Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoimmunity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3Kδ signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3Kδ. Here, 31 patients with APDS aged ≥12 years were enrolled in a global, phase 3, triple-blinded trial and randomized 2:1 to receive 70 mg leniolisib or placebo twice daily for 12 weeks. Coprimary outcomes were differences from baseline in the index lymph node size and the percentage of naïve B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary outcomes were met: the difference in the adjusted mean change (95% confidence interval [CI]) between leniolisib and placebo for lymph node size was -0.25 (-0.38, -0.12; P = .0006; N = 26) and for percentage of naïve B cells, was 37.30 (24.06, 50.54; P = .0002; N = 13). Leniolisib reduced spleen volume compared with placebo (adjusted mean difference in 3-dimensional volume [cm3], -186; 95% CI, -297 to -76.2; P = .0020) and improved key immune cell subsets. Fewer patients receiving leniolisib reported study treatment-related adverse events (AEs; mostly grades 1-2) than those receiving placebo (23.8% vs 30.0%). Overall, leniolisib was well tolerated and significant improvement over placebo was notable in the coprimary endpoints, reducing lymphadenopathy and increasing the percentage of naïve B cells, reflecting a favorable impact on the immune dysregulation and deficiency seen in patients with APDS. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

• MeSH
• Double-Blind Method MeSH
• Class I Phosphatidylinositol 3-Kinases MeSH
• Phosphatidylinositol 3-Kinases * MeSH
• Humans MeSH
• Pyridines MeSH
• Pyrimidines * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH
• Names of Substances
• Class I Phosphatidylinositol 3-Kinases MeSH
• Phosphatidylinositol 3-Kinases * MeSH
• leniolisib MeSH Browser
• Pyridines MeSH
• Pyrimidines * MeSH

Pathogenic gain-of-function variants in the genes encoding phosphoinositide 3-kinase δ (PI3Kδ) lead to accumulation of transitional B cells and senescent T cells, lymphadenopathy, and immune deficiency (activated PI3Kδ syndrome [APDS]). Knowing the genetic etiology of APDS afforded us the opportunity to explore PI3Kδ inhibition as a precision-medicine therapy. Here, we report in vitro and in vivo effects of inhibiting PI3Kδ in APDS. Treatment with leniolisib (CDZ173), a selective PI3Kδ inhibitor, caused dose-dependent suppression of PI3Kδ 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 6 APDS patients was conducted as a 12-week, open-label, multisite, 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 naive B cells, reduction in PD-1+CD4+ and senescent CD57+CD4- T cells, and decreases in elevated serum immunoglobulin M and inflammatory markers including interferon γ, tumor necrosis factor, 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 PI3Kδ as a promising new targeted therapy in APDS and other diseases characterized by overactivation of the PI3Kδ pathway. This trial was registered at www.clinicaltrials.gov as #NCT02435173.

• MeSH
• Lymphocyte Activation drug effects   MeSH
• Chemokines blood   MeSH
• Molecular Targeted Therapy * MeSH
• Demography MeSH
• Child MeSH
• Phenotype MeSH
• Class I Phosphatidylinositol 3-Kinases antagonists & inhibitors   immunology   metabolism   MeSH
• Immunoglobulin M blood   MeSH
• Protein Kinase Inhibitors pharmacology   MeSH
• Infant MeSH
• Rats MeSH
• Humans MeSH
• Lymph Nodes drug effects   pathology   MeSH
• Mutation genetics   MeSH
• Child, Preschool MeSH
• Primary Immunodeficiency Diseases MeSH
• Pyridines pharmacokinetics   pharmacology   MeSH
• Pyrimidines pharmacokinetics   pharmacology   MeSH
• Spleen drug effects   pathology   MeSH
• Immunologic Deficiency Syndromes drug therapy   enzymology   immunology   pathology   MeSH
• T-Lymphocytes drug effects   immunology   MeSH
• TOR Serine-Threonine Kinases antagonists & inhibitors   metabolism   MeSH
• Transfection MeSH
• Organ Size MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Rats MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Chemokines MeSH
• Class I Phosphatidylinositol 3-Kinases MeSH
• Immunoglobulin M MeSH
• Protein Kinase Inhibitors MeSH
• leniolisib MeSH Browser
• Pyridines MeSH
• Pyrimidines MeSH
• TOR Serine-Threonine Kinases MeSH