Unique insight into the cyclic GMP-AMP synthase (cGAS) active site provided a framework for rational optimization of cGAS inhibitors
Phase 2 trial with Ventus’ first-in-class cGAS inhibitor, VENT-03, in patients with lupus expected to initiate in 2025
WALTHAM, Mass. & MONTREAL — March 25, 2025 — (BUSINESS WIRE) — Ventus Therapeutics, a leading Phase 2 clinical-stage biopharmaceutical company advancing two novel small-molecule programs for immunological, inflammatory, and neurological disorders, today announced a publication in the peer-reviewed journal Communications Chemistry from Nature Portfolio entitled “Structural insight into the cGAS active site explains therapeutic relevant species differences.” The publication can be accessed here (doi: 10.1038/s42004-025-01481-7).
The publication provides insights into the mechanism of action and binding mode of known cGAS inhibitors, including the identification of key structural differences driving potency shifts between species. Investigators leveraged these findings to inform a structure-based design approach, which they used to develop a novel, highly potent cGAS inhibitor. This work provides the framework for rational and efficient optimization of cGAS inhibitors and potential preclinical translational strategies, adding to Ventus’ growing body of research on cGAS biology.
“Despite robust evidence linking the cGAS-STING pathway to numerous inflammatory and neurodegenerative conditions, the target has historically eluded drug discovery efforts, partially due to a lack of available information about the binding mode of cGAS inhibitors,” said Kelly Pike, Ph.D., corresponding author on this article and Head of Biology at Ventus. “The studies described in this publication will inform our strategies to develop the next generation of potent cGAS inhibitors beyond VENT-03.”
Ventus’ VENT-03 is the first oral cGAS inhibitor to successfully complete a first-in-human Phase 1 study and was discovered using Ventus’ proprietary ReSOLVE® platform. In the Phase 1 study, VENT-03 was shown to be safe and well-tolerated at all tested dose levels with a favorable pharmacokinetic (PK) profile that enables once-daily dosing.
“Our deep understanding of cGAS inhibitor development has allowed us to generate optimized molecules that are potential treatment options for a wide range of autoimmune disorders and cardiometabolic diseases,” said Michael Crackower, Ph.D., Chief Scientific Officer of Ventus. “We will commence our first Phase 2 trial for VENT-03 in patients with lupus in 2025 and are planning additional trials given the strong biological evidence supporting the role of cGAS in the pathogenesis of multiple diseases.”
About cGAS
cGAS is an intracellular pattern recognition receptor that is activated after binding to double-stranded DNA (dsDNA) in the cytoplasm. The presence of dsDNA in the cytoplasm is often the result of cellular dysfunction, which is a hallmark of many autoimmune and inflammatory diseases. Activation of cGAS leads to cGAMP formation, activation of STING, pronounced inflammation, and tissue damage. In both patients and preclinical models of disease, the cGAS pathway has been shown to be a key driver of lupus and other inflammatory diseases, such as rheumatoid arthritis, systemic sclerosis, dermatomyositis, and Sjögren’s disease.
About Ventus Therapeutics
Ventus Therapeutics is a leading Phase 2 clinical-stage biopharmaceutical company advancing two novel small-molecule programs 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 in Phase 2 for Parkinson’s disease, and is expected to enter Phase 2 development in osteoarthritis in obese patients later 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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