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* = Presenting author

P069 TD-1473, a novel, potent, and orally administered, GI-targeted, pan-Janus kinase (JAK) inhibitor

D. Beattie*, P. Tsuruda, F. Shen, P. Brassil, C. Langrish, J. Janc, Z. Ren, R. Hudson, J. Smith, S. Hegde

Theravance Biopharma, South San Francisco, United States

Background

Inflammatory bowel diseases (IBDs) negatively affect the quality of life of patients. Available therapies can be associated with modest efficacy and serious adverse effects. Proinflammatory cytokines play an important role in IBD, many of which signal via the JAK/signal transducer and activator of transcription (STAT) pathway. Tofacitinib (Xeljanz®), an oral, systemically available, JAK inhibitor, is efficacious in ulcerative colitis patients (Sandborn et al., 2012). Unlike tofacitinib, TD-1473, a novel pan-JAK inhibitor, was designed to inhibit JAK in the GI tract upon oral dosing without significant systemic exposure. This study compares the preclinical properties of TD-1473 and tofacitinib.

Methods

The in-vitro pharmacology of the compounds was evaluated in biochemical assays with human isolated JAK kinase domains, and in cellular assays monitoring cytokine-evoked STAT phosphorylation and cellular responses in human immune and epithelial cells. The off-target kinase potency of TD-1473 was investigated to assess its JAK selectivity using both binding and function-based assays. The murine oxazolone-induced colitis model was used to study the anticolitic effects of TD-1473 and tofacitinib in vivo. Murine splenic natural killer (NK) cell counts were monitored by flow cytometry to provide a measure of systemic JAK inhibition.

Results

TD-1473 was a potent JAK1, JAK2, JAK3, and TYK2 inhibitor at the human JAK kinase domains (pKi values of 10.0, 10.0, 8.8, and 9.5, respectively). TD-1473 inhibited cytokine-evoked STAT phosphorylation in human peripheral blood mononuclear cells (PBMCs) and in a human colonic epithelial cell line (pIC50 ≥ 6.7). TD-1473 inhibited downstream cytokine-evoked responses, inhibiting IL-2/CD3-stimulated IFN γ release from human PBMCs (pIC50 = 7.2) and IL-13/IL-1 α -induced IL-8 production in colonic epithelial cells (pIC50 = 7.1). In general, tofacitinib and TD-1473 had similar inhibitory potencies in the cellular assays. The selectivity of TD-1473 for JAK1, relative to its off-target activity, was at least 100-fold. Oral dosing of TD-1473 (1 mg/kg BID) and tofacitinib (10 and 15 mg/kg TID) inhibited, to a similar extent, the oxazolone-induced disease activity index (an average of body weight, stool consistency, and occult blood scores) in mice. Systemic levels of TD-1473 (1 mg/kg PO) were approximately 1 000-fold lower than those of tofacitinib (15 mg/kg PO). Tofacitinib (10–30 mg/kg orally TID) reduced, by up to 60%, splenic NK cell counts, whereas TD-1473 (1–100 mg/kg BID) had no effect.

Conclusion

A JAK inhibitor, such as TD-1473, has the potential to act selectively within the GI tract to treat IBD without systemically mediated adverse effects.