Zasocitinib, an investigational oral tyrosine kinase 2 (TYK2) inhibitor, has demonstrated significant improvements in patients with active psoriatic arthritis, according to a recent study published in Annals of the Rheumatic Diseases. The findings highlight the potential of targeted oral therapies to address both joint and skin symptoms in immune-mediated inflammatory diseases.
TYK2, a Janus kinase–related enzyme, plays a critical role in intracellular signaling via the JAK–STAT pathway, which regulates immune responses and inflammation. Genome-wide association studies have shown that certain loss-of-function TYK2 variants protect against several inflammatory conditions, including psoriasis. These insights have made TYK2 an attractive target for novel therapies aimed at modulating immune function without broader immunosuppression.
Zasocitinib (TAK-279) is a highly selective, potent, orally administered allosteric TYK2 inhibitor currently in late-stage clinical development for autoimmune and inflammatory conditions, including psoriasis and psoriatic arthritis. Its discovery was aided by an artificial intelligence–driven computational design platform, which optimized candidate compounds for strong binding to the TYK2 Janus homology 2 domain while minimizing off-target activity.
The phase 2b, randomized, multicenter, double-blind, placebo-controlled study enrolled 290 adults aged 18 years or older who had experienced psoriatic arthritis symptoms for at least six months. Participants received daily doses of zasocitinib at 5 mg, 15 mg, or 30 mg, or placebo for 12 weeks, followed by a four-week safety follow-up. The mean age of participants was 49.9 years, with 57.2 percent female representation.
At week 12, patients receiving 15 mg or 30 mg of zasocitinib achieved significantly higher ACR20 response rates than placebo (53.3% and 54.2% versus 29.2%). Responses for ACR50 and ACR70, which indicate higher levels of improvement, were also numerically higher in the 15 mg and 30 mg groups. Among patients with at least three percent body surface area involvement at baseline, PASI 75 responses reached 45.7% in the 30 mg group compared to 15.4% with placebo. Minimal disease activity was achieved in 29.2% of patients receiving 30 mg, versus 12.5% for placebo. Notably, rapid improvements in both joint and skin symptoms were observed as early as week 2.
Safety outcomes were consistent with previous studies in psoriasis. Most adverse events were mild to moderate and occurred more frequently in the higher dose group. No new safety signals or dose-dependent laboratory abnormalities were detected. The lack of adverse events associated with JAK1, JAK2, or JAK3 inhibition underscores the high selectivity of zasocitinib for TYK2.
These promising results have paved the way for ongoing phase 3 trials, which aim to confirm efficacy and safety in larger and more diverse patient populations. If these findings are validated, zasocitinib could offer patients an effective, orally administered treatment option for psoriatic arthritis, targeting both the joints and skin with a favorable safety profile.
References
- Kivitz A, Baraliakos X, Muensterman ET, Kavanaugh A, van der Heijde D, Klimiuk PA, et al. Highly selective tyrosine kinase 2 inhibition with zasocitinib (TAK-279) improves outcomes in patients with active psoriatic arthritis: a randomised phase 2b study. Ann Rheum Dis. 2025 Oct;84(10):1660-1674.
- Armstrong AW, Gooderham M, Lynde C, Maari C, Forman S, Green L, et al. Tyrosine Kinase 2 Inhibition With Zasocitinib (TAK-279) in Psoriasis: A Randomized Clinical Trial. JAMA Dermatol. 2024 Oct 1;160(10):1066-1074.
- Mehrotra S, Sano Y, Halkowycz P, Wilson E, Durairaj C, Kong KF,et al. Pharmacological Characterization of Zasocitinib (TAK-279): An Oral, Highly Selective, and Potent Allosteric TYK2 Inhibitor. J Invest Dermatol. 2025 May 27:S0022-202X(25)00531-7.