A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung


  • V. Koneti Rao - , National Institutes of Health (NIH) (Autor:in)
  • Sharon Webster - , National Institutes of Health (NIH) (Autor:in)
  • Anna Šedivá - , Karlsuniversität Prag (Autor:in)
  • Alessandro Plebani - , University of Brescia (Autor:in)
  • Catharina Schuetz - , Klinik und Poliklinik für Kinder- und Jugendmedizin (Autor:in)
  • Anna Shcherbina - , Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology (Autor:in)
  • Niall Conlon - , Trinity College Dublin (Autor:in)
  • Tanya Coulter - , Belfast Health and Social Care Trust (Autor:in)
  • Virgil A. Dalm - , Erasmus University Rotterdam (Autor:in)
  • Antonino Trizzino - , ARNAS Ospedali Civico Di Cristina Benfratelli (Autor:in)
  • Yulia Zharankova - , Belarusian Research Center for Pediatric Oncology (Autor:in)
  • Elaine Kulm - , Leidos Inc (Autor:in)
  • Julia Körholz - , Klinik und Poliklinik für Kinder- und Jugendmedizin (Autor:in)
  • Vassilios Lougaris - , University of Brescia (Autor:in)
  • Yulia Rodina - , Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology (Autor:in)
  • Kath Radford - , Novartis Pharmaceuticals UK Ltd (Autor:in)
  • Jason Bradt - , Pharming Healthcare Inc. (Autor:in)
  • Klaus Kucher - , Novartis AG (Autor:in)
  • Anurag Relan - , Pharming Healthcare Inc. (Autor:in)
  • Steven M. Holland - , National Institutes of Health (NIH) (Autor:in)
  • Michael J. Lenardo - , National Institutes of Health (NIH) (Autor:in)
  • Gulbu Uzel - , National Institutes of Health (NIH) (Autor:in)


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.


Seiten (von - bis)971-983
PublikationsstatusVeröffentlicht - 2 März 2023

Externe IDs

PubMed 36399712
ORCID /0009-0003-6519-0482/work/146644424
ORCID /0000-0001-6313-4434/work/147143702



  • Pyridines, Pyrimidines, Class I Phosphatidylinositol 3-Kinases, Double-Blind Method, Humans, Phosphatidylinositol 3-Kinases