Preclinical Evaluation of Effects of KP-001, a Selective Phosphatidylinositol 3-Kinase Alpha (PI3Kα) Inhibitor, on Human Immune Cell Function in Comparison with Existing Drugs for Refractory Vascular Malformations

Vascular malformations (VMs) are morphogenesis defects of blood and lymphatic vessels, and excessive activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B/mammalian target of rapamycin (mTOR) pathway via PI3Kα contributes to their pathogenesis. Sirolimus (an mTOR inhibitor used for the treatment of VMs in Japan) poses immunosuppression-related infection risks resulting from the blockade of signaling downstream of the PI3Kδ pathway. In this study, the human PI3K isoform inhibitory activity of KP-001 (a PI3Kα inhibitor currently in a Phase 3 trial for treating refractory VMs in Japan) was compared with that of alpelisib (a PI3Kα inhibitor for treating PIK3CA-related overgrowth spectrum in the United States). Additionally, we compared the inhibitory effects of KP-001 with those of sirolimus and alpelisib on human immune cells in vitro. KP-001 showed selective inhibitory activity against PI3Kα, including its mutant forms, and approximately 8-fold higher selectivity for PI3Kα over PI3Kδ than alpelisib. The IC50 of KP-001 for human T-cell proliferation and immunoglobulin G (IgG) production in human B cells was the highest among the test substances. Furthermore, compared with sirolimus and alpelisib, KP-001 demonstrated greater separation (IC50/Cmax ss, free ratio) between the IC50 for T-cell proliferation or B-cell IgG production and the effective plasma concentration in clinical settings (Cmax ss, free), estimated as the maximum plasma-free concentration of the test substance at steady state at the clinical dose. KP-001 may represent a beneficial treatment option for refractory VMs, with less immunological impact, owing to its superior PI3Kα selectivity and higher IC50/Cmax ss, free ratio than those of existing drugs.