The global weight-loss drug sector is undergoing a profound transformation, shifting from “single-target” to “multi-target” approaches and from “efficacy competition” to “multidimensional value competition.” The focus of attention in this race is increasingly centered on “how to achieve the safest and most sustainable weight loss.”Gastrointestinal Tolerability—This pain point, long overshadowed by the halo of efficacy, is emerging as a key variable determining the commercial value of GLP-1 weight-loss products. In real-world clinical practice, only 32% to 46% of patients remain adherent to GLP-1 therapy after 12 months, with gastrointestinal adverse events being the primary barrier leading to discontinuation. While efficacy remains important, the incidence of adverse events is gaining increasing attention in clinical use and is gradually becoming a new consensus among prescribers.At this critical juncture, Hansoh Pharma’s dual-target weight-loss drug, olepatide, reached two important milestones:- On June 3, its New Drug Application (NDA) was officially accepted by the National Medical Products Administration (NMPA);
- Less than two weeks later, on June 13, olezarsen presented its dual-biased study data at the annual meeting of the American Endocrine Society.
From China’s Phase III Trials to the Global Stage: This Domestically Developed GLP-1/GIP Dual-Target Product Is Making a Critical Leap.ENDO Debut of the Dual-Bias Mechanism DataOn June 13, the 108th Annual Meeting of the Endocrine Society (ENDO 2026) opened in Chicago. As one of the largest and most influential academic conferences in the global field of endocrinology, this year’s ENDO annual meeting gathered more than 7,000 professionals from around the world, featured nearly 2,000 abstracts, and included over 200 specialized sessions covering cutting-edge areas directly related to the GLP-1 sector, such as obesity, diabetes, and lipid metabolism.Hansoh Pharma presented the dual-biased study data of olepatide in poster format at the conference.This marks the first public disclosure of this mechanism worldwide.Oleparatide is a glucagon-like peptide-1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) dual receptor agonist independently developed by Hansoh Pharma. By selectively activating GLP-1/GIP receptors, it regulates metabolic pathways associated with appetite control, glucose metabolism, and energy balance, and is administered via once-weekly subcutaneous injection.Several months ago, Hansoh Pharma announced that the Phase III study of olepatide (HS-20094-301) had yielded impressive results: after 48 weeks of treatment, the mean weight reduction from baseline in the olepatide group reached up to 19.3%, and the proportion of subjects achieving a weight loss of ≥5% was as high as 97.2%. More critically, the safety data—The incidence of nausea averaged less than 10%, and that of vomiting averaged less than 5%. Compared with published Phase III trial data for dual agonists, the incidence of gastrointestinal adverse events and the treatment discontinuation rate were lower.The mechanistic study presented at ENDO 2026,Further elucidates the molecular basis underlying olezepatide’s superior performance.HS-20094 is a novel long-acting dual-biased agonist composed of 40 amino acids and modified with a fatty acid side chain. The research team employed homogeneous time-resolved fluorescence (HTRF) technology to measure cAMP levels and the NanoLuc luciferase detection system to assess β-arrestin2 recruitment and receptor internalization. By comparing these results with those of native human GLP-1(7-37) and GIP, they systematically characterized the signaling bias profiles of HS-20094 at the human glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR).The study results clearly demonstrate the unique characteristics of olezarsen.- In the cAMP pathway, HS-20094's activity on GIPR (EC50) was 0.0089 nM, with an EC for GLP-1R50was 0.0617 nM, with GIPR activity approximately 7-fold that of GLP-1R, demonstrating a moderate activity advantage for GIPR.
- Compared with natural ligands, the β-arrestin2 recruitment efficacy of HS-20094 at GLP-1R (Emax) was only 31%, whereas natural GLP-1 reached as high as 93%; on GIPR, Emaxwas 55%, whereas that of native GIP was as high as 101%, and β-arrestin2 recruitment was effectively attenuated.
- HS-20094 also significantly attenuated receptor internalization: GLP-1R Internalization Emaxwas 65% (natural GLP-1 was 99%), GIPR internalization Emax26% (98% for native GIP). This attenuation favors prolonged receptor residence time on the cell surface, thereby sustaining cAMP signaling.
Understanding this mechanism of orforglipron requires revisiting the fundamental physiology of GLP-1 and GIP. These two hormones synergistically regulate blood glucose, food intake, and body weight, while GIP receptor activation itself can also reduce the incidence of nausea and vomiting. Upon activation of either the GLP-1 receptor or the GIP receptor, two pathways are simultaneously initiated:The cyclic adenosine monophosphate (cAMP) pathway confers metabolic benefits, whereas the β-arrestin2 pathway leads to receptor internalization, negatively impacting weight loss and glucose-lowering efficacy.The design strategy for biased agonists prioritizes activation of the cAMP pathway while reducing β-arrestin2 recruitment and receptor internalization, thereby maintaining potent therapeutic efficacy while minimizing gastrointestinal adverse effects.Olepatide is a dual biased receptor agonist that exhibits cAMP bias in the activation of both GLP-1 and GIP receptors. Previously, Professor Ji Linong disclosed at the 2025 Academic Conference of the Chinese Diabetes Society,Orforglipron recruits GIPR β-arrestin2 to a degree 30% lower than tirzepatide, which helps reduce GIPR desensitization and maintain long-term efficacy.The launch of ENDO provides more comprehensive scientific evidence for this mechanism at the molecular pathway level.It can be said that the strategic value of its debut at ENDO 2026 is self-evident. Previously, the Phase III tolerability data for oleforglutide had already drawn industry attention, while the disclosure of mechanistic data at ENDO provided a foundational scientific explanation for “potent weight loss with minimal nausea,” holding promise for greater recognition from the international academic community.It is worth noting that the global narrative of orforglipron has already unfolded. In June 2025,Hansoh Pharma and Regeneron Sign Licensing Agreement; Regeneron Secures Exclusive Global Rights to Develop, Manufacture, and Commercialize Olezarsir Outside Mainland China, Hong Kong, and Macau, with Deal Including an $80 Million Upfront Payment and Up to $1.93 Billion in Milestone PaymentsThe dual-biased mechanism data presented at the ENDO Annual Meeting will directly provide scientific support for Regeneron’s global clinical development strategy and lay the foundation for the academic positioning of olefraglutide in international markets.Domestic Dual-Target Weight-Loss Drug Enters Final Sprint for Market LaunchJust days before Orforglipron’s standout presence at ENDO 2026, Hansoh Pharma completed a key regulatory milestone: the National Medical Products Administration (NMPA) accepted its New Drug Application (NDA) for Orforglipron injection, indicated for long-term weight management in adults with obesity or overweight. From the release of Phase III data in March to the NDA acceptance, only about three months elapsed, demonstrating Hansoh’s accelerated timeline in advancing this domestically produced GLP-1/GIP dual-target agent into the marketing approval process.Robust clinical data underpin the acceptance of its marketing application.Results from the first Chinese Phase III registration study (HS-20094-301), announced in March this year, showed that treatment with olezepatide for 48 weeks resulted in a mean weight reduction of up to 19.3% from baseline, with up to 97.2% of participants achieving a weight loss of ≥5%, and efficacy sustained through Week 48.In terms of safety, the olepatide treatment group demonstrated excellent gastrointestinal tolerability, with an average incidence of nausea of less than 10% and vomiting of less than 5%. Compared with the published Phase III trial data for existing GLP-1 receptor agonist-based dual agonists, the incidence of gastrointestinal adverse events and the rate of treatment discontinuation were lower. Professor Ji Linong, Director of the Department of Endocrinology at Peking University People’s Hospital and the principal investigator of the study, commented that,“Orforglipron demonstrates superior gastrointestinal tolerability compared to other GLP-1 receptor agonists, which further enhances treatment acceptability and adherence, representing a key differentiating feature of orforglipron from its peers.”Beyond its weight-loss indication, the development pipeline for olezepatide is continuing to expand. Its indication for the treatment of type 2 diabetes has also entered Phase III clinical trials in China, with related studies having administered the drug to more than 1,000 subjects. This signifies that Hansoh Pharma’s comprehensive strategic layout for major indications targeting the dual GLP-1/GIP pathway is now fully unfolding.However, the most pressing challenge facing Orforglipron is the domestic market competitive landscape, which is drastically different from that of a year ago.In 2026, the weight-loss drug sector underwent a broad round of price adjustments.Effective January 1, 2026, the National Reimbursement Drug List (NRDL) price for Eli Lilly’s tirzepatide in the indication of type 2 diabetes officially came into effect. The starting dose specification (2.5 mg × 4 doses) dropped from RMB 1,758 to RMB 324.12, representing a reduction of over 80%. Novo Nordisk’s semaglutide injection also underwent a voluntary price cut starting in late December 2025, with a reduction of nearly 50%. Meanwhile, the core compound patent for semaglutide expired on March 20, 2026. As of the expiration date, at least 10 domestic pharmaceutical companies had submitted marketing applications for generic versions of semaglutide in China. In this market environment,The post-launch commercialization strategy and pricing scheme for olezepatide will remain a focal point of sustained industry attention.From the perspective of Hansoh Pharma itself, metabolic diseases are one of its key strategic focus areas. In 2025, revenue from the metabolic and other disease sectors reached approximately RMB 2.158 billion, accounting for 14.3% of total revenue. Marketed products in this therapeutic area include the innovative drug Fulai Mei (pegylated loxenatide injection), among others.The approval of olezepatide will fill Hansoh Pharma’s gap in the GLP-1 dual-target field, completing its strategic puzzle across the full chain of metabolic disease treatment.As the weight-loss drug sector transitions from a “blue ocean” to a “red ocean,” the true test is no longer merely the absolute reduction in body weight, but rather safety, durability, and differentiation, as well as the sustainability of commercialization strategies and the ability to chart a clear path in global expansion.First Review | Shi Wanjia
Second Review | Li Fangchen
Third Review | Li Jingzhi
