Kinetics of Nirogacestat-Mediated Increases in B-cell Maturation Antigen on Plasma Cells Inform Therapeutic Combinations in Multiple Myeloma

Abstract

B-cell maturation antigen (BCMA) is the target of several investigational serum nirogacestat concentrations rapidly increased (Tmax ∼1 hour), and and approved drugs for multiple myeloma. BCMA expressed on plasma a two-compartment model with linear absorption and clearance best cells (PC) and multiple myeloma cells is cleaved by the enzyme described nirogacestat pharmacokinetics. In multiple myeloma cells and γ-secretase, reducing membrane-bound BCMA (mbBCMA) receptor healthy volunteers’ PCs, nirogacestat resulted in rapid and robust in-density. γ-Secretase inhibitors (GSI) have been shown to increase creases in mbBCMA density, with increases up to 20-fold within 4 to mbBCMA density and may enhance efficacy of BCMA-targeted thera- 8 hours of exposure. Concomitant decreases in soluble BCMA were pies. The pharmacodynamic profile of the GSI nirogacestat was evaluated observed. Nirogacestat is currently being evaluated in combination with in multiple myeloma cell lines and a phase I study in healthy volunteers. several BCMA-directed therapeutic agents in patients with multiple In multiple myeloma cell lines, mbBCMA density and soluble BCMA myeloma. Elucidating the kinetics of BCMA in response to nirogacestat concentrations were measured before and after short-duration nir- is key to guiding dosing and therapeutic strategies in multiple myeloma. ogacestat exposure and at serial time points following washout. In the phase I study, 23 participants were administered a single oral dose of Significance: GSIs can enhance multiple myeloma therapies targeting nirogacestat 50, 150, or 300 mg or repeated doses of 100 mg every BCMA by increasing mbBCMA on plasma cells. In response to the GSI 12 hours for up to 48 hours; mbBCMA density on PCs (from whole nirogacestat, mbBCMA rapidly and robustly increased in vitro and in blood and bone marrow) and nirogacestat plasma concentrations were vivo. Elucidating nirogacestat’s effects on BCMA kinetics will guide measured at baseline and postdose. After single-dose administration, potential multiple myeloma dosing strategies.