Research: Trevogrumab May Preserve Lean Mass With Semaglutide

New research to be presented at the Annual Meeting of The European Association for the Study of Diabetes (EASD) in Milan, Italy (Sept 28 – Oct 2) and in press with The Lancet* shows that using the trevogrumab to inhibit myostatin, a protein that negatively regulates muscle mass, can reduce lean mass loss during treatment with semaglutide by 50% compared with semaglutide and placebo. The study is by Dr Ofri Mosenzon, Regeneron, Tarrytown, NY, USA, and Dr Julio Rosenstock, University of Texas Southwestern Medical Center, Dallas, TX, USA and colleagues. The study was sponsored by Regeneron, the manufacturer of trevogrumab.

Rapid weight loss – as induced by glucagon-like peptide-1 receptor agonists (GLP-1 RAs) – is accompanied by pronounced muscle loss. Growth differentiation factor 8 (GDF8) is a negative regulator of muscle mass. The researchers explored the impact on semaglutide-induced weight and muscle loss of antibodies blocking GDF8 (trevogrumab, Trevo) and ActA (garetosmab, Gar).

The phase 2 study was performed as a two-part trial in participants with obesity (BMI ≥30kg/m²). In part A, participants treated for 26 weeks with semaglutide (Sema) were randomised to concomitant treatment with placebo (Sema+Pbo), or with high doses of Trevo (Sema+Trevo^200mg; Sema+Trevo^400mg), or with both Trevo and Gar (Sema+Trevo^400mg+Gar^10mg/kg); Part A also included a subsequent Sema withdrawal period, at which participants received Trevo^400mg or placebo for an additional 26 weeks.

Participants in Part B were treated with Sema for 52 weeks and randomised to concomitant treatment with placebo (Sema+placebo) or lower doses of Trevo (Sema+Trevo^25mg; Sema+Trevo^75mg). Primary endpoints were percent change in lean mass (LM), fat mass (FM), and body weight (BW) from baseline to week 26 (Part A; n=599) or week 52 (Part B; n=376). An exploratory MRI substudy (n=76) assessed muscle volume in Part B.

A total of 975 participants were enrolled. Mean age was 49 years and for BMI was 36·7 kg/m²; 64% (627/975) were female. Lean mass was assessed using dual-energy X-ray absorptiometry (DXA) and skeletal muscle using magnetic resonance imaging (MRI). MRI was used to directly measure skeletal muscle volume, isolating the effect on muscle specifically rather than lean mass more broadly.

Part A confirmed substantial decrease in LM in the Sema+Pbo group at week 26 (-6.6%). Adding trevogrumab reduced that loss by roughly half, to about 3.4% with the 200mg dose and 3.9% with the 400mg dose, while the triplet combination with garetosmab reduced it further, to about 2.1%.

At the end of the initial 26-week treatment period, all participants discontinued Sema and were randomised to Trevo^400mg or Pbo for an additional 26 weeks. Among those who originally treated with semaglutide and switched to Pbo for the final 26 weeks, mean percentage change from baseline in LM at week 52 was -2.4%, which was still below baseline. Meanwhile those who switched to Trevo^400mg had a mean percentage change from baseline of +0.4% — a difference of 2.8 percentage points between those treated with trevogrumab and those with placebo. FM and BW remained below baseline in both groups.

Part B LM percent change from baseline to week 52 for Sema+Pbo was -7.3%; LM ETD for Sema+Trevo^25mg versus Sema+Pbo was +1.5% (not statistically significant), and +3.1% (for Sema+Trevo^75mg (statistically significant).

Sema+Trevo^{25mg/75mg/200mg/400mg} was generally well tolerated with a safety profile comparable to Sema+Pbo. Sema+Trevo^400mg+Gar^10mg/kg had a substantially higher incidence of serious adverse events and treatment discontinuations than the other Part A arms. Rates of serious adverse events and treatment discontinuations, captured through each part's primary endpoint (week 26 for Part A, week 52 for Part B), are summarized below:

Further, while the incidence of most commonly reported AEs was generally comparable across treatment arms, muscle spasms occurred more frequently in the Sema+Trevo^400mg+Gar^10mg/kg arm (41%, 61/149) compared to the Sema+Trevo^200mg/400mg arms (8%, 23/299) and Sema+Pbo arms (5%, 7/151). Most of these events were mild to moderate in severity. Two deaths occurred during the study, both in the Sema+Trevo^400mg+Gar^10mg/kg arm; a causal association between treatment and these events has not been identified.

In the MRI substudy of Part B evaluating thigh muscle volume, Trevo co-treatment reduced muscle loss by 69-72% compared to Sema+Pbo.

The authors note that while the combination of trevogrumab and garetosmab had numerically greater lean mass preservation than trevogrumab, the combination was not well tolerated due to the high adverse event rate including muscle spasms in the garetosmab group.

Trevogrumab alone showed greater preservation of lean mass than what has been reported with a GLP-1 RA combined with moderate-to-vigorous-intensity exercise, though differences in trial design preclude direct comparison. Importantly, individuals meeting the imaging component of the sarcopenia definition for low lean mass (participants meeting this definition were older on average, at 53 years, than those who did not, at 46 years) – and therefore presumably with a higher unmet need for muscle preservation – had greater lean mass loss with semaglutide treatment, and numerically greater preservation with trevogrumab co-treatment. In this important subgroup, trevogrumab performed as well as the combination with garetosmab.

Concerns have been raised for some time about the composition of mass people may put back on if and when they stop GLP-1 RA treatment – and that it could be mostly fat and hardly any lean mass. The authors say: "Treatment with Trevo following cessation of GLP-1 RA during the subsequent period of weight regain suggests that Trevo has the potential to help regain the lean mass loss that occurred during weight loss."

They conclude: "These findings strengthen evidence supporting selective myostatin inhibition as an adjunct to GLP-1 RA therapy to improve body composition during pharmacological weight loss with an acceptable safety profile. These results suggest that obesity treatment may be further optimised by considering not only the magnitude of weight loss but also lean mass and skeletal muscle preservation. Whether preservation of muscle during intentional weight loss translates into long-term improvements in physical function, metabolic health, and clinical outcomes, particularly in high-risk individuals vulnerable to functional decline, requires further investigation."