Understanding VTX3232’s Effects on Patients with Early-Stage Parkinson Disease

VTX3232, an investigational drug in development for Parkinson disease (PD), is an inhibitor of the NLRP3 inflammasome developed by Ventyx Biosciences. The therapy, which has been previously evaluated in phase 1 studies, is currently being tested in a single-center, open-label, phase 2 trial of 10 patients with early-stage PD. In the trial, VTX3232, designed to disrupt the self-perpetuating inflammatory loop driven by alpha-synuclein aggregation and chronic inflammasome activation in PD, was administered to patients once per day for 40 days.¹

At the 2025 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held October 5-9, in Honolulu, Hawaii, Mark Foreman, MD, PhD, chief medical officer at Ventyx Biosciences, presented late-breaking data from the phase 2 trial. Foreman, senior author of the study, sat down with NeurologyLive^® during the meeting to discuss the findings in greater detail, and what they mean for the clinical community.

In the conversation, Foreman provided context on the safety findings along with the pharmacokinetic and pharmacodynamic data from the trial, both of which showed a favorable outcome with VTX3232. Foreman also spoke about the mechanism of action of VTX3232 as a NLRP3 inhibitor, and its role in fighting Parkinson Disease. Of note, Foreman accounted for the study’s limitations, including the size and length of the study, when considering the positive results and advocated for longer and controlled trials in the future.

NeurologyLive: For those who couldn’t attend, could you offer a summary of what was presented regarding the safety, tolerability, and pharmacokinetics (PK) and Pharmacodynamic (PD) data for VTX3232?

Mark Foreman, MD, PhD: The trial that we ran was a small, open-label, single-site study of VTX3232. We tested once-daily doses of 40 milligrams of VTX3232 for 28 days. It’s a small study, with a focus on safety first and foremost. It’s our first study in patients with PD, but we were also looking at exposure and pharmacodynamic activity.

We had a lot of exploratory objectives, one of which was looking at clinical assessments. Again, we didn’t really expect to see improvement in clinical outcomes. We assume this is a disease-modifying approach, but we looked at that nonetheless.

What the data really showed were three key things that we’re excited about. First, the drug was very well tolerated. In fact, there were no treatment-related adverse events in the trial. Again, only 10 patients, only 28 days, but nonetheless, to the extent we observed, it was very well tolerated.

Second, the PK was exactly as we observed in our healthy volunteer studies. In both blood and CSF, we had exposures that were strong at troughs, meaning before the last dose, so these are the lowest levels of drug that you’ll see, we were over threefold the IC90 for NLRP3 inhibition. So, we feel that with once-daily administration, we can really hit the target well, which will allow us to go forward and test this mechanism in a traditional efficacy trial.

Lastly, we looked for evidence of target engagement in pharmacodynamic biomarkers, and we saw the cascade of NLRP3 inhibition. We saw robust evidence of target engagement. We knocked down IL-1β and IL-18, which are the most proximal markers you can measure as a result of NLRP3 activity. Downstream, we saw reductions in IL-6 and in acute-phase reactants, CRP, and serum amyloid A, and we saw these changes in both plasma and CSF. So, we’re seeing really good evidence of pharmacodynamic activity.

Much to our surprise, we saw a significant improvement in clinical benefit, both in motor and non-motor aspects of the UPDRS. I’ll put a big asterisk next to that. It’s a small, open-label study, in a disease area like PD that’s notorious for placebo effects. While it’s exciting to see, it needs to be replicated in a properly conducted, controlled study.

What stands out most to you from the data presented?

Let me talk first and foremost about the trial itself, and what we were really excited about. We had three things we needed to see to decide whether to move forward with this program: a good safety profile, good exposure, and evidence of pharmacodynamic activity.

We achieved all three. The drug was safe, exposures were sufficient to hit the target both in the periphery and in the CNS. CSF levels were more than threefold above the IC90 at trough, and the PK matched what we saw in healthy volunteers. It’s a very well-behaved drug pharmacokinetically.

And third, we got those pharmacodynamic readouts showing that the drug is doing what it should be doing. Everything else is a bonus. That’s critical, because when we run a properly conducted efficacy trial, if it fails, we’ll know that we hit the target correctly and that the mechanism, not the drug, was the issue. What’s also unique about this mechanism, and maybe we can expand on this, is the role of NLRP3 inhibition in PD.

 How would you describe the mechanism of action of VTX3232, and what makes it unique or relevant in Parkinson disease?

VTX-3232 is an NLRP3 inhibitor. It’s very potent, low nanomolar potency, and has strong CNS activity. The inflammasome, which includes NLRP3, is a key regulator of the innate immune system. In PD and other neurodegenerative diseases, there’s low-grade chronic inflammation that we believe is a key contributor to disease processes.

The inflammasome senses triggers like infection, chronic damage, or misfolded proteins, and activates a cascade through caspase-1, which converts pro–IL-1β and pro–IL-18 into their active forms. These then drive inflammatory activity, including IL-6 and acute-phase reactants downstream.

In PD, aggregated alpha-synuclein activates the NLRP3 inflammasome. Once activated, NLRP3 further promotes alpha-synuclein fibrillation, creating a self-perpetuating inflammatory loop. By inhibiting NLRP3, we aim to interrupt that loop and slow disease progression.

In multiple animal models, including alpha-synuclein and MPTP models, NLRP3 inhibition has improved function, reduced pathology, and lowered inflammation. This mechanism directly addresses one of the root inflammatory drivers of neurodegeneration.

Does this approach align with the idea of early-phase disease targeting, trying to intervene as early as possible in Parkinson progression?

By the time someone becomes symptomatic, significant damage has already occurred in the affected brain regions. We know from both PD and Alzheimer disease (AD) that pathology begins years, even decades, before symptoms appear.

So, if we can identify and treat patients at the very earliest stages, we may be able to slow progression, preserve function, and improve quality of life. The challenge is identifying those early-stage patients. PD lacks robust early diagnostic tools, something the AD field has advanced in recent years. If we can build that same toolbox for PD, we’ll be able to design and run early-intervention trials more effectively.

Is there anything else about VTX3232 that you want the clinical or neurology community to take away from this presentation?

The NLRP3 pathway has been implicated in a wide range of systemic and CNS diseases. We, and the broader field, see it as a potential pipeline in a pill because modulating this pathway could impact multiple conditions.

At Ventyx, we’re studying NLRP3 inhibition not only in PD but also in other CNS and systemic diseases. PD is our lead indication because the biology is so strong here, but we see opportunities to expand into AD and ALS, where the innate immune system also plays a key role.

This program is really our first step into what we hope will be a much broader effort to explore the therapeutic potential of NLRP3 inhibition across neurodegenerative and systemic diseases.

Transcript edited for clarity. Click here for more coverage of MDS 2025.

REFERENCES
1. 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.