GPCR therapies: Eight promising biotechs hacking the cell signaling pathway

Photo credits: Karolina Grabowska
GPCR drugs

G protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors in the body. They are responsible for many physiological responses in the body and are attractive drug targets because of their many signaling pathways. 

Many drugs and biologics target GPCRs, including allergy medicines such as antihistamines, pain relief drugs, and diabetes treatments. Still, around 75% of GPCR therapeutic targets are yet to be drugged, representing untapped opportunities for drug discovery and development to address numerous diseases. 

In this article, we take a look at eight biotechs that have acquired funding in recent years to fortify their GPCR-focused pipelines, most of which have hit the clinic. 

Table of contents

    Confo Therapeutics

    A significant player in the Belgian biotech industry, Confo Therapeutics has devised a technology to keep GPCRs stable, enabling the mass screening and identification of GPCRs in different diseases. GPCRs tend to be hard to screen in the lab because they are unstable in vitro. 

    GPCRs have seven structures called transmembrane helices that span the cell membrane and intervening loops. Confo’s agonist drugs bind to GPCRs at a binding pocket that then initiates changes to the loops. This triggers various signaling pathways.

    Confo’s pipeline includes its clinical candidate CFTX-1554 for neuropathic pain. This is a condition where the nerves that carry sensory signals to the brain malfunction. CFTX-1554 inhibits angiotensin II type 2 receptor (AT2R), a target for the relief of neuropathic pain. Unlike painkillers like opioids, which are currently given to patients, Confo’s drug is designed to avoid side effects like addiction and sedation. CFTX-1554 is being evaluated in a phase 1 trial in a collaboration with pharma giant Lilly.

    According to the licensing deal, Confo received $40 million upfront, and is eligible to secure up to $590 million in milestone payments. Confo has also partnered with Japanese multinational Daiichi Sankyo to discover medicines for diseases that affect the central nervous system (CNS).

    More recently, it reeled in €60 million ($64.94 million) in a series B funding round to push its preclinical candidates to the clinic. And making a name for itself in the metabolic disease therapeutics space, Confo has discovered antibody-based GPCR agonists that target the melanocortin 4 receptor (MC4R) – a key regulator for hunger and satiety. 

    Domain Therapeutics

    Set on bringing precision medicine to the forefront of cancer care, French-Canadian biotech Domain Therapeutics’ pipeline has two phase 1 drug candidates targeting GPCRs that it is progressing in the clinic along with pharma giant Merck.

    As some tumor cells release immunosuppressive molecules to inhibit immune cells from working against cancer, immune checkpoint inhibitor drugs that are meant to kill cancer cells are not able to do their job effectively because they are mediated by GPCRs. Domain’s research and development (R&D) is focused on GPCR-targeted drugs that are designed to overcome immunosuppression, having identified over 70 GPCRs involved in immuno-surveillance mechanisms.

    One of its clinical candidates is the EP4 receptor antagonist DT-9081. It is an oral small molecule that can reverse the immunosuppressive effects of the chemical prostaglandin E2 (PGE2), which is produced by certain tumors. Preclinically, the drug has expressed antitumor properties in cancer cell models when administered along with immune checkpoint inhibitor drugs.

    The other candidate in the clinic is an A2aR/A2bR antagonist that targets adenosine released by tumors. 

    Back in January, the biotech was awarded €10 million ($10.82 million) by the Hospital-University Research in Health SPRINT consortium to push one of its preclinical candidates to the clinic. This contributes to a total $100.1 million raised since Domain’s inception in 2001.

    Escient Pharmaceuticals

    MAS-related GPCRs (MRGPRs) are a family of receptors sensitive to chemicals that are expressed on sensory neurons and immune cells, which reside in key barrier tissues such as the skin, airways, and the gastrointestinal (GI) tract. MRGPRs mediate the neuro-immune overactivation that is a hallmark of numerous chronic disorders. California-based Escient Pharmaceuticals has found a way to block the activation of MRGPRs. 

    Its two lead candidates are small molecules that address conditions such as chronic urticaria, atopic dermatitis, and cholestatic and uremic pruritus – itching caused by liver and kidney diseases. EP262 is an oral drug that targets MRGPRs, which are present in white blood cells called mast cells. When the receptor MRGPRX2 is activated, mast cells cause inflammation, which is what EP262 aims to counter.

    A phase 1 safety study found that EP262 adverse events were all mild, lower than placebo, and did not get worse with an increase in dosage in patients with chronic urticaria and atopic dermatitis (eczema).

    The other candidate in phase 1 is EP547, which inhibits the receptor MRGPRX4, expressed on neurons and activated by the bile enzyme in patients with chronic kidney and liver diseases.

    In May, Escient was acquired by American multinational Incyte to strengthen the latter’s Inflammation and Autoimmunity pipeline. The deal was worth $750 million.

    Orion Biotechnology

    Centered on drugging GPCRs, Orion Biotechnology’s technology is based on precision engineering GPCR proteins to develop analogs with higher binding affinity and potency. 

    Its PROcisionXTM Discovery Platform is credited with discovering its pipeline of drugs, which are currently in IND-enabling and proof-of-concept phases to treat obesity and other metabolic diseases. 

    Its phage display approach enables millions of peptide and small protein analogs to be screened directly on cells expressing the targeted receptor, eliminating the need for receptor purification, hence making the process quicker. Then, with the help of multiplex chemical synthesis technology – basically, a series of chemical reactions for protein synthesis – candidate analogs are produced. 

    Headquartered in Canada with operations in Poland and Switzerland, Orion has previously worked on funded projects in HIV prevention and cancer immunotherapies, which were supported by the European Union and the European Regional Development Fund.

    Orion runs on an $11.5 million series A funding round that took place a few years ago, which at the time revolved around GPCR-targeting cancer therapies, but has since shifted gears. 

    Septerna Therapeutics 

    California-based Septerna Therapeutics made the news last week when it went public for $288 million, a sign that investors are warming up to early-stage drug development companies. This adds to the $150 million series B financing Septerna snagged last year to advance its pipeline.

    Septerna’s Native Complex Platform is designed to unlock GPCRs, which represent the largest and most diverse family of cell membrane receptors as hundreds of different GPCRs regulate physiological processes in almost every organ of the human body. Septerna has come up with a way to target difficult-to-drug GPCRs. 

    Septerna’s technology isolates, purifies, and reconstitutes GPCRs into complexes with ligands, transducer proteins, and lipid bilayers that mimic cell membranes. By uncovering new binding pockets for receptors, it intends to take control of GPCR signaling to achieve therapeutic effects in patients. 

    Its most advanced candidate is SEP-786, which is currently in phase trials to treat people with hypoparathyroidism, a condition in which the body produces abnormally low levels of parathyroid hormone, resulting in an imbalance in calcium and phosphorous levels in the blood. The small molecule works by replacing the parathyroid hormone by activating the hormone’s receptor PTH1R in the bones and the kidneys to restore normal calcium levels. 

    Its other candidates are in the discovery and Investigational New Drug (IND)-enabling stages to address different kinds of diseases like autoimmune disorder Graves’ disease – caused by excess thyroid hormone production – chronic spontaneous urticaria – a skin condition that causes hives – and metabolic diseases. 

    Structure Therapeutics

    California-based Structure Therapeutics follows suit with other obesity drug companies with its pipeline of GPCR-targeting oral incretin drugs. The most advanced out of all of them is phase 2 candidate GSBR-1290.

    According to topline data published in June, the drug holds promise. GSBR-1290 was tested in a phase 2a study and a capsule to tablet pharmacokinetic study was conducted as well. In both studies, primary and secondary endpoints were met. In the phase 2a trial with GSBR-1290, 67% of patients had a reduction in weight by at least 6%, and 33% had a weight loss of more than 10% compared to 0% for placebo after 12 weeks.

    The capsule to tablet pharmacokinetic study was designed to evaluate how well a new tablet formulation of the same drug would work. It demonstrated a placebo-adjusted mean weight loss of up to 6.9% after 12 weeks. Moreover, the new formulation’s pharmacokinetic data – based on how the body affects a drug – support the once-daily dosage of GSBR-1290 and the dose-proportional exposure of the drug. The daily dosage of up to 120 mg was found to be well-tolerable and safe.

    Following phase 2 success, Structure closed a $547.4 million public offering in June. This came after the biotech secured $300 million in a private investment in public equity (PIPE) late last year to support its lead candidate’s development. The biotech has three other incretin drugs targeting metabolic diseases in preclinical stages.

    Tectonic Therapeutics

    California-based Tectonic Therapeutics is another GPCR-focused biotech that is moving up the ranks in the field. With expertise in the biochemistry and biophysics of GPCRs, Tectonic’s GEODe platform has helped create the clinical pipeline.

    The lead candidate targets the RXFP1 receptor, the GPCR of the hormone relaxin. This hormone, which is normally expressed at low levels, is upregulated during pregnancy where it exhibits vasodilative effects, meaning that it prevents blood vessels from constricting thereby allowing more blood to flow to organs. As the name suggests, the hormone helps relax the pelvis during childbirth to aid the delivery of the baby.  

    Relaxin is usually cleared by the body, so Tectonic’s candidate TX45 has been engineered to deliver active levels of relaxin with infrequent dosing to treat pulmonary hypertension (high blood pressure) in the presence of heart failure with preserved ejection. A phase 1 safety study demonstrated that “TX45 had minimal adverse events and no evidence of immune-mediated clearance.” Further data will be presented at the American Heart Association 2024 next month.

    Tectonic has other candidates as well – one being a GPCR antagonist poised to enter the clinic next year to treat the genetic bleeding disorder hereditary hemorrhagic telangiectasia.

    Recently, it merged with gene therapy company AVROBIO and raked in $130.7 million in a private placement to boost its pipeline.

    Teon Therapeutics

    With a goal to boost anti-tumor immunity, Teon Therapeutics specializes in GPCR-based cancer therapies. Its lead drug is the small molecule TT-816, which is designed to improve immunity by targeting the cannabinoid CB2 receptor that regulates inflammation and immune responses. Overexpression of the CB2 receptor has been linked to higher aggressiveness of cancer.

    The drug is in phase 1 to treat non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC) – kidney cancer – and ovarian cancer after achieving IND status from the FDA in 2022. Its development is in partnership with pharma giant Merck as its effectiveness is being tested as a monotherapy as well as in combination with Merck’s immunotherapy drug Keytruda. 

    Its other clinical candidate TT-702 targets overexpressed A2B receptors, which are present on tumor cells. This receptor contributes to the suppression of immune activity. TT-702 works by making cancer more visible to the immune system so that the cells can be destroyed. It is currently in phase 1 trials to treat difficult-to-treat cancers such as metastatic castration-resistant prostate cancer (mCRPC) and triple-negative breast cancer (TNBC).

    The California-based startup racked up $30 million in a series A financing round three years ago to build its growing pipeline.

    GPCR drugs: an ever-growing sector

    Drugs that target GPCRs make up about 27% of the global market share of therapeutic drugs. A study published in the National Library of Medicine revealed that ​​34% of all marketed medicines in the U.S. act on GPCR targets. 

    Moreover, this space is only expected to grow. The market was valued at $3.46 billion in 2022, and is anticipated to increase at a compound annual growth rate (CAGR) of 5.1% from 2023 to 2030. Big pharma collaborations are proof of this rise. Japanese biopharma Nxera Pharma – formerly known as Sosei Heptares – which maintains a stronghold in the GPCR sector, joined hands with big pharma AbbVie to develop drugs to treat neurological diseases. 

    Other major deals influencing the space include Confo’s licensing deal with Lilly, Domain and Teon’s alliances with Merck, as investors pump more money to encourage R&D.

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