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NLRP3 is a member of a family of proteins known as inflammasome receptors. Aberrant activation of the NLRP3 inflammasome has been associated with systemic conditions, including fibrotic, dermatological, and rheumatological diseases, and is also a key driver of disease pathology in several neurological disorders. Ventus is developing a portfolio of both systemic and brain-penetrant NLRP3 inhibitors, including VENT-02.


NLRP3 is the best understood member of a family of proteins known as inflammasome receptors. When inactive monomeric NLRP3 senses intracellular damage, it oligomerizes into its active conformation, forming a highly organized inflammasome complex. This inflammasome complex leads to the activation of IL-1β, IL-18, and Gasdermin D (GSDMD) to promote a downstream inflammatory response as well as pyroptosis, a type of cell death triggered by pro-inflammatory signals and associated with inflammation.

NLRP3 is activated by numerous markers of tissue damage, such as abnormal protein aggregates and the accumulation of lipids. All of these are known triggers of disease. Because NLRP3 can be activated by such a broad and diverse set of markers of tissue damage, it is a critical regulator of the innate immune response in systemic inflammation and neuroinflammation.

Aberrant activation of the NLRP3 inflammasome is a key driver in many diseases

NLRP3 was first recognized as playing an essential role in human disease with the discovery that activating mutations of NLRP3 cause a group of genetic auto-inflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS). These diseases are characterized by IL-1β-mediated systemic inflammation and clinical symptoms involving the skin, joints, central nervous system, and eyes. NLRP3 is also implicated in a broad spectrum of disease pathologies, including:

Validation of the NLRP3 pathway

The role of NLRP3 in disease is validated by the approval of multiple anti-IL-1β therapies, which are efficacious for treating many of the diseases shown above. Two important differences between these therapies and NLRP3 inhibition should be noted. First, these therapies target the IL-1β pathway as a whole, which can potentially lead to deleterious effects by broadly turning off this pathway. They knock-out the entire system while NLRP3 inhibitors would only block the pathway that is relevant to disease. Second, NLRP3 inhibitors not only block disease-relevant IL-1β, but also the inflammatory consequences of IL-18 activation and pyroptosis. We believe our approach of selectively targeting the IL-1β pathway through the inhibition of NLRP3 while simultaneously targeting other inflammatory drivers has the potential to demonstrate efficacy and safety advantages over currently approved IL-1β targeting therapies.

VENT-01, an oral systemic inhibitor of NLRP3, was the first development candidate nominated by Ventus 

In September 2022, we entered into an exclusive development and license agreement with Novo Nordisk A/S to develop and commercialize candidates from our portfolio of systemic NLRP3 inhibitors, including VENT-01. Learn more about the collaboration here.

A Phase 1 clinical trial of VENT-01 is ongoing. Learn more about the Phase 1 study here.

VENT-02: A potential best-in-class oral brain-penetrant inhibitor of NLRP3 

Phase 1 clinical trial completed 

VENT-02, our most advanced wholly-owned program, is a highly potent and selective brain-penetrant NLRP3 inhibitor.

The Phase 1 clinical trial of VENT-02 has been completed. The trial evaluated the pharmacodynamics, pharmacokinetics, safety, and tolerability of VENT-02 across a broad range of single and multiple ascending doses. In this Phase 1 clinical trial, VENT-02 was well-tolerated, with no dose-limiting toxicities or serious adverse events reported. VENT-02 demonstrated full target engagement through 100% inhibition of IL-1β in the blood in an ex vivo whole blood challenge assay, significant drug levels in the CSF for 24 hours, and robust reduction of inflammatory biomarkers such as hsCRP. In addition, VENT-02 demonstrated potential for once-daily dosing. Learn more about the Phase 1 study here.

Beyond VENT-02

Ventus retains the right to develop chemically distinct systemic NLRP3 inhibitors for specific inflammatory and respiratory diseases. We are in lead optimization for our wholly-owned systemic NLRP3 inhibitor.

NLRP3-related publications

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