THU0220 Seletalisib, a novel selective pi3kΔ inhibitor with therapeutic potential in inflammation and autoimmunity
Authors: A Payne, M Juarez, GI Johnston, E Helmer, M Thomson
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> PI3Kδ is predominantly expressed in lymphocytes; the role it plays in immune disease has encouraged the development of inhibitors targeting its kinase activity. Inhibitors of PI3Kδ have been approved or are in clinical development for the treatment of B cell malignancies; their therapeutic potential in inflammatory and autoimmune disease is being explored. Seletalisib is a selective and potent PI3Kδ inhibitor that has been profiled in preclinical and early clinical studies. <h3>Objectives</h3> To assess the therapeutic potential of seletalisib in inflammatory and autoimmune disease. <h3>Methods</h3> <i>In vitro</i> cell-based studies were performed on blood samples taken from healthy volunteers (HV) or from patients with primary Sjogren9s Syndrome (pSS) and/or psoriasis. In addition, samples were analysed from a single ascending dose study in HV (NCT02207595) and a multiple ascending dose study in HV and psoriasis patients (NCT02303509). T and B cell responses in the presence and absence of seletalisib were assessed by flow cytometry or a Meso-Scale discovery assay (Meso-Scale Diagnostics, MD, USA), following activation of the T cell- or B cell-receptor by receptor cross-linking or via stimulation with specific antigens. The functional selectivity of seletalisib was assessed in the BioMap system (DiscoverX, CA, USA). Translational studies used flow cytometry and/or immunofluorescence to demonstrate the presence of active PI3K signalling in diseased tissue, through expression of phosphorylated-AKT (pAKT) or -ribosomal protein S6 (pS6). The effect of seletalisib on PI3K signalling was determined by phospho-flow cytometry. Target engagement was determined through measurement of basophil degranulation in healthy subjects, and assessment of lesion severity score in skin biopsies from patients with psoriasis that were treated with seletalisib. <h3>Results</h3> Preclinical studies showed seletalisib potently inhibited T cell differentiation and function (IC<sub>50</sub> range: 2–31 nM). Further, it blocked activation and proliferation of B cells (IC<sub>50</sub> range: 16–49 nM). When profiled in a wide range of primary cell assay systems, including fibroblasts, epithelial, endothelial and vascular smooth muscle cells, seletalisib showed significant activity only in those systems containing lymphocytes, demonstrating its functional selectivity towards PI3Kδ-expressing cells. Expression of the PI3K pathway in lymphocytes was shown at the site of disease in clinical samples both from patients with psoriasis and pSS. Seletalisib inhibited PI3K signalling, measured by a reduction in pAKT and pS6 expression, in T cells derived from patients with psoriasis. In first-in-man studies, mean seletalisib plasma concentration-time profiles increased with increasing dose after single and multiple dosing, with no major deviations from dose proportionality. There was no unexpected accumulation or loss of exposure after multiple dosing (time-independent pharmacokinetic (PK) profile) and apparent t<sub>1/2</sub> values (approx. 20h) were supportive of once-daily dosing. Inhibition of basophil degranulation in healthy subjects and effects on the cellular composition in lesional skin biopsies from patients with psoriasis, provided indications of target engagement, following treatment with seletalisib. <h3>Conclusions</h3> Seletalisib is a potent, selective PI3Kδ inhibitor with an attractive preclinical and human PK profile; clinical studies are ongoing. <h3>Disclosure of Interest</h3> A. Payne Shareholder of: UCB Pharma, Employee of: UCB Pharma, M. Juarez Shareholder of: UCB Pharma, Employee of: UCB Pharma, G. Johnston Shareholder of: UCB Pharma, Employee of: UCB Pharma, E. Helmer Shareholder of: UCB Pharma, Employee of: UCB Pharma, M. Thomson Shareholder of: UCB Pharma, Employee of: UCB Pharma