Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial

Vermeire, Séverine; Sandborn, William J.; Danese, Silvio; Hébuterne, Xavier; Salzberg, Bruce; Kłopocka, Maria; Tarabar, Dino; Vaňásek, Tomáš; Greguš, Miloš; Hellstern, Paul; Kim, Sang Woo; Sparrow, Miles P.; Gorelick, Kenneth J.; Hinz, Michelle; Ahmad, Alaa; Pradhan, Vivek; Hassan‐Zahraee, Mina; Clare, Robert; Cataldi, Fabio; Reinisch, Walter

doi:10.1016/s0140-6736(17)30930-3

Cited by 162 publications

(113 citation statements)

References 21 publications

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“…E‐cadherin is one of the most important enzymes that maintain the epithelium barrier. Also, anti‐adhesion mono‐antibody are tested in clinical trials that turned out to be efficient in plenty patient so far (Bravata, Fiorino, Allocca, Repici, & Danese, ; Vermeire et al, ; Zundler, Becker, Weidinger, & Siegmund, ). Our results demonstrated that the E‐cadherin were diminished, whereas casticin restore its expression partially.…”

Section: Discussionmentioning

confidence: 99%

Casticin prevents DSS induced ulcerative colitis in mice through inhibitions of NF‐κB pathway and ROS signaling

Yin

et al. 2018

Phytotherapy Research

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Casticin, a compound purified from the Chinese herb Viticis Fructus, has been proven effective in preventing tumor progression in previous studies. Ulcerative colitis (UC) is a common inflammatory bowel disease that affects millions of people worldwide, but no effective and safe drugs are available. In this study, we aimed to study how did casticin affect UC by evaluating its effects on dextran sulfate sodium (DSS)-induced colitis in mice. Our data suggested that casticin attenuated body weight loss, colon length shortening, and pathological damage in the colon of DSS-treated mice. Casticin decreased reactive oxygen species level and chemocytokines (IL-1β, IL-6, TNF-α) productions in colon tissue. The decreased reactive oxygen species level and suppressed proinflammatory cytokines productions were also confirmed in casticin-treated LPS-stimulated RAW264.7 cells and hydrogen peroxide-treated CACO-2 cells in vitro. Mechanistically, casticin treatment prevented the profound activation of AKT signaling caused by DSS administration. And casticin inhibited the productions of proinflammatory chemocytokines through downregulating AKT/NF-κB pathway in macrophages. Meanwhile, data revealed that casticin increased expressions of endogenous antioxidants peroxiredoxin 3 and MnSOD were through activation in FOXO3α signaling by downregulating AKT signaling in colon epithelium cells. Our findings demonstrated that casticin alleviated DSS-induced UC by increasing the antioxidant enzyme peroxiredoxin 3 and MnSOD expressions, and decreasing the production of proinflammatory chemocytokines through inhibition of AKT signaling.

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Section: Discussionmentioning

confidence: 99%

Casticin prevents DSS induced ulcerative colitis in mice through inhibitions of NF‐κB pathway and ROS signaling

Yin

et al. 2018

Phytotherapy Research

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“…A total of 32 studies were included (23 induction trials and nine combined induction and maintenance trials) . The PRISMA flow diagram is presented in Figure S1 and baseline trial characteristics are summarised in Table and Table S1.…”

Section: Resultsmentioning

confidence: 99%

Systematic review with meta‐analysis: high prevalence and cost of continued aminosalicylate use in patients with ulcerative colitis escalated to immunosuppressive and biological therapies

Guizzetti

Cipriano

et al. 2018

Aliment Pharmacol Ther

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Summary Background Aminosalicylates are the most frequently prescribed treatment for ulcerative colitis (UC). In the absence of empirical evidence, clinicians are uncertain whether to continue aminosalicylates in patients with UC after escalating therapy. Aims To quantify concomitant aminosalicylate use in UC randomised clinical trials (RCTs), identify factors associated with their use, and estimate treatment costs of concomitant aminosalicylate therapy. Methods MEDLINE, Embase, and CENTRAL were searched from inception to 1 March 2017 for placebo‐controlled RCTs of immunosuppressants, biologics, or oral small molecules in adults with UC. The proportion of patients prescribed concomitant aminosalicylates at trial entry was pooled using a random‐effects model. Meta‐regression was performed to assess trial‐level factors associated with aminosalicylate use. Treatment costs were estimated using 2018 formulary data from five Canadian provinces. Results Thirty‐two trials were included (23 induction only, nine induction, and maintenance trials). The pooled proportion of patients co‐prescribed aminosalicylates was 80.7% (95% CI 75.5%‐85.1%), with considerable observed heterogeneity (I2 = 95%). In univariable meta‐regression, aminosalicylate use was not associated with trial design, setting, year of publication, disease severity, disease duration, or drug class. The estimated direct annual treatment cost of concomitant aminosalicylates is ~$20 million for the Canadian UC population, assuming conservative estimates of UC prevalence, aminosalicylate use and dose, and the lowest cost formulation. Conclusions Approximately 80% of UC patients entering clinical trials of immunosuppressants, biologics, or oral small molecules continue to use aminosalicylates. An RCT is needed to inform the benefits and harms of continuing vs stopping aminosalicylates in patients escalating therapy.

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“…In addition to anti‐integrin therapies, the anti–MAdCAM‐1 monoclonal antibody, SHP647/ontamalimab (formerly PF‐00547659), is being evaluated for the treatment of IBD. In the phase 2 TURANDOT trial in patients with moderate to severe UC, 12 weeks of SHP647/ontamalimab treatment resulted in significantly greater remission rates at 7.5 mg, 22.5 mg, and 75 mg doses every 4 weeks compared with placebo . However, the phase 2 OPERA study in patients with active refractory CD failed to meet its primary end point, despite evidence of target engagement .…”

Section: A Model For Integrins and T Lymphocytes As Therapeutic Targementioning

confidence: 99%

“…In the phase 2 TURANDOT trial in patients with moderate to severe UC, 12 weeks of SHP647/ontamalimab treatment resulted in significantly greater remission rates at 7.5 mg, 22.5 mg, and 75 mg doses every 4 weeks compared with placebo. 134 However, the phase 2 OPERA study in patients with active refractory CD failed to meet its primary end point, despite evidence of target engagement. 135 In the phase 1 safety study, TOSCA, in patients with active CD, 12 weeks of SHP647/ontamalimab induction therapy did not result in a reduction in CSF lymphocytes or T-cell subsets or CD4:CD8 ratio.…”

Section: Madcam-1 As a Target For The Treatment Of Ibdmentioning

confidence: 99%

The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies

Dotan

Allez

Danese

et al. 2019

Medicinal Research Reviews

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Inflammatory bowel disease (IBD) is characterized by uncontrolled inflammation in the gastrointestinal tract. The underlying pathobiology of IBD includes an increase in infiltrating gut‐homing lymphocytes. Although lymphocyte homing is typically a tightly regulated and stepwise process involving multiple integrins and adhesion molecules expressed on endothelial cells, the distinct roles of integrin‐expressing immune cells is not fully understood in the pathology of IBD. In this review, we detail the involvement of integrins expressed on specific lymphocyte subsets in the pathogenesis of IBD and discuss the current status of approved and investigational integrin‐targeted therapies.

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Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial

Cited by 162 publications

References 21 publications

Casticin prevents DSS induced ulcerative colitis in mice through inhibitions of NF‐κB pathway and ROS signaling

Casticin prevents DSS induced ulcerative colitis in mice through inhibitions of NF‐κB pathway and ROS signaling

Systematic review with meta‐analysis: high prevalence and cost of continued aminosalicylate use in patients with ulcerative colitis escalated to immunosuppressive and biological therapies

The role of integrins in the pathogenesis of inflammatory bowel disease: Approved and investigational anti‐integrin therapies

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