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.

Belarusian Research Center for Pediatric Oncology Hematology and Immunology Minsk Belarus

Clinical Research Directorate Frederick National Laboratory for Cancer Research Bethesda MD

Department of Immunology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Immunology Dmitry Rogachev National Medical Research Center of Pediatric Hematology Oncology and Immunology Moscow Russia

Department of Pediatric Hematology and Oncology ARNAS Ospedali Civico Di Cristina Benfratelli Hospital Palermo Italy

Department of Pediatric Immunology University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

Division of Allergy and Clinical Immunology Department of Internal Medicine and Department of Immunology Erasmus Medical Center University Medical Center Rotterdam the Netherlands

National Institute of Allergy and Infectious Diseases National Institutes of Health Bethesda MD

Novartis Institutes for Biomedical Research Basel Switzerland

Novartis Pharmaceuticals UK Limited London United Kingdom

Pediatrics Clinic Department of Clinical and Experimental Sciences University of Brescia Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia Brescia Italy

Pharming Healthcare Inc Warren NJ

Regional Immunology Services of Northern Ireland Belfast Health and Social Care Trust Belfast United Kingdom

Wellcome Trust Clinical Research Facility St James's Hospital and Department of Clinical Immunology Trinity College Dublin Dublin Ireland

Blood. 2023 Mar 2;141(9):963-964. doi: 10.1182/blood.2022019105. PubMed

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ClinicalTrials.gov
NCT02435173