DUBLIN – After 18 months in stealth mode, Ventus Therapeutics Inc. has emerged with $60 million in series A funding and big ambitions to bring insights from structural biology to bear on two key aspects of innate immunity, inflammasome activation and cGAS-Sting signaling.

Founding investor Versant Ventures, of San Francisco, led the financing and was joined by GV (formerly Google Ventures), of Mountain View, Calif. Founding CEO and Versant venture partner Marcelo Bigal initially became interested in the area because of new developments in neuroinflammation, Versant managing director Jerel Davis told BioWorld. But Bigal’s company formation effort has led to a much broader vision for the initiative, which embraces autoimmune disease, inflammatory disease and resistant cancer. Bigal, the former chief scientific officer of Teva Pharmaceutical Industries Ltd., has assembled a veritable “Magnificent Seven” of scientific founders, who have deep insights into the structural biology of key innate immune system targets and into the mechanisms and pathways underpinning innate immune signaling.

Those include Hao Wu, of Harvard Medical School, who has pioneered the field of structural immunology, using X-ray crystallography and cryo-electron microscopy to probe in detail the structures of “signalosomes,” or the large intracellular molecular complexes that assemble following the binding of pathogen-associated molecular patterns or endogenous damage-associated molecular patterns to extracellular or cytoplasmic sensors. A former lab member, Feng Shao, now at the National Institute of Biological Sciences in Beijing, is also part of the founding group. The other five are prominent figures in immunology. They include Richard Flavell at Yale University, Judy Lieberman at Harvard, Thomas Tuschl at Rockefeller University, Douglas Green at St. Jude Children’s Hospital and Russell Vane, of the University of California at Berkeley.

Marcelo Bigal, CEO, Ventus Therapeutics

Inflammasome activation has been an important thread in innate immune research over the past two decades. The best known system is the NLRP3 [NOD-like receptor [NLR] family, pyrin domain-containing protein 3] inflammasome, the activation of which results in the maturation of the inflammatory cytokines interleukin-1beta (IL-1beta) and IL-18 and, by a separate pathway, in the induction of pyroptosis, a form of inflammatory cell death. Its chronic overactivation causes sterile inflammation and has been linked to a broad range of autoimmune, cardiometabolic, neurodegenerative and respiratory conditions, as well as to rare genetic conditions arising from mutations in the relevant genes.

There are more than a dozen inflammasomes in all, all of which potentially fall within the company’s purview. So, too, does the cGAS-Sting [cyclic-GMP-AMP-synthase-stimulator-of-interferon-genes] pathway, which triggers the production of interferons in response to the detection of cytosolic DNA, arising either from an invading virus or from cellular damage.

The signal pathways underpinning those two sensory systems contain a plethora of validated drug targets that Ventus is actively interrogating. “We have structural information on nearly a dozen of these targets,” CEO Bigal told BioWorld. The company’s key differentiator, he said, is its ability to combine structural biology with diverse protein engineering capabilities that enable it to study monomeric proteins in isolation from the complexes they normally become part of. “We express, we purify and we stabilize the monomers in vitro,” Bigal said. That allows for detailed structural studies of drug-target complexes, which are then complemented by biochemical assays to confirm the molecules’ mode of action.

Jerel Davis, managing director, Versant Ventures

Versant’s Inception Sciences Discovery Engine in Montreal has done a share of the scientific spade work, assembling a discovery platform that builds on the collective knowledge and capabilities of the founders. “We have access to structures and assays for some of the targets, which we believe are very enabling for the company,” Davis said. It has already been put to work. “We have chemical matter on multiple targets, which is promising but still early,” Davis said. Ventus will operate from both Montreal, which has a rich tradition in drug discovery, he said, and from Boston, which will focus on structural biology and immunology. “At this point we have a fully-fledged team,” he said. It includes former members of Wu’s lab. “That heritage is quite important,” he said.

In GV, Versant has found an investment partner with deep pockets. “Marcelo went out to bring in one other group into this investment,” Davis said. “He had many parties interested.” The GV life sciences team included scientists who had prior experience of the field. “They understood what was different here incredibly quickly,” he said.

Ventus is, of course, some ways behind its rivals. Innate immune signaling has been a fertile area for biotech investing and M&A activity in recent years. Novartis AG moved into the area just over a year ago by acquiring the IFM Tre arm of IFM Therapeutics LLC for $310 million up front and more than $1.2 billion in possible milestones. That brought on board NLRP3 antagonist IFM-2427, in clinical development for a range of chronic inflammatory conditions, as well as preclinical programs directed at inflammatory bowel disease and central nervous system disorders.

Shortly before that, the Genentech arm of Basel, Switzerland-based Roche Holding AG acquired Jecure Therapeutics – another Versant investee – for an undisclosed sum, giving it access to a portfolio of preclinical NLRP3 inhibitors aimed at nonalcoholic steatohepatitis and liver fibrosis. Dublin-based Inflazome Ltd. and Cambridge, U.K.-based Nodthera Ltd. are still independent. Inflazome has completed phase I studies of two NLRP3 inhibitors, inzomelid, which is a brain-penetrant molecule in development for Parkinson’s disease and cryopyrin-associated periodic syndrome, and somalix, which is peripherally restricted. Nodthera is in pre-IND development with its lead molecule, NT-0167.

Despite the buzz, the field has been hampered by several constraints. “There’s been a dearth of chemical matter,” Davis said. “The vast majority of companies in the field, including those acquired by multiple pharmaceutical companies, had the same starting point.” That is largely due to the lack of structural information, which has hampered discovery efforts and forced most companies to pursue trial-and-error processes. “It’s like drug development with the lights off,” Bigal said.

The development of cGAS-Sting antagonists is even less advanced – but Novartis moved into that emerging field last fall, by optioning another IFM subsidiary, IFM Due, in a deal worth up to $840 million. Aduro Biotech Inc., of Berkeley, Calif., has a preclinical alliance in the area with Indianapolis-based Eli Lilly and Co.

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