A randomized, placebo-controlled phase 3 trial of the PI3K8 inhibitor leniolisib for activated PI3K8 syndrome

Activated phosphoinositide 3-kinase delta (PI3K delta) syndrome (APDS) is an inborn error of immunity with clinical manifestations including infections, lymphoproliferation, autoim-munity, enteropathy, bronchiectasis, increased risk of lymphoma, and early mortality. Hyperactive PI3K delta signaling causes APDS and is selectively targeted with leniolisib, an oral, small molecule inhibitor of PI3K delta. 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 naive B cells in peripheral blood, assessed as proxies for immune dysregulation and deficiency. Both primary out-comes 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 naive 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 naive 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.