Interim Analysis: Open-Label Extension Study of Leniolisib for Patients with APDS

Activated phosphoinositide 3-kinase delta (PI3Kd) syndrome (APDS; or p110d-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency; PASLI) is an inborn error of immunity caused by PI3Kd hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. Leniolisib, a selective PI3Kd 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. Patients with APDS aged =12 years who completed NCT02435173 or had prior exposure to PI3Kd inhibitors were eligible. The primary endpoint is safety, assessed via investigator-reported adverse events and clinical/laboratory evaluations. Secondary and exploratory endpoints include health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled - consisting of 26, 9 and 2 patients who previously received leniolisib, placebo or other PI3Kd inhibitors, respectively. At the data cut-off (13 Dec 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE; most AEs were grades 1-3, none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (p=0.004) and reductions in immunoglobulin replacement therapy occurred in 10/27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias and normalized lymphocyte subsets. Leniolisib was well-tolerated and maintained durable outcomes with up to 5-years exposure in 37 patients with APDS. Copyright © 2023. Published by Elsevier Inc.

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