GLP-1 receptor agonists are very effective at helping obese and overweight patients lose weight, but reductions in muscle accompany the fat loss. Mounting evidence suggests muscle loss contributes to poor health outcomes, especially for elderly patients, but clinical trials rarely incorporate the quality of weight loss—muscle vs. fat—into their analyses.
Instead, in obesity, primary trial endpoints for glucan-like peptide-1 (GLP-1) receptor agonists usually measure only reductions in body weight or body mass.
Some drug developers are recognizing that body composition matters. Veru Pharmaceuticals, Regeneron and Altimmune, in clinical trials, and Eli Lilly, in preclinical development, are each working on GLP-1 companion therapeutics that either build or conserve muscle mass.
GLP-1 inhibitors were first shown to lower plasma glucose in 1993, but the attention given to fat-vs.-muscle loss is relatively new. Therefore, the FDA, citing its 2007 draft guidance for industry, Developing Products for Weight Management, still does not recommend using changes in either fat mass or lean mass as endpoints in clinical trials for weight loss drugs. As an FDA spokesperson told BioSpace, “To date, we have not identified an adverse clinical impact related to reductions in lean mass.”
Others, including Fatima Cody Stanford, associate professor of medicine and pediatrics at Harvard Medical School, writing in JAMA, consider weight loss alone an inaccurate measurement of a medication’s efficacy. More concerningly, a literature review notes that low muscle mass contributes to a variety of conditions, including mortality.
Measure Body Mass
In managing weight loss, “There’s a balance between having good quality weight loss and having a metabolic reset so patients don’t have to stay on these therapies for too long,” Mayank Mamtani, head of healthcare research at B. Riley Securities, told BioSpace.
Key opinion leaders recognize that, according to Global Data. When interviewed by the industry analyst, they called for changes in the clinical trial design to assess the quality of weight loss so that healthcare providers can better select therapeutic options for their patients. Specifically, they suggested using bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA) scanning to better assess body composition during weight loss.
“To ensure that drug-induced weight loss is caused primarily by a reduction in fat mass, the FDA recommends that sponsors . . . conduct an evaluation of body composition . . . in a representative sample of subjects enrolled in the clinical trials,” the same FDA spokesperson told BioSpace. “DEXA or a suitable alternative” is recommended.
However, “DEXA and MRI measure lean mass, not muscle mass,” Scott Harris, chief medical officer at Altimmune, told BioSpace. “Lean mass includes muscle, but it also includes integuments and other soft tissue. MRI can distinguish muscle from lean mass, but the techniques are not universally accepted, so studies usually report out on lean mass instead.”
“If the trial is not set up with [either DEXA or magnetic resonance imaging—MRI] modalities in advance, lean mass and fat mass cannot be assessed,” Harris said. Altimmune is developing a dual-action therapeutic, pemvidutide, that, in Phase II trials,reduced appetite and preserved lean muscle mass.
Is Muscle Loss a Problem?
As the FDA notes, weight loss involves the loss of both fat and muscle mass, regardless of whether the loss occurs through pharmacotherapy, bariatric surgery or lifestyle changes.
“A reduction in fat-free mass can occur because, with lower fat mass, there is less weight acting on skeletal muscle (leading to reduction in bone and muscle mass), reduced organ size (liver, kidneys and pancreas), and reduced body water weight. These changes in body composition are not considered adverse,” the FDA spokesperson reiterated.
So far, the spokesperson continued, “Safety data from clinical trials of approved weight loss drugs have not demonstrated adverse effects . . . such as increased incidence of falls, or muscle or tendon injuries,” that would be related to loss of lean body mass. Nor have patient-reported outcomes.
But if they aren’t included among the endpoints, are they being tracked?
Expanding Endpoints
“The next wave of innovation will be around muscle preservation,” Mamtani predicted.
Measuring changes in lean mass “is critical for assessing the quality of weight loss,” Harris stressed.“At Altimmune, we believe the quality of weight loss is as important as the quantity. Thus, we took steps to incorporate this into MOMENTUM, our recently completed Phase II obesity trial.”
Additionally, Mamtani called for endpoints to measure weight regain and physical function. “Currently, almost two-thirds of the weight lost comes back when patients quit GLP-1 therapies.” Likewise, he continued, “If you’ve gone from 250 to 200 pounds, has your quality of life improved?”
Several biopharmaceutical companies are building such additional endpoints into their clinical trials for GLP-1 combination therapies.
For example, the percentage change in lean body mass after 112 days is the primary endpoint for Veru’s Phase II dose-finding study of enobosarm, which conserves muscle mass, combined with GLP-1 receptor agonist semaglutide for weight loss.A series of late-stage trials for enobosarm alone indicates significant improvements in muscle mass compared to placebo.
At Regeneron, a small Phase II study for trevogrumab, which builds muscle mass, was enrolling in March. It will be followed by a larger, four-arm study mid-year to compare outcomes for the combination of trevogrumab and semaglutide. That combination will then be compared to outcomes with or without garetosmab, also developed by Regeneron, which preserves muscle. Primary endpoints include the percent change in both total fat mass and body weight. Secondary endpoints include changes in body weight, lean mass, waist circumference and the total lean mass to fat ratio.
Part C of that trial will evaluate patients’ weight maintenance and function. Once patients cease taking semaglutide, “Roughly half will continue on high-dose trevogrumab to see if the weight can stay off,” Ryan Crowe, senior vice president of investor relations and strategic analysis at Regeneron, said at the Barclays Global Healthcare Conference in March. Regeneron did not respond to BioSpace’s requests for updates. Qualitative endpoints will include how well people can complete day-to-day tasks, such as a stand-and-sit test, he added. “That will probably inform what we do next in terms of measuring functional muscle.”
AsMamtani put it, “It’s the Wild West right now” for obesity drugs, “and having all this clinical data is going to be important.” The future of weight loss drugs may not depend on having the best GLP-1 receptor agonist, he said, but rather a combination of therapeutics that cause weight loss while building or conserving muscle or that improve metabolic health or maintain weight loss.
“Almost every serious company in this space is trying to work on that shift,” Mamtani said.
Gail Dutton is a freelance science writer who has covered the biopharma industry since soon after its inception. She can be reached at gaildutton@gmail.com. Follow her on LinkedIn or see more of her work on MuckRack.
