Targeting Obesity: GLP-1R/GIPR, GDF8 Leading the Way

Targeting Obesity: GLP-1R/GIPR, GDF8 Leading the Way

By Mallory Griffin

Rising Obesity Rates: A Global Threat

Obesity, a chronic metabolic disease, has significantly impacted the health and quality of life for countless individuals. According to the 2024 World Obesity Report, the global prevalence of obesity is steadily increasing, with projections indicating that by 2035, over half of the world's population will be classified as overweight [1]. Alarmingly, this trend is growing and increasingly affecting younger populations at an accelerating rate [2].

Table 1. 2020 global estimate and projected number of adults through 2035 with an overweight BMI [1]. 

Obesity is a significant independent risk factor contributing to numerous chronic conditions, including diabetes, hypertension, cardiovascular disease, and obstructive sleep apnea syndrome. Addressing obesity has become both a critical focus and a persistent challenge in medical research. In recent years, peptide-based weight-loss drugs, such as GLP-1R agonists and GLP-1R/GIPR dual receptor agonists, have gained widespread global use. While challenges with adherence, side effects, and weight regain upon discontinuation have prompted the search for additional strategies, targets like GLP-1R, GIPR, and GDF8 (Myostatin) still remain the most highly relevant and active areas of research for developing effective obesity treatments. In this article, we explore the role and therapeutic potential of these well-established obesity drug targets.

Traditional Therapeutic Targets Related to Obesity

GDF8

GDF8 (Growth Differentiation Factor 8), commonly known as Myostatin (MSTN), is a protein predominantly expressed by skeletal muscle cells and is a member of the TGF-β (Transforming Growth Factor-β) superfamily. GDF8 GDF8 inhibits fatty acid oxidation in adipose tissue, hinders the formation of brown adipose tissue, and reduces glucose uptake in liver tissue [3]. These effects collectively may contribute to or exacerbate the progression of obesity.

GLP-1R/GIPR

GLP-1R (glucagon-like peptide-1 receptor) is a Class B G-protein-coupled receptor (GPCR) expressed in various tissues and organs, including pancreatic β-cells, the stomach, small intestine, heart, kidneys, lungs, and brain. It is a major therapeutic target for type 2 diabetes and obesity. In pancreatic β-cells, GLP-1R binds to GLP-1 or its analogs, stimulating insulin production while suppressing glucagon release, thereby effectively regulating blood glucose levels. In the gastrointestinal tract, GLP-1R reduces gastric acid secretion, slows gastrointestinal motility, delays gastric emptying, and increases satiety, thereby aiding weight management. 

Several GLP-1R targeting therapeutics are dual agonists for GIPR as well. GIPR (glucose-dependent insulinotropic polypeptide receptor) is also a Class B G-protein-coupled receptor (GPCR). GIPR is primarily expressed in pancreatic β-cells, adipose tissue, the small intestine, and the central nervous system playing a key role in energy metabolism and nutrient homeostasis. In pancreatic β-cells, GIPR binds to its ligand GIP, stimulating insulin secretion in response to nutrient intake, particularly glucose and lipids, while suppressing glucagon release. In adipose tissue, GIPR promotes lipid storage and reduces lipolysis, contributing to energy balance. Given the functional synergy and complementary mechanisms between GLP-1R and GIPR, therapies targeting both GIPR and GLP-1R activation have emerged as promising approaches for obesity and type 2 diabetes treatment to improve weight loss and metabolic outcomes.

The Role of the GLP-1R Signaling Pathway in the Mechanism of Obesity Development [6]. 

Drugs Targeting Traditional Metabolic Pathways

GDF8-Targeting Drugs

Drugs targeting GDF8 focus on either its latent or mature forms. Apitegromab (SRK-015), an investigational new drug developed by Scholar Rock,  is a fully human IgG4λ monoclonal antibody that specifically binds to human Pro-GDF8 or latent GDF8 without binding to mature GDF8 or other closely related growth factors. By inhibiting the latent GDF8, SRK-015 achieves high selectivity with minimal side effects. It is currently in Phase 2 clinical trials for the treatment of overweight and obesity.

Design Principle of Apitegromab [4]

Meanwhile, Roche has updated the status of its monoclonal antibody RG6237, another  Anti-Latent GDF8, adding a Phase 1 trial for obesity treatment. Regeneron, however, adopts a different strategy by targeting the mature form of GDF8 rather than the latent form. In collaboration with Eli Lilly, Regeneron has conducted Phase 2 clinical trials to evaluate whether their Trevogrumab can maintain weight loss by increasing muscle mass. Notably, sKER-065, is an investigational new drug developed by Keros Therapeutics with a unique design. KER-065 is a modified Activin RII ligand trap that binds GDF8 and Activin A [5], which can be used as a standalone therapy or in combination with glucagon-like peptide-1 (GLP-1) receptor agonists. 

Overview of Keros Therapeutics protein drug KER-065 [5].

GLP-1R/GIPR-Targeting Drugs

GLP-1 Peptide Drugs

Novo Nordisk's semaglutide-based medicines—Wegovy®, Ozempic®, and Rybelsus®—have significantly advanced the management of obesity and type 2 diabetes. As GLP-1 receptor agonists, these peptide drugs mimic the incretin hormone GLP-1, enhancing glucose-dependent insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite [9]. Wegovy® is specifically approved for chronic weight management, while Ozempic® and Rybelsus® are primarily indicated for glycemic control in type 2 diabetes patients, with notable secondary benefits of weight reduction. Clinical trials have demonstrated that these medications can lead to significant weight loss and improvements in metabolic health, setting a new benchmark in GLP-1 receptor-targeting therapies [10].

GLP-1R/GIPR Antibody Drugs

While peptide-based therapies like semaglutide have shown remarkable efficacy, they are not without limitations, including gastrointestinal side effects and frequent dosing requirements. To address these challenges, companies like Gmax Biopharm are focusing on antibody-based therapies as potential alternatives. Gmax Biopharm is one of the earliest companies to develop GLP-1R antibody drugs, with GMA105 and GMA106 currently undergoing clinical trials for obesity treatment [7]. GMA105 is a fusion protein that combines GLP-1 fragments with a humanized monoclonal antibody against GLP-1R, while GMA106 includes an antagonistic GIPR antibody fused with GLP-1 molecules, achieving dual receptor activation. These antibody drugs have a relatively long half-life, allowing less frequent dosing compared to traditional peptide drugs.

Similarly, Amgen’s AMG133 (Aridebart Cafraglutide) combines a GIPR monoclonal antibody antagonist and two GLP-1 agonist peptides. In a Phase 1 randomized, double-blind clinical study targeting obese participants (NCT04478708), AMG133 demonstrated acceptable safety, tolerability, and significant dose-dependent weight loss. In the multiple ascending dose groups, weight loss persisted for up to 150 days after the final dose [8].

Structure of Amgen’s AMG133 [8]. 

Undoubtedly, anti-obesity treatment is currently the hottest topic in the biomedical drug research and development field. A number of investigational new drugs targeting GLP-1R, GIPR and GDF-8 pathways are under clinical trials (Table 2). In the meantime, early-stage discoveries against these targets are also being actively pursued, with the hope of winning the “Best In Class” laureate in the future. 

Targets
Company
Drug Name
Synonyms
Latest Clinical Stage
Clinical registration number
GDF-8, Activin RII
Biohaven
Taldefgrobep alfa
BHV-2000, BMS-986089
Phase 1
NA
GDF-8
Regeneron
Trevogrumab
REGN-1033
Phase 2
NCT06299098
GDF-8, Activin A
Keros
KER-065
NA
Phase 1
ACTRN12623001233617
Latent GDF-8
Scholar Rock
Apitegromab
SRK-015
Phase 2
NCT06445075
Roche
GYM329
RG6237, RO7204239
Phase 1
NA
GLP-1R
Gmax Biopharm
GMA105
N/A
Phase 3
NA
GLP-1R, GIPR
Gmax Biopharm
GMA106
N/A
Phase 1
NCT05054530
Amgen
AMG133
Maridebart cafraglutide, MariTide
Phase 2
NCT05669599
Xintrum Pharmaceuticals
ZX2010
N/A
Phase 1
CTR20241290
GLP-1R, FGF21R
Sunshine Lake Pharma
APL-18881
HEC88473
Phase 1
NCT05943886
GLP-1R, GCGR, FGF21R
Doer Biologics
DR10624
N/A
Phase 1
NCT05378893
GLP-1R, GIPR, GCGR
Xintrum Pharmaceuticals
ZX2021
N/A
Phase 1
CTR20241288

Table 2. Clinical-stage obesity-related drugs targeting GLP-1R, GIPR, or GDF-8 through November 2024. 

Quality, Off-the-Shelf, Metabolic Pathway Proteins from KACTUS

The targets involved in obesity treatment encompass various pathways that contribute to the onset and progression of the condition. KACTUS provides a broad spectrum of high-quality recombinant proteins that are relevant to obesity therapeutic studies.  including traditional targets like GDF8 and GLP-1R:

Product Validation Data

Immobilized Human Latent GDF-8, His Tag at 1 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-GDF8 Antibody, hFc Tag with the EC50 of 22.8 ng/ml determined by ELISA.

Immobilized Human GLP-1R, mFc Tag at 1 μg/ml (100 μl/well) on the plate. Dose response curve for Anti-GLP-1R Antibody, hFc Tag with the EC50 of 17.0 ng/ml determined by ELISA.

Ordering Information

Target

Catalog No.

Product Description




GDF-8

GDF-HM008

Human/Mouse/Rat GDF-8, No Tag Tag

GDF-HM108

Human Latent GDF-8, His Tag




GLP-1R

GLP-HM30R

Human GLP-1R, mFc Tag




GIPR

GIP-HM40R

Human GIPR, His-Avi Tag

GIP-HM20R

Human GIPR, hFc Tag

GIP-HM40RB

Biotinylated Human GIPR, His-Avi Tag

GIP-CM40R

Cynomolgus GIPR, His-Avi Tag

GIP-CM40RB

Biotinylated Cynomolgus GIPR, His-Avi Tag


References

[1] https://www.worldobesityday.org/assets/downloads/WOF_Obesity_Atlas_2024.pdf

[2] Explaining adult obesity, severe obesity, and BMI: Five decades of change. Heliyon. 2023 May 19;9(5):e16210. doi: 10.1016/j.heliyon.2023.e16210. PMID: 37251838; PMCID: PMC10213181.

[3] Myostatin: a potential therapeutic target for metabolic syndrome. Front Endocrinol (Lausanne). 2023 May 23;14:1181913. doi: 10.3389/fendo.2023.1181913. PMID: 37288303; PMCID: PMC10242177.

[4] https://scholarrock.com

[5] https://ir.kerostx.com/static-files/d666096b-07f9-47ea-b9ad-205f7c89895f

[6] Signaling pathways in obesity: mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2022 Aug 28;7(1):298. doi: 10.1038/s41392-022-01149-x. Erratum in: Signal Transduct Target Ther. 2022 Oct 21;7(1):369. doi: 10.1038/s41392-022-01188-4. PMID: 36031641; PMCID: PMC9420733.

[7] https://www.gmaxbiopharm.com/pipeline_zh/id/7.html

[8] A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings. Nat Metab. 2024 Feb;6(2):290-303. doi: 10.1038/s42255-023-00966-w. Epub 2024 Feb 5. PMID: 38316982; PMCID: PMC10896721.

[9] Drugs.com. (n.d.). Semaglutide. Retrieved December 10, 2024, from https://www.drugs.com/semaglutide.html

[10] Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Moiz, Areesha et al. American Journal of Cardiology, Volume 222, 121 - 130

Latest Posts

MSLN Targeted Drugs Entering the Fast Lane
Base Editing Technology Leads a New Chapter in Drug Development
Deciphering LY6G6D - An Emerging Target in Colorectal Cancer
1 2 3