The Rationale and Early Supportive Data for NLRP3 Inhibitor VTX3232 in Parkinson Disease: Mark Forman, MD, PhD

WATCH TIME: 4 minutes

"We’re seeing compelling pharmacodynamic evidence of target engagement and an encouraging safety profile. The ability to inhibit the NLRP3 pathway in the CNS may open a new door for disease modification in Parkinson disease."

The NLRP3 inflammasome is a key component of the innate immune system’s response to cellular stress, damage-associated molecular patterns (DAMPs), protein aggregates and other insults. Activation of NLRP3 leads to caspase-1 activation and release of pro-inflammatory cytokines IL-1β and IL-18, which drive chronic neuroinflammation, microglial activation, and neuronal damage. In Parkinson disease (PD), misfolded α-synuclein, mitochondrial dysfunction, and dopaminergic neuron stress are thought to trigger neuroinflammatory cascades in which NLRP3 plays a central role.

There are a number of drugs in the therapeutic pipeline for PD, including Ventyx Biosciences’ VTX3232, which aims to reduce neuroinflammation and decrease microglial-driven damage. At the 2025 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held October 5-9, in Honolulu, Hawaii, Mark Forman, MD, PhD, presented late-breaking data from a phase 2 trial testing the efficacy, safety, pharmacokinetics and pharmacodynamics of VTX3232 in patients with PD. Overall, the drug was found to be well-tolerated with no drug-related treatment-emergent adverse events (TEAEs) among 10 patients with early-stage PD.

Additional data from the trial showed that treatment with the agent was associated with improvement on the Movement Disorders Society Unified PD Rating Scale (MDS-UPDRS) in both motor and nonmotor symptoms of PD (Part I mean, -2.4, P = .0118; Part II mean, -2.7, P = .0471; Part III mean, -5.2, P = .0054). By 28 days, interleukin (IL)-1β and IL-18 levels were reduced by 14% to 52% in both plasma and CSF.

Forman, chief medical officer at Ventyx Biosciences, sat down with NeurologyLive^® during the meeting to give an overview of the presented data, and the clinical takeaways movement disorders experts should understand. In the interview, Forman spoke on the most notable findings from the study, including VTX3232’s effect on efficacy and PK end points. Furthermore, while Forman emphasized the need for validation in a larger, controlled trial, these data support continued exploration of VTX3232 as a disease-modifying approach in PD.

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REFERENCES
1. Patel B, Greenland JC, Williams-Gray CH. Clinical Trial Highlights: Anti-Inflammatory and Immunomodulatory Agents. J Parkinsons Dis. 2024;14(7):1283-1300. doi:10.3233/JPD-240353.
2. Gregg R, Christianson C, Liu K, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of VTX3232, a CNS-penetrant NRLP3 inhibitor, in participants with early-stage Parkinson’s disease. Presented at: 2025 MDS Congress; October 5-9, 2025; Honolulu, HI. Abstract LBA-12.