Most treatments for inflammatory diseases have single targets, such as an inflammation-promoting cytokine or a protein complex called an inflammasome. Quench Bio is taking aim at a family of proteins involved in inflammatory cell death—and it’s picked up $50 million to do so.
Incubated at Atlas Venture since its inception in 2018, Quench’s first target is gasdermin D, the best understood member of the gasdermin family of proteins. With its $50 million in series A cash, the company expects to fund three years’ worth of research as well as come up with its first clinical candidate, CEO Samantha Truex told FierceBiotech. It also hopes to screen for drug candidates that inhibit other members of the gasdermin family.
Gasdermin D plays a role in multiple inflammatory cell death pathways; when those pathways are activated, the protein forms pores in the cell membrane.
“By forming pores, it does two things: one is it allows for the release of inflammatory signals. Those can be inflammatory cytokines, alarmins, or what we call DAMPs: danger-associated molecular patterns,” Truex told FierceBiotech.
“In addition, once enough of those pores form, the cell membrane loses its integrity and the cell literally explodes in an inflammatory way,” she added.
One of those types of cell death is called pyroptosis, derived from “pyro”—literally “fire”—while another is NETosis, a type of cell death linked to white blood cells called neutrophils. The hope is that inhibiting gasdermin D will delay cell death or lead cells to die by apoptosis, a “quieter, calmer, noninflammatory” form of cell death, Truex said.
Gasdermin could be a more “complete” way to treat inflammatory diseases as it is downstream of inflammasome targets like NLRP3 and upstream of pro-inflammatory cytokines like IL-1 beta, Truex said. For example, targeting NLRP3 could stop cells on their way to pyroptosis if NLRP3 is indeed the inflammasome that is triggered, she said. But the drug would be ineffective if the cell has another inflammasome triggered, such as NLRC4 or pyrin, she said.
And Quench believes going upstream of the release of cytokines and heading off explosive cell death could be a better approach than aiming to block a cytokine that is already being released. Truex said.
“It’s almost like an hourglass, with inflammatory targets at the top, and at the bottom there are things leaking out of the cell. If we hit at the middle, we can have an impact on all of it,” she said.
Quench spent most of 2019 coming up with its clinical game plan. As it looks to 2020, the company still has much to learn about its targets.
“We assessed over 25 diseases in the autoimmune, autoinflammatory and severe inflammatory category and we have come to the conclusion that pyroptosis and NETosis are known to be associated with numerous inflammatory diseases,” Truex said. Those include rheumatoid arthritis, lupus, nonalcoholic steatohepatitis and multiple sclerosis. The company isn’t sharing yet which ones it’s going after first, but Truex noted that the company plans to work on treatments for diseases that have no treatments or those that have many treatments but still unmet need.
“We could start with rare diseases and subsets of patients with lupus and rheumatoid arthritis who appear specifically to have disease driven by gasdermin D. Our center of excellence in gasdermin biology will do more research in gasdermin’s role in those diseases in parallel with our efforts to discover inhibitors of gasdermin,” she said.
Quench draws its series A funding from RA Capital Management and AbbVie Ventures as well as Atlas Venture and Arix Bioscience.