NLRP3 inhibitor found safe, well tolerated in Parkinson’s trial
Daily dosing of VTX3232 met primary goal in study of early-stage disease
VTX3232, an NLRP3 inhibitor being developed by Ventyx Biosciences as a treatment for Parkinson’s disease, was found to be safe and well tolerated after nearly one month of daily dosing in a clinical trial involving people with early-stage disease, according to the company.
With these results, VTX3232 met the primary goal of the Phase 2a study (NCT06556173), which was conducted in Connecticut, Ventyx announced in a company press release.
The open-label trial — one in which both participants and researchers know the medication being given to patients — also showed that the experimental therapy, which targets and blocks the inflammatory protein NLRP3, reduced levels of inflammation markers associated with NLRP3 activation.
Based on these data, Ventyx said it is now planning to launch a Phase 2 trial to assess the treatment’s efficacy against a placebo in Parkinson’s disease and potentially other neurodegenerative conditions.
“We are delighted that this trial met its goals of establishing that treatment with VTX3232 was safe and well tolerated, with high exposure levels in [cerebrospinal fluid (CSF)] and clear reductions in NLRP3-related biomarkers in a Parkinson’s disease patient population,” said Raju Mohan, PhD, CEO of Ventyx. The CSF is the liquid that surrounds the brain and spinal cord.
The NLRP3 protein is a key component of the inflammasome, a molecular complex that, when activated, triggers a strong inflammatory response by promoting the release of pro-inflammatory molecules called cytokines. Among such cytokines is interleukin-1 beta, known as IL-1beta. Excessive activation of the NLRP3 inflammasome is thought to contribute to chronic neuroinflammation (brain inflammation) in Parkinson’s, potentially leading to nerve cell damage and accelerating disease progression.
Inhibitor aims to block NLRP2 protein, reduce brain inflammation
VTX3232 is an oral medication designed to efficiently enter the brain and reach target cells, which is expected to reduce neuroinflammation and slow disease progression. The treatment had earlier been found to be well tolerated in healthy volunteers who participated in a Phase 1 study. It also was seen to significantly reduce the production of IL-1beta in that trial.
“By inhibiting NLRP3-mediated cytokine production and inflammatory markers in the [brain and spinal cord], VTX3232 provides a unique opportunity for a disease-modifying therapy for Parkinson’s disease,” Mohan said.
The Phase 2a trial tested VTX3232 in 1o patients with early-stage Parkinson’s, who received a 40 mg daily dose over 28 days, or about one month, and then were followed up for an additional 14 days, or two weeks.
The trial met its main goal of showing that VTX3232 was well tolerated, with all adverse events considered mild to moderate in severity and unrelated to the treatment. Adverse events were mainly associated with procedures performed to assess the treatment effects and eventually resolved on their own.
With the caveat that this was a small, open-label study, all patients reported a subjective sense of improvement.
Additionally, according to Ventyx, VTX3232 achieved sustained concentrations in both blood and CSF that exceeded the threshold needed to inhibit NLRP3 activity for a full 24 hours post-dose, supporting its potential as an effective once-daily oral therapy for Parkinson’s. The treatment also reduced biomarkers associated with NLRP3 activation, including IL-1beta and IL-18, and other markers of inflammation
Other exploratory biomarkers remained unchanged or were within normal levels, the data showed. These included neurofilament light chain and markers of microglial and astrocyte activation, which when elevated are indicators of neurodegeneration. Microglia are the brain’s resident immune cells, while astrocytes provide support for neuronal function and survival.
Participants also experienced a significant easing of both motor and nonmotor symptoms of Parkinson’s, as assessed by the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 1 (non-motor experiences of daily living), part 2 (motor experiences of daily living), and part 3 (motor examination).
“With the caveat that this was a small, open-label study, all patients reported a subjective sense of improvement,” said David Russell, MD, PhD, principal investigator on the trial and professor at Yale University.
“This was a thorough and well-conducted trial demonstrating clear evidence of target engagement in the CSF,” Russell said.
Ventyx also is running a Phase 2a trial testing VTX3232 for obesity and other risk factors for cardiovascular disease, with top-line results expected in the second half of 2025.
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