Inventory of GPCR Targeted Drugs Applying for Listing (I)

This article will review currently applied listed GPCR-targeting drugs, and the associated popular GPCR class targets and drug development opportunities worth paying attention to.

1.Eli Lilly: Tirzepatide

Target:GIPR + GLP-1R

Tirzepatide is a novel GIPR and GLP-1R dual agonist developed by Eli Lilly. In preclinical and clinical trials, compared to selective GLP-1 receptor agonists, GIP/GLP-1 dual agonists have been shown to better control blood sugar and reduce weight. Therefore, it is receiving increasing attention as a new therapeutic drug for controlling blood sugar and weight.

In 2022, Tirzepatide was approved for the first time in the United States for the treatment of adult type II diabetes as an adjunct to diet and exercise. Subsequently, Tirzepatide was approved in the European Union and Japan for the treatment of type II diabetes.

👇Please click on the image below to directly access the latest data (R&D Status | Core Patent | Clinical Trial | Approval status in Global countries) of this drug.

2.ChemoCentryx: Avacopan

Target:C5aR

Avacopan(Tavneos) is an orally administered, first-in-class selective complement 5a receptor (C5aR) antagonist, discovered and developed by ChemoCentryx. This drug is used as an adjunctive therapy for ANCA-associated vasculitis in adult patients.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a rare ("oligo-immune") systemic small-vessel vasculitis, with an estimated incidence of 3 per 100,000 annually, characterized by the presence of ANCAs in the serum. The entire course of AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and drug-induced AAV. Despite its complex pathophysiology, research over the past approx. 20 years has determined the crucial role of the alternative complement pathway, particularly the interaction of C5a with the C5aR receptor in AAV.

Avacopan was first approved for marketing in Japan on September 27, 2021, and was subsequently approved in the United States, European Union, Canada, and Australia for the treatment of adult patients with ANCA-associated vasculitis, granulomatosis with polyangiitis, and microscopic polyangiitis.

In addition, research is ongoing for other potential clinical indications, such as hidradenitis suppurativa and C3 glomerulopathy.

3.Pfizer: Rimegepant Sulfate 

Target:CGRP Receptor

Rimegepant is an orally administered CGRP receptor antagonist used for the acute treatment of migraine in adults, with or without aura. 

Initially developed by the BMS(BMS-742413), the newly established biotech company Biohaven Pharmaceutical acquired the exclusive global development and commercialization rights to Rimegepant in 2016. The Biohaven team conducted a series of clinical studies and analyses around Rimegepant and developed the derivative migraine nasal spray drug, Zavegepant. 

In May 2022, Pfizer announced that it would acquire Biohaven for a total cash consideration of approximately 11.6 billion USD.

Rimegepant was first approved for marketing in the United States on February 27, 2020, and subsequently received approval in Israel, the United Arab Emirates, Kuwait, the European Union, and Iceland, among others.

Currently, the drug is being tested in clinical trials for conditions like chronic sinusitis, nasal polyps, and trigeminal neuralgia.

4. Glenmark:RYALTRIS

Target:H1R+GR

RYALTRIS is a new compound prescription nasal spray developed by the Indian pharmaceutical company, Glenmark. This medication has the dual efficacy of activating glucocorticoid receptor (GR) and antagonizing histamine H1 receptor (H1R).

Mometasone is a moderately potent synthetic corticosteroid that acts as a glucocorticoid receptor agonist, possessing anti-inflammatory, anti-itch, and vasoconstrictive properties. Olopatadine, on the other hand, is an antagonist of histamine H1 receptors used for the treatment of allergic conjunctivitis and rhinitis. Since histamine is the primary inflammatory mediator causing inflammation and allergic reactions, Olopatadine works by blocking the action of histamine receptors. Compared to other anti-allergic ophthalmic drugs, Olopatadine does not interfere with the cell membrane, thus offering good comfort and tolerability.

RYALTRIS was first approved for marketing in Australia in 2019, and subsequently received approval for listing in South Africa, the UK, the US, Canada, and other countries. 

In 2019, Grand Pharmaceutical and Glenmark signed an exclusive licensing agreement, in which Glenmark granted Grand Pharmaceutical the exclusive rights to sell RYALTRIS in China. Glenmark would be responsible for the manufacture and supply of the authorized product, while Grand Pharmaceutical would be in charge of the clinical trials and registration work for the authorized product in China and can exclusively sell the approved product in China for 20 years upon approval.

5. Amgen:Erenumab

Target:CGRP

Erenumab is a human monoclonal antibody developed by Amgen and is the first monoclonal antibody drug targeting GPCR approved by the FDA. Erenumab can specifically bind to and antagonize the Calcitonin Gene-Related Peptide Receptor (CGRPR), thus preventing migraines.

In April 2017, Amgen announced an expanded commercial collaboration with Novartis on Erenumab, which is being studied for the prevention of migraine. This expanded business cooperation is based on the global neuroscience collaboration established by Novartis and Amgen in 2015 in the areas of Alzheimer's disease and migraine. 

Novartis initiated two clinical trials in China in 2019 to evaluate the safety and efficacy of Erenumab injection in the treatment of migraines. 

Erenumab was first approved for marketing in the United States in 2018, and was subsequently approved in Australia, Iceland, Norway, Switzerland, Canada, and Japan. 

In addition to the treatment of migraines, clinical trial research is ongoing for other indications, including headaches, hot flashes, temporomandibular joint dysfunction syndrome, stable angina.

6. Kyowa Kirin:Evocalcet

Target:CaSR

Evocalcet is a Calcium-Sensing Receptor (CaSR) agonist developed by Kyowa Kirin, used for the treatment of hypercalcemia, secondary hyperparathyroidism, and other related conditions. 

Kyowa Kirin has applied for two clinical trials in China to evaluate the effectiveness of Evocalcet in treating secondary hyperparathyroidism in patients undergoing maintenance dialysis for chronic kidney disease. 

As of now, Evocalcet has only been approved for marketing in Japan.

7. Otsuka Pharmaceutical: Brexpiprazole

Target:5-HT1A+5-HT2A+D2R

Brexpiprazole is a serotonin-dopamine activity modulator developed by Otsuka Pharmaceutical, used as an adjunctive treatment for severe depression, schizophrenia, and agitation associated with dementia caused by Alzheimer's disease. Brexpiprazole is an atypical antipsychotic and a novel D2 dopamine and serotonin 1A partial agonist, known as a serotonin-dopamine activity modulator. It has a high affinity for serotonin, dopamine, and alpha-adrenergic receptors.

Structurally, Brexpiprazole is very similar to another atypical antipsychotic drug, Aripiprazole, but Brexpiprazole has a different affinity for binding with dopamine and serotonin receptors. Compared to Aripiprazole, Brexpiprazole is less likely to produce adverse reactions mediated by partial agonist, such as extrapyramidal symptoms, due to its lower intrinsic activity at the D2 receptor.

Brexpiprazole was first approved in the United States in 2015, and subsequently approved in Canada, Japan, and the European Union.

In addition to treating depression, this drug is undergoing global clinical trials and research for multiple indications including agitation, schizophrenia, Alzheimer's disease, and performance anxiety.

8. Santen: Tapcom

Target:PTGFR+βAR

Tapcom is a combination eye drop medication containing Tafluprost and Timolol Maleate, developed by Santen.

Tafluprost is a prostaglandin analogue used in ophthalmology to reduce intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Chemically, Tafluprost is a fluorinated analogue of prostaglandin F2-α. Timolol is a non-selective beta-adrenergic antagonist, used for the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. 

Tapcom was first approved for marketing in Japan in 2013, and subsequently received approval in countries including Iceland, France, Poland, and Germany.

9. Takeda:Teduglutide

Target:GLP-2R

Teduglutide is a glucagon-like peptide-2 (GLP-2) analog developed by the British rare disease pharmaceutical giant, Shire Development, for the treatment of patients with short bowel syndrome (SBS) who require parenteral nutrition support. Teduglutide is comprised of 33 amino acids, and is manufactured using strains of E. coli that have been modified through DNA recombinant technology. Teduglutide differs from GLP-2 by one amino acid (alanine is replaced with glycine). This substitution results in Teduglutide having a longer duration of action than endogenous GLP-2 and a higher resistance to hydrolysis by the enzyme dipeptidyl peptidase-4. 

Teduglutide first received regulatory approval within the European Union in 2012, followed by approval in the United States and Japan, in all cases for the treatment of SBS. 

In 2019, Takeda Pharmaceuticals spent an astounding £46 billion to acquire Shire Development, in a move that has been dubbed as a "snake swallowing an elephant" merger in the pharmaceutical world. This acquisition propelled Takeda Pharmaceuticals into the list of top 10 global biopharmaceutical companies. Clinical research on the application of Teduglutide for the treatment of Crohn's Disease and kidney disorders was discontinued due to this acquisition.

10. AstraZeneca: Duaklir Genuair

Target:M3R+β2AR

Duaklir Genuair is a combined Aclidinium Bromide/Formoterol Fumarate inhalation powder developed by AstraZeneca. This medication is used as a maintenance bronchodilator to alleviate the symptoms of disease in adults with chronic obstructive pulmonary disease (COPD). Among them, Aclidinium bromide is a novel long-acting muscarinic antagonist, and Formoterol fumarate is a long-acting β2 receptor agonist. 

Duaklir Genuair is administered by the Genuair dry powder inhaler twice a day and is the first combined medication that has shown a statistically significant improvement over monotherapy in terms of shortness of breath.

Duaklir Genuair was first approved in the European Union in 2012, and subsequently in the United States in 2019, for the treatment of chronic obstructive pulmonary disease.