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Effective 'Activated PI3Kd Syndrome' -targeted therapy with PI3Kd inhibitor leniolisib

Koneti, Rao 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, Uzel , Gulbu, Leonardo, Michael J, Patel, Dhavalkumar, Lucas, Carrie L and Burkhart, Christoph (2017) Effective 'Activated PI3Kd Syndrome' -targeted therapy with PI3Kd inhibitor leniolisib. The New England journal of medicine : NEJM. ISSN 0028-4793; 1533-4406


Gain-of-function mutations driving PI3K (phosphoinositide 3-kinase delta) enzyme activity lead to accumulation of senescent T cells, lymphadenopathy and immune-deficiency (PASLI disease), also known as Activated PI3K Syndrome (APDS). Inhibition of PI3K is a new therapeutic approach for the treatment of APDS.
We assessed leniolisib (CDZ173), a potent and selective PI3K inhibitor, in vitro for its effect on PI3K pathway activation induced by four APDS-causative p110δ variants in cell lines and in T cell blasts from patients. We then conducted a clinical trial with six APDS patients who completed a 12-week, open-label, multi-site, within-subject dose-escalation study of leniolisib to assess safety, pharmacokinetics and effects on lymphoproliferation and immune dysregulation.
Expression of APDS mutant p110δ in cell lines and patient-derived lymphocytes led to increased pathway activity, measured as phosphorylation of AKT or S6, which was suppressed by leniolisib in a concentration dependent way. Oral leniolisib led to a dose-dependent reduction in PI3K/AKT pathway activity assessed ex vivo and resolved the immune dysregulation with normalization of circulating transitional and naïve B cells and reduction in PD-1+CD4+ and senescent CD57+CD8+ T cells. 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.
Targeting hyperactive p110 in APDS patients using leniolisib was well tolerated and showed consistent laboratory and clinical improvement, including reduction in cellular immune dysfunction and lymphoproliferation (Funded by Novartis and NIAID DIR; number, NCT02435173).

Item Type: Article
Date Deposited: 23 May 2017 00:45
Last Modified: 23 May 2017 00:45