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.

•GLP-1 Receptor Agonists: Weighing the Costs, Losing the Gains?

Unexpected side effect of GLP-1RAs

Semaglutide (Ozempic, Wegovy) and Tirzepatide (Mounjaro) have transformed the treatment of type 2 diabetes and obesity. These GLP-1 receptor agonists (GLP-1RAs) are highly effective for weight loss. But here’s the catch: they may also cause a significant loss of muscle mass, not just fat.

GLP-1 Receptor Agonists and Lean Mass Loss

Emerging research shows that 30–40% of the weight lost while using GLP-1RAs comes from lean mass, i.e., muscle, not fat. This is especially concerning for older adults or those already at risk for muscle loss.

This is concerning, as muscle mass plays a critical role in maintaining metabolic health, physical function, and overall quality of life. In addition, lean muscle mass plays an important role in fat loss, by burning fat.  The plateauing of weight loss for patients taking GLP-1RAs is in part attributed to this loss of lean mass.

Weight loss, especially following treatment with GLP-1 receptor agonists is associated with not only loss of fat, but also loss of muscle, i.e., loss of lean mass. Adapted from (https://upload.wikimedia.org/wikipedia/commons/6/61/1025_Atrophy.png) 

The loss of lean mass in patients taking the GLP1 class of drugs is likely multifactorial:

• Reduced caloric intake may contribute, as the body breaks down muscle tissue for energy when in a calorie deficit.

• Hormonal changes induced by GLP-1 agonists could directly influence muscle protein synthesis and breakdown.

  
  

The net result is a loss of muscle tissue, which might offset some of the metabolic benefits gained from fat loss and potentially increase the risk of frailty, especially in older adults.

Myostatin Inhibition as a Protective Strategy

The future may lie in combining fat-burning drugs like Ozempic with muscle-preserving therapies.

Several pharmaceutical and biotech companies are running clinical trials combining GLP-1 therapies with myostatin inhibitors to test this approach—not just in obesity, but in serious diseases like Duchenne muscular dystrophy and spinal muscular atrophy.

Myostatin is a myokine that negatively regulates muscle growth. Myostatin functions by binding to activin receptors on muscle cells, suppressing satellite cell activation and protein synthesis pathways. In animal models and early human studies, inhibition of myostatin induces significant increases in muscle mass and strength.

Antibodies that bind myostatin or block its access to its receptor prevent the ability of myostatin to decrease muscle mass.

Loss of myostatin function can be so profound that it can create "super" humans and animals. Naturally occurring or laboratory generated genetic loss of myostatin leads to animals with substantially greater muscle mass. 

Combining GLP-1RAs with myostatin inhibitors may make it possible to achieve the best of both worlds: substantial fat loss without sacrificing lean mass.

If animal studies and early clinical trials are any indication, we are not far off. 

Summit Therapeutics' Ivonescimab Shows "Positive Trend" in Overall Survival, but Misses Statistical Significance in Key Global Lung Cancer Trial

NEW YORK, NY – May 30, 2025 – Summit Therapeutics (NASDAQ: SMMT) today announced top-line results from its pivotal Phase III HARMONi clinical trial, evaluating its investigational bispecific antibody, ivonescimab, in combination with chemotherapy for patients with EGFR-mutant non-small cell lung cancer (NSCLC) who have progressed after EGFR TKI therapy. While the trial met its primary endpoint of progression-free survival (PFS) with a statistically significant and clinically meaningful improvement, the other co-primary endpoint, overall survival (OS), did not achieve statistical significance, although it showed a positive trend.

The HARMONi trial demonstrated that ivonescimab plus chemotherapy significantly reduced the risk of disease progression or death, with a hazard ratio of 0.52 (95% CI: 0.41 – 0.66; p<0.00001). This robust PFS benefit was consistent across both Asian and Western patient populations, highlighting the potential global impact of ivonescimab.

After previously showing PFS that bested the stalwart Keytruda, it was with great anticipation that Summit Therapeutics reported overall survival for their HARMONi trial for EGFR-mutant non-small cell lung cancer (NSCLC) who have progressed after EGFR TKI therapy. 

While the trial successfully met its primary endpoint of progression-free survival (PFS), the other co-primary endpoint, overall survival (OS), showed a positive trend but did not achieve statistical significance, with a hazard ratio of 0.79 (95% CI: 0.62 – 1.01; p=0.057). This did not cross the predefined threshold for statistical significance.

The FDA has previously indicated that a statistically significant overall survival benefit is a necessary factor to support marketing authorization for ivonescimab in this indication, which will be a key consideration for Summit's future regulatory filing plans.

Despite the miss on statistical significance for overall survival in this initial analysis, the clinically meaningful progression-free survival benefit and the positive trend in overall survival still represent a significant development for patients with this challenging form of lung cancer.

Currently, there are no FDA-approved regimens that have demonstrated a statistically significant overall survival benefit in this specific patient setting.

The safety profile of ivonescimab in combination with chemotherapy was reported as acceptable and manageable, with no new safety signals identified. Grade 3 or higher treatment-emergent adverse events were observed in 56.9% of patients in the ivonescimab arm versus 50.0% in the chemotherapy alone arm.

Summit Therapeutics plans to continue following patients for long-term outcomes to further mature the overall survival data. The full data set for HARMONi is expected to be presented at an upcoming major medical conference later this year, which will provide further insights into the potential of ivonescimab in this patient population.

This announcement comes after Summit Therapeutics' partner, Akeso, previously reported positive interim overall survival data for ivonescimab from the HARMONi-2 study in China, demonstrating a clinically meaningful trend favoring ivonescimab monotherapy over pembrolizumab in PD-L1 positive advanced NSCLC. The HARMONi-2 analysis showed a hazard ratio of 0.777 at 39% data maturity.

Investors will be closely watching for further updates from Summit Therapeutics as they navigate the regulatory path forward, particularly concerning the overall survival data which remains a critical component for potential marketing authorization in key global markets.

Implications for other bispecifics with PDL1/VEGF

Summit Therapeutics' ivonescimab miss on overall survival (OS) in the HARMONi trial has important implications for other PD-L1/VEGF bispecific antibodies and the broader oncology landscape.

1. OS Remains the Gold Standard for Regulatory Approval and Clinical Practice:

• FDA Scrutiny: The FDA's stance, reiterated by Summit, that a statistically significant OS benefit is generally required for approval in this indication.

• Physician Acceptance: Oncologists often prioritize therapies that demonstrate a clear OS advantage, especially in advanced disease settings. The lack of statistical significance for OS might temper enthusiasm and uptake, at least until further, more mature OS data becomes available.

• Competitive Landscape: The current standard of care in NSCLC, particularly for PD-L1 positive or negative disease in combination with chemotherapy, often involves regimens that have shown OS benefits New agents need to demonstrate competitive OS to displace these established treatments.

2. Challenges in Translating PFS to OS with Bispecifics:

• Subsequent Therapies: One of the most significant challenges in demonstrating an OS benefit in later-line settings (like EGFR TKI-resistant NSCLC) is the impact of subsequent therapies. Patients who progress on the control arm often receive other effective treatments, which can "dilute" or mask the OS benefit of the investigational drug in the earlier line. This is a common issue in oncology trials, especially with the increasing availability of effective subsequent lines of therapy.

• Toxicity and Treatment Duration: While ivonescimab’s safety profile was reported as manageable, any drug, especially a bispecific with dual mechanisms, carries potential for adverse events. If toxicities, even manageable ones, lead to treatment discontinuations, it can impact the ability to deliver sustained anti-tumor effect, which is crucial for OS. The balance between efficacy and tolerability for long-term treatment is key.

3. Implications for Other PD-L1/VEGF Bispecific Antibodies in Development:

• Higher Bar for OS: The ivonescimab results raises the bar for other PD-L1/VEGF bispecifics. These programs will likely face increased scrutiny regarding their OS data and will need to demonstrate clear and statistically significant OS benefits to gain regulatory approval and market traction.

• Focus on Patient Selection and Early Lines: Developers might increasingly focus on patient populations where the unmet need is higher or where the impact of subsequent therapies is less confounding (e.g., first-line settings, or specific biomarker-driven subgroups).

• Different Formats and Fc Regions: The design of bispecific antibodies, including the presence or absence of an Fc region (which impacts half-life and effector functions), could become a more prominent discussion point. Ivonescimab has Fc-silencing mutations, in order to reduce certain immune-related adverse events. Other bispecific formats might have different safety and efficacy profiles that could influence OS.

4. Continued Promise Despite the OS Miss (for now):

• Strong PFS is Still Valuable: It's important to remember that a statistically significant and clinically meaningful PFS benefit is still a strong positive. For patients who have progressed on EGFR TKIs, delaying disease progression is a significant outcome, even if OS isn't yet statistically improved. This could still lead to conditional approvals or specific indications where PFS is deemed sufficient.

• Longer Follow-up: As Summit noted, the OS data is not yet fully mature, especially for Western patients. Longer follow-up could eventually reveal a statistically significant OS benefit.

• Different Settings: Ivonescimab has shown positive results in other NSCLC settings (e.g., first-line squamous NSCLC head-to-head against a PD-1 inhibitor), suggesting its potential is broad. The implications of this specific OS miss might be limited to this particular patient population (EGFR-mutant, post-TKI).

In summary, Summit's HARMONi OS data highlights the inherent challenges of translating strong PFS benefits into statistically significant OS improvements in certain oncology settings, particularly with the confounder of subsequent therapies. While the strong PFS for ivonescimab is encouraging, the OS miss places a greater burden on the company to provide more mature data or explore alternative regulatory pathways. For the broader class of PD-L1/VEGF bispecifics, it reinforces the need for robust OS data to achieve widespread adoption and regulatory success.

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