PMID- 37797893 OWN - NLM STAT- MEDLINE DCOM- 20240108 LR - 20240216 IS - 1097-6825 (Electronic) IS - 0091-6749 (Print) IS - 0091-6749 (Linking) VI - 153 IP - 1 DP - 2024 Jan TI - Interim analysis: Open-label extension study of leniolisib for patients with APDS. PG - 265-274.e9 LID - S0091-6749(23)01244-7 [pii] LID - 10.1016/j.jaci.2023.09.032 [doi] AB - BACKGROUND: Activated phosphoinositide 3-kinase delta (PI3Kdelta) syndrome (APDS; or p110delta-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kdelta hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. OBJECTIVE: Leniolisib, a selective PI3Kdelta inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. METHODS: Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kdelta inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. RESULTS: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kdelta inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P = .004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. CONCLUSIONS: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. CLINICALTRIALS: gov identifier: NCT02859727. CI - Published by Elsevier Inc. FAU - Rao, V Koneti AU - Rao VK AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. Electronic address: korao@niaid.nih.gov. FAU - Kulm, Elaine AU - Kulm E AD - Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Bethesda, Md. FAU - Sediva, Anna AU - Sediva A AD - Department of Immunology, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic. FAU - Plebani, Alessandro AU - Plebani A AD - Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy. FAU - Schuetz, Catharina AU - Schuetz C AD - Department of Pediatric Immunology, University Hospital Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany. FAU - Shcherbina, Anna AU - Shcherbina A AD - Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia. FAU - Dalm, Virgil A AU - Dalm VA AD - Division of Allergy & Clinical Immunology, Department of Internal Medicine, Rotterdam, The Netherlands; Department of Immunology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. FAU - Trizzino, Antonino AU - Trizzino A AD - Department of Pediatric Hematology and Oncology, ARNAS Civico Di Cristina Benfratelli Hospital, Palermo, Italy. FAU - Zharankova, Yulia AU - Zharankova Y AD - Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus. FAU - Webster, Sharon AU - Webster S AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. FAU - Orpia, Alanvin AU - Orpia A AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. FAU - Korholz, Julia AU - Korholz J AD - Department of Pediatric Immunology, University Hospital Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany. FAU - Lougaris, Vassilios AU - Lougaris V AD - Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia, ASST Spedali Civili of Brescia, Brescia, Italy. FAU - Rodina, Yulia AU - Rodina Y AD - Department of Immunology, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia. FAU - Radford, Kath AU - Radford K AD - Novartis Pharmaceuticals UK Ltd, London, United Kingdom. FAU - Bradt, Jason AU - Bradt J AD - Pharming Healthcare, Inc, Warren, NJ. FAU - Relan, Anurag AU - Relan A AD - Pharming Healthcare, Inc, Warren, NJ. FAU - Holland, Steven M AU - Holland SM AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. FAU - Lenardo, Michael J AU - Lenardo MJ AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. FAU - Uzel, Gulbu AU - Uzel G AD - National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. LA - eng SI - ClinicalTrials.gov/NCT02859727 GR - Z01 AI000732/ImNIH/Intramural NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20231004 PL - United States TA - J Allergy Clin Immunol JT - The Journal of allergy and clinical immunology JID - 1275002 RN - 0 (leniolisib) RN - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) SB - IM MH - Humans MH - Female MH - Young Adult MH - Adult MH - Male MH - Class I Phosphatidylinositol 3-Kinases/genetics MH - Phosphatidylinositol 3-Kinases/genetics MH - Quality of Life MH - Mutation MH - *Immunologic Deficiency Syndromes/genetics MH - *Lymphadenopathy/complications PMC - PMC10841669 MID - NIHMS1943933 OTO - NOTNLM OT - APDS OT - B cells OT - PI3Kdelta inhibitor OT - PIK3CD OT - PIK3R1 OT - T cells OT - clinical trial OT - long-term safety OT - lymphoproliferation OT - primary immunodeficiency COIS- Conflict Of Interest Disclosures V.K.R., A.P., V.L., A.O., G.U., S.M.J., and M.J.L. have no competing financial interests. S.W. is a consultant for Pharming Group, NV. A. Sediva is a consultant for Octapharma, Takeda, and Pharming NV. A. Shcherbina receives honoraria from and is a consultant for Octapharma, CSL Behring, and Novartis. E.K. is an employee of Leidos Biomedical Research, Inc. J.K. has received honorarium from Pharming Group, NV. V.A.D. is a consultant for and/or receives honoraria from AstraZeneca, Kedrion, Takeda, CSL Behring, Pfizer, and Pharming Group, NV. V.A.D. also receives honoraria from Pfizer, and research funding from Takeda. K.K. is an employee and shareholder of Novartis Pharma AG. K.R. is an employee of Novartis Pharma AG. A.R. and J.B. are current employees and stock option holders of Pharming Group, NV, and J.B. holds individual stock in Neoclone. EDAT- 2023/10/06 00:43 MHDA- 2024/01/08 06:42 PMCR- 2025/01/01 CRDT- 2023/10/05 19:34 PHST- 2023/04/06 00:00 [received] PHST- 2023/09/01 00:00 [revised] PHST- 2023/09/22 00:00 [accepted] PHST- 2025/01/01 00:00 [pmc-release] PHST- 2024/01/08 06:42 [medline] PHST- 2023/10/06 00:43 [pubmed] PHST- 2023/10/05 19:34 [entrez] AID - S0091-6749(23)01244-7 [pii] AID - 10.1016/j.jaci.2023.09.032 [doi] PST - ppublish SO - J Allergy Clin Immunol. 2024 Jan;153(1):265-274.e9. doi: 10.1016/j.jaci.2023.09.032. Epub 2023 Oct 4.