Basic Information:
- Chemical Name: Retatrutide
- CAS Registration Number: 2381089-83-2
- Molecular Formula: C187H281N43O60
- Molecular Weight: 4,731.33 g/mol
Mechanism of Action:
- Triple Agonist: Targets glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors.
- Therapeutic Areas: Primarily for obesity and type 2 diabetes management, with ongoing investigations for metabolic-associated fatty liver disease (MASLD), obstructive sleep apnea, and knee osteoarthritis.
Clinical Trials:
- Phase 2 Trial Results:
- Published June 2023 in The New England Journal of Medicine: 17.5% weight loss at 24 weeks, 24.2% weight loss at 48 weeks for the 12 mg dose group.
- Published August 2023 in The Lancet: Superior efficacy in reducing HbA1c and body weight compared to Dulaglutide.
Development and Production:
- Synthetic Method:
- Peptide Synthesis: Utilizes Solid Phase Peptide Synthesis (SPPS) for precision and efficiency.
- Purification Techniques: Includes gel filtration, ion exchange chromatography, and RP-HPLC for high purity.
- Characterization: Includes mass spectrometry, NMR spectroscopy, CD spectroscopy, and bioactivity assays.
Structural Features:
- Peptide Sequence Modifications:
- Glycine (G) at position 3 and α-methyl-L-leucine (aMeL) at position 13 to enhance receptor activity.
- Lysine (K) at position 17 modified with AEEA and γ-Glutamic acid (γGlu) linkers for bivalent fatty acid side chains.
- Aib (α-aminoisobutyric acid) at position 20 to prevent degradation by DPP4.
- Glutamic acid (E) at positions 24 and 28, Tyrosine (Y) at position 25 for optimized receptor interaction.
Market Potential:
- Label Extensions: Potential for broad therapeutic applications beyond the initial indications of obesity and type 2 diabetes.
- Comparative Advantage: Builds on dual agonists like Tirzepatide (Mounjaro) but offers enhanced efficacy due to triple receptor activity.
Retatrutide is a promising next-generation peptide therapy that combines the benefits of multiple receptor targeting to improve glucose regulation and weight management. Its ongoing trials and structural design highlight its potential as a significant treatment option for various metabolic conditions.
References
266-OR: Retatrutide, an Agonist of GIP, GLP-1, and Glucagon Receptors, Improves Markers of Pancreatic Beta-Cell Function and Insulin Sensitivity
Diabetes 2024;73(Supplement_1):266-OR DOI: 10.2337/db24-266-OR
Retatrutide (RETA), an agonist of GIP, GLP-1 and glucagon receptors, significantly reduced HbA1c up to 2.2% in T2D and body weight up to 17% in T2D at wk 36 and 24% in obesity without T2D (OB) at wk 48 in Ph2 trials. Proinsulin and proinsulin/C-peptide ratios, measures of beta-cell stress and dysfunction, decreased from baseline with RETA, by up to 71% and 62%, respectively, in T2D (p<0.001). In conclusion, RETA improved markers of beta-cell function in T2D and markers of insulin sensitivity in T2D and OB.
Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial
Nature Medicine volume 30, pages2037–2048 (2024) DOI: 10.1038/s41591-024-03018-2
Retatrutide is a novel triple agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptors. A 48-week phase 2 obesity study demonstrated weight reductions of 22.8% and 24.2% with retatrutide 8 and 12 mg, respectively. The main study was a 48-week, phase 2, multicenter, randomized, double-blind, placebo-controlled study designed to examine the safety and efficacy of retatrutide, administered subcutaneously once weekly in participants with obesity (BMI of 30 kg m−2 or greater), or overweight (BMI ≥27 and <30 kg m−2) with weight-related complications other than T2D.