Impact of Selective Tyrosine Kinase 2 Inhibition With Zasocitinib (TAK-279) on Molecular Pathways and Correlated Clinical Response in Patients With Active Psoriatic Arthritis.

OBJECTIVE: This post hoc analysis evaluated the effect of zasocitinib, an investigational, oral, allosteric, highly selective, and potent tyrosine kinase 2 (TYK2) inhibitor in late-stage clinical development, on TYK2 signaling response and disease-related biomarkers and the association of these changes with clinical response in patients with active psoriatic arthritis from a phase 2b trial (NCT05153148). METHODS: Blood samples were collected predose from patients receiving zasocitinib 15 mg, 30 mg, or placebo once daily on Day 1 (baseline), Week 4, and Week 12. Plasma biomarkers related to TYK2 signaling response, inflammation, skin and joint pathogenesis, cartilage/bone turnover, and bone formation were measured using Olink Explore HT, Olink Target 48, or Nordic BioScience platforms. RESULTS: As early as Week 4 and through Week 12, in patients receiving zasocitinib 15 or 30 mg, reductions in analyzed biomarkers were observed. Among American College of Rheumatology 20% improvement criteria (ACR20) and Psoriasis Area and Severity Index 75% improvement criteria (PASI 75) responders, reductions in TYK2- and skin-joint-related biomarkers occurred following zasocitinib treatment from baseline to Week 12. Maintenance of baseline bone formation biomarkers was observed in ACR20 responders receiving zasocitinib. Patients with high baseline levels (≥ median) of TYK2- and skin-joint-related biomarkers receiving zasocitinib achieved greater ACR20 and PASI 75 response rates than those receiving placebo. CONCLUSION: Reductions in biomarkers related to TYK2 signaling response, inflammation, skin and joint pathogenesis, and cartilage/bone turnover, along with maintenance of bone formation biomarkers at Week 4, occurred following zasocitinib treatment; associations with clinical response (ACR20 and PASI 75) were observed.