Ventus to Advance cGAS Inhibitor as New Treatment for Lupus
VENT-03 targets cGAS protein implicated in autoimmune diseases
Ventus Therapeutics plans to develop a new treatment candidate for lupus and other inflammatory diseases marked by the activation of the type 1 interferon immune system pathway, the company recently announced.
Called VENT-03, the investigational treatment will target cGAS, a protein whose activation has been implicated in a range of autoimmune diseases, including systemic lupus erythematosus (SLE).
Last year, Ventus received a Lupus Research Program Idea Award from the U.S. Department of Defense, which came with funding to study the potential role of cGAS in lupus and the therapeutic potential of a molecule to inhibit it.
“cGAS is a highly coveted target for pro-inflammatory and neurodegenerative diseases for which no inhibitor has advanced into clinical development to date, despite significant efforts from the drug discovery industry over the past decade,” Marcelo Bigal, MD, PhD, Ventus’ president and CEO, said in a press release.
“We expect VENT-03 to be the first cGAS inhibitor to enter the clinic, with a clinical development plan tailored to provide multiple data readouts prior to Phase 2 trials,” Bigal said.
What is cGAS?
Double-stranded DNA (dsDNA) is usually housed inside a cell’s core, or nucleus. When it’s found outside of the nucleus in the cytoplasm, it is a sign of cellular damage. This is seen in diseases like SLE and cutaneous lupus erythematosus (CLE), a form of lupus affecting predominately the skin.
cGAS is a receptor inside cells that senses the presence of this cytoplasmic dsDNA and initiates a cascade of signaling events to activate the immune system. Specifically, it drives the production of type 1 interferons, a family of inflammatory molecules.
Type 1 interferon responses are implicated in a wide range of diseases, including SLE and CLE. Genetic mutations that activate these signaling pathways are also responsible for genetic forms of chilblain lupus, a rare form of CLE.
VENT-03 was designed to inhibit cGAS so as to diminish this damaging activation of the interferon pathways. It was developed using ReSOLVE, Ventus’ drug discovery platform.
First, the company generated a novel crystal structure — a type of model of cGAS’ molecular form — and used it to determine the best place on the protein for a potential inhibitor to bind. This was a “major breakthrough that transformed our ability to achieve high potency in our cGAS inhibitors,” said Michael Crackower, PhD, Ventus’ chief scientific officer.
In disease-relevant preclinical studies, the experimental therapy demonstrated “robust” pharmacodynamic activity, meaning it actively engaged with cGAS as intended, and was also efficacious, according to Ventus.
We expect VENT-03 to be the first cGAS inhibitor to enter the clinic, with a clinical development plan tailored to provide multiple data readouts prior to Phase 2 trials
The company says that Phase 1 clinical trials will include patients with multiple distinct interferonopathies, or those in which type 1 interferon activation is implicated in their disease mechanisms.
Internally validated analyses of skin and blood biomarkers of inflammation and cGAS engagement will be used to evaluate the therapy. Ventus believes that by evaluating these factors in distinct diseases, it will “de-risk” late-stage development of VENT-03 if it moves forward in clinical testing.
Additional cGAS inhibitors from Ventus are also on the horizon.
“Given the highly validated role of the cGAS pathway as a driver of disease, we are now developing additional cGAS inhibitors to achieve the full potential of this attractive target in distinct therapeutic areas,” Crackower said.
VENT-03 is the third developmental candidate Ventus has put forward in the last year. VENT-01, which is being developed for kidney, cardiovascular, and liver conditions in collaboration with Novo Nordisk, and VENT-02, which is under development for neuroinflammatory and neurodegenerative conditions, are also in the company’s pipeline.