FC14 Modulation of the IL23/IL17 axis beyond IL-17A drives response to risankizumab in palmoplantar psoriasis

Abstract Palmoplantar psoriasis (PPPsO) is a variant of plaque psoriasis (PsO) that is characterized by difficult-to-treat lesions on the hands and feet and is associated with substantial physical disability and discomfort. A better understanding of pathogenic disease drivers is critical to ensuring patients receive treatments that will drive high levels of efficacy. Data from non-head-to-head randomized clinical trials suggest that IL-23 blockade may be more efficacious than IL17A blockade in PPPsO. Here, we evaluated changes in downstream mediators of the IL-23/IL-17 axis following treatment with risankizumab, an interleukin (IL)-23 inhibitor approved for the treatment of PsO and demonstrate that broad coverage of the IL-23 pathway beyond IL-17A may be required to achieve >90% improvement in clinical score in PPPsO. IMMprint (NCT04713592) is an ongoing Phase 3b, multicentre, randomized, double-blind, placebo-controlled study for patients with PPPsO. Patients were randomized 1:1 to receive either blinded 150 mg risankizumab or placebo at Weeks 0 and 4. At Week 16 all patients entered the open-label extension and received risankizumab at Week 16 and every 12 weeks thereafter. Whole blood was collected (N = 35 in each arm) at baseline and Weeks 4, 16, and 52. Serum cytokine levels of IL-17A and IL-17C were assessed by proximity extension assay and IL-22 and beta-defensin 2 (BD-2) were assessed by high sensitivity individual assays. Efficacy at Week 16 was assessed by psoriasis area and severity index (PASI) and palmoplantar PASI (PPASI). Response to risankizumab was defined as achieving the PPASI 90 endpoint. A total of 13 patients receiving risankizumab and 2 patients receiving placebo achieved PPASI 90 at Week 16. Patients that achieved PPASI 90 with risankizumab had a significant reduction in serum levels of IL-22 (pro-inflammatory cytokine), BD-2 (host defence), and IL-17C (amplification of epithelial inflammation) as early as 4 weeks after treatment, continuing through Week 52, compared with patients that did not achieve PPASI 90. Further, a positive correlation between reduction in IL-22, BD-2, and IL-17C and PASI and PPASI scores was observed at Week 16 for patients receiving risankizumab but not placebo. No association was observed between other inflammatory molecules, including IL-17A, and patient achievement of PPASI 90. The data suggest that the IL-23/IL17 axis beyond just IL-17A is important for driving disease pathology in PPPsO.