Novo Nordisk Bets $300M on Unproven Oral Dual Agonist: Mechanism Validated, Formulation Is Not

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

Novo Nordisk has entered an exclusive license agreement with Hengrui Pharma for HRS-1596, a phase 1-ready glucagon-like peptide-1 receptor (GLP-1R) and gastric inhibitory polypeptide receptor (GIPR) dual agonist. This agreement grants Novo Nordisk global rights (excluding mainland China, Hong Kong, Macao, and Taiwan) to develop, manufacture, and commercialize HRS-1596, which has potential for once-weekly oral dosing for obesity, type 2 diabetes, and other metabolic diseases. The deal is valued at up to $2.6 billion, including a $300 million upfront payment and potential sales royalties.

• Novo Nordisk secured exclusive global rights (excluding mainland China, Hong Kong, Macao, and Taiwan) to HRS-1596 from Hengrui Pharma. The agreement includes an upfront payment of $300 million, with potential total payments reaching $2.6 billion contingent on development, regulatory, and commercial milestones, plus royalties on net sales.
• HRS-1596 is a novel glucagon-like peptide-1 receptor (GLP-1R) and gastric inhibitory polypeptide receptor (GIPR) dual agonist. It is designed for once-weekly oral administration, aiming to improve convenience and reduce dosing frequency for patients with obesity, type 2 diabetes, and other metabolic diseases by suppressing appetite, stimulating insulin secretion, and improving insulin sensitivity.
• This acquisition strengthens Novo Nordisk's leadership in oral peptides and its broad pipeline across cardiometabolic diseases. The addition of HRS-1596, which has received approval in China to initiate Phase 1 clinical trials for weight management and type 2 diabetes, underscores Novo Nordisk's commitment to external innovation and raising the bar for patient convenience.

Addressing Key Challenges in Obesity and Type 2 Diabetes Care

Current treatment approaches for obesity and type 2 diabetes face persistent biological, pharmacological, and systemic barriers that limit long-term therapeutic success. No uniformly effective treatment for beta-cell preservation has been identified, and the progressive loss of beta-cell mass remains a critical mechanism underlying deteriorating glycemic control in T2DM. Addressing these challenges requires coordinated clinical, policy, and lifestyle strategies.

• Beta-cell function decline is difficult to reverse. Glucagon-like peptide-1 agonists, dipeptidyl-peptidase-4 inhibitors, and thiazolidinediones support maintenance and often improvement of beta-cell function during active use, but data on their ability to preserve beta-cell function when patients are not receiving active treatment are limited. Initial beta-cell reserve and HbA1c at randomization are independent predictors of glycemic durability, underscoring the need for early intervention before significant loss occurs.

• Weight regain following GLP-1 receptor agonist discontinuation is a major limitation. GLP-1 medications can reduce body weight in obese patients by between 15% and 25% on average after about 1 year, but discontinuation is associated with a high rate of weight regain — and weight regain can be composed primarily of fat. Multiple cycles of weight cycling may actually increase obesity in individuals. High cost and limited availability of new weight loss drugs contribute to large rates of discontinuation.

• Loss of lean mass accompanies pharmacologically induced weight loss. Weight loss by any means is accompanied by loss of lean mass, specifically muscle and bone. Use in elderly patients may be harmful, and long-term consequences of use in children and adolescents remain unknown. Protein supplementation and resistance training are effective in mitigating muscle and bone loss, yet the optimal timing, frequency, and content of such lifestyle interventions alongside obesity management medications remain unclear.

• Gastrointestinal adverse events and rare serious risks complicate GLP-1RA use. Common side effects are predominantly gastrointestinal, including nausea, vomiting, diarrhea, and constipation. Accumulating evidence has identified additional GI complications including cholelithiasis, cholecystitis, gastroparesis, and bowel obstruction. Rare but serious adverse events include acute pancreatitis, and associations with nonarteritic anterior ischemic optic neuropathy, medullary thyroid carcinoma, and acute kidney injury have been reported through pharmacovigilance and case-based evidence. GLP-1 drugs carry a boxed warning for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2.

• Insulin rationing due to cost and access barriers remains unresolved despite policy intervention. In 2024, 24.1% of insulin-prescribed patients reported cost-related insulin rationing, statistically unchanged from 25.5% in 2017 (p = 0.41). Over one-third (37.7%) reported rationing due to broader access barriers including cost, insurance delays, or pharmacy shortages. Patients with type 2 diabetes had lower odds of rationing (OR 0.34, 95% CI 0.13–0.87) compared with type 1 diabetes patients, but the overall burden remains substantial.

• Access to monitoring technologies such as CGM is constrained by insurance, cost, and provider familiarity. Insurance and cost-related barriers were the most commonly cited obstacles to continuous glucose monitoring (CGM) prescription in primary care, alongside distance to endocrinology when greater than 40 miles away. With limited access to endocrinologists, many patients who could benefit from CGM are not receiving it through primary care, exacerbating disparities in diabetes control among underserved populations.

Novo Nordisk's Strategic Leap into Next-Gen Oral Metabolic Therapies

Novo Nordisk's recent licensing agreement for HRS-1596 underscores a pivotal moment in the pharmaceutical race for next-generation metabolic disease treatments. With the market for obesity and type 2 diabetes therapies experiencing unprecedented growth, driven by the success of incretin-based drugs, companies are aggressively pursuing compounds that offer enhanced efficacy and convenience.

This deal highlights several key trends:

• The Shift to Dual Agonism: Research indicates that dual GLP-1R/GIPR agonists, such as tirzepatide, offer superior weight loss and glycemic control compared to GLP-1R monotherapy. This sets a new standard for efficacy, with some advanced candidates demonstrating weight reductions exceeding 20%. Novo Nordisk's move into this space is a direct response to this evolving landscape, aiming to secure a competitive edge beyond its current GLP-1R offerings.

• The Premium on Oral Formulations: While injectable incretin therapies have revolutionized treatment, an oral, once-weekly option could significantly improve patient adherence and expand market access. The success of existing oral GLP-1RAs demonstrates the strong patient preference for non-injectable routes, making HRS-1596's potential for once-weekly oral dosing a critical strategic advantage.

However, this ambitious move is not without its challenges. HRS-1596 is still in its early development phase, meaning substantial clinical development risks remain. The compound must demonstrate comparable or superior efficacy and a favorable safety profile against an increasingly competitive backdrop of highly effective approved and pipeline therapies. Successfully navigating these development hurdles will be crucial for Novo Nordisk to realize the full potential of this significant investment and solidify its long-term leadership in the metabolic disease arena.