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

The NLRP3 inflammasome is a central mediator of innate immunity and a key driver of inflammatory and neurodegenerative diseases. VENT-02 is orally bioavailable, central nervous system-penetrant, selective small-molecule inhibitor of NLRP3. This first-in-human, randomized, double-blind, placebo-controlled study assessed the safety, tolerability, pharmacokinetics, and pharmacodynamics of VENT-02 freebase in healthy volunteers. The study consisted of single and multiple ascending dose phases, a food-effect cohort, and a cerebrospinal fluid sampling cohort. VENT-02 was safe and well tolerated at single doses up to 1600 mg and at multiple doses up to 200 mg twice daily (b.i.d.), with only mild treatment-related adverse events at these dose levels. At 400 mg b.i.d., moderate treatment-emergent adverse events occurred in 5 of 12 participants (41.7%). VENT-02 was rapidly absorbed in plasma, with a median T_max 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.