1st healthy volunteer dosed in trial of potential ALS therapy VTX3232

VTX3232 blocks the NLRP3 inflammasome, a protein complex that drives inflammation

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by Andrea Lobo |

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The first healthy volunteer has been dosed in a Phase 1 clinical trial evaluating VTX3232, Ventyx Biosciences’ investigational oral therapy for amyotrophic lateral sclerosis (ALS) and other neurodegenerative conditions.

Top-line data from the trial are expected in the first half of 2024.

“VTX3232 is our fourth internally discovered compound to enter the clinic and an exciting addition to our broad, wholly-owned clinical-stage pipeline of orally delivered small molecules targeting large disease populations with high unmet need,” Raju Mohan, PhD, CEO at Ventyx, said in a company press release.

ALS is a progressive neurological disorder that damages motor neurons, the nerve cells that control voluntary movements, causing them to degenerate and die. This results in a loss of control over muscle movements and patients lose the ability to perform everyday tasks.

Although genetic causes have been linked with developing ALS, other biological changes, like inflammation, are thought to contribute.

VTX3232 works by blocking the NLRP3 inflammasome, a protein complex within cells that drives inflammation in response to certain triggers. This inflammatory response involves the release of pro-inflammatory molecules such as interleukin-1 beta (IL-1 beta) and IL-18 and the induction of an inflammatory form of cell death.

The activation of NLRP3 inflammasome is thought to be implicated in the progressive nerve cell damage that occurs in neurodegenerative diseases like ALS.

Given that VTX3232 can reach the central nervous system (CNS; the brain and spinal cord), it may have therapeutic potential in a range of neuroinflammatory diseases with high unmet medical needs, including ALS, Parkinson’s disease, and Alzheimer’s disease.

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About the Phase 1 trial of VTX3232

The Phase 1 trial is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending doses of VTX3232 against a placebo in adult healthy volunteers. Pharmacokinetics refers to the therapy’s movement into, through, and out of the body, and pharmacodynamics comprises its effects on the body.

The trial will include a serial sampling of cerebrospinal fluid (CSF) — the fluid that bathes the brain and the spinal cord — to assess brain exposure to the compound.

The company is also developing another oral NLRP3 inhibitor, VTX2735, for treating systemic inflammatory diseases, that’s now in clinical trials.

“We believe we are well positioned to explore the therapeutic potential of NLRP3 inhibition and its effect on [IL-1 beta] biology across both systemic [whole-body] and neuroinflammatory diseases with VTX2735, which is peripherally restricted, and VTX3232, a novel CNS-penetrant NLRP3 inhibitor,” Mohan said.