsing multiple sclerosis in DAYBREAK: an open-label extension study of ozanimod phase 13 trials. Ozanimod: first approval. 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. The incidence. Lamb YN. and Feagan, {Brian G.} and Geert D'Haens and Wolf, {Douglas C.} and Igor Jovanovic and Hanauer, {Stephen B.} Sandborn WJ, Feagan BG, Hanauer S, Vermeire S, Ghosh S, Liu WJ, Petersen A, Charles L, Huang V, Usiskin K, Wolf DC, D'Haens G. J Crohns Colitis. Ozanimod, a selective sphingosine-1- phosphate receptor modulator . Together they form a unique fingerprint. Tables S1 and S2 list the prespecified efficacy end points. Safety Findings through the Final Safety Visit in the Induction and Maintenance Periods. 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. "Ozanimod is an oral, sphingosine-1-phosphate (S1P) receptor modulator . 2022 Sep 8;18:913-927. doi: 10.2147/TCRM.S336139. The sphingosine-1-phosphate (S1P) subtype 1 (S1P1) receptor is a member of a family of five widely expressed receptors (S1P1 through S1P5) that are responsible for regulating multiple immunologic and cardiovascular effects.3,4 Cell-surfaceassociated S1P1 receptor plays a crucial role in the trafficking of lymphocytes from lymphoid organs.5,6 S1P1-receptor agonists induce internalization and degradation of the S1P1 receptor, rendering B and T lymphocytes incapable of migrating from secondary lymphoid organs, which leads to a reversible reduction in circulating lymphocytes in the blood.4,5,7, Patients treated with fingolimod (Gilenya, Novartis), a S1P-receptor modulator that has been approved for the treatment of relapsing multiple sclerosis,8,9 have a decrease from baseline of 70 to 80% in the peripheral-blood lymphocyte count owing to lymph-node sequestration of naive and central memory lymphocytes. Accessibility Tran JQ, Zhang P, Surapaneni S, Selkirk J, Yan G, Palmisano M. Absorption, metabolism, and excretion, in vitro pharmacology, and clinical pharmacokinetics of ozanimod, a novel sphingosine 1-phosphate receptor agonist. The confidence intervals were not adjusted for multiple comparisons and should not be used to infer definitive treatment effects. Epub 2021 Dec 8. Stool samples were obtained at baseline and at weeks 8 and 32 for the measurement of fecal calprotectin and lactoferrin concentrations. N Engl J Med 1987;317:1625-1629, 19. 2022 Feb;7(2):128-140. doi: 10.1016/S2468-1253(21)00298-3. Ozanimod for treating moderately to severely active ulcerative colitis (TA828) Evidence-based recommendations on ozanimod (Zeposia) for treating moderately to severely active ulcerative colitis in adults when conventional or biological . Results: 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. J Clin Pharmacol 2017;57:988-996. 2021 Sep 30;385(14):1280-1291. doi: 10.1056/NEJMoa2033617. 17. Clinical response (decrease in Mayo Clinic score of 3 points and 30% and decrease in rectal-bleeding subscore of 1 point or a subscore 1) at 8 weeks occurred in 57% of those receiving 1 mg of ozanimod and 54% of those receiving 0.5 mg, as compared with 37% of those receiving placebo. S99 Upadacitinib in the Treatment of Ulcerative Colitis. At 10 weeks, patients with a clinical response to ozanimod in either cohort underwent randomization again to receive double-blind ozanimod or placebo for the maintenance period (through week 52). 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. (1) All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. NEW! Epub 2022 Aug 22. AB - BACKGROUND Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. 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. Patients were required to have received stable doses of oral aminosalicylates or glucocorticoids (prednisone at a dose of 20 mg per day or budesonide) or both for at least 2 weeks before screening endoscopy and to continue receiving the same dose for the duration of the induction period; the glucocorticoid dose had to be tapered once the patient entered the maintenance period. Elevated liver aminotransferase levels were more common with ozanimod. Ozanimod: A Review in Ulcerative Colitis. Patients underwent dose escalation during the first week after randomization; thereafter, the patients received the randomly assigned dose for 8 weeks (see the Supplementary Appendix). Feagan BG, Sandborn WJ, Danese S, Wolf DC, Liu WJ, Hua SY, Minton N, Olson A, D'Haens G. Lancet Gastroenterol Hepatol. Ozanimod is a sphingosine 1-phosphate receptor modulator marketed under the brand name Zeposia . Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1R) and receptor-5 (S1P5R) agonist with autoimmune disease-modifying activity. 2021 Aug;6(8):616-627. doi: 10.1016/S2468-1253(21)00142-4. (%). 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. The ranked secondary end points for the maintenance period (at week 52) were the percentages of patients with a clinical response, endoscopic improvement, maintenance of clinical remission (remission at week 52 in the subgroup of patients with remission at week 10), glucocorticoid-free remission (remission with no glucocorticoid use for 12 weeks), mucosal healing, and durable clinical remission (remission at weeks 10 and 52, assessed in all patients in the maintenance period). Clin Gastroenterol Hepatol 2020;18(11):2510.e5-2517.e5. 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. 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) (Figure 2A). 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. S3 in the Supplementary Appendix). Address reprint requests to Dr. Sandborn at the Division of Gastroenterology, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0956, or at [emailprotected]. 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. 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. Data were collected by a contract research organization (Pharmaceutical Product Development) and analyzed by the sponsor. Additional eligibility criteria and the exclusion criteria are provided in the Supplementary Appendix. 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 Division of Gastroenterology, University Hospital Medical Center Beanijska Kosa, Belgrade, Serbia (I.J. Epub 2021 Aug 22. Publisher Copyright: {\textcopyright} 2015 Inderscience Enterprises Ltd.. All rights reserved.". 1. DOI: 10.1056/NEJMoa1513248, Tap into groundbreaking research and clinically relevant insights. View Record in Scopus Google Scholar. Therap Adv Gastroenterol. 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. 20. 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. The full enrollment criteria are provided in the Supplementary Appendix, available at NEJM.org. 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). Ozanimod Intravenous glucocorticoids SURGERY MAINTENANCE OF REMISSION Goals of therapy Monitoring Patients who relapse Specific regimens based on induction response Anti-TNF agent-induced remission Vedolizumab-induced remission Ustekinumab-induced remission Glucocorticoid-induced remission Thiopurines Small molecule-induced remission NUTRITION PMC The first author wrote the first draft of the manuscript. journal = "New England Journal of Medicine". Infliximab for induction and maintenance therapy for ulcerative colitis. 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. 2016 Aug 25;375(8):e17. FASEB J 2004;18:551-553, 8. 2022 May;56(5):592-599. doi: 10.1177/10600280211041907. Princeton, NJ: Bristol-Myers Squibb, 2020 (package insert). Tran JQ, Hartung JP, Peach RJ, et al. We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Nonserious infections were more common with ozanimod than with placebo during the maintenance phase of the trial. Of the 1831 patients who underwent screening, 1012 were enrolled in the trial. Laboratory values were flagged by the central laboratory if they fell outside the standard reference range. Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. Gastroenterol Hepatol (N Y). The frequency of serious infections was less than 2% in each group. Finding a way out: lymphocyte egress from lymphoid organs. Before This site needs JavaScript to work properly. 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. Editorial assistance was funded by Bristol Myers Squibb. Even more important, avoidance of sensitization with the formation of antidrug antibodies has the potential to eliminate one of the most important reasons for the failure of treatment with monoclonal antibodies. Ozanimod induction therapy for patients with moderate to severe Crohn's disease: a single-arm, phase 2, prospective observer-blinded endpoint study . Table 2. Epub 2021 Nov 17. zeposia (ozanimod) is a sphingosine 1-phosphate (s1p) receptor modulator that binds with high affinity to s1p receptors 1 and 5. NEW! Flexible sigmoidoscopy with colonic biopsy was performed at screening and at weeks 8 and 32. A data sharing statement provided by the authors is available with the full text of this article at NEJM.org. Gilenya (package insert). We aim to describe the trial design of the YELLOWSTONE phase 3 program evaluating the . 25. ULN denotes upper limit of the normal range. Bradycardia occurred more frequently with ozanimod therapy than with placebo during the induction period but not during the maintenance period. The key secondary efficacy end points were assessed in a closed, prespecified hierarchical testing procedure. No patients met Hys law criteria suggestive of drug-induced liver injury or had severe liver injury. 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. Third, ozanimod treatment resulted in large reductions from baseline in absolute lymphocyte counts, with most patients in the group that received 1 mg having counts below the lower limit of the normal range at week 8 a finding that is consistent with the mechanism of the drug. Nat Immunol 2007;8:1295-1301, 7. At week 8, absolute lymphocyte counts declined 49% from baseline in the group that received 1 mg of ozanimod and 32% from baseline in the group that received 0.5 mg. The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. The time to disease relapse was examined as an exploratory end point. Treatment with oral aminosalicylates or prednisone (30 mg per day) was required to be at stable doses. A total of 9 of 67 patients in the group that received 1 mg of ozanimod had grade 3 reductions in the lymphocyte count, and no patient in either ozanimod group had grade 4 lymphopenia (Table S6 in the Supplementary Appendix). If approved, Zeposia would be the first oral sphingosine-1-phosphate (S1P) receptor modulator for the treatment . This potent. 4. 2. TA830: Pembrolizumab for Safety was also assessed. 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). publisher = "Massachussetts Medical Society", Ozanimod as induction and maintenance therapy for ulcerative colitis. 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. Gastroenterology 2011;141:1194-1201. Panel D shows the percentage of patients with histologic remission (Geboes score <2, on a scale from 0 to 5, with higher scores indicating more severe histologic inflammation) at week 8. Aliment Pharmacol Ther 2020;52:1008-1016. Alternatively, small molecules can be less selective than monoclonal antibodies, and off-target binding may result in adverse effects. Ann Pharmacother. Liver events were mostly mild or moderate in severity and led to the discontinuation of the trial regimen in less than 1% of the patients. Mosli MH, Zou G, Garg SK, et al. The members of the steering committee (see the Supplementary Appendix, available at NEJM.org) designed the trial in collaboration with the sponsor (Receptos). Editorial assistance was funded by Bristol Myers Squibb. No important differences were observed in subgroup analyses that were based on demographic characteristics and disease characteristics at baseline (Fig. Confidentiality agreements were in place between the sponsor and all the authors. Analysis in the maintenance period was based on the two-sided CochranMantelHaenszel test and stratified according to clinical remission status at week 10 of the induction period and glucocorticoid use at week 10 of the induction period. note = "Funding Information: The members of the steering committee designed the trial in collaboration with the sponsor (Bristol Myers Squibb). N Engl J Med 2010;362:402-415, 10. Lancet Neurol 2016;15:373-381. Future studies are needed to assess the risk of infections associated with ozanimod. sharing sensitive information, make sure youre on a federal Patients who did not have a response at week 8 were allowed to cross over to optional open-label treatment. Other prespecified end points included histologic remission and clinical remission in subgroups defined according to demographic and disease-based characteristics. 2022 Sep 6;11(18):2780. doi: 10.3390/cells11182780. 27. Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis. The plan specified that formal testing would stop if the results were not significant, and all subsequent analyses would be considered to be exploratory and the corresponding P values nominal. All the authors had full access to the data. Biometrika 1976;63:581-592. Feagan BG, Sandborn WJ, Danese S, et al. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. By continuing you agree to the use of cookies. ); APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland (S.G.); Bristol Myers Squibb, Princeton, NJ (A.P., S.Y.H., J.H.L., L.C., D.C., K.U. Patients with clinically significant cardiovascular disease, including those with bradycardia and those taking medications that affect the cardiac conduction system, were excluded from the trial, so our findings cannot be extrapolated to these patient populations. 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. 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). 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. The most common adverse events overall were anemia and headache. 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. The ranked secondary end points for the induction period (at week 10) were the percentages of patients with a clinical response (based on the three-component Mayo score; see above), endoscopic improvement (defined as a mucosal endoscopy subscore of 1 without friability), and mucosal healing (endoscopic improvement plus histologic remission, defined as a mucosal endoscopy score of 1 and a Geboes score of <2.0 [on a scale from 0 to 5.4, with higher scores indicating more severe inflammation20]). Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. Hierarchically ranked secondary outcomes at week 8 were clinical response (reduction in the Mayo Clinic score of 3 points and 30% from baseline, with a decrease in the rectal-bleeding subscore of 1 point or a subscore of 119,20), change from baseline in the Mayo Clinic score, and mucosal healing (endoscopy subscore 119,20). (Funded by Receptos; TOUCHSTONE ClinicalTrials.gov number, NCT01647516.). A total of 91 of the 103 patients who entered the maintenance phase (88%) completed the trial. 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. Patients without previous TNF antagonist exposure continued to undergo randomization in cohort 1 until enrollment was closed, at which time such patients were assigned to cohort 2. The https:// ensures that you are connecting to the ACG clinical guideline: ulcerative colitis in adults. The absolute lymphocyte count decreased by a mean of approximately 54% from baseline to week 10 in patients who received ozanimod. Ords I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Treatment with ozanimod led to significant improvements, as compared with placebo, in the incidence of clinical remission (primary end point) and in all key secondary clinical, endoscopic, and histologic end points at weeks 10 and 52. Supplemental New Drug Application is supported by positive results from the pivotal Phase 3 True North study evaluating oral Zeposia (ozanimod) in adults with moderately to severely active ulcerative colitis. The product is currently approved for the treatment of relapsing forms of multiple sclerosis,. 2022 Jan;7(1):28-37. doi: 10.1016/S2468-1253(21)00295-8. DOI: 10.1056/NEJMoa2033617, Tap into groundbreaking research and clinically relevant insights. Matloubian M, Lo CG, Cinamon G, et al. / True North Study Group. A total of 2 of 4 patients with remission at week 8 in the placebo group, 7 of 9 in the group that received 0.5 mg of ozanimod, and 5 of 11 in the group that received 1 mg of ozanimod still had remission at week 32. IMPORTANT SAFETY INFORMATION Contraindications: Patients were assessed on day 1 (baseline), at weeks 4 and 8 (during the induction period), and at weeks 20 and 32 (during the maintenance period). 24. 2022 Jun;162(7):2104-2106. doi: 10.1053/j.gastro.2022.01.033. In this preliminary trial, ozanimod at a daily dose of 1 mg resulted in a slightly higher rate of clinical remission of ulcerative colitis than placebo. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. Xeljanz. The first author wrote the first draft of the manuscript. 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. 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. A total of 186 of the 197 patients (94%) completed the induction period. 2021 Jul 5;15(7):1120-1129. doi: 10.1093/ecco-jcc/jjab012. European evidence-based consensus on the diagnosis and management of ulcerative colitis: definitions and diagnosis. 26. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. 5. Drugs. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Eligible patients were 18 to 75 years of age and had moderately to severely active ulcerative colitis, defined as a total Mayo score of 6 to 12, with an endoscopy subscore of 2 or higher, a rectal-bleeding subscore of 1 or higher, and a stool-frequency subscore of 1 or higher. Efficacy Outcomes at Week 8 in the Trial of Ozanimod as Induction Therapy. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. 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. Etrolizumab for maintenance therapy in patients with moderately to severely active ulcerative colitis (LAUREL): a randomised, placebo-controlled, double-blind, phase 3 study. Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Lfberg R. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. 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