Ventus Therapeutics Completes Phase 1 Trial of VENT-03, an Oral cGAS Inhibitor

Ventus Therapeutics, a biopharmaceutical company focused on discovering and developing small-molecule therapeutics, announced successful results from its Phase 1 clinical trial of VENT-03, a cyclic GMP-AMP synthase (cGAS) inhibitor. This trial marks the first time a cGAS inhibitor has completed a first-in-human study. The Phase 1 trial assessed the pharmacokinetics (PK), target engagement, safety, and tolerability of VENT-03 in 72 healthy adult volunteers, using a variety of single and multiple ascending doses.

Marcelo Bigal, President and CEO of Ventus, highlighted the significance of the trial’s outcomes, stating that VENT-03 is positioned as a first- and best-in-class anti-cGAS medication. He emphasized that the results validate the capability of the ReSOLVE™ platform, which Ventus uses to develop high-quality small molecules for targets that have been challenging to address in the past. Bigal noted that these findings open up opportunities to explore the potential of cGAS inhibition in various autoimmune and cardiometabolic diseases, starting with lupus. Ventus is preparing to commence a Phase 2 trial with VENT-03 in systemic lupus erythematosus (SLE) in 2025.

The Phase 1 trial demonstrated that VENT-03 was safe and well-tolerated at all tested dose levels, with no dose-limiting or dose-related toxicities. There were no serious adverse events or changes in clinical laboratory parameters, ECG, or vital signs. Any treatment-related adverse events were mild, transient, and manageable.

VENT-03 exhibited a favorable pharmacokinetic profile, supporting once-daily dosing. It also achieved plasma concentrations necessary for full target inhibition and showed strong pharmacodynamics. Ventus plans to present the complete data from the Phase 1 trial at a future medical conference.

Xavier Valencia, Head of Clinical Development at Ventus, discussed the potential impact of VENT-03 on lupus treatment. He noted that current treatments for lupus, which include injectable medicines targeting the type I interferon or BAFF pathways, address only limited aspects of the disease. A once-daily oral cGAS inhibitor like VENT-03 could potentially modulate both pathways validated by biologics, affect multiple aspects of SLE, and offer superior efficacy compared to existing treatments and therapies in development.

The role of cGAS in autoimmune and inflammatory diseases is significant. cGAS is an intracellular pattern recognition receptor activated by binding to double-stranded DNA (dsDNA) in the cytoplasm. This binding often results from cellular dysfunction, which is common in many autoimmune and inflammatory diseases. Activation of cGAS leads to the formation of cGAMP, activation of STING, and pronounced inflammation and tissue damage. The cGAS pathway is a key driver of lupus and other inflammatory diseases, such as systemic sclerosis, dermatomyositis, and Sjögren’s disease, in both patients and preclinical models.

Ventus Therapeutics specializes in developing small molecule therapeutics for immunology, inflammation, and neurology disorders. The company utilizes its ReSOLVE™ platform, which integrates artificial intelligence, structural biology, and biophysics to model protein dynamics with high precision. Ventus initiated its first target screening in 2020, selected three development candidates in 2022, and advanced its two wholly-owned product candidates into clinical trials by 2023. By 2024, Ventus had completed Phase 1 trials for its programs, including VENT-03, an oral cGAS inhibitor, and VENT-02, an oral NLRP3 inhibitor. Additionally, Ventus has out-licensed VENT-01, an NLRP3 inhibitor, to Novo Nordisk A/S.