Ulcerative colitis: shedding light on emerging agents and strategies in preclinical and early clinical development

ABSTRACT

Introduction

Ulcerative colitis (UC) is an inflammatory disease of the large intestine. Progress in preclinical therapeutic target discovery and clinical trial design has resulted in the approval of new therapies. Nonetheless, remission rates remain below 30% thus underlining the need for novel, more effective therapies.

Areas covered

This paper reviews current experimental techniques available for drug testing in intestinal inflammation and examines new therapies in clinical development for the treatment of UC. The authors searched the literature for ‘ulcerative colitis’ AND ‘preclinical’ OR ‘drug target/drug name’ (i.e. infliximab, vedolizumab, IL-12, IL-23, JAK, etc.). Studies that included preclinical in vivo or in vitro experiments are discussed. The clinicaltrial.gov site was searched for ‘ulcerative colitis’ AND ‘Recruiting’ OR ‘Active, not recruiting’ AND ‘Interventional (Clinical Trial)’ AND ‘early phase 1’ OR ‘phase 1’ OR ‘phase 2’ OR ‘phase 3.’

Expert opinion

Using in vivo, ex vivo, and/or in vitro models could increase the success rates of drugs moving to clinical trials, and hence increase the efficiency of this costly process. Selective JAK1 inhibitors, S1P modulators, and anti-p19 antibodies are the most promising options to improve treatment effectiveness. The development of drugs with gut-restricted exposure may provide increased efficacy and an improved safety.

KEYWORDS:

• Ulcerative colitis
• Crohn’s disease
• clinical trials
• inflammatory bowel disease
• preclinical studies

Article highlights

• Multi-omic analysis of patient samples has accelerated early drug development, in particular the identification of druggable targets.

• Animal models are required to assess toxicity but have a limited ability to predict clinical efficacy.

• Ex vivo/in vitro culture of intestinal biopsies, lamina propria mononuclear cells (LMPCs) or organoids exposed to candidate drugs are useful tools to study target engagement and assess drug efficacy.

• In the context of clinical trials, transcriptional analysis of patient samples provides a precise assessment of the modulation of signaling pathways and supports the identification of biomarkers of response.

• The development of agents with completely new mechanisms of action such as S1P modulators, or higher target selectivity such as highly specific JAK1 or TYK2 inhibitors, will expand our ability to treat refractory UC.

• New drugs with restricted or highly predominant gastrointestinal exposure offer the possibility to increase safety by avoiding systemic exposure and increase efficacy as a result of achieving higher drug concentrations in target organs.

Declaration of interest

JPanes has received research grants from AbbVie and Pfizer; speaker’s fees from AbbVie, Ferring, Janssen, Merck, Pfizer, Shire, Takeda, and Theravance; and has been a consultant for AbbVie, Arena, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Genentech, GlaxoSmithKline, GoodGut, Janssen, Merck, Nestlé, Origo, Pandion, Pfizer, Progenity, Robarts Clinical Trials, Roche, Takeda, Theravance, and Wassermann. ASalas reports research grants from Roche-Genentech, Abbvie, GSK, Scipher Medicine, Alimentiv, Inc, Boehringer Ingelheim, and Origo Biopharma; consulting fees from Genentech, GSK, Pfizer, HotSpot Therapeutics, Surrozen, Alimentiv, Origo Biopharma, and Morphic Therapeutic. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

BC is funded by an “Emili Letang - Josep Font” Research fellowship from Hospital Clinic, Barcelona. VG is supported by a grant from The Leona and Harry Helmsley Charitable Trust. This work was also supported by grants from the Agència de Gestió d’Ajuts Universitaris i de Recerca [2017SGR-992] and the Ministerio de Ciencia e Innovación [RTI2018-096946-B-I00].