PF-06700841 (PF-841), is a selective TYK2/JAK1 kinase inhibitor, that reduces IL-23 expression and directly attenuates IL-23 signaling via TYK2. 30 patients were randomized to receive 30mg or 100mg doses of PF-841 or placebo daily for 4 weeks (wks) in the PF-841 phase 1 clinical study (NCT02310750). Skin biopsies were collected at baseline and wks 2 & 4 and analyzed by RTPCR and gene arrays. Expression of IL17A and IL17F genes significantly decreased by wk2 (FC¼5.1, FC¼3.2) and wk4 (FC¼36, FC¼104) in the 100mg dose group. Decreases in IL23/p19 (FC¼2.4) and IL12/IL23p40 (FC¼16) were observed as early as wk2 with further decreases in p40 (FC¼182) at wk4. The top treatment-responsive genes (DEG, FC>2, FDR < 0.05) after 4 wks included IL12/23p40, KRT16, IL-17 pathway genes (S100A7A, A9, A12, IL19, IL36G), IFNrelated genes (CXCL1,9,10, IFI27), and granzyme b. The effect of PF-841 on psoriasis-relevant pathways was assessed using gene set variation analysis. At wk4, up-regulated genes in the psoriasis phenotype, defined by the Meta-Analysis Derived psoriasis transcriptome, improved by 110% (100mg) and 73.5% (30mg) with reference to non-lesional skin, with similar improvement for down-regulated genes, effectively normalizing expression. A dose dependent response was also observed in genes up-regulated by IL-17 stimulation of keratinocytes (127%, 75%), or reconstructed human epidermis (114%, 77%) and genes associated with Super-Enhancers of Th17 (134%, 84%), Th1(142%, 86%) and Th2 (149%, 80%) cells for 100mg and 30mg dose respectively. In contrast placebo treatment failed to significantly modulate these pathways. These results suggest that targeting TYK2 and JAK1 kinases with PF-841 induces a rapid attenuation of the IL-23/Type 17 T-cell axis that is critical in psoriasis pathogenesis along with full suppression of the disease-defining molecular phenotype.