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

Journal of Inflammation, Dec 2017

An 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. The 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. Tofacitinib, 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. Localized 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.

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

Beattie et al. Journal of Inflammation Intestinally-restricted Janus Kinase inhibition: a potential approach to maximize the therapeutic index in inflammatory bowel disease therapy David T. Beattie 1 M. Teresa Pulido-Rios 1 Fei Shen 1 Melissa Ho 0 Eva Situ 0 Pam R. Tsuruda 1 Patrick Brassil 2 Melanie Kleinschek 0 Sharath Hegde 1 0 Department of Biology, Theravance Biopharma US, Inc , 901 Gateway Boulevard, South San Francisco 1 Department of Pharmacology , Theravance Biopharma US, Inc , 901 Gateway Boulevard, South San Francisco, CA 94080 , USA 2 Department of Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc , 901 Gateway Boulevard, South San Francisco, CA 94080 , USA Background: An 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. Methods: The 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. Results: Tofacitinib, 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. Conclusions: Localized 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. Inflammatory bowel disease; Tofacitinib; Janus kinase inhibitor; Pharmacokinetics; Pharmacodynamics Background Inflammatory bowel diseases (IBDs), such as ulcerative colitis and Crohn’s disease, have a significant, detrimental impact on the quality of life of patients [ 1 ]. Common IBD symptoms experienced during an active phase of the disease include diarrhea, rectal bleeding, abdominal pain, weight loss, fatigue, nausea and vomiting [ 2 ]. While a variety of therapeutic options exists to induce and maintain disease remission in IBD patients, each has its limitations. Aminosalicylates, often effective in mild disease, are much less so in moderate and severe disease, while long-term use of steroids for maintenance therapy has safety concerns (e.g., osteoporosis, muscle wasting, and neuropsychiatric disorders) [ 3 ]. Systemic immunosuppressants, such as azathioprine, mercaptopurine and methotrexate, often have modest efficacy in moderate/ severe patients, and their prolonged use is problematic due to the consequences of long-term systemic immunosuppression (e.g., increased risk of infection and lymphoma) [ 4–6 ]. Anti-tumor necrosis factor (TNF) antibodies (e.g., infliximab and adalimumab) require subcutaneous or intravenous administration, and up to one third of patients fail to respond adequately, while another third of initial responders lose responsiveness due to the generation of antibodies to the drugs [ 7 ]. It is clear that an unmet medical need remains for an effective oral therapy to induce and maintain remission of IBD without the safety concerns resulting from chronic, systemic immunosuppression. Selective targeting of anti-inflammatory drug activity directly to the intestinal mucosa is an appealing means to achieve this objective, and several approaches appear feasible [ 8, 9 ]. Compounds with appropriate physicochemical properties, and optimized formulations have been developed, and mechanisms selective for the intestine have also been targeted. An inactive prodrug that undergoes enzymatic cleavage during gastrointestinal transit to generate an active parent drug is another option to target the intestine selectively. Examples of IBD therapies selectively targeting the intestine already exist. Upon rectal dosing to ulcerative (...truncated)


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David T. Beattie, M. Teresa Pulido-Rios, Fei Shen, Melissa Ho, Eva Situ, Pam R. Tsuruda, Patrick Brassil, Melanie Kleinschek, Sharath Hegde. Intestinally-restricted Janus Kinase inhibition: a potential approach to maximize the therapeutic index in inflammatory bowel disease therapy, Journal of Inflammation, pp. 28,