Description

Survodutide: A Novel Dual Glucagon/GLP-1 Receptor Agonist for Metabolic Disorders

Survodutide (BI 456906) represents a promising advancement in the treatment of metabolic disorders as a novel dual glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) agonist. This investigational peptide has demonstrated remarkable efficacy in clinical trials for both obesity and metabolic dysfunction-associated steatohepatitis (MASH), with a mechanism of action that differentiates it from existing single-receptor therapies. Currently in late-stage clinical development by Boehringer Ingelheim in collaboration with Zealand Pharma, survodutide’s dual-action approach shows potential to address multiple aspects of metabolic dysfunction simultaneously.

Molecular Structure and Mechanism of Action

Survodutide represents a distinctive approach to metabolic regulation through its unique molecular structure and dual-receptor targeting mechanism.

Chemical Structure

Survodutide is a 29-amino acid peptide specifically designed based on the glucagon sequence with strategic modifications that enhance its therapeutic properties:

·         Molecular formula of C192H289N47O61 with a molar mass of 4231.692 g·mol−1^[1]

·         Contains an unnatural amino acid (1-aminocyclobutane-1-carboxylic acid or Ac4c) in position 2 to enhance proteolytic stability^[2]

·         Features a glycine-serine linker at position 24 carrying a C18 di-acid that mediates albumin binding to extend the half-life^[2]

·         Unlike other dual GLP-1/glucagon dual agonists, survodutide is a glucagon analog rather than an analog of oxyntomodulin^[1]

These structural modifications were developed through extensive optimization to create a balanced dual GCGR/GLP-1R agonist with the desired pharmacological profile.

Dual Receptor Targeting

The central mechanism distinguishing survodutide from existing metabolic therapies is its simultaneous activation of two complementary receptor systems:

·         Activates both the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R)^[3][4][5]

·         The balanced dual-receptor agonism was carefully calibrated during the development process^[4]

·         Survodutide was selected as the clinical candidate based on its balanced dual GCGR/GLP-1R pharmacology, specifically engaging the GCGR for robust body weight-lowering effects^[4]

·         This dual activation leverages the body weight reduction and glycemic control of GLP-1 receptors while adding the beneficial effects of glucagon receptors present in the liver^[5]

Physiological Effects

The simultaneous engagement of both receptors produces several complementary effects that contribute to survodutide’s therapeutic benefits:

·         Increases energy expenditure through GCGR activation, creating a key differentiator from GLP-1R agonists alone^[6][7]

·         Reduces food intake through GLP-1R activation^[5]

·         Potentiates glucose-stimulated insulin secretion from rodent and human islets^[6]

·         Inhibits glycogen synthesis as demonstrated in preclinical studies^[6]

·         Produces superior body weight reduction compared to GLP-1R agonists alone, attributed to increased energy expenditure^[6]

In preclinical studies, survodutide achieved superior body weight-lowering compared to a maximally effective dose of the GLP-1R agonist semaglutide (32% vs. 27%; p<0.05), with the difference attributed to increased energy expenditure^[6].

Pharmacokinetic Profile

Survodutide demonstrates favorable pharmacokinetic properties that support its clinical application across different patient populations.

In clinical trials, survodutide has shown:

·         A half-life of more than 100 hours, supporting convenient once-weekly administration similar to semaglutide^[7]

·         Dose-proportional increases in exposure (Cmax and AUC values)^[7]

·         Similar pharmacokinetics in people with cirrhosis compared to healthy individuals, with 90% confidence intervals for adjusted geometric mean ratios spanning 1^[8]

·         No requirement for pharmacokinetic-related dose adjustment in people with compensated or decompensated cirrhosis^[8]

These pharmacokinetic properties make survodutide suitable for once-weekly subcutaneous injection, enhancing convenience and potentially supporting patient adherence to treatment.

Clinical Development and Efficacy

Survodutide has demonstrated impressive efficacy across multiple clinical trials in different indications, with particularly strong results in obesity and MASH.

Obesity Management

Phase 2 trials have established survodutide’s significant efficacy for weight reduction:

·         In a 46-week randomized, double-blind, placebo-controlled dose-finding phase 2 trial, survodutide demonstrated dose-dependent weight loss with mean changes from baseline of -6.2% (0.6 mg), -12.5% (2.4 mg), -13.2% (3.6 mg), and -14.9% (4.8 mg) compared to -2.8% with placebo^[9]

·         In June 2023, Boehringer Ingelheim reported phase 2 data showing weight loss of approximately 20% at 46 weeks, with weight loss not yet plateaued, suggesting potential for greater efficacy with longer treatment duration^[10]

·         Survodutide’s superior weight-reducing effects compared to GLP-1R agonists alone are attributed to its dual mechanism, which adds increased energy expenditure to the appetite-suppressing effects of GLP-1R activation^[6][7]

These results position survodutide as a potentially powerful tool for obesity management, with efficacy that may exceed current single-receptor therapies.

Metabolic Dysfunction-Associated Steatohepatitis (MASH)

Survodutide has shown particularly promising results for MASH, a serious liver condition often associated with obesity:

·         In 48-week phase 2 trial results announced in July 2024, 83% of patients treated with survodutide achieved significant biopsy-proven improvement in MASH without worsening of fibrosis stages, compared to only 18.2% with placebo (difference of 64.8%, p<0.0001)^[10]

·         The treatment also demonstrated improvements in secondary endpoints including reduced liver fibrosis and lower liver fat content as measured by magnetic resonance imaging^[10]

·         Boehringer Ingelheim believes survodutide’s “true differentiator is the action of the glucagon receptor agonism which works directly on the liver,” making it particularly valuable for liver-related metabolic conditions^[10]

·         A trial in people with cirrhosis showed survodutide may improve liver-related non-invasive tests, supporting its investigation for MASH-related cirrhosis^[8]

These results suggest survodutide may offer significant benefits for patients with MASH, potentially addressing both the metabolic and fibrotic components of the disease.

Additional Applications

Beyond obesity and MASH, survodutide has demonstrated potential benefits for several related conditions:

·         Type 2 diabetes: A phase 2 trial with survodutide in people with type 2 diabetes on stable metformin background therapy showed dose-dependent decreases in blood sugar (HbA1c) after 16 weeks^[5]

·         Cirrhosis: Survodutide appears generally tolerable in people with compensated or decompensated cirrhosis, with reductions in liver fat content, liver stiffness, liver volume, body weight, and other hepatic and metabolic disease markers observed after 28 weeks of treatment^[8]

·         Cardiovascular risk: Currently being evaluated in patients with cardiovascular disease, chronic kidney disease, or with risk factors for cardiovascular disease^[5][11]

Safety Profile

Survodutide’s safety profile appears consistent with other peptide therapies in this class, with predominantly gastrointestinal adverse events.

In clinical trials, survodutide has shown:

·         Adverse events occurred in 91% of survodutide recipients versus 75% of placebo recipients in the phase 2 obesity trial^[9]

·         Gastrointestinal effects were most common, occurring in 75% of survodutide recipients versus 42% of placebo recipients^[9]

·         In single-dose cohorts, drug-related adverse events occurred in ≤25.0% of those with cirrhosis after single doses, and 87.5% in multiple-dose cohorts over 28 weeks, similar to rates in healthy individuals^[8]

·         Survodutide is generally tolerable in people with compensated or decompensated cirrhosis^[8][3]

·         Expert opinion indicates the drug is generally well tolerated, with primarily manageable gastrointestinal adverse effects^[3]

These findings suggest a safety profile similar to other medications in this class, with most adverse events being mild to moderate and primarily affecting the gastrointestinal system.

Ongoing Clinical Trials

Survodutide is currently being evaluated in multiple phase 3 clinical trials across different indications:

Obesity Trials

·         SYNCHRONIZE-1: A phase 3 trial for people with obesity (BMI ≥30 kg/m²) or overweight (BMI ≥27 kg/m²) with at least one obesity-related complication but without type 2 diabetes^[12]

·         SYNCHRONIZE-2: A phase 3 trial for people with BMI ≥27 kg/m² and type 2 diabetes^[12]

·         SYNCHRONIZE-CVOT: A cardiovascular outcomes trial evaluating survodutide in adults with BMI ≥27 kg/m² and established cardiovascular disease, chronic kidney disease, and/or at least 2 weight-related complications or risk factors for cardiovascular disease^[11]

·         Regional trials: SYNCHRONIZE-JP (Japan) and SYNCHRONIZE-CN (China) for specific populations of people living with obesity^[5]

MASH Trials

·         LIVERAGE: Investigating survodutide in adults with MASH and fibrosis stages 2 or 3^[5]

·         LIVERAGE-Cirrhosis: Evaluating survodutide in people with compensated MASH cirrhosis (stage 4)^[5]

These comprehensive phase 3 programs will provide crucial data on survodutide’s efficacy and safety across different patient populations and indications.

Conclusion

Survodutide represents a significant advancement in the treatment of metabolic disorders through its novel dual glucagon/GLP-1 receptor agonist mechanism. By simultaneously targeting both receptors, survodutide appears to offer advantages over single-receptor therapies, particularly in terms of weight reduction and improvements in liver health for patients with MASH.

The impressive phase 2 results, showing up to 20% weight loss and 83% MASH improvement, position survodutide as a potentially best-in-class treatment for these conditions. The ongoing phase 3 clinical trial program across multiple indications will further define survodutide’s role in treating obesity, MASH, and related metabolic disorders.

As Boehringer Ingelheim works to “move forward as quickly as possible” with development, survodutide may soon offer an important new therapeutic option for patients struggling with these challenging metabolic conditions. If approved, survodutide would be the first GLP-1R/GCGR dual agonist to reach the market, potentially expanding the treatment landscape for metabolic disorders with its unique dual-receptor mechanism.

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1.       https://en.wikipedia.org/wiki/Survodutide 

2.      https://pmc.ncbi.nlm.nih.gov/articles/PMC9679702/ 

3.      https://pubmed.ncbi.nlm.nih.gov/39663847/  

4.      https://dom-pubs.onlinelibrary.wiley.com/doi/10.1111/dom.15551  

5.       https://www.zealandpharma.com/pipeline/survodutide/       

6.      https://careers.boehringer-ingelheim.com/biberach/what-we-do/publications/articles/bi-456906-structural-properties-and-pharmacology-of-the-novel-glucagon-and-glucagon-like-peptide-1-receptor-gcgrglp-1r-dual-agonist     

7.       https://doi.org/10.1111/dom.14948   

8.      https://pubmed.ncbi.nlm.nih.gov/38857788/     

9.      https://pubmed.ncbi.nlm.nih.gov/38330987/  

10.   https://www.biospace.com/boehringer-s-obesity-candidate-shows-strong-potential-in-mash   

11.    https://www.jacc.org/doi/10.1016/j.jchf.2024.09.004 

12.   https://pubmed.ncbi.nlm.nih.gov/39495965/