The race is on to develop the first daily weight-loss pill that would be both cheaper and less invasive than the current injectable drugs on the market, with the latest strong trial results from US company Terns following similarly positive outcomes from competitors including Eli Lilly, Roche and Structure Therapeutics.
The one-a-day glucagon-like peptide-1 receptor (GLP-1R) agonist tablet would work much like the current suite of medications including Wegovy and Ozempic, (semaglutide) and Zepbound (tirzepatide), but would take away the need to self-inject the drug in order to achieve the same weight-loss results. These small-molecule drugs effectively target the gastrointestinal tract, doing away with the need to administer the medication by injection.
The latest results come from California's Terns Pharmaceuticals, which has reported its findings following a 28-day Phase I clinical trial of its TERN-601 oral medication, testing for tolerability and safety.
“These compelling results underscore TERN-601’s potential to be a class-leading GLP-1R agonist based on its composite profile of initial indications of efficacy, tolerability and manufacturing scalability,” said Amy Burroughs, chief executive officer of Terns. “With operational preparations well underway, we look forward to swiftly advancing this promising product candidate into Phase 2 clinical development in 2025.”
In the study, TERN-601 was tested at different doses on 37 healthy but overweight or obese individuals. The randomized trial, split the participants into three cohorts (high, medium and low dose, in addition to a placebo control group). The high-dose (740 mg) participants had the best results, with 67% achieving an average weight loss of 5.5% after the four-week trial. In the other groups, 33% of the medium-dose participants lost 5% of their body weight, while just 11% of the low-dose individuals reached the 5% weight-loss benchmark. Among the placebo group, the average weight loss was 0.6%.
Side effects were reported as mild or medium – much like the gastrointestinal issues that come with existing GLP-1 receptor agonist drugs.
“We are delighted to demonstrate potent GLP-1R agonism with TERN-601 as its distinct drug properties allowed for sustained target coverage with once-daily dosing and the evaluation of doses up to 740 mg, while being tolerable,” noted Emil Kuriakose, chief medical officer of Terns. “Importantly, we believe we have successfully identified an optimal range of clinically active, well tolerated doses to take forward in Phase 2 clinical trials, with no new dose range exploration anticipated.”
However, the company has some catching up to do, with pharmaceutical competitors already at advanced trial stages for oral GLP-1 medications.
In February 2025, Eli Lilly is pushing forward with Phase III trials for its drug known as orforglipron, which showed promising results from its 2023 Phase II testing. While the assessment time frame was much longer at 26 weeks, it achieved between 8.6% and 12.6% weight-loss results among the 272 participants recruited for the trial. A placebo cohort, in comparison, had an average of 2% weight loss. Once again, higher doses resulted in more weight lost.
At 36 weeks, orforglipron saw participants lose between 9.4% and 14.7% of their body weight, compared to 2.3% in the placebo group.
“These study results support the continued development of orforglipron in Phase III,” said Jeff Emmick, Lilly’s senior vice president for product development, in a statement in 2023.
Pfizer is also in the race, working on the oral weight-loss medication danuglipron, but has pivoted from a twice-daily pill to a once-a-day format.
“We believe an improved once-daily formulation of danuglipron could play an important role in the obesity treatment paradigm, and we will focus our efforts on gathering the data to understand its potential profile,” said Mikael Dolsten, chief scientific officer and president of Pfizer research and development, in a 2023 statement. “Results from ongoing and future studies of the once-daily danuglipron modified release formulation will inform a potential path forward with an aim to improve the tolerability profile and optimize both study design and execution.”
Meanwhile, Viking Therapeutics is working on both a subcutaneous and oral medication, and Structure Therapeutics has been buoyed by promising Phase II trial results of its oral small molecule medication. After eight weeks, the average weight loss of participants was 5.5%, and a Phase IIb study is set to begin in the fourth quarter of 2024.
“Safe and effective oral small molecule GLP-1 receptor agonists would be a significant advance in that they could expand access for many patients for whom this is not now possible,” said Structure CEO Raymond Stevens in a statement.
In July, Roche also reported strong results from its small molecule oral drug known as CT-996, with participants experiencing an average of 7.3% weight loss, compared to 1.2% for the placebo group.
"We are pleased to see the clinically meaningful weight loss in people treated with our oral GLP-1 therapy CT-996, which could eventually help patients address both chronic weight management and glycaemic control indications,” said Levi Garraway, Roche’s chief medical officer in a statement.
While drug developers believe oral obesity drugs will essentially dominate the weight-loss drug market, they're also expected to still be several years away from being commercially available.
The Terns results were published in an investor presentation paper.
Sources: Terns, Eli Lilly, Roche, Structure Therapeutics
