Eli Lilly, Rivus Pharmaceuticals and more target different biological processes in hopes of generating higher-quality weight loss and avoiding metabolic issues.
Mitochondria over abstract background/Taylor Tieden for BioSpace
Recent Phase Ib trial results showed strong weight reduction and a favorable tolerability profile for Zealand Pharma’s investigational amylin analog petrelintide, highlighting that GLP-1 receptor agonists are not the be-all and end-all of weight-loss treatments. Indeed, Zealand is positioning petrelintide as a competitor to GLP-1s, offering better tolerability and higher-quality weight loss, with preserved lean mass.
These data “further support the potential of this long-acting amylin analog to deliver weight loss comparable to GLP-1 receptor agonists with a better patient experience,” Zealand Chief Medical Officer David Kendall said in a statement.
Expected to reach total sales of more than $110 billion by 2033, there isn’t a hotter drug class than GLP-1 receptor agonists. Novo Nordisk brought in around $1.35 billion from Wegovy in the first quarter of 2024, while Eli Lilly’s Zepbound brought in over $517 million. But while these drugs are extremely effective at helping people to lose weight, reductions in weight loss are accompanied by reduction in muscle—something that can be especially problematic for elderly patients.
“GLP-1s are tantamount to starvation,” Shaharyar Khan, chief scientific officer at Rivus Pharmaceuticals, told BioSpace. “You’re reducing caloric input. Your body is now becoming more stingy with its resources. It starts stealing from muscle to feed itself.”
In addition to Zealand, Rivus and several other biopharma companies are pursuing different approaches. Even Novo and Lilly are not satisfied with the success of Wegovy and Zepbound. In January, Novo struck new partnerships with Cellarity and Omega Therapeutics to develop new cardiometabolic drugs, just six months after Lilly’s July 2023 acquisition of Versanis and its lead asset bimagrumab, a monoclonal antibody that aims to reduce fat without affecting muscle mass.
Michael Vallis, a psychologist and associate professor of family medicine at Dalhousie University in Nova Scotia, said he is excited about new scientific approaches to treating obesity. “I would hope that we’ll really start to see a lot more differentiation because in this field, we really do need more and more medical therapies to help people.”
Mitochondrial Uncoupling
Vallis argued that calorie restriction is necessary for weight loss. “The only way you can lose weight is by calorie reduction,” he told BioSpace. “You either reduce your calories by taking fewer calories in . . . or you reduce your calories by burning off so many calories . . . through activity,” increasing energy expenditure.
While GLP-1s go after the energy input side of the equation, Rivus is targeting the energy expenditure side, Khan said, adding that this approach is more sustainable. “It supports your muscle mass. It doesn’t steal from it,” he said. Specifically, Rivus is leveraging the science of mitochondrial uncoupling. Mitochondria are the powerhouse of the cell, Rivus CEO Jayson Dallas explained. “About 20% of the energy that we consume in a day comes from what’s called [mitochondrial] uncoupling,” which forces the cell to selectively consume fat.
David Lau, a professor emeritus of medicine, biochemistry and molecular biology at the University of Calgary, is intrigued by this strategy as well. “Drugs that target mitochondrial uncoupling can increase energy expenditure and lead to weight loss,” he said.
Mitochondrial uncoupling as a weight loss mechanism is itself not a new idea; the drug 2,4-dinitrophenol (DNP), whose weight-loss effects were discovered in 1933, is highly effective but can be deadly because it can cause users to overheat.
Rivus is targeting mitochondrial uncoupling therapeutically with its lead candidate HU6. While not currently being studied for weight loss specifically, HU6 activates mitochondrial uncoupling and leads to fat-specific weight loss, preservation of muscle mass, reduction of liver and visceral fat, improved glycemic control and reductions in oxidative stress and inflammation, according to the company’s website.
HU6 increases resting energy consumption by about 30% at its highest dose, “and it does that 24/7,” Dallas said. “You’re essentially burning 30% more energy than you otherwise would, all day, and therefore you’re burning an extra 3600 to 4000 calories a week in the background.”
Dallas also suggested that the process by which GLP-1s generate weight loss may be too fast. “The more you shock your body, the more it goes into panic mode, and when you’re losing 30% of your body weight in 12 weeks, that’s a crisis metabolically.” With HU6, Khan explained, “we’re able to increase our patient’s metabolism in modest ways, but that over the treatment durations lead to fat-specific weight loss that is very meaningful.”
Trial participants taking HU6 have lost three to four pounds per month—consistently, Dallas said. “There’s no plateau.”
HU6 is currently being investigated in a Phase IIa study for obese patients with heart failure with preserved ejection fraction (HFpEF) and a Phase IIb study for patients with metabolic dysfunction-associated steatohepatitis.
Preserving Muscle Mass
Lilly is also hoping to preserve muscle mass while helping patients lose weight with bimagrumab, an antibody to activin receptors that are found in various tissues around the body. Myostatin and the activin type IIA receptors prevent muscle growth. Bimagrumab attempts to “disinhibit that muscle growth,” explained Ken Attie, vice president of diabetes and metabolic research at Lilly and chief medical officer at Versanis.
Axel Haupt, senior vice president of diabetes and metabolic research at Lilly, told BioSpace that Lilly does not see any safety issues with tirzepatide, the active ingredient in Zepbound. “It’s a normal phenomenon of weight loss that you lose lean body mass,” he said. Patient-reported outcomes show that people are more active and able to do more, “but I think we are aiming to even improve that.”
Bimagrumab also acts on the adipose tissue “to essentially mobilize fat out of the lipid droplets, and hopefully get those calories to be burned off in the fat tissue,” Attie said. By maintaining or growing muscle, people can have a “longer, more maintained weight loss rate,” Haupt added.
Bimagrumab is currently being evaluated in a Phase II study with or without semaglutide (Wegovy), from which Lilly expects results later this year. Attie said the company plans to combine bimagrumab with other obesity meds, the next of which would be Zepbound, and that the drugs could be given separately or combined into one injection.
Lau said the obesity treatment landscape has completely changed over the past five to ten years. “I think we’re now entering into the era that we expect a minimum of 15% to even upwards of 20% to 30% of weight loss,” he said.
In addition to trying to preserve muscle mass, new weight-loss drugs are also looking to avoid the gastrointestinal (GI) side effects that can come with GLP-1s. Lau said drugs that work along the amylin and calcitonin receptor agonist pathway “are associated with less GI side effects than those caused by GLP-1 receptor agonist drugs.”
The newly launched Metsera—which debuted in April with $290 million in financing—is developing a dual amylin/calcitonin receptor agonist, which it is combining with a GLP-1 agonist.
Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.
