Semaglutide’s Shortfall Gets a Fix? Regeneron COURAGE Data Suggests Muscle-Sparing Myostatin Inhibition

Interim Results from Ongoing Phase 2 COURAGE Trial Confirm Potential to Improve the Quality of Semaglutide (GLP-1 receptor agonist)-induced Weight Loss by Preserving Lean Mass

SUMMARY: Regeneron has released interim results from its ongoing Phase 2 COURAGE trial, which investigates novel combinations of semaglutide (a GLP-1 receptor agonist) with trevogrumab (an anti-GDF8/anti-myostatin antibody) and garetosmab (an anti-activin A antibody) for obesity treatment.

The trial's interim analysis, conducted when 50% of patients reached week 26, showed that approximately 35% of semaglutide-induced weight loss was due to lean mass loss. However, combining semaglutide with muscle-preserving antibodies, specifically trevogrumab with or without garetosmab, helped preserve lean mass while increasing fat mass loss. Patients in the combination groups preserved more lean mass and experienced greater fat loss compared to semaglutide alone.

Study Overview

Regeneron Pharmaceuticals, Inc.

Trial Name: COURAGE (Phase 2)Date of Interim Results Release: June 2, 2025Purpose: Evaluate whether combining semaglutide (GLP-1 receptor agonist) with trevogrumab (anti-GDF8/myostatin) ± garetosmab (anti-activin A) can preserve lean mass during weight loss in obese patients.

Key Findings from Interim Analysis (50% patients at Week 26)

Protection against Semaglutide induced lean mass loss (Negative Outcome of GLP-1 Monotherapy)

• 35% of the total weight lost from semaglutide alone came from lean mass (muscle), a concerning outcome for long-term health.

Combination Therapy Benefits

• Combining semaglutide with trevogrumab preserved 50-80% of lean mass that would otherwise be lost.

• Also increased fat mass loss compared to semaglutide alone.

Group	% Lean Mass Loss	% Fat Mass Loss	% Lean Mass Preserved vs Mono	% Fat Loss Increase
Semaglutide (mono)	34.5%	66.3%	—	—
+ Low-dose Trevogrumab	17.0%***	78.1%	50.8%	+17.8%
+ High-dose Trevogrumab	16.8%***	76.3%*	51.3%	+15.1%
+ High-dose Trevogrumab + Garetosmab (Triplet)	6.6%***	84.4%***	80.9%	+27.3%

Total Body Weight Loss at Week 26

Semaglutide monotherapy:        -10.4%

 +Low-dose Trevogrumab:         -9.9%

+ High-dose Trevogrumab:       -11.3%

+Triplet group lost the most:     -13.2%

⚠️ Safety Data (Week 26)

Group	Any TEAE	Severe TEAE	Serious TEAE	Discontinuation due to TEAE
Semaglutide only	64.9%	2.0%	0.7%	4.6%
Low-dose combo	68.2%	1.4%	0.7%	4.1%
High-dose combo	68.2%	3.3%	1.3%	10.6%
Triplet	77.2%	10.1%	6.7%	28.3%

The triplet combo had higher tolerability issues.

Scientific and Clinical Significance

• The results validate the role of GDF8 (myostatin) and activin A inhibition in sparing muscle while enhancing fat loss under GLP-1 therapy.

• Potential to improve quality of weight loss — not just quantity — by preserving muscle mass, important for long-term health.

• Patients have entered the weight-maintenance phase (Week 26–52) using trevogrumab or placebo.

• Full dataset expected later in 2025 to guide future dosing and trial design.