GLP-1 Players Seek to Differentiate in Increasingly Crowded Weight Loss Space

The rise of GLP-1 receptor agonists has changed the therapeutic weight loss industry forever. Now, as more companies jostle to join the lucrative market, touting the highest percentage weight loss may take a back seat to a different competitive edge: overall health outcomes.

Certainly, the efficacy the market leaders boast has generated unprecedented demand. Eli Lilly’s Zepbound elicited up to 21% weight loss, while Novo Nordisk’s Wegovy led to around 15% weight loss in clinical studies over 72 and 68 weeks, respectively. Contenders from Novo and Amgen are similarly positioned. Novo’s CagriSema has shown between 15.7% and 22.7% weight loss at 32 and 68 weeks in Phase III trials, while last year, Amgen’s MariTide demonstrated up to 20% average weight loss at 52 weeks in Phase II studies.

“I think at the end of the day we’re going to have half a dozen or more medicines that will produce 15%–25% weight loss,” Daniel Drucker, an obesity expert at Mount Sinai’s Lunenfeld-Tanenbaum Research in Toronto said on a January call hosted by Guggenheim.

But investors don’t seem satisfied with this, given that both CagriSema’s and MariTide’s readouts have led to disappointment. For Drucker, other health benefits of GLP-1s are what make the drugs most compelling. Additionally, in a landscape where payers are increasingly reluctant to cover these expensive medications only for weight loss, outcomes studies indicating GLP-1s’ uses in other indications, such as sleep apnea, metabolic and kidney disease, reduction of heart attack and stroke risk and more, will become increasingly important, Drucker said.

“If we have all these medicines that are in that ballpark of 20% weight loss, outcomes will drive the discussion for many physicians because we do have patients who have multiple comorbidities.”

Eli Lilly’s Zepbound snagged the first ever FDA drug approval for obstructive sleep apnea in December. This followed Novo Nordisk’s label expansion for Wegovy last spring that made it the first GLP-1 approved to reduce heart health risks in adults who have cardiovascular disease and are obese or overweight.

And neither company is stopping there as they race for supremacy in the space. Both are engaged in myriad clinical trials for a handful of indications, including metabolic dysfunction-associated steatohepatitis (MASH), chronic kidney disease and even Alzheimer’s disease.

Physicians aren’t too focused on using GLP-1s to manage these comorbidities, many of which have reliable standards of care, according to a recent survey of 50 physicians. But Drucker said that while the additional approvals may not significantly expand sales of the products, they will have “a meaningful impact” on how patients and practitioners might perceive the value of a particular GLP-1 drug. Other obesity arena hopefuls seem to agree. Amgen is testing MariTide, a GLP-1 agonist/GIP receptor antagonist antibody peptide-conjugate, for various obesity-related conditions, including heart disease, heart failure, kidney disease and sleep apnea in an upcoming Phase III trial. The primary endpoint of the study, however, remains change in body weight at week 72.

Another company chasing indications outside obesity is Altimmune, which is expecting Phase IIb data in the second quarter of this year on its GLP-1/glucagon dual receptor agonist pemvidutide in MASH. The addition of glucagon drives reduction of liver fat and lipids and preservation of lean muscle mass, according to the company. Altimmune has structured its program so that each pivotal trial focuses on these outcomes in addition to weight loss.

“We are trying to treat not just obesity in general, but actually the comorbidities of obesity,” Altimmune CEO Vipin Garg said at Leerink’s Global Healthcare Conference last week. The company is preparing to forge ahead into a Phase III MASH study while actively seeking a partner for pemvidutide in obesity. By going after a more coverable disease with obesity as a comorbidity, Garg noted that there will be less pressure to lower pricing than is faced by GLP-1s currently on the market for obesity.

In addition to discovering and marketing the additional therapeutic benefits of GLP-1s, the development of oral formulations may also contribute to improved overall health outcomes.

Accessibility and patient persistence remain key issues negatively affecting long-term use of approved GLP-1s, which are administered via subcutaneous injection. Just 15% of patients are still on the drugs after two years, according to a recently conducted real-world study by Prime Therapeutics—though experts expect this to rise to 25% with a “more modern product mix” led by Wegovy and Zepbound.

“It’s not about absolute weight loss; it’s about the patient experience. If they don’t stay on the drug, have we really solved the problem?” Structure Therapeutics CEO Ray Stevens asked.

Oral formulations could help solve this dilemma, Stevens told BioSpace, by increasing accessibility and tolerability by way of easier titration and dosage adjustments.

At the JP Morgan Healthcare Conference in January, Stevens polled attendees on the biggest readout of 2025. Across the entire healthcare industry, he found that, “without hesitation,” respondents said the readout of Lilly’s Phase III trial of orforglipron—the company’s oral GLP-1 contender—will be the biggest news story in 2025. The ATTAIN-2 study, which is testing the pill in patients with obesity and type 2 diabetes, is slated for completion in August.

Meanwhile, Structure is expecting a Phase II readout for its oral GLP-1 aleniglipron in the fourth quarter of this year. Capturing the full spectrum of effects the GLP-1s are providing—including reduced blood pressure, lowered lipids and improved systemic inflammation—is “really critical,” Chief Medical Officer Blai Coll told BioSpace.

“I think there’s a full plethora of effects that can be captured through these studies, and that’s what we are currently doing and planning to do,” Coll said.

Terns Pharmaceuticals is also launching a Phase II study for a weight loss pill, TERN-601, which the company touts as being “well tolerated with no treatment-related dose interruptions, reductions or discontinuations, even with rapid dose titration.” Terns is currently testing its thyroid hormone receptor beta agonist in combination with a GLP-1 in MASH.

Overall, the experts who spoke with BioSpace agreed that high efficacy levels are not the be-all-end-all in this space.

“This idea of maximum weight loss is not really the metric we should be shooting for,” contends Richard Yu, CEO of Abalone Bio, adding that by maximizing for weight loss, companies deprioritize gastrointestinal side effects, which he said are turning out to be a huge factor in patient compliance. Abalone is focused on addressing that gap with its novel approach that targets amylin, potentially alongside a GLP-1, in order to limit off-target interactions and avoid side effects.

Yu said the additional indications being studied and approved for GLP-1s in cardiovascular or inflammation-adjacent conditions are “encouraging,” adding that hitting an upstream node like obesity also results in massive downstream benefits.

But Drucker outlined the challenge such additional trials pose for a small biotech hoping to compete with approved GLP-1s in indications beyond obesity. “That’s a huge spend,” he said, adding most would likely need a well-resourced partner to do so.

In the future, Yu believes the ultimate treatment for obesity will be polypharmacological. Multiple drugs will synergize for greater tolerability with a net benefit that goes beyond weight loss effects to broader health benefits, he said. “Having different levers to pull, that’s going to be an important part of the ultimate solutions.”