Dosing begins in Phase 1 trial of VENT-03, potential cGAS inhibitor

cGAS, once activated, initiates a signaling cascade that promotes inflammation

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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A first person has been dosed in a Phase 1 clinical trial of VENT-03, Ventus Therapeutics’ oral treatment candidate for lupus and other inflammatory diseases.

VENT-03 is an inhibitor of cGAS, a protein whose activation has been implicated in lupus and other autoimmune diseases.

“cGAS has historically proven an elusive target despite significant industry efforts to develop a viable inhibitor. We have broken that cycle with the initiation of this Phase 1 clinical trial,” Marcelo Bigal, MD, PhD, president and CEO of Ventus, said in a company press release.

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Results of trial, in healthy volunteers, likely before year’s end

The Phase 1 trial will assess the pharmacokinetics (the movement of a medicine into, through, and out of the body), pharmacodynamics (the effects of a compound on the body), and the safety of VENT-03, administered as single and multiple ascending doses, to healthy volunteers. Results are expected in the second half of this year.

cGAS is a receptor inside cells that recognizes double-stranded DNA in the cell’s cytoplasm, or cell body. Double-stranded DNA is generally found in the cell nucleus. When present in the cytoplasm — where it typically is associated with cellular damage — it activates cGAS. This activation initiates a signaling cascade that culminates in the production of type 1 interferons, a group of molecules that cause significant inflammation and tissue damage.

“We are eager to advance this therapeutic candidate and bring the potential of cGAS inhibition to patients suffering from inflammatory disorders with significant unmet needs,” Bigal said.

According to Ventus, in both preclinical models and patients, the cGAS pathway has been identified as a major driver of lupus, also known as systemic lupus erythematosus, and other inflammatory diseases. By inhibiting cGAS, VENT-03 is expected to halt the damaging activation of the interferon pathways.

The investigative treatment was developed using Ventus’ drug discovery platform, called ReSOLVE.

“The commencement of the Phase 1 VENT-03 trial demonstrates Ventus’ ability to drug a target that has been undruggable to date, made possible because of ReSOLVE,” said Mike Crackower, PhD, Ventus’ chief scientific officer. “ReSOLVE, which combines machine learning with physics and computational chemistry, provided us with unique insights about the binding pocket that allowed us to design VENT-03 as a first-in-class cGAS inhibitor with excellent potency.”