The blockbuster success of Novo Nordisk’s Ozempic/Wegovy and Lilly’s Mounjaro/Zepbound, all injectables, have put GLP-1/GIP agonists on the map, but will new oral drugs be a game-changer?

By Patricia Van Arnum, Editorial Director, DCAT, pvanarnum@dcat.org

What’s next
Glucagon-like peptide 1 (GLP-1) agonists, used to treat Type 2 diabetes and obesity, have been a success story in the industry, with Novo Nordisk riding a blockbuster wave with Ozempic/Wegovy (semaglutide), respectively for treating Type 2 diabetes and obesity, and Eli Lilly and Company also riding the wave with Mounjaro/Zepbound (tirzepatide), a dual-activating GIP (glucose-dependent insulinotropic polypeptide) and GLP-1 medication, respectively for treating Type 2 diabetes and obesity. Administered as injectable drugs, oral forms of GLP-1 drugs are another area of strong market interest, and Novo, Lilly and other companies are advancing oral GLP-1 agonists.

Novo Nordisk already has an oral version of semaglutide, the active ingredient in Ozempic and Wegovy, on the market in Rybelsus, which was first approved in 2019, but that is indicated for treating Type 2 diabetes, not obesity. Last month (May 2025), Novo announced that the US Food and Drug Administration (FDA) accepted its new drug application (NDA) submission for an investigational once-daily oral formulation of Wegovy (semaglutide) for chronic weight management in adults living with obesity or overweight with one or more comorbid conditions and to reduce the risk of major adverse cardiovascular events in adults with overweight or obesity and established cardiovascular disease. If approved, Wegovy would become the first oral formulation of a GLP-1 indicated for chronic weight management. The FDA action date to decide on the Wegovy oral formulation NDA is in the fourth quarter of 2025.

“We are entering a new era of obesity care where patients want individualized treatment plans that address their needs and provide choices, including oral formulations,” said Anna Windle, PhD, Senior Vice President, Clinical Development, Medical & Regulatory Affairs at Novo Nordisk Inc, in a May 2, 2025, statement.  “… We are pleased that the FDA has accepted our submission and look forward to working with regulatory authorities on what would be the first oral GLP-1 treatment for obesity.”

Novo is advancing other oral drugs for treating obesity. Earlier this month (June 2025), Novo Nordisk reported that it will advance to Phase III trials both subcutaneous and oral amycretin in weight management based on completed clinical studies. Amycretin is a long-acting GLP-1 and amylin receptor agonist under development for treating adults with overweight or obesity and for Type 2 diabetes. The company says it is planning to initiate a Phase III development program with amycretin for adults with overweight or obesity during the first quarter of 2026.

Lilly is also advancing oral GLP-1 agonists. Earlier this year (April 2025), Lilly reported positive Phase III results for orforglipron, an oral small-molecule (non-peptide) GLP-1 receptor agonist, for treating Type 2 diabetes and obesity. Orforglipron was discovered by Chugai Pharmaceutical and licensed by Lilly in 2018. Chugai and Lilly published the preclinical pharmacology data of this molecule together, and Lilly is running Phase III studies on orforglipron for the treatment of Type 2 diabetes and for weight management in adults with obesity or overweight with at least one weight-related medical problem. It is also being studied as a potential treatment for obstructive sleep apnea and hypertension in adults with obesity.

Roche is advancing an oral GLP-1 receptor agonist, CT-996, which it gained through its 2024 acquisition of  Carmot Therapeutics, a Berkeley, California-based bio/pharmaceutical company, in a deal worth up to $3.1 billion ($2.7 billion at closing plus $400 million in potential milestone payments). The acquisition provided Roche with three clinical-stage assets with potential in treating obesity and diabetes. These included CT-996, a once-daily oral small-molecule oral GLP-1 receptor agonist, in Phase I, for treating obesity in patients with and without Type 2 diabetes, as well as two injectable clinical drug candidates: CT-388, a once-weekly subcutaneous injectable in Phase II, for treating obesity in patients with and without Type 2 diabetes, and CT-868, a once-daily subcutaneous injectable, in Phase II, for treating Type 1 diabetes patients with overweight or obesity.

Oral GLP-1’s for obesity saw a recent setback when in April (April 2025), Pfizer announced that it was discontinuing development of danuglipron, an oral GLP-1 receptor agonist, which was being investigated for chronic weight management, due to potential liver toxicity. Pfizer reported that its dose-optimization studies of once-daily formulations of danuglipron met key pharmacokinetic objectives and confirmed a formulation and dose with the potential to deliver a competitive efficacy and tolerability profile in Phase III testing, based on earlier studies of twice-daily danuglipron. Pfizer reported that while the overall frequency of liver enzyme elevations across the over 1,400 participant safety database of danuglipron was in line with approved agents in the class, a single asymptomatic participant in one of the dose-optimization studies experienced potential drug-induced liver injury that resolved after discontinuation of danuglipron. After a review of the totality of information, including all clinical data generated to date for danuglipron and recent input from regulators, Pfizer decided to discontinue development of the molecule.

Other recent highlights for oral obesity drugs
Novo Nordisk is further building its pipeline with oral obesity drugs. Earlier this month, (June 2025), Novo inked a deal worth up to $815 million with Deep Apple Therapeutics, a South San Francisco-based company specializing in small-molecule drug discovery to discover, develop, and commercialize oral small-molecule therapeutics directed at a non-incretin G protein-coupled receptors (GPCR) target for cardiometabolic diseases, including obesity, in a deal worth up to $812 million.

Last month (May 2025), Novo Nordisk and Septerna, a San Francisco, California-based bio/pharmaceutical company focused on GCPRs, formed an exclusive global collaboration and license agreement to discover, develop, and commercialize oral small-molecule medicines for treating obesity, Type 2 diabetes, and other cardiometabolic diseases, in a deal worth up to $2.2 billion ($200 million upfront and near-term funding and $2 billion in milestone payments). 

The companies will initially commence four development programs for potential small-molecule therapies directed to one or more select GPCR targets, including GLP-1, GIP, and glucagon receptors. The companies will jointly conduct research activities from discovery through development candidate selection. Starting at investigational new drug-enabling activities, Novo Nordisk will have sole responsibility for all global development and commercialization activities. In addition, Septerna has the right to opt in to a worldwide profit share for one program in the collaboration in lieu of future milestones and royalties for that product candidate. The agreement is subject to customary closing conditions, including the expiration or termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976. Closing is expected to occur in the second quarter of 2025. 

Viking Therapeutics, a San Diego, California-based clinical-stage bio/pharmaceutical company, is advancing a dual GLP-1/GIP agonist, VK2735, for treating obesity for both subcutaneous and oral administration. The oral formulation is in Phase II development and the subcutaneous formulation is planned for Phase III testing in 2025. In March (March 2025), Viking Therapeutics signed a multi-year contract with the CDMO CordenPharma to provide development and manufacturing services for clinical and commercial scale (drug substance and drug product) of VK2735 for both the subcutaneous and oral peptide formulations.