PI3Kδ inhibition treatment of APDS: efficacy, safety and tolerability of targeted therapy with leniolisib

PI3Kδ Activation Syndrome (APDS) is a rare congenital immunodeficiency caused by mutations that result in hyperactivation of the PI3Kδ signaling pathway. The persistent activation of the AKT/mTOR signaling pathway leads to impaired survival, proliferation and activation of both B and T lymphocytes. There are two genetic forms of APDS, associated with autosomal dominant transmission. APDS patients face recurrent bacterial and viral infections, frequent respiratory symptoms due to infections or bronchospasm, and persistent benign lymphoproliferations (lymphadenopathies and hepatosplenomegaly) with a high risk of develop lymphomas and/or autoimmune diseases (e.g. cytopenia). APDS treatments are similar to those implemented in management of immunodeficiencies, such as immune prophylaxis and antimicrobial therapies, administration of replacement immunoglobulins and various anti-inflammatory and immunosuppressive drugs. Several PI3Kδ inhibitors have been evaluated in clinical trials for the treatment of APDS, but only leniolisib has been approved by the FDA (March 2023) as an orphan drug for APDS due to its good efficacy, safety and tolerability profile. Leniolisib has the high potential to be disease modifying drug for the treatment of APDS patients, also considering its pharmacodynamic properties (selectivity for the δ isoform of PI3K). Further studies and clinical trials have been performed and are ongoing to confirm the long-term effect and safety profile of the drug. Preliminary results show positive data in terms of efficacy, safety and long-term tolerability.