Rao, Koneti V, Webster, Sharon, Dalm, Virgil ASH, Sediva, Anna, van Hagen, Martin P, Holland, Steven, Rosenzweig, Sergio D, Christ, Andreas Dominik, Sloth, Birgitte, Cabanski, Maciej, Joshi, Aniket, De Buck, Stefan, Doucet, Julie, Guerini, Danilo, Kalis, Christoph, Pylvaenaeinen, Ilona, Soldermann, Nicolas, Kashyap, Anuj, Gulbu, Uzel, Leonardo, Michael J, Patel, Dhavalkumar, Lucas, Carrie L and Burkhart, Christoph (2017) Effective ‘Activated PI3Kdelta Syndrome’-targeted therapy with PI3Kdelta inhibitor leniolisib. Blood, 130 (21). pp. 2307-2316. ISSN 1528-0020; 0006-4971

Abstract

Pathogenic gain-of-function variants in the genes encoding PI3Kdelta (phosphoinositide 3-kinase delta) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy and immune-deficiency (Activated PI3Kdelta Syndrome, APDS). Knowing genetic etiology of APDS afforded us the opportunity to explore PI3Kdelta inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kdelta in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kdelta inhibitor, caused a dose-dependent suppression of PI3Kdelta pathway hyperactivation (measured as phosphorylation of AKT/S6) in cell lines ectopically expressing APDS-causative p110δ variants and in T cell blasts derived from patients. A clinical trial with six APDS patients was conducted as a 12-week, open-label, multi-site, within-subject dose-escalation study of oral leniolisib to assess safety, pharmacokinetics and effects on lymphoproliferation and immune dysregulation. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and improved immune dysregulation. We observed normalization of circulating transitional and naïve B cells, reduction in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum IgM and inflammatory markers including IFNgamma, TNF, CXCL13 and CXCL10 with leniolisib therapy. After 12 weeks of treatment, all patients showed amelioration of lymphoproliferation with lymph node sizes and spleen volumes reduced by 39% (mean, range 26-57%) and 40% (mean, range: 13-65%), respectively. Thus, leniolisib was well tolerated and improved laboratory and clinical parameters in APDS, supporting the specific inhibition of PI3Kdelta as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kdelta pathway.

Item Type:	Article
Date Deposited:	09 Dec 2017 00:45
Last Modified:	09 Dec 2017 00:45
URI:	https://oak.novartis.com/id/eprint/33974