Objective: The objectives of this first-in-human study were to assess the safety, tolerability, pharmacokinetics (PK), food-effect and pharmacodynamics of VENT-02 in healthy volunteers

Background: Vent-02 is a novel, brain-penetrant NLRP3 inhibitor. Therapeutic inhibition of NLPR3 prevents the formation of inflammasomes responsible for the production of IL-1β and IL-18 and induction of pyroptosis leading to cell death. Abnormal activation of NLRP3 has been implicated in Parkinson’s Disease pathology.

Method: A total of 87 healthy volunteers received a single oral dose of VENT-02 or placebo up to 1600 mg, or twice daily (BID) multiple oral doses of VENT-02 or placebo up to 400 mg BID for 6.5 days. Participants were monitored for adverse events (AEs) and changes in clinical laboratory parameters, ECG and vital signs. PK was assessed in blood and CSF. Pharmacodynamics was assessed by measuring IL-1β and IL-18 release following LPS/ATP stimulation of whole-blood, and changes in serum hsCRP and plasma IL-6.

Results: Vent-02 was safe and well-tolerated following single doses up to 1600 mg and multiple doses up to 200 mg BID. Overall, there were no significant safety findings, and most AEs were mild and transient. Following multiple dosing, AEs occurred at approximately similar frequencies with vent-02 and placebo. Some participants on 400 mg BID had moderate AEs that resolved spontaneously after discontinuation of treatment. Peak plasma levels (T_max) appeared 2h post dose, t½ was 10-15h and PK steady state was achieved in 3-4 days. Food did not significantly affect vent-02 PK. Exposure in CSF was lower than in plasma following a single 225 mg dose. A single 225 mg dose resulted in sustained inhibition of IL-1β and IL-18 release >80% over 24h, with maximal inhibition 2h post dose, consistent with T_max. At steady state, the median IL-1β and IL-18 inhibition was continuously >80% with the lowest dose tested and complete inhibition was seen at higher doses. Multiple dosing of vent-02 reduced serum hsCRP and plasma IL-6 levels.

Conclusion: Vent-02 is safe and generally well-tolerated and has a favorable PK and pharmacodynamic profile in healthy volunteers. The activity of vent-02 in mild to moderate Parkinson’s Disease patients will be assessed in a Phase 1b study.

References: 1. von Herrmann KM, Salas LA, Martinez EM, Young AL, Howard JM, Feldman MS, Christensen BC, Wilkins OM, Lee SL, Hickey WF, Havrda MC. NLRP3 expression in mesencephalic neurons and characterization of a rare NLRP3 polymorphism associated with decreased risk of Parkinson’s disease. NPJ Parkinsons Dis. 2018 Aug 15;4:24.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/safety-tolerability-pharmacokinetics-and-pharmacodynamics-of-vent-02-a-novel-cns-penetrant-nlrp3-inhibitor-for-the-treatment-of-parkinsons-disease/