Background: The detection of foreign DNA by the innate immune system is a vital component of the host response to pathogens. In mammalian cells, this task is performed in large part by cyclic GMP AMP synthase (cGAS). Although the indiscriminate detection of DNA by cGAS ensures the detection of almost all pathogens, it can also trigger autoinflammation in response to the aberrant accumulation of self-DNA, central to the immunopathology of multiple diseases such as systemic lupus erythematosus (SLE), systemic sclerosis, dermatomyositis, and several forms of cardiomyopathies. cGAS is therefore a drug target with a broad therapeutic potential across autoimmune disorders. VENT-03 is a potent, selective and orally available cGAS inhibitor discovered by Ventus Therapeutics using a proprietary platform for identifying novel small molecule therapeutics (ReSOLVE ^TM ). VENT-03 is the first cGAS inhibitor to be tested in humans and herein we describe its safety, tolerability, pharmacokinetics and pharmacodynamics in healthy volunteers.

Objectives: To report the safety, tolerability and PK of single and multiple doses of vent-03 in a FIH trial.

Methods: 72 healthy male and female volunteers received single ascending oral doses (SAD) of VENT-03 or placebo up to 2000 mg, or multiple ascending doses (MAD) up to 900 mg administered once daily (QD) for 10 days. Each SAD and MAD cohort included 8 participants, of which 6 received VENT-03 and 2 received placebo in a double-blind manner. Volunteers were monitored for adverse events, clinical laboratory parameters, ECG and vital signs. Serial blood samples were taken to characterize the pharmacokinetics of VENT-03, and pharmacodynamics was assessed using a novel proprietary whole blood assay.

Results: There were no deaths or serious adverse effects during the trial. VENT-03 was safe and well-tolerated across all tested SAD and MAD dose levels. There were no significant changes in clinical laboratory parameters, ECG or vital signs. There were no dose-related adverse effects, and the observed adverse effects were mild, transient and easily managed. Absorption of VENT-03 in a fasted state was rapid with peak plasma concentrations appearing 4-6 hours post dose. Exposure increased with ascending doses, and the pharmacokinetic profile of VENT-03 supports a QD dosing regimen. Pharmacokinetic steady state is reached in approximately 7 days with significant accumulation in plasma. Administration of VENT-03 with food delayed the time of peak plasma levels but did not significantly affect the overall exposure. VENT-03 demonstrated robust target engagement, and plasma levels exceed what is required to fully inhibit the activity of cGAS in patients.

Conclusion: VENT-03 was safe and well-tolerated in healthy volunteers, demonstrating a favorable pharmacokinetic profile and robust target engagement. The efficacy of VENT-03 in SLE patients with active cutaneous manifestations will be evaluated in an upcoming Phase 2a stud.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Dr. Xavier Valencia Ventus Therapeutics, Ofer Spiegelstein Ventus Therapeutics, Nadine Fradet Ventus Therapeutics, Amadine Chefson Ventus Therapeutics, Patrick Cyr Ventus Therapeutics, Kelly Pike Ventus Therapeutics, Jeanne Stewart Ventus Therapeutics, Ramsay Beveridge Ventus Therapeutics.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.