Old targets are also getting renewed attention. One example is the cannabinoid receptor CB1, originally pursued after researchers discovered its role in marijuana-induced appetite stimulation, commonly known as the munchies. In the late-2000s, a drug designed to counteract this effect was briefly sold in Europe as a weight-loss therapy. But inhibiting cannabinoid receptors in the brain was associated with an increased risk of depression, anxiety and suicidal thoughts in some people. The drug, known as rimonabant, was withdrawn from the market after less than three years, and rival companies abandoned similar candidates.


But George Kunos, a neuroendocrinologist at the US National Institute on Alcohol Abuse and Alcoholism in Bethesda, Maryland, never gave up on the cannabinoid-blocking strategy. Around 15 years ago, his team and others demonstrated in rodents that much of the anti-obesity effects of CB1 inhibitors came from metabolic pathways in the liver, muscle, pancreas and other organs outside the brain. If a drug such as rimonabant could be chemically modified to prevent it from crossing the blood–brain barrier, it might deliver metabolic benefits without the serious side effects.


Kunos’s laboratory created such a next-generation cannabinoid blocker, now known as monlunabant and being advanced by Novo Nordisk. Last year, phase II trial results indicated that monlunabant can still cause anxiety, irritability and sleep disturbances. Even so, Kunos predicts that drug makers will “arrive at a dose that causes significant weight reduction with acceptable levels of side effects”.


Big flex

A variety of other therapeutic tactics are being explored. For instance, an agent that blocks food absorption in the intestines and another that inhibits an enzyme that metabolizes fat are in phase II trials. But muscle-directed therapies such as bimagrumab are garnering the most industry interest, in large part because around one-third of the weight reduction in individuals taking semaglutide or tirzepatide comes from the loss of muscle, not fat.


The depletion of muscle mass raises cosmetic concerns and can reduce strength, mobility and overall physiological health. Muscle also has a crucial role in glucose regulation and energy expenditure. Muscle loss is therefore “a major impediment to continued, sustainable weight loss”, says Melanie Haines, an endocrinologist at Massachusetts General Hospital in Boston who studies bimagrumab.


A high-angle view of a young girl sitting on a chair and injecting medicine into her left leg

Oral obesity drugs could be an alternative to current once-weekly injectable treatments.Credit: Joe Buglewicz for The Washington Post/Getty


People who take GLP-1 drugs are now advised to eat protein-rich foods and to engage in resistance training to preserve muscle. But a drug directed at myostatin signalling — the main molecular brake on muscle growth — could offer a more practical and potent solution, says Se-Jin Lee, a muscle biologist at the The Jackson Laboratory for Genomic Medicine in Farmington, Connecticut. Lee, who first discovered myostatin in the 1990s, consults for several drug companies.


The experimental drug that Cook took, bimagrumab, works in just this way. It blocks a receptor through which myostatin and related proteins inhibit muscle growth and promote fat retention. After taking the therapy alongside semaglutide for close to a year, Cook dropped nearly 18 kilograms of fat while gaining one kilogram of muscle. The main downside, he says, was that he experienced sporadic cramps and spasms — in the groin, shoulder, even the muscles at the back of his tongue.


Now that he is off the drugs entirely, Cook has regained some fat. But he remains more than 10% below his peak weight, and his muscle mass has held relatively stable. “For me, it was a life-changing experience,” Cook says.


Bimagrumab began as a drug candidate for age-related muscle loss and other conditions that deplete muscle. Trials show it increased muscle mass with no major safety issues, but the drug proved no better than a placebo in functional tests of handgrip strength and walking ability. Novartis, a pharmaceutical company in Basel, Switzerland, discontinued the drug’s development in 2017.


Still, two senior Novartis executives remained steadfast in their confidence of bimagrumab, which improved measures of blood sugar control and showed promise for reducing fat in small trials of people at risk of or already living with type 2 diabetes. The drug was “very potent and actually quite safe”, says Mark Fishman, Novartis’s former president of biomedical research. His team just needed to find the right reason to use it.


Fishman is now at Harvard University in Cambridge and leads the scientific advisory board at Aditum Bio, an investment firm in Oakland, California, which he cofounded with former Novartis chief executive Joe Jimenez. In 2021, Aditum helped to launch a company focused on repositioning bimagrumab as a weight-loss solution. (That start-up was later acquired by Eli Lilly, which has yet to release results from the now-completed 500-person trial that Cook joined.)


Other companies are following the bimagrumab playbook, resurrecting shelved muscle-targeted therapies that were originally developed for conditions unrelated to weight loss and exploring new mechanisms to promote muscle growth and metabolic health. “Everyone wants to dust off their myostatin compounds from the shelf to see if they can repurpose them for the obesity landscape,” says Paul Titchenell, a molecular metabolism researcher at the University of Pennsylvania Perelman School of Medicine in Philadelphia.


How important muscle preservation will be for long-term weight management is still an open question. According to US health-care records and insurance claims, most people who start taking semaglutide or tirzepatide for weight loss end up quitting treatment in a year or two, leading weight to rebound — with most weight regained in the form of fat.


Repeat that cycle a few times, as people go on and off weight-loss drugs, and the cumulative loss of muscle could have lasting consequences. “We may be creating a generation of people with sarcopenia,” says Carla Prado, a nutrition researcher at the University of Alberta in Edmonton, Canada, using the medical term for a condition marked by a progressive loss of muscle mass and strength.


But for now, says Caterina Conte, an obesity specialist at the San Raffaele Roma University in Rome, “the concern is not supported by the evidence”. (Prado and Conte published opposing commentaries last year debating the role of muscle preservation in obesity treatments5,6.)

Many proponents of muscle-targeted therapies acknowledge the uncertainties. “We’re pushing into territory that really hasn’t been studied before,” says Steven Heymsfield, an obesity specialist at the Pennington Biomedical Research Center in Baton Rouge, Louisiana, who has been involved in bimagrumab and other weight-loss medication trials. Either way, Heymsfield and others expect muscle-directed agents to become part of a diverse pharmacopoeia for treating people with obesity and related health challenges.


Semaglutide and tirzepatide won’t be alone for long, notes Boaz Hirshberg, senior vice-president and head of the internal medicine clinical development unit at Regeneron, which has muscle-targeted therapies in the works. As other options arrive, he says, “we can actually start thinking about how to tailor treatment based on patients’ needs”.