Treating multiple inflammatory diseases by targeting a protein middleman
CEO: Samantha Truex
Based: Cambridge, Massachusetts
Clinical focus: Blocking gasdermin D protein with oral inhibitors to treat inflammatory diseases
The scoop: Many marketed anti-inflammation drugs, such as Novartis’ IL-1 beta antibody Ilaris (canakinumab), target interleukins or their receptors as they are directly responsible for inflammatory responses. Some experimental therapies, including those being developed by Novartis’ newly bought IFM Tre, go upstream in inflammatory signaling, blocking inflammasome activity like that of NLRP3.
Is there a possible way to stop inflammation in the middle? Quench Bio believes gasdermin D could be the central node that serves that purpose.
What makes Quench Fierce: Gasdermin D is relatively new science; its role in inflammation was first described in two Nature papers (here and here) in 2015, the first study of its X-ray crystal structure was only published last year, and the exact mechanisms of this protein are still being elucidated.
“Not only are we going after a really important target, but we’re going after a target that’s still being understood,” Quench Bio CEO Samantha Treux said. “Some people talk about flying a plane while it’s still being built. At Quench, we’re trying to fly a plane while the drawing of the plane is still on the architectural table.”
At least there’s already enough known for Quench to view gasdermin D as a valuable target.
Normally, a cell dies in the well-characterized “quiet” apoptosis process, Treux explained. But as the cell senses and responds to external inflammatory stimulus, gasdermin D may be cut in two pieces, one of which could rearrange with other copies of itself to form a pore in the cell membrane. This pore not only allows for the release of inflammatory molecules such as interleukins and alarmins but can also trigger a more violent, pro-inflammatory type of cell death called pyroptosis, which literally indicates “fire.”
The beauty of gasdermin D as the middleman of the pathway is that it could be a more inclusive approach to inhibiting the inflammatory process, according to Treux. A drug that goes after any one of several upstream sensor inflammasomes like NLRP3 or a downstream cytokine like IL-1 beta may be useful when a disease just happens to be driven by that one element, she said.
Plus, there’s another pathway in which no inflammatory sensor proteins are involved, and a third one induces a type of cell death called NETosis that’s linked to the while blood cells neutrophils. But they all appear to go through a common link—gasdermin D.
More understanding of gasdermin D keeps coming through. While it’s a promising target, the protein alone might not be the magic bullet that can solve everything, Truex cautioned. “It’s really important that we as an industry have different approaches to the same diseases because almost no diseases are singularly driven,” she said.
For Quench, it’s been looking for inflammatory and autoimmune diseases that are affected by at least two of those three pathways, Truex said. The potential list is long and lucrative, including lupus, rheumatoid arthritis, pyoderma gangrenosum, severe asthma, multiple sclerosis, nonalcoholic steatohepatitis and alcoholic hepatitis.
It has put together an experienced team for its endeavor. Truex had previously held business leadership roles at Biogen and Genzyme before becoming chief business officer of Padlock Therapeutics, a 2015 Fierce 15 winner whose protein-arginine deiminases approach at tackling autoimmune diseases attracted Bristol Myers Squibb in a $600 million buyout in 2016.
The company’s first two employees, Chief Technology Officer Mark Tebbe and Senior Director of Biology Mike Nolan had Big Pharma experience at Eli Lilly and GlaxoSmithKline, respectively. Chief Scientific Officer Iain Kilty was previously vice president overseeing immunology and inflammation early research at Pfizer, and he later lured ex-Pfizer colleague and immunologist Wei Li to run Quench’s labs.
Right now, with the $50 million it has raised, Quench is investing heavily in different drug discovery tools to go after gasdermin D and aims to move into animal tests next year and approach first-in-human studies a few years later.
Investors: RA Capital, AbbVie Ventures, Atlas Venture and Arix Bioscience.