Targeting GPR75 (ConfometRx)

Founded nearly a decade ago to develop GPCR-targeting drugs, Confo Therapeutics has found itself in a prime position as the industry-wide weight-loss craze — driven by GPCR family member, GLP-1— reaches new heights. The Belgium-based biotech raised €60 million ($65.1 million) in a series B financing Friday to advance its GPR75-targeting obesity candidate along with three others in the endocrine and metabolic disease space. Confo isn’t sharing much about the other programmes it’s progressing, but the funds will advance two through Phase I testing, and help another pair ready for IND. According to the company’s website, it has a mix of antibodies and small molecules in development for conditions such as hyperparathyroidism, hyperinsulinemia, and fibrotic diseases.The firm also has an AT2R-targeting peripheral pain candidate in a Phase I trial. Eli Lilly paid $40 million upfront last year to gain rights to that therapy, and is on the hook for $590 million more in milestones.GPCR stabilisationWhile Confo’s pipeline may seem wide-reaching, that’s only because GPCRs “play a role in almost any disease you can think of,” CEO Cedric Ververken told FirstWord, naming asthma and diabetes, as well as central nervous system and cardiovascular disorders. Despite the strong scientific rationale behind modulating GPCRs for various diseases, there are hundreds of receptors that have yet to be successfully targeted. That’s due to two factors, Ververken explained: the proteins are deeply embedded in the cell membrane, and they’re conformationally unstable, making them difficult to study. That’s where the ConfoBodies platform comes in. The company has developed a suite of tool antibodies to stabilise GPCR proteins in their therapeutically relevant conformation, enabling increased screening sensitivity for drug discovery.The technology is so powerful, Ververken said, that Confo can pick up on fragments, which are “really tiny chemical starting points” that wouldn’t be detected in a normal signalling assay. “Starting from something that small allows us to build up these drugs in a very efficient way without built-in toxicophores or lipophilic parts,” he added. “We can really maintain favourable drug-like properties from the start.” Plus, Confo isn’t limited to small molecules. The company also boasts a therapeutic antibody generation platform geared specifically towards agonists, “which is quite a unique feat in the industry,” Ververken said.There are three GPCR-targeted antibodies on the market, but none are agonists. Confo’s agonist antibody capabilities are part of what’s helped the firm to attract deals with Regeneron and AbCellera, he added. All systems go on obesityFor its internal pipeline, Confo is initially focusing on endocrine and metabolic diseases because there’s a wealth of biologically relevant GPCRs in that space — with GLP-1 as a prime example. Plus, the pharmacology of these particular receptors is well-established, making therapeutic activity easier to confirm in Phase I healthy volunteer studies, Ververken said. From there, it’s a straightforward path to clinical proof-of-concept.The space also has a healthy mix of rare disease opportunities that can be tackled by a small biotech, as well as big indications like obesity that are attractive to pharma. “It allows us to build a pipeline towards an IPO, but it also allows us to work on projects that could potentially drive an M&A deal at some point,” Ververken commented. Obesity is where Confo is planning on allocating the majority of its resources as it races to be first in the clinic with its GPR75 agonist, he added. The target was first linked to obesity in 2021 when a genetic study showed that individuals with a loss-of-function mutation in the gene had a lower risk of obesity and improvements in certain metabolic measures that suggested the protein played a role in muscle-mass preservation.  That muscle benefit falls squarely within the next-generation weight-loss drug wish list, along with improved tolerability. For more, see Spotlight On: How obesity drug developers aim to combat muscle loss.Ververken said that several phamas looking for new obesity assets are interested in GPR75, and other companies are working to develop their own agonists. “But we intend to lead the race,” he asserted.