Intestinally-restricted Janus Kinase inhibition: a potential approach to maximize the therapeutic index in inflammatory bowel disease therapy

Abstract

BackgroundAn unmet need remains for safe and effective treatments to induce and maintain remission in inflammatory bowel disease (IBD) patients. The Janus kinase (JAK) inhibitor, tofacitinib, has demonstrated robust efficacy in ulcerative colitis patients although, like other systemic immunosuppressants, there may be safety concerns associated with its use. This preclinical study evaluated whether modulating intestinal inflammation via local JAK inhibition can provide efficacy without systemic immunosuppression.MethodsThe influence of tofacitinib, dosed orally or intracecally, on oxazolone-induced colitis, oxazolone or interferon-γ (IFNγ)-induced elevation of colonic phosphorylated signal transducer and activator of transcription1 (pSTAT1) levels, and basal splenic natural killer (NK) cell counts was investigated in mice.ResultsTofacitinib, dosed orally or intracecally, inhibited, with similar efficacy, oxazolone-induced colitis, represented by improvements in the disease activity index and its sub-scores (body weight, stool consistency and blood content). Intracecal dosing of tofacitinib resulted in a higher colon:plasma drug exposure ratio compared to oral dosing. At equieffective oral and intracecal doses, colonic levels of tofacitinib were similar, while the plasma levels for the latter were markedly lower, consistent with a lack of effect on splenic NK cell counts. Tofacitinib, dosed orally, intracecally, or applied to the colonic lumen in vitro, produced dose-dependent, and maximal inhibition of oxazolone or IFNγ-induced STAT1 phosphorylation in the colon.ConclusionsLocalized colonic JAK inhibition, by intracecal delivery of tofacitinib, provides colonic target engagement and efficacy in a mouse colitis model at doses which do not impact splenic NK cell counts. Intestinal targeting of JAK may permit separation of local anti-inflammatory activity from systemic immunosuppression, and thus provide a larger therapeutic index compared to systemic JAK inhibitors.

Development of Gut-Selective Pan-Janus Kinase Inhibitor TD-1473 for Ulcerative Colitis: A Translational Medicine Programme

“…We previously demonstrated that tofacitinib dosed directly to the large intestine in mice limited colitis with minimal systemic exposure. 10 These data provided proof-of-concept for the potential therapeutic value of a gut-selective JAK inhibitor in patients with UC. To capture the efficacy of JAK inhibition in UC treatment while minimizing systemic toxicity, we designed TD-1473 as a novel, orally administered, gut-selective pan-JAK inhibitor.…”

“…Two days after intrarectal oxazolone, colitis disease activity index [DAI] and its subscores [stool consistency, gross bleeding, weight loss] were measured as previously described. 10 Assessment of target engagement in mouse colon is described in the Supplementary methods.…”

“…The mice were killed via CO 2 inhalation, and then spleens were removed and processed for counting of natural killer [NK] and T and B cells by flow cytometry [BD LSR II, FCS Express 4 Flow Research program, Becton Dickinson], as previously described. 10 …”

Recent updates on the basic mechanisms and pathogenesis of inflammatory bowel diseases in experimental animal models

“…67 The effect of tofacitinib had also been shown to exhibit similar efficacy, when dosed orally or intra-cecally, in oxazolone-induced colitis in mice, but noting that intra-cecal provides colonic target engagement which do not impact splenic natural killer (NK) cell counts. 68 Consistent with the notion that oxazoloneinduced colitis represents features of human UC condition, tofacitinib had been found effective for UC patients and was approved recently in May 2019 for use in moderately to severely active UC in clinical settings. Conversely, tofacitinib did not show significant improvements in remission rates, in comparison with placebo, in a phase II clinical trial for CD.…”

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

“…In addition to topical dosing of the skin for disease, such as alopecia areata and vitiligo, IBD presents opportunities for direct application of JAK inhibitors to the intestinal mucosa. Proof of concept for the utility of directly inhibiting JAK signaling in the gut lumen has been provided by intracecal dosing of tofacitinib compared to oral dosing in a murine model of colitis . Achieving high local concentrations—but minimal systemic exposure as assessed by changes in splenic NK cells—was as efficacious as systemic administration.…”