Regeneron, Lilly grapple with clinical endpoints as obesity space moves to improving weight loss

The next frontier for pharma in the obesity space is improving the quality of weight loss. The approved GLP-1 medicines, Novo Nordisk’s Wegovy and Eli Lilly’s Zepbound, are known to cause lean muscle loss as well as the overall weight loss patients are looking for.

But as potential combo drugs inch closer to phase 3, what exactly will the FDA be looking for in terms of a clinical endpoint?

Regeneron Chief Scientific Officer George Yancopoulos, M.D., Ph.D., took a stab at answering the question during his company’s first-quarter earnings call Thursday. Regeneron is about to start testing the addition of trevogrumab to Novo’s semaglutide (marketed for weight loss as Wegovy) with and without Regeneron's bone disease candidate garetosmab in a phase 2 trial. The goal is to see if the combo can improve the quality of weight loss and/or maintain weight loss after stopping semaglutide.

First off, Yancopoulos said they want to see if there is an increase in weight loss with the combo. “And that might be the simplest regulatory endpoint of all,” the executive said.

“If we don't see that, but we see better quality of weight loss, that could be manifested in a variety of ways. Though, we of course recognize that those would perhaps create more complicated ways of being regulated,” Yancopoulos admitted.

If fat loss increases while muscle mass remains consistent, Yancopoulos said there would be metabolic parameters that they could look to for an endpoint, such as maintenance of function, which is used in the diabetes field. That’s of course where drugs like Wegovy and Zepbound got their start; Wegovy is marketed as Ozempic and Zepbound is called Mounjaro in the diabetes field.

“But to us, the most important thing in the phase 2 study is to really just demonstrate the quality of the weight loss in terms of fat versus muscle. Because, ultimately, if you're preserving muscle and increasing the fat loss, it has to be much better for patients and may avoid a lot of catastrophic long-term effects of widespread GLP-1 use,” Yancopoulos said.

“And so if we see that, we think that we have a real opportunity to turn that into real, widespread benefit for patients using this class of drugs.”

Enrollment of patients in the mid-phase trevogrumab trial is expected to begin in mid-2024. Regeneron had previously said May was the goal. Another trial featuring healthy volunteers testing a high dose of trevogrumab is fully enrolled.

Lilly’s Daniel Skovronsky, M.D., Ph.D., chief scientific officer and president of Lilly Research Laboratories & Lilly Immunology, fielded a similar question in the context of his company’s up-and-coming muscle-preserving weight loss med bimagrumab during a first-quarter earnings call on Tuesday.

“Bimagrumab is a very different mechanism of weight loss versus incretins but one that we think could be important in combination with incretins,” Skovronsky said. Lilly acquired bimagrumab through the $1.9 billion buyout of Versanis Bio in July 2023.

The monoclonal antibody binds the activin/myostatin type II receptors ActRIIA and ActRIIB, and is being tested in combination with semaglutide in a phase 2 trial. The study is looking to see if bimagrumab can preserve or increase muscle mass as weight or fat loss occurs. The primary endpoint is the change in baseline in body weight at 48 weeks. Secondary endpoints include change in waist circumference, total body fat mass, body fat percentage, visceral adipose tissue, lean mass, body mass index, HbA1c and quality of life.

Lilly is hoping to see an effect on adipose tissue, or body fat, and muscle mass, specifically an increased ratio of lean-to-fat mass when bimagrumab is added to an incretin med like semaglutide.

“We'll see if weight loss effects on fat tissue stack and we'll see if effects on lean body mass that we're seeing in previous bimagrumab monotherapy studies work in combination with incretin,” Skovronsky said.

Regeneron’s phase 2 study has some similar secondary endpoints as Lilly’s test, such as change in physical function, body weight, thigh muscle volume, lean mass, waist circumference and others. But the maintenance of muscle mass versus weight loss in general remains key, according to Yancopoulos.

“If we see that, we think that we have a real opportunity to turn that into real, widespread benefit for patients using this class of drugs,” he said.