PN-881: First-in-class oral peptide targeting the IL–17 pathway

Summary: Abstract Body: IL-17 is a key mediator of psoriasis, psoriatic arthritis, hidradenitis suppurativa, and spondyloarthritis. There are currently multiple approved injectable IL-17 antagonists but no orally delivered antagonists. Clinical trials of these agents have shown that inhibition of IL-17A and F and their 3 dimeric forms (AA, AF, and FF) yield greater efficacy in psoriasis than inhibition of IL-17A alone. Here we report for the first time the preclinical characterization of PN-881, an orally delivered macrocyclic peptide that potently and selectively binds IL-17A and F, thus blocking all 3 dimeric forms. PN-881 inhibits IL-17-induced IL-6 production in human HT-1080 fibrosarcoma cells and in primary human dermal fibroblasts (nHDF) with concentration-dependent potency (IC50) values comparable to bimekizumab. The HT-1080 IC50 values for PN-881 are 0.13 nM (AA), 27 nM (AF), and 14 nM (FF) and for bimekizumab are 0.17 nM (AA), 19 nM (AF), and 13 nM (FF). PN-881 is resistant to the proteolytic and reducing environment of the gastrointestinal tract and stable in serum after absorption, making it a suitable candidate for oral delivery. Pharmacokinetic (PK) evaluations in a variety of preclinical species indicate PN-881 achieves systemic exposures and skin distribution multiple folds above the IC50 after oral administration. Orally dosed PN-881 blocked IL-17-induced chemokine ligand 1 (CXCL1) production in mice in a dose-dependent manner. PN-881 also dose-dependently inhibited IL-23-induced rat skin inflammation and thickening with significant effects at oral doses as low as 2 mg/kg/day. These preclinical potency, PK, PD, and efficacy results support the potential for a first-in-class oral peptide targeting IL-17-mediated diseases. Jason Halladay¹, Jenny Zhang², Mariana Manrique¹, Li Zhao¹, Padmapriya Kumaraswamy¹, Bo Yang¹, Catarina Tran¹, James Tovera¹, Ashok Bhandari¹ 1. Protagonist Therapeutics Inc, Newark, CA, United States. 2. Protagonist Pty Ltd, St. Lucia, Brisbane, QLD, Australia. Adaptive and Auto-Immunity