Oral GLP-1/GIP Dual Agonism at Phase 1: Novo Nordisk Bets $300M on Unproven Formulation

Hengrui Licenses Oral GLP-1/GIP Agonist HRS-1596 to Novo Nordisk

Hengrui Medicine has announced an exclusive license agreement with Novo Nordisk for HRS-1596, a GLP-1/GIP dual receptor agonist designed for once-weekly oral administration. The deal, potentially valued at up to $2.6 billion, includes a $300 million upfront payment and additional milestone payments, plus sales royalties. Novo Nordisk gains exclusive rights to develop, manufacture, and commercialize HRS-1596 globally, excluding mainland China, Hong Kong SAR, Macau SAR, and Taiwan region. HRS-1596 is being developed for obesity, type 2 diabetes, and other metabolic diseases, with Phase 1 clinical trials already approved in China for weight management and type 2 diabetes.

• Novo Nordisk has secured exclusive global rights, excluding Greater China, to Hengrui Medicine's HRS-1596, a GLP-1/GIP dual receptor agonist. The comprehensive agreement is valued at up to $2.6 billion, encompassing a $300 million upfront payment, along with subsequent payments contingent on achieving specific development, regulatory, and commercial milestones. Hengrui Medicine is also eligible to receive royalties based on the net sales of HRS-1596 within the licensed territories.
• HRS-1596 is an innovative GLP-1/GIP dual receptor agonist poised for once-weekly oral administration, aiming to significantly enhance patient convenience and adherence. Its therapeutic action involves a multi-pronged approach, including appetite inhibition, promotion of insulin secretion, and improvement of insulin sensitivity. This mechanism positions HRS-1596 as a promising candidate for treating obesity, type 2 diabetes, and various other metabolic disorders.
• This strategic collaboration leverages Hengrui Medicine's robust innovation capabilities in the metabolic disease space and Novo Nordisk's established global leadership in GLP-1 therapies and obesity treatment. Both companies anticipate that HRS-1596 will offer a more convenient and effective treatment option for patients worldwide, expanding Novo Nordisk's oral drug pipeline and facilitating the global reach of Hengrui's innovative therapies.

Addressing Unmet Needs in Obesity and Type 2 Diabetes Treatment

Despite significant advances driven by GLP-1-based therapies, substantial unmet needs persist in obesity and type 2 diabetes management — particularly around muscle preservation, comorbidity resolution, and populations with inadequate responses to current agents. Emerging pipeline strategies and mechanistic research are actively targeting these gaps.

• Muscle mass loss during weight reduction: Up to 40% of weight lost with GLP-1 receptor agonists comes from lean body mass, raising concerns about adverse effects on skeletal muscle function, physical functionality, quality of life, and long-term metabolic health — particularly in individuals with sarcopenic obesity or those at risk of frailty. Myostatin-activin pathway inhibitors are under development specifically to preserve muscle mass during weight loss interventions.

• Obesity-related comorbidities requiring dedicated therapeutic strategies: Conditions including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), heart failure with preserved ejection fraction, and obstructive sleep apnea (OSA) represent populations where additional therapeutic strategies beyond standard GLP-1 monotherapy are needed. Trials such as ESSENCE and SYNERGY-NASH are evaluating GLP-1-based co-agonists in MASLD/MASH, and combination therapies with glucagon agonists are being developed to address hepatic disease specifically.

• Patients intolerant of or insufficiently responsive to GLP-1 analogs: Amylin agonists are identified as a promising alternative for those unable to tolerate GLP-1 analogs, and dual or triple hormonal receptor agonists (GLP-1/GIP and GLP-1/GIP/glucagon) are being developed to maximize weight loss and optimize tolerability beyond what single-agent GLP-1 receptor agonists achieve.

• Rebound weight gain and reduced energy expenditure: Weight loss achieved through lifestyle changes or medication frequently leads to reduced energy expenditure, resulting in rebound weight gain. Mitochondrial uncouplers are under investigation for enhancing energy expenditure, and NLRP-3 inhibitors are being explored for reducing obesity-associated inflammation, addressing the metabolic adaptation that undermines sustained weight management.

• Chronic kidney disease (CKD) in the context of obesity and diabetes: Semaglutide has been associated with a reduction in renal events and slower disease progression in CKD, identifying this population as one where GLP-1-based therapies offer benefits extending beyond glycemic and weight control.

• Mitochondrial dysfunction in skeletal muscle: Mitochondrial dysfunction — characterized by reduced mitochondrial size and activity — is prevalent in individuals with obesity and type 2 diabetes and contributes to muscle wasting. Evidence from animal and in vitro models suggests GLP-1 receptor agonists increase mitochondrial area, number, and morphology, though effects on mitochondrial mass, respiration, and expression of uncoupling proteins and PGC-1α remain inconclusive, representing a critical gap requiring human studies.

The Dynamic Evolution of Obesity and Type 2 Diabetes Treatment

The past five years have witnessed a fundamental shift in the pharmacological management of obesity and type 2 diabetes mellitus (T2DM), driven by the clinical maturation of incretin-based therapies. GLP-1 receptor agonists (GLP-1 RAs) — particularly semaglutide and liraglutide — established the foundational evidence base, with semaglutide demonstrating a placebo-corrected weight loss of 12% in clinical trials and a mean difference of -11.85% (95% CI: -12.81 to -10.90; P < .00001) versus placebo in nondiabetic adults with overweight or obesity. Head-to-head data from a prospective randomized study further reinforced semaglutide's superiority, with participants losing -14.7 ± 5.8% of body weight at 68 weeks versus -6.2 ± 4.9% with liraglutide (p < 0.001), alongside greater HbA1c reductions (-1.6 ± 0.4% vs. -1.0 ± 0.4%; p < 0.001). Beyond glycemic and weight outcomes, semaglutide demonstrated a more significant MACE-preventive effect among patients with T2DM on continuous therapy exceeding 365 days, with a MACE hazard ratio of 0.681 (CI: 0.635–0.731) observed for a single MACE-preventive glucose-lowering medication used continuously.

The approval and rapid clinical uptake of tirzepatide — a first-in-class dual GIP/GLP-1 receptor agonist — marked a further inflection point. Across the SURPASS program in T2DM, tirzepatide produced large, dose-dependent reductions in HbA1c and substantial weight loss versus active comparators, while the SURMOUNT trials demonstrated marked and durable weight reduction with clinically relevant improvements in waist circumference, blood pressure, triglycerides, and inflammatory biomarkers. A systematic review and meta-analysis of Phase 3 SURMOUNT trials reported that tirzepatide 15 mg or maximum tolerated dose produced an 18.04% greater reduction in body weight versus placebo (95% CI: -19.86 to -16.22; p < 0.00001), with broadly comparable relative efficacy across Asian (-18.16%) and non-Asian (-17.92%) trial populations. In obesity-related HFpEF, the SUMMIT trial showed reductions in worsening heart failure events and improvements in health status. A meta-analysis of randomized controlled trials further quantified the cardiovascular benefit of incretin mimetics in nondiabetic adults with obesity, with GLP-1 RAs reducing MACE risk by 32% (RR 0.68; 95% CI: 0.53–0.87; P = 0.002) and tirzepatide by 59% (RR 0.41; 95% CI: 0.18–0.92; P = 0.03).

Most recently, retatrutide — a novel triple receptor agonist targeting GLP-1, GIP, and glucagon receptors simultaneously — has emerged as a potentially transformative next step. Phase 2 trial data demonstrated dose-dependent weight loss and HbA1c reductions in individuals with T2DM, as well as substantial weight loss and improved glucose levels in non-T2DM individuals, with the 12 mg dose producing the maximum reductions across all outcomes evaluated in a systematic review and meta-analysis of four randomized controlled trials. Improvements in liver steatosis and diabetic kidney disease have also been reported. Ongoing Phase 3 TRIUMPH studies are evaluating retatrutide's long-term safety and efficacy across diverse patient populations. Across all agents in this class, gastrointestinal adverse events — nausea, vomiting, diarrhea, and constipation — remain the most consistently reported safety signal, generally emerging during dose escalation, while rarer events including cholelithiasis, acute pancreatitis, and gastroparesis warrant continued pharmacovigilance. The durability of weight loss following treatment cessation also remains an active area of investigation, with real-world follow-up data from SURMOUNT-CN showing mean weight regain of 9.1% and 12.3% at 26 weeks post-cessation in the tirzepatide 10 mg and 15 mg groups, respectively, though net weight loss from baseline remained substantial.

Oral Dual Agonism: Novo Nordisk's Strategic Leap in Metabolic Care

The recent licensing agreement between Hengrui Medicine and Novo Nordisk for HRS-1596 marks a pivotal moment in the pursuit of more effective and convenient treatments for metabolic diseases. Novo Nordisk, a recognized leader in the GLP-1 space, has made a strategic investment in an early-stage, once-weekly oral GLP-1/GIP dual receptor agonist. This move signals a clear intent to diversify its portfolio beyond injectable therapies and capture a larger share of the rapidly expanding markets for obesity and type 2 diabetes.

The appeal of an oral, once-weekly formulation cannot be overstated. Patient preference for non-injectable options is a significant driver of adherence, which is crucial for chronic conditions. Furthermore, the dual agonism of GLP-1 and GIP receptors holds promise for enhanced efficacy, building on existing evidence that GLP1R agonism can lead to a recovery of islet-wide Ca2+ dynamics and the re-emergence of hub cells, critical for insulin secretion. This synergistic approach could offer superior metabolic control compared to single-target therapies.

For Hengrui Medicine, this deal provides substantial non-dilutive capital, validating their innovative research capabilities on a global stage. It allows them to reinvest in their pipeline, including their established oncology programs and advancements in clinical data management through AI, while retaining commercialization rights in key Asian markets. This hybrid strategy allows for both global reach and localized market control.

However, the path forward is not without its challenges. HRS-1596 is still in early Phase 1 development, and the attrition rate for drugs at this stage is high. The competitive landscape for GLP-1 and dual agonists is also intensely crowded, meaning HRS-1596 will need to demonstrate clear differentiation in terms of efficacy, safety, or patient experience to succeed. Additionally, the global manufacturing and commercialization of a potentially high-demand oral product will require significant investment and strategic execution. Despite these risks, the potential for an effective, convenient oral dual agonist to reshape metabolic disease management is immense, offering a new horizon for patient care.