AT2R

Algiax Pharmaceuticals’ non-opioid candidate has achieved “clinically meaningful” pain reduction in a mid-stage trial of people with peripheral post-surgical neuropathic pain, marking another success in an area that has recently been gaining momentum despite a challenging history. More than a quarter of patients treated with the German biotech’s GABAA-receptor modulator, dubbed AP-325, saw at least 50% pain reduction compared with 11% of placebo patients, according to data shared with Endpoints News . The Phase 2a study enrolled almost 100 patients across 27 trial sites in Germany, Spain, the Czech Republic, Belgium and France. Further, over half the patients in the treatment cohort didn’t need any rescue pain medication versus 21% of placebo patients. AP-325 was well-tolerated with no serious adverse events observed and zero central nervous system symptoms such as drowsiness or sedation, chief scientific officer Guido Koopmans told Endpoints in an interview. The drug’s strong safety profile has to do with the fact that it acts peripherally, compared with standard-of-care options that affect the central nervous system. “What we basically do in the periphery [of the nervous system] is restore inhibitory control, because that’s one of the aspects that is lost in neuropathic pain,” Koopmans said. “We bring back this inhibitory control and that triggers a cascade of other things that happen like neuroplasticity, which causes the [analgesic] effect.” Algiax is now looking at a range of options for further development of AP-325, including a large Phase 3 study as well as pathways for more “rapid” advancement. CEO Ingo Lehrke did not disclose the company’s timeline for starting a potential Phase 3, but said in the interview it is focused on gathering detailed feedback from trial investigators and refining a clinical plan. The Phase 2a data suggest it’s possible to develop new safe and effective treatments for chronic neuropathic pain — an area that has seen a “graveyard of failed products” over the past two decades, Lehrke says. In December, Vertex’s NaV1.8 pain signal inhibitor suzetrigine performed similarly to placebo in a Phase 2 chronic pain study despite technically passing the test. The drug fared better in the acute pain setting, where it secured an FDA approval last week. In 2019, Aptinyx’s NMDA receptor modulator flunked a mid-stage trial in diabetic peripheral neuropathy. Three years later, Lexicon Pharmaceuticals’ AAK1-targeting asset disappointed in a Phase 2 proof-of-concept study in postherpetic neuralgia. From 2000 to 2020, the chances of a Phase 1 pain drug going on to win approval was just 10%, and even that was primarily driven by reformulated opioids. But pharma companies and investors are starting to show renewed interest in non-opioid pain relief. In 2023, Eli Lilly licensed an angiotensin II type 2 receptor inhibitor for neuropathic pain from Confo Therapeutics in a deal featuring $40 million upfront. That same year, Hoba Therapeutics — which was founded by Novo Holdings — raised $25 million in a Series A to help advance its recombinant human meteorin asset.

On July 26, Belgian biotech company Confo Therapeutics (Confo) announced that it has completed a €60 million Series B financing round. This round was led by Ackermans & van Haaren (AvH), and received participation from new investors Driehaus Capital Management and Quest for Growth (QfG), alongside existing investors BioGeneration Ventures (BGV), Capricorn Health-tech Fund (CHF), Fund+, MINTS, Perceptive Advisors, Qbic, PMV, V-Bio Ventures, VIB, and Wellington Partners. The funding will be used to advance two wholly owned projects into Phase I clinical trials, and move two other projects to the Investigational New Drug (IND) approval stage, including the GPR75 target molecule for obesity. Confo is a platform-based biotech company focused on the discovery and development of GPCR class drug targets. At the beginning of 2023, Confo announced a global licensing agreement with Eli Lilly on the clinical treatment of neuropathic pain related to their investigational drug CFTX-1554 and alternative compounds, jointly advancing the AT2R antagonist drug. The current status of the company's pipeline is as follows: Confo Therapeutics is a Belgian company specializing in new drug discovery on GPCR family targets. The company possesses a proprietary drug discovery engine (accurately locking in the required GPCR conformation using nanobodies), this unique ability allows Confo to tap into vast untapped potentialities, discovering and developing breakthrough drugs. The company's main technology route is as follows: ConfoBody can stably keep GPCR in its active conformation, thereby increasing the chances of identifying ligands with conformational selectivity. For example, the active state-specific ConfoBody can stabilize the agonist-GPCR complex, enhancing sensitivity to the agonist. The proprietary ConfoScreen method has a high sensitivity, capable of identifying smaller chemical starting points, including compound fragments with a molecular weight of <300 MW. By developing ConfoBody that specifically recognizes receptors, on one hand, it can stabilize the conformation of the receptor in the expected state, on the other hand, some nanobodies can also stabilize the receptor-G protein (mainly Gs subtype) complex. The company has obtained the exclusive license for MegaBody™ technology, which is a new scaffold based on ConfoBody. It retains the conformational selectivity of the parent ConfoBody, while providing more mass and structural features for high-resolution cryo-electron microscopy. MegaBodies™ are able to capture protein conformations, influence particle orientation, serve as a handle for three-dimensional image reconstruction, and increase the size of protein complexes, thus making GPCR more suitable for study through cryo-electron microscopy. With ConfoStructures, a method based on structure-based drug design is used to quickly and efficiently improve µM chemical starting points into nM affinity lead compounds, and endow them with excellent drug-like characteristics. How to obtain the latest research advancements in the field of biopharmaceuticals? In the Synapse database, you can keep abreast of the latest research and development advances in drugs, targets, indications, organizations, etc., anywhere and anytime, on a daily or weekly basis. Click on the image below to embark on a brand new journey of drug discovery!

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.