ozanimod as induction and maintenance therapy for ulcerative colitis

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. The primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. 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. All the ranked key secondary end points were also significantly improved with ozanimod therapy, as compared with placebo, at week 52; improvement in the incidence of histologic remission (an additional secondary end point) also occurred with ozanimod therapy (Figure 2B and Tables S4 and S6). Results: Nat Immunol 2007;8:1295-1301, 7. Aim: The relative treatment effects of filgotinib and adalimumab, golimumab, infliximab, tofacitinib, ustekinumab and vedolizumab were estimated using a network meta-analysis (NMA). Epub 2021 Dec 8. Safety was also assessed. 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. Jangi S, Yoon H, Dulai PS, et al. At week 32, the rate of clinical remission was 21% in the group that received 1 mg of ozanimod, 26% in the group that received 0.5 mg of ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively. ); 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. Squamous-cell carcinoma of the skin developed in one patient who received 1 mg of ozanimod; this patient had previously been treated with mercaptopurine for more than 2 years. 4. Key secondary clinical, endoscopic, and histologic end points were evaluated with the use of ranked, hierarchical testing. The most trusted, influential source of new medical knowledge and clinical best practices in the world. Zeposia (ozanimod) is an oral, sphingosine-1-phosphate (S1P) receptor modulator that binds with high affinity to S1P receptors 1 and 5. One death (in cohort 2) occurred in a patient with a history of ischemic cardiomyopathy and prolonged tobacco use, in whom influenza and acute respiratory distress syndrome developed. 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). Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. 5. The product is currently approved for the treatment of relapsing forms of multiple sclerosis,. 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. Sandborn WJ, Feagan BG, Wolf DC, et al. eCollection 2022. 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. MeSH Treatment with oral aminosalicylates or prednisone (30 mg per day) was required to be at stable doses. 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. 30. 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. Valuable tools for building a rewarding career in health care. We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. 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. Epub 2022 Nov 3. Grler MH, Goetzl EJ. Moderately to severely active ulcerative colitis (UC) in adults. Mucosal healing at week 8 occurred in 8 of 65 patients (12%) in the placebo group, as compared with 18 of 65 (28%) in the group that received 0.5 mg of ozanimod (P=0.03) and 23 of 67 (34%) in the group that received 1 mg of ozanimod (P=0.002) (Figure 1C). Ustekinumab as induction and maintenance therapy for ulcerative colitis. Geboes K, Riddell R, Ost A, Jensfelt B, Persson T, Lfberg R. A reproducible grading scale for histological assessment of inflammation in ulcerative colitis. 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. Primary nonresponse was defined as signs and symptoms of persistently active disease despite an adequate trial of induction treatment with an anti-TNF agent. Zeposia reduces the capacity of lymphocytes to exit from lymph nodes, reducing the number of circulating lymphocytes in peripheral blood. A documented presence of varicellazoster virus IgG antibody or complete varicellazoster vaccination was required in order to minimize the risk of infection. T1 - Ozanimod as induction and maintenance therapy for ulcerative colitis. Br J Pharmacol 2016 March 15 (Epub ahead of print). Kappos L, Bar-Or A, Cree BAC, et al. 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. S2). 6. From December 2012 through April 2015, we conducted this randomized, double-blind, placebo-controlled phase 2 trial of induction and maintenance therapy at 57 centers in 13 countries. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher values indicating more severe disease18; subscores range from 0 to 3, with higher scores indicating more severe disease. 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. J Crohns Colitis 2008;2:1-23. Methods: Disclaimer, National Library of Medicine Multiple post hoc subgroup analyses were also performed (see the Supplementary Appendix). 19 this was a double-blind, placebo-controlled trial. 2022 Jan;7(1):28-37. doi: 10.1016/S2468-1253(21)00295-8. Elevated liver aminotransferase levels were more common with ozanimod therapy than with placebo. ); the Feinberg School of Medicine, Chicago (S.B.H. Colitis, Ulcerative, Colitis, Ulcer, Golimumab . Cancer was diagnosed in 1 patient who received ozanimod during the induction period (basal-cell carcinoma). 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, 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 (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. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. FTY720 therapy exerts differential effects on T cell subsets in multiple sclerosis. 18. 17. Feagan BG, Sandborn WJ, Danese S, Wolf DC, Liu WJ, Hua SY, Minton N, Olson A, D'Haens G. Lancet Gastroenterol Hepatol. 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). 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. Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. maintenance treatment of acute myeloid leukaemia after induction therapy The formulary will reflect the TAG - NHS England is the responsible commissioner. 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. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. Mehling M, Lindberg R, Raulf F, et al. 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. Disclaimer, National Library of Medicine Clinical remission was defined as a rectal-bleeding subscore of 0, a stool-frequency subscore of 1 or less (plus a 1-point reduction from baseline), and a mucosal endoscopy subscore of 1 or less, without friability. Ozanimod has recently received US Food and Drug Administration approval for moderate-to-severe ulcerative colitis. One patient receiving ozanimod had a hypertensive crisis on day 1 of the induction period; the event was moderate and resolved on the same day without treatment interruption. Neurology 2012;78:672-680. J Clin Pharmacol 2017;57:988-996. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992.). New York: Pfizer Labs, 2018 (package insert). Drugs 2020;80:841-848. 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 . 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. A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis. Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor modulator that selectively targets S1P 1 and S1P 5 receptors, is approved in the United States and European Union for the treatment of ulcerative colitis (UC) [, , ].The pathogenesis of inflammatory bowel disease (IBD) is mediated in part by lymphocyte trafficking to and from inflamed tissues in the gut []. Stay connected to what's important in medical research and clinical practice, Subscribe to the most trusted and influential source ofmedical knowledge. Lancet 2012;380:1606-1619, 2. The content of this site is intended for health care professionals. N Engl J Med. 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. The time to disease relapse was examined as an exploratory end point. 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. For the primary analysis, as well as for the analyses of all secondary outcomes that were defined as proportions, patients who had missing data were classified as not having had a response. FormalPara Hintergrund. The body-mass index is the weight in kilograms divided by the square of the height in meters. N Engl J Med 2005;353:2462-2476, 20. 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. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. Am J Gastroenterol 2015;110:802-819, May 5, 2016N Engl J Med 2016; 374:1754-1762 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 primary end point for both periods was the percentage of patients with clinical remission, as assessed with the three-component Mayo score. "Ozanimod is an oral, sphingosine-1-phosphate (S1P) receptor modulator . 1. 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). Figure 2 shows the proportions of patients with clinical remission, clinical response, mucosal healing, and histologic remission at week 32. ); the Division of Gastroenterology, University Hospital Medical Center Beanijska Kosa, Belgrade, Serbia (I.J. 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. 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. (Funded by Receptos; TOUCHSTONE ClinicalTrials.gov number, NCT01647516.). 3. 26. S99 Upadacitinib in the Treatment of Ulcerative Colitis. 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. Patients who did not proceed to the maintenance period were considered not to have had a response at week 32. The key secondary end points were evaluated with the use of a two-sided CochranMantelHaenszel test following a closed, prespecified hierarchical testing procedure to control the overall type I error rate for multiple end points (with an alpha of 0.05 allocated for each of the induction and maintenance periods of the trial). Long-term . Ozanimod is an oral sphingosine 1-phosphate receptor modulator. Ozanimod as induction and maintenance therapy for ulcerative colitis. The demographic and clinical characteristics of the patients at baseline were summarized descriptively. ULN denotes upper limit of the normal range. 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. Ozanimod induction and maintenance treatment for ulcerative colitis. Lancet Gastroenterol Hepatol 2020;5:819-828. All the authors had full access to the data. (%), Serious adverse event related to ozanimod or placebo no. Another limitation is the lack of long-term data; the open-label extension phase of this trial is ongoing. official website and that any information you provide is encrypted Lancet Gastroenterol Hepatol. 4 it is taken orally 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. [3] [4] [5] [6] It acts as a sphingosine-1-phosphate (S1P) receptor agonist, sequestering lymphocytes to peripheral lymphoid organs and away from their sites of chronic inflammation. Randomization was conducted by means of a centralized interactive voice- and Web-based activated response system (IxRS). 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. 16. Efficacy analyses were performed according to the intention-to-treat principle. 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). Elevated liver aminotransferase levels were more common with ozanimod. Aslam N, Lo SW, Sikafi R, Barnes T, Segal J, Smith PJ, Limdi JK. The absence of clinically significant bradycardia or cardiac conduction abnormalities may have been due to mitigation by the 7-day dose-escalation schedule.13-15,24-26 It should be noted that the eligibility criteria for this trial excluded patients with conditions such as recent myocardial infarction, unstable angina or other clinically significant cardiovascular disease, or active or chronic infection. Macular edema occurred in 3 patients receiving ozanimod; all cases resolved after treatment discontinuation (, Presented at the Annual Meeting of the European Committee for Treatment and Research in Multiple Sclerosis, Presented at the Triennial Joint Meeting of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (MSVirtual2020), Case Records of the Massachusetts General Hospital, 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, Time since diagnosis of ulcerative colitis yr, Had a primary nonresponse no./total no. Prespecified subgroup analyses for the primary end point of clinical remission during the maintenance period are shown in Figure S5. 2015 Inderscience Enterprises Ltd.. All rights reserved. 29. 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. Figueroa, Gabriela; Forster, Erin . 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). and Subrata Ghosh and Petersen, {Ann Katrin} and Hua, {Steven Y.} Scores were assessed by a central reader. This trial was not large enough or of sufficiently long duration to assess safety. At week 32, the rate of clinical remission was 21% in the group that received 1 mg of ozanimod, 26% in the group that received 0.5 mg of ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. N1 - Funding Information: BACKGROUND Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. This trial was not large enough or of sufficiently long duration to assess the safety of ozanimod. Complete resolution of mucosal neutrophils associates with improved long-term clinical outcomes of patients with ulcerative colitis. Gastroenterology 2011;141:1194-1201. Nonserious infections were more common with ozanimod than with placebo during the maintenance phase of the trial. AB - BACKGROUND Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. 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. 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). Valuable tools for building a rewarding career in health care. Elevated liver aminotransferase levels were more common with ozanimod. 1. Ozanimod: A Review in Ulcerative Colitis. FASEB J 2004;18:551-553, 8. 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. 84 The patients were randomized to placebo, 0.5, or 1 mg of ozanimod daily. EP. Macular edema occurred in 3 patients receiving ozanimod; all cases resolved after treatment discontinuation (Table 2). The emerging role of histologic disease activity assessment in ulcerative colitis. Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery. 83 A phase 2 trial (TOUCHSTONE) evaluated the induction and maintenance treatment of ozanimod in 197 moderate to severe UC patients. Glucocorticoid doses were maintained unchanged through week 8, after which time the doses could be tapered at the discretion of the investigator. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. 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. 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. All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. 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. N Engl J Med 2013;369:699-710, 3. Rubin DB. 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). Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. Serious infection occurred in less than 2% of the patients in each group during the 52-week trial. 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). eCollection 2022. Patients without a clinical response during the induction period could enter an open-label extension trial at week 10, whereas patients who were included in the maintenance period could enter the extension trial at week 52 or after disease relapse (defined as a partial Mayo score [i.e., the rectal-bleeding subscore, stool-frequency subscore, and physicians global assessment subscore] of 4 points or a 2-point increase from week 10, as well as an endoscopy subscore of 2 points) (Fig. Cohen JA, Arnold DL, Comi G, et al. METHODS: We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Ozanimod is a sphingosine 1-phosphate receptor modulator marketed under the brand name Zeposia . 2022 Jan 13;386(2):194. doi: 10.1056/NEJMc2117224. 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). All the authors had full access to the data. 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. FOIA ); 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. Brinkmann V, Baumruker T. Pulmonary and vascular pharmacology of sphingosine 1-phosphate. DOI: 10.1056/NEJMoa2033617, Tap into groundbreaking research and clinically relevant insights. 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. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. The first author wrote the first draft of the manuscript. The sponsor and the steering committee interpreted the data jointly. Lewis JD, Chuai S, Nessel L, Lichtenstein GR, Aberra FN, Ellenberg JH. The https:// ensures that you are connecting to the Efficacy Outcomes at Week 8 in the Trial of Ozanimod as Induction Therapy. Throughout the 52-week trial, 17 patients had an absolute lymphocyte count of less than 200 cells per cubic millimeter, which subsequently increased and remained at a level at or above 200 cells per cubic millimeter during ozanimod treatment. Efficacy and safety of adalimumab in paediatric patients with moderate-to-severe ulcerative colitis (ENVISION I): a randomised, controlled, phase 3 study. After a screening period of up to 5 weeks, patients entered a 10-week induction period. Infliximab for induction and maintenance therapy for ulcerative colitis. Gordon JP, McEwan PC, Maguire A, Sugrue DM, Puelles J. Characterizing unmet medical need and the potential role of new biologic treatment options in patients with ulcerative colitis and Crohns disease: a systematic review and clinician surveys. 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. 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. Ozanimod (RPC1063) is a new oral S1P1-receptor and S1P5-receptor modulator with no activity on S1P2, S1P3, and S1P4.16 A phase 2 trial of ozanimod in patients with relapsing multiple sclerosis showed a dose-dependent reduction in circulating lymphocytes that was associated with significant reductions in inflammatory and neurodegenerative brain lesions, with minimal effects on heart rate and liver enzymes.17 We evaluated the efficacy and safety of ozanimod in patients with moderately to severely active ulcerative colitis. Ozanimod induction and maintenance treatment for ulcerative colitis. Stange EF, Travis SPL, Vermeire S, et al. Biometrika 1976;63:581-592. 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). 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. Scores were assessed by a central reader. Neurology 2010;75:403-410, 12. Analyses of outcomes at week 32 were prespecified as other secondary outcomes and were considered to be exploratory. Elevated liver aminotransferase levels were more common with ozanimod therapy than with placebo. Safety Findings through the Final Safety Visit in the Induction and Maintenance Periods. Oral azacitidine for maintenance treatment of acute myeloid leukaemia after induction therapy (TA827) . The main study is composed of an induction period, maintenance period, safety follow-up, and participants meeting certain criteria will be given the opportunity to . 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). Results: Ozanimod, a selective sphingosine-1- phosphate receptor modulator . 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 first author wrote the first draft of the manuscript. S3 in the Supplementary Appendix). Conclusions: Mult Scler 2014;20:471-480, 13. conducted a 52-week, phase 3 trial to evaluate ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. (Funded by Bristol Myers Squibb; True North ClinicalTrials.gov number, NCT02435992. abstract = "BACKGROUND Ozanimod, a selective sphingosine-1-phosphate receptor modulator, is under investigation for the treatment of inflammatory bowel disease. Unable to load your collection due to an error, Unable to load your delegates due to an error, Collaborators, N Engl J Med 2019; 381 (13) 1201-1214 ; 47 Sandborn WJ, Feagan BG, D'Haens G. et al; True North Study Group. Lancet Neurol 2019;18:1021-1033. Utrecht, the Netherlands: Celgene Distribution B.V., 2020 (summary of product characteristics). Herpes zoster infection did not occur in any patient who did not receive ozanimod. 2022 Oct 20;12(10):997. doi: 10.3390/metabo12100997. All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. ); Yale School of Medicine, New Haven, and the Veterans Affairs Connecticut Healthcare System, West Haven both in Connecticut (L.L. 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). 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). Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis. 23. 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]. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM): a multicentre, randomised, minimum 12-month, phase 3 trial. Bianchi Porro G, Cassinotti A, Ferrara E, Maconi G, Ardizzone S. The management of steroid dependency in ulcerative colitis. Epub 2021 Nov 17. The incidence. 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. No important differences were observed among the groups in the most commonly reported adverse events during the trial (Table 2). Secondary nonresponse was defined as the recurrence of symptoms during maintenance therapy after a previous clinical benefit. Flexible sigmoidoscopy with colonic biopsy was performed at screening and at weeks 8 and 32. Selmaj KW, Steinman L, Comi G, et al. Rectal bleeding and stool frequency were reported by patients in an electronic diary. Lancet Neurol 2016;15:373-381. N Engl J Med, 374 (2016), pp. Adverse events and use of concomitant medications were recorded through 32 weeks. A Literature Review of Ozanimod Therapy in Inflammatory Bowel Disease: From Concept to Practical Application. 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. Br J Pharmacol 2016;173:1778-1792. 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. The trial included blinded induction and maintenance periods and an optional open-label period (Fig. 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. 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. Ords I, Eckmann L, Talamini M, Baumgart DC, Sandborn WJ. Mandala S, Hajdu R, Bergstrom J, et al. From the University of California San Diego, La Jolla (W.J.S. Blinded central reading of endoscopic videos and histologic findings was performed. The trial was conducted from May 2015 through June 2020. Safety was also assessed. 2021 Jul 5;15(7):1120-1129. doi: 10.1093/ecco-jcc/jjab012. 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. DHaens G. Systematic review: second-generation vs. conventional corticosteroids for induction of remission in 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. 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. A total of 91 of the 103 patients who entered the maintenance phase (88%) completed the trial. 22. Science 2002;296:346-349, 6. 27. Additional eligibility criteria and the exclusion criteria are provided in the Supplementary Appendix. PDF Ozanimod for the treatment of relapsing remitting multiple sclerosis Ludwig Rasche, F. Paul Biology, Psychology 21. Accessibility We anticipated that 10% of the patients in the placebo group would have clinical remission after induction therapy. Cohen JA, Barkhof F, Comi G, et al. Intest Res 2018;16:26-42. 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. 2022 May;18(5):265-271. Mehling M, Brinkmann V, Antel J, et al. ), and the University of Calgary, Calgary, AB (S. Ghosh) all in Canada; Atlanta Gastroenterology Associates, Atlanta (D.C.W. sharing sensitive information, make sure youre on a federal Information, resources, and support needed to approach rotations - and life as a resident. Publisher Copyright: No patient with a serious or opportunistic infection had an absolute lymphocyte count of less than 200 cells per cubic millimeter. publisher = "Massachussetts Medical Society", Ozanimod as induction and maintenance therapy for ulcerative colitis. No important differences were observed in subgroup analyses that were based on demographic characteristics and disease characteristics at baseline (Fig. 15. Our trial had some limitations. Before TNF inhibitors (TNFi) (TA 329) Adalimumab# Review at 8 weeks Infliximab# (S/C or IV) Review at 14 weeks Data were from case-report forms. 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. View Record in Scopus Google Scholar. journal = "New England Journal of Medicine". Ozanimod as induction and main-tenance therapy for ulcerative colitis. 1754-1762. 1,2 During the 10-week induction period, patients in cohort 1 were randomly assigned in a 2:1 ratio to receive daily ozanimod hydrochloride (1 mg, equivalent to 0.92 mg . Bookshelf Additional information about the methods is provided in the Supplementary Appendix. (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 . 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. Inference and missing data. Would you like email updates of new search results? Presented at the Annual Meeting of the European Committee for Treatment and Research in Multiple Sclerosis, Stockholm, September 1113, 2019. abstract. 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%). Tables S1 and S2 list the prespecified efficacy end points. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. 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. Laboratory values were flagged by the central laboratory if they fell outside the standard reference range. N Engl J Med 2010;362:402-415, 10. 2022 Aug;82(12):1303-1313. doi: 10.1007/s40265-022-01762-8. The members of the steering committee designed the trial in collaboration with the sponsor (Bristol Myers Squibb). Introduction. Gastroenterol Hepatol (N Y). 2020 Sep;5(9):819-828. doi: 10.1016/S2468-1253(20)30188-6. The current study consisted of a 10-week. Leukocyte counts, including lymphocyte subsets, were not provided to investigators. and transmitted securely. Other prespecified end points included histologic remission and clinical remission in subgroups defined according to demographic and disease-based characteristics. Confidentiality agreements were in place between the sponsor and all the authors. Sandborn et al. All the authors had full access to the data. We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Annu Rev Biochem 2009;78:743-768, 4. 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. *Plusminus values are means SD. 15. Li X, Zhang H, Zheng W, Sun J, Wang L, He Z. Mol Neurobiol. 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. Exploratory Efficacy Outcomes at Week 32 in the Trial of Ozanimod as Maintenance Therapy. All other key secondary end points were significantly improved with ozanimod as compared with placebo in both periods. Drugs. 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). 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). End points are shown in the order from the hierarchical testing procedure. Ozanimod is a sphingosine 1-phosphate receptor modulator marketed under the brand name Zeposia. The primary outcome was clinical remission (Mayo Clinic score 2, with no subscore >1) at 8 weeks. A review of the therapeutic management of 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. 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. Safety was also assessed. Lancet 2018;391:1263-1273. The time to disease relapse (an exploratory end point) during the maintenance period is shown in Figure S4. Information, resources, and support needed to approach rotations - and life as a resident. and transmitted securely. We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. The overall incidence of adverse events was higher in the ozanimod group than in the placebo group during the maintenance period and was similar among the groups during the induction period. Li M, Zhang R, Xin M, Xu Y, Liu S, Yu B, Zhang B, Liu J. Metabolites. Glucocorticoid-free remission was defined as clinical remission at 52 weeks without receipt of glucocorticoids for at least 12 weeks. 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. 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). Epub 2022 Feb 2. official website and that any information you provide is encrypted 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. 2. Elevated liver aminotransferase levels were more common with ozanimod. Lee SH, Kwon JE, Cho M-L. Immunological pathogenesis of inflammatory bowel disease. Randomization and Follow-up of the Patients in the Induction and Maintenance Periods. Feagan BG, Sandborn WJ, Danese S, et al. Ozanimod induction therapy for patients with moderate to severe Crohn's disease: a single-arm, phase 2, prospective observer-blinded endpoint study. 8. The key secondary efficacy end points were assessed in a closed, prespecified hierarchical testing procedure. Knauss A, Gabel M, Neurath MF, Weigmann B. Patients with ulcerative colitis achieved a significantly greater remission rate with daily ozanimod induction therapy compared to placebo, and that benefit was maintained with ozanimod maintenance therapy, researchers report in The New England Journal of Medicine.. William J. Sandborn, MD, of the University of California San Diego in La Jolla, and True North co-investigators studied ozanimod . 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). 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. 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). NEW! The three-component Mayo score is defined as the sum of the rectal-bleeding subscore, the stool-frequency subscore, and the endoscopy subscore. The protocol, available with the full text of this article at NEJM.org, was approved by the institutional review board at each center. The .gov means its official. 2021 Sep 30;385 (14):1280-1291. doi: 10.1056/NEJMoa2033617. Gut 2000;47:404-409, 22. HHS Vulnerability Disclosure, Help 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). Editorial assistance was funded by Bristol Myers Squibb. Safety was also assessed. Multiple sclerosis treatment with fingolimod: profile of non-cardiologic adverse events. Bethesda, MD 20894, Web Policies (%). 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). 16. 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. 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. 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). Patients who did not have a response at week 8 were allowed to cross over to optional open-label treatment. Careers. Gut 2000;47:404-409. 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