Eli Lilly and Novo Nordisk are the established titans of the weight loss market with blockbuster drugs that can help patients quickly shed around a quarter of their total body weight. But as the obesity field grows and drugmakers push to outdo one another in the clinic, some companies are developing candidates that deliver what they consider higher-quality weight loss.
Studies indicate that nearly 40% of the weight lost while taking GLP-1 drugs can come from muscle mass, which is drawing concern from clinicians about the health risks of long-term use.
Significant muscle loss can trigger downstream issues, including reduced physical function, mobility and strength, which can increase the risk of falls and broken bones, according to the Cleveland Clinic.
Biohaven is in the hunt to overcome that challenge and is developing taldefgrobep alfa, an experimental phase 2 myostatin-activating pathway inhibitor that targets both fat loss and muscle growth.
T-alfa, which Biohaven licensed from Bristol Myers Squibb in 2022, works by interrupting myostatin signaling through activin type 2 receptors on the surface of both skeletal muscle and adipose tissue.
By blocking myostatin, a natural protein that prevents excessive muscle development, T-alfa essentially removes the brake on muscle growth, allowing mass to increase. The treatment also works on fat by reducing storage and creating a reduction in adipose tissue — a process known as lipolysis.
"That combination [can lead to] a higher quality shift in overall body composition," said Dr. Pete Ackerman, senior vice president of clinical development at Biohaven, who's been working on the T-alfa obesity program for almost four years. Despite Lilly and Novo’s hold on the obesity market, Ackerman believes there's room for something new.
"Not everyone is looking to lose 25% or 30% of their total body weight," Ackerman pointed out, and not all body mass carries the same health risks.
"The treatment of overweight and obesity is more than just reducing excess mass,"
Ackerman added. "It's [reducing] excess abnormal or ectopic fat — which is the primary pathological tissue."
Ectopic fat, the buildup of triglycerides in tissues and organs not meant to store fat, can disrupt cellular and metabolic processes, raising the risk of other serious health issues like type 2 diabetes, heart disease, high blood pressure and stroke.
Skeletal muscle, on the other hand, enables essential activities and supports metabolic health, as well as being associated with a lower risk of diabetes.
"Muscle is much more than a mechanical engine," Akerman said. "It's the largest metabolic organ in the body and a major reservoir of glucose."
Making the case for less
Although Biohaven's myostatin inhibitor could lead to meaningful improvements in body composition, it could be a hard pitch in a market that now expects 20% or more weight loss from an obesity drug. But Ackerman pushed back on that notion.
"Are patients losing 25%? No," he said. "But, of that 5% to 10% that is being lost, the quality of [their] body composition is significantly better. That's the play we're [pulling] here."
The FDA's published draft guidance on chronic weight management proposes that a drug achieve a total body weight reduction of at least 5% within a year to be considered effective, which is a bar that Ackerman says T-alfa can clear.
Ackerman suggests ectopic fat loss, muscle preservation and metabolic improvement may be more beneficial for long-term outcomes than the number on the scale, especially for patients who are already losing muscle as they age.
"Obesity is heterogeneous in its nature," Ackerman said. "There are different subtypes. And that level of complexity requires different treatment modalities to meet the needs of a very large patient population. Not only can a drug in this class be successful — it's absolutely needed."
Myostatin inhibitors: a growing class
Although T-alfa failed to significantly improve motor function in patients with spinal muscular atrophy in 2024, it helped cut total body fat and improve lean muscle mass and bone density compared to placebo. Biohaven is now evaluating T-alfa as a monotherapy delivered as either a weekly or monthly injection, with topline data expected in the second half of the year. A positive readout would open the door to combination studies with a GLP-1 drug, Ackerman said, which could lead to greater weight loss results.
But Biohaven isn't the only biotech taking the muscle-sparing approach. Lilly, Regeneron Pharmaceuticals and Scholar Rock are all developing anti-myostatin antibodies that aim to build lean muscle while helping patients trim fat. They are also all testing their assets in combination with approved weight loss drugs.
Lilly's bimagrumab, acquired from Versanis Bio in 2023 for nearly $2 billion, is being tested in a phase 2 study alone and in combination with the blockbuster GLP-1 Zepbound. Lilly has also partnered with Chinese drugmaker Laekna to develop a similar drug in early testing.
Scholar Rock's apitegromab is also being studied in combination with Zepbound. Its mid-stage readout showed that patients preserved more lean mass with the combination treatment than on Zepbound alone.
Regeneron is testing trevogrumab alongside Novo’s GLP-1 Wegovy and a second experimental therapy, garetosmab, in a three-part phase 2 study expected to be completed in October.
"We need different mechanisms to optimize the care of people living with obesity," Ackerman concluded. "The current drugs that are available — as remarkable and valuable as they are — are not the single answer.”
