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Biological Therapies in Inflammatory Bowel Disease Beyond Anti-TNF Therapies

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Biological Therapies in Inflammatory Bowel Disease Beyond Anti-TNF Therapies Clinical Immunology 206 (2019) 9–14 Contents lists available at ScienceDirect Clinical Immunology journal homepage: www.elsevier.com/locate/yclim Biological therapies in inflammatory bowel disease: Beyond anti-TNF therapies T Konstantinos H. Katsanosa,1, Konstantinos Papamichaelb,1, Joseph D. Feuersteinb, ⁎ Dimitrios K. Christodouloua, Adam S. Cheifetzb, a Division of Gastroenterology, University Hospital & Faculty of Medicine, School of Health Sciences, University of Ioannina, Greece b Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard University, Boston, MA, USA ARTICLE INFO ABSTRACT Keywords: The pharmacological management of inflammatory bowel disease (IBD) over the last two decades has transi- Ulcerative colitis tioned from reliance on aminosalycilates, corticosteroids and immunomodulators to earlier treatment with anti- Crohn's disease tumor necrosis factor (anti-TNF) therapy. Nevertheless, 20–30% of patients discontinue anti-TNF therapy for Biologics primary non-response and another 30–40% for losing response within one year of treatment. These undesirable Novel therapies therapeutic outcomes can be attributed to pharmacokinetic (anti-drug antibodies and/or low drug concentra- S1P receptors tions) or pharmacodynamic issues characterized by a non-TNF driven inflammation. The latter issues necessitate Integrins ff Janus kinases the use of medications with di erent mechanisms of action. Besides the biologics natalizumab, vedolizumab and ustekinumab that have already been approved for the treatment of IBD new non-anti-TNF therapies are currently under investigation including small molecule drugs against Janus kinase and sphingosine-1-phosphate receptors. This manuscript will review the medications that are in the later stages of development for the treatment of IBD and directed against immune targets other than TNF. 1. Introduction (primary non-responders), and another 30–40% lose response during the first year of treatment, requiring dose-escalation or a switch to Inflammatory bowel diseases (IBD), encompassing Crohn's disease another biologic [6]. These undesired therapeutic outcomes are due to (CD) and ulcerative colitis (UC), are chronic, relapsing, immune- either pharmacokinetic issues, characterized by increased drug clear- mediated inflammatory disorders with significant morbidity and effects ance mostly due to immunogenicity and development of anti-drug an- on quality of life [1]. The incidence and prevalence of these diseases is tibodies, or pharmacodynamic issues, characterized by non-TNF driven increasing worldwide, particularly in the East [2]. Although the exact inflammation [7]. Moreover, although the overall safety profile of anti- etiopathogenesis of IBD remains largely unknown, the advent of more TNF is satisfactory, there are some concerns with respect to infusion/ advanced molecular and cellular biology techniques has greatly con- injection site reactions, infections and some rare malignancies, such as tributed to improving our understanding of the inflammatory pathways melanoma and lymphoma [8,9]. Thus it is crucial to develop new that drive tissue damage in these disorders [3]. These discoveries, in biological therapies with different mechanisms of action with equiva- turn, have led to more specific and targeted pharmacological treatment lent or even improved safety and efficacy profiles. The latter refer of IBD [4]. mostly to clinical response typically defined as a decrease from baseline Anti-tumor necrosis factor (anti-TNF) therapies have revolutionized of the Crohn's disease activity index by 70 points for CD and the Mayo the treatment of IBD. These agents have been shown to be steroid score by ≥30% and ≥ 3 points, with decrease in rectal bleeding sub- sparing, to reduce IBD-related hospitalizations and surgeries, induce score of ≥1 or rectal bleeding subscore of 0 or 1 for UC. mucosal healing, and improve patients' quality of life [5]. However, up Major advances of knowledge in the immunology and pathophy- to 30% of patients show no clinical benefit after induction therapy siology of the intestinal inflammatory processes have helped to identify Abbreviations: CD, Crohn's disease; CDAI, Crohn's disease activity index; FDA, Food and Drug Administration; IBD, inflammatory bowel disease; IL, interleukin; JAK, Janus-activated kinase; JCV, John Cunningham virus; MAdCAM-1, mucosal addressin cell adhesion molecule 1; PML, progressive multifocal leukoencephalopathy; S1P, sphingosine-1-phosphate; TDM, therapeutic drug monitoring; TNF, tumor necrosis factor; SLR, secondary loss of response; UC, ulcerative colitis; RCT, randomized clinical trials. ⁎ Corresponding author at: Center for Inflammatory Bowel Disease, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Rabb 425, Boston, MA 02215, Harvard Medical School, USA. E-mail address: [email protected] (A.S. Cheifetz). 1 Equal contribution. https://doi.org/10.1016/j.clim.2018.03.004 Received 19 December 2017; Received in revised form 10 March 2018; Accepted 11 March 2018 Available online 12 March 2018 1521-6616/ © 2018 Elsevier Inc. All rights reserved. K.H. Katsanos et al. Clinical Immunology 206 (2019) 9–14 novel molecular targets for drugs and potential new therapeutic ap- 23 – proaches for the treatment of IBD. At present, there are only three non- 45 46 38, 39 36 Ref. 35 48, 49 anti-TNF biologics approved for the treatment of IBD; natalizumab (a recombinant humanized monoclonal IgG4 antibody against the integrin α ammatory bowel subunit 4), vedolizumab (a humanized IgG1 monoclonal antibody that fl α β nal selectively blocks the 4 7 integrin) and ustekinumab (a fully human fi IgG1 monoclonal antibody directed against the shared p40 subunit of interleukin (IL)-12 and IL23) [10,11]. In addition, there are several new biologics currently under development that are projected to reach the III II II III Study phase approval pharmaceutical market in the near future [12,13]. These agents include other anti-adhesion molecule inhibitors (anti-integrins) and anti-IL drugs as well as small molecules, such as Janus kinases (JAK) and sphingosine-1-phosphatase (S1P) receptor inhibitors (Table 1). The aim of this review is to provide an overview of non-anti-TNF therapies for the treatment of IBD that were studied or are still being CD CD CD/UC UC IBD type UC III 33, 34 UC Awaits FDA CD/UCCD/UC II/III II/III 50 51 studied in clinical trials with an emphasis on the most promising agents already in late-stage clinical development. 2. Anti-adhesion molecule inhibitors (anti-integrins) 2.1. Natalizumab 7 integrin CD/UC FDA approved 20 Natalizumab is a recombinant humanized monoclonal IgG4 anti- β 4 α α β α β α body against the integrin subunit 4 that blocks both 4 7 and 4 1 preventing the migration of lymphocytes into most tissues, including the intestine, skin and the brain. Natalizumab was the first anti-adhe- 7 subunit of the heterodimeric integrins sion molecule inhibitor approved by the Food and Drug Administration β (FDA) for CD. The efficacy of natalizumab was demonstrated by the ENACT-2 [14] and ENCORE [15] placebo-controlled randomized clin- ical trials (RCTs). In the ENACT-2 trial, 339 patients who had re- sponded to induction natalizumab therapy were randomly assigned to receive either 300 mg of active drug or placebo every 4 weeks through week 56. Natalizumab compared to placebo resulted in higher rates of sustained response (61% vs. 28%, p < 0.001) and remission (44% vs. 26% p < 0.003) at week 36, respectively [14]. In the ENCORE study 509 patients with moderately to severely active CD and active in- flammation characterized by elevated C-reactive protein concentrations 4 integrin antagonist 7 α were randomized to receive either natalizumab 300 mg or placebo at β E α weeks 0, 4, and 8. Natalizumab compared to placebo resulted in higher ammatory properties CD II 53 fl rates of sustained response (48% vs. 32%, p < 0.001) and remission 7 and cation; p.o.: per os; i.v.: intravenous; s.c.: subcutaneous; p.r.: per rectum; w: week; FDA: Food and Drug Administration. β (26% vs. 16% p = 0.002) at week 8 through week 12, respectively [15]. uman IgG2 monoclonal antibody directed against MAdCAM-1 umanized IgG1monoclonal antibody that selectively blocks the uman IgG1 monoclonal antibody against the p40 subunit of IL12 and 23 CD FDA approved 42, 43 4 fi Mechanism of action Human IgG2 monoclonal antibody that targets the p19 subunit of IL23 Humanized IgG1 monoclonal antibody against the p19 subunit of IL23 Orally active Η α Η Η Moreover, a recent meta-analysis showed that natalizumab was su- perior to placebo for the induction of remission in CD [16]. However, natalizumab in some rare cases promoted reactivation of John Cunningham virus (JCV) in the brain and the development of progressive multifocal leukoencephalopathy (PML) due to inhibition of leukocyte migration to the central nervous system [17,18]. Thus, na- talizumab was voluntarily withdrawn from the market in the US and b Europe but was then reintroduced in the US in combination with a surveillance program and careful monitoring. The use of natalizumab is limited to patients without other immunosuppressive therapy and those a ammatory bowel diseases. fl p.o. maintenance who are JCV negative, preferably for short-term treatment (< 2 years) [19]. Monitoring of JCV antibody development on therapy is re- commended [19]. 2.2. Vedolizumab Vedolizumab is a humanized IgG1 monoclonal antibody that se- lectively blocks the α4β7 integrin and mainly targets gut homing leu- kocytes. Due to the gut-selective nature of the compound and the fact Compound (PubChem SID) Mode of administration that it does not cross the blood brain barrier, it is not associated with PML. Vedolizumab was approved by the FDA and the European Medicines Agency for the treatment of moderate to severe CD [20] and UC [21]. The efficacy of vedolizumab was confirmed by the GEMINI 260-520 mg at w0 and then 90 mg q8w. 300mg at w0, 2, 6 and then q8w. phase III RCTs. a b Target Integrins Vedolizumab (160666632) i.v. CytokinesCytokines Brazicumab (318164812) Ustekinumab (103771533) i.v.
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