Survodutide dosage protocol

What Survodutide Is

Survodutide (also known as BI 456906) is an investigational drug that acts as a dual agonist for both the glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R) (PMID 38847460, PMID 36356832). It is a potent, acylated peptide containing a C18 fatty acid, which helps to extend its half-life to support once-weekly dosing in humans (PMID 36356832). This dual action distinguishes it from medicines that only target the GLP-1 receptor (PMID 38843460).

How It Is Thought to Work

Survodutide’s mechanism involves simultaneous activation of both glucagon and GLP-1 receptors (PMID 38843460). This dual agonism is believed to be more effective than GLP-1 receptor agonism alone for certain conditions (PMID 38847460). Preclinical studies in animals indicate that survodutide reduces body weight by increasing energy expenditure and reducing energy intake (PMID 36356832). Engagement of both receptors in animals was demonstrated through tests related to glucose tolerance, food intake, and gastric emptying (for GLP-1R), and liver nicotinamide N-methyltransferase mRNA expression and circulating biomarkers (for GCGR) (PMID 36356832).

What Laboratory and Animal Studies Report

In cell-based in vitro assays, survodutide demonstrated functional agonism of both GCGR and GLP-1R (PMID 36356832). In animal studies (mice), pharmacological doses of survodutide led to greater body weight reductions compared to maximally effective doses of the GLP-1R agonist semaglutide (PMID 36356832). This superior efficacy was attributed to increased energy expenditure and decreased food intake (PMID 36356832). Its dual activity was further supported using GLP-1R knockout and transgenic reporter mice, and an ex vivo bioactivity assay (PMID 36356832).

Human Evidence So Far

In a 48-week, phase 2 human trial involving adults with metabolic dysfunction-associated steatohepatitis (MASH) and liver fibrosis (stages F1-F3), survodutide was administered once-weekly via subcutaneous injections. Improvement in MASH without worsening of fibrosis occurred in 47% (2.4-mg group), 62% (4.8-mg group), and 43% (6.0-mg group) of participants, compared to 14% in the placebo group (P<0.001) (PMID 38847460). A decrease in liver fat content by at least 30% was observed in 63% (2.4-mg group), 67% (4.8-mg group), 57% (6.0-mg group), versus 14% in the placebo group (PMID 38847460). Fibrosis improvement by at least one stage occurred in 34%, 36%, 34% (survodutide groups) and 22% (placebo group) (PMID 38847460).

Another phase 2 human trial investigated survodutide for obesity management in adults without diabetes. Participants received once-weekly subcutaneous injections for 46 weeks. Mean percentage changes in bodyweight from baseline to week 46 were -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% in the placebo group (PMID 38330987). A phase 3 trial in adults with obesity (BMI ≥30 or ≥27 with complications, excluding diabetes) found mean body weight changes at week 76 of -12.2% (3.6-mg group) and -13.0% (6.0-mg group) versus -5.4% in the placebo group (PMID 42253238).

Common adverse events in human trials included gastrointestinal symptoms like nausea (66% vs. 23% for placebo), diarrhea (49% vs. 23% for placebo), and vomiting (41% vs. 4% for placebo) (PMID 38847460). These were typically mild to moderate (PMID 42253238). Serious adverse events occurred in 8% with survodutide and 7% with placebo in the MASH trial (PMID 38847460). No deaths were reported in the obesity phase 3 trial (PMID 42253238).

Open Questions and Limitations

While survodutide shows promise, especially for MASH and obesity, ongoing phase 3 trials are necessary (PMID 38847460, PMID 39952695). Future research needs to address response heterogeneity, the long-term adherence to treatment, and the optimal duration of treatment (PMID 40590228). Data on mortality, obesity-related complications such as cardio-renal-metabolic events, and long-term safety and efficacy of weight maintenance are also needed (PMID 39952695). Studies focusing on underrepresented populations, cost-effectiveness assessments, and drug availability are important to bridge care gaps for people with obesity (PMID 39952695).

Key Terms Explained

<b>Glucagon Receptor (GCGR):</b> A protein on cell surfaces that glucagon, a hormone, binds to. This binding helps regulate glucose levels in the body.

<b>GLP-1 Receptor (GLP-1R):</b> A protein on cell surfaces that glucagon-like peptide-1 (GLP-1), a hormone, binds to. This binding plays a role in glucose metabolism, appetite, and gut motility.

<b>Dual Agonist:</b> A substance that activates two different types of receptors.

<b>Metabolic Dysfunction-Associated Steatohepatitis (MASH):</b> A progressive inflammatory form of metabolic dysfunction-associated steatotic liver disease (MASLD), characterized by inflammation and liver cell damage, often linked to obesity and type 2 diabetes (PMID 40590228).

<b>Fibrosis:</b> The thickening and scarring of connective tissue, in this context, in the liver, which can lead to more severe liver disease (PMID 38847460).