Ileocolonic-Targeted JAK Inhibitor: A Safer and More Effective Treatment for Inflammatory Bowel Disease

Abstract

Janus kinase (JAK) inhibitors, such as tofacitinib (Xeljanz) and filgotinib (Jyseleca), have been approved for treatment of ulcerative colitis with several other JAK inhibitors in late-stage clinical trials for inflammatory bowel disease (IBD). Despite their impressive efficacy, the risk of adverse effects accompanying the use of JAK inhibitors has brought the entire class under scrutiny, leading to them receiving an FDA black box warning. In this study we investigated whether ileocolonic-targeted delivery of a pan-JAK inhibitor, tofacitinib, can lead to increased tissue exposure and reduced systemic exposure compared to untargeted formulations. The stability of tofacitinib in the presence of rat colonic microbiota was first confirmed. Next, in vivo computed tomography imaging was performed in rats to determine the transit time and disintegration site of ileocolonic-targeted capsules compared to gastric release capsules. Pharmacokinetic studies demonstrated that systemic drug exposure was significantly decreased, and colonic tissue exposure increased at 10 mg/kg tofacitinib dosed in ileocolonic-targeted capsules compared to gastric release capsules and an oral solution. Finally, in a rat model of LPS-induced colonic inflammation, targeted tofacitinib capsules significantly reduced concentrations of proinflammatory interleukin 6 in colonic tissue compared to a vehicle-treated control (p = 0.0408), unlike gastric release tofacitinib capsules and orally administered dexamethasone. Overall, these results support further development of ileocolonic-targeted tofacitinib, and potentially other specific JAK inhibitors in pre-clinical and clinical development, for the treatment of IBD.

Impact of Peptide Structure on Colonic Stability and Tissue Permeability

“…As such, this combined approach could be a promising technique for the colonic delivery of peptides intended for local and systemic action. This modification could be beneficial for increasing the colonic permeability of other peptides indicated for IBD or colorectal cancer [ 65 ]. Cyclisation can facilitate peptides to adopt open and closed molecular conformations, based on intramolecular hydrogen bonding, that facilitate movement across the cell membrane [ 66 ].…”

A Phase I, Randomized, Multi‐Dose Study to Evaluate the Enteric Selectivity and Safety of JAK Inhibitor, Lorpucitinib, in Healthy Participants

“…Enteric‐selective JAK inhibitors, 18,19 including lorpucitinib (Compound 2), 17 have the potential to minimize the risk of AEs, some severe, associated with systemic pan‐JAK drug activity 11,14,23 . We hypothesized that lorpucitinib would preferentially localize to the GI tract of healthy human participants and block JAK activity with minimal systemic exposure, thereby supporting the enteric‐selective approach to JAK inhibition for patients with GI inflammatory diseases.…”

“…One strategy was to increase compound selectivity within the JAK family, emphasizing JAK1 as the main target while reducing activity vs. other isoforms 12,13 . Other strategies were considered specifically for gastrointestinal (GI) conditions, including oral formulations to release drugs at defined locations in the GI tract, 14 prodrugs, 15 and preparations designed for direct application at diseased sites 16 . As an alternative strategy, medicinal chemistry campaigns have produced JAK inhibitors that achieved high colonic exposures and lower contemporaneous plasma exposures after oral dosing in mice 17,18 .…”

Colonic drug delivery: Formulating the next generation of colon-targeted therapeutics

“…Resistant starch on the other hand, serves as a substrate for colonic microbiota, providing an alternative method for triggering drug release if the critical pH threshold of Eudragit® S is not attained. Indeed, the Phloral® technology has been successfully shown positive outcomes in the treatment of IBD, irrespective of patients' feeding status [7,51]. Phloral® has also been successfully applied to treat Clostridioides difficile infection [4] and obesity [3].…”

“…Traditionally, colonic drug delivery has focused primarily on local diseases, such as inflammatory bowel disease (IBD) and colorectal cancer [5,6]. Colonic drug delivery can improve the treatment of local diseases by optimising drug concentration at the target site whilst limiting systemic exposure [7,8]. Increasing characterisation of the colonic and rectal environments has led to the recognition of new local targets, such as the microbiome, enteric immune system, and lymphatic system [9,10].…”