Abstract CT150: A first in humans trial of PLX-4545, a molecular glue degrader of IKZF2, in healthy volunteers, shows pharmacologic modulation of Tregs at well-tolerated doses

Abstract Background: PLX-4545 is a potent and selective, orally bioavailable, cereblon-mediated molecular glue degrader of IKZF2 (Helios), a lineage defining transcription factor for immunosuppressive Treg cells, that induces loss of Treg suppressive function and acquisition of an effector T cell (Teff)-like phenotype. In pre-clinical xenograft models, PLX-4545 demonstrates single-agent anti-tumor activity comparable to PD-1 inhibition as well as combination benefit with PD-1 inhibitors. This study evaluated the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of PLX-4545 in healthy adult subjects to identify a pharmacologically active dose window. Methods: PLX-4545 was evaluated in a Phase 1, randomized, double-blind, placebo-controlled study with Single Ascending Dose (SAD), Multiple Ascending Dose (MAD) and Food Effect (FE) arms. Cohorts of 8 healthy adult volunteers were randomized to receive either PLX-4545 or placebo in a 3:1 ratio in both the SAD and MAD phases. Subjects in the SAD arm received a single dose of PLX-4545 ranging from 2.5 mg to 200 mg. In the MAD portion of the study, subjects received 14 daily doses of PLX-4545 at 10, 25, 50 and 100 mg. Subjects in the FE cohort received a 100 mg dose of PLX4545 in either a fasted or fed state. Individual samples were analyzed for plasma PLX-4545 concentrations. IKZF2 protein levels and cell surface marker expression in peripheral blood mononuclear cells was assessed by flow cytometry. Results: PLX-4545 demonstrated dose-proportional increases in AUC0-∞ and slightly greater than proportional increases in Cmaxand AUC0-last in the SAD study from 10 mg to 200 mg. Tmax was similar across doses, ranging from 0.75 - 1.0 hours. In the MAD study, AUC0-∞ also increased dose-proportionally, while Cmax increased slightly less than proportionally. PLX-4545 did not show appreciable accumulation over time, and the terminal elimination half-life varied from 4.4 to 5.2 hours. Food intake significantly increased both peak (Cmax) and overall (AUC0-∞) exposures of PLX-4545.Pharmacodynamically, PLX-4545 led to rapid degradation of IKZF2 protein levels in FOXP3+ Tregs within 2 hours, reaching maximal degradation by 24 hours, with resynthesis taking more than 6 days. In the SAD cohorts, dose-dependent degradation of IKZF2 was observed, with higher doses achieving near complete degradation at 2 hours. In the MAD arm, subjects achieved near complete degradation of IKZF2 at >24 hours for all dose levels upon repeat dosing. IKZF2 degradation was associated with a time-dependent shift of peripheral Tregs to a Teff-like immunophenotype. This study established a 40-fold dose range for PLX-4545 on a daily for 14 days schedule, that is safe, well-tolerated, and pharmacologically active. A study of PLX-4545 in subjects with advanced cancer is currently in development. Citation Format: Jorge F. DiMartino, Peggy Thompson, Yujun Huang, Kevin Freeman-Cook, Christine Farrell, Pengyu Yang. A first in humans trial of PLX-4545, a molecular glue degrader of IKZF2, in healthy volunteers, shows pharmacologic modulation of Tregs at well-tolerated doses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr CT150.