Septerna Secures Over $200 Million Upfront in $2.2 Billion Oral Small Molecule Deal with Novo Nordisk

Mid-May, Novo Nordisk Faces a "Summer of Challenges".

On May 14, Novo Nordisk announced an exclusive global collaboration and licensing agreement with Septerna to discover, develop, and commercialize oral small-molecule drugs for the treatment of obesity, type 2 diabetes, and other cardiometabolic diseases. Septerna is eligible to receive payments from Novo Nordisk.Total upfront, R&D, and commercial milestone payments of approximately $2.2 billion, includingMore than 200 million US dollars (approximately 1.4 billion Chinese yuan) in upfront and near-term milestone payments, and may also receive tiered royalties on the global net sales of the marketed products in the future.In addition, Novo Nordisk will bear all the R&D expenses of the cooperation project.

On May 16, according to a mutual agreement with the Novo Nordisk Board of Directors,Lars Fruergaard Jorgensen to Step Down as CEO of Novo NordiskHe will continue to serve as CEO for a period of time to support a smooth transition to the new leadership. Notably, Novo Nordisk stated that the successor to Lars Fruergaard Jorgensen is still being sought.

The analysis pointed out that Lars Fruergaard Jorgensen's resignation might be related to the nearly year-long decline in stock prices.Since hitting a peak of nearly 1,000 Danish kroner in June 2024, Novo Nordisk's share price has plummeted by 59%.

Under the external constraints of the capital market, Novo Nordisk also faces fierce competition in the weight-loss drug market. On May 7, Novo Nordisk released its Q1 financial report, showing revenue of 78.087 billion Danish kroner (approximately 11.8 billion US dollars), a year-on-year increase of 19%; operating profit of 38.791 billion Danish kroner (approximately 5.9 billion US dollars), a year-on-year increase of 22%; net profit of 29.034 billion Danish kroner (approximately 4.4 billion US dollars), a year-on-year increase of 14%.Although both revenue and net profit grew, Novo Nordisk still lowered its full-year growth forecast, reducing its 2025 outlook by three percentage points.

According to the agreement, in the collaboration with Septerna exceeding $2 billion, the partnership will initially launch four potential small molecule new drug development projects targeting one or more selected G protein-coupled receptor (GPCR) targets, including GLP-1, GIP, and glucagon receptors.

Septerna Focuses on the Discovery and Development of Oral Small Molecule Drug Pipelines, Covering Therapeutic Areas Such as Endocrinology, Immunology, Inflammation, and Metabolic Diseases. Its Proprietary Native Complex Platform Completely Detaches GPCRs from the Cell Membrane, Reconstructing a "Native Complex" Comprising Ligands, Signaling Proteins, and Lipid Bilayers to Accurately Mimic the Natural Conformation of Receptors. Using High-Throughput Screening Systems, It Enables Comprehensive Scanning of Agonists, Antagonists, and Allosteric Modulators Across Hundreds of Millions of Molecules, Breaking Through Traditional Target Limitations.

As the largest family of cell membrane receptors, 75% of GPCR targets remain undeveloped. Septerna's proprietary technology is expected to unlock new target combinations beyond GLP-1/GIP/GCGR, paving the way for the next generation of oral "super metabolic drugs."Preclinical data show that the weight loss effect of its single GIPR agonist combined with semaglutide in mouse models surpasses Eli Lilly's tirzepatide.

It is reported that Novo Nordisk and Septerna will jointly carry out research activities from discovery to the selection of development candidate pipelines.From the IND onwards, Novo Nordisk will assume full responsibility for all global development and commercialization activities, and bear all R&D costs associated with the collaboration project.In addition, Septerna has the right to opt into a global profit-sharing arrangement for one project in the collaboration, in lieu of future milestones and royalties for that candidate product.

Behind the deep cooperation and considerable potential dividends lies Novo Nordisk's high trust and optimism in Septerna's technology, as well as its anxiety over the progress of oral small-molecule weight loss drugs.

For Novo Nordisk, oral weight-loss drugs were once a key leading point in the type 2 diabetes field: as early as 2019, the oral semaglutide Rybelsus was approved for marketing in the U.S. as an adjunct to diet and exercise to help improve glycemic control in adults with type 2 diabetes. Rybelsus was approved in China in January 2024 for the treatment of type 2 diabetes. In August 2024, Rybelsus (25mg) successfully completed a Phase III weight-loss study, with the test group’s average body weight decreasing by 13.6%. A market application for this weight-loss version has been submitted and is expected to become...The World's First Oral GLP-1 Class Weight Loss Drug。

However, Novo Nordisk's advantage in peptide oral weight-loss drugs has not yet extended to the next generation of oral small-molecule weight-loss drugs. Competitor Eli Lilly has already taken the lead.On April 18, Eli Lilly's oral small-molecule GLP-1 receptor agonist Orforglipron became the first oral small-molecule GLP-1 drug to complete Phase III studies, with an anticipated market application by the end of 2025.

Compared with polypeptide drugs (such as semaglutide and teriparatide), small-molecule GLP-1 not only has more advantages in oral administration, but more importantly, its cost and production capacity advantages are very prominent.Lilly has expressed confidence in launching Orforglipron globally without being constrained by production capacity or supply issues, directly addressing the longstanding global supply problem that has plagued weight-loss drugs for years.

How to quickly get a share of the small molecule GLP-1 pie has become a key strategy for several MNCs.AstraZeneca acquired ECC5004, a small molecule GLP-1 receptor agonist from Eccogene, with a potential total amount of $1.825 billion; Merck obtained HS-10535, a preclinical oral small molecule GLP-1 receptor agonist from Hansoh Pharma, with a potential total amount of $2.012 billion.

However, oral small-molecule weight-loss drugs remain "the high-hanging fruit."——Pfizer has successively terminated its oral small molecule GLP-1 pipeline, including the first-generation Danuglipron and the second-generation Lotiglipron, due to reasons such as pharmacokinetic data and safety issues like elevated transaminase levels.

As a result, Novo Nordisk has reached multiple collaborations in oral small-molecule weight loss drugs, including a $256 million collaboration agreement with EraCal Therapeutics to develop and commercialize an oral small-molecule weight loss drug project; and a $600 million total collaboration agreement with Metaphore Biotechnologies to develop two next-generation GLP-1 receptor agonists for the treatment of obesity.

"Considering recent market challenges, the decline in stock prices, and the wishes of the Novo Nordisk Foundation, the Board of Directors of Novo Nordisk and Lars Fruergaard Jorgensen have jointly concluded that initiating the CEO succession process is in the best interest of the company and its shareholders." The announcement explicitly states that market competition and the drop in stock prices are the main reasons for launching the CEO succession process.

At the same time, Lars Rebien Sorensen, who served as CEO of Novo Nordisk for 16 years and is now chairman of the Novo Nordisk Foundation, will immediately join the board as an observer, with the goal of securing a seat at the next annual general meeting.

In terms of actual performance, during Lars Fruergaard Jorgensen's eight-year tenure as CEO, Novo Nordisk's product sales, profits, and stock price nearly tripled.But in the past year, Novo Nordisk's stock price has retreated from its "myth" — down 59% from its historical high in June last year, and it has fallen 32% so far in 2025.

When the rapid growth driven by semaglutide's first-mover advantage slows down, Novo Nordisk's subsequent momentum remains to be supplemented.

In clinical research, Eli Lilly's tirzepatide has been proven superior to Novo Nordisk's semaglutide. In May, the SURMOUNT-5 study published by Eli Lilly showed that at week 72, tirzepatide met the primary endpoint and all five key secondary endpoints, demonstrating superiority over semaglutide throughout the trial.

More importantly, the stone of R&D data has already stirred up ripples at the market end.In the critical U.S. market, the total prescriptions for tirzepatide have surpassed those of Novo Nordisk, increasing its share to 53.3%. Among these, Mounjaro's revenue reached $2.66 billion, marking a 75% year-over-year growth.Total prescriptions (TRx) account for 39%, and new prescriptions (NBRx) account for 46%.; Zepbound revenue was $2.31 billion,Total prescription volume accounts for over 60%, and new prescription volume accounts for 74%.

Perhaps as a result, Novo Nordisk has lowered its performance forecast for 2025. Sales growth at constant exchange rates has been adjusted from 16%-24% to 13%-21%, and operating profit growth has been revised from 19%-27% to 16%-24%.

In 2024, Semaglutide fell short of claiming the throne of the world's top drug by less than $200 million.However, in 2025 Q1, semaglutide achieved a quarterly sales surpassing Keytruda (sales of $7.2 billion) with revenue of 55.776 billion Danish kroner (approximately $7.864 billion).

At this rate, semaglutide is expected to become the next global blockbuster drug by 2025. However, Novo Nordisk needs to address longer-term growth challenges.