TYK2 Inhibition with Zasocitinib Delivers Early Benefit Across PsA Domains

Despite the array of treatment options for psoriatic arthritis (PsA), many patients continue to experience residual symptoms and functional limitations. Oral therapies that can meaningfully impact musculoskeletal and skin manifestations without introducing new safety concerns are especially needed. A phase 2b trial published in Annals of the Rheumatic Diseases evaluates zasocitinib (TAK-279), a highly selective tyrosine kinase 2 (TYK2) inhibitor, as a potential oral alternative for patients with active PsA.

Study Designed for Targeted, Oral Intervention

This randomized, double-blind, placebo-controlled trial enrolled 290 adults with active PsA across 45 centers in the US and Europe. Patients were randomized to receive 5 mg, 15 mg, or 30 mg zasocitinib or placebo once daily for 12 weeks, with a 4-week follow-up.

The primary endpoint was ACR20 response at week 12. Secondary endpoints included ACR50 and ACR70, PASI 75, minimal disease activity (MDA), and composite disease activity scores such as DAPSA and PASDAS. Skin endpoints were also evaluated in patients with ≥3% body surface area involvement at baseline.

Early Clinical Responses with 15 mg and 30 mg Doses

At 12 weeks, both the 15 mg and 30 mg doses of zasocitinib achieved significantly higher ACR20 response rates (53.3% and 54.2%, respectively) compared with placebo (29.2%). These improvements were accompanied by numerically greater ACR50 and ACR70 responses, although not all reached statistical significance.

Skin responses were also notable, with the 30 mg group achieving PASI 75 in 45.7% of patients versus 15.4% in placebo. PASI 90 and PASI 100 responses at this dose were 37.0% and 26.1%, respectively. Improvements in skin symptoms were observed as early as week 2.

Across composite measures:

• MDA was reached by 29.2% (30 mg) and 28.0% (15 mg) vs 12.5% in placebo.
• DAPSA and PASDAS scores improved across all zasocitinib groups, with the largest reductions seen at higher doses.
• Patient-reported outcomes (pain, PtGA, HAQ-DI) also trended favorably.

Safety Profile Supports Selective TYK2 Targeting

Adverse events were more common in the 30 mg group (77.8%) than placebo (54.2%), largely driven by mild/moderate infections and dermatologic reactions such as acneiform rash. Serious adverse events and discontinuations were infrequent. Importantly, no new safety signals, no major adverse cardiovascular events, and no laboratory evidence of JAK1–3 inhibition were observed, supporting the drug’s selectivity for TYK2.

Limitations and Next Steps

While the 12-week duration limits insight into long-term safety or structural outcomes, the consistent directional benefit across multiple PsA domains and patient-reported measures provides early validation of this mechanism. Notably, efficacy trends were observed despite the inclusion of patients with prior biologic exposure and variable baseline inflammation (hsCRP not required for entry).

Regional variability in placebo response (higher in Eastern Europe) and small sample sizes for some subgroup analyses (e.g., dactylitis, enthesitis) may impact generalizability.

Clinical Takeaway

Zasocitinib demonstrates promise as a well-tolerated oral TYK2 inhibitor that can impact both joint and skin manifestations of PsA. Its rapid onset and domain-wide efficacy suggest potential utility in personalized PsA care, particularly for patients seeking alternatives to injectable biologics. Ongoing phase 3 studies will be critical to establish its role among targeted synthetic DMARDs.

Reference:
Kivitz A, Baraliakos X, Muensterman ET, 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;84(10):1660-1674. doi:10.1016/j.ard.2025.05.023