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Chen M, Gao X, Cao Q, Rossiter G, Kitagawa T, Sun Y, Yang L. Efficacy and safety of intravenous vedolizumab treatment in Chinese patients with moderate-to-severe Crohn's disease. Clin Res Hepatol Gastroenterol 2025; 49:102591. [PMID: 40228712 DOI: 10.1016/j.clinre.2025.102591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 03/24/2025] [Accepted: 03/31/2025] [Indexed: 04/16/2025]
Abstract
BACKGROUND & AIMS Vedolizumab is a gut-selective monoclonal anti-α4β7 integrin antibody treatment for Crohn's disease (CD). A multicenter, randomized, double-blind, placebo-controlled, phase 3 trial (NCT03234907) assessed vedolizumab efficacy and safety in Chinese patients with moderate-to-severe CD and inadequate/loss of response/intolerance to previous conventional or anti-tumor necrosis factor-α therapy. METHODS Eligible patients aged ≥18 to ≤80 years with moderate-to-severe CD (CD Activity Index [CDAI] total score 220-400) were randomized 2:1 to vedolizumab 300 mg intravenous infusion or placebo at Weeks 0, 2, 6 of induction, and every 4/8 weeks during Week 14-58 maintenance treatment. Primary and secondary endpoints at Week 10 were enhanced clinical response (≥100-point decrease from baseline CDAI score), and clinical remission (CDAI score ≤150), respectively. Additional Week 10 and/or Week 60 assessments included endoscopic and biomarker (C-reactive protein and fecal calprotectin) measurements. RESULTS The study was conducted at 30 centers (August 2017 through August 2020). Enrolled patients (n = 215) were randomized to vedolizumab (n = 144) or placebo (n = 71). By Week 10, 19.4 % vedolizumab-treated versus 24.3 % placebo-treated patients achieved an enhanced clinical response. The Cui-Hung-Wang-adjusted p-value for the primary endpoint was 0.347. After maintenance treatment at Week 60, rates of enhanced clinical response, clinical remission, endoscopic response, mucosal healing, and biomarker improvements appeared greater for vedolizumab-treated than placebo-treated patients. CONCLUSIONS There were no new safety findings for vedolizumab treatment of Chinese patients with CD. Although the primary endpoint was not met, vedolizumab-treated patients showed improvements in other disease activity measures at Weeks 10 and 60.
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Affiliation(s)
- Minhu Chen
- The First Affiliated Hospital, Sun Yat-sen University, Guangdong, PR China
| | - Xiang Gao
- The Sixth Affiliated Hospital, Sun Yat-sen University, Guangdong, PR China
| | - Qian Cao
- Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Zhejiang, PR China
| | | | | | - Yue Sun
- Takeda APAC Biopharmaceutical Research and Development Company Limited, Beijing, PR China
| | - Lili Yang
- Takeda Development Center Americas Inc., Cambridge, MA, USA
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Goto T, Okamura H, Ikeda T, Mori Y, Shiratori S, Fujiwara SI, Doki N, Matsuoka KI, Katayama Y, Chen YB, Fløisand Y, Rossiter G, Jansson J, Nakaya R, Teshima T. Vedolizumab for prevention of lower-GI acute GVHD in the Japanese subgroup analysis of the phase 3 GRAPHITE study. Int J Hematol 2025:10.1007/s12185-025-03955-9. [PMID: 40072824 DOI: 10.1007/s12185-025-03955-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 02/14/2025] [Accepted: 02/16/2025] [Indexed: 03/14/2025]
Abstract
In the randomized, double-blind, phase 3 GRAPHITE study (NCT03657160), anti-α4β7 integrin antibody vedolizumab showed greater efficacy than placebo for prevention of lower-gastrointestinal (GI) acute graft-versus-host disease (aGVHD) after unrelated allogenic hematopoietic stem cell transplantation (allo-HSCT). This post hoc analysis assessed the efficacy and safety of vedolizumab versus placebo for lower-GI aGVHD prevention in Japanese and non-Japanese patients, when added to standard GVHD prophylaxis (calcineurin inhibitor + methotrexate/mycophenolate mofetil + / - anti-thymocyte globulin [ATG]). The analysis included 35 (18 vedolizumab-treated, 17 placebo-treated) Japanese and 298 (150 vedolizumab-treated, 148 placebo-treated) non-Japanese patients. Lower-GI aGVHD-free survival by day + 180 after allo-HSCT (primary endpoint) was 94% in vedolizumab-treated versus 81% in placebo-treated Japanese patients (HR 0.36; 95% CI 0.03-4.01; P = 0.2) and 84% in vedolizumab-treated versus 70% in placebo-treated non-Japanese patients (HR 0.47; 95% CI 0.28-0.78; P = 0.002). The number of events for the 5 key secondary endpoints (lower-GI aGVHD-free and relapse-free survival, Grade C-D aGVHD-free survival, non-relapse mortality, overall survival, and Grade B-D aGVHD-free survival) by day + 180 was lower in vedolizumab- versus placebo-treated Japanese patients. No safety concerns were identified for vedolizumab use as lower-GI aGVHD prophylaxis in Japanese patients.
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Affiliation(s)
- Tatsunori Goto
- Department of Hematology, Japanese Red Cross Aichi Medical Center Nagoya Daiichi Hospital, Nagoya, Japan
| | - Hiroshi Okamura
- Department of Hematology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Takashi Ikeda
- Division of Hematology and Stem Cell Transplantation, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yasuo Mori
- Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan
| | - Souichi Shiratori
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | | | - Noriko Doki
- Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Ken-Ichi Matsuoka
- Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan
- Department of Hematology, Endocrinology and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan
| | - Yuta Katayama
- Department of Hematology, Hiroshima Red Cross Hospital & Atomic-Bomb Survivors Hospital, Hiroshima, Japan
| | - Yi-Bin Chen
- Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA, USA
| | - Yngvar Fløisand
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0379, Oslo, Norway
| | - Guillermo Rossiter
- Takeda Development Center Americas, Inc. (at the time of the study), Cambridge, MA, USA
| | - Johan Jansson
- Takeda Development Center Americas, Inc. (at the time of the study), Cambridge, MA, USA
| | - Ryou Nakaya
- Takeda Pharmaceutical Company Limited, Tokyo, Japan
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.
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3
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Friedrich S, Chua L, Adams DH, Crandall W, Zhang XC. Mirikizumab Exposure-Response Relationships in Patients with Moderately-to-Severely Active Ulcerative Colitis in Randomized Phase II and III Studies. Clin Pharmacol Ther 2024; 116:435-447. [PMID: 38797892 DOI: 10.1002/cpt.3305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Accepted: 04/24/2024] [Indexed: 05/29/2024]
Abstract
Mirikizumab is a humanized anti-interleukin-23p19 monoclonal antibody being developed for ulcerative colitis (UC) and Crohn's disease. We characterized the relationship of mirikizumab systemic exposure with efficacy and safety end points in patients with UC using phase II (NCT02589665) and III (NCT03518086, NCT03524092) trial data. Exposure-response models were developed for clinical remission, clinical response, endoscopic remission, and change in modified Mayo score following induction (50-1,000 mg i.v. every 4 weeks) and maintenance (200 mg s.c. every 4 or 12 weeks) treatment. These models evaluated observed and pharmacokinetic model-predicted mirikizumab exposures as the exposure measure. Key safety event rates were compared across mirikizumab exposure quartiles in the phase III trial. Mirikizumab efficacy in patients with UC showed an apparent positive association with systemic exposure following both induction and maintenance. However, further analysis found this relationship to be overstated by the presence of confounding factors that were not among the tested patient covariates. While prior biologic experience and baseline disease severity showed statistically significant influences on estimated placebo effect, no patient factors affected the mirikizumab effect parameters in any of the phase III exposure-response models. There was no apparent mirikizumab concentration relationship with any adverse event of special interest. When the phase II and III data and confounding are considered together, efficacy was unlikely to be strongly affected by variation in exposures across individual patients at the phase III dose. Together with the previously demonstrated mirikizumab exposure insensitivity to patient factors, these findings indicate that mirikizumab dose adjustment to patient characteristics is not required.
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MESH Headings
- Humans
- Colitis, Ulcerative/drug therapy
- Dose-Response Relationship, Drug
- Male
- Severity of Illness Index
- Female
- Adult
- Antibodies, Monoclonal/pharmacokinetics
- Antibodies, Monoclonal/adverse effects
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal/administration & dosage
- Treatment Outcome
- Middle Aged
- Gastrointestinal Agents/adverse effects
- Gastrointestinal Agents/pharmacokinetics
- Gastrointestinal Agents/therapeutic use
- Gastrointestinal Agents/administration & dosage
- Interleukin-23 Subunit p19/antagonists & inhibitors
- Remission Induction
- Antibodies, Monoclonal, Humanized/pharmacokinetics
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
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Affiliation(s)
| | - Laiyi Chua
- Eli Lilly Singapore, Singapore, Singapore
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4
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D’Ambrosio A, Altomare A, Boscarino T, Gori M, Balestrieri P, Putignani L, Del Chierico F, Carotti S, Cicala M, Guarino MPL, Piemonte V. Mathematical Modeling of Vedolizumab Treatment's Effect on Microbiota and Intestinal Permeability in Inflammatory Bowel Disease Patients. Bioengineering (Basel) 2024; 11:710. [PMID: 39061792 PMCID: PMC11274165 DOI: 10.3390/bioengineering11070710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 07/04/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Growing evidence suggests that impaired gut permeability and gut microbiota alterations are involved in the pathogenesis of Inflammatory Bowel Diseases (IBDs), which include Ulcerative Colitis (UC) and Crohn's Disease (CD). Vedolizumab is an anti-α4β7 antibody approved for IBD treatment, used as the first treatment or second-line therapy when the first line results in inadequate effectiveness. The aim of this study is to develop a mathematical model capable of describing the pathophysiological mechanisms of Vedolizumab treatment in IBD patients. In particular, the relationship between drug concentration in the blood, colonic mucosal permeability and fecal microbiota composition was investigated and modeled to detect and predict trends in order to support and tailor Vedolizumab therapies. To pursue this aim, clinical data from a pilot study on a cluster of 11 IBD patients were analyzed. Enrolled patients underwent colonoscopy in three phases (before (t0), after 24 weeks of (t1) and after 52 weeks of (t2 ) Vedolizumab treatment) to collect mucosal biopsies for transepithelial electrical resistance (TEER) evaluation (permeability to ions), intestinal permeability measurement and histological analysis. Moreover, fecal samples were collected for the intestinal microbiota analysis at the three time points. The collected data were compared to those of 11 healthy subjects at t0, who underwent colonoscopy for screening surveillance, and used to implement a three-compartmental mathematical model (comprising central blood, peripheral blood and the intestine). The latter extends previous evidence from the literature, based on the regression of experimental data, to link drug concentration in the peripheral blood compartment with Roseburia abundance and intestinal permeability. The clinical data showed that Vedolizumab treatment leads to an increase in TEER and a reduction in intestinal permeability to a paracellular probe, improving tissue inflammation status. Microbiota analysis showed increasing values of Roseburia, albeit not statistically significant. This trend was adequately reproduced by the mathematical model, which offers a useful tool to describe the pathophysiological effects of Vedolizumab therapy on colonic mucosal permeability and fecal microbiota composition. The model's satisfactory predictive capabilities and simplicity shed light on the relationship between the drug, the microbiota and permeability and allow for its straightforward extension to diverse therapeutic conditions.
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Affiliation(s)
- Antonio D’Ambrosio
- Unit of Chemical-Physics Fundamentals in Chemical Engineering, Department of Science and Technology for Sustainable Development and One Health, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy; (T.B.); (V.P.)
| | - Annamaria Altomare
- Department of Sciences and Technology of Sustainable Development and Human Health, Università Campus Biomedico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy;
- Gastroenterology Research Unit, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy; (M.G.); (M.C.); (M.P.L.G.)
| | - Tamara Boscarino
- Unit of Chemical-Physics Fundamentals in Chemical Engineering, Department of Science and Technology for Sustainable Development and One Health, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy; (T.B.); (V.P.)
| | - Manuele Gori
- Gastroenterology Research Unit, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy; (M.G.); (M.C.); (M.P.L.G.)
- Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR), International Campus “A. Buzzati-Traverso”, Via E. Ramarini 32, Monterotondo Scalo, 00015 Rome, Italy
| | - Paola Balestrieri
- Gastroenterology Unit, Fondazione Policlinico Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, 00128 Rome, Italy;
| | - Lorenza Putignani
- Units of Microbiomics and Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy;
| | - Federica Del Chierico
- Unit of Human Microbiome, Bambino Gesù Children’s Hospital, IRCCS, Piazza Sant’Onofrio 4, 00165 Rome, Italy;
| | - Simone Carotti
- Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
| | - Michele Cicala
- Gastroenterology Research Unit, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy; (M.G.); (M.C.); (M.P.L.G.)
- Microscopic and Ultrastructural Anatomy Research Unit, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, 00128 Rome, Italy;
| | - Michele Pier Luca Guarino
- Gastroenterology Research Unit, Università Campus Bio-Medico di Roma, Via Alvaro del Portillo 21, 00128 Rome, Italy; (M.G.); (M.C.); (M.P.L.G.)
- Gastroenterology Unit, Fondazione Policlinico Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, 00128 Rome, Italy;
| | - Vincenzo Piemonte
- Unit of Chemical-Physics Fundamentals in Chemical Engineering, Department of Science and Technology for Sustainable Development and One Health, University Campus Bio-Medico of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy; (T.B.); (V.P.)
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5
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Honap S, Jairath V, Danese S, Peyrin-Biroulet L. Navigating the complexities of drug development for inflammatory bowel disease. Nat Rev Drug Discov 2024; 23:546-562. [PMID: 38778181 DOI: 10.1038/s41573-024-00953-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/11/2024] [Indexed: 05/25/2024]
Abstract
Inflammatory bowel disease (IBD) - consisting of ulcerative colitis and Crohn's disease - is a complex, heterogeneous, immune-mediated inflammatory condition with a multifactorial aetiopathogenesis. Despite therapeutic advances in this arena, a ceiling effect has been reached with both single-agent monoclonal antibodies and advanced small molecules. Therefore, there is a need to identify novel targets, and the development of companion biomarkers to select responders is vital. In this Perspective, we examine how advances in machine learning and tissue engineering could be used at the preclinical stage where attrition rates are high. For novel agents reaching clinical trials, we explore factors decelerating progression, particularly the decline in IBD trial recruitment, and assess how innovative approaches such as reconfiguring trial designs, harmonizing end points and incorporating digital technologies into clinical trials can address this. Harnessing opportunities at each stage of the drug development process may allow for incremental gains towards more effective therapies.
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Affiliation(s)
- Sailish Honap
- Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK.
- School of Immunology and Microbial Sciences, King's College London, London, UK.
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France.
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University, London, Ontario, Canada
- Lawson Health Research Institute, Western University, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, Vita-Salute San Raffaele University, Milan, Italy
| | - Laurent Peyrin-Biroulet
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France.
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy, France.
- INSERM, NGERE, University of Lorraine, Nancy, France.
- FHU-CURE, Nancy University Hospital, Vandœuvre-lès-Nancy, France.
- Groupe Hospitalier privé Ambroise Paré - Hartmann, Paris IBD Center, Neuilly sur Seine, France.
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada.
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Steenholdt C, Lorentsen RD, Petersen PN, Widigson ES, Kloft C, Klaasen RA, Brynskov J. Therapeutic drug monitoring of vedolizumab therapy in inflammatory bowel disease. J Gastroenterol Hepatol 2024; 39:1088-1098. [PMID: 38380724 DOI: 10.1111/jgh.16518] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 01/01/2024] [Accepted: 02/03/2024] [Indexed: 02/22/2024]
Abstract
BACKGROUND Therapeutic drug monitoring is effective for optimizing anti-tumor necrosis factor therapies in inflammatory bowel disease, but for vedolizumab, a gut-selective leucocyte migration inhibitor, data are scarce. METHODS Observational cohort study including 116 bio-experienced inflammatory bowel disease patients treated with vedolizumab for active luminal disease. Biobanked trough blood samples (n = 676) covering 96% of patients were analyzed using a drug-binding immunofluorometric assay. Steroid-free treatment outcomes were classified by clinical disease activity indices and objective findings, primarily endoscopy. RESULTS Patients with clinical remission to vedolizumab induction therapy (37%) had significantly higher trough levels than those without at weeks 6 (mean 34.1 vs 28.0 μg/mL, P = 0.03) and 10 (34.8 vs 27.5 μg/mL, P = 0.01). Optimal thresholds for discrimination were 32.4 μg/mL (AUCROC 0.66, P = 0.04) and 23.5 (AUCROC 0.67, P = 0.01), respectively. This positive association persisted during maintenance phase with 11.9 μg/mL (AUCROC 0.69, P < 0.01) associated with clinical remission (37%) and 15.3 (AUCROC 0.74, P < 0.001) for objective remission (46%). Stratification by temporal evolution of treatment effects revealed higher induction and maintenance vedolizumab levels in persistent and slow responders as compared to secondary or persistent failures. Pharmacokinetics was influenced by rare formation of anti-vedolizumab antibodies (2%), and to a lesser extent gender and albumin during induction, but not disease severity, concomitant steroids, or thiopurine metabolites. Switching to subcutaneous administrations resulted in 2.3-fold increase in steady-state trough levels. CONCLUSION Our study supports maintaining adequate drug exposure being essential for sustained positive outcomes of vedolizumab and emphasizes individualized, therapeutic drug monitoring-based treatment regimens. Controlled trials and pharmacokinetic modeling are, however, needed.
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Affiliation(s)
- Casper Steenholdt
- Department of Gastroenterology, Herlev and Gentofte Hospital, Herlev, Denmark
| | - Ruben Due Lorentsen
- Department of Gastroenterology, Herlev and Gentofte Hospital, Herlev, Denmark
| | | | - Ella Sk Widigson
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität, Berlin, Germany
- Graduate Research Training Program PharMetrX, Berlin, Germany
| | - Charlotte Kloft
- Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universität, Berlin, Germany
| | - Rolf Anton Klaasen
- Department of Medical Biochemistry, Oslo University Hospital, Oslo, Norway
| | - Jørn Brynskov
- Department of Gastroenterology, Herlev and Gentofte Hospital, Herlev, Denmark
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Boden EK, Kongala R, Hindmarch DC, Shows DM, Juarez JG, Lord JD. Vedolizumab Efficacy Is Associated With Decreased Intracolonic Dendritic Cells, Not Memory T Cells. Inflamm Bowel Dis 2024; 30:704-717. [PMID: 37837660 PMCID: PMC11063563 DOI: 10.1093/ibd/izad224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Indexed: 10/16/2023]
Abstract
BACKGROUND Vedolizumab, an antibody blocking integrin α4β7, is a safe and effective therapy for Crohn's disease and ulcerative colitis. Blocking α4β7 from binding its cognate addressin MAdCAM-1 on intestinal blood vessel endothelial cells prevents T cells from migrating to the gut mucosa in animal models. However, data supporting this mechanism of action in humans is limited. METHODS We conducted a cross-sectional case-control study to evaluate the effect of vedolizumab on intestinal immune cell populations while avoiding the confounding effect of resolving inflammation on the cellularity of the colonic mucosa in treatment-responsive patients. Colon biopsies from 65 case subjects receiving vedolizumab were matched with biopsies from 65 control individuals, similar in disease type, medications, anatomic location, and inflammation. Biopsies were analyzed by flow cytometry and full messenger RNA transcriptome sequencing of sorted T cells. RESULTS No difference was seen between vedolizumab recipients and control individuals in the quantity of any antigen-experienced T lymphocyte subset or in the quality of the transcriptome in any experienced T cell subset. Fewer naïve colonic B and T cells were seen in vedolizumab recipients than control individuals, regardless of response. However, the most striking finding was a marked reduction in CD1c+ (BDCA1+) dendritic cells exclusively in vedolizumab-responsive patients. In blood, these dendritic cells ubiquitously express high levels of α4β7, which is rapidly downregulated upon vedolizumab exposure. CONCLUSIONS The clinical effects of vedolizumab reveal integrin α4β7-dependent dendritic cell migration to the intestinal mucosa to be central to inflammatory bowel disease pathogenesis.
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Affiliation(s)
- Elisa K Boden
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
- Division of Gastroenterology, Oregon Health and Science University, Portland, OR, USA
| | - Ramya Kongala
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
| | - Duncan C Hindmarch
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
| | - Donna M Shows
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
| | - Julius G Juarez
- GI Drug Discovery, Takeda Pharmaceuticals, Cambridge, MA, USA
| | - James D Lord
- Center for Translational Research, Benaroya Research Institute, Seattle, WA, USA
- Division of Gastroenterology, Virginia Mason Medical Center, Seattle, WA, USA
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8
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Hanzel J, Solitano V, Zou L, Zou G, Peyrin-Biroulet L, Danese S, Singh S, Ma C, Wils P, Jairath V. A Comparison of Treatment Effect Sizes in Matched Phase 2 and Phase 3 Trials of Advanced Therapeutics in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis. Clin Transl Gastroenterol 2023; 14:e00629. [PMID: 37578211 PMCID: PMC10684248 DOI: 10.14309/ctg.0000000000000629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 08/02/2023] [Indexed: 08/15/2023] Open
Abstract
INTRODUCTION Phase 2 trials are fundamental to the rational and efficient design of phase 3 trials. We aimed to determine the relationship of treatment effect size estimates from phase 2 and phase 3 clinical trials on advanced therapeutics in inflammatory bowel disease. METHODS MEDLINE, EMBASE, CENTRAL, and the Cochrane library were searched from inception to December 19, 2022, to identify paired phase 2 and 3 placebo-controlled induction studies of advanced therapeutics for Crohn's disease (CD) and ulcerative colitis (UC). Treatment effect sizes were expressed as a risk ratio (RR) between the active arm and placebo arm. For the same therapeutics, RRs from phase 2 trials were divided by the RR from phase 3 trial to quantify the relationship of effect sizes between phases. RESULTS Twenty-two studies (9 phase 2 trials, 13 phase 3 trials) were included for CD and 30 studies (12 phase 2 trials, 18 phase 3 trials) for UC. In UC (pooled RR 0.72; 95% confidence interval: 0.58-0.86; RR <1 indicates smaller treatment effect sizes in phase 2 trials), but not CD (pooled RR 1.01; 95% confidence interval: 0.84-1.18), phase 2 trials systematically underestimated treatment effect sizes for the primary endpoint compared with phase 3 trials. The underestimation was observed for clinical, but not endoscopic, endpoints in UC. DISCUSSION Treatment effect sizes for the primary and clinical endpoints were similar across clinical trial phases in CD, but not UC, where only endoscopic endpoints were comparable. This will help inform clinical development plans and future trial design.
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Affiliation(s)
- Jurij Hanzel
- Department of Gastroenterology and Hepatology, University Medical Center Ljubljana, Ljubljana, Slovenia
- Alimentiv Inc, London, Ontario, Canada
| | - Virginia Solitano
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Lily Zou
- Department of Statistics and Actuarial Sciences, University of Waterloo, Waterloo, Ontario, Canada
| | - G.Y. Zou
- Alimentiv Inc, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
- Robarts Research Institute, Western University, London, Ontario, Canada
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Nancy, France
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita‐Salute San Raffaele, Milan, Italy
| | - Siddharth Singh
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
| | - Christopher Ma
- Alimentiv Inc, London, Ontario, Canada
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Pauline Wils
- Department of Gastroenterology, Claude Huriez Hospital, University of Lille 2, Lille, France
- Inserm, CHU Lille, U1286 Infinite, Institute for Translational Research in Inflammation, University of Lille, Lille, France
| | - Vipul Jairath
- Alimentiv Inc, London, Ontario, Canada
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
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9
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Chu X, Biao Y, Liu C, Zhang Y, Liu C, Ma JZ, Guo Y, Gu Y. Network meta-analysis on efficacy and safety of different biologics for ulcerative colitis. BMC Gastroenterol 2023; 23:346. [PMID: 37803294 PMCID: PMC10557260 DOI: 10.1186/s12876-023-02938-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Accepted: 08/29/2023] [Indexed: 10/08/2023] Open
Abstract
BACKGROUND Therapeutic options for ulcerative colitis (UC) have increased since the introduction of biologics a few decades ago. Due to the wide range of biologics available, physicians have difficulty in selecting biologics and do not know how to balance the best drug between clinical efficacy and safety. This study aimed to compare the efficacy and safety of biologics in treating ulcerative colitis. METHODS In this study, eight electronic databases (PubMed, Web of Science, Cochrane, Embase, Sinomed, China National Knowledge Infrastructure, Chongqing VIP Information, and WanFang Data) were searched to collect eligible studies without language restrictions. Retrieved 1 June 2023, from inception. All articles included in the mesh analysis are randomised controlled trials (RCTs). The inclusion of drugs for each outcome was ranked using a curved surface under cumulative ranking (SUCRA). Higher SUCRA scores were associated with better outcomes, whereas lower SUCRA scores were associated with better safety. This study has registered with PROSPERO, CRD42023389483. RESULTS Induction Therapy: Among the biologic therapies evaluated for induction therapy, vedolizumab demonstrated the highest efficacy in achieving clinical remission (OR vs daclizumab, 9.09; 95% CI, 1.01-81.61; SUCRA 94.1) and clinical response. Guselkumab showed the lowest risk of recurrence of UC (SUCRA 94.9%), adverse events resulting in treatment discontinuation (SUCRA 94.8%), and serious infections (SUCRA 78.0%). Maintenance Therapy: For maintenance therapy, vedolizumab ranked highest in maintaining clinical remission (OR vs mesalazine 4.36; 95% CI, 1.65-11.49; SUCRA 89.7) and endoscopic improvement (SUCRA 92.6). Infliximab demonstrated the highest efficacy in endoscopic improvement (SUCRA 92.6%). Ustekinumab had the lowest risk of infections (SUCRA 92.9%), serious adverse events (SUCRA 91.3%), and serious infections (SUCRA 67.6%). CONCLUSION Our network meta-analysis suggests that vedolizumab is the most effective biologic therapy for inducing and maintaining clinical remission in UC patients. Guselkumab shows promise in reducing the risk of recurrence and adverse events during induction therapy. Infliximab is effective in improving endoscopic outcomes during maintenance therapy. Ustekinumab appears to have a favorable safety profile. These findings provide valuable insights for clinicians in selecting the most appropriate biologic therapy for UC patients.
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Affiliation(s)
- Xinqiao Chu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences - No.5, Beixian Pavilion, Xicheng District, Beijing, 100053, China
| | - Yaning Biao
- School of Pharmacy, Hebei University of Chinese Medicine, 326 New Shinan Road, Qiaoxi District, Shijiazhuang, Hebei, 050091, China
| | - Chengjiang Liu
- Department of General Medicine, Affiliated Anqing First People's Hospital of Anhui Medical University, Anqing, Anhui, China
| | - Yixin Zhang
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China
| | - Chenxu Liu
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China
| | - Ji-Zheng Ma
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences - No.5, Beixian Pavilion, Xicheng District, Beijing, 100053, China
| | - Yufeng Guo
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences - No.5, Beixian Pavilion, Xicheng District, Beijing, 100053, China.
| | - Yaru Gu
- School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, China.
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10
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Honap S, Netter P, Danese S, Peyrin-Biroulet L. An update on the safety of long-term vedolizumab use in inflammatory bowel disease. Expert Opin Drug Saf 2023; 22:767-776. [PMID: 37610086 DOI: 10.1080/14740338.2023.2247976] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/10/2023] [Indexed: 08/24/2023]
Abstract
INTRODUCTION Vedolizumab (Entyvio) is a humanized monoclonal antibody that disrupts the interaction between α4β7 integrin on circulating T-lymphocytes and MAdCAM-1 on the vascular endothelium to prevent their egress to sites of gut inflammation. It has proven therapeutic efficacy for the treatment of moderate-to-severe Crohn's disease, ulcerative colitis, and pouchitis. AREAS COVERED This narrative review assesses the safety profile of vedolizumab from the registration trial programs, open-label extension studies, observational real-world data, and pooled safety analyses. This includes an evaluation of the long-term overall safety in special populations typically underrepresented in clinical trials. EXPERT OPINION Vedolizumab is an effective therapy for inflammatory bowel disease with a well-established safety profile. No unexpected long-term safety signals have been identified. Safety data in pregnancy, in pediatric and elderly populations, in patients undergoing surgery, and in patients with a prior history of cancer are reassuring. Due to its safety merits, we propose that vedolizumab is an excellent candidate for advanced combination treatment with an anti-cytokine approach using another biologic or novel small molecule inhibitor. This is important in patients with medically refractory IBD, in patients at high risk of developing disease-related complications, or in patients with concomitant uncontrolled immune-mediated inflammatory diseases.
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Affiliation(s)
- Sailish Honap
- Department of Gastroenterology, St George's University Hospitals NHS Foundation Trust, London, UK
- School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Patrick Netter
- Ingénierie Moléculaire et Ingénierie Articulaire (IMoPA), UMR-7365 CNRS, Faculté de Médecine, University of Lorraine and University Hospital of Nancy, Nancy, France
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital and Vita-Salute San Raffaele University, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- Groupe Hospitalier privé Ambroise Paré - Hartmann, Paris IBD center, Neuilly sur Seine, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
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11
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Tang HJ, Bie CQ, Guo LL, Zhong LX, Tang SH. Efficacy and safety of vedolizumab in the treatment of patients with inflammatory bowel disease: A systematic review and meta‑analysis of randomized controlled trials. Exp Ther Med 2023; 25:298. [PMID: 37229320 PMCID: PMC10203751 DOI: 10.3892/etm.2023.11997] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 04/05/2023] [Indexed: 05/27/2023] Open
Abstract
Few studies have thoroughly assessed the efficacy and safety of vedolizumab (VDZ) in the treatment of inflammatory bowel disease (IBD). Therefore, this systematic review and meta-analysis was performed to further evaluate this association. PubMed, Embase, and the Cochrane databases were searched until April 2022. Randomized controlled trials (RCTs) evaluating the efficacy and safety of VDZ in the treatment of IBD were included. The risk ratio (RR) and 95% confidence intervals (CI) were estimated for each outcome using a random effects model. A total of 12 RCTs, including 4,865 patients, met the inclusion criteria. In the induction phase, VDZ was more effective than placebo for patients with ulcerative colitis and Crohn's disease (CD) in clinical remission (RR=2.09; 95% CI=1.66-2.62) and clinical response (RR=1.54; 95% CI=1.34-1.78). In the maintenance therapy group, VDZ reached higher clinical remission (RR=1.98; 95% CI=1.58-2.49) and clinical response (RR=1.78; 95% CI=1.40-2.26) rates compared with the placebo group. VDZ particularly improved clinical remission (RR=2.07; 95% CI=1.48-2.89) and clinical response (RR=1.84; 95% CI=1.54-2.21) in patients with TNF antagonist failure. In terms of corticosteroid-free remission, VDZ was also more effective than placebo in patients with IBD (RR=1.98; 95% CI=1.51-2.59). In Crohn's patients, VDZ was more effective than placebo in terms of mucosal healing (RR=1.78; 95% CI=1.27-2.51). With respect to adverse events, VDZ significantly reduced the risk of IBD exacerbation compared with the placebo (RR=0.60; 95% CI=0.39-0.93; P=0.023). However, when compared with the placebo, VDZ increased the risk of nasopharyngitis in patients with CD (RR=1.77; 95% CI=1.01-3.10; P=0.045). No significant differences in other adverse events were observed. Although there might be underlying risk, such as selection bias, in the present study it can be safely concluded that VDZ is a safe and effective biological agent for IBD, particularly for patients with TNF antagonist failure.
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Affiliation(s)
- Hui-Jun Tang
- Department of Gastroenterology, Shenzhen Integrated Traditional Chinese and Western Medicine Hospital, Shenzhen, Guangdong 518104, P.R. China
| | - Cai-Qun Bie
- Department of Gastroenterology, Shenzhen Integrated Traditional Chinese and Western Medicine Hospital, Shenzhen, Guangdong 518104, P.R. China
| | - Li-Liangzi Guo
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Li-Xian Zhong
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, P.R. China
| | - Shao-Hui Tang
- Department of Gastroenterology, The First Affiliated Hospital, Jinan University, Guangzhou, Guangdong 510632, P.R. China
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12
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Olivera PA, Lasa JS, Zubiaurre I, Jairath V, Abreu MT, Rubin DT, Reinisch W, Magro F, Rahier JF, Danese S, Rabaud C, Peyrin-Biroulet L. Opportunistic Infections in Patients with Inflammatory Bowel Disease Treated with Advanced Therapies: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Crohns Colitis 2023; 17:199-210. [PMID: 36087107 DOI: 10.1093/ecco-jcc/jjac133] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Advanced therapies for inflammatory bowel disease [IBD] could potentially lead to a state of immunosuppression with an increased risk of opportunistic infections [OIs]. We aimed to provide an update on the incidence of OIs among adult IBD patients in randomized controlled trials [RCTs] of approved biologics and small-molecule drugs [SMDs]. Also, we aimed to describe OI definitions utilized in RCTs, to ultimately propose a standardized definition. METHODS Electronic databases were searched from January 1, 1990, until April 16, 2022. Our primary outcome was incidence rate of overall OIs among IBD patients exposed and unexposed to biologics or SMDs. We also describe specific OIs reported in included trials, as well as definitions of OIs within studies when provided. RESULTS Ninety studies were included. The incidence rates of reported OIs were 0.42 and 0.21 per 100 person-years in patients exposed to advanced therapies and placebo, respectively. This was highest for anti-tumour necrosis factors [0.83 per 100 person-years] and Janus kinase inhibitors [0.55 per 100 person-years] and lowest for anti-integrins and ozanimod. On meta-analysis, no increased risk of OIs was observed. None of the studies provided a detailed definition of OIs, or a comprehensive list of infections considered as OIs. CONCLUSION Different mechanisms of action may have specific OI profiles. In the absence of a uniform definition of OIs, these estimates are less reliable. We propose a definition to be used in future studies to help provide standardized reporting. When using this definition, we saw significant differences in incidence rates of OIs across mechanisms of action.
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Affiliation(s)
- Pablo A Olivera
- IBD Unit, Gastroenterology Section, Department of Internal Medicine, Centro de Educación Médica e Investigación Clínica (CEMIC), Buenos Aires, Argentina
- Zane Cohen Centre for Digestive Diseases, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Juan S Lasa
- IBD Unit, Gastroenterology Section, Department of Internal Medicine, Centro de Educación Médica e Investigación Clínica (CEMIC), Buenos Aires, Argentina
- Gastroenterology Department, Hospital Británico de Buenos Aires, Argentina
| | - Ignacio Zubiaurre
- Gastroenterology Department, Hospital Británico de Buenos Aires, Argentina
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada
- Department of Epidemiology and Biostatistics, Western University, London, ON, Canada
- Alimentiv Inc., London, ON, Canada
| | - Maria T Abreu
- Department of Medicine, Division of Gastroenterology, Crohn's and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - David T Rubin
- University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, IL, USA
| | - Walter Reinisch
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Fernando Magro
- Department of Pharmacology & Therapeutics; CINTESIS, Faculty of Medicine University of Porto, and Department of Gastroenterology, Hospital de São João, Porto, Portugal
| | - Jean-François Rahier
- Department of Gastroenterology and Hepatology, CHU UCL Namur, Université Catholique de Louvain, Yvoir, Belgium
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milano, Italy
| | - Christian Rabaud
- Department of Infectious Disease, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Laurent Peyrin-Biroulet
- INSERM NGERE and Department of Hepatogastroenterology, Nancy University Hospital, Lorraine University, Vandoeuvre-lés-Nancy, France
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13
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Colman RJ, Mizuno T, Fukushima K, Haslam DB, Hyams JS, Boyle B, Noe JD, D’Haens GR, Limbergen JV, Chun K, Yang J, Denson LA, Ollberding NJ, Vinks AA, Minar P. Real world population pharmacokinetic study in children and young adults with inflammatory bowel disease discovers novel blood and stool microbial predictors of vedolizumab clearance. Aliment Pharmacol Ther 2023; 57:524-539. [PMID: 36314265 PMCID: PMC9931651 DOI: 10.1111/apt.17277] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/04/2022] [Accepted: 10/15/2022] [Indexed: 12/09/2022]
Abstract
BACKGROUND Vedolizumab for inflammatory bowel disease (IBD) is often intensified based on distinct pharmacokinetics in children. Prior adult-specific population pharmacokinetic models have identified limited covariates of drug clearance. AIMS To establish a population pharmacokinetic model for children and young adults to identify novel covariates of drug clearance to better account for paediatric-specific inter-patient variability in vedolizumab pharmacokinetics; a key secondary exploratory aim was to identify microbial signatures of pharmacokinetic outcomes in a subset of patients. METHODS The study included data from 463 observed vedolizumab concentrations (59 peaks and 404 troughs) from 74 patients with IBD (52 with Crohn's disease and 22 with ulcerative colitis or unclassified IBD, median age 16 years). Pharmacokinetic analysis was conducted with non-linear mixed effects modelling. For the evaluation of the exposure-response relationship, clinical outcomes were evaluated by trough levels, clearance and vedolizumab exposure. Whole-genome metagenomic sequencing was conducted at baseline and week 2. RESULTS A two-compartment population pharmacokinetic model was identified with a clear correlation between CL and weight, erythrocyte sedimentation rate, and hypoalbuminemia. Trough concentrations before infusion 3 (37 μg/ml) and before infusion 4 (20 μg/ml) best predicted steroid-free clinical remission at infusion 4. Using faecal metagenomics, we identified an early (baseline and week 2) abundance of butyrate-producing species and pathways that were associated with an infusion 4 trough concentration >20 μg/ml. CONCLUSIONS This novel paediatric vedolizumab pharmacokinetic model could inform precision dosing. While additional studies are needed, an abundance of faecal butyrate producers is associated with early response to vedolizumab, suggesting that microbial analysis may be beneficial to biological selection.
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Affiliation(s)
- Ruben J. Colman
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center
| | - Tomoyuki Mizuno
- Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center
- Department of Pediatrics, University of Cincinnati College of Medicine
| | - Keizo Fukushima
- Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center
| | - David B. Haslam
- Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center
- Department of Pediatrics, University of Cincinnati College of Medicine
| | - Jeffrey S. Hyams
- Division of Digestive Diseases, Hepatology and Nutrition, Connecticut Children’s Medical Center
| | - Brendan Boyle
- Division of Gastroenterology, Hepatology and Nutrition, Nationwide Children’s Hospital
| | - Joshua D. Noe
- Division of Gastroenterology, Hepatology and Nutrition, Children’s Hospital of Wisconsin
| | - Geert R. D’Haens
- Gastroenterology and Hepatology, Amsterdam University Medical Centers – location University of Amsterdam, Amsterdam, the Netherlands
| | - Johan Van Limbergen
- Department of Pediatric Gastroenterology and Nutrition, Amsterdam University Medical Centers – Location University of Amsterdam, Emma Children’s Hospital, Amsterdam, the Netherlands
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam, Amsterdam, Netherlands
| | | | | | - Lee A. Denson
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center
- Department of Pediatrics, University of Cincinnati College of Medicine
| | - Nicholas J. Ollberding
- Department of Pediatrics, University of Cincinnati College of Medicine
- Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center
| | - Alexander A. Vinks
- Division of Clinical Pharmacology, Cincinnati Children’s Hospital Medical Center
- Department of Pediatrics, University of Cincinnati College of Medicine
| | - Phillip Minar
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center
- Department of Pediatrics, University of Cincinnati College of Medicine
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14
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Long-Term Outcomes of Early vs Delayed Responders to Vedolizumab and Adalimumab: A Post Hoc Analysis of the VARSITY Study. Am J Gastroenterol 2023; 118:121-128. [PMID: 36066459 DOI: 10.14309/ajg.0000000000001987] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 08/15/2022] [Indexed: 01/12/2023]
Abstract
INTRODUCTION It is uncertain whether patients with ulcerative colitis (UC) and delayed symptomatic response to therapy have as robust and durable a response as earlier responders to therapy. We compared clinical outcomes of early and delayed responders to vedolizumab and adalimumab for patients with moderate-severe UC. METHODS This was a post hoc analysis of the VARSITY study. Patients with early partial Mayo score (PMS) remission (PMS ≤1 at week 4/6 of therapy) were compared with those with delayed PMS remission (PMS ≤1 at week 14 and not week 4/6). Differences in proportions of patients achieving week 52 clinical remission (CR) (PMS = 0), endoscopic improvement (EI) (Mayo endoscopic subscore ≤1), and histoendoscopic mucosal improvement (HEMI) (Mayo endoscopic subscore ≤1 and Geboes score highest grade <3.2) were assessed. Confounders were adjusted for using multivariate logistic regression. RESULTS A total of 147 vedolizumab-treated and 110 adalimumab-treated patients attained early or late PMS remission. Those who attained early PMS remission with vedolizumab were more likely to attain week 52 CR than participants with delayed PMS remission with vedolizumab (69.1% [67/97] vs 50.0% [25/50], aOR 2.43 [95% CI 1.11-5.33], P = 0.027). Week 52 HEMI was more likely among early vedolizumab PMS remitters (63.9% [62/97] vs 40.0% [20/50], aOR 2.60 [95% CI 1.20-5.62], P = 0.015). Week 52 EI was similar between early and delayed PMS remitters to vedolizumab. No differences were observed in week 52 CR, EI, or HEMI between early and delayed PMS remitters to adalimumab. DISCUSSION Patients with UC who achieve early PMS remission with vedolizumab have greater odds of week 52 remission compared with delayed responders.
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15
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Becker E, Dedden M, Gall C, Wiendl M, Ekici AB, Schulz-Kuhnt A, Schweda A, Voskens C, Hegazy A, Vitali F, Atreya R, Müller TM, Atreya I, Neurath MF, Zundler S. Residual homing of α4β7-expressing β1 +PI16 + regulatory T cells with potent suppressive activity correlates with exposure-efficacy of vedolizumab. Gut 2022; 71:1551-1566. [PMID: 34462337 DOI: 10.1136/gutjnl-2021-324868] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2021] [Accepted: 08/08/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The anti-α4β7 integrin antibody vedolizumab is administered at a fixed dose for the treatment of IBDs. This leads to a wide range of serum concentrations in patients and previous studies had suggested that highest exposure levels are associated with suboptimal clinical response. We aimed to determine the mechanisms underlying these non-linear exposure-efficacy characteristics of vedolizumab. DESIGN We characterised over 500 samples from more than 300 subjects. We studied the binding of vedolizumab to T cells and investigated the functional consequences for dynamic adhesion, transmigration, gut homing and free binding sites in vivo. Employing single-cell RNA sequencing, we characterised α4β7 integrin-expressing T cell populations 'resistant' to vedolizumab and validated our findings in vitro and in samples from vedolizumab-treated patients with IBD. We also correlated our findings with a post-hoc analysis of the Gemini II and III studies. RESULTS Regulatory T (TReg) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (TEff) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional α4β7 on TReg cells in vivo was higher than that of/on TEff cells. We identified a vedolizumab-'resistant' α4β7-expressing β1+PI16+ TReg cell subset with pronounced regulatory properties as the substrate for this effect. Our observations correlated with exposure-efficacy data from Gemini II and III trials. CONCLUSION Completely blocking TEff cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful TReg cells in an optimal 'therapeutic window' based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.
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Affiliation(s)
- Emily Becker
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Mark Dedden
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Christine Gall
- Institute for Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Maximilian Wiendl
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Arif Bülent Ekici
- Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Anja Schulz-Kuhnt
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Anna Schweda
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Caroline Voskens
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany.,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Bayern, Germany
| | - Ahmed Hegazy
- Department of Gastroenterology, Infectiology and Rheumatology, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Berlin, Germany.,Berlin Institute of Health (BIH), Berlin, Germany.,Deutsches Rheumaforschungszentrum Berlin (DRFZ), an Institute of the Leibniz Association, Berlin, Germany
| | - Francesco Vitali
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany
| | - Raja Atreya
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany.,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Bayern, Germany
| | - Tanja Martina Müller
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany.,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Bayern, Germany
| | - Imke Atreya
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany.,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Bayern, Germany
| | - Markus F Neurath
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany.,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Bayern, Germany
| | - Sebastian Zundler
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universitat Erlangen-Nürnberg, Erlangen, Bayern, Germany .,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Bayern, Germany
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16
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Adolph TE, Siegmund B. Deciphering the vedolizumab dosing conundrum in IBD: when less is more. Gut 2022; 71:1455-1456. [PMID: 34497148 PMCID: PMC9279744 DOI: 10.1136/gutjnl-2021-325893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 08/31/2021] [Indexed: 12/08/2022]
Affiliation(s)
- Timon Erik Adolph
- Internal Medicine I, Medizinische Universitat Innsbruck, Innsbruck, Austria
| | - Britta Siegmund
- Medical Department I, Charite Universitatsmedizin Berlin Campus Benjamin Franklin, Berlin, Berlin, Germany
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17
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Gabriëls RY, Bourgonje AR, von Martels JZH, Blokzijl T, Weersma RK, Galinsky K, Juarez J, Faber KN, Kats-Ugurlu G, Dijkstra G. Mucosal Eosinophil Abundance in Non-Inflamed Colonic Tissue Is Associated with Response to Vedolizumab Induction Therapy in Inflammatory Bowel Disease. J Clin Med 2022; 11:4141. [PMID: 35887905 PMCID: PMC9318498 DOI: 10.3390/jcm11144141] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/07/2022] [Accepted: 07/14/2022] [Indexed: 02/04/2023] Open
Abstract
Vedolizumab is used as a treatment for patients with inflammatory bowel disease (IBD), but induction therapy leads to clinical response and remission in approximately 55% and 30% of patients with IBD, respectively. In this study, we aimed to explore the predictive value of mucosal eosinophils and serum eotaxin-1 regarding response to vedolizumab induction therapy. Eighty-four (84) patients with IBD (37 Crohn’s disease [CD], 47 ulcerative colitis [UC]) were included. For 24 patients with IBD, histopathology was assessed for eosinophil counts in non-inflamed colonic tissue prior to vedolizumab treatment. For 64 patients with IBD, serum eotaxin-1 levels were quantified prior to (baseline) and during vedolizumab treatment. Serum samples of 100 patients with IBD (34 CD, 66 UC) from the GEMINI 1 and 2 trials were used for external validation. Baseline mucosal eosinophil numbers in non-inflamed colonic tissue were significantly higher in responders to vedolizumab induction therapy when compared to primary non-responders (69 [34−138] vs. 24 [18−28] eosinophils/high-power field, respectively, p < 0.01). Baseline serum eotaxin-1 levels in the discovery cohort were significantly elevated in responders, compared to primary non-responders (0.33 [0.23−0.44] vs. 0.20 [0.16−0.29] ng/mL, p < 0.01). Prediction models based on mucosal eosinophil counts and serum eotaxin-1 showed an area under the curve (AUC) of 0.90 and 0.79, respectively. However, the predictive capacity of baseline serum eotaxin-1 levels could not be validated in the GEMINI cohort. Mucosal eosinophil abundance in non-inflamed colonic tissue was associated with response to vedolizumab induction therapy in patients with IBD. Future studies are warranted to further validate the potential value of mucosal eosinophils and serum eotaxin-1 as biomarkers for response to vedolizumab therapy.
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Affiliation(s)
- Ruben Y. Gabriëls
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (A.R.B.); (J.Z.H.v.M.); (T.B.); (R.K.W.); (K.N.F.); (G.D.)
| | - Arno R. Bourgonje
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (A.R.B.); (J.Z.H.v.M.); (T.B.); (R.K.W.); (K.N.F.); (G.D.)
| | - Julius Z. H. von Martels
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (A.R.B.); (J.Z.H.v.M.); (T.B.); (R.K.W.); (K.N.F.); (G.D.)
| | - Tjasso Blokzijl
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (A.R.B.); (J.Z.H.v.M.); (T.B.); (R.K.W.); (K.N.F.); (G.D.)
| | - Rinse K. Weersma
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (A.R.B.); (J.Z.H.v.M.); (T.B.); (R.K.W.); (K.N.F.); (G.D.)
| | - Kevin Galinsky
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceuticals, Cambridge, MA 02139, USA; (K.G.); (J.J.)
| | - Julius Juarez
- Gastroenterology Drug Discovery Unit, Takeda Pharmaceuticals, Cambridge, MA 02139, USA; (K.G.); (J.J.)
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (A.R.B.); (J.Z.H.v.M.); (T.B.); (R.K.W.); (K.N.F.); (G.D.)
| | - Gursah Kats-Ugurlu
- Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
| | - Gerard Dijkstra
- Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands; (A.R.B.); (J.Z.H.v.M.); (T.B.); (R.K.W.); (K.N.F.); (G.D.)
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18
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Becker E, Schweda A, Ullrich KAM, Voskens C, Atreya R, Müller TM, Atreya I, Neurath MF, Zundler S. Limited Dose-Dependent Effects of Vedolizumab on Various Leukocyte Subsets. Clin Transl Gastroenterol 2022; 13:e00494. [PMID: 35575178 PMCID: PMC9236604 DOI: 10.14309/ctg.0000000000000494] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 04/06/2022] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVES The anti-α4β7 integrin antibody vedolizumab (VDZ) is successfully used for the treatment of inflammatory bowel diseases. However, only a subgroup of patients respond to therapy. VDZ is administered at a fixed dose, leading to a wide range of serum concentrations in patients. Previous work from our group showed a dose-dependent preferential binding of VDZ to effector compared with regulatory CD4 + T cells. Therefore, we aimed to determine the dose-dependent binding profile of VDZ to other leukocyte subsets. METHODS We characterized α4β7 integrin expression on CD8 + T cells, CD19 + B cells, CD14 + monocytes, natural killer cells, and eosinophils from patients with inflammatory bowel disease and healthy controls. We studied the binding of VDZ to these cells at different concentrations and investigated the functional consequences for dynamic adhesion and transmigration in vitro . RESULTS The expression of α4β7 differed between the analyzed leukocyte subsets and was significantly higher on eosinophils from inflammatory bowel disease patients compared with controls. Almost all α4β7-expressing cells from these subsets were bound by VDZ at a concentration of 10 μg/mL. Dynamic cell adhesion was significantly impaired in all subsets, but there were no dose-dependent differences in the inhibition of adhesion. DISCUSSION Our data suggest that α4β7-expressing CD8 + T cells, CD19 + B cells, CD14 + monocytes, natural killer cells, and eosinophils are a target of VDZ. However, there do not seem to be concentration-dependent differences, regarding the effects on these cells in the clinically relevant range. Thus, the reported exposure-efficacy characteristic of VDZ can probably mainly be attributed to CD4 + T-cell subsets.
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Affiliation(s)
- Emily Becker
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;
| | - Anna Schweda
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;
| | - Karen A. -M. Ullrich
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;
| | - Caroline Voskens
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany.
| | - Raja Atreya
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany.
| | - Tanja M. Müller
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany.
| | - Imke Atreya
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany.
| | - Markus F. Neurath
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany.
| | - Sebastian Zundler
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Germany;
- Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Germany.
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19
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Nassar IO, Cheesbrough J, Quraishi MN, Sharma N. Proposed pathway for therapeutic drug monitoring and dose escalation of vedolizumab. Frontline Gastroenterol 2022; 13:430-435. [PMID: 36051956 PMCID: PMC9380766 DOI: 10.1136/flgastro-2021-102032] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/10/2022] [Indexed: 02/05/2023] Open
Abstract
Vedolizumab is a gut-selective monoclonal antibody approved for the management of Crohn's disease and ulcerative colitis. The available data demonstrate a favourable response to dose escalation in patients with primary non-response or secondary loss of response to vedolizumab. While therapeutic drug monitoring has a proven clinical utility for tumour necrosis factor antagonists, the available guidance for therapeutic drug monitoring and dose escalation of vedolizumab is rather limited. The present review proposes a practical algorithm to use vedolizumab trough levels in the management of treatment failure. Therapeutic drug monitoring can differentiate underexposed patients from those with mechanistic failure. Underdosed patients can respond to dose escalation instead of unnecessarily switching to other treatment modalities. We also review the safety and potential cost-effectiveness of vedolizumab dose escalation, the role of antidrug antibodies and the possible applicability of this strategy to subcutaneous vedolizumab.
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Affiliation(s)
- Islam Osama Nassar
- Gastroenterology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Jonathan Cheesbrough
- Gastroenterology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Mohammed Nabil Quraishi
- Gastroenterology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Naveen Sharma
- Gastroenterology Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
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20
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Optimal Placement of Colectomy in the Treatment of Ulcerative Colitis: a Markov Model Analysis. J Gastrointest Surg 2021; 25:3208-3217. [PMID: 34725785 DOI: 10.1007/s11605-021-05180-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 10/14/2021] [Indexed: 01/31/2023]
Abstract
BACKGROUND Treatment for moderate-to-severe ulcerative colitis (UC) includes medical therapies such as immunosuppressive agents or surgical options such as colectomy. While prior studies have indicated a mortality benefit with elective surgery, the timing and effectiveness of colectomy in the UC treatment algorithm have not been assessed. We hypothesize that the ideal placement of colectomy occurs prior to the exhaustion of all medical therapies. METHODS We designed a Markov model to assess the ideal position of colectomy. The base case was a 50-year-old male with steroid-dependent moderate-to-severe UC without prior treatment with immunomodulator or biologic therapies. We developed 4 separate algorithms incorporating elective colectomy: (1) prior to biologics, (2) after infliximab monotherapy failure, (3) after infliximab and azathioprine combination therapy failure, and (4) after medically refractory to all medical therapies including vedolizumab. Transition probabilities were obtained from published literature. First-order Monte Carlo simulations of 100 trials of 100,000 individuals were used to calculate quality-adjusted life-year (QALY) estimates. One-way sensitivity analyses were conducted for all variables. RESULTS Algorithm 3 (colectomy following combination therapy) was the preferred strategy with 1.864 QALYs (95% CI [1.863, 1.865]) over a 3-year period and the preferred strategy in the probabilistic sensitivity analysis 92.77% of the time. CONCLUSIONS This simulation suggests that early incorporation of colectomy for patients medically refractory to infliximab and azathioprine combination therapy may yield greater quality of life for patients with steroid-dependent UC. These findings suggest avenues for more patient-centered preference work and a combined medical-surgical approach to UC.
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21
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Melde M, Müller TM, Schneider I, Geppert CI, Mühl L, Besendorf L, Allner C, Becker E, Atreya I, Vitali F, Atreya R, Neurath MF, Zundler S. α4β7 integrin-dependent adhesion of T cells to MAdCAM-1 is blocked by vedolizumab in patients with chronic refractory pouchitis. Therap Adv Gastroenterol 2021; 14:17562848211054707. [PMID: 34868349 PMCID: PMC8640978 DOI: 10.1177/17562848211054707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 10/04/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The anti-α4β7 integrin antibody vedolizumab is an established therapeutic option for the treatment of inflammatory bowel disease (IBD). It has also been successfully used in patients with chronic antibiotic-refractory pouchitis following proctocolectomey with ileal pouch-anal anastomosis. However, the expression and function of gut-homing markers as well as strategies to predict the response to vedolizumab in pouchitis are understudied so far. METHODS We used flow cytometry and dynamic adhesion assays to study the expression and function of gut-homing integrins on T cells from patients with pouchitis and controls as well as longitudinally during therapy of pouchitis with vedolizumab. Moreover, we describe clinical effects of vedolizumab in a cohort of patients with pouchitis. RESULTS T cells from patients with pouchitis express a specific profile of gut-homing integrins. Integrin α4β7 on T cells from patients with pouchitis mediates adhesion to mucosal addressin cell adhesion molecule (MAdCAM)-1, which can be blocked by vedolizumab in vitro. Vedolizumab efficiently treats pouchitis in a portion of patients and response correlates with dynamic adhesion profiles to MAdCAM-1. CONCLUSION Our data suggest that T cell trafficking seems to be important for the pathogenesis of pouchitis and support the therapeutic use of vedolizumab. Integrin function might serve as a biomarker to predict response to vedolizumab.
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Affiliation(s)
| | | | - Ines Schneider
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Carol-Immanuel Geppert
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Laura Mühl
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Laura Besendorf
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Clarissa Allner
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Emily Becker
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
| | - Imke Atreya
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
| | - Francesco Vitali
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
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22
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Handley G, Hand J. Adverse Effects of Immunosuppression: Infections. Handb Exp Pharmacol 2021; 272:287-314. [PMID: 34671868 DOI: 10.1007/164_2021_550] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Immunosuppressive therapies are currently indicated for a wide range of diseases. As new agents emerge and indications evolve the landscape grows increasingly complex. Therapies can target pathologic immune system over-activation in rheumatologic or autoimmune disease, or conditioning and graft versus host disease (GVHD) prophylactic regimens may eliminate or inhibit host immune function to improve graft survival and risk of complication in solid organ transplantation (SOT) or hematopoietic stem cell transplantation (HSCT). With immunosuppressive therapy, infections occur. Complex disease states, host factors, and concomitant therapies contribute to a "net state" of immunosuppression that must be considered and may confound perceived increased infection risks in patients receiving treatment.
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Affiliation(s)
- Guy Handley
- Division of Infectious Disease and International Medicine, Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Jonathan Hand
- Department of Infectious Diseases, Ochsner Health, The University of Queensland School of Medicine, Ochsner Clinical School, New Orleans, LA, USA.
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23
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A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease. Bone Marrow Transplant 2021; 56:2477-2488. [PMID: 34108672 PMCID: PMC8486663 DOI: 10.1038/s41409-021-01356-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 04/23/2021] [Accepted: 05/12/2021] [Indexed: 01/10/2023]
Abstract
Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn’s disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD.
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24
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Jairath V, Chan K, Lasch K, Keeping S, Agboton C, Blake A, Patel H. Integrating efficacy and safety of vedolizumab compared with other advanced therapies to assess net clinical benefit of ulcerative colitis treatments: a network meta-analysis. Expert Rev Gastroenterol Hepatol 2021; 15:711-722. [PMID: 33599181 DOI: 10.1080/17474124.2021.1880319] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Objectives: Because only one head-to-head randomized trial of biologics for moderate-to-severe UC has been performed, indirect treatment comparisons remain important. This systematic review and network meta-analysis examined efficacy and safety of biologics and tofacitinib for moderate-to-severe UC, using vedolizumab as reference.Methods: Relevant studies (N = 19) of vedolizumab, adalimumab, infliximab, golimumab, ustekinumab, and tofacitinib were identified. Study design differences were addressed by assessing efficacy outcomes conditional on response at maintenance initiation. Primary analysis used fixed-effect models to estimate odds ratios for efficacy and safety endpoints.Results: Compared with vedolizumab 300 mg, adalimumab 160/80 mg was associated with less clinical remission (odds ratio, 0.69 [95% credible interval, 0.54-0.88]), and infliximab 5 mg/kg was associated with more clinical remission (1.67 [1.16-2.42]) and response (1.63 [1.15-2.30]). Adalimumab 40 mg, golimumab 50 mg, and ustekinumab 90 mg Q12W had significantly lower clinical remission rates during maintenance (0.62 [0.45-0.86], 0.55 [0.32-0.95], and 0.59 [0.35-0.99]) versus vedolizumab 300 mg Q8W. Response results were similar. Tofacitinib 10 mg had the highest maintenance treatment efficacy estimates and highest infection risk.Conclusion: Network meta-analysis and novel integrated benefit-risk analysis suggest a potentially favorable efficacy-safety balance for vedolizumab vs adalimumab and other advanced UC therapies.
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Affiliation(s)
- Vipul Jairath
- Western University Schulich School of Medicine and Dentistry, London, ON, Canada
| | | | - Karen Lasch
- Takeda Pharmaceuticals U.S.A., Inc., Lexington, Massachusetts, USA
| | | | | | - Aimee Blake
- Takeda Pharmaceuticals International Inc., Cambridge, Massachusetts, USA
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25
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Restellini S, Afif W. Update on TDM (Therapeutic Drug Monitoring) with Ustekinumab, Vedolizumab and Tofacitinib in Inflammatory Bowel Disease. J Clin Med 2021; 10:1242. [PMID: 33802816 PMCID: PMC8002563 DOI: 10.3390/jcm10061242] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/08/2021] [Accepted: 03/11/2021] [Indexed: 02/06/2023] Open
Abstract
The goal of therapeutic drug monitoring (TDM) is to optimize anti-TNF (tumor necrosis factor) biologic treatment in patients with inflammatory bowel disease (IBD). Although commercial assays are readily available for both ustekinumab and vedolizumab, the use of TDM with these newer biologic medications is at its infancy. The clinical utility of TDM with non-anti-TNF mechanisms of action is not clear. This review summarizes the latest available data on the pharmacokinetics of newer biologic and oral small molecules and highlights the threshold concentrations that have been associated with improved outcomes in IBD patients.
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Affiliation(s)
- Sophie Restellini
- Division of Gastroenterology, McGill University Health Centre, Montreal, QC H3G 1A4, Canada;
- Division of Gastroenterology and Hepatology, Geneva’s University Hospitals and University of Geneva, 1205 Geneva, Switzerland
| | - Waqqas Afif
- Division of Gastroenterology, McGill University Health Centre, Montreal, QC H3G 1A4, Canada;
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26
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Diel R, Schaberg T, Nienhaus A, Otto-Knapp R, Kneitz C, Krause A, Fabri M, Mrowietz U, Bauer T, Häcker B. Joint Statement (DZK, DGRh, DDG) on the Tuberculosis Risk with Treatment Using Novel Non-TNF-Alpha Biologicals. Pneumologie 2021; 75:293-303. [PMID: 33598901 DOI: 10.1055/a-1294-1580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
BACKGROUND While the risk of tuberculosis (TB) reactivation is adequately documented in relation to TNF-alpha inhibitors (TNFi), the question of what the tuberculosis risk is for newer, non-TNF biologics (non-TNFi) has not been thoroughly addressed. METHODS We conducted a systematic review of randomized phase 2 and phase 3 studies, and long-term extensions of same, published through March 2019. Of interest was information pertaining to screening and treating of latent tuberculosis (LTBI) in association with the use of 12 particular non-TNFi. Only rituximab was excluded. We searched MEDLINE and the ClinicalTrial.gov database for any and all candidate studies meeting these criteria. RESULTS 677 citations were retrieved; 127 studies comprising a total of 34,293 patients who received non-TNFi were eligible for evaluation. Only 80 out of the 127 studies, or 63 %, captured active TB (or at least opportunistic diseases) as potential outcomes and 25 TB cases were reported. More than two thirds of publications (86/127, 68 %) mentioned LTBI screening prior to inclusion of study participants in the respective trial, whereas in only 4 studies LTBI screening was explicitly considered redundant. In 21 studies, patients with LTBI were generally excluded from the trials and in 42 out of the 127 trials, or 33 %, latently infected patients were reported to receive preventive therapy (PT) at least 3 weeks prior to non-TNFi treatment. CONCLUSIONS The lack of information in many non-TNFi studies on the number of patients with LTBI who were either excluded prior to participating or had been offered PT hampers assessment of the actual TB risk when applying the novel biologics. Therefore, in case of insufficient information about drugs or drug classes, the existing recommendations of the German Central Committee against Tuberculosis should be applied in the same way as is done prior to administering TNFi. Well designed, long-term "real world" register studies on TB progression risk in relation to individual substances for IGRA-positive cases without prior or concomitant PT may help to reduce selection bias and to achieve valid conclusions in the future.
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Affiliation(s)
- R Diel
- Institute for Epidemiology, University Medical Hospital Schleswig-Holstein, Campus Kiel, Germany. Member of the German Center for Lung Research (ARCN).,LungClinic Grosshansdorf, Germany. Airway Research Center North (ARCN), German Center for Lung Research (DZL).,German Central Committee against Tuberculosis, Berlin, Germany
| | - T Schaberg
- German Central Committee against Tuberculosis, Berlin, Germany
| | - A Nienhaus
- Institution for Statutory Accident Insurance and Prevention in the Health and Welfare Services (BGW), Hamburg, Germany.,Institute for Health Service Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - R Otto-Knapp
- German Central Committee against Tuberculosis, Berlin, Germany
| | - C Kneitz
- Medicine, Rheumatology, rheumatological main practice Schwerin, Germany
| | - A Krause
- Department of Rheumatology, Clinical Immunology and Osteology, Immanuel Hospital Berlin, Germany
| | - M Fabri
- Department of Dermatology, University of Cologne, Germany
| | - U Mrowietz
- Psoriasis Center, Department of Dermatology, University Medical Center Schleswig-Holstein, Campus Kiel, Germany
| | - T Bauer
- German Central Committee against Tuberculosis, Berlin, Germany
| | - B Häcker
- German Central Committee against Tuberculosis, Berlin, Germany
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27
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Marafini I, Troncone E, Rocchetti I, Monteleone G. Respiratory Tract Infections in Inflammatory Bowel Disease Patients Taking Vedolizumab: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front Pharmacol 2021; 11:585732. [PMID: 33551798 PMCID: PMC7862105 DOI: 10.3389/fphar.2020.585732] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Accepted: 12/03/2020] [Indexed: 01/08/2023] Open
Abstract
The ongoing COVID-19 pandemic has raised concerns about the risk of SARS-CoV-2 infection in patients with Crohn’s disease (CD) and patients with ulcerative colitis (UC) taking immunosuppressants or biologics. We conducted a systematic review and meta-analysis to assess the risk of respiratory infections in patients with inflammatory bowel disease (IBD) treated with vedolizumab. We searched PubMed, EMBASE and Scopus to identify randomized controlled trials (RCT) comparing vedolizumab to placebo in patients with IBD. Outcomes were the rate of respiratory tract infections (RTI), upper respiratory tract infections (URTI) and lower respiratory tract infections (LRTI) among patients receiving vedolizumab as compared with placebo. Pooled rates were reported as Odds Ratios (OR) with 95% Confidence Interval (CI). Eight RCT involving 3,287 patients (1873 CD and 1415 UC) were analyzed; 2,493 patients received vedolizumab and 794 received placebo. The rates of RTI and URTI were statistically higher in vedolizumab-treated patients compared to placebo [OR = 1.63; 95% CI (1.07–2.49); OR = 1.64 95% CI (1.07–2.53) respectively]. UC patients, but not CD patients, receiving vedolizumab had a higher risk to develop RTI and URTI [OR = 1.98; 95% CI (1.41–2.77); OR = 2.02; 95% CI (1.42–2.87)] compared to placebo-treated patients. The number of LRTI was small in both treatment groups. Data confirm the good safety profile of vedolizumab even though RTI were more frequent in patients receiving vedolizumab and the risk of URTIs was significantly higher in patients with UC.
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Affiliation(s)
- Irene Marafini
- Chair of Gastroenterology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Edoardo Troncone
- Chair of Gastroenterology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Irene Rocchetti
- Statistical Office, Superior Council of Judiciary, Rome, Italy
| | - Giovanni Monteleone
- Chair of Gastroenterology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
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McGuinty M, Angel JB, Cooper CL, Cowan J, MacPherson PA, Kumar A, Murthy S, Sy R, Dennehy M, Tremblay N, Byrareddy SN, Cameron DW. Vedolizumab treatment across antiretroviral treatment interruption in chronic HIV infection: the HAVARTI protocol for a pilot dose-ranging clinical trial to assess safety, tolerance, immunological and virological activity. BMJ Open 2020; 10:e041359. [PMID: 33033101 PMCID: PMC7545629 DOI: 10.1136/bmjopen-2020-041359] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
INTRODUCTION Continuous antiretroviral therapy (ART) suppresses HIV plasma viral load (pVL) to very low levels, which allows for some immune recovery. Discontinuation of ART leads to pVL rebound from reservoirs of persistence and latency, and progressive immunodeficiency. One promising but controversial strategy targeting CD4+ T lymphocytes with a monoclonal antibody (mAb) against α4β7 integrin has shown promise through sustained virological remission of pVL (SVR) in SIV239-infected rhesus macaques. We propose to assess the safety and tolerability of vedolizumab, a licensed humanised mAb against human α4β7 integrin, in healthy HIV-infected adults on ART. This study will also assess, by analytical treatment interruption (ATI), whether vedolizumab treatment can induce SVR beyond ART and vedolizumab treatment. METHODS AND ANALYSIS The HIV-ART-vedolizumab-ATI (HAVARTI) trial is a single-arm, dose-ranging pilot trial in healthy HIV-positive adult volunteers receiving ART. Twelve consenting persons will be enrolled in sequential groups of 4 to each serial dosing vedolizumab regimen (300 mg, 150 mg, 75 mg). The primary outcomes are: (1) to assess the safety and tolerability of seven serial infusions of vedolizumab at each of three doses; (2) to identify the immunovirological measures, including pVL and T-cell kinetics, that characterise HIV/ART cases before, during, after vedolizumab treatment and ATI; and (3) to seek SVR of pVL after ATI. Secondary outcomes will include immune reconstitution and pVL suppression as well as immune reconstitution and long-term safety following re-initiation of ART in the absence of SVR. ETHICS AND DISSEMINATION The study protocol was approved by the Ottawa Health Science Network-REB and by the Health Canada Therapeutic Products Directorate. A Data Safety Monitor will review safety information at regular intervals. The final manuscript will be submitted to an open access journal within a year of study completion. TRIAL REGISTRATION NUMBER ClinicalTrials.gov NCT03147859; https://clinicaltrials.gov/ct2/show/NCT03147859.
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Affiliation(s)
- Michaeline McGuinty
- Medicine, Division of Infectious Diseases, Ottawa Hospital General Campus, Ottawa, Ontario, Canada
| | - Jonathan B Angel
- Medicine, Division of Infectious Diseases, Ottawa Hospital General Campus, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Curtis L Cooper
- Medicine, Division of Infectious Diseases, Ottawa Hospital General Campus, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Juthaporn Cowan
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Ottawa Hospital, Ottawa, Ontario, Canada
| | - Paul A MacPherson
- Medicine, Division of Infectious Diseases, Ottawa Hospital General Campus, Ottawa, Ontario, Canada
| | - Ashok Kumar
- Pathology, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
| | - Sanjay Murthy
- Medicine, Division of Gastroenterology, Ottawa Hospital General Campus, Ottawa, Ontario, Canada
| | - Richmond Sy
- Medicine, Division of Gastroenterology, Ottawa Hospital General Campus, Ottawa, Ontario, Canada
| | | | - Nancy Tremblay
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Siddappa N Byrareddy
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - D William Cameron
- Medicine, Division of Infectious Diseases, Ottawa Hospital General Campus, Ottawa, Ontario, Canada
- Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
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Pulusu SSR, Srinivasan A, Krishnaprasad K, Cheng D, Begun J, Keung C, Van Langenberg D, Thin L, Mogilevski T, De Cruz P, Radford-Smith G, Flanagan E, Bell S, Kashkooli S, Sparrow M, Ghaly S, Bampton P, Sawyer E, Connor S, Rizvi QUA, Andrews JM, Mahy G, Chivers P, Travis S, Lawrance IC. Vedolizumab for ulcerative colitis: Real world outcomes from a multicenter observational cohort of Australia and Oxford. World J Gastroenterol 2020; 26:4428-4441. [PMID: 32874055 PMCID: PMC7438197 DOI: 10.3748/wjg.v26.i30.4428] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Revised: 07/18/2020] [Accepted: 07/30/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Vedolizumab (VDZ), a humanised monoclonal antibody that selectively inhibits alpha4-beta7 integrins is approved for use in adult moderate to severe ulcerative colitis (UC) patients.
AIM To assess the efficacy and safety of VDZ in the real-world management of UC in a large multicenter cohort involving two countries and to identify predictors of achieving remission.
METHODS A retrospective review of Australian and Oxford, United Kingdom data for UC patients. Clinical response at 3 mo, endoscopic remission at 6 mo and clinical remission at 3, 6 and 12 mo were assessed. Cox regression models and Kaplan Meier curves were performed to assess the time to remission, time to failure and the covariates influencing them. Safety outcomes were recorded.
RESULTS Three hundred and three UC patients from 14 centres in Australia and United Kingdom, [60% n = 182, anti-TNF naïve] were included. The clinical response was 79% at 3 mo with more Australian patients achieving clinical response compared to Oxford (83% vs 70% P = 0.01). Clinical remission for all patients was 56%, 62% and 60% at 3, 6 and 12 mo respectively. Anti-TNF naive patients were more likely to achieve remission than exposed patients at all the time points (3 mo 66% vs 40% P < 0.001, 6 mo 73% vs 46% P < 0.001, 12 mo 66% vs 51% P = 0.03). More Australian patients achieved endoscopic remission at 6 mo compared to Oxford (69% vs 43% P = 0.01). On multi-variate analysis, anti-TNF naïve patients were 1.8 (95%CI: 1.3-2.3) times more likely to achieve remission than anti-TNF exposed (P < 0.001). 32 patients (11%) had colectomy by 12 mo.
CONCLUSION VDZ was safe and effective with 60% of UC patients achieving clinical remission at 12 mo and prior anti-TNF exposure influenced this outcome.
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Affiliation(s)
- Samba Siva Reddy Pulusu
- Centre for Inflammatory Bowel Diseases, St John of God Hospital, Subiaco 6008, Western Australia, Australia
| | - Ashish Srinivasan
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - Krupa Krishnaprasad
- Inflammatory Bowel Disease Research Group, Queensland institute of Medical Research, Herston 4006, Queensland, Australia
| | - Daniel Cheng
- Department of Gastroenterology, Mater Hospital, Brisbane 4101, Queensland, Australia
| | - Jakob Begun
- Department of Gastroenterology, Mater Hospital, South Brisbane 4101, Queensland, Australia
| | - Charlotte Keung
- Department of Gastroenterology, Eastern Health, Box Hill 3128, Victoria, Australia
| | | | - Lena Thin
- Department of Gastroenterology, Fiona Stanley Hospital, Murdoch 6150, Western Australia, Australia
| | - Tamara Mogilevski
- Department of Gastroenterology, Austin Health, Heidelberg 3084, Victoria, Australia
| | - Peter De Cruz
- Department of Gastroenterology, Austin Health, Heidelberg 3084, Victoria, Australia
| | - Graham Radford-Smith
- Department of Gastroenterology, Mater Hospital, South Brisbane 4101, Queensland, Australia
| | - Emma Flanagan
- Department of Gastroenterology, St Vincent’s Hospital, Fitzroy 3065, Victoria, Australia
| | - Sally Bell
- Department of Gastroenterology, St Vincent’s Hospital, Fitzroy 3065, Victoria, Australia
| | - Soleiman Kashkooli
- Department of Gastroenterology, Northern Health, Epping 3076, Victoria, Australia
| | - Miles Sparrow
- Department of Gastroenterology, The Alfred Hospital, Melbourne 3004, Victoria, Australia
| | - Simon Ghaly
- Department of Gastroenterology, St Vincent’s Hospital, Darlinghurst 2010, New South Wales, Australia
| | - Peter Bampton
- Department of Gastroenterology, Flinders Medical Centre, Bedford Park 5042, South Australia, Australia
| | - Elise Sawyer
- Department of Gastroenterology, Liverpool Hospital, Sydney 2170, New South Wales, Australia
| | - Susan Connor
- Department of Gastroenterology, Liverpool Hospital, Sydney 2170, New South Wales, Australia
| | - Quart-ul-ain Rizvi
- Department of Gastroenterology, Royal Adelaide Hospital & University of Adelaide, Adelaide 5000, South Australia, Australia
| | - Jane M Andrews
- Department of Gastroenterology, Royal Adelaide Hospital & University of Adelaide, Adelaide 5000, South Australia, Australia
| | - Gillian Mahy
- Department of Gastroenterology, Townsville Hospital, Douglas 4814, Queensland, Australia
| | - Paola Chivers
- Institute for Health Research, University of Notre Dame, Fremantle 6160, Western Australia, Australia
| | - Simon Travis
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom
| | - Ian Craig Lawrance
- Centre for Inflammatory Bowel Diseases, St John of God Hospital, Subiaco 6008, Western Australia, Australia
- School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Western Australia, Australia
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Okamoto H, Dirks NL, Rosario M, Hori T, Hibi T. Population pharmacokinetics of vedolizumab in Asian and non-Asian patients with ulcerative colitis and Crohn's disease. Intest Res 2020; 19:95-105. [PMID: 32635680 PMCID: PMC7873400 DOI: 10.5217/ir.2019.09167] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/17/2020] [Indexed: 12/25/2022] Open
Abstract
Background/Aims Vedolizumab is indicated for moderately-to-severely active ulcerative colitis (UC) and Crohn’s disease (CD). Because multiple factors may result in different pharmacokinetics and clinical efficacies, understanding determinants of vedolizumab clearance may enhance dose and treatment strategies. The aim was to characterize vedolizumab pharmacokinetics in Asian and non-Asian UC and CD patients. Methods Population pharmacokinetic analysis for repeated measures, using data from 5 studies, was conducted using nonlinear mixed-effects modeling. A Bayesian estimation approach in NONMEM 7.3 was utilized to leverage the predominantly sparse data available for this analysis with results from a prior population pharmacokinetic analysis of vedolizumab. Results Vedolizumab pharmacokinetics were described by a 2-compartment model with parallel linear and nonlinear elimination. Using reference covariate values, linear elimination half life of vedolizumab was 24.7 days for anti-vedolizumab antibody (AVA)-negative patients and 18.1 days for AVA-positive patients; linear clearance (CLL) was 0.165 L/day for AVA-negative patients and 0.246 L/day for AVA-positive patients; central (Vc) and peripheral compartment volumes of distribution were 3.16 L and 1.84 L, respectively. Interindividual variabilities (percent coefficient of variation) were 30.8% for CLL and 19% for Vc; interoccasion variability on CLL was 20.3%; residual variance was 17.8%. For albumin, body weight and AVA, only extreme values were identified as potentially clinically important predictors of CLL. The effect of race (Asian/non-Asian) and diagnosis (UC/CD) on CLL was negligible and likely not of clinical importance. Conclusions Pharmacokinetic parameters were similar in Asian and non-Asian patients with moderately-to-severely active UC and CD. This analysis supports use of vedolizumab flat-fixed dosing in these patients. (Clinicaltrials.gov Identifiers: NCT00783718 (GEMINI 1); NCT00783692 (GEMINI 2). CCT 101; NCT02039505 and CCT-001; NCT02038920)
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Affiliation(s)
| | | | - Maria Rosario
- Takeda Development Center Americas Inc, Cambridge, MA, USA
| | | | - Toshifumi Hibi
- Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, Tokyo, Japan
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Dulai PS, Battat R, Barsky M, Nguyen NH, Ma C, Narula N, Mosli M, Casteele NV, Boland BS, Prokop L, Murad MH, D’Haens G, Feagan BG, Sandborn WJ, Jairath V, Singh S. Incorporating Fecal Calprotectin Into Clinical Practice for Patients With Moderate-to-Severely Active Ulcerative Colitis Treated With Biologics or Small-Molecule Inhibitors. Am J Gastroenterol 2020; 115:885-894. [PMID: 32384283 PMCID: PMC7274901 DOI: 10.14309/ajg.0000000000000596] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION We applied the Grading of Recommendations, Assessment, Development, and Evaluation framework to evaluate the performance of fecal calprotectin (FC) as an alternative to endoscopy in patients with moderate-to-severe ulcerative colitis (UC) treated with a biologic agent or tofacitinib. METHODS Individual participant data from the trials of infliximab, golimumab, vedolizumab, and tofacitinib for UC were pooled to generate prevalence of endoscopic activity (Mayo endoscopy score) across different combinations of the rectal bleeding score (RBS) and stool frequency score (SFS). These estimates were then combined with the data from an updated systematic review of the operating properties of FC to generate clinical scenario-specific assessments of the performance of FC as a predictor of endoscopic disease activity. A prespecified threshold of acceptability for false-negative (FN) and false-positive (FP) test results was set at 5%. RESULTS For patients with UC achieving RBS 0 + SFS 0/1, FC ≤ 50 μg/g may avoid endoscopy in 50% patients with a FN rate <5%. Similarly, for patients with RBS 2/3 + SFS 2/3, FC ≥ 250 μg/g potentially avoids endoscopy in approximately 50% patients with an FP rate <5%. The greatest uncertainty in the diagnostic performance for FC was observed in patients with UC achieving RBS 0 but having SFS 2/3, where FN and FP rates were consistently >10%, and endoscopic evaluation may be warranted. DISCUSSION Two clinical scenarios were identified where FC can be used with confidence for monitoring treatment response to biologics or tofacitinib in patients with UC without the requirement for endoscopy.
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Affiliation(s)
| | - Robert Battat
- University of California San Diego, La Jolla, CA, USA
| | - Maria Barsky
- University of California San Diego, La Jolla, CA, USA
| | | | | | | | | | | | | | - Larry Prokop
- Evidence-based Practice center,; Mayo Clinic, Rochester, MN, USA
| | - M. Hassan Murad
- Evidence-based Practice center,; Mayo Clinic, Rochester, MN, USA
| | | | | | | | - Vipul Jairath
- University of Western Ontario, London, Ontario, Canada
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Sparrow MP, Papamichael K, Ward MG, Riviere P, Laharie D, Paul S, Roblin X. Therapeutic Drug Monitoring of Biologics During Induction to Prevent Primary Non-Response. J Crohns Colitis 2020; 14:542-556. [PMID: 31549158 PMCID: PMC7392326 DOI: 10.1093/ecco-jcc/jjz162] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Biologic therapies have revolutionized the management of inflammatory bowel disease [IBD], but primary and secondary non-responses occur in a significant proportion of patients. Therapeutic drug monitoring [TDM] now has an established role in the treatment algorithm for managing secondary loss of response to anti-tumour necrosis factor [anti-TNF] agents during maintenance therapy. Data to support the use of TDM in the management of secondary loss of response to vedolizumab and ustekinumab are emerging. The potential to prevent primary non-response to biologic agents during induction is of equal, and potentially greater, clinical importance. Again, most data supporting the use of 'proactive' TDM during induction pertains to the use of anti-TNF agents, but signals of efficacy for the use of TDM during induction with other biologic classes are now appearing. This review aims to summarize data on the use of TDM during induction to prevent pharmacokinetic primary non-response to all three classes of biologic therapy currently available for the treatment of IBD.
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Affiliation(s)
- Miles P Sparrow
- Department of Gastroenterology, Alfred Hospital and Monash University, Melbourne, Victoria, Australia
| | - Konstantinos Papamichael
- Division of Gastroenterology, Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Mark G Ward
- Department of Gastroenterology, Alfred Hospital and Monash University, Melbourne, Victoria, Australia
| | | | - David Laharie
- Gastroenterology Unit, Pessac University Hospital, France
| | - Stephane Paul
- Department of Immunology, University Hospital of Saint Etienne, Saint-Etienne, France
| | - Xavier Roblin
- Gastroenterology Unit, University Hospital of Saint Etienne, Saint-Etienne, France
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Takatsu N, Hisabe T, Higashi D, Ueki T, Matsui T. Vedolizumab in the Treatment of Ulcerative Colitis: An Evidence-Based Review of Safety, Efficacy, and Place of Therapy. CORE EVIDENCE 2020; 15:7-20. [PMID: 32280316 PMCID: PMC7131995 DOI: 10.2147/ce.s179053] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Accepted: 03/08/2020] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Selective blockade of the integrins and mucosal adhesion molecules is a promising therapeutic strategy for ulcerative colitis (UC). Vedolizumab (VDZ), a humanized IgG1 monoclonal antibody against α4β7 integrin, selectively blocks the trafficking of the leukocytes into the gastrointestinal tract through its binding with the α4β7 integrin. AIM In this review, we provide an overview of the unique mechanism of VDZ, along with its efficacy, safety, and pharmacokinetic and pharmacodynamic data obtained from clinical trials, observational studies, and meta-analyses. EVIDENCE REVIEW A positive exposure-efficacy relationship with regard to clinical remission and clinical response was apparent in VDZ induction therapy. No drug-specific safety signals are currently available. PLACE IN THERAPY VDZ has been shown to be effective as first- or second-line induction and maintenance therapy in UC. CONCLUSION VDZ is a safe and effective treatment option for patients with UC. Prolonged VDZ induction therapy may contribute to improved outcomes in patients with UC, particularly those previously treated with tumor necrosis factor-α. Prospective head-to-head study of VDZ and other biologics would alter the positioning of VDZ much more clearly.
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Affiliation(s)
- Noritaka Takatsu
- Department Of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Takashi Hisabe
- Department Of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Daijiro Higashi
- Department Of Surgery, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Toshiharu Ueki
- Department Of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
| | - Toshiyuki Matsui
- Department Of Gastroenterology, Fukuoka University Chikushi Hospital, Fukuoka, Japan
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Berends SE, Strik AS, Löwenberg M, D'Haens GR, Mathôt RAA. Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis. Clin Pharmacokinet 2020; 58:15-37. [PMID: 29752633 PMCID: PMC6326086 DOI: 10.1007/s40262-018-0676-z] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) of unknown etiology, probably caused by a combination of genetic and environmental factors. The treatment of patients with active UC depends on the severity, localization and history of IBD medication. According to the classic step-up approach, treatment with 5-aminosalicylic acid compounds is the first step in the treatment of mild to moderately active UC. Corticosteroids, such as prednisolone are used in UC patients with moderate to severe disease activity, but only for remission induction therapy because of side effects associated with long-term use. Thiopurines are the next step in the treatment of active UC but monotherapy during induction therapy in UC patients is not preferred because of their slow onset. Therapeutic drug monitoring (TDM) of the pharmacologically active metabolites of thiopurines, 6-thioguanine nucleotide (6-TGN), has proven to be beneficial. Thiopurine S-methyltransferase (TMPT) plays a role in the metabolic conversion pathway of thiopurines and exhibits genetic polymorphism; however, the clinical benefit and relevance of TPMT genotyping is not well established. In patients with severely active UC refractory to corticosteroids, calcineurin inhibitors such as ciclosporin A (CsA) and tacrolimus are potential therapeutic options. These agents usually have a rather rapid onset of action. Monoclonal antibodies (anti-tumor necrosis factor [TNF] agents, vedolizumab) are the last pharmacotherapeutic option for UC patients before surgery becomes inevitable. Body weight, albumin status and antidrug antibodies contribute to the variability in the pharmacokinetics of anti-TNF agents. Additionally, the use of concomitant immunomodulators (thiopurines/methotrexate) lowers the rate of immunogenicity, and therefore the concomitant use of anti-TNF therapy with an immunomodulator may confer some advantage compared with monotherapy in certain patients. TDM of anti-TNF agents could be beneficial in patients with primary nonresponse and secondary loss of response. The potential benefit of applying TDM during vedolizumab treatment has yet to be determined.
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Affiliation(s)
- Sophie E Berends
- Department Hospital Pharmacy, Academic Medical Center, Amsterdam, The Netherlands.
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
| | - Anne S Strik
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Mark Löwenberg
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Geert R D'Haens
- Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands
| | - Ron A A Mathôt
- Department Hospital Pharmacy, Academic Medical Center, Amsterdam, The Netherlands
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Factors Influencing Drug Disposition of Monoclonal Antibodies in Inflammatory Bowel Disease: Implications for Personalized Medicine. BioDrugs 2020; 33:453-468. [PMID: 31301024 DOI: 10.1007/s40259-019-00366-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Monoclonal antibody (mAb) therapies have revolutionized the treatment of several chronic inflammatory diseases, including the inflammatory bowel diseases (IBD), Crohn's disease, and ulcerative colitis. While efficacious, responses to these therapies vary considerably from patient to patient, due in part to inter- and intra-individual variability in pharmacokinetics (PK) and drug exposure. The concept of personalized medicine to monitor drug exposure and to adjust dosing in individual patients is consequently gaining acceptance as a powerful tool to optimize mAb therapy for improved outcomes in IBD. This review provides a brief overview of the different mAbs currently approved or in development for the treatment of IBD, including their presumed mechanisms of action and PK properties. Specifically described are (1) the factors known to affect mAb PK and drug exposure in patients with IBD, (2) the value of population PK/pharmacodynamic (PD) modeling to identify and understand the influence of these factors on drug exposure and effect, and (3) the clinical evidence for the potential of therapeutic drug monitoring (TDM) to improve IBD outcomes in response to mAb-based therapy. Incorporation of PK/PD parameters into clinical decision support tools has the potential to guide therapeutic decision making and aid implementation of personalized medicine strategies in patients with IBD.
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Sandborn WJ, Ferrante M, Bhandari BR, Berliba E, Feagan BG, Hibi T, Tuttle JL, Klekotka P, Friedrich S, Durante M, Morgan-Cox M, Laskowski J, Schmitz J, D'Haens GR. Efficacy and Safety of Mirikizumab in a Randomized Phase 2 Study of Patients With Ulcerative Colitis. Gastroenterology 2020; 158:537-549.e10. [PMID: 31493397 DOI: 10.1053/j.gastro.2019.08.043] [Citation(s) in RCA: 144] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 08/02/2019] [Accepted: 08/25/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND & AIMS Interleukin 23 contributes to the pathogenesis of ulcerative colitis (UC). We investigated the effects of mirikizumab, a monoclonal antibody against the p19 subunit of interleukin 23, in a phase 2 study of patients with UC. METHODS We performed a trial of the efficacy and safety of mirikizumab in patients with moderate to severely active UC, enrolling patients from 14 countries from January 2016 through September 2017. Patients were randomly assigned to groups given intravenous placebo (N = 63), mirikizumab 50 mg (N = 63) or 200 mg (N = 62) with exposure-based dosing, or mirikizumab 600 mg with fixed dosing (N = 61) at weeks 0, 4, and 8. Of assigned patients, 63% had prior exposure to a biologic agent. Clinical responders (decrease in 9-point Mayo score, including ≥2 points and ≥35% from baseline with either a decrease of rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 12 who had received mirikizumab were randomly assigned to groups that received maintenance treatment with mirikizumab 200 mg subcutaneously every 4 weeks (N = 47) or every 12 weeks (N = 46). The primary endpoint was clinical remission (Mayo subscores of 0 for rectal bleeding, with 1-point decrease from baseline for stool frequency, and 0 or 1 for endoscopy) at week 12. A multiple testing procedure was used that began with the 600-mg dose group, and any nonsignificant comparison result ended the formal statistical testing procedure. RESULTS At week 12, 15.9% (P = .066), 22.6% (P = .004), and 11.5% (P = .142) of patients in the 50-mg, 200-mg, and 600-mg groups achieved clinical remission, respectively, compared with 4.8% of patients given placebo. The primary endpoint was not significant (comparison to 600 mg, P > .05). Clinical responses occurred in 41.3% (P = .014), 59.7% (P < .001), and 49.2% (P = .001) of patients in the 50-mg, 200-mg, and 600-mg groups, respectively, compared with 20.6% of patients given placebo. At week 52, 46.8% of patients given subcutaneous mirikizumab 200 mg every 4 weeks and 37.0% given subcutaneous mirikizumab 200 mg every 12 weeks were in clinical remission. CONCLUSIONS In a randomized trial of patients with UC, mirikizumab was effective in inducing a clinical response after 12 weeks. Additional studies are required to determine the optimal dose for induction of remission. Mirikizumab showed durable efficacy throughout the maintenance period. Clinicaltrials.gov, Number NCT02589665.
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Affiliation(s)
| | - Marc Ferrante
- Department of Gastroenterology and Hepatology, Universitaire Ziekenhuizen Leuven, Katholieke Universiteit Leuven, Leuven, Belgium
| | | | - Elina Berliba
- Nicolae Testemitanu State University of Medicine, Arsenia Exploratory Medicine, Chisinau, Moldova
| | - Brian G Feagan
- Western University, Robarts Clinical Trials Inc, London, Ontario, Canada
| | - Toshifumi Hibi
- Kitasato Institute Hospital Center for Advanced Inflammatory Bowel Disease Research and Treatment, Minato-ku, Tokyo, Japan
| | - Jay L Tuttle
- Eli Lilly and Company, Lilly Biotechnology Center, San Diego, California
| | - Paul Klekotka
- Eli Lilly and Company, Lilly Biotechnology Center, San Diego, California
| | | | | | | | - Janelle Laskowski
- Eli Lilly and Company, Lilly Biotechnology Center, San Diego, California
| | | | - Geert R D'Haens
- Amsterdam University Medical Centers, Amsterdam, The Netherlands
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Singh S, Dulai PS, Casteele NV, Battat R, Fumery M, Boland BS, Sandborn WJ. Systematic review with meta-analysis: association between vedolizumab trough concentration and clinical outcomes in patients with inflammatory bowel diseases. Aliment Pharmacol Ther 2019; 50:848-857. [PMID: 31483522 PMCID: PMC7083298 DOI: 10.1111/apt.15484] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2019] [Revised: 05/12/2019] [Accepted: 08/09/2019] [Indexed: 12/20/2022]
Abstract
BACKGROUND There has been limited evaluation of the association between vedolizumab trough concentration and clinical outcomes in patients with inflammatory bowel diseases (IBD). AIM To perform a systematic review and meta-analysis to evaluate the potential role of therapeutic drug monitoring (TDM) for vedolizumab. METHODS Through a systematic literature search through 28 February 2019, we identified five cohort studies (558 patients, 42% with ulcerative colitis) reporting the association between vedolizumab trough concentration and clinical outcomes in patients with IBD. We calculated mean difference (MD) in vedolizumab trough concentration in patients achieving vs not achieving clinical outcomes, and qualitatively synthesized thresholds associated with favourable outcomes. RESULTS In patients with UC, median vedolizumab trough concentrations were consistently higher in patients achieving clinical remission (median, 14.3 μg/mL vs 10.5 μg/mL; MD, 5.1 μg/mL, 95% CI, 2.8-7.4) or endoscopic remission (median, 13.0 μg/mL vs 9.7; MD, 5.1 μg/mL, 95% CI, 2.2-7.9). In patients with CD, there was no significant difference in median vedolizumab trough concentrations in patients achieving vs not achieving clinical remission (MD, 2.0 μg/mL; 95% CI, -0.5 to 4.5) or endoscopic remission (MD, 3.6 μg/mL; 95% CI, -1.4 to 8.6). In patients with UC, week 6 vedolizumab trough concentrations ≥18.5-20.8 μg/mL, and maintenance trough concentrations ≥9.0-12.6 μg/mL were associated with favourable clinical outcomes. Antibodies to vedolizumab were reported in 1.7%-3.0% patients on maintenance therapy. CONCLUSION Based on meta-analysis, patients with UC who achieve endoscopic and clinical remission have significantly higher vedolizumab trough concentration during maintenance therapy. Vedolizumab trough concentration >20 μg/mL at week 6, and >12 μg/mL during maintenance may be associated with better outcomes, though cause-effect relationship remains unclear. Prospective studies on reactive and proactive therapeutic drug monitoring of vedolizumab (vs empiric dose escalation) are warranted.
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Affiliation(s)
- Siddharth Singh
- Division of Gastroenterology, University of California San Diego, La Jolla, California;,Division of Biomedical Informatics, University of California San Diego, La Jolla, California
| | - Parambir S. Dulai
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Niels Vande Casteele
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Robert Battat
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Mathurin Fumery
- Gastroenterology Unit, Amiens University and Hospital, Université de Picardie Jules Verne, Amiens, France
| | - Brigid S. Boland
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - William J. Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California
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Dulai PS, Peyrin-Biroulet L, Danese S, Sands BE, Dignass A, Turner D, Mantzaris G, Schölmerich J, Mary JY, Reinisch W, Sandborn WJ. Approaches to Integrating Biomarkers Into Clinical Trials and Care Pathways as Targets for the Treatment of Inflammatory Bowel Diseases. Gastroenterology 2019; 157:1032-1043.e1. [PMID: 31228441 DOI: 10.1053/j.gastro.2019.06.018] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Revised: 06/06/2019] [Accepted: 06/13/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There is no consensus on the best way to integrate biomarkers into inflammatory bowel disease (IBD) research and clinical practice. The International Organization for the Study of Inflammatory Bowel Disease aimed to outline biomarker definitions, categories, and operating properties required for their use in registration trials and clinical practice. Using fecal calprotectin as an example, we provide a framework for biomarker development and validation in patients with IBD. METHODS We reviewed international society guidelines, regulatory agency guidance documents, and standardized reporting guidelines for biomarkers, in combination with publications on fecal calprotectin levels in patients with IBD. We assessed the validity of fecal calprotectin to serve as a surrogate biomarker of IBD activity and outlined a framework for further validation and development of biomarkers. RESULTS No endpoints have been fully validated as surrogates of risk of disease complications; mucosal healing is the most valid endpoint used to determine risk of disease complications. Fecal level of calprotectin has not been validated as a biomarker for IBD activity because of lack of technical and clinical reliability, assessment of performance when used as a replacement for endoscopy, and assessment of responsiveness to changes in disease states. The level of fecal calprotectin can be used only as a prognostic factor for disease recurrence in patients in remission after medical or surgical treatment. CONCLUSIONS We reviewed guidelines, regulatory documents, and publications to identify properties required for the development of biomarkers of IBD activity and areas in need of clarification from regulatory agencies and societies. We propose a path forward for research of biomarkers for IBD.
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Affiliation(s)
- Parambir S Dulai
- Division of Gastroenterology, University of California San Diego, La Jolla, California.
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Lorraine University, Nancy, France
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Humanitas Clinical and Research Centre, Milan, Italy
| | - Bruce E Sands
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Axel Dignass
- Department of Medicine I, Agaplesion Markus Hospital and Crohn Colitis Clinical Research Center Rhein-Main, Frankfurt/Main, Germany
| | - Dan Turner
- Institute of Paediatric Gastroenterology, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Gerassimos Mantzaris
- Department of Gastroenterology, Evaggelismos-Ophthalmiatreion Athinon-Polycliniki, Athens, Greece
| | | | - Jean-Yves Mary
- INSERM UMR, Paris Diderot University, Saint Louis Hospital, Paris, France
| | | | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California
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Sneller MC, Clarridge KE, Seamon C, Shi V, Zorawski MD, Justement JS, Blazkova J, Huiting ED, Proschan MA, Mora JR, Shetzline M, Moir S, Lane HC, Chun TW, Fauci AS. An open-label phase 1 clinical trial of the anti-α 4β 7 monoclonal antibody vedolizumab in HIV-infected individuals. Sci Transl Med 2019; 11:scitranslmed.aax3447. [PMID: 31488581 DOI: 10.1126/scitranslmed.aax3447] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Accepted: 08/09/2019] [Indexed: 12/17/2022]
Abstract
Despite the substantial clinical benefits of antiretroviral therapy (ART), complete eradication of HIV has not been possible. The gastrointestinal tract and associated lymphoid tissues may play an important role in the pathogenesis of HIV infection. The integrin α4β7 facilitates homing of T lymphocytes to the gut by binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on venules in gut-associated lymphoid tissue. CD4+ T cells with increased expression of α4β7 are susceptible to HIV infection and may be key players in subsequent virus dissemination. Data from nonhuman primate models infected with simian immunodeficiency virus (SIV) have suggested that blockade of the α4β7/MAdCAM-1 interaction may be effective at preventing SIV infection and may have beneficial effects in animals with established viral infection. To explore whether these findings could be reproduced in HIV-infected individuals after interruption of ART, we conducted an open-label phase 1 clinical trial of vedolizumab, a monoclonal antibody against α4β7 integrin. Vedolizumab infusions in 20 HIV-infected individuals were well tolerated with no serious adverse events related to the study drug. After interruption of ART, the median time to meeting protocol criteria to restart therapy was 13 weeks. The median duration of plasma viremia of <400 copies/ml was 5.4 weeks. Only a single subject in the trial experienced prolonged suppression of plasma viremia after interruption of ART. These results suggest that blockade of α4β7 may not be an effective strategy for inducing virological remission in HIV-infected individuals after ART interruption.
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Affiliation(s)
- Michael C Sneller
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Katherine E Clarridge
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Catherine Seamon
- Critical Care Medicine Department, Clinical Center, NIH, Bethesda, MD 20892, USA
| | - Victoria Shi
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Marek D Zorawski
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Jesse Shawn Justement
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Jana Blazkova
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Erin D Huiting
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | | | | | | | - Susan Moir
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Henry Clifford Lane
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Tae-Wook Chun
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
| | - Anthony S Fauci
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA
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Jairath V, Peyrin-Biroulet L, Zou G, Mosli M, Vande Casteele N, Pai RK, Valasek MA, Marchal-Bressenot A, Stitt LW, Shackelton LM, Khanna R, D'Haens GR, Sandborn WJ, Olson A, Feagan BG, Pai RK. Responsiveness of histological disease activity indices in ulcerative colitis: a post hoc analysis using data from the TOUCHSTONE randomised controlled trial. Gut 2019; 68:1162-1168. [PMID: 30076171 DOI: 10.1136/gutjnl-2018-316702] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 07/02/2018] [Accepted: 07/18/2018] [Indexed: 12/13/2022]
Abstract
OBJECTIVE We evaluated the reliability and responsiveness of available but incompletely validated UC histological disease activity indices using standardised rules for centralised assessment. DESIGN Disease activity was assessed in biopsies collected in a phase II placebo-controlled ozanimod trial by four blinded pathologists using the Geboes (GS) and modified Riley (MRS) scores, the Robarts Histopathology (RHI) and Nancy Histological (NHI) indices and a Visual Analogue Scale. Reliability was assessed with intraclass correlation coefficients (ICCs). Index responsiveness was evaluated by assessing longitudinal validity (Pearson correlations of changes in index scores and other disease measures), and effect size estimates (standardised effect size (SES)) using two criteria for change (treatment assignment and >2 point decrease in total Mayo Clinic score). Area under the receiver operating characteristic (AUROC) curve estimates evaluated the probability of the indices to discriminate between treatment and placebo. RESULTS Inter-rater reliability of the histological indices was substantial to almost perfect (ICC>0.61), and responsiveness was moderate to large (SES estimates>0.5); 0.81 (0.52, 1.10), 0.87 (0.58, 1.17), 0.57 (0.30, 0.84) and 0.81 (0.52, 1.09) when treatment assignment was the criterion for change and 1.05 (0.80, 1.31), 1.13 (0.87, 1.39), 0.88 (0.64, 1.12) and 1.06 (0.80, 1.31) for the change in Mayo score criterion for the GS, MRS, RHI and NHI, respectively. The indices had similar drisciminative ability based on AUROC estimates (range 0.608-0.649). CONCLUSION All four existing histological indices were similarly reliable and responsive based on this dataset.
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Affiliation(s)
- Vipul Jairath
- Robarts Clinical Trials Inc., London, Ontario, Canada
| | | | - Guangyong Zou
- Robarts Clinical Trials Inc., London, Ontario, Canada
| | - Mahmoud Mosli
- Department of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | | | - Reetesh K Pai
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Mark A Valasek
- Department of Pathology, University of California, San Diego, La Jolla, California, USA
| | | | - Larry W Stitt
- Robarts Clinical Trials Inc., London, Ontario, Canada
| | | | - Reena Khanna
- Robarts Clinical Trials Inc., London, Ontario, Canada
| | | | | | | | | | - Rish K Pai
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, Arizona, USA
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Battat R, Dulai PS, Jairath V, Vande Casteele N. A product review of vedolizumab in inflammatory bowel disease. Hum Vaccin Immunother 2019; 15:2482-2490. [PMID: 30897022 DOI: 10.1080/21645515.2019.1591139] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Vedolizumab is a monoclonal antibody to the α4β7 integrin that selectively reduces intestinal lymphocyte trafficking, thereby providing a safe and effective treatment option for patients with inflammatory bowel disease (IBD). This product review outlines the unique mechanism of vedolizumab in addition to efficacy, safety, pharmacokinetic and pharmacodynamic data from clinical trials, observational studies and meta-analyses. Vedolizumab has been shown to be effective as a first- or second-line induction and maintenance therapy in both ulcerative colitis (UC) and Crohn's disease (CD). Prolonged induction therapy may increase efficacy, particularly in tumor necrosis factor-alpha-exposed CD patients. To date, no drug-specific safety signals have been identified. In addition to the presence of an apparent exposure-response relationship, vedolizumab has demonstrated consistent pharmacodynamic effects on α4β7, mucosal vascular addressin cell adhesion molecule 1 and other cell adhesion molecules. Future efforts should focus on identifying predictive biomarkers capable of guiding personalized IBD treatment with vedolizumab.
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Affiliation(s)
- Robert Battat
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, University of California San Diego , La Jolla , CA , USA.,Robarts Clinical Trials Inc ., London , ON , Canada
| | - Parambir S Dulai
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, University of California San Diego , La Jolla , CA , USA.,Robarts Clinical Trials Inc ., London , ON , Canada
| | - Vipul Jairath
- Robarts Clinical Trials Inc ., London , ON , Canada.,Department of Medicine, University of Western Ontario , London , ON , Canada.,Department of Epidemiology and Biostatistics, University of Western Ontario , London , ON , Canada
| | - Niels Vande Casteele
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, University of California San Diego , La Jolla , CA , USA.,Robarts Clinical Trials Inc ., London , ON , Canada
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Fløisand Y, Lazarevic VL, Maertens J, Mattsson J, Shah NN, Zachée P, Taylor A, Akbari M, Quadri S, Parfionovas A, Chen YB. Safety and Effectiveness of Vedolizumab in Patients with Steroid-Refractory Gastrointestinal Acute Graft-versus-Host Disease: A Retrospective Record Review. Biol Blood Marrow Transplant 2019; 25:720-727. [PMID: 30468919 DOI: 10.1016/j.bbmt.2018.11.013] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 11/13/2018] [Indexed: 01/01/2023]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative in patients with hematologic malignancies but carries a significant risk of graft-versus-host disease (GVHD). There are no standard treatments for steroid-refractory (SR) gastrointestinal (GI) acute GVHD (aGVHD). This multicenter, international, retrospective medical record review aimed to evaluate the off-label use of vedolizumab, a gut-selective immunomodulator, for treating SR GI aGVHD. Data were collected from patients' medical records; criteria for extraction included no more than 1 allo-HCT and at least 1 dose of vedolizumab as treatment for SR GI aGVHD (ie, stage 1 to 4 GI aGVHD following ≥1 previous treatment regimen(s) containing ≥1 mg/kg methylprednisolone or equivalent). Descriptive analyses of response rate, overall survival (OS), and serious adverse effects (SAEs) were performed. Twenty-nine patients were identified from 7 sites who had received 1 to 10 doses of vedolizumab 300 mg i.v. (median 3 doses) as treatment for SR GI aGVHD. The overall response rate at 6 to 10 weeks after vedolizumab initiation was 64%, and OS at 6 months was 54%. There were 29 SAEs, including 12 infections; 3 SAEs were considered possibly related to vedolizumab, 2 of which were infections. Thirteen SAEs were fatal, 1 of which was possibly vedolizumab-related. There were 8 nonserious infections and 1 serious infection with confirmed GI origin in 8 patients; there was no apparent pattern in the timing of these infections relative to the initiation of vedolizumab treatment. Further data on the efficacy and safety of vedolizumab in this setting from prospective trials are needed.
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Affiliation(s)
- Yngvar Fløisand
- Department of Hematology, Oslo University Hospital, Oslo, Norway.
| | - Vladimir Lj Lazarevic
- Department of Hematology, Oncology and Radiation Physics, Skåne University Hospital, Lund University, Lund, Sweden
| | - Johan Maertens
- Department of Hematology, University Hospitals Leuven, Leuven, Belgium
| | - Jonas Mattsson
- Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden
| | - Nirav N Shah
- Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Pierre Zachée
- Hematology Service, ZNA Stuivenberg, Antwerp, Belgium
| | - Aliki Taylor
- Takeda Development Centre Europe Ltd, London, UK
| | - Mona Akbari
- Takeda Pharmaceuticals International Co., Cambridge, Massachusetts
| | - Syed Quadri
- Takeda Pharmaceuticals International Co., Cambridge, Massachusetts
| | | | - Yi-Bin Chen
- Blood and Marrow Transplant Program, Massachusetts General Hospital, Boston, Massachusetts
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Ling L, Wu T, To KKW, Cheung KW, Lui KOL, Niu M, Lam KS, Wang CC, Li J, Wang H, Yuen KY, Chen Z. Vedolizumab-mediated integrin α4β7 blockade does not control HIV-1SF162 rebound after combination antiretroviral therapy interruption in humanized mice. AIDS 2019; 33:F1-F12. [PMID: 30829743 DOI: 10.1097/qad.0000000000002149] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
OBJECTIVE The combined combination antiretroviral therapy (cART) and anti-α4β7 RM-Act-1 antibody therapy allows macaques to durably control simian immunodeficiency virus (SIV) rebound after withdrawal of the interventions. Here, we aimed to investigate whether vedolizumab (VDZ), a clinical-grade humanized anti-α4β7 antibody, would have similar effects in controlling live HIV-1 infection in humanized mice. DESIGN AND METHODS The integrin α4β7 blockade by VDZ was evaluated on human primary memory CD4+ T (MEMT) cells and retinoic acid-induced gut-homing α4β7+MEMT cells (α4β7+MEMT) in vitro. The antiretroviral activity of VDZ was determined using pseudotyped R5-tropic HIV-1SF162, which displays binding activity to α4β7. The preventive and immunotherapeutic efficacies of VDZ were further investigated in humanized mice using the live HIV-1SF162 strain compared with RM-Act-1. RESULTS VDZ effectively and dose-dependently blocked the binding of mucosal vascular addressin cell adhesion molecule-1 (MAdCAM-1), the native ligand of α4β7, to α4β7+MEMT cells. HIV-1SF162 not only displayed binding capacity to α4β7-expressing cells, but also showed an increased infectivity in retinoic acid-induced α4β7+MEMT cells pretreated with VDZ. Moreover, VDZ failed to prevent live HIV-1SF162 infection and did not reduce the peak viral load when administrated prior to viral challenge in humanized mice. Lastly, in immunotherapeutic settings, the withdrawal of combined cART with either VDZ or RM-Act-1 resulted in an uncontrolled HIV-1SF162 rebound in humanized mice, whereas the α4β7 molecules remained significantly blocked on circulating CD4+ T cells. CONCLUSION VDZ neither prevents nor controls HIV-1SF162 infection both in vitro and in humanized mice. Our findings have significant implications to the clinical application of VDZ in HIV-1 preventive and immunotherapeutic interventions.
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Affiliation(s)
- Lijun Ling
- AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region
- HKU-AIDS Institute Shenzhen Research Laboratory, Guangdong Key Laboratory of Emerging Infectious Diseases and Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Shenzhen
| | - Tongjin Wu
- AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region
| | - Kelvin Kai Wang To
- AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region
| | - Ka-Wai Cheung
- AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region
| | - Kathy Oi Lan Lui
- Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Mengyue Niu
- AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region
| | - Ka Shing Lam
- AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region
| | - Chi Chi Wang
- Department of Obstetrics and Gynaecology, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China
| | - Jiatao Li
- Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong Special Administrative Region
| | - Hui Wang
- HKU-AIDS Institute Shenzhen Research Laboratory, Guangdong Key Laboratory of Emerging Infectious Diseases and Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Shenzhen
| | - Kwok-Yung Yuen
- AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region
| | - Zhiwei Chen
- AIDS Institute and Department of Microbiology, State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region
- HKU-AIDS Institute Shenzhen Research Laboratory, Guangdong Key Laboratory of Emerging Infectious Diseases and Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Shenzhen
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Battat R, Ma C, Jairath V, Khanna R, Feagan BG. Benefit–Risk Assessment of Vedolizumab in the Treatment of Crohn’s Disease and Ulcerative Colitis. Drug Saf 2019; 42:617-632. [DOI: 10.1007/s40264-018-00783-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Battat R, Dulai PS, Vande Casteele N, Evans E, Hester KD, Webster E, Jain A, Proudfoot JA, Mairalles A, Neill J, Singh S, Chang JT, Rivera-Nieves J, Sandborn WJ, Boland BS. Biomarkers Are Associated With Clinical and Endoscopic Outcomes With Vedolizumab Treatment in Ulcerative Colitis. Inflamm Bowel Dis 2019; 25:410-420. [PMID: 30295781 PMCID: PMC6327228 DOI: 10.1093/ibd/izy307] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Indexed: 02/07/2023]
Abstract
Background Vedolizumab inhibits α4β7-mediated lymphocyte trafficking and is effective in ulcerative colitis (UC). This study evaluated drug and biomarker concentrations and patient outcomes during vedolizumab treatment in UC. Methods Prospectively scored maintenance clinical (26.5 weeks; interquartile range [IQR], 16.3-37.0 weeks) and endoscopic (23.5 weeks; IQR, 16.8-35.6 weeks) outcomes were compared with serum vedolizumab concentrations, antivedolizumab antibodies, and serum biomarkers at baseline and weeks 2, 6, 14, and 26. A linear mixed-effects model compared biomarker trajectories over time between clinical and endoscopic remitters and nonremitters. Results Thirty-two patients were included. Soluble (s)-tumor necrosis factor (TNF)-α, s-α4β7, s-mucosal addressin cell adhesion molecule (s-MAdCAM-1), and s-amyloid A (s-AA) significantly changed with treatment. A linear mixed-effects model demonstrated that s-α4β7 (P = 0.044) increased and s-MAdCAM-1 (P = 0.006) and s-vascular cell adhesion molecule-1 (s-VCAM-1, P = 0.001) decreased more rapidly in patients achieving clinical remission in maintenance. S-MAdCAM-1 (P = 0.005), s-intracellular adhesion molecule-1 (ICAM-1; P = 0.014), s-VCAM-1 (P < 0.001), and s-TNF (P = 0.052) decreased more rapidly in endoscopic remitters. In clinical remitters, higher week 14 (20.3 ng/mL vs 6.0 ng/mL; P = 0.013) and week 26 (14.1 ng/mL vs 8.6 ng/mL; P = 0.05) s-α4β7 were observed. In endoscopic remitters, week 2 (6.7 pg/mL vs 17.8 pg/mL; P = 0.038) and week 6 (3.9 pg/mL vs 15.6 pg/mL; P = 0.005) s-TNF and week 14 s-VCAM (589.1 ng/mL vs 746.0 ng/mL; P = 0.05) were lower. Conclusion Serum biomarkers were associated with outcomes in vedolizumab-treated UC patients. s-α4β7 increased, whereas s-MAdCAM-1, s-VCAM-1, s-ICAM-1, and s-TNF decreased more rapidly in remitters. At individual time points, induction s-TNF and maintenance s-VCAM-1 concentrations were lower, whereas maintenance s-α4β7 concentrations were higher in remitters.
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Affiliation(s)
- Robert Battat
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Parambir S Dulai
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Niels Vande Casteele
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Elisabeth Evans
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | | | | | - Anjali Jain
- Prometheus Laboratories Inc., San Diego, California
| | - James A Proudfoot
- Clinical and Translational Research Institute, University of California, San Diego, La Jolla, California
| | - Ara Mairalles
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Jennifer Neill
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Siddharth Singh
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - John T Chang
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Jesus Rivera-Nieves
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - William J Sandborn
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
| | - Brigid S Boland
- Division of Gastroenterology, Department of Medicine, Inflammatory Bowel Disease Center, University of California, San Diego, La Jolla, California
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Hemperly A, Sandborn WJ, Vande Casteele N. Clinical Pharmacology in Adult and Pediatric Inflammatory Bowel Disease. Inflamm Bowel Dis 2018; 24:2527-2542. [PMID: 29788338 PMCID: PMC11187819 DOI: 10.1093/ibd/izy189] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Indexed: 12/14/2022]
Abstract
This review describes the clinical pharmacology of the major drugs used for the treatment of patients with inflammatory bowel disease (IBD). Pharmacokinetics, drug metabolism, mechanism of action, efficacy, and safety profile are discussed. Some small molecules were developed to act systemically (eg, ozanimod) or locally (eg, aminosalicylates) and thus have disparate pharmacokinetic properties. In addition, locally acting compounds have been optimized to mitigate systemic exposure-eg, budesonide, which undergoes extensive first-pass metabolism-thereby reducing systemic bioavailability and side effects. Other small molecules such as thiopurines are precursors of their active metabolites and differences in genotype or phenotype of metabolizing enzymes may affect efficacy and safety, requiring therapeutic drug monitoring (TDM). Monoclonal antibodies (MAs) are large molecules administered parenterally, and their pharmacokinetics may be influenced not only by the general immunoglobulin (Ig) G metabolism and recycling pathways but also by antigen properties such as antigen distribution and antigen concentration. In addition, antibody structure, host factors, concurrent medications, and immunogenicity may contribute to the substantial inter- and intrapatient variability in drug exposure and response observed for MAs. Current guidelines recommend reactive TDM of tumor necrosis factor antagonists at the time of loss of response. Evidence for proactive TDM and for the role of TDM for biologics with a different mechanism of action is emerging. Although small molecules offer potential benefits over biologics with oral administration and lack of immunogenicity, there may be risk for more systemic side effects due to off-target binding. Understanding drug metabolism, pharmacokinetic characteristics, and mechanism of action are important in selecting the right drug at the right time at the right dose for patients with IBD.10.1093/ibd/izy189_video1izy189.video15786062223001.
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Affiliation(s)
- Amy Hemperly
- Department of Pediatric Gastroenterology, La Jolla, California
| | - William J Sandborn
- Department of Medicine, Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Niels Vande Casteele
- Department of Pediatric Gastroenterology, La Jolla, California
- Department of Medicine, Division of Gastroenterology, University of California San Diego, La Jolla, California
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48
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Parikh A, Stephens K, Major E, Fox I, Milch C, Sankoh S, Lev MH, Provenzale JM, Shick J, Patti M, McAuliffe M, Berger JR, Clifford DB. A Programme for Risk Assessment and Minimisation of Progressive Multifocal Leukoencephalopathy Developed for Vedolizumab Clinical Trials. Drug Saf 2018; 41:807-816. [PMID: 29737503 PMCID: PMC6061428 DOI: 10.1007/s40264-018-0669-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Introduction Over the past decade, the potential for drug-associated progressive multifocal leukoencephalopathy (PML) has become an increasingly important consideration in certain drug development programmes, particularly those of immunomodulatory biologics. Whether the risk of PML with an investigational agent is proven (e.g. extrapolated from relevant experience, such as a class effect) or merely theoretical, the serious consequences of acquiring PML require careful risk minimisation and assessment. No single standard for such risk minimisation exists. Vedolizumab is a recently developed monoclonal antibody to α4β7 integrin. Its clinical development necessitated a dedicated PML risk minimisation assessment as part of a global preapproval regulatory requirement. Objective The aim of this study was to describe the multiple risk minimisation elements that were incorporated in vedolizumab clinical trials in inflammatory bowel disease patients as part of the risk assessment and minimisation of PML programme for vedolizumab. Methods A case evaluation algorithm was developed for sequential screening and diagnostic evaluation of subjects who met criteria that indicated a clinical suspicion of PML. An Independent Adjudication Committee provided an independent, unbiased opinion regarding the likelihood of PML. Results Although no cases were detected, all suspected PML events were thoroughly reviewed and successfully adjudicated, making it unlikely that cases were missed. Conclusion We suggest that this programme could serve as a model for pragmatic screening for PML during the clinical development of new drugs. Electronic supplementary material The online version of this article (10.1007/s40264-018-0669-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Asit Parikh
- Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, MA, 02139, USA.
| | - Kristin Stephens
- Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, MA, 02139, USA.,Syros Pharmaceuticals, Cambridge, MA, USA
| | - Eugene Major
- National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA
| | - Irving Fox
- Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, MA, 02139, USA
| | - Catherine Milch
- Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, MA, 02139, USA.,Eli Lilly and Company, Indianapolis, IN, USA
| | - Serap Sankoh
- Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, MA, 02139, USA.,Syndax Pharmaceuticals, Waltham, MA, USA
| | | | | | - Jesse Shick
- Takeda Pharmaceuticals International, Inc, Deerfield, IL, USA.,Gilead Sciences, Foster City, CA, USA
| | - Mark Patti
- Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, MA, 02139, USA
| | - Megan McAuliffe
- Takeda Pharmaceuticals International Co., 40 Landsdowne Street, Cambridge, MA, 02139, USA.,Biogen, Cambridge, MA, USA
| | - Joseph R Berger
- University of Kentucky, Lexington, KY, USA.,University of Pennsylvania, Philadelphia, PA, USA
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Becker E, Schramm S, Binder MT, Allner C, Wiendl M, Neufert C, Atreya I, Neurath M, Zundler S. Dynamic Adhesion Assay for the Functional Analysis of Anti-adhesion Therapies in Inflammatory Bowel Disease. J Vis Exp 2018. [PMID: 30295649 DOI: 10.3791/58210] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Gut homing of immune cells is important for the pathogenesis of inflammatory bowel diseases (IBD). Integrin-dependent cell adhesion to addressins is a crucial step in this process and therapeutic strategies interfering with adhesion have been successfully established. The anti-α4β7 integrin antibody, vedolizumab, is used for the clinical treatment of Crohn's disease (CD) and ulcerative colitis (UC) and further compounds are likely to follow. The details of the adhesion procedure and the action mechanisms of anti-integrin antibodies are still unclear in many regards due to the limited available techniques for the functional research in this field. Here, we present a dynamic adhesion assay for the functional analysis of human cell adhesion under flow conditions and the impact of anti-integrin therapies in the context of IBD. It is based on the perfusion of primary human cells through addressin-coated ultrathin glass capillaries with real-time microscopic analysis. The assay offers a variety of opportunities for refinements and modifications and holds potentials for mechanistic discoveries and translational applications.
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Affiliation(s)
- Emily Becker
- Department of Medicine 1, University of Erlangen-Nuremberg
| | | | | | | | | | | | - Imke Atreya
- Department of Medicine 1, University of Erlangen-Nuremberg
| | - Markus Neurath
- Department of Medicine 1, University of Erlangen-Nuremberg
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50
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Restellini S, Khanna R, Afif W. Therapeutic Drug Monitoring With Ustekinumab and Vedolizumab in Inflammatory Bowel Disease. Inflamm Bowel Dis 2018; 24:2165-2172. [PMID: 29788272 DOI: 10.1093/ibd/izy134] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Indexed: 12/12/2022]
Abstract
In patients with Crohn's disease (CD) and ulcerative colitis (UC), the use of therapeutic drug monitoring (TDM) with TNF-α antagonists has led to a personalized approach to optimize treatment and has been shown to be cost-effective. The utility of this TDM-based personalized approach for novel biologic agents, which target different inflammatory pathways, is unclear. Commercial assays for ustekinumab (UST) and vedolizumab (VDZ) are available, but there is little available guidance for clinicians regarding the use of TDM with these drugs. Although there is limited evidence for definitive threshold concentrations for UST and VDZ, this review highlights the available literature on the pharmacokinetics of these medications, the association of clinical and endoscopic outcomes with drug concentrations, and the clinical utility of TDM to guide treatment decisions.
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Affiliation(s)
- Sophie Restellini
- Division of Gastroenterology, McGill University Health Centre, Montreal, Quebec, Canada.,Division of Gastroenterology and Hepatology, Geneva's University Hospitals and University of Geneva, Switzerland
| | - Reena Khanna
- Department of Medicine, Division of Gastroenterology, University of Western Ontario, London, Ontario, Canada
| | - Waqqas Afif
- Division of Gastroenterology, McGill University Health Centre, Montreal, Quebec, Canada
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