Sometimes, even in drug development that emphasizes strict scientific rigor, one cannot help but marvel at the unpredictable twists of fate.
Last Friday (May 16), Novo Nordisk announced that CEO Lars Fruergaard J?rgensen will step down. According to FiercePharma, the CEO change was due to "weight of market pressure."
Just one month ago, Eli Lilly’s oral small molecule GLP-1 product orforglipron’s Phase 3 clinical trial ACHIEVE-1 showed positive results, striking like a sharp sword at Novo Nordisk’s core.
Almost simultaneously, Pfizer announced termination of clinical development of its oral GLP-1 receptor agonist danuglipron due to failure in safety hurdles. No one knows Pfizer’s regrets at this moment, nor its determination when it restarts clinical trials again.
With Novo Nordisk’s oral version of weight loss semaglutide Wegovy (25mg) receiving FDA acceptance for U.S. market application on April 21, a new story is taking shape: How will oral products shake up the GLP-1 world?
In fact, GLP-1 products already have one foot in the oral era.
As early as 2019, oral semaglutide for diabetes (Rybelsus) was approved by the FDA. In Q1 2025, semaglutide generated DKK 55.776 billion (approx. USD 7.864 billion) for Novo Nordisk, becoming the top new drug for the quarter. Among this, the oral diabetes product Rybelsus brought in DKK 5.695 billion (approx. USD 803 million).
As the pioneer of GLP-1, oral semaglutide uses SNAC absorption enhancer technology to overcome the intrinsic bioavailability limitations of peptide drugs. So, when Eli Lilly’s orforglipron delivered positive Phase 3 results, did it spell crisis for Novo Nordisk or mutual respect among top competitors?
According to Eli Lilly, in the ACHIEVE-1 study, orforglipron met the primary endpoint: at 40 weeks, treatment with orforglipron significantly reduced glycated hemoglobin (A1C) compared to placebo, lowering A1C from a baseline average of 8.0% by 1.3% to 1.6% (using efficacy estimand). Additionally, over 65% of patients receiving the highest dose achieved A1C ≤ 6.5%, below the diabetes threshold defined by the American Diabetes Association. Another key secondary endpoint showed that patients on the highest dose lost an average of 7.3 kg (7.9%), and since patients had not reached a weight plateau by study end, further weight loss might still occur.
To prove oral semaglutide is as safe and effective as injectable forms, Novo Nordisk conducted the PIONEER series of Phase 3 trials. Results showed that at 26 weeks, oral semaglutide outperformed placebo, empagliflozin, and sitagliptin in reducing HbA1c, comparable to liraglutide. The proportion achieving ADA recommended HbA1c <7.0% was higher for oral semaglutide (7mg: 42%–69%; 14mg: 55%–77%) than placebo (7%–31%) and other comparators (25%–62%).
??Related Read: Oral Semaglutide: Clinical Trial Breakthroughs in Diabetes Treatment
“Generally, large molecules can’t compete with small molecules, which is why after large molecule drugs succeed, people keep searching for small molecule alternatives. The opposite never happens. Small molecules have an absolute advantage in oral bioavailability. Though it remains a challenging medicinal chemistry problem, it is solvable — that is the consensus among drug developers,” said Dr. Liang Guibai, who participated in the development of sitagliptin at Merck.
“Half-life is reversed. Large molecule drugs have many weekly, monthly, or even biannual injections — Novo Nordisk’s semaglutide lasts 160 hours. Small molecules rarely achieve weekly dosing. But oral drugs don’t need to; once daily is ideal for best patient adherence,” Liang added, sharing views on advantages and disadvantages of oral small molecules and peptides.
Safety is a potential risk small molecules find hard to avoid. “Side effects of small molecules are hard to predict and mostly come from the molecule itself. Medicinal chemistry tries to optimize by changing lead structures, but good leads for small molecule GLP-1 receptor agonists are very hard to find. If Eli Lilly’s orforglipron has no significant weaknesses in efficacy or side effects, it is a rare molecule, with some luck involved as well.”
Orforglipron was originally discovered by Chugai Pharmaceutical. In 2018, Eli Lilly acquired its development and commercialization rights for USD 50 million. According to Eli Lilly, orforglipron has a complex structure with a molecular weight of 882.96, close to the upper limit of small molecule drugs (~1000). It requires 28 steps from starting materials to active pharmaceutical ingredient, increasing difficulty to replicate.
Looking back at Pfizer’s danuglipron, it was never well regarded in the industry, and the restart of Phase 2 trials ended predictably. How its followers choose at this crossroads is unknown. This is not Pfizer’s first failure in oral GLP-1 drugs — development of lotiglipron was halted in 2023 due to elevated liver enzymes.
In January this year, JAMA Network Open published a study: A cohort study of 125,474 patients using GLP-1 receptor agonists showed that 81,919 discontinued within two years. Accounting for censoring, 53.6% stopped after 1 year and 72.2% after 2 years. Patients with type 2 diabetes had lower discontinuation rates (46.5% at 1 year, 64.1% at 2 years); those without T2D had rates of 64.8% and 84.4% respectively.
Dr. Robert Gabbay, head of diabetes, obesity, and technology at Harvard Medical School, stated on social media, “Although GLP-1 drugs show significant weight loss, this study found 65% of obese patients stopped within one year. There is no good data explaining this. Possible reasons include cost/access, side effects, ineffectiveness (weight loss often takes months), and convenience.”
Structure Therapeutics CEO Raymond Stevens recently said in a media interview, “85% of GLP-1 users stop within two years. Does this imply oral products will fully overtake?”
Dr. Qian Lei, Senior VP at Innovent Biologics, told R&D media that oral vs injectable drugs have been roughly “50-50,” with some patients preferring injections, others oral.
“Small molecules and injectables each have pros and cons. Small molecules cost less, are convenient but prone to off-target risks like liver injury and drug interactions. Injectables cost more and might affect compliance, but weekly injections are already convenient, and monthly injections may improve adherence. Injectables are also more targeted, with better safety and efficacy than small molecules currently,” Qian said.
At least Eli Lilly hasn’t slowed injection product development. Just two days ago, it released detailed results from the SURMOUNT-5 head-to-head study of tirzepatide vs. semaglutide. At week 72, tirzepatide met the primary endpoint and all five key secondary endpoints, once again challenging semaglutide.
??Related Read: Semaglutide vs Tirzepatide in Weight Loss
“Actually, Eli Lilly is conducting a study where tirzepatide reduces weight first, then oral small molecule drugs provide long-term sequential treatment. This is a very reasonable approach,” Qian revealed.
It’s been one month since Pfizer announced halting danuglipron development. The news boosted stocks of Structure Therapeutics and Viking, both holding small molecule oral GLP-1 candidates.
Structure’s founder and CEO Raymond Stevens is confident. He believes 2025 will be a transformative year for oral GLP-1 small molecules in obesity and related disease treatment. The company’s 2024 report states small molecule oral GLP-1 product aleniglipron’s ACCESS and ACCESS II studies have completed recruitment and expect top-line data by end 2025.
Undoubtedly, many Chinese companies are already on this track and have signed multiple deals. Chengyi Biotech’s ECC5004 was licensed to AstraZeneca with a USD 60 million upfront, following Eli Lilly’s orforglipron technology path.
Hansoh Pharma’s HS10535 is licensed to Merck with USD 112 million upfront.
Jixing Pharmaceuticals introduced a GLP-1 small molecule from Wintai Medicine. Xianwei Bio signed a licensing deal worth over USD 2.4 billion with Verdiva Bio earlier this year; their pipeline includes a small molecule GLP-1.
In March, Hengrui Medicine started Phase 3 for its self-developed oral GLP-1 receptor agonist HRS-7535 for overweight or obese patients. Huadong Medicine’s HDM1002 (conveglipron) has enrolled its first patient in a Phase 3 weight management study. Innovent Biologics is developing oral small molecule GLP-1, GIP antibody-conjugated GLP-1/GCG dual agonist, and PCSK9-conjugated GIP/GCG/GLP-1 triple agonist. Other companies like Regor Medicine, Derui Zhiyao, Hisun, Xintai, and Geli Pharmaceuticals have products at various clinical stages.
With new players entering, will there be more dark horses?
“Actually, small molecule drug development has a low threshold; many think they can do it, so competition appears fierce. But few have true strength. Small molecule GLP-1 receptor agonist development is very challenging due to GLP-1 receptor structure and activation mechanism. The key is a lead compound with good druggability. Currently, the focus is to work around orforglipron’s patents and aim for differentiation. The obesity drug market is large enough for multiple differentiated small molecules. AI might play a role in finding better molecules,” Liang said.
Of course, Pfizer probably won’t give up on this expanding market. It remains to be seen where it will find “gold” in China.
