JAK inhibitors in crohn’s disease: ready to go?

ABSTRACT

Introduction

Crohn’s disease (CD) is a chronic, relapsing inflammatory bowel disease that can lead to significant organ damage and impaired quality of life. To date, a considerable proportion of patients does not respond to biologic compounds. It is, therefore, necessary to find alternative options with adequate efficacy and safety profiles in order to increase the chances of obtaining an enduring remission of disease. Janus kinase (JAK) inhibitors are a new class of compounds that might well serve this purpose. The aim of our review is to report the available data from clinical trials testing these new drugs in patients suffering from CD.

Areas covered

PubMed database and ClinicalTrials.gov website were consulted in order to find the clinical trials evaluating the efficacy and safety profiles of JAK-inhibitors in CD patients, including the following compounds: tofacitinib, filgotinib, upadacitinib, TD-1473, and Pf-06651600/Pf-06700841.

Expert opinion

JAK-inhibitors are a promising class of oral compounds in moderate-severe CD. Further clinical trials are necessary in order to implement the available knowledge, especially on their long-term safety issues.

KEYWORDS:

• Crohn’s disease
• JAK inhibitors
• small molecules
• inflammatory bowel disease
• IBD

Authors contributions

CD wrote the article and created tables and figures. FD, ADB, RG, NP, AZ, FF, MA, GF, LPB and SD critically reviewed the content of the paper and supervised the project. The manuscript was approved by all authors.

Declaration of interest

S Danese has served as a speaker, a consultant and an advisory board member for Abbvie, Allergan, Biogen, Boehringer Ingelheim, Celgene, Celltrion, Ferring, Hospira, Johnson & Johnson, Merck, MSD, Takeda, Mundipharma, Pfizer, Sandoz, Tigenix, UCB Pharma and Vifor.

F Furfaro received consulting fees from MSD and Abbvie and lecture fees from Janssen and Pfizer.

G Fiorino served as a consultant and advisory board member for MSD, AbbVie, Takeda, Janssen, Mundipharma, Sandoz, Pfizer.

M Allocca received consulting fees from Nikkiso Europe and lecture fees from Janssen and Pfizer.

L Peyrin-Biroulet has served as a speaker, consultant and advisory board member for Merck, Abbvie, Janssen, Genentech, Mitsubishi, Ferring, Norgine, Tillots, Vifor, Hospira/Pfizer, Celltrion, Takeda, Biogaran, Boerhinger-Ingelheim, Lilly, HAC- Pharma, Index Pharmaceuticals, Amgen, Sandoz, Forward Pharma GmbH, Celgene, Biogen, Lycera, Samsung Bioepis, and Theravance.

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 Disclosure statement

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

Abbreviations

Table

Article highlights

• In CD, multiple cytokines play a central role in mediating the disrupted innate and adaptive immune responses responsible for disease activity.

• Animal and genetic studies have demonstrated that at the basis of the deranged immune system activity, a central role is played by members of the janus kinase (JAK) pathways.

• JAK inhibitors are a new class of orally administered compound; they are gaining attention in the inflammatory bowel disease (IBD) field.

• JAK-inhibitors are potential therapeutic options for the management of Crohn’s disease (CD). They could change treatment approaches and improve prospects for reaching and maintaining an enduring remission.

• Filgotinib and upadacitinib show therapeutic potential. Preliminary data suggest their superiority over placebo at inducing clinical remission and they appear to be effective in patients who are naïve to previous anti-TNF therapies or those who have failed previous biologic therapies.

• The gut-selective TD-1473 and the novel Pf-6,700,841 and Pf-06651600 likewise appear as promising compounds.

• The adverse effects of JAK inhibitors stem from their mechanism of action (inhibition of signal transduction as elicited by a number of different cytokines as they bind to the extracellular portions of JAK molecules). Concerns about the potential increased risk of infections and malignancies have been raised.

• Phase III clinical trials are necessary to confirm the long-term efficacy and safety profiles of these new molecules.

This box summarizes key points contained in the article.

Additional information

Funding

This paper was not funded.