Confo Therapeutics raises $60 million to focus on agonistic GPCR antibodies

Confo GPCR

After CatalYm’s $150 million and Asceneuron’s $100 million financing rounds, it is Confo Therapeutics’ turn to complete a significant funding round led by Ackermans & van Haaren. Confo announced today it raised over $60 million (EUR 60 million).

Cedric Ververken, chief executive officer (CEO) of the G protein-coupled receptors (GPCRs)-focused company, explained how the proceeds of this series B will be allocated: “The proceeds from this round will fund two phase 1 studies for two of our proprietary pipeline programs and fund the advancement of two additional programs up to IND (investigational new drug)/CTA (clinical trial approval). We have not shared details on which programs, but look forward to sharing more information as the programs advance.”

The company also declared it would increase its research and development (R&D) efforts to discover new development candidates for rare endocrinal diseases as well as obesity, including those targeting ​​GPCRs. Indeed, all eyes have been on drugs targetting the GLP-1 in the obesity field lately, and Confo is shedding yet more light on the technology with a specific focus on agonistic GPCR antibodies.

“Over 30% of all drug sales today are molecules that work via GPCRs. Given the enormous success of GLP-1 agonists in diabetes and obesity, this is only set to increase,” said Ververken. We agree and take a closer look into it.

Table of contents

    GPCR modulation: how does it work?

    “GPCRs are integral membrane proteins that play fundamental roles in many physiological processes. There are about 400 druggable GPCRs in the genome. Depending on the GPCR and the associated disease setting, it may be necessary to activate a GPCR using an agonist, or alternatively to inactivate it using an antagonist,” explained Ververken.

    When a ligand such as a drug binds to the extracellular domain of a GPCR, it causes a conformational change in the receptor. This change is crucial for the next steps in the signaling pathway. This conformational change enables the receptor to interact with G-proteins, leading to their activation. Once activated the G-protein dissociates into the GTP-bound alpha subunit and the beta-gamma dimer, both of which can regulate various signaling pathways within the cell. 

    GPCR modulation is specific while being versatile. As GPCR modulators can be designed to target specific receptors there is a reduced risk of off-target effects. As we touched upon, GPCRs regulate a wide range of physiological processes, so modulating them can be used to treat a variety of conditions.

    What does Confo Therapeutics bring to GPCR modulation?

    “When Confo was founded in 2015, the technology was in its infancy, but over the past several years, the team has refined it into a true discovery platform. It can quickly generate drug-like molecules to class A and B GPCRs, and we are also seeing success with orphan receptors. The platform allows us to discover novel small molecules on difficult-to-drug GPCRs, as well as to efficiently generate therapeutic antibodies targeting GPCRs, including agonistic antibodies. The industry has struggled to generate agonistic GPCR antibodies for many years and our approach opens up a new avenue to deliver novel therapies,” said Ververken.

    The company’s approach revolves around its ConfoBodies, conformation-specific llama-derived antibody fragments (VHHs), which “promote GPCRs into functionally relevant states,” as Ververken put it. “ConfoBodies are used in our discovery process to generate highly sensitive screening assays for small molecule discovery or to stabilize GPCRs for the next generation of therapeutic antibodies. They are also used to stabilize GPCR complexes for structure determination.”

    Confo Therapeutics to increase R&D in agonistic GPCR antibody

    In today’s announcement, Confo said its pipeline will increase its focus on GPCR agonist antibodies and the company’s CEO confirmed it: “Our platform especially stands out for its ability to discover agonists, either as small molecules or antibodies.”

    “Our plans include potential new therapies for severe rare endocrine diseases, as well as next-generation obesity drugs which could be used in combination with, or as an alternative to, GLP-1R agonists,” declared Ververken in the press release. 

    Ververken explained how GPCR antibodies could significantly improve the treatment solutions for endocrine diseases. “Often, in the endocrine space, a disease is caused by a very low level of a particular hormone in the body. Replacing the hormone with an analog can be used as a treatment. However, these molecules can have poor drug-like properties and may generate side effects by activating other receptors in addition to your target GPCR, or may require injections every day. Such limitations can be potentially overcome by creating a highly specific therapeutic antibody that can be injected monthly.”

    Historically, developing agonistic antibodies for GPCRs has been challenging due to the complex nature of these receptors and the difficulty in stabilizing their active conformations. Achieving the right balance of efficacy and safety has also been a significant hurdle. But agonistic GPCR antibodies hold great promise and with its technology, Confo stands at the forefront of the field. 

    Agonistic GPCR antibodies are being explored for their potential to modulate immune responses in cancer therapy. By activating certain GPCRs, these antibodies can enhance the anti-tumor immune response. They also show promise in cardiovascular diseases as well as neurodegenerative diseases.

    Recent advancements in structural biology and antibody engineering have made it possible to design and develop more effective agonistic GPCR antibodies. Techniques such as high-throughput screening and structure-based drug design are crucial in identifying and optimizing these therapeutic agents.

    Who else is in the agonistic GPCR antibody business? 

    As of now, there are no agonistic GPCR antibodies that have been fully approved and brought to market. But this emerging market counts several promising companies in addition to Confo Therapeutics and its ConfoBodies. 

    Twist Bioscience

    Twist Bioscience’s Twist Biopharma division is developing antibody leads targeting hard-to-drug GPCRs such as ADORA2A and GLP1R. ADORA2A is an adenosine receptor involved in immune modulation, making it a significant target in immuno-oncology. Inhibiting ADORA2A can enhance the immune system’s ability to attack tumor cells.

    GLP1R is a receptor that regulates insulin secretion and blood glucose levels, making it an important target for diabetes treatment. Agonistic antibodies targeting GLP1R can mimic the effects of GLP-1 peptide, promoting insulin release and blood glucose control.

    Its candidate TB206-001 has shown promise in binding to ADORA2A and inhibiting it in preclinical settings. This could make TB206-001 a potential new approach to treating cancer.  Twist Biopharma has identified several potent GLP1R antibodies. One notable candidate, TB59-2, has shown strong preclinical efficacy in controlling blood glucose levels with a favorable pharmacokinetic profile. Another candidate, TB01-3, demonstrated effective blood glucose regulation in preclinical models.

    Biocytogen Pharmaceutical and LiberoThera

    Biocytogen Pharmaceuticals and LiberoThera have partnered to co-develop fully human GPCR antibodies, focusing initially on the CCR8 receptor, which is interesting for tumor immunotherapy. This collaboration combines Biocytogen’s RenMab antibody discovery platform with LiberoThera’s expertise in membrane antigen preparation.

    CCR8 is a chemokine receptor predominantly expressed on regulatory T cells (Tregs) within the tumor microenvironment. Targeting CCR8 can help deplete these immunosuppressive cells, enhancing the anti-tumor immune response.

    Approximately a year after the collaboration began, the two companies have identified multiple therapeutic antibody clones against CCR8. These clones have demonstrated good anti-tumor activity both in vitro and in vivo preclinical models.

    Agonistic GPCR antibodies, what’s next?

    When it comes to GPCR antibodies Confo appears as a frontrunner: “Today, there are only three GPCR antibodies on the market and very few in development in comparison to other target classes. This demonstrates that it is very challenging for companies to discover antibodies to GPCRs, especially agonists. Recent advances in our Confo technology enable us to do this and we intend to continue to leverage our competitive advantage to generate antibodies targeting multiple GPCRs and continue to be in a leading position in this space.” Ververken said.

    According to Confo’s CEO, there are two big challenges in the GPCR space. ”The first is being able to discover molecules to specific GPCRs that are important in a disease but no company has found drugs to yet, generally because of the limitations found with current discovery technologies. A good example of this is the orphan GPCR, GPR75 which is implicated in obesity. The second is to discover products with the best drug-like profile for the disease in question. Current GPCR-targeting drugs have limitations including side effects due to specificity issues or inconvenient dosing frequency.”

    Confo Therapeutics has made the strategic choice to focus its pipeline on endocrine and metabolic diseases. “Rare endocrine diseases can be an opportunity for Confo to go into late-stage development and even commercialization, while big indications like obesity are interesting to large pharma and hence, could provide strategic options for the company in the future,” said Ververken.

    While GPCR modulation has already proven itself, its subcategory of agonistic GPCR antibodies hasn’t reached the market yet but isn’t without promise. In this area, Confo is a convincing contestant to bring new treatment options for obesity and endocrine diseases. While developing agonistic antibodies for GPCRs has been historically challenging, companies like Confo are making progress and this is definitely worth keeping an eye on.

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