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

Abstract

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].

Keywords: JAK inhibitor; Ulcerative colitis; gut-selective.

© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.

Figures

Figure 1.

Plasma and colon tissue homogenate levels of [A] TD-1473 and [B] tofacitinib following oral administration of TD-1473 [10 mg/kg] or tofacitinib [10 mg/kg] to mice. Data are expressed as mean ± SD [n = 4]. Samples collected from 0 to 24 h; lower limit of quantification = 0.00025 µM plasma or colon. IC50, concentration producing 50% maximal inhibition of mouse colonic epithelium interleukin-6/phosphorylated signal transducer and activator of transcription [STAT]-1 signalling; JAK, Janus kinase; SD, standard deviation.

Figure 2.

Effects of orally dosed [A] TD-1473 [0.1–30 mg/kg BID] and [B] tofacitinib [5–30 mg/kg TID] on the disease activity index following Oxa challenge to sensitized mice. Data are expressed as mean ± SD [n = 5–34]. ****p < 0.0001 vs Veh/Veh using Student’s unpaired t-test; #p < 0.05 vs Veh/Oxa using one-way ANOVA with Fisher’s LSD; ##p < 0.01 vs Veh/Oxa using one-way ANOVA with Fisher’s LSD; ###p < 0.001 vs Veh/Oxa using one-way ANOVA with Fisher’s LSD; ####p < 0.0001 vs Veh/Oxa using one-way ANOVA with Fisher’s LSD. ANOVA, analysis of variance; BID, twice daily; LSD, least significant difference; Oxa, oxazolone; SD, standard deviation; TID, three times daily; Veh, vehicle.

Figure 3.

Effects of orally dosed TD-1473 [1, 10 and 100 mg/kg BID] and tofacitinib [5, 10, 15 and 30 mg/kg TID] on splenic NK, T and B cells following 3 days of dosing to mice. All data are expressed as mean ± SD [n = 5–8]. All statistical analyses used one-way ANOVA with Fisher’s LSD. **p = 0.003 vs vehicle; ***p = 0.0004 vs vehicle; ****p < 0.0001 vs vehicle. ANOVA, analysis of variance; BID, twice daily; LSD, least significant difference; NK, natural killer; SD, standard deviation; TID, three times daily.

Figure 4.

Concentrations of TD-1473 following oral administration. [A] Steady-state plasma concentrations on day 14 in first-time-in-human study; [B] steady-state plasma concentrations on day 14 in Phase 1b UC study; [C] colonic tissue concentrations on day 28 in Phase 1b study. Geometric mean [95% confidence interval] TD-1473 colonic tissue concentration was 4090 [2270–7380] pg/g, 65 300 [28 200–151 000] pg/g, and 43 500 [15 200–124 000] pg/g for TD-1473 20, 80 and 270 mg, respectively. Grey shading represents IC50 values [nM] of cellular cytokine/pSTAT assays in human epithelial and immune cells representing all JAK pairings [compare to Table 1]. IC50, 50% of the concentration producing half-maximal inhibition; JAK, Janus kinase; QD, once daily; SD, standard deviation; UC, ulcerative colitis.

Figure 5.

Efficacy of TD-1473 in subjects with moderately to severely active ulcerative colitis. [A] Rates of clinical response and endoscopic response on day 28; [B] rates of modified Mayo endoscopic and Mayo rectal bleeding subscore improvement from baseline at day 28; [C] change in Robarts Histopathology Index from baseline to day 28. Clinical response, decrease in total Mayo score of ≥3 points and ≥30% with decrease in rectal bleeding subscore by ≥1 or an absolute rectal bleeding subscore of ≤1. Endoscopic response, endoscopic subscore of ≤1. Endoscopic and rectal bleeding subscore improvement, reduction by ≥1 point. SD, standard deviation.

Figure 6.

Placebo-adjusted changes in disease surrogate biomarkers of ulcerative colitis. [A] Change in faecal calprotectin level at day 1 and day 14; [B] change in serum C-reactive protein by visit and dose. Gray dots and dashed line, subject[s] with faecal calprotectin level ≤150 at day 28; open squares and gray line, subject[s] with faecal calprotectin level reduced by ≥75% from baseline to day 28. CI, confidence interval.