How unimolecular multi-agonists are compared with therapeutic cocktails of nutrient stimulated hormones?
Metsera, now acquired by Pzifer, has introduced a concept of therapeutic NuSH cocktails, in which ultra-long-acting injectable GLP-1, GIP, glucagon, and amylin peptides are co-administered, in other words mixed and matches for personal needs (health risks, co-existing diseases, body weight target).
Conceptually,
Unimolecular milti-agonists, like tirzepitide (GLP1/GIP), or retatritude (GLP1/GIP/glucagone), impose a fixed engagement of discrete NuSH mechanisms, which may reduce flexibility and limit the potential benefits of targeting multiple pathways.
Multimolecular NuSH cocktails enable optimized engagement of multiple mechanisms, potentially maximizing both weight-loss efficacy and tolerability.
In preclinical studies
Metsera’s peptides demonstrated their mixability and concerted efficacy were demonstrated.
Coadministration of four analogues of GLP-1, GIP, glucagon, and amylin over 25 days induced >25% body-weight loss in rats, significantly greater than the dual GLP1/GIP combination of discrete GLP-1R and amylin agonists, and also greater than retatrutide.
Clinical studies suggest that
by combining individual NuSH analog peptides at optimized ratios on top of a fully-biased GLP-1 receptor agonist backbone, a better tolerability and weight loss efficacy can be achieved, while also improving outcomes in other metabolic parameters.
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