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Ozanimod Ulcerative Colitis Phase 3

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Efficacy And Safety Of Extended Induction Treatment With Upadacitinib 45 Mg Once Daily Followed By Maintenance Upadacitinib 15 Or 30 Mg Once Daily In Patients With Moderately To Severely Active Ulcerative Colitis

FDA Approves Ozanimod for Ulcerative Colitis

Phase 2b and phase 3 studies have demonstrated the safety and efficacy of upadacitinib when administered daily for 8 weeks as induction treatment for patients with moderately to severely active ulcerative colitis.1-3 A study evaluated the safety and efficacy of 16 weeks of induction therapy with daily upadacitinib at 45 mg, followed by 52 weeks of maintenance therapy with daily upadacitinib administered at 15 mg or 30 mg.4 The patient population consisted of 125 patients with ulcerative colitis without a clinical response after 8 weeks of induction therapy with upadacitinib in the U-ACHIEVE study. Clinical response was defined as a decrease in the adapted Mayo score of 2 or more points and 30% from baseline, plus a decrease of at least 1 point in the rectal bleeding score or an absolute rectal bleeding score of 1 or lower. A response to extended induction therapy was reported in 73 of 125 patients , and 45 of these patients completed the U-ACHIEVE maintenance study.

The rates of adverse events were similar for both doses of maintenance upadacitinib. Similar rates were reported for AEs of special interest, such as anemia , elevated creatine phosphokinase , and serious infection . AEs of special interest that were observed only among the patients who received the higher dose of upadacitinib included hepatic disorder , herpes zoster , neutropenia , adjudicated major adverse cardiovascular events , and nonmelanoma skin cancer .

References

To Evaluate Efficacy And Long

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
First Posted : April 16, 2019Last Update Posted : February 8, 2022
Condition or disease
Phase 3
Layout table for study information

Study Type :
Quadruple
Primary Purpose: Treatment
Official Title:A Phase 2/3, Multicenter, Randomized, Double-blind, Placebo-controlled Study of Oral Ozanimod to Evaluate Efficacy and Long-term Safety in Japanese Subjects With Moderately to Severely Active Ulcerative Colitis
Actual Study Start Date :
  • Proportion of subjects with clinical response Defined as a reduction from Baseline in the complete Mayo score of 3 points and 30%, and a reduction from Baseline in the rectal bleeding subscore of 1 point or an absolute rectal bleeding subscore of 1 point
  • Proportion of subjects with clinical remission Defined as: Definition 1. Complete Mayo score of 2 points with no individual subscore of > 1 point, Definition 2. Rectal bleeding subscore = 0 and stool frequency subscore 1 and endoscopy subscore 1
  • Adverse Event Number of participants with adverse event.
  • Ozanimod Yields Clinical Response Remission In Ulcerative Colitis Patients

    Serious infections occurred in less than 2% of patients treated with the medication during the duration of the 52-week trial.

    Results from both an induction and maintenance therapy trial show ozanimod can be an effective treatment for patients with inflammatory bowel disease .

    A team, led by William J. Sandborn, MD, University of California San Diego, compared ozanimod with placebo in achieving both clinical remission and clinical response in patients with moderate to severely active ulcerative colitis.

    Ozanimod is a selective sphingosine-1-phosphate receptor modulator currently being studied for the treatment of patients with IBD.

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    A Phase 3 Multicenter Randomized Double

    Clinical Trial Details

    YELLOWSTONE Induction Study : This study is designed to determine the safety and effectiveness of the oral investigational study drug, ozanimod, versus a placebo in achieving symptom remission in patients with active Crohn’s disease symptoms. An induction study is the first in a series of studies. Participation in this clinical study is expected to last 12 weeks .

    Depending on response and the study doctor’s recommendation, participants may have the opportunity to continue participation in the YELLOWSTONE Maintenance RPC01-3203 or YELLOWSTONE Open-Label Extension Study . An open label extension study means you may be able to continue taking the investigational study drug, if you qualify and choose to participate

    Ozanimod is thought to act on the immune system by encouraging certain types of white blood cells called lymphocytes, which include T cells, to stay in the lymph nodes and other places in the body, thereby keeping them away from sites of inflammation.

    Lymphocytes, which act as the body’s mechanism to fight off invaders, are responsible for initiating the immune response. However, in Crohn’s disease, lymphocytes misread the inflammation caused by the disease as an area where their help is needed.

    You may be able to take part in this ozanimod study if you:

    Eligible prior medications include corticosteroids, immunomodulators or biologic therapy .

    The presence of any of the following will exclude you from participation in the study:

    Dop69 Ozanimod For Induction Treatment Of Moderate

    True North Ozanimod Phase III in Ulcerative Colitis (UC) Completed ...

    Eaton, K. Duperrouzel, C. Bhandari, P. Craigie, S. Bonner, A. Cameron, C. Tencer, T. Kumar, J.

    CRG-EVERSANA, Value & Evidence Division- Marketing and Market Access, Ontario, Canada CRG-EVERSANA, Value & Evidence Division- Marketing and Market Access, Sydney- Nova Scotia, Canada Bristol Myers Squibb, Global HEOR, Princeton, United States

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    Bristol Myers Squibb Presents Interim Results From Long

    The percentage of patients achieving clinical remission, clinical response, endoscopic improvement and corticosteroid-free remission was maintained through Week 142

    Zeposia is the first and only oral sphingosine 1-phosphate receptor modulator approved to treat patients with ulcerative colitis

    PRINCETON, N.J.—-Bristol Myers Squibb today announced interim results from the True North open-label extension study evaluating the long-term efficacy and safety profile of Zeposia in patients with moderately to severely active ulcerative colitis . Findings show that the percentage of patients achieving clinical remission, clinical response, endoscopic improvement and corticosteroid-free remission was maintained through Week 142. No new safety signals emerged in the study. These data will be presented at the 17th Congress of the European Crohn’s and Colitis Organisation , taking place February 16-19, 2022.

    Additional Bristol Myers Squibb-sponsored abstracts presented at the ECCO 2022 Congress can be accessed online here.

    Visit this page on BMS.com for more information on Bristol Myers Squibbs scientific approach and resources on gastrointestinal immune-mediated diseases.

    About True North

    Bristol Myers Squibb thanks the patients and investigators involved in the True North clinical trial.

    About Ulcerative Colitis

    About Zeposia

    U.S. FDA APPROVED INDICATIONS

    ZEPOSIA is indicated for the treatment of:

    IMPORTANT SAFETY INFORMATION

    Contraindications:

    About Bristol Myers Squibb

    Ozanimod Improves Ulcerative Colitis Symptoms

    A phase 3 study involving 645 patients with moderate to severe ulcerative colitis showed treatment with ozanimod improved several critical symptoms, including rectal bleeding and stool frequency.

    The True North study evaluated the efficacy of the ozanimod versus placebo on those two symptoms, as well as fecal calprotectin and C-reactive protein during the induction phase, with the researchers assessing how quickly the patients saw improvement.

    According to results presented at the virtual Digestive Disease Week meeting, the baseline rectal bleeding scores were 1.7 and 1.6 in the drug and placebo arms, respectively. The mean baseline stool frequency score was 2.4 in both groups.

    The researchers noted improvement in rectal bleeding was seen starting at week 2 and SFS at week 5 . At week 10, 52% of patients in the ozanimod arm reported no rectal bleeding compared to 30.1% in the placebo arm . More improvement was also seen in stool frequency .

    The mean change in FCP concentration at week 10 was -470.2 µg/g with ozanimod and 21.1 µg/g with placebo . The mean change in CRP from baseline to weeks 5 and 10 were also greater with ozanimod than placebo .

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    The Effects Of Maintenance Therapy With Upadacitinib On Abdominal Pain Bowel Urgency And Fatigue In Patients With Moderately To Severely Active Ulcerative Colitis: Phase 3 U

    Upadacitinib is a reversible, selective Janus kinase inhibitor.1 In the phase 3 U-ACHIEVE and U-ACCOMPLISH trials, induction therapy with upadacitinib was superior to placebo in patients with moderately to severely active ulcerative colitis who required treatment after previous therapy.2,3 Improvements were reported in symptoms such as abdominal pain, bowel urgency, and fatigue, which can be debilitating to these patients.4

    Patients who demonstrated a clinical response during the 8-week induction period with daily upadacitinib were enrolled in the U-ACHIEVE maintenance trial. Silvio Danese, MD, PhD, presented results for this cohort.5This study randomly assigned 451 patients to receive upadacitinib at 15 mg, upadacitinib at 30 mg, or placebo, in a double-blind manner. Patient-reported outcomes of abdominal pain and bowel urgency were assessed during maintenance treatment. The Functional Assessment of Chronic Illness Therapy Fatigue instrument was used to measure fatigue. A change of 5 or more points from baseline in the FACIT-F score was considered a meaningful within-person change, and an increase of 40 or more points was considered normalization of fatigue.

    References

    1. Kim JW, Kim SY. The era of Janus kinase inhibitors for inflammatory bowel disease treatment. Int J Mol Sci. 2021 22 :11322.

    2. Sandborn WJ, Ghosh S, Panes J, et al. Efficacy of upadacitinib in a randomized trial of patients with active ulcerative colitis. Gastroenterology. 2020 158:2139-2149.e14.

    Efficacy And Safety Of Combination Induction Therapy With Guselkumab And Golimumab In Participants With Moderately To Severely Active Ulcerative Colitis: Results Through Week 12 Of A Phase 2a Randomized Double

    Investigator Insights: Updates in Ulcerative Colitis

    Guselkumab is an antagonist of the p19 subunit of IL-23 that is approved to treat plaque psoriasis. Golimumab is an antagonist of TNF and is approved for the treatment of ulcerative colitis.1 The phase 2a VEGA study evaluated the safety and efficacy of induction therapy with guselkumab plus golimumab vs monotherapy with guselkumab or golimumab in adults with moderately to severely active ulcerative colitis.2The trial enrolled patients with a Mayo score of 6 to 12 and an endoscopy subscore of 2 or lower according to central review. The patients had received prior therapy that was either intolerable or unsuccessful. The trial excluded patients previously treated with a TNF antagonist.

    Patients were randomly assigned into the 3 arms. In the golimumab monotherapy arm, this agent was administered at 200 mg subcutaneously at week 0, followed by 100 mg administered at weeks 2, 6, and 10. In the guselkumab monotherapy arm, treatment was administered at 200 mg intravenously at weeks 0, 4, and 8. For combination therapy, the 2 antibodies were administered in combination at the same doses and schedules. The induction phase for all 3 arms continued for 12 weeks. The primary endpoint was clinical response, defined as a decrease from baseline in the Mayo score of at least 30% and 3 points, with either a decrease in the rectal bleeding subscore of 1 or more or a rectal bleeding subscore of 0 or 1.

    References

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    Clinically Meaningful Improvements With Ozanimod In Uc Trial

      The phase 3 True North trial evaluating the efficacy of ozanimod as an induction and maintenance therapy for adults with moderate to severe ulcerative colitis met both primary and key secondary end points, according to Bristol Myers Squibb.

      Ozanimod is a sphingosine 1-phosphate receptor modulator marketed under the brand name Zeposia®. The product is currently approved for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

      The multicenter, double-blind, placebo-controlled True North study included patients with moderate to severe ulcerative colitis who had an inadequate response to prior treatment. In the induction phase, patients were randomized to receive either ozanimod 1mg orally once daily or placebo for 10 weeks. Patients who achieved a clinical response in the induction phase or who were part of an open-label arm were eligible to proceed into the maintenance phase, in which they were re-randomized to receive ozanimod or placebo through week 52.

      Results showed that ozanimod met both primary end points achieving statistically significant clinical remission at week 10 in the induction phase and at week 52 in the maintenance phase .

      Ozanimod Is An Efficacious Oral Therapy After 5

      A post hoc analysis of data from the phase 3 True North trial assessed the efficacy of10 weeks of ozanimod induction therapy, with or without concomitant corticosteroid treatment.1,2 The patients had received prior treatment with 5-aminosalicylic acid, but not with immunomodulators or biologic therapies. Bruce Sands, MD, presented the results.1 Among 464 enrolled patients, 101 received placebo and 205 received ozanimod in cohort 1, while 158 received open-label ozanimod in cohort 2.

      Among all patients in the analysis, clinical remission at week 10 was reported in 23.4% of cohort 1, 30.4% of cohort 2, and 8.9% of the placebo arm . A clinical response occurred in 53.7% of cohort 1, 62.7% of cohort 2, and 30.7% of the placebo arm . Endoscopic improvement was reported in 35.6% of cohort 1, 38% of cohort 2, and 14.9% of the placebo arm . Mucosal healing occurred in 18% of cohort 1, 14.6% of cohort 2, and 5.0% of the placebo arm .

      At week 10, in cohort 1, the rate of clinical remission was 19.0% with ozanimod vs 5.0% with placebo among the patients receiving concomitant corticosteroids. Among patients who were not receiving cor-ticosteroids, clinical remission was reported in 24.5% of the ozanimod arm vs 9.9% of the placebo arm . The rate of clinical response was 59.5% with ozanimod vs 30.0% with placebo in patients who concomi-tantly used corticosteroids , and 52.1% vs 30.9% in those who did not.

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      Pk Of Ozanimod With Gemfibrozil Itraconazole Or Rifampin

      This phase 1, randomized, open-label study focused on assessing the single-dose pharmacokinetics of ozanimod and its metabolites as well as to assess the effects of gemfibrozil, itraconazole, and rifampin on the single-dose PK of ozanimod. A total of 40 patients were randomized to receive either a single oral dose of ozanimod, oral doses of gemfibrozil + a single dose of ozanimod, oral doses of itraconazole + a single dose of ozanimod, or oral doses of rifampin + a single dose of ozanimod. In the single dose of ozanimod alone group, there were dose-proportional increases in Cmax and AUC for both the parent drug, ozanimod as well as its metabolites CC112273 and CC1084037. Itraconazole, a strong inhibitor of CYP3A and P-glycoprotein increased ozanimod AUC by 13%, while rifampin, a strong inducer of CYP3A and P-gp, reduced the AUC of ozanimod by 24%. This implies that there is a CYP3A4 and P-gp involvement in the metabolism of ozanimod. Gemfibrozil, a strong inhibitor of the CYP450 system, increased the AUC for the metabolites of ozanimod, CC112273 and CC1084037 by 47% and 69%, respectively. The metabolites of ozanimod were found to have similar single-dose PK properties, with CYP2C8 being the main enzyme in the metabolism of these metabolites, and CYP3A4 and P-gp being enzymes for the metabolism of ozanimod .

      L.R. Fitzpatrick, T. Woldemariam, in, 2017

      S1p Receptor Modulator Effective For Both Induction And Maintenance

      BMY 10Oct2020 PR " Bristol Myers Squibb Presents Positive Late

      This article is a collaboration between MedPage Today and:

      The oral sphingosine-1-phosphate receptor modulator ozanimod was effective for induction in moderately to severely active ulcerative colitis , meeting the primary endpoint in a phase III trial.

      At week 10, clinical remission was achieved by 18.4% of patients randomized to ozanimod 0.92 mg daily compared with 6% of those given placebo, which represented a difference of 12.4% , reported Brian Feagan, MD, of Western University in London, Ontario.

      Clinical remission was defined as having the following on the 3-component Mayo score: rectal bleeding score of zero, stool frequency score of 1 or less and decrease from baseline of at least 1, and endoscopy subscore of 1 or less without friability, he explained during a poster presentation at the Advances in Inflammatory Bowel Diseases virtual meeting.

      In physiologic conditions, approximately 2% of the total lymphocyte pool is located in the circulation. S1P regulates lymphocyte migration from lymphoid tissue to sites of inflammation. Ozanimod binds to and internalizes the S1P subtype 1 receptor, preventing certain proinflammatory lymphocytes from exiting the lymph nodes and circulating to the intestinal tissue. This mechanism has also been seen to be effective in multiple sclerosis, the original indication for which ozanimod was approved earlier this year.

      The current study consisted of a 10-week induction period and a 52-week maintenance phase.

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      E Targeting Leukocyte Circulation Outside The Intestine

      Blockade of lymphocyte recirculation in lymph nodes can be targeted through modulation of sphingosine 1-phosphate receptors. Sphingosine 1-phosphate is a bioactive lysophospholipid metabolite that can act as an intercellular lipid mediator of inflammation. Interaction between S1P and the five known S1P receptors regulate the response and function of biological processes, including cell differentiation, migration, proliferation and trafficking of T and B cells.

      Fingolimod was the first S1P receptor modulator to reach the market, initially approved for the treatment of MS . The drug is phosphorylated in vivo, acquiring a structure similar to that of S1P, and functions as a non-selective small-molecule agonist to four of the five S1P receptors. Fingolimod causes peripheral blood lymphopenia due to sequestration of lymphocytes within lymphoid tissue and is associated with cardiovascular side effects, such as bradycardia and hypotension. This led to the development of more specific S1P receptor modulators with preferential actions on S1PR1, S1PR4 and S1PR5, since fingolimod also showed beneficial effects in murine models of colitis .

      Carolyn Goldschmidt DO, Marisa P. McGinley DO, MSc, in, 2021

      Fda Approves Ozanimod For Adults With Ulcerative Colitis

      The treatment is also being studied for safety and efficacy in patients with Crohns disease.

      The US Food and Drug Administration has approved ozanimod 0.92 mg, an oral agent that selectively targets sphingosine-1-phosphate receptor subtypes 1 and 5, for adult patients with moderately to severely active ulcerative colitis.

      The approval, awarded to Bristol Myers Squibb, was based on the data from a placebo-controlled phase 3 trial dubbed True North. In the study, researchers evaluated ozanimod as a single, daily oral therapy for both adults and pediatric patients at least 12 years old with moderately to severely active ulcerative colitis.

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

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