Emerging oral targeted therapies in inflammatory bowel diseases: opportunities and challenges

Abstract

To improve quality of life and prevent long-term risks in patients with inflammatory bowel diseases (IBDs: Crohn's disease, ulcerative colitis), it is essential to suppress inflammatory activity adequately. However, corticosteroids are only suitable for therapy of acute flares and the evidence for positive effects of immunosuppressive substances like azathioprine or 6-mercapropurine is mainly limited to maintenance of remission. In addition, only subgroups of patients benefit from biologicals targeting tumour necrosis factor α or α4β7 integrins. In summary, until now the disease activity is not sufficiently controlled in a relevant fraction of the patients with IBD. Thus, there is an urge for the development of new substances in the therapy of ulcerative colitis and Crohn's disease. Fortunately, new oral and parenteral substances are in the pipeline. This review will focus on oral substances, which have already passed phase II studies successfully at this stage. In this article, we summarize data regarding AJM300, phosphatidylcholine (LT-02), mongersen, ozanimod, filgotinib and tofacitinib. AJM300 and ozanimod were tested in patients with ulcerative colitis and target lymphocyte trafficking through inhibition of the α subunit of integrin, respectively binding to the sphingosine-1-phosphate receptor (subtypes 1 and 5) on lymphocytes. Mongersen was utilized in patients with Crohn's disease and accelerates the degradation of SMAD7 mRNA, which consequently strengthens the mainly anti-inflammatory signalling pathway of transforming growth factor β1. Various Janus kinase (JAK) inhibitors were developed, which inhibit the intracellular signalling pathway of cytokines. For example, the JAK1 blocker filgotinib was tested in Crohn's disease, whereas the JAK1/3 inhibitor tofacitinib was tested in clinical trials for both Crohn's disease and ulcerative colitis. A different therapeutic approach is the substitution of phosphatidylcholine (LT-02), which might recover the colonic mucus. Taken together, clinical trials with these new agents have opened avenues for further clinical studies and it can be expected that at least some of these agents will be finally approved for clinical therapy.

Peroxisome Proliferator-Activated Receptors: Experimental Targeting for the Treatment of Inflammatory Bowel Diseases

“…CD features include discontinuous, transmural inflammation in the bowel wall and an inflammatory response associated with granulomas and lymphoid aggregates (Abraham and Cho, 2009). Current treatments include traditional anti-inflammatory agents (corticosteroids) (Greenberg et al, 1994;Rezaie et al, 2015), immunomodulators (thiopurines and methotrexate), biological agents, such as antibodies directed against TNF-a, antibiotics, and surgery (Baumgart, 2016;Vetter and Neurath, 2017). The most relevant treatments targeting PPARs in different experimental models to improve the symptoms of IBD are summarized in Table 1.…”

Targeted therapy of inflammatory bowel diseases: realities and prospects

“…Новые горизонты таргетной терапии БК и ЯК заключа-ются в использовании ингибиторов Янус-киназы (JAK), антител к интерлейкину 12/23, а также антиадгезионных молекул (блокаторов миграции и хоуминга лейкоцитов) (рис. 2) [35,40].…”

“…JAK экспрессиру-ются в иммунокомпетентных клетках, включая гранулоциты и лимфоциты, и играют важнейшее значение в сиг-нальных путях IL-2, IL-4, IL-6, IL-7, IL-9, IL-12, IL-15, IL-21, интерферона-γ и других цитокинов [42,43]. Исходя из этого, блокировка JAK является пер-спективной стратегией таргетной терапии ВЗК [35,40]. В настоящее время два ингибитора JAK (тофациниб и филготиниб) исследуются у пациен-тов с ВЗК [40].…”

“…Исходя из этого, блокировка JAK является пер-спективной стратегией таргетной терапии ВЗК [35,40]. В настоящее время два ингибитора JAK (тофациниб и филготиниб) исследуются у пациен-тов с ВЗК [40].…”

Therapeutic drug monitoring-based dosing of TNF inhibitors in inflammatory bowel disease: the way forward?

“…Various therapeuticals are currently being evaluated in phase 2 and 3 clinical trials targeting inflammatory cytokines (such as anti-IL-23 and anti-IL36), leukocyte trafficking (anti-MadCam antibodies, anti-αEβ7 antibodies, and sphingosine-1-phosphate receptor agonists) or the intestinal microbiome [1][2][3][4][5]. Phosphodiesterase-4 inhibitors (such as apremilast and roflumilast) and JAK inhibitors (including filgotinib and upadacitinib) are promising small molecules [6][7][8]. Hence, treatment options for IBD patients are rapidly increasing.…”