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Drug Discovery

Ventus Therapeutics launches to drug inflammasomes, cGAS, and more

The Versant-founded start-up raised $60 million to develop small molecules that target innate immune system proteins

by Ryan Cross
May 6, 2020 | APPEARED IN VOLUME 98, ISSUE 18

09818-buscon2-inflam.jpg
Credit: C&EN/Protein Data Bank, PDB ID 3JBL (NLRP3); Protein Data Bank, PDB ID 6CB8 (gasdermin-D)
Cryogenic electron microscopy models of inflammasome rings (foreground, right) and gasdermin pores (background, left)

In 2017, the health care-focused venture capital firm Versant Ventures funded Jecure Therapeutics with $20 million. The start-up was founded to drug proteins of the innate immune system, particularly the NLRP3 inflammasome, which has been implicated in a dizzying list of diseases including Alzheimer’s, cancer, and nonalcoholic steatohepatitis (NASH). It didn’t take long for that investment to pay off. In late 2018, Genentech acquired Jecure for an undisclosed sum.

In the eyes of Versant managing director Jeral Davis, Jecure had barely tapped the potential of drugging inflammasomes, let alone other proteins of the innate immune system. So he planned a sequel. Today, a new company called Ventus Therapeutics formally launches with $60 million in series A financing from Versant and GV, the former Google Ventures.

The start-up will use the money to progress drug-discovery programs against an expanded cast of innate immune system drug targets implicated in autoimmune diseases and cancer.

Ventus CEO Marcelo Bigal, who joined the company in May 2019, says Ventus will first focus on three undisclosed targets, with the ability to work on 10 more. All of these targets relate to two parts of the innate immune system—the inflammasome pathways and nucleic-acid sensing pathways.

Both pathways are full of tough-to-drug proteins such as gasdermin, NLRP3, STING, and cGAS that have garnered attention from well over a dozen drug companies.

Collectively, these proteins detect and respond to danger such as infections, cancer, or toxic molecules. Inflammasome proteins like NLRP3 trigger cells to release inflammatory cytokines and self-destruct using donut-shaped gasdermin proteins that poke holes in the cell. Nucleic-acid sensing proteins like STING and cGAS alert the immune system to the presence of infected or sick cells.

In some cases, drug developers are working to activate these inflammatory pathways to energize the immune system to attack tumors. In other cases, they want to inhibit the pathways to treat autoimmune diseases or conditions linked to chronic inflammation.

The start-up was founded and seed-funded at Versant’s Inception Discovery Engine incubator in Montreal. Ventus was based on the work of five scientific cofounders from four institutions who have collectively solved the molecular structures of 10 innate immune system targets. These targets include inflammasomes, whose structures are notoriously difficult to resolve, partly because the individual proteins are prone to aggregate in laboratory settings.

“It was like trial-and-error drug development with the lights off,” Bigal says.

To turn the lights on, Ventus leans heavily on help from the five founders to “paralyze” the proteins—with approaches including protein engineering—to prevent them from clumping, Bigal says. That allows the scientists to resolve the proteins’ molecular structures, a quintessential step of any structure-based drug-design program. It also enables them to design new assays to study how small molecules activate or inhibit the proteins.

Ventus is not wedded to working on any diseases in particular, Bigal says. The company was founded on the notion that many proteins of the innate immune system are implicated in multiple diseases including lupus, NASH, osteoarthritis, traumatic brain injury, Parkinson’s, and Alzheimer’s, he explains. Respiratory diseases, cardiometabolic diseases, and solid tumors will be areas of exploration as well.

Bigal argues that this disease diversity sets his company up to strike partnerships with a number of larger drug firms that specialize in particular disease areas. Ventus is also taking a page from the playbook of many inflammasome drug-discovery companies and developing two drug candidates for one of its targets—one compound that can enter the brain and one that doesn’t.

Although Ventus isn’t disclosing its targets yet, the work of its five scientific founders offers clues.

For instance, Feng Shao from the National Institute of Biological Sciences in Beijing has led pioneering studies on the structure and function of gasdermin proteins. Hao Wu and Judy Lieberman from Harvard Medical School are also experts on gasdermin proteins, and Wu has published studies on the structure and activation of inflammasome proteins including NLRP3. Richard Flavell of Yale University School of Medicine studies inflammasomes, and Thomas Tuschl from Rockefeller University studies cGAS.

Today, Ventus has 28 employees at its sites in Montreal and Boston, and 30 outsourced chemists. since the company was backed by Versant from the beginning, the financing discussions were well underway and remained unrushed by the COVID-19 pandemic, Bigal says. In fact, he adds, Ventus raised more money than it initially intended.

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