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Kim KO, Lee SH. [Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti Integrins]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2024; 84:43-50. [PMID: 39176460 DOI: 10.4166/kjg.2024.070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/04/2024] [Accepted: 08/12/2024] [Indexed: 08/24/2024]
Abstract
Recently, novel biologics or small molecular drugs have been introduced for overcoming the unmet needs associated with anti-tumor necrosis factor α agents for inflammtory bowel disease (IBD) treatment. Among these novel drugs, anti integrin agents block leukocyte trafficking to the intestine by blocking the interaction between integrin and cell adhesion molecules. Vedolizumab (anti-α4β7) is most widely used anti-integrin approved in both ulcerative colitis and Crohn's disease .It has been shown to be effective in both induction and maintenance therapy with a favorable safety profile due to gut selectivity. Several models incorporating clinical, genetic, immune and gut microbial markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).
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Affiliation(s)
- Kyeong Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Si Hyung Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
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AlAmeel T, AlMutairdi A, Al-Bawardy B. Emerging Therapies for Ulcerative Colitis: Updates from Recent Clinical Trials. Clin Exp Gastroenterol 2023; 16:147-167. [PMID: 37609124 PMCID: PMC10441644 DOI: 10.2147/ceg.s375969] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 08/03/2023] [Indexed: 08/24/2023] Open
Abstract
Ulcerative colitis (UC) is a chronic and progressive inflammatory disorder that affects the colon. The advent of advanced therapies such as biologic agents and small molecules has revolutionized the management of UC. Despite the expanding therapeutic armamentarium of advanced therapies to treat UC, the overall net remission rates and durability of currently available agents are relatively low. This highlights the need for further drug development and more innovative clinical trial design. There are currently multiple emerging agents in the pipeline for the management of UC. This includes agents with alternative routes of administration such as oral or subcutaneous tumor necrosis factor inhibitors or novel mechanisms of action such as toll-like receptor 9 (TLR9) agonist cobitolimod and phosphodiesterase 4 inhibitor apremilast. In this review, we will highlight novel and emerging advanced therapies currently in the pipeline for the management of UC.
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Affiliation(s)
- Turki AlAmeel
- Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Abdulelah AlMutairdi
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Badr Al-Bawardy
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
- Department of Internal Medicine, Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
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Yamamoto-Furusho JK, Parra-Holguín NN. Emerging therapeutic options in inflammatory bowel disease. World J Gastroenterol 2021; 27:8242-8261. [PMID: 35068868 PMCID: PMC8717021 DOI: 10.3748/wjg.v27.i48.8242] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/04/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic disease that requires chronic treatment throughout the evolution of the disease, with a complex physiopathology that entails great challenges for the development of new and specific treatments for ulcerative colitis and Crohn´s disease. The anti-tumor necrosis factor alpha therapy has impacted the clinical course of IBD in those patients who do not respond to conventional treatment, so there is a need to develop new therapies and markers of treatment response. Various pathways involved in the development of the disease are known and the new therapies have focused on blocking the inflammatory process at the gastrointestinal level by oral, intravenous, subcutaneous, and topical route. All these new therapies can lead to more personalized treatments with higher success rates and fewer relapses. These treatments have not only focused on clinical remission, but also on achieving macroscopic changes at the endoscopic level and microscopic changes by achieving mucosal healing. These treatments are mainly based on modifying signaling pathways, by blocking receptors or ligands, reducing cell migration and maintaining the integrity of the epithelial barrier. Therefore, this review presents the efficacy and safety of the new treatments that are currently under study and the advances that have been made in this area in recent years.
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Affiliation(s)
- Jesus K Yamamoto-Furusho
- Gastroenterology Unit, Inflammatory Bowel Disease Clinic, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City 14080, Mexico
| | - Norma N Parra-Holguín
- Gastroenterology Unit, Inflammatory Bowel Disease Clinic, Instituto Nacional de Ciencias Medicas y Nutricion, Mexico City 14080, Mexico
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Solitano V, Parigi TL, Ragaini E, Danese S. Anti-integrin drugs in clinical trials for inflammatory bowel disease (IBD): insights into promising agents. Expert Opin Investig Drugs 2021; 30:1037-1046. [PMID: 34449288 DOI: 10.1080/13543784.2021.1974396] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Despite huge and increasing developments in the treatment of inflammatory bowel disease (IBD), a significant percentage of patients with Crohn's disease (CD) and ulcerative colitis (UC) is still in need of an effective and safe therapeutic option. Tackling the trafficking of leukocytes specifically within or directed to the inflamed gut appears to be a particularly promising strategy, and several new anti-integrin agents are currently under investigation in clinical trials. AREAS COVERED This review summarizes efficacy and safety data from phase 1, 2 and 3 clinical trials on investigational drugs, including monoclonal antibodies (etrolizumab, abrilumab, ontamalimab) and oral small molecules (AJM300, PTG-100). It also discusses the future perspectives for the treatment of IBD patients with this class of agents. EXPERT OPINION The pipeline of anti-integrin agents is well assorted, and it is reasonable to expect that some will be introduced in the market soon. Among the most exciting features of this class are the gut selectivity, the convenient subcutaneous and oral administrations and the reassuring safety profiles. Most of the new anti-integrins seem to improve outcomes in UC but not in CD, however these data are far from definitive and several pivotal trials are still under way.
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Affiliation(s)
- Virginia Solitano
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Tommaso Lorenzo Parigi
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK
| | - Elisa Ragaini
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,IBD Center, Humanitas Clinical and Research Center, Milan, Italy
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Gubatan J, Keyashian K, Rubin SJS, Wang J, Buckman CA, Sinha S. Anti-Integrins for the Treatment of Inflammatory Bowel Disease: Current Evidence and Perspectives. Clin Exp Gastroenterol 2021; 14:333-342. [PMID: 34466013 PMCID: PMC8402953 DOI: 10.2147/ceg.s293272] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Leukocyte trafficking to the gastrointestinal tract is recognized to play a role in the pathogenesis of inflammatory bowel disease (IBD). Integrins are expressed on immune cells and interact with cell adhesion molecules (CAM) to mediate leukocyte trafficking. Blockade of the gut-tropic integrin α4β7 and its subunits has been exploited as a therapeutic target in IBD. Natalizumab (anti-α4) is approved for moderate to severe Crohn's disease (CD), but its use is limited due to potential risk of progressive multifocal leukoencephalopathy. Vedolizumab (anti-α4β7) is approved for the treatment of ulcerative colitis (UC) and CD. It is the most widely used anti-integrin therapy in IBD and has been shown to be effective in both induction and maintenance therapy, with a favorable safety profile. Several models incorporating clinical, genetic, immune, gut microbial, and vitamin D markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. Large phase 3 clinical trials evaluating efficacy of etrolizumab in the induction and maintenance of patients with IBD are underway. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).
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Affiliation(s)
- John Gubatan
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Kian Keyashian
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Samuel J S Rubin
- Stanford University School of Medicine, Stanford, CA, USA
- Immunology Program, Stanford University School of Medicine, Stanford, CA, USA
| | - Jenny Wang
- Stanford University School of Medicine, Stanford, CA, USA
| | | | - Sidhartha Sinha
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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Yoon H. Subcutaneous integrin inhibitors may provide more treatment options for patients with moderate-to-severe ulcerative colitis. Intest Res 2019; 17:283-284. [PMID: 31352773 PMCID: PMC6667369 DOI: 10.5217/ir.2019.00070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 06/09/2019] [Indexed: 11/28/2022] Open
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Retnakumar SV, Muller S. Pharmacological Autophagy Regulators as Therapeutic Agents for Inflammatory Bowel Diseases. Trends Mol Med 2019; 25:516-537. [PMID: 30952481 DOI: 10.1016/j.molmed.2019.03.002] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 03/03/2019] [Accepted: 03/06/2019] [Indexed: 12/12/2022]
Abstract
The arsenal of effective molecules to treat patients with chronic inflammatory bowel diseases (IBDs) remains limited. These remitting-relapsing diseases have become a global health issue and new therapeutic strategies are eagerly awaited to regulate the course of these disorders. Since the association between autophagy-related gene polymorphism and an increased risk of Crohn's disease (CD) has been discovered, a new domain of investigation has emerged, focused on the intracellular degradation system, with the objective of generating new medicines that are safer and more targeted. This review summarizes the drugs administered to IBD patients and describes recently emerged therapeutic agents. We compile evidence on the contribution of autophagy to IBD pathogenesis, give an overview of pharmacological autophagy regulators in animal models of colitis, and propose novel therapeutic avenues based on autophagy components.
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Affiliation(s)
- Sruthi Vijaya Retnakumar
- CNRS-University of Strasbourg, Biotechnology and Cell signaling, Institut de Science et d'ingénierie Supramoléculaire, 67000 Strasbourg, France
| | - Sylviane Muller
- CNRS-University of Strasbourg, Biotechnology and Cell signaling, Institut de Science et d'ingénierie Supramoléculaire, 67000 Strasbourg, France; University of Strasbourg Institute for Advanced Study, 67000 Strasbourg, France.
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Sandborn WJ, Cyrille M, Hansen MB, Feagan BG, Loftus EV, Rogler G, Vermeire S, Cruz ML, Yang J, Boedigheimer MJ, Abuqayyas L, Evangelista CM, Sullivan BA, Reinisch W. Efficacy and Safety of Abrilumab in a Randomized, Placebo-Controlled Trial for Moderate-to-Severe Ulcerative Colitis. Gastroenterology 2019; 156:946-957.e18. [PMID: 30472236 DOI: 10.1053/j.gastro.2018.11.035] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 11/02/2018] [Accepted: 11/17/2018] [Indexed: 12/02/2022]
Abstract
BACKGROUND & AIMS The α4β7 integrin is a validated target in inflammatory bowel disease. This randomized, phase 2b, placebo-controlled, double-blind study evaluated the efficacy and safety of the anti-α4β7 antibody abrilumab in patients with moderate-to-severe ulcerative colitis despite treatment with conventional therapies. METHODS Patients (total Mayo Score 6-12, recto-sigmoidoscopy score ≥2) with inadequate response or intolerance to conventional therapies were randomized to receive subcutaneous abrilumab (7, 21, or 70 mg) on day 1, weeks 2 and 4, and every 4 weeks; abrilumab 210 mg on day 1; or placebo. The primary end point was remission (total Mayo Score ≤2 points, no individual sub-score >1 point) for the 2 highest dosages at week 8. Key secondary end points were response and mucosal healing (centrally read) at week 8. RESULTS For 354 patients who received ≥1 dose of investigational product (placebo, n = 116; 7 mg, n = 21; 21 mg, n = 40; 70 mg, n = 98; 210 mg, n = 79), non-adjusted remission rates at week 8 were 4.3%, 13.3%, and 12.7% for the placebo and abrilumab 70-mg and 210-mg groups, respectively (P < .05 for 70 and 210 mg vs placebo); odds of achieving remission were significantly greater with abrilumab 70 mg (odds ratio 3.35; 90% CI 1.41-7.95; P = .021) and 210 mg (odds ratio 3.33; 90% confidence interval 1.34-8.26; P = .030) than with placebo. Response and mucosal healing rates with these dosages also were significantly greater than with placebo. Higher baseline α4β7 levels on naïve CD4+ T cells were a prognostic indicator for overall outcome, but not a predictive biomarker of abrilumab response. There were no cases of progressive multifocal leukoencephalopathy or deaths. CONCLUSIONS Abrilumab treatment for 8 weeks induced remission, clinical response, and mucosal healing in patients with moderate-to-severe ulcerative colitis. ClinicalTrials.gov, number NCT01694485.
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Affiliation(s)
- William J Sandborn
- University of California San Diego and UC San Diego Health System, La Jolla, California.
| | | | | | - Brian G Feagan
- Robarts Clinical Trials, Western University, London, Ontario, Canada
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
| | | | | | - Jun Yang
- Amgen Inc, Thousand Oaks, California
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Li H, Huang SY, Shi FH, Gu ZC, Zhang SG, Wei JF. α 4β 7 integrin inhibitors: a patent review. Expert Opin Ther Pat 2018; 28:903-917. [PMID: 30444683 DOI: 10.1080/13543776.2018.1549227] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The α4β7 integrin is heterodimeric cell surface receptors expressed on most leukocytes. Mucosal addressing cell adhesion molecule 1(MAdCAM-1) is an exclusive ligand for α4β7 integrin. Areas covered: This article will highlight the progress that has been made in the discovery and development of α4β7 integrin inhibitors, and their use in the treatment of inflammatory bowel diseases, multiple sclerosis, asthma, hepatic disorders, human immunodeficiency virus, allergic conjunctivitis and type 1 diabetes. Expert opinion: α4β7 integrin inhibitors have attracted much interest for their clinical implication. Natalizumab and Vedolizumab are monoclonal antibodies (mAbs) successfully utilized clinically. Natalizumab is a mAbs of α4-subunit blocking both α4β1 and α4β7 integrin. Vedolizumab selectively targets the α4β7 integrin. Several mAbs are still in the process of research and development. Among these mAbs, etrolizumab selectively against the β7-subunit and AMG-181 specifically against the α4β7 integrin are the most promising anti-α4β7 integrin antibodies. Despite the unclear development stage of TR-14035 and R411, several low molecular compounds show bright future of further development, such as AJM300 and CDP323. In addition, results from laboratory data show that peptide inhibitors, such as peptide X, are effective α4β7 integrin inhibitors.
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Affiliation(s)
- Hao Li
- a Department of Pharmacy , Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Shi-Ying Huang
- a Department of Pharmacy , Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Fang-Hong Shi
- b Department of Pharmacy, Renji Hospital , School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Zhi-Chun Gu
- b Department of Pharmacy, Renji Hospital , School of Medicine, Shanghai Jiao Tong University , Shanghai , China
| | - Shun-Guo Zhang
- a Department of Pharmacy , Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Ji-Fu Wei
- c Research Division of Clinical Pharmacology , Τhe First Affiliated Hospital of Nanjing Medical University , Nanjing , China
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Abstract
Inflammatory bowel disease (IBD) is a chronic heterogeneous group of diseases that has undergone major advances in the understanding of its etiology and pathogenesis in recent years. The development of biologics had resulted in better overall management of the disease, including lower rates of surgery and better long-term clinical and patient-reported outcomes. Treatment modalities have either been newly developed or extrapolated from their approved use for a different indication. Modes of action and treatment targets have varied as well. Treatments such as vedolizumab and ustekinumab, as well as second-generation corticosteroids have been approved by the US Food and Drug Administration (FDA) for the treatment of IBD. Other agents are currently being developed at various stages of clinical trials including anti-adhesion agents such as etrolizumab and abrilumab, JAK inhibitors such as tofacitinib, and anti-trafficking molecules. Toll-like receptors and phosphatidylcholine are also new promising emerging targets that are being investigated in phase 3 clinical trials. It is projected that many therapies will become available in the coming years if supported by the results of current clinical trials. This will provide IBD patients with a wide array of options and allow physicians to choose the best therapies for each individual patient.
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Affiliation(s)
- Roni Weisshof
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Katia El Jurdi
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - Nada Zmeter
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA
| | - David T Rubin
- Inflammatory Bowel Disease Center, University of Chicago Medicine, Chicago, IL, USA.
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Lamb CA, O'Byrne S, Keir ME, Butcher EC. Gut-Selective Integrin-Targeted Therapies for Inflammatory Bowel Disease. J Crohns Colitis 2018; 12:S653-S668. [PMID: 29767705 DOI: 10.1093/ecco-jcc/jjy060] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Integrins are cell surface receptors with bidirectional signalling capabilities that can bind to adhesion molecules in order to mediate homing of leukocytes to peripheral tissues. Gut-selective leukocyte homing is facilitated by interactions between α4β7 and its ligand, mucosal addressin cellular adhesion molecule-1 [MAdCAM-1], while retention of lymphocytes in mucosal tissues is mediated by αEβ7 binding to its ligand E-cadherin. Therapies targeting gut-selective trafficking have shown efficacy in inflammatory bowel disease [IBD], confirming the importance of leukocyte trafficking in disease pathobiology. This review will provide an overview of integrin structure, function and signalling, and highlight the role that these molecules play in leukocyte homing and retention. Anti-integrin therapeutics, including gut-selective antibodies against the β7 integrin subunit [etrolizumab] and the α4β7 integrin heterodimer [vedolizumab and abrilumab], and the non-gut selective anti-α4 integrin [natalizumab], will be discussed, as well as novel targeting approaches using small molecules.
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Affiliation(s)
- Christopher A Lamb
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.,Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Sharon O'Byrne
- Global Medical Affairs, Takeda Pharmaceuticals International AG, Zurich, Switzerland
| | - Mary E Keir
- Genentech Research & Early Development, South San Francisco, CA, USA
| | - Eugene C Butcher
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.,Veterans Affairs Palo Alto Health Care System and The Palo Alto Veterans Institute for Research, Palo Alto, CA, USA
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Allocca M, Gilardi D, Fiorino G, Furfaro F, Argollo M, Peyrin-Biroulet L, Danese S. PF-00547659 for the treatment of Crohn's disease and ulcerative colitis. Expert Opin Investig Drugs 2018; 27:623-629. [PMID: 29985060 DOI: 10.1080/13543784.2018.1494722] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Gut-specific homing is mainly mediated by the expression of MAdCAM-1 on endothelial cells. An increase in MAdCAM-1 expression has been shown in patients with inflammatory bowel disease (IBD). Areas covered: PF-00547659 is a fully human monoclonal antibody (mAb) toward MAdCAM-1 on endothelial cells, blocking its binding with the α4β7 integrin on leukocytes. This review discusses the available data on effectiveness and safety of PF-00547659 in IBD. Expert opinion: A phase II study in moderate-to-severe ulcerative colitis (UC) patients, both naïve and previously exposed to anti-tumor necrosis factors, showed that PF-00547659 was superior to placebo for induction of remission, response, and mucosal healing at week 12. In contrast, preliminary results in a similar study in Crohn's disease (CD) did not show a superiority of PF-00547659, suggesting that PF-00547659 may have limited impact over CD outcomes. However, the time frame needed to evaluate clinical effectiveness of PF-00547659 may be longer in CD patients, given its transmural characteristic. In addition, it should be taken into consideration the possibility of incorporating new tools and more objective parameters in disease assessment that are proven to better correlate with inflammation. Future randomized-controlled trials are needed to confirm the efficacy of PF-00547659 in CD.
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Affiliation(s)
| | - Daniela Gilardi
- a IBD Centre, Humanitas Clinical and Research Centre , Milan , Italy
| | - Gionata Fiorino
- a IBD Centre, Humanitas Clinical and Research Centre , Milan , Italy
| | - Federica Furfaro
- a IBD Centre, Humanitas Clinical and Research Centre , Milan , Italy
| | - Marjorie Argollo
- a IBD Centre, Humanitas Clinical and Research Centre , Milan , Italy
| | | | - Silvio Danese
- a IBD Centre, Humanitas Clinical and Research Centre , Milan , Italy.,c Department of Biomedical Sciences , Humanitas University , Milan , Italy
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Argollo M, Fiorino G, Hindryckx P, Peyrin-Biroulet L, Danese S. Novel therapeutic targets for inflammatory bowel disease. J Autoimmun 2017; 85:103-116. [DOI: 10.1016/j.jaut.2017.07.004] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Revised: 07/03/2017] [Accepted: 07/05/2017] [Indexed: 02/06/2023]
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Currò D, Pugliese D, Armuzzi A. Frontiers in Drug Research and Development for Inflammatory Bowel Disease. Front Pharmacol 2017; 8:400. [PMID: 28690543 PMCID: PMC5481609 DOI: 10.3389/fphar.2017.00400] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 06/07/2017] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel disease (IBD) is idiopathic, lifelong, immune-mediated diseases, for which curative therapies are not yet available. In the last 15 years, the introduction of monoclonal antibodies targeting tumor necrosis factor-α, a cytokine playing a key role in bowel inflammation, has revolutionized treatment paradigms for IBD. Despite their proven long-term efficacy, however, many patients do not respond or progressively lose response to these drugs. Major advances of knowledge in immunology and pathophysiology of intestinal inflammatory processes have made possible the identification of new molecular targets for drugs, thus opening several new potential therapeutic opportunities for IBD. The abnormal response of intestinal immunity to unknown antigens leads to the activation of T helper lymphocytes and triggers the inflammatory cascade. Sphingosine 1-phosphate receptor agonists negatively modulate the egress of lymphocytes, inducted by antigen-presenting cells, from secondary lymphoid tissues to intestinal wall. Leukocyte adhesion inhibitors (both anti-integrin and anti-Mucosal Vascular Addressin Cell Adhesion Molecule 1) interfere with the tissue homing processes. Activated T helper lymphocytes increase the levels of pro-inflammatory cytokines, such as interleukin 12, 23, and 6, offering several potential pharmacological interventions. The Janus kinases, intracellular enzymes mediating the transduction of several cytokine signals, are other explored targets for treating immune-mediated diseases. Finally, the impact of modulating Smad7 pathway, which is responsible for the down-regulation of the immunosuppressive cytokine transforming growth factor-β signaling, is currently under investigation. The purpose of this review is to discuss the most promising molecules in late-stage clinical development, with a special emphasis on pharmacological properties.
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Affiliation(s)
- Diego Currò
- Institute of Pharmacology, School of Medicine, Catholic University of the Sacred HeartRome, Italy
| | - Daniela Pugliese
- IBD Unit, Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario “A. Gemelli” Presidio Columbus, Catholic University of the Sacred HeartRome, Italy
| | - Alessandro Armuzzi
- IBD Unit, Internal Medicine and Gastroenterology, Fondazione Policlinico Universitario “A. Gemelli” Presidio Columbus, Catholic University of the Sacred HeartRome, Italy
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Coskun M, Vermeire S, Nielsen OH. Novel Targeted Therapies for Inflammatory Bowel Disease. Trends Pharmacol Sci 2016; 38:127-142. [PMID: 27916280 DOI: 10.1016/j.tips.2016.10.014] [Citation(s) in RCA: 144] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 10/21/2016] [Accepted: 10/26/2016] [Indexed: 02/07/2023]
Abstract
Our growing understanding of the immunopathogenesis of inflammatory bowel disease (IBD) has opened new avenues for developing targeted therapies. These advances in treatment options targeting different mechanisms of action offer new hope for personalized management. In this review we highlight emerging novel and easily administered therapeutics that may be viable candidates for the management of IBD, such as antibodies against interleukin 6 (IL-6) and IL-12/23, small molecules including Janus kinase inhibitors, antisense oligonucleotide against SMAD7 mRNA, and inhibitors of leukocyte trafficking to intestinal sites of inflammation (e.g., sphingosine 1-phosphate receptor modulators). We also provide an update on the current status in clinical development of these new classes of therapeutics.
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Affiliation(s)
- Mehmet Coskun
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Denmark; The Bioinformatics Centre, Department of Biology, and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Denmark
| | - Severine Vermeire
- Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, Denmark.
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McLean LP, Cross RK. Integrin antagonists as potential therapeutic options for the treatment of Crohn's disease. Expert Opin Investig Drugs 2016; 25:263-73. [PMID: 26822204 DOI: 10.1517/13543784.2016.1148137] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
INTRODUCTION Anti-integrin therapy for the treatment of patients with Crohn's disease is rapidly evolving. Two agents, natalizumab and vedolizumab, are approved by the United States Food and Drug Administration for the treatment of Crohn's disease, with vedolizumab the primary anti-integrin used due to a more favorable safety profile. Several other anti-integrins are in various stages of development. AREAS COVERED This review discusses the current state of anti-integrin therapy as well as suggestions for positioning of these agents in clinical practice. Emerging anti-integrin therapies, their underlying mechanisms of action, and available safety and clinical data are also reviewed. EXPERT OPINION Anti-integrins are effective for the treatment of Crohn's disease, even in patients refractory to other therapies. Their use should be considered in patients with Crohn's disease who do not respond to, develop non-response to, or have contraindications to anti-TNF therapy. Anti-integrin therapies can be offered as a first biologic therapy, in particular for older patients, patients with concurrent multiple sclerosis (natalizumab only), and in patients with contraindications to anti-TNF therapy. In patients with more severe symptoms, providers should consider co-induction with corticosteroids if possible to hasten remission.
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Affiliation(s)
- Leon P McLean
- a Department of Medicine, Division of Gastroenterology and Hepatology , University of Maryland, Baltimore , Baltimore , MD , USA
| | - Raymond K Cross
- a Department of Medicine, Division of Gastroenterology and Hepatology , University of Maryland, Baltimore , Baltimore , MD , USA
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Bravatà I, Allocca M, Fiorino G, Danese S. Integrins and adhesion molecules as targets to treat inflammatory bowel disease. Curr Opin Pharmacol 2016; 25:67-71. [PMID: 26687159 DOI: 10.1016/j.coph.2015.11.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Inflammatory bowel diseases (IBD) present a typically relapsing-remitting behavior and are characterized by a disabling and progressive course. Anti-tumor necrosis factor (TNF)-α agents have drastically changed the therapeutic management of IBD. However, a significant proportion of patients does not have a primary response, some patients lose response overtime and/or experience side effects. Recently, anti-adhesion molecules were investigated and showed efficacy with a good safety profile. Vedolizumab was recently approved for both Crohn's disease (CD) and ulcerative colitis (UC) and several other molecules are under evaluation in this field. Anti-adhesion molecules could represent a potential therapeutic option for future therapy in IBD. In this review we report the efficacy and safety of major anti-adhesion drugs in active IBD patients.
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Affiliation(s)
- Ivana Bravatà
- IBD Center, Gastroenterology, IRCCS Humanitas, Rozzano, Milan, Italy
| | | | - Gionata Fiorino
- IBD Center, Gastroenterology, IRCCS Humanitas, Rozzano, Milan, Italy
| | - Silvio Danese
- IBD Center, Gastroenterology, IRCCS Humanitas, Rozzano, Milan, Italy; Humanitas University, Department of Biomedical Sciences, Rozzano, Milan, Italy.
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18
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Furfaro F, Fiorino G, Allocca M, Gilardi D, Danese S. Emerging therapeutic targets and strategies in Crohn's disease. Expert Rev Gastroenterol Hepatol 2016; 10:735-44. [PMID: 26766496 DOI: 10.1586/17474124.2016.1142372] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Crohn's disease (CD) is an immune-mediated inflammatory bowel disease, in which inflammation is driven by a complex interaction between the microbiota, immune cells, genes and mediators. New mechanisms of action and several cytokines have been identified as factors involved in the inflammatory process in CD, and many new molecules have been developed to treat this complex disease. New agents have been developed that target leukocyte trafficking, block or adhesion molecules for example, as well as the development of antibodies against classic inflammatory cytokines or therapies directed against IL-12/23 and Janus kinases. The development of selective mechanisms of action and targeting of different cytokines or inflammatory mediators for each patient presents the biggest challenge for the future in CD therapy. Such agents are currently at different phases of development. We aim to review the current literature data on a targeted approach in CD, which could be promising alternative approach for CD patients in the near future.
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Affiliation(s)
- Federica Furfaro
- a IBD Center, Department of Gastroenterology , Humanitas Research Hospital , Rozzano , Milan , Italy.,b Department of Gastroenterology , University Study of Milan , Milan , Italy
| | - Gionata Fiorino
- a IBD Center, Department of Gastroenterology , Humanitas Research Hospital , Rozzano , Milan , Italy
| | - Mariangela Allocca
- a IBD Center, Department of Gastroenterology , Humanitas Research Hospital , Rozzano , Milan , Italy
| | - Daniela Gilardi
- a IBD Center, Department of Gastroenterology , Humanitas Research Hospital , Rozzano , Milan , Italy
| | - Silvio Danese
- a IBD Center, Department of Gastroenterology , Humanitas Research Hospital , Rozzano , Milan , Italy
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19
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Ley K, Rivera-Nieves J, Sandborn WJ, Shattil S. Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat Rev Drug Discov 2016; 15:173-83. [PMID: 26822833 PMCID: PMC4890615 DOI: 10.1038/nrd.2015.10] [Citation(s) in RCA: 307] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Integrins are activatable molecules that are involved in adhesion and signalling. Of the 24 known human integrins, 3 are currently targeted therapeutically by monoclonal antibodies, peptides or small molecules: drugs targeting the platelet αIIbβ3 integrin are used to prevent thrombotic complications after percutaneous coronary interventions, and compounds targeting the lymphocyte α4β1 and α4β7 integrins have indications in multiple sclerosis and inflammatory bowel disease. New antibodies and small molecules targeting β7 integrins (α4β7 and αEβ7 integrins) and their ligands are in clinical development for the treatment of inflammatory bowel diseases. Integrin-based therapeutics have shown clinically significant benefits in many patients, leading to continued medical interest in the further development of novel integrin inhibitors. Of note, almost all integrin antagonists in use or in late-stage clinical trials target either the ligand-binding site or the ligand itself.
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Affiliation(s)
- Klaus Ley
- La Jolla Institute for Allergy and Immunology, 9420 Athena Circle Drive, La Jolla, Califoria 92037, USA, and the Department of Bioengineering, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093 USA
| | - Jesus Rivera-Nieves
- La Jolla Institute for Allergy and the Immunology, 9420 Athena Circle Drive, La Jolla, Califoria 92037, USA, and the Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093 USA
| | - William J Sandborn
- Immunology and the Inflammatory Bowel Disease Center, Division of Gastroenterology, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093 USA
| | - Sanford Shattil
- Division of Haematology-Oncology, Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093 USA
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20
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Green CL, Stewart JJ, Högerkorp CM, Lackey A, Jones N, Liang M, Xu Y, Ferbas J, Moulard M, Czechowska K, Mc Closkey TW, van der Strate BW, Wilkins DE, Lanham D, Wyant T, Litwin V. Recommendations for the development and validation of flow cytometry-based receptor occupancy assays. CYTOMETRY PART B-CLINICAL CYTOMETRY 2016; 90:141-9. [DOI: 10.1002/cyto.b.21339] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Revised: 10/26/2015] [Accepted: 11/04/2015] [Indexed: 12/14/2022]
Affiliation(s)
- Cherie L. Green
- Amgen, Inc; 1 Amgen Center Drive, Mailstop 30E-3-C Thousand Oaks California 91320
| | - Jennifer J. Stewart
- Flow Contract Site Laboratory, LLC; 13029 NE 126th PL, Unit A229 Kirkland Washington 98034
| | | | - Alan Lackey
- Laboratory Corporation of America® Holdings; LabCorp Clinical Trials; 201 Summit View Dr, Suite 200 Brentwood Tennessee 37027
| | - Nicholas Jones
- Laboratory Corporation of America® Holdings; LabCorp Clinical Trials; 201 Summit View Dr, Suite 200 Brentwood Tennessee 37027
| | - Meina Liang
- Medimmune, LLC; 319 North Bernardo Avenue Mountain View California 94043
| | - Yuanxin Xu
- Alnylam Pharmaceuticals; Bioanalytical Sciences; 300 Third Street Cambridge Massachusetts 02142
| | - John Ferbas
- Amgen, Inc; 1 Amgen Center Drive, Mailstop 30E-3-C Thousand Oaks California 91320
| | - Maxime Moulard
- BioCytex; 140 Chemin De L'armée D'afrique Marseille 13010 France
| | | | | | | | - Danice E.C. Wilkins
- Charles River Laboratories International, Inc; 6995 Longley Lane Reno Nevada 89511
| | - David Lanham
- Eurofins Pharma Bioanalysis Services UK Limited; 91 Park Drive Milton Park Abingdon OX14 4RY United Kingdom
| | - Timothy Wyant
- Takeda Pharmaceuticals; 35 Landsdown St Cambridge Massachusetts 02139
| | - Virginia Litwin
- Covance Central Laboratory Services; 8211 SciCor Dr Indianapolis Indiana 46214
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21
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Gómez-Gómez GJ, Masedo &A, Yela C, Martínez-Montiel MDP, Casís B. Current stage in inflammatory bowel disease: What is next? World J Gastroenterol 2015; 21:11282-11303. [PMID: 26525013 PMCID: PMC4616205 DOI: 10.3748/wjg.v21.i40.11282] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/12/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In recent years, the incidence of inflammatory bowel disease (IBD) has been on the rise, extending to countries where it was infrequent in the past. As a result, the gap between high and low incidence countries is decreasing. The disease, therefore, has an important economic impact on the healthcare system. Advances in recent years in pharmacogenetics and clinical pharmacology have allowed for the development of treatment strategies adjusted to the patient profile. Concurrently, new drugs aimed at inflammatory targets have been developed that may expand future treatment options. This review examines advances in the optimization of existing drug treatments and the development of novel treatment options for IBD.
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22
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Sternebring O, Alifrangis L, Christensen TF, Ji H, Hegelund AC, Högerkorp CM. A weighted method for estimation of receptor occupancy for pharmacodynamic measurements in drug development. CYTOMETRY PART B-CLINICAL CYTOMETRY 2015. [DOI: 10.1002/cyto.b.21277] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Ola Sternebring
- Department of Development DMPK; Novo Nordisk A/S; DK-2760 Maaloev Denmark
| | - Lene Alifrangis
- Department of Development DMPK; Novo Nordisk A/S; DK-2760 Maaloev Denmark
| | - Toke Folke Christensen
- Department of Quantitative Clinical Pharmacology; Novo Nordisk A/S; DK-2860 Soeborg Denmark
| | - Hong Ji
- Department of Pharmacodynamics; Novo Nordisk A/S; DK-2760 Maaloev Denmark
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23
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Abstract
After a relatively long time of failed developments and negative clinical trials in pharmacological inflammatory bowel disease (IBD) therapy we now phase a time of a great number of successful studies and new therapy principles that will most likely make it into clinical practice. This will change the landscape of IBD therapy in future markedly. Many new therapeutic principles have been developed and old ones that seemed to have failed such as anti-sense technology suddenly now provide promising results. Some initially promising therapies will need further development or have failed such as Trichuris suis ova therapy (but not helminth therapy in general), CCR9 targeted therapies or recombinant IL-10. In contrast anti-leukocate trafficking therapies appear to be quite promising. Vedolizumab is the first in class anti-integrin antibody that was approved for the therapy of CD and UC recently. Other anti-integrin antibodies and small molecule adhesion inhibitors will most likely be approved in the next years for IBD therapy. Tofacitinib, a small molecule JAK inhibitor, is a promising candidate for the treatment of UC. Phosphatidylcholine may be a future option for patients with 5-ASA refractory UC or 5-ASA intolerance. The preliminary data for Mongersen, a Smad7 antisense oligonucleotide, are promising despite some concerns about long term effect of TGFβ induction. Anti IL6 strategies will hopefully be further evaluated keeping in mind the caveat of a lack of CRP induction in anti-IL6 treated patients. Stem cell transplantation will become an option for patients that have experienced failure of established medications. Fecal microbiota transplantation and also perhaps combined probiotic therapy is a field that will be evaluated in more detail in the near future especially for UC patients. Based on these new developments treatment algorithms need to be updated. This review will reflect these current developments and give a perspective for future IBD therapy.
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24
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Liang M, Schwickart M, Schneider AK, Vainshtein I, Del Nagro C, Standifer N, Roskos LK. Receptor occupancy assessment by flow cytometry as a pharmacodynamic biomarker in biopharmaceutical development. CYTOMETRY PART B-CLINICAL CYTOMETRY 2015; 90:117-27. [PMID: 26054054 PMCID: PMC5042057 DOI: 10.1002/cyto.b.21259] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2014] [Revised: 04/20/2015] [Accepted: 05/28/2015] [Indexed: 12/19/2022]
Abstract
Receptor occupancy (RO) assays are designed to quantify the binding of therapeutics to their targets on the cell surface and are frequently used to generate pharmacodynamic (PD) biomarker data in nonclinical and clinical studies of biopharmaceuticals. When combined with the pharmacokinetic (PK) profile, RO data can establish PKPD relationships, which are crucial for informing dose decisions. RO is commonly measured by flow cytometry on fresh blood specimens and is subject to numerous technical and logistical challenges. To ensure that reliable and high quality results are generated from RO assays, careful assay design, key reagent characterization, data normalization/reporting, and thorough planning for implementation are of critical importance during development. In this article, the authors share their experiences and perspectives in these areas and discuss challenges and potential solutions when developing and implementing a flow cytometry‐based RO method in support of biopharmaceutical drug development. © 2015 The Authors Cytometry Part B: Clinical Cytometry Published by Wiley Periodicals, Inc.
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Affiliation(s)
- Meina Liang
- Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043
| | - Martin Schwickart
- Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043
| | - Amy K Schneider
- Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043
| | - Inna Vainshtein
- Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043
| | - Christopher Del Nagro
- Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043
| | - Nathan Standifer
- Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043
| | - Lorin K Roskos
- Department of Clinical Pharmacology and DMPK, Medimmune, LLC, Mountain View, California, 94043
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25
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Lichtenstein GR, Hanauer SB, Sandborn WJ. Emerging Treatment Options in Mild to Moderate Ulcerative Colitis. Gastroenterol Hepatol (N Y) 2015; 11:1-16. [PMID: 26491415 PMCID: PMC4609145] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory condition associated with rectal bleeding and urgency, tenesmus, and diarrhea. Several medical therapies can be used in the treatment of UC. Aminosalicylates are widely used based on their efficacy in the induction and maintenance of remission. Although corticosteroids are effective in patients with more severe disease, systemic use is associated with significant safety concerns. The newer corticosteroid budesonide has lower systemic bioavailability and, consequently, a more favorable safety profile. A budesonide extended-release formulation allows once-daily dosing and delivers the agent locally throughout the colon. Biologic agents used for the treatment of moderate to severe UC include the tumor necrosis factor inhibitors infliximab, adalimumab, and golimumab, and the integrin inhibitor vedolizumab. Rectally administered therapy can also be useful in the treatment of UC. In October 2014, the US Food and Drug Administration approved a budesonide foam formulation for inducing remission in patients with active mild to moderate distal UC extending up to 40 cm from the anal verge. Budesonide foam rapidly distributes to the sigmoid colon and the rectum and avoids some of the drawbacks of suppositories and enemas.
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Affiliation(s)
- Gary R Lichtenstein
- Professor of Medicine Director, Center for Inflammatory Bowel Disease University of Pennsylvania Health System Hospital of the University of Pennsylvania Philadelphia, Pennsylvania
| | - Stephen B Hanauer
- Professor of Medicine Feinberg School of Medicine Medical Director, Digestive Health Center Northwestern Medicine Chicago, Illinois
| | - William J Sandborn
- Professor of Medicine and Adjunct Professor of Surgery Chief, Division of Gastroenterology Director, UCSD IBD Center University of California San Diego University of California San Diego Health System La Jolla, California
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26
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Bravatà I, Fiorino G, Allocca M, Repici A, Danese S. New targeted therapies such as anti-adhesion molecules, anti-IL-12/23 and anti-Janus kinases are looking toward a more effective treatment of inflammatory bowel disease. Scand J Gastroenterol 2015; 50:113-20. [PMID: 25523561 DOI: 10.3109/00365521.2014.993700] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Antitumor necrosis factor α agents have dramatically changed the management of inflammatory bowel disease (IBD). However, a significant proportion of patients does not respond or lose response over time. Hence, there is an urgent need for new molecules, with different mechanisms of action, and with a targeted and more effective approach. These new drugs include either small molecules or biological agents. We describe the three most promising classes of molecules in the field of IBD: anti-adhesion, anti-interleukin 12/23 and anti-Janus Kinases therapies.
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Affiliation(s)
- Ivana Bravatà
- Department of Gastroenterology, Endoscopy Unit, Humanitas Research Hospital , Rozzano, Milan , Italy
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27
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Krupka N, Baumgart DC. Designing biologic selectivity for inflammatory bowel disease--role of vedolizumab. DRUG DESIGN DEVELOPMENT AND THERAPY 2014; 9:147-54. [PMID: 25552903 PMCID: PMC4277125 DOI: 10.2147/dddt.s50348] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Crohn's disease and ulcerative colitis are two chronic inflammatory bowel conditions. Current approved biologic therapies are limited to blocking tumor necrosis factor alpha. Unfortunately, some patients are primary nonresponders, experiencing a loss of response, intolerance, or side effects. This defines an unmet need for novel therapeutic strategies. The rapid recruitment and inappropriate retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. Here we discuss the clinical trial results of vedolizumab (anti-α4β7, LDP-02, MLN-02, and MLN0002) and its impact on future management of inflammatory bowel disease.
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Affiliation(s)
- Niklas Krupka
- Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt-University of Berlin, Berlin, Germany
| | - Daniel C Baumgart
- Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical School, Humboldt-University of Berlin, Berlin, Germany
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28
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Li H, Köck K, Wisler JA, Rees WA, Prince PJ, Reynhardt KO, Hsu H, Yu Z, Borie DC, Salinger DH, Pan WJ. Prediction of clinical pharmacokinetics of AMG 181, a human anti-α 4 β 7 monoclonal antibody for treating inflammatory bowel diseases. Pharmacol Res Perspect 2014; 3:e00098. [PMID: 25692016 PMCID: PMC4317229 DOI: 10.1002/prp2.98] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 09/12/2014] [Indexed: 01/05/2023] Open
Abstract
The purpose of this study was to predict a safe starting dose of AMG 181, a human anti-α4β7 antibody for treating inflammatory bowel diseases, based on cynomolgus monkey pharmacokinetic (PK) and pharmacodynamic (PD) data. A two-compartment model with parallel linear and target-mediated drug disposition for AMG 181 PK in cynomolgus monkey was developed. The estimated parameters were allometrically scaled to predict human PK. An Emax PD model was used to relate AMG 181 concentration and free α4β7 receptor data in cynomolgus monkey. AMG 181 clinical doses were selected based on observed exposures at the no adverse effect level of 80 mg·kg−1 in monkeys, the predicted human exposures, and AMG 181 concentration expected to produce greater than 50% α4β7 receptor occupancy in humans. The predicted human AMG 181 clearance and central volume of distribution were 144 mL·day−1 and 2900 mL, respectively. The estimated EC50 for free α4β7 receptor was 14 ng·mL−1. At the 0.7 mg starting dose in humans, the predicted exposure margins were greater than 490,000 and AMG 181 concentrations were predicted to only briefly cover the free α4β7 receptor EC10. Predictions for both Cmax and AUC matched with those observed in the first-in-human study within the 7 mg subcutaneous to 420 mg intravenous dose range. The developed model aided in selection of a safe starting dose and a pharmacological relevant dose escalation strategy for testing of AMG 181 in humans. The clinically observed human AMG 181 PK data validated the modeling approach based on cynomolgus monkey data alone.
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Affiliation(s)
- Hong Li
- Pharmacokinetics and Drug Metabolism, Amgen Inc. Seattle, Washington
| | - Kathleen Köck
- Pharmacokinetics and Drug Metabolism, Amgen Inc. Seattle, Washington
| | - John A Wisler
- Comparative Biology and Safety Sciences, Amgen Inc. Thousand Oaks, California
| | | | - Peter J Prince
- Pharmacokinetics and Drug Metabolism, Amgen Inc. Seattle, Washington
| | | | - Hailing Hsu
- Inflammation Discovery Research, Amgen Inc. Thousand Oaks, California
| | - Zhigang Yu
- Medical Sciences, Amgen Inc. Thousand Oaks, California
| | - Dominic C Borie
- Global Development, Amgen Inc. South San Francisco, California
| | - David H Salinger
- Pharmacokinetics and Drug Metabolism, Amgen Inc. Seattle, Washington
| | - Wei-Jian Pan
- Pharmacokinetics and Drug Metabolism, Amgen Inc. Seattle, Washington
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