Background and Aims Oral systemic pan-Janus kinase [JAK] inhibition is effective for ulcerative colitis [UC] but is limited by toxicities. We describe preclinical to clinical translation of TD-1473—an oral gut-selective pan-JAK inhibitor—from in vitro characterization through a Phase 1b study in patients with UC. Methods TD-1473 JAK inhibition potency was evaluated in vitro; plasma pharmacokinetics, safety and efficacy were assessed in mice. In a first-time-in-human study, plasma pharmacokinetics and safety were assessed after single and multiple [14 days] ascending doses administered orally to healthy subjects. The Phase 1b study randomized patients with moderately to severely active UC to receive once-daily oral TD-1473 20, 80 or 270 mg, or placebo for 28 days. Plasma and colonic tissue concentrations were measured; safety was assessed; and efficacy was evaluated by UC clinical parameters, disease-surrogate biomarkers, endoscopy, histology and colonic tissue JAK signalling. Results TD-1473 exhibited potent pan-JAK inhibitory activity in vitro. Oral TD-1473 administration to mice achieved high, biologically active colonic tissue concentrations with low plasma exposure and decreased oxazolone-induced colitis activity without reducing blood cell counts vs placebo. TD-1473 administration in healthy human subjects and patients with UC yielded low plasma exposure and was generally well tolerated; treatment in patients with UC resulted in biologically active colonic tissue concentrations and descriptive trends toward reduced clinical, endoscopic and histological disease activity vs placebo. Conclusion Gut-selective pan-JAK inhibition with TD-1473 administration resulted in high intestinal vs plasma drug exposure, local target engagement, and trends toward reduced UC disease activity. [Clinicaltrials.gov NCT02657122, NCT02818686]

RESULTS. In IOBA-NHC, TNFa, and IFNc induced MPTP opening, DWm loss, and increased cell apoptosis. This was accompanied by upregulation of Fas/FasL; Bax; and caspase-3, -8, and -9 activation. Addition of CsA prevented IOBA-NHC from cell death by blocking MPTP opening, DWm loss, Fas/FasL, and caspase activation. In PMA/aCD3-activated Jurkat T cells, MPTP opening and DWm loss were increased along with cell apoptosis and upregulated Fas/FasL/ caspase expressions. CsA further promoted T-cell apoptosis, DWm loss, and upregulation of Fas/FasL/caspase. CONCLUSIONS.Inflammation induces aberrant MPTP opening, resulting in an increased apoptosis in conjunctival epithelial cells. CsA protected IOBA-NHC from cell death by blocking both intrinsic and extrinsic apoptosis pathways. CsA promoted T-cell apoptosis via upregulating Fas/FasL and caspase activities with a minimal effect on MPTP. The findings suggest that the differential effect of CsA on T cells versus ocular surface resident epithelial cells may contribute to its therapeutic efficacy in treating ocular inflammation such as dry eye disease.

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RATIONALE: Allergic rhinitis (AR) is a known comorbidity in asthmatic adolescents that may exacerbate symptoms. School-based programs have demonstrated that preventive asthma therapy administered under school nurse supervision reduces morbidity. However a subgroup of adolescents continue to have difficult to control asthma despite monitored preventive treatment. Using the unified airway paradigm, we hypothesized that this cohort of adolescents would have significant burden of AR, and AR would be associated with worse asthma outcomes. METHODS: We included adolescents aged 12-16 years from the Rochester City School District who participated in the School Based Asthma Care for Teens trial between 2016-2017. History of AR and asthma outcomes were assessed via clinical history and spirometry. Bivariate and multivariate regression models adjusting for age, gender, race, ethnicity, insurance, and smoke exposure estimated the association between AR and asthma morbidity. RESULTS: We used baseline data from 387 adolescents with persistent asthma (mean age 13, 55% Black, 32% Hispanic, 85% Medicaid). 77% of adolescents reported a history of AR. Adolescents with AR were more likely to be seen in the ED for asthma compared to adolescents without AR (aOR 2.64; 95%CI 1.29-5.44). Adolescents with AR were more likely to use rescue medication and miss school due to asthma compared to those without AR. FENO was elevated in adolescents with AR vs. those without AR. Importantly, only 52% of adolescents with AR reported taking allergy medication. CONCLUSIONS: Allergic rhinitis is prevalent in high-risk adolescents with persistent asthma and is associated with significant asthma morbidity and under-treatment.