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

Background 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. Methods 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. Results 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 naive 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. Conclusions 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; ClinicalTrials.gov number, NCT02435173).