Pipeline of IBD drugs

In a clinical update on inflammatory bowel disease (IBD) drugs in the developmental stage, Prof. William Sandborn (University of California San Diego, USA) said he expected a large majority of agents currently in phase 2 and phase 3 trials to reach the market. He claimed the drug armamentarium at the disposal of clinicians may double by 2025. All studies he mentioned were performed in patients with moderate-to-severe ulcerative colitis (UC) and Crohn’s disease (CD).

In IBD, 2 integrin-targeting therapies are already available: natalizumab and vedolizumab, the latter being gut-selective. Investigational anti-integrin therapies are etrolizumab (RG7413), ontamalimab, abrilumab, AJM 300, and PTG-100. Etrolizumab selectively binds the β7 subunit of the heterodimeric integrins α4β7 and αEβ7. Positive results in a phase 2 study in UC patients [1] paved the way for a series of trials: 6 for patients with UC and 2 for patients with CD. Prof. Sandborn expected to receive phase 3 results of etrolizumab in the fall of 2020. Abrilumab, targeting the integrin α4β7, also showed promising results in UC after 8 weeks induction therapy in a phase 2b study [2]. Ontamalimab targets the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) and showed promising results in UC [3].

Prof. Sandborn named 3 JAK inhibitors of which clinical data are available. TD-1473 is an orally administered topical pan-JAK inhibitor that is intestinally restricted, thus minimising systemic absorption. In an exploratory phase 1b study in UC, TD-1473 showed clinical response [4]; it is currently being tested in phase 2 and 3 trials. Two other JAK1 inhibitors, filgotinib and upadacitinib, showed encouraging results in phase 2 studies in CD [5,6].

Sphingosine-1-phosphate receptor 1 (S1P1)-modulators currently under investigation include fingolimod, ozanimod, etrasimod (APD334), and amiselimod. Ozanimod was tested in a preliminary trial in UC patients [7], but efficacy as well as safety requires further assessment in larger trials. In a phase 2 trial, etrasimod was effective in producing clinical and endoscopic improvements in UC patients [8].

Anti-IL-23 receptor monoclonal antibodies also hold promise for IBD treatment, Prof. Sandborn stated. He found phase 2 results of induction therapy with risankizumab in CD patients who had failed TNF inhibitors “the most encouraging endoscopic data I have ever seen in this population” [9]. Two other promising anti-IL-23-agents, brazikumab and mirikizumab, are in development for both UC and CD.

1. 1. 1. Vermeire S, et al. Lancet. 2014 ;384(9940):309-18.
      2. Sandborn WJ, et al. Gastroenterology. 2019;156(4):946-957.e18.
      3. Vermeire S, et al. Lancet. 2017;390(10090):135-44.
      4. Sandborn WJ, et al. UEGW 2018, LB05.
      5. Vermeire S, et al. Lancet. 2017;389(10066):266-75.
      6. Sandborn WJ, et al. Gastroenterology. 2020 Feb 7. pii: S0016-5085(20)30167-0.
      7. Sandborn WJ, et al. N Engl J Med. 2016;374(18):1754-62.
      8. Sandborn WJ, et al. Gastroenterology. 2020;158(3):550–61.
      9. Feagan BG, et al. Lancet. 2017;389(10080):1699-1709.

Posted on 14 April, 20205 August, 2021