First‐In‐Human Safety, Pharmacokinetics, and Pharmacodynamics of VENT‐02 Freebase, a CNS‐Penetrant NLRP3 Inhibitor

of 1.5-2.0 h in fasted state and had a terminal half-life of 10-14 h at doses up to 500 mg. Exposure was dose-proportional up to 500 mg, and a high-fat, high-calorie meal did not affect exposure significantly. VENT-02 demonstrated central nervous system penetration, with a cerebrospinal fluid-to-plasma unbound concentration ratio of 0.43. VENT-02 dose-dependently inhibited release of IL-1β and IL-18 ex vivo in whole blood, with complete inhibition throughout the dosing interval at ≥ 200 mg b.i.d. VENT-02 also dose-dependently attenuated IL-6 levels in plasma. In conclusion, 1 week of VENT-02 b.i.d. dosing was found to be safe and tolerable at doses achieving complete systemic NLPR3-inhibition. These findings support further clinical development of VENT-02 in inflammatory and neurodegenerative diseases.