Population Pharmacokinetics and Pharmacodynamics of Ontamalimab (SHP647), a Fully Human Monoclonal Antibody Against Mucosal Addressin Cell Adhesion Molecule‐1 (MAdCAM‐1), in Patients With Ulcerative Colitis or Crohn's Disease

Wang, Yi; Marier, Jean‐François; Lavigne, Jean; Kassir, Nastya; Martin, Patrick

doi:10.1002/jcph.1590

Cited by 9 publications

(5 citation statements)

References 18 publications

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“…The observed concentrations in pharmacokinetic samples collected over 20 weeks suggest that the steady state was achieved around Week 12 for both doses of ontamalimab [ Supplementary Figure 3 ], consistent with the molecule’s half-life of approximately 17 days. 23 …”

Section: Resultsmentioning

confidence: 99%

Long-term Safety and Efficacy of the Anti-MAdCAM-1 Monoclonal Antibody Ontamalimab [SHP647] for the Treatment of Ulcerative Colitis: The Open-label Study TURANDOT II

Reinisch

Sandborn

Danese

et al. 2021

Journal of Crohn's and Colitis

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Background and Aims Ontamalimab, a fully-human monoclonal antibody targeting MAdCAM1, induced remission in patients with moderate-to-severe ulcerative colitis (UC) in TURANDOT. We assessed long-term safety, tolerability and efficacy of ontamalimab in TURANDOT II. Methods TURANDOT II was a phase 2, multicentre, open-label (OL) study in patients with moderate-to-severe UC who completed TURANDOT on placebo or ontamalimab. Patients were randomized to 75mg or 225mg ontamalimab every 4 weeks for 72 weeks (OL1). Dosage could be increased to 225mg from week 8 at the investigator’s discretion. All patients then received 75mg every 4 weeks for 72 weeks (OL2), followed by 6-month safety follow-up. The primary objective was safety, measured by adverse events (AEs), serious AEs (SAEs) and AEs leading to withdrawal. Mucosal healing (MH; centrally read endoscopy) was assessed. Results Of 330 patients, 180 completed OL1; 94 escalated to 225mg; 127 completed OL2. Overall, 36.1% experienced drug-related AEs. The most common SAE (10.0%) was worsening/ongoing UC; 5.5% of patients had serious infections, the most common being gastroenteritis (0.9%). One death and four cancers (all unrelated to ontamalimab) occurred. No PML/lymphoproliferative disorders occurred. Geometric mean hsCRP and faecal calprotectin decreased across OL1 in both dose groups. The proportion of patients assigned placebo in TURANDOT achieving MH increased from 8.8% (6/68) at baseline to 35.3% at week 16 (24/68; non-responder imputation). The corresponding increase in the ontamalimab group was from 23.3% (61/262) to 26.7% (70/262). Conclusions Ontamalimab was well tolerated up to 144 weeks in patients with moderate-to-severe UC, with good safety and efficacy.

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Section: Resultsmentioning

confidence: 99%

Long-term Safety and Efficacy of the Anti-MAdCAM-1 Monoclonal Antibody Ontamalimab [SHP647] for the Treatment of Ulcerative Colitis: The Open-label Study TURANDOT II

Reinisch

Sandborn

Danese

et al. 2021

Journal of Crohn's and Colitis

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“…Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is an adhesion molecule for lymphocytes which is expressed on mucosal venules, mainly in the intestines, stomach, esophagus, and pancreas, and less in the lungs, liver, and bladder [ 21 ]. It has also been found in the eyes, joints, and skin [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

“…α 4 β 7 integrin is a ligand for MAdCAM-1, and is expressed on CD4 + and CD8 + T lymphocytes, as well as on B lymphocytes, which allows them to be distinguished as unique gut-homing lymphocytes [ 21 ]. α 4 β 7 integrin forms when integrin β 7 (ITGB7) pairs with integrin α 4 (ITGA4, CD49d) [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…MAdCAM-1, expressed on venules endothelium in tissues involved with inflammation, has been discovered to take part in leukocytes extravasation [ 25 ]. Research has shown that MAdCAM-1 is overexpressed in the sites involved with inflammatory processes in persons with Crohn’s disease (CD) and the interaction between α 4 β 7 integrin and MAdCAM-1 is possibly even responsible for the state of chronic inflammation observed in intestinal diseases [ 21 ]. IBD has been proved to occur nearly twice as frequently in psoriatic patients than in the general population [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Circulating MAdCAM-1 and ITGB7 in Patients with Plaque Psoriasis and Eruptive Lichen Planus—Preliminary Data

Baran

Nowowiejska

Kamiński

et al. 2021

Biology

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Plaque psoriasis (PSO) and lichen planus (LP) are skin diseases with some similarities in pathogenesis, comorbidities, and clinical presentation. Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and its ligand, α4β7 integrin, are involved in inflammatory bowel diseases and liver dysfunctions, which occur more frequently in PSO and LP. Serum MAdCAM-1 and ITGB7 levels in patients with plaque PSO and eruptive LP have never been studied before. The study included 42 patients with PSO, 13 with LP, and 23 controls. Serum molecules levels were evaluated using the immune–enzymatic method. ITGB7 concentration was not statistically different, both in patients with PSO and LP, compared to controls (both p > 0.05). MAdCAM-1 level was significantly lower in PSO subjects than in controls (p = 0.041), whereas in the LP group, a downward trend was observed (p = 0.088) with p = 0.0455 in ANOVA. Multiple linear regression revealed independent associations between ITGB7 and HDL and BMI and RBC in the LP group. In psoriatic patients with elevated CRP, there was an upward trend for MAdCAM-1, and also a positive correlation between MAdCAM-1 and WBC. ITGB7 and MAdCAM-1 cannot serve as markers of disease activity or liver pathology neither in patients with PSO nor LP. MAdCAM-1 might play a role as an inflammation indicator in PSO and a beneficial influence on the lipid profile in LP.

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“… 146 The role of integrins in the biology of leukocyte trafficking is well described, providing several potential targets in addition to the approved therapy in this category, vedolizumab (which binds the α4β7 integrin). While integrins are well-validated therapeutic targets, 147 , 148 several integrin programs have been terminated recently, including etrolizumab, due to limited efficacy, 149 and ontamalimab, which was advanced to Phase 3 150–153 but was terminated for commercial reasons. 154 Assets from the Phase 3 trials of ontamalimab are being made available to the research community via IBD Plexus.…”

Section: Introductionmentioning

confidence: 99%

Research-Based Product Innovation to Address Critical Unmet Needs of Patients with Inflammatory Bowel Diseases

Honig

Larkin

Heller

et al. 2021

Inflammatory Bowel Diseases

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Despite progress in recent decades, patients with inflammatory bowel diseases face many critical unmet needs, demonstrating the limitations of available treatment options. Addressing these unmet needs will require interventions targeting multiple aspects of inflammatory bowel disease pathology, including disease drivers that are not targeted by available therapies. The vast majority of late-stage investigational therapies also focus primarily on a narrow range of fundamental mechanisms. Thus, there is a pressing need to advance to clinical stage differentiated investigational therapies directly targeting a broader range of key mechanistic drivers of inflammatory bowel diseases. In addition, innovations are critically needed to enable treatments to be tailored to the specific underlying abnormal biological pathways of patients; interventions with improved safety profiles; biomarkers to develop prognostic, predictive, and monitoring tests; novel devices for nonpharmacological approaches such as minimally invasive monitoring; and digital health technologies. To address these needs, the Crohn’s & Colitis Foundation launched IBD Ventures, a venture philanthropy–funding mechanism, and IBD Innovate®, an innovative, product-focused scientific conference. This special IBD Innovate® supplement is a collection of articles reflecting the diverse and exciting research and development that is currently ongoing in the inflammatory bowel disease field to deliver innovative and differentiated products addressing critical unmet needs of patients. Here, we highlight the pipeline of new product opportunities currently advancing at the preclinical and early clinical development stages. We categorize and describe novel and differentiated potential product opportunities based on their potential to address the following critical unmet patient needs: (1) biomarkers for prognosis of disease course and prediction/monitoring of treatment response; (2) restoration of eubiosis; (3) restoration of barrier function and mucosal healing; (4) more effective and safer anti-inflammatories; (5) neuromodulatory and behavioral therapies; (6) management of disease complications; and (7) targeted drug delivery.

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Population Pharmacokinetics and Pharmacodynamics of Ontamalimab (SHP647), a Fully Human Monoclonal Antibody Against Mucosal Addressin Cell Adhesion Molecule‐1 (MAdCAM‐1), in Patients With Ulcerative Colitis or Crohn's Disease

Cited by 9 publications

References 18 publications

Long-term Safety and Efficacy of the Anti-MAdCAM-1 Monoclonal Antibody Ontamalimab [SHP647] for the Treatment of Ulcerative Colitis: The Open-label Study TURANDOT II

Long-term Safety and Efficacy of the Anti-MAdCAM-1 Monoclonal Antibody Ontamalimab [SHP647] for the Treatment of Ulcerative Colitis: The Open-label Study TURANDOT II

Circulating MAdCAM-1 and ITGB7 in Patients with Plaque Psoriasis and Eruptive Lichen Planus—Preliminary Data

Research-Based Product Innovation to Address Critical Unmet Needs of Patients with Inflammatory Bowel Diseases

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