Objective: To describe the innovative Phase 2 study design aimed to investigate vent-02 in the treatment of PD.

Background: NLRP3 hyperactivation plays a critical role in inflammatory and degenerative diseases, including PD, where NLRP3 is activated by alpha-synuclein and then, in turn, it promotes further synuclein aggregation. VENT-02 is an orally bioavailable, brain-penetrant, potent, and reversible inhibitor of NLRP3, with the potential of providing symptomatic and disease-modifying effects for the treatment of PD.

Method: This is a randomized, double-blind, placebo-controlled study enrolling patients with mild and moderate PD, using or not using levodopa. The primary endpoint is safety, and the secondary endpoints are PK and PD in plasma and CSF. We will analyze plasma and CSF biomarkers categorized into three tiers as a function of known levels in PD versus controls, causality to PD, and likelihood of being modulated in a 28-day study. We will incorporate Digital Health Technology (DHT) to assess daily functions and enable a correlation between motor activity, speech, and sleep with biomarker kinetics. Exploratory assessments for cognition, brain fog, pain, and fatigue will be conducted. A total of 30 patients will be enrolled into 1 active arm and 1 PBO arm and followed through a 28-day treatment period (and a 7-day follow-up period).

Results: The study will assess impacts of NLRP3 inhibition on neuroinflammation that could be relevant to other diseases of the central nervous system and provide preliminary evidence of symptomatic effects through use of highly sensitive DHT sensors.

Conclusion: We expect to demonstrate that NLRP3 inhibition has the potential to be disease-modifying. The intention of DHT assessments is to also provide evidence of early symptomatic effects of NLRP3 inhibition with vent-02.

References: Gordon R, Albornoz EA, Christie DC, Langley MR, Kumar V, Mantovani S, Robertson AAB, Butler MS, Rowe DB, O’Neill LA, Kanthasamy AG, Schroder K, Cooper MA, Woodruff TM. Inflammasome inhibition prevents α-synuclein pathology and dopaminergic neurodegeneration in mice. Sci Transl Med. 2018 Oct 31;10(465):eaah4066. doi: 10.1126/scitranslmed.aah4066. PMID: 30381407; PMCID: PMC6483075.

Chatterjee K, Roy A, Banerjee R, Choudhury S, Mondal B, Halder S, Basu P, Shubham S, Dey S, Kumar H. Inflammasome and α-synuclein in Parkinson’s disease: A cross-sectional study. J Neuroimmunol. 2020 Jan 15;338:577089. doi: 10.1016/j.jneuroim.2019.577089. Epub 2019 Oct 25. PMID: 31704453.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-randomized-double-blind-placebo-controlled-phase-2-study-of-the-nlrp3-inhibitor-vent-02-in-patients-with-mild-to-moderate-parkinsons-disease/