Novel TYK2 inhibitor Zasocitinib Save

Following the success of janus kinase (JAK) inhibitor use in rheumatic disease, interest has mounted regarding a member of the JAK family, tyrosine kinase 2 (TYK2). Similar to JAKs, TYK2 is an important mediator of innate and adaptive immune activation. Unlike JAKs, however, TYK2 is thought to play a minimal role in other pathways, such as metabolic and hematopoietic axes. Therefore, it is hypothesized that TYK2-targeted agents could be effective in rheumatic disease, with a potential for less off-target adverse effects.

Zasocitinib is a new, oral TYK2 inhibitor generated using artificial intelligence-assisted compound design. It is posited to be incredibly selective, with a reported >1 millionfold greater binding affinity for TYK2 compared to JAK 1, 2, or 3. Mehrotra et al. performed pharmacokinetic analysis using whole blood from healthy volunteers to examine this selectivity in comparison with another TYK2 inhibitor deucravacitinib and compared to existing JAK inhibitors (Abstract 0877).

As hypothesized, Zasocitinib exhibited excellent specificity with no observed off-target JAK 1/3 inhibition as measured by half-maximal inhibitory concentration (IC50) values. Deucravacitinib also displayed high specificity for TYK2, only with an estimated 3% daily inhibition of JAK1/3, in comparison with >90% daily inhibition for all studied JAK inhibitors (baricitinib, upadacitinib, and tofacitinib). The main difference between Zasocitinib and Deucravacitinib appeared to be the duration of inhibition of TYK2 – when dosed once daily, the plasma concentration of Zasocitinib 30mg exceeded TYK2 IC50 for 24 hours, corresponding to an estimated 91% daily inhibition of TYK2. This is in contrast to once daily Deucravacitinib 6mg, which spent an estimated 3 hours exceeding the TYK2 IC50 and corresponding to a 24% estimated daily inhibition.

A phase 2b trial demonstrated significantly more ACR20 response in PsA patients treated with Zasocitinib 15mg and 30mg daily, compared to placebo (53% vs. 54% vs 29% respectively). Additional clinical and laboratory applications of Zasocitinib in psoriatic arthritis (PsA) were reported at ACR24 (Abstracts 1477, 2361).

At the 30mg daily dose, Zasocitinib demonstrated significantly higher rates of PASI 75 (46% vs. 15%), PASI 90 (37% vs. 10%), and PASI 100 (26% vs. 10%) responses compared to placebo by week 12. Patients on Zasocitinib 30mg achieved the greatest Physician Global Assessment of PsO response rates, and a greater proportion of Zasocitinib 30mg patients achieved minimal disease activity at week 12 compared to placebo (28% vs. 12.5%).

To further explore the pathway specificity of Zasocitinib, hematologic, chemistry, and lipid panels were followed throughout the phase 2b study. Anemia was the most common observed hematologic abnormality with rates equivalent (13.9%) in both the PBO and high dose (30mg daily) Zasocitinib groups. Lymphopenia occurred more often in the PBO group compared to the 30mg daily Zasocitinib group. Neutropenia did not occur and thrombocytopenia was rare in all groups. Liver enzyme elevations and creatinine elevations were numerically higher in the Zasocitinib 30mg group compared to placebo (ALT 15.3% vs. 12.5%, AST 12.5% vs 8.3%, Cr 11.1% vs. 6.9%). Cholesterol and triglyceride elevations were equivalent between PBO and 30mg groups while LDL elevations occurred more frequently with Zasocitinib 30mg daily (16.7% vs. 6.9%).

In summary, Zasocitinib appears to be a highly selective TYK2 inhibitor with longer inhibitory effects as compared to Deucravacitinib. Zasocitinib has shown early efficacy in PsA, including in skin response. While hematologic lab monitoring was unremarkable, liver enzyme, creatinine elevation, and LDL elevations were more frequently seen in the Zasocitinib 30mg daily group compared to placebo, and will need to be examined further in future trials, especially as it relates to possible clinical events.