Regeneron, Lilly face clinical endpoint challenges in obesity weight loss advancements

As pharmaceutical companies delve further into obesity treatments, there is a growing focus on enhancing the quality of weight loss, rather than just the quantity. Novo Nordisk's Wegovy and Eli Lilly's Zepbound, two leading GLP-1 medications, have been successful in promoting overall weight loss but have also been associated with lean muscle loss. This has prompted researchers to explore combination therapies that not only sustain weight reduction but also preserve muscle mass.

Addressing these concerns, Regeneron Chief Scientific Officer George Yancopoulos, M.D., Ph.D., discussed the company's upcoming trials during a recent earnings call. Regeneron is set to begin testing the effects of adding trevogrumab to Novo Nordisk’s semaglutide (marketed as Wegovy for weight loss) with and without Regeneron's bone disease candidate garetosmab in a phase 2 trial. The primary objective is to determine whether this combination can enhance the quality of weight loss and maintain it even after discontinuing semaglutide.

Yancopoulos emphasized that the simplest regulatory endpoint would be an increase in weight loss. However, he noted that even if this is not achieved, an improvement in the quality of weight loss could be significant. This could be indicated by a higher fat loss while preserving muscle mass, which would involve exploring metabolic parameters similar to those used in diabetes treatments. Wegovy and Zepbound, known as Ozempic and Mounjaro in the diabetes field, respectively, initially emerged in this context.

The central aim of the phase 2 study is to demonstrate the quality of weight loss in terms of fat versus muscle. Yancopoulos believes that preserving muscle while increasing fat loss would be far more beneficial for patients, potentially mitigating long-term adverse effects commonly seen with extensive GLP-1 usage. If successful, this could translate into substantial benefits for patients using this class of medications.

Regeneron plans to enroll patients for the mid-phase trevogrumab trial by mid-2024, slightly later than the previously targeted May. Another trial involving healthy volunteers and a high dose of trevogrumab is already fully enrolled.

Eli Lilly is also pursuing muscle-preserving weight loss therapies. During a recent earnings call, Daniel Skovronsky, M.D., Ph.D., Chief Scientific Officer and President of Lilly Research Laboratories & Lilly Immunology, discussed their development of bimagrumab. Acquired through the $1.9 billion purchase of Versanis Bio in July 2023, bimagrumab employs a different weight loss mechanism compared to incretins but holds potential when used in combination with them.

Bimagrumab, a monoclonal antibody that binds to activin/myostatin type II receptors ActRIIA and ActRIIB, is currently being tested with semaglutide in a phase 2 trial. This study aims to see if bimagrumab can preserve or even increase muscle mass as fat is lost. The primary endpoint is the change in body weight at 48 weeks, with secondary endpoints including changes in waist circumference, total body fat mass, body fat percentage, visceral adipose tissue, lean mass, body mass index, HbA1c, and quality of life.

Lilly aims to observe effects on both adipose tissue and muscle mass, particularly an improved lean-to-fat mass ratio when bimagrumab is combined with an incretin like semaglutide. Skovronsky expressed optimism about the potential benefits of combining these therapies, based on the positive outcomes observed in previous bimagrumab monotherapy studies.

Yancopoulos noted that Regeneron's phase 2 study shares some secondary endpoints with Lilly’s trial, such as changes in physical function, body weight, thigh muscle volume, lean mass, and waist circumference. However, the main focus remains on maintaining muscle mass while achieving weight loss, which could lead to significant patient benefits if successful.