FC24 Zasocitinib (TAK-279), an oral, allosteric, highly selective TYK2 inhibitor, modulates disease-central cytokine pathways that define clinical response in patients with moderate-to-severe plaque psoriasis

Abstract Zasocitinib (TAK-279) demonstrated promising efficacy and was generally well tolerated in a completed Phase 2b study (NCT04999839) in patients with moderate-to-severe plaque psoriasis, with the primary endpoint [75% improvement in psoriasis area and severity (PASI75)] achieved at doses ≥5 mg vs. placebo at Week 12. In an exploratory analysis of this study, associations between zasocitinib treatment, psoriasis/tyrosine kinase 2 (TYK2) biomarkers, and clinical/histological response were investigated. Lesional/non-lesional serum samples and skin biopsies were obtained with consent at Day 1 (pre-dose) and Weeks 4 and 12 from patients receiving zasocitinib (2, 5, 15, and 30 mg) or placebo orally once daily. RT-qPCR, RNA-seq and immunohistochemistry were used to assess changes in lesion keratinocyte proliferation (KRT16 expression), psoriasis/TYK2 biomarkers and lesion gene signatures, and their associations with clinical (PASI75) and histological (plaque resolution) response. Serum samples from 252 patients and biopsy samples from 63 patients were analysed. At Week 12, most clinical responders (n = 21/24, 88%) experienced reductions in KRT16 expression of >87% vs. baseline lesion levels. Pooled analysis showed that, in most histological responders (n = 18/25, 72%), interleukin (IL)17A and IL17F expression reduced by >80% vs. baseline lesion levels. Reductions in lesional type I interferon, IL-12 and IL-23 pathway gene expression were observed at zasocitinib 15 and 30 mg doses compared with baseline levels (P < 0.05). Dose- and time-dependent reductions in serum IL-17A, IL-17C and IL-17F were observed in all zasocitinib groups vs. placebo. In the 15 and 30 mg groups (n = 23), expression of key psoriasis/TYK2 biomarkers (e.g. DEFB4A, IL36G, IL23A) reverted to non-lesional levels at Week 12. Among evaluable PASI90 responders at Week 12 (n = 12), 48/50 of the top upregulated genes in lesions reverted to non-lesional expression levels. In all dose groups, patients had reduced lesional epidermal thickness, CD3+ T-cell counts and CD11c+ myeloid dendritic cell counts with zasocitinib vs. baseline. Zasocitinib treatment did not result in clinically meaningful longitudinal changes in laboratory parameters associated with Janus kinase inhibition. Zasocitinib modulated psoriasis/TYK2 biomarkers were associated with clinical and histological response in patients with moderate-to-severe plaque psoriasis.