MetaVia CEO says tolerability is key to the long-term success of next-gen obesity drugs if the goal is to improve healthspan.
The remarkable success of GLP-1 receptor agonist drugs for weight loss like semaglutide (Wegovy, Ozempic) and tirzepatide (Mounjaro, Zepbound) has transformed obesity treatment, and inspired a wave of innovation across the pharmaceutical industry. These medications have demonstrated unprecedented efficacy, often achieving weight reductions far surpassing previous interventions, along with broader implications, ranging from cardioprotective to neuroprotective effects. Indeed, the seemingly ever-increasing scope of potential health benefits has led to suggestions that GLP-1s could even be considered “longevity drugs”, an argument supported by recent research indicating that semaglutide may even slow biological aging.
Not only have these drugs become blockbusters for the likes of Novo Nordisk and Eli Lilly, but they have also galvanized the research community and biotech sector to address their limitations and to further push the boundaries of obesity therapeutics. However, if these drugs are ever going to be accepted as healthspan-boosting therapies, the issue of tolerability must be addressed.
Longevity.Technology: Despite their obvious benefits, the first-generation of GLP-1 drugs also come with limitations, including significant costs, frequent injections, gastrointestinal side effects and inconsistent long-term sustainability of weight loss after discontinuation. In response, drug makers are now fiercely competing to develop next-generation therapies that are more convenient, potent and tolerable. And it’s not just Big Pharma, a host of smaller biotechs are joining the race to become the next big thing in weight loss, seeking to deliver even greater weight loss and cardiometabolic improvements by harnessing synergistic effects.
One such company is Cambridge, MA-based MetaVia, which is developing a drug that activates both GLP-1 and glucagon receptors to suppress appetite, reduce nutrient intake and elicit fat burning. Equally as important to the company, though, is ensuring its drugs come with minimal side-effects. To learn more about how MetaVia intends to succeed in this increasingly crowded marketplace, we caught up with CEO Hyung Heon Kim.
Reflecting on the approvals of Novo and Lilly’s GLP-1 drugs, Kim says they changed the world view of obesity, almost overnight.
“Suddenly, obesity was being recognized as a disease – one that involves complex cravings and can benefit from medical treatment,” he recalls. “Novo and Lilly have positioned GLP-1s and obesity drugs as being intended for long-term use, much like type 2 diabetes medications. The logic is that, just as untreated type 2 diabetes eventually requires medication for life, weight regain after stopping treatment makes a case for staying on these drugs indefinitely.”
Long-term GLP-1 use unrealistic
While staying on GLP-1s for life might sound like a reasonable proposition to some, Kim says that the reality of the situation isn’t quite so simple.
“The problem is that many obesity patients starting GLP-1 therapy drop out within the first two or three months, often due to intolerable side effects,” he explains. “After a full year, data shows many more discontinue treatment, whether due to price, reaching their weight goal, or other reasons. So while companies hope for long-term use and broad insurance coverage, current dropout rates suggest that’s unlikely to happen as planned.”
Comparing obesity drugs to cancer therapies, Kim points out that weight loss isn’t a life-or-death situation where severe side effects are justified.
“The real end goal for obesity treatment should be to create a drug that’s effective, well-tolerated, and allows patients to reach their target weight in 6–12 months, and then return to normal life while maintaining their results,” he says. “For those with complications like type 2 diabetes or MASH, the approach may be different, but tolerability is still key.”
Prioritizing tolerability over headlines
As development of new drugs continues apace, the industry continues to emphasize percentage weight lost as a primary measure of success, with headlines frequently hailing ever more dramatic results. Kim argues that, while these figures can be impressive, they obscure an important truth: a therapy that achieves dramatic results in only a subset of patients who can tolerate it is not a universal solution.
“Current GLP-1 drugs do effectively control appetite and cravings, but they come with significant side effects,” he says. “And some of the newer entrants show higher early-stage weight loss, but side effect rates can be extreme – I’ve seen reports of 100% nausea, 80% vomiting in some trials.”
Kim believes that there is an irony in companies working on drugs designed to help patients lose weight and maintain health that make them feel unwell for the duration of their treatment.
“That’s not sustainable,” he says. “When we developed our drug, we prioritized tolerability over headline numbers. Side effects shouldn’t be the price of progress.”
While Kim agrees that some users might tolerate side effects as a necessary evil to lose weight, he suggests that better segmentation of patient groups is needed.
“Severely obese patients may accept significant side effects for major weight loss, but healthier individuals seeking modest weight loss need something far more tolerable,” he says. “And there’s also a middle group – those who need treatment but can’t tolerate current drugs – and we believe that group represents a huge unmet need.”
A dual approach
Aiming to address these challenges, MetaVia, with R&D operations in South Korea and the US, has developed what Kim calls a “true dual agonist”. The company’s obesity drug candidate, DA-1726, is described as a long acting oxyntomodulin peptide analog that can bind and activate both the GLP-1 and glucagon receptors.
“Balancing these receptors is tricky because GLP-1 lowers blood glucose while glucagon raises it,” says Kim. “Our team in Korea tested many ratios and settled one that appears to maximize benefits while controlling side effects. In animal studies, our drug matched or exceeded semaglutide’s weight loss and was comparable to tirzepatide, but the mice ate 25% more food. That’s key: patients need energy to build a healthier lifestyle during weight loss.”
Citing initial data from the company’s ongoing Phase 1 trial, using a fixed 32 mg weekly dose with no titration, Kim says that the drug has delivered up to 6.3% in four weeks, with a mean waist circumference reduction of 1.4 inches in 33 days.
“Crucially, tolerability has been good – some mild GI effects, including a few cases of nausea and vomiting after the first dose, and zero diarrhea,” says Kim. “Also, our starting population had a mean weight of 93 kg, which is lower than many early trials that start with participants weighing more than 100 kg to inflate results. Our goal isn’t to post record numbers by making people sick.”
So why does DA-1726 appear to have fewer side effects than other therapies? Kim suggests it could be down to the drug’s unique peptide sequence.
“We think it may cross the blood-brain barrier less aggressively than others – reducing side effects without weakening the effect, thanks to glucagon’s fat-breaking and energy-boosting action,” he says. “But we need to do more studies to confirm.”
With MetaVia already in Phase 1 trials, the company expects a readout this year, with the goal being to move straight into Phase 2, assuming everything goes to plan.
“The future hinges on tolerability,” says Kim. “The drug that succeeds next will be one that is safer and more tolerable than current late-stage options – something patients can take without most of them experiencing side effects. That’s what will open the market beyond the obesity population and into broader healthspan support.”
