VENT-03 is a systemic oral cGAS inhibitor with a potent and selective profile that has the potential to be both first-in-class and best-in-class. Enabled by our proprietary RESOLVE® platform and expertise in structural biology, VENT-03 is, to our knowledge, the first cGAS inhibitor to enter clinical development. VENT-03 successfully completed a Phase 1 trial in healthy volunteers and is entering Phase 2 development for a broad range of immunological and inflammatory diseases, with an initial focus on lupus and treatment-refractory rheumatoid arthritis.
VENT-03
cGAS is an innate immune sensor of nucleic acids in the cytoplasm, a key feature of many chronic diseases. Aberrant activation of cGAS leads to auto-inflammation and tissue damage, playing a key role in pro-inflammatory diseases such as lupus and numerous other autoimmune diseases.
VENT-03 is currently under clinical investigation; find out more here.
VENT-03: A first-in-class oral small molecule inhibitor of cGAS
Despite significant efforts in the industry over the past decade, no cGAS inhibitor had entered clinical development until VENT-03. Using our expertise in structural biology, we generated accurate co-crystal structures of cGAS with proprietary inhibitors using our RESOLVE® platform. Through further work with ReSOLVE®, we developed a more detailed understanding of the catalytic pocket including previously unknown conformations. We used these proprietary insights to develop highly potent chemical matter, leading to our portfolio of orally bioavailable small-molecule cGAS inhibitors, including VENT-03.
cGAS is a primary sensor of cytoplasmic double-stranded DNA (dsDNA) and plays a key role in the innate immune response. When aberrantly activated, it triggers a signaling cascade that leads to the release of Type 1 interferons and NF-kB-driven pro-inflammatory cytokines, resulting in auto-inflammation and tissue damage. This aberrant activation of the cGAS pathway is implicated in numerous autoimmune diseases.
Aberrant Accumulation of Cytoplasmic dsDNA
cGAS-STING Pathway Activation
Inflammation
Tissue Damage
A crucial element of the innate immune response is the recognition of foreign nucleic acids by pattern recognition receptors (PRRs), including cGAS. The presence of dsDNA in the cytoplasm often happens in cellular stress secondary to DNA leakage from the mitochondria or the nucleus.
Role of cGAS inhibition with VENT-03 in systemic lupus erythematosus(SLE)
The pathogenesis of SLE is driven by a Type 1 interferon response as well as the release of other cytokines triggered by the detection of self-DNA by cGAS. Targeting Type 1 interferons has been validated for the treatment of lupus.
Current standard of care for SLE consists of non-targeted therapies, such as hydroxychloroquine, steroids, and immunosuppressants, which often result in incomplete responses and have suboptimal safety and tolerability profiles. Only two new medications – belimumab and anifrolumab – have been approved for SLE since 2011. However, there are several challenges associated with these biologics, including the risk of serious infections as well as the inability to address all of the symptoms of SLE with either drug.
cGAS signaling regulates Type 1 interferon responses, NF-κB activation, and aryl hydrocarbon receptor (AHR) activity. Through inhibition of the cGAS pathway, VENT-03 can selectively target DNA-driven Type 1 interferon responses, and has the potential to demonstrate efficacy in SLE without the safety concerns of immunosuppressants and approved biologics. VENT-03 can also inhibit the NF-κB-mediated inflammatory responses associated with arthritis and B cell activity – therefore able to potentially improve efficacy relative to available medications, addressing remaining unmet clinical need in lupus.
If you would like to learn more about cGAS, we curated a bibliography of comprehensive publications here.
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