The 2021 US approval of Novo Nordisk’s breakthrough therapy Wegovy (semaglutide) for obesity transformed the disease landscape, prompting companies to not only develop drugs with a similar mechanism of action (MOA), but also to explore and investigate novel targets.

While Wegovy was not the first GLP-1 receptor agonist (GLP-1RA) approved for weight loss—that was the same company’s Saxenda (liraglutide)—its longer-lasting effects and the accompanying rush of established clinical data with the GLP-1RA approach accelerated the growth in this space. According to GlobalData, the projected value of the obesity drugs market is estimated to reach $37.1bn by 2031.  

Although GLP-1RA therapies currently are and will remain the main player in the obesity space, the introduction of upcoming pipeline therapies into the market will bring new pharmacological treatments with a novel MOA, says Sara Reci, senior analyst, GlobalData.

In an increasingly saturated obesity market, new products will need to distinguish themselves by showcasing clear advantages over existing options to effectively compete. Consequently, pharmaceutical companies have started investigating novel molecular targets with alternate routes of administration, extended treatment intervals, and other strategies such as new double- and triple-agonist mechanisms to address the demands in the obesity market, according to GlobalData.

Still, according to Reci, non-GLP-1RA therapies are forecast to only constitute approximately 6.3% of the obesity market across the seven major markets (7MM: US, France, Germany, Italy, Spain, UK, and Japan) by the end of the forecast period in 2031. Nonetheless, in the drug pipeline for obesity, smaller pharmaceutical companies seem to be the ones developing agents with novel MOAs, says Kevin Marcaida, analyst, GlobalData.

GlobalData is a parent company of Pharmaceutical Technology.

Investigating novel agents for obesity

In 2024, several updates on obesity drugs, apart from GLP-1RA therapies, that hold therapeutic potential may be catalytic for the market.

One example is the Phase II proof-of-concept trial readout for Zug, Switzerland-based Aphaia Pharma’s APHD-012, which is expected by March. APHD-012 acts by mimicking the metabolic benefits of bypass surgery while avoiding negative side effects, and comprises distal jejunal-release dextrose beads.

Another asset offering a novel non-GLP-1RA approach to weight loss is Shionogi’s S-309309, an oral monoacylglycerol acyltransferase 2 (MGAT2) inhibitor. MGAT2 is highly expressed in the small intestine and facilitates the conversion of monoacylglycerol and acyl-CoA into diacylglycerol, significantly influencing lipid metabolism within this organ. Results from a Phase II trial in 365 obese participants are expected in June.

In the same month, a Phase IIb trial (NCT05616013) for New York-based Versanis Bio’s bimagrumab, an activin receptor type 2 (ACTR2) antagonist, is expected to read out. Even prior to these results, the drug was on the radar of another major obesity player—Eli Lilly, which acquired Versanis in August 2023. Reci notes that the frequency of bimagrumab administration could be as low as only five times per year, which could represent a considerable relief in the patient’s treatment burden.

Bimagrumab is an interesting drug due to its slightly thermogenic properties, notes Dr. Nicholas Finer, a former senior principal clinical scientist at Novo Nordisk, and honorary clinical professor in the National Centre for Cardiovascular Prevention and Outcomes, Institute of Cardiovascular Science at University College London. In a Phase IIa study, bimagrumab increased lean mass by 4.5%, while reducing fat mass by 21.9% in patients with obesity and type 2 diabetes, as per 48-week data shared in a January 12, 2023, release. Moreover, such effects were observed without much change in the total caloric intake in patients, Reci adds. The ongoing Phase IIb study is assessing the efficacy of bimagrumab alone or in combination with semaglutide (GLP-1RA) in 507 overweight or obese subjects. Finer highlights the interest in combining bimagrumab with another drug, to achieve weight loss while preserving lean body mass.

Still, the substantial annual cost of intravenous therapies and hospital administration could likely impact its reimbursement and market availability.

According to Finer, another promising novel agent is a long-acting amylin analogue called cagrilintide, which is a CALCR agonist. Novo Nordisk is studying the drug with subcutaneous semaglutide in obese patients in the Phase III REDEFINE 1 trial (NCT05567796), the results of which are expected by December. CALCR agonists are set to reach $55 million in sales this year and projected to achieve $13.8 billion in sales by 2029, Marcaida noted, displaying a huge growth.

Dual agonists close behind

In November 2023, Eli Lilly’s dual agonist GIPR and GLP-1RA Zepbound (tirzepatide) joined the high-profile club of obesity drugs, with an FDA approval. It was formerly sold as Mounjaro for treating type 2 diabetes.

Berkeley, California-based Carmot Therapeutics, which Roche acquired for $2.7 billion in December 2023, is also developing two GIPR/GLP-1R agonists—CT-388 and CT-868. The latter is being evaluated in obese patients with type 1 diabetes. Both dual agonist therapies are subcutaneous injections, but CT-388 is a once-daily injection, while CT-868 is a once-weekly injection.

Dual agonists may present increased efficacy in the treatment of obesity by acting on two targets. They promote insulin secretion and contribute significantly to lipid metabolism and the storage of fat. These drugs can decrease gastric emptying, thereby reducing food intake and resulting in weight loss. Marcaida notes GIPR as a drug target is forecast to surpass GLP-1R in sales by 2026.

Dual GIPR antagonists/GLP-1RA agonists in the running include Amgen’s AMG-133 (maridebart cafraglutide), which is in a Phase II study for obese or overweight patients with or without type 2 diabetes. According to Reci, dual and triple receptor agonists, which include GLP-1RAs as one of their mechanisms of action, “will be the way to go for companies developing therapies in the obesity space” and thus “inevitably dominate the obesity market.”

Reci says people who do not experience the optimal benefits from therapies that employ just the GLP-1RA alone may be more suitable candidates for dual agonists. When it comes to obesity, like other indications, therapies are “not a one-size-fits-all,” she adds.

However, for therapies that don't target the GLP-1 receptor at all, patients would have to strictly fail GLP-1RAs before being used to help with weight loss and maintenance.

In addition to already marketed GLP-1RAs, new GLP-1RA therapies by other companies will also likely crowd the market. Pfizer’s GLP-1RA, danuglipron tromethamine, is in a Phase II trial, while Sciwind Biosciences’ GLP-1RA, XW0003 (ecnoglutide) is in a Phase III trial. Results from both trials are expected later this year. Zealand Pharma is also developing a dual agonist, dapiglutide, which targets GLP-1R and GLP-2R, and its Phase II trial readout is expected in 1H this year.

Catalytic events for obesity drugs after 2024

According to Reci, Eli Lily’s retatrutide (LY3437943), a triple agonist targeting GIPR, GLP-1R, and glucagon receptor (GCGR), is demonstrating superior weight loss benefits, specifically a mean percentage body weight loss of up to 24.2% by 48 weeks at the highest dose in a Phase II trial. Reci says these results render it an “overall promising contender in the obesity space.” While late-stage results are expected in the coming years, the drug’s launch may happen in 2027, as per GlobalData forecasts.

In addition to these approaches, others continue to be explored. According to Finer, in the future, the focus for obesity therapeutics will shift toward increasing energy expenditure. One way to do this would be by trying to increase the amount of “brown fat,” which is the sort of fat that can be used to dispose of excess energy, he explains. This has been shown to increase energy expenditure, he adds. However, the challenge lies in finding a method to stimulate brown fat by activating only the associated beta-adrenergic C receptor and not other beta receptors that elevate blood pressure, in order to avoid cardiovascular risks, he notes. Thus, in the future there will be a lot of interest in ways of either targeting the beta receptor, or other ways of increasing brown fat, he concluded.

Update: Paragraphs 8, 13 and 20 have been updated to clarify the correct timelines for the specified trial results. A previous version stated specific months that reflected the end of a particular quarter by when results are expected.