A review of the scientific literature suggests the potential of caspase-4/5 as targets for a broad range of inflammatory diseases, including inflammatory bowel disease, hidradenitis suppurativa, and sepsis
Using its ReSOLVE® platform, Ventus has identified highly potent and selective small molecules that inhibit caspase-4/5 via a novel allosteric mechanism
WALTHAM, Mass. & MONTREAL--(BUSINESS WIRE)--Ventus Therapeutics, a clinical-stage biopharmaceutical company with two novel small-molecule programs entering Phase 2 development for immunological, inflammatory, and neurological disorders, today announced a publication in the peer-reviewed journal Nature Reviews Immunology entitled “New insights into the noncanonical inflammasome point to caspase-4 as a druggable target.” The article can be accessed here (doi: 10.1038/s41577-025-01142-9).
Despite the therapeutic potential of caspase inhibitors, developing potent and selective inhibitors against caspases has been a challenge for the industry. Previously developed caspase inhibitors demonstrated efficacy in clinical trials but required high doses that led to toxicity and program discontinuations. Using its proprietary ReSOLVE® platform, Ventus has identified selective, highly potent, small-molecule caspase-4/5 inhibitors that work via a novel allosteric inhibitory mechanism. These inhibitors have demonstrated significantly improved cellular potency compared to earlier caspase inhibitors and thus have the potential to be advanced into clinical development with a lower clinical dose and an improved safety profile.
“Ventus is leading the way in the pursuit of caspase-4/5 inhibitors,” said Michael Crackower, Ph.D., Chief Scientific Officer of Ventus. “We founded Ventus to leverage the ReSOLVE® platform and our expertise in structural biology to drug the most challenging targets in innate immunity. Following our oral NLRP3 and cGAS programs, which are both expected to enter Phase 2 clinical development in 2025, tackling caspase-4/5 is the next step in this journey.”
Caspase-4 and -5 are inflammatory caspases expressed in certain immune cells as well as epithelial and endothelial cells. This review discusses the therapeutic potential of modulating caspase-4/5 activity, insights into caspase-4/5 expression, and the identification of a novel inflammatory substrate (pro-IL-18) for caspase-4/5, as well as structural models depicting how caspase-4 interacts with pro-IL-18. Caspase-4/5 is at times the only inflammasome expressed in certain disease-relevant cells, playing a crucial role in multiple diseases associated with increased IL-18 levels, such as inflammatory bowel disease and hidradenitis suppurativa. Additionally, this review highlights the involvement of caspase-4 activation in systemic and neural vascular leakage, suggesting a role in the pathogenesis of diseases such as sepsis, acute kidney injury, and acute lung injury.
“Inflammatory caspases, including caspase-4/5, respond to dysbiosis by inducing a disruption in epithelial and endothelial barriers and promote an inflammatory response by activating immune cells,” said Elad Elkayam, Ph.D., lead author on this article and Principal Investigator, Protein Sciences at Ventus. “We believe that caspase-4/5 are very promising targets for a range of inflammatory conditions with limited treatment options. We are excited to further advance our caspase-4/5 inhibitors through preclinical development and look forward to demonstrating the therapeutic potential of these targets.”
About Caspase-4/5
Caspase-4/5 are cysteine-dependent proteases that are part of a subset of caspases known as inflammatory caspases. Caspase-4 has been reported to be constitutively expressed in immune cells such as monocytes, macrophages, and neutrophils, and is also expressed in various epithelial and endothelial cells. Caspase-5 has limited basal expression, with slightly higher levels in the gut. Caspase-4/5 plays a critical role in pathogen recognition, drives inflammation and pyroptosis (a form of cell death), and is a major mediator of vascular integrity disruption in multiple diseases. A number of conditions have been linked to vascular disruption and organ failure, including sepsis, acute lung injury, acute kidney injury, diabetic nephropathy, and diabetic retinopathy. Emerging evidence supports the roles of caspase-4/5 in diseases associated with increased IL-18 levels, such as inflammatory bowel disease and hidradenitis suppurativa.
About Ventus Therapeutics
Ventus Therapeutics is a clinical-stage biopharmaceutical company with two novel small-molecule programs entering Phase 2 development for immunological, inflammatory, and neurological disorders. Using its proprietary drug discovery platform, ReSOLVE®, the company has established a robust pipeline, including two wholly-owned programs. VENT-03 is a first-in-class, oral cGAS inhibitor expected to enter Phase 2 development for lupus in 2025. VENT-02 is a best-in-class, brain-penetrant, oral NLRP3 inhibitor expected to enter Phase 2 development for Parkinson’s disease and osteoarthritis in obese patients in 2025. In addition, Ventus has out-licensed VENT-01, a peripherally-restricted, oral NLRP3 inhibitor in Phase 1, to Novo Nordisk A/S. For more information, please visit www.ventustx.com and engage with Ventus on LinkedIn.
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