What’s Next for Obesity Therapeutics? Higher Quality Weight Loss

 GLP-1 agonists are set to become the best-selling drugs in 2024, but the biopharma industry isn’t resting on its collective laurels. Instead, some companies are pushing to improve upon the popular obesity medicines with therapies that promote higher-quality weight loss.

There’s no question that the currently approved GLP-1 drugs are highly effective and on a “path to save countless lives and have a major impact,” Paul Titchenell, an associate professor of physiology at the University of Pennsylvania’s Perelman School of Medicine, told BioSpace.

However, clinical studies have shown that up to 40% of the weight patients have lost on Novo Nordisk’s Wegovy (semaglutide) may have come from muscle, which is associated with poor health outcomes, especially among elderly patients.

Still, the rate of muscle mass loss isn’t exactly cause for alarm for the general population taking GLP-1s, Titchenell clarified, but rather provides an opportunity to think about adding another tool to the toolbox. “It’s just thinking about what’s next.”

Quantity Is King but Quality Matters Too

When weight is lost through diet and exercise, it’s generally accepted that about 25% of that loss will be lean and 75% will be fat, said Scott Harris, chief medical officer at Altimmune. In the SUSTAIN 8 trial of Wegovy, that split was 40%-60%, with patients losing an average of 5 lbs of muscle mass for every 7.5 lbs of fat mass.  

Loss of muscle mass is associated with poor outcomes, particularly in the elderly population, where it is already on a steady decline from sarcopenia. For people over 65, additional reduction leads to loss of function, higher rates of bone fractures and even higher rates of mortality, he said. Research also shows that greater lean mass leads to better cardiovascular health in the elderly.

In additional to the risk of losing muscle, weight loss often plateaus for patients after more than a year on GLP-1 drugs, Titchenell said. Though there are many hypotheses as to the reason, one is that the loss of muscle mass contributes to a decrease in resting metabolic rate, he said. Obesity players, including Eli Lilly, Altimmune and Biohaven, are pushing weight loss even further by adding mechanisms to affect energy expenditure.

Another point of contention is the sustainability of weight loss induced by GLP-1 drugs. Clinical trial extension studies reveal a rapid regain of weight if patients stop taking the injection, which is not unexpected, Titchenell said. “Anytime you take a drug affecting a chronic condition, you would expect these things to come back . . . unless there are other modifications put in place.” Titchenell said he believes that preserving more muscle in the weight loss process could result in a more sustainable effect for patients—a prospect the drug development world is eager to take on.

Committing to Higher-Quality Weight Loss

Interest in expanding options in the weight loss space is clear from recent biopharma activity. In July 2023, Eli Lilly dropped close to $2 billion to acquire Versanis and its lead asset bimagrumab. Originally developed by Novartis for muscle disorders, the monoclonal antibody is being trialed for its apparent ability to reduce fat mass without affecting muscle mass.

While Lilly’s GLP-1 drug Zepbound regulates blood sugar and acts on appetite suppression, bimagrumab is a myostatin that targets signaling pathways that keep skeletal muscle from growing too large. A paper published earlier this year in Molecular Metabolism showed the drug induced a 10% increase in lean mass in mice while simultaneously decreasing fat mass. Bimagrumab is currently being evaluated in a Phase II study for efficacy both as a monotherapy and as an add-on therapeutic to semaglutide in obese patients, and analysts are watching for a topline data readout sometime this summer.

Elsewhere, Biohaven plans to initiate a Phase II trial of its own myostatin, taldefgrobep, in obesity in the second quarter of this year. Taldefgrobep is already being tested in a Phase III trial for spinal muscular atrophy, providing an established safety profile.

Mayank Mamtani, head of healthcare research at B. Riley Securities, said he is interested in seeing what the endpoints for these trials will be. With these newer formulations, patients would ideally build muscle while losing fat. Therefore, the traditional endpoint of percentage of total body weight lost by patients is not necessarily indicative of the drug’s efficacy, Mamtani told BioSpace.

This seeming contradiction may cause the drugs to appear inferior on paper when compared to the control arm, Mamtani said, “but you’re losing better quality of weight.”

Altimmune is investigating pemvidutide, a dual mechanism candidate that targets both GLP-1 and glucagon receptors—the former reducing appetite and the latter increasing energy expenditure. While GLP-1 drugs have shown amazing potential for reducing A1C levels, the glucagon component of pemvidutide reduces serum lipids and liver fat and preserves lean mass. The injectable has undergone a Phase II trial in obesity and is in an ongoing Phase IIb trial in metabolic dysfunction-associated steatohepatitis.

Compared to the possible 40% lean mass loss caused by GLP-1 agonists, only 25% of the weight loss induced by pemvidutide has been muscle loss, Harris said, adding that he believes the candidate is the “class leader” in preserving lean mass. In the Phase II obesity trial, the treatment achieved mean weight loss of 15.6% in 48 weeks, in addition to robust reductions of triglycerides, total cholesterol and LDL cholesterol.

Differentiating the Market for Targeted Treatment

“[GLP-1s] are great drugs, but there’s room for further improvement and further segmentation in the marketplace,” Altimmune CEO Vipin Garg told BioSpace.

Garg expects the market to eventually differentiate between mechanisms of action for specific patient needs. While Wegovy and Zepbound have a solid customer base in people with obesity and diabetes, Vipin sees Altimmune’s drug as ideally suited for obese patients with dyslipidemia—the imbalance of lipids such as cholesterol and triglycerides. “There’s going to be room for multiple blockbuster drugs and multiple mechanisms of actions, which is what happens in every therapeutic area,” he said.

Ultimately, Mamtani said he believes the next-gen GLP-1s and other obesity drugs currently in development will have synergistic mechanisms to both preserve muscle and achieve maximum weight loss, perhaps even moving toward sustainable weight loss where the drug can be stopped for periods of time. However, he added, “none of these things are going to replace or supplant the GLP-1 drugs." 

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