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Ozanimod Phase 3 Ulcerative Colitis

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Fda Approves Ozanimod For Adults With Ulcerative Colitis

FDA Approves Ozanimod for 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.

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

Recapture Of Response With Ozanimod In Patients With Moderately To Severely Active Ulcerative Colitis Who Withdrew Therapy: Data From The True North Open

Ozanimod is an oral, selective agonist of the sphingosine-1-phosphate receptor that is approved in the United States and Europe for the treatment of moderately to severely active ulcerative colitis .1,2 Treatment with ozanimod results in the retention of lymphocytes in the peripheral lymphoid organs, preventing their access to sites of chronic inflammation.3 The US Food and Drug Administration approved ozanimod for UC based on results from the randomized, double-blind phase 3 True North trial.4 In cohort 1 of the trial, 645 patients with moderately to severely active UC were randomly assigned 2:1 to receive ozanimod or placebo.4 In cohort 2, 367 patients received open-label ozanimod . Treatment with ozanimod led to significantly higher rates of clinical remission compared with placebo, as both induction and maintenance .4The rates of clinical response were also higher with ozanimod than placebo, during both induction and maintenance .

Patients with a clinical response at the end of week 10 were randomly assigned a second time to receive either ozanimod or placebo as maintenance therapy. Patients who developed relapsed UC while receiving placebo during the maintenance period and those who completed the maintenance period through week 52 were offered enrollment into the open-label extension phase of the study.

References

2. Zeposia . Summit NJ: Celgene Corporation 2022.

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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 Crohnâs 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 doctorâs 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 bodyâs mechanism to fight off invaders, are responsible for initiating the immune response. However, in Crohnâs 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:

Clinical Trials: Crohns Disease

Trustworthy information about Crohn

Phase Two

The Phase 2 Stepstone trial38 was an uncontrolled, international, multicenter trial of ozanimod as induction therapy for adults with moderate to severe Crohns Disease, defined by a Crohns Disease Activity Index score of 220450, with a Simple Endoscopic Score for Crohns Disease of 6 or greater and an average daily stool score of 4 or more points or an average daily abdominal pain score of 2 or more points, or both. The trial consisted of 69 patients evaluated for induction therapy for a period of 12 weeks. To minimize the risk of bradycardia, patients received ozanimod in a dose escalated fashion during the first week, with goal dosing of 1mg daily, which was achieved at week 1 and continued for an additional 11 weeks.

The primary outcome was the change in SES-CD from baseline to week 12. The proportions of patients with endoscopic response and endoscopic remission at week 12 were also assessed. Secondary endpoints were the change in CDAI score from baseline to week 12, proportion of patients with clinical remission at week 12, and proportion of patients with clinical response at week 12. Patient reported outcomes were evaluated as the change from baseline two-item PRO score to week 12. The proportions of patients with clinical remission and clinical response were also assessed at week 12. Finally, changes from baseline histologic samples, C-reactive protein , and fecal calprotectin were also assessed at week 12.

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Letter: Ozanimod And Latent Tuberculosis

Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia

Correspondence

Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia

Contribution: Writing – original draft , Writing – review & editing

Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia

Contribution: Writing – original draft , Writing – review & editing

Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia

Correspondence

Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia

Contribution: Writing – original draft , Writing – review & editing

Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia

Contribution: Writing – original draft , Writing – review & editing

Safety And Efficacy Trial Of Rpc1063 For Moderate To Severe Ulcerative Colitis

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. Read our disclaimer for details.
First Posted : May 6, 2015Results First Posted : September 1, 2021Last Update Posted : September 1, 2021
Condition or disease
Phase 3
Layout table for study information

Study Type :
Quadruple
Primary Purpose: Treatment
Official Title: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Trial of Oral RPC1063 as Induction and Maintenance Therapy for Moderate to Severe Ulcerative Colitis
Actual Study Start Date :
1mg, daily oral administration during Induction and Maintenance periods. Drug: RPC1063
Daily oral administration during Induction and Maintenance periods. Drug: Placebo
  • Percentage of Participants in Clinical Remission at 10 Weeks Percentage of participants that are in Clinical remission at 10 weeks
  • Percentage of Participants in Clinical Remission at 52 Weeks Percentage of participants that are in Clinical remission at 52 weeks
  • Percentage of Participants With Clinical Response at 10 Weeks Percentage of participants that are in Clinical response at 10 weeks
  • Percentage of Participants With Mucosal Healing at 10 Weeks Percentage of participants with mucosal healing at 10 weeks
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    Disease Control Also Maintained With Temporary Withdrawal At Least Initially

    byZaina Hamza, Staff Writer, MedPage Today October 28, 2022

    This article is a collaboration between MedPage Today and:

    Ulcerative colitis relapses in patients with moderate-to-severe disease were seen as early as 8 weeks among responders who stopped ozanimod after induction therapy, a post-hoc analysis of the phase III True North study found.

    Through 52 weeks, 86.1% of those who continued onto maintenance treatment with the sphingosine 1-phosphate receptor modulator were without relapse, as compared with 62.6% of those re-randomized to placebo after the 10-week induction phase , reported Bruce Sands, MD, MS, of the Icahn School of Medicine at Mount Sinai in New York City.

    And a significant separation was seen between the two arms as early as 8 weeks into the maintenance period , he said during his presentation at the American College of Gastroenterology annual meeting.

    “These data show that ozanimod maintains disease control even in the event of temporary discontinuation, at least for a period of time,” Sands said. “Disease activity at the start of maintenance did influence subsequent rates of disease relapse.”

    Non-relapse rates at 52 weeks were higher among those starting in clinical remission after induction compared with those only in clinical response for both the ozanimod group and the placebo group .

    Ozanimod was approved by the FDA for the treatment of moderate-to-severe ulcerative colitis in May 2021 based on data from True North.

    Disclosures

    Analyses Of Data From The Phase 3 True North Trial Of Ozanimod: Rapidity Of Responses The Value Of Extended Induction And The Correlation Between Early Responses And Outcomes At 52 Weeks

    My Unbiased Breakdown of Zeposia (Ozanimod) for Ulcerative Colitis

    Three analyses of data from the True North trial demonstrated the rapidity of responses from ozanimod, the value of extended induction with ozanimod, and the correlation between early responses and outcomes at 52 weeks.1 In cohort 1, the rate of symptomatic response was superior with ozanimod vs placebo as early as week 2 of treatment .2 A superior rate of response with ozanimod vs placebo was observed as early as 2 weeks after initiation of treatment in patients without prior exposure to a tumor necrosis factor inhibitor and as early as 4 weeks after initiation of treatment in patients with prior exposure to a TNF inhibitor.

    Among the overall study population, symptomatic remission 5 weeks after the initiation of treatment was reported in 26.3% of the ozanimod arm vs 16.7% of the placebo arm . In cohort 1, 150 patients did not have a clinical response at week 10 and entered the OLE study.3 Despite a lack of clinical response, these patients experienced a reduction in their mean total Mayo score from 9.2±1.3 at baseline to 8.5±1.6 at week 10. The rate of patients with a rectal bleeding score of 0 increased to 23.3% at week 10 from 0.7% at baseline. At week 10 of the OLE, 48.7% of patients had a symptomatic clinical response.

    References

    1. Sandborn WJ, Feagan BG, DHaens G, et al True North Study Group. Ozanimod as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 2021 385:1280-1291.

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    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.

    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.

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    Highlights In Ulcerative Colitis From Digestive Disease Week 202: Commentary

    Multiple presentations at Digestive Disease Week 2022 provided novel insights into the management of ulcerative colitis . Data were presented for existing and emerging agents, including vedolizumab, mirikizumab, tofacitinib, upadacitinib, ozanimod, etrasimod, and deucravacitinib.

    Vedolizumab

    Patients who had a primary nonresponse at week 6 and had high drug clearance did not achieve better results with dose optimization compared with standard dosing . This finding suggests that dose optimization in the setting of primary nonresponse to vedolizumab may not benefit patients. This study does not address whether patients who respond early to therapy and then lose response laterthe so-called attenuation of responsemight still benefit from dose escalation. In my practice, similar to these findings, I have observed that patients who do not respond to vedolizumab after the loading dose do not benefit from subsequent dose escalation. In contrast, patients who respond to therapy at first, but then lose the response, may benefit from dose escalation.

    Mirikizumab

    Tofacitinib

    Upadacitinib

    Ozanimod

    Etrasimod

    Deucravacitinib

    Disclosure

    Dr Rubin has received grant support from Takeda, and he has served as a consultant for AbbVie, AltruBio, Arena Pharmaceuticals, Bristol Myers Squibb, Genentech/Roche, Gilead Sciences, Iterative Scopes, Janssen Pharmaceuticals, Lilly, Pfizer, Prometheus Biosciences, Takeda, and TechLab Inc.

    References

    Q: What Adverse Events Are Associated With S1p Receptor Modulation

    Trustworthy information about Crohn

    A: Bradycardia, cardiac conduction abnormalities , macular edema, cancer, serious or opportunistic infection, pulmonary effects, and hepatic effects were examined as adverse events of special interest in the trial by Sandborn et al. on the basis of previous associations with S1P receptor modulation. In the trial, bradycardia occurred more frequently with ozanimod therapy than with placebo during the induction period but not during the maintenance period. No cases of second-degree type 2 atrioventricular block or third-degree atrioventricular block occurred. Elevated liver aminotransferase levels were more common with ozanimod therapy than with placebo. Macular edema occurred in 3 patients receiving ozanimod all cases resolved after treatment discontinuation. 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. The frequency of serious infections was less than 2% in each group.

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    How Effective Was Ozanimod As Compared With Placebo For Moderately To Severely Active Ulcerative Colitis In The Trial By Sandborn Et Al

    Ulcerative colitis is a chronic disease that is characterized by a dysregulated immune response and chronic inflammation in the colonic mucosa. Sandborn et al. conducted a 52-week, phase 3 trial to evaluate ozanimod as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Read the NEJM Original Article here.

    Clinical Pearls

    Q: What are the limitations of current therapies for ulcerative colitis?

    A: Conventional therapies such as aminosalicylates are modestly effective in patients with moderate, but not severe, disease. Glucocorticoids have been associated with adverse events and long-term adverse health consequences and are not recommended as maintenance therapy. 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. Thus, the need remains for new oral treatments for ulcerative colitis that are safe and glucocorticoid-sparing and that have durable efficacy.

    Q: What is ozanimod?

    Ozanimod As Therapy For Ulcerative Colitis

    The New England Journal of Medicine

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