33226 Analysis of histologic and molecular improvement in moderate-to-severe psoriasis: Results from a phase 1b trial of the novel allosteric Tyk2 inhibitor NTX-973

Abstract

We report the results of histologic and molecular analyses of skin biopsies from a phase 1b, randomized, double-blind, placebo-controlled trial of NTX-973, an oral allosteric Tyk2 inhibitor, in patients with moderate-to-severe psoriasis. A total of 25 patients were treated with one of three active doses (5 mg, 10 mg, or 30 mg) of NTX-973 or placebo daily for 28 days. The primary objective was assessment of safety and tolerability of NTX-973. Secondary objectives included assessment of pharmacokinetic and pharmacodynamic parameters. The pharmacodynamic assessment included lesional and nonlesional skin biopsies at Day 1 and lesional skin biopsy at Day 28. Histologic appearance, immune infiltration, and gene expression of inflammatory pathways in lesional skin at Day 28 versus Day 1 were compared using immunohistochemical staining, RT-PCR, and microarray analysis. After 28 days of treatment with 5 mg of NTX-973, we observe significant decreases in the thickness of lesional skin (P < .05), suggestive decreases in the expression of several psoriasis-related genes by RT-PCR (such as KRT16, IL17A, IL17F, and IL22), and up to 50% improvement in the expression of a number of pathways (P < .01 compared with placebo treatment) previously associated with psoriasis in lesional skin through microarray analysis. Results indicate that NTX-973 treatment for 28 days results in improvements across multiple measures of disease pathology and normalization of molecular and inflammatory pathways dysregulated in psoriasis.