bamadutide (SAR425899) / Sanofi - LARVOL DELTA

Structural analysis of the dual agonism at GLP-1R and GCGR. (PubMed, Proc Natl Acad Sci U S A) - "Structural investigation of lipid modification showed a better interaction between lipid moiety of MEDI0382 and TM1-TM2 cleft, in line with its increased potency at GCGR than SAR425899. Together, the results provide insightful information for the design and development of improved therapeutics targeting these two receptors simultaneously."

Journal

Glucagon-like peptide-1/glucagon receptor agonism associates with reduced metabolic adaptation and higher fat oxidation: A randomized trial. (PubMed, Obesity (Silver Spring)) - "SAR425899 led to reduced selective metabolic adaptation and increased lipid oxidation, which are believed to be beneficial for weight loss and weight-loss maintenance."

Journal • Genetic Disorders • Obesity

Effects of site-directed mutagenesis of GLP-1 and glucagon receptors on signal transduction activated by dual and triple agonists. (PubMed, Acta Pharmacol Sin) - "Three dual agonists (peptide 15, MEDI0382 and SAR425899) and one triple agonist (peptide 20) were evaluated at GLP-1R and GCGR, relative to the native peptidic ligands (GLP-1 and glucagon). Our results reveal the existence of residue networks crucial for unimolecular agonist-mediated receptor activation and their distinct signaling patterns, which might be useful to the rational design of biased drug leads."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Emerging glucagon-like peptide 1 receptor agonists for the treatment of obesity. (PubMed, Expert Opin Emerg Drugs) - "There is a strong interest in developing obesity treatments based on glucagon-like peptide-1 (GLP-1) agonism, which have proved to limit morbidity and mortality in type 2 diabetes.Areas covered: This review provides an overview of current compounds containing GLP-1 receptor agonism in clinical development for obesity, with mono-activity at the GLP-1 receptor (PF-0688296, glutazumab, semaglutide) or engaging one or more other endogenous hormonal systems involved in energy balance and metabolism, including glucagon, oxyntomodulin, glucose-dependent inhibitory peptide and amylin (CT-868, CT-388, AMG 133, tirzepatide, NNC9204-1177, JNJ-54728518, SAR425899, pegapamodutide, MK8521, cotadutide, efinopegdutide, BI-456906, cagrilintide + semaglutide 2,4 mg, HM15211, NNC9204-1706).Expert opinion: Many novel compounds employing GLP-1 receptor agonism are in clinical development. Semaglutide is farthest in clinical development and will presumably become a benchmark for this class of..."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Improved Postprandial Glucose Metabolism in Type 2 Diabetes by Dual Glucagon-like Peptide-1 / Glucagon Receptor Agonist SAR425899 in Comparison to Liraglutide. (PubMed, Diabetes Obes Metab) - "SAR425899 and Liraglutide improved postprandial glucose control in overweight to obese subjects with T2D. A significantly higher enhancement in β-cell function was shown by SAR425899 than Liraglutide."

Journal • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Imaging of the glucagon receptor in subjects with type 2 diabetes. (PubMed, J Nucl Med) - " The biodistribution and dosimetry of Ga-Tuna-2 was assessed by PET/Computed Tomography (CT) in n = 13 individuals with Type 2 Diabetes (T2D) as part of a clinical study assessing the occupancy of dual GCGR/Glucagon Like Peptide-1 Receptor (GLP-1R) agonist SAR425899...Ga-Tuna-2 can be used for safe and accurate assessment of the GCGR in human. It may serve as an important tool in understanding the in vivo pharmacology of novel drugs engaging the GCGR."

Clinical • Journal • Diabetes • Genetic Disorders • Hepatology • Metabolic Disorders • Type 2 Diabetes Mellitus

Receptor occupancy of dual glucagon-like peptide 1/glucagon receptor agonist SAR425899 in individuals with type 2 diabetes. (PubMed, Sci Rep) - "Patients with T2D were examined by [Ga]Ga-DO3A-Tuna-2 and [Ga]Ga-DO3A-Exendin4 by PET, to assess the GCGR in liver and GLP1R in pancreas, respectively. In conclusion, SAR425899 demonstrated strong interactions at the GLP1R, but no clear occupancy at the GCGR. The study demonstrates that quantitative target engagement of dual agonists can be assessed by PET."

Clinical • Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Evaluation of biased agonism mediated by dual agonists of the GLP-1 and glucagon receptors. (PubMed, Biochem Pharmacol) - "Three distinct dual agonists that have different relative cAMP production potency for GLP-1R versus GCGR, "peptide 15", MEDI0382 and SAR425899, and one triagonist of the GLP-1R, GCGR and GIPR were examined. We demonstrated that all novel peptides have distinct biased agonism profiles relative to either of the cognate agonists of the receptors, and to each other. This is an important feature of the pharmacology of this drug class that needs to be considered alongside selectivity, bioavailability and pharmacokinetics for rational optimization of new therapeutics."

Journal • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A Clinical Study to Investigate if SAR425899 Binds to the Liver and Pancreas in Overweight to Obese Type 2 Diabetes Mellitus Patients (clinicaltrials.gov) - P1; N=14; Not yet recruiting; Sponsor: Sanofi

New P1 trial • Biosimilar • Diabetes • Metabolic Disorders • Obesity

Dual GLP-1R/GCGR Agonist SAR425899 Improves Beta-cell Function in Type 2 Diabetes. (PubMed, Diabetes Obes Metab) - P1; "After 28 days of treatment, SAR425899 improved postprandial glucose control by significantly enhancing β-cell function, and slowing glucose absorption rate."

Journal

A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo-controlled first-in-human and first-in-patient trials. (PubMed, Diabetes Obes Metab) - P1; "SAR425899 was well tolerated and led to favourable glycaemic effects in patients with type 2 diabetes and weight reduction in both healthy volunteers and patients. Whether dual GLP-1 R/glucagon receptor agonism represents a treatment modality superior to pure GLP-1 R agonists for obesity and diabetes treatment remains to be confirmed."

Clinical • Journal • P1 data

Restore: Assessment of the Safety and Effect of SAR425899 Versus Placebo for the Treatment of Non-alcoholic Fatty Liver Disease (clinicaltrials.gov) - P2; N=0; Withdrawn; Sponsor: Sanofi; N=126 ➔ 0; Not yet recruiting ➔ Withdrawn

Clinical • Enrollment change • Trial withdrawal

A Clinical Study to Investigate the Effect of SAR425899 on Energy Expenditure in Obese Subjects (clinicaltrials.gov) - P1; N=24; Completed; Sponsor: Sanofi; Recruiting ➔ Completed

Clinical • Trial completion