Background/Purpose: Zasocitinib (TAK-279), an oral, allosteric, selective, tyrosine kinase 2 (TYK2) inhibitor in late-stage clinical development for the treatment of immune-mediated inflammatory diseases including psoriatic arthritis, was developed using AI-assisted compound design to create a next-generation TYK2 inhibitor with >1.3 millionfold greater affinity for TYK2 than Janus kinase (JAK)1/2/3.¹

Methods: Whole blood culture from 12–13 healthy volunteers was used to characterize concentration–response (defined as percentage inhibition) curves for TYK2- (IL-12/18 IFN-γ) and JAK1/3- (IL-2 pSTAT5) dependent pathways for zasocitinib and licensed TYK2 and JAK inhibitors. Statistical modeling determined the relationship between concentration and percentage inhibition, and half-maximal inhibitory concentration (IC₅₀) values were estimated. Plasma concentrations at clinically relevant/approved doses for each drug were simulated using population pharmacokinetic models from the literature. The time over which plasma concentrations exceeded the IC₅₀, as well as the percentage daily inhibition, were compared between drugs for each pathway.

Results: Simulated plasma concentrations remained above the TYK2 IC₅₀ for 24 hours for zasocitinib 30 mg QD versus 3 hours for deucravacitinib 6 mg QD, and 0 hours for baricitinib 4 mg once daily [QD], tofacitinib 10 mg twice daily [BID] and upadacitinib 30 mg QD (Table 1, Figure 1). Daily inhibition of TYK2 was 91% for zasocitinib 30 mg and 23% for deucravacitinib 6 mg, and minimal TYK2 inhibition was observed for baricitinib 4 mg, upadacitinib 30 mg and tofacitinib 10 mg (0–8%; Figure 2). Simulated plasma concentrations of zasocitinib 30 mg and deucravacitinib 6 mg did not reach the JAK1/3 IC₅₀, and those of baricitinib 4 mg, upadacitinib 30 mg and tofacitinib 10 mg remained above the JAK1/3 IC₅₀ for 24 hours (Table 1, Figure 1). Daily inhibition of JAK1/3 was 0% for zasocitinib 30 mg and 3% for deucravacitinib 6 mg versus 91–97% for baricitinib 4 mg, upadacitinib 30 mg and tofacitinib 10 mg (Figure 2).

Conclusion: Zasocitinib exhibits selective inhibition of TYK2-mediated signaling, with greater and longer inhibition than deucravacitinib at its clinical dosage, without affecting JAK1/3-mediated signaling. These data show selective inhibition of TYK2 offers a distinct cytokine receptor inhibition profile versus when JAK is inhibited, and may contribute to an improved safety profile.

Reference:

1. Leit S et al. J Med Chem 2023;66:10473–96.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/zasocitinib-tak-279-displays-high-levels-of-tyk2-inhibition-and-no-inhibition-of-jak-1-3-compared-with-licensed-tyk2-and-jak-inhibitors/