Source of Survodutide

{{Infobox compound | name = Survodutide | subtitle = Investigational | Development code = BI 456906 | Class = Dual glucagon/GLP-1 receptor agonist | Route = Subcutaneous, weekly | Status = Phase 3; not approved }} {{medical|talk=Investigational status}} '''Survodutide''' (development code '''BI 456906''') is an investigational peptide that agonises both the [[Glucagon|glucagon]] receptor and the [[GLP-1 receptor]]. It is under phase 3 evaluation for obesity and has been studied in metabolic dysfunction-associated steatohepatitis. It is not approved for use in any indication.{{r|zimmermann2022}} Unlike the GIP/GLP-1 pairing of [[Tirzepatide|tirzepatide]], the glucagon/GLP-1 pairing sets two opposing glycaemic effects against each other deliberately. Glucagon-receptor agonism raises hepatic glucose output and energy expenditure; [[GLP-1 receptor agonist|GLP-1 agonism]] lowers glucose and food intake. The design intent is to capture the energy-expenditure and hepatic-fat effects of the former while the latter dominates the net glycaemic balance.{{r|zimmermann2022}} Reported phase 2 weight reduction reached approximately 19% at 46 weeks at the highest dose studied. The hepatic programme is of independent interest, since glucagon-receptor agonism reduces liver fat by a mechanism that GLP-1 agonism does not share.{{r|blueher2024}} == Design and rationale == Survodutide is a 29-residue acylated peptide derived from the glucagon sequence, with substitutions conferring GLP-1-receptor activity and a fatty-acid chain for [[Albumin binding half-life extension|albumin binding]]. Its natural template is oxyntomodulin, a product of [[Proglucagon|proglucagon]] processing that is a weak agonist at both receptors — the existence of which is why the combination was thought physiologically coherent rather than merely chemically possible.{{r|zimmermann2022,campbell2013}} The potency ratio is the central design variable. Too much glucagon activity relative to GLP-1 activity raises fasting glucose; too little forfeits the energy-expenditure benefit that motivated the design. This is a fixed intramolecular property, so the balance must hold across the whole dose range rather than at one point in it. Reported ''in vitro'' ratios place survodutide closer to balanced than the triple agonist [[Retatrutide|retatrutide]], though as always such ratios are assay-dependent and are not comparable across publications.{{r|blueher2024}} == Reported clinical findings == A 46-week phase 2 trial in adults with obesity and without diabetes reported dose-dependent weight reduction reaching approximately 19% at the highest dose, against approximately 2% for placebo. Escalation was over 20 weeks, longer than in comparable programmes, reflecting tolerability constraints.{{r|blueher2024}} A separate phase 2 trial in biopsy-confirmed metabolic dysfunction-associated steatohepatitis reported improvement in histological endpoints at 48 weeks. Histological endpoints in that condition are notoriously variable between readers, and the trial's own reporting acknowledges the limitation. Gastrointestinal adverse events dominated and were dose-related. A heart-rate increase attributable to the glucagon component was reported, as it was for retatrutide, and rises in fasting glucose were observed early in escalation in some participants — the anticipated consequence of glucagon agonism outpacing GLP-1 agonism at low total dose.{{r|zimmermann2022}} == Status and material sold under the name == Survodutide has not been approved in any jurisdiction. Phase 3 programmes in obesity and in steatohepatitis are ongoing, and this article will require revision as they report. Material offered as survodutide by research-chemical suppliers is an unapproved investigational compound. As with [[Retatrutide|retatrutide]], there is no marketed reference product and therefore no generally available [[Reference standard|reference standard]] against which identity could be confirmed by comparison, so a purity figure on a certificate rests on an unverified identity assignment.{{r|usp1503}} This wiki records what documents state and does not represent investigational compounds as suitable for human use; see [[Research use only]]. == References == {{reflist}} <ref name="zimmermann2022">Zimmermann T, Thomas L, Baader-Pagler T, et al. "BI 456906: discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy." ''Molecular Metabolism'' 66:101633 (2022). DOI:10.1016/j.molmet.2022.101633. PMID 36372428.</ref> <ref name="blueher2024">Blüher M, Rosenstock J, Hoefler J, Manuel R, Hennige AM. "Dose-response effects on HbA1c and bodyweight reduction of survodutide, a dual glucagon/GLP-1 receptor agonist." ''Diabetologia'' 67(3):470–482 (2024). PMID 38095713.</ref> <ref name="usp1503">United States Pharmacopeia, General Chapter <1503>, ''Quality Attributes of Synthetic Peptide Drug Substances''.</ref> <ref name="campbell2013">Campbell JE, Drucker DJ. "Pharmacology, physiology, and mechanisms of incretin hormone action." ''Cell Metabolism'' 17(6):819–837 (2013). PMID 23684623.</ref> == See also == * [[Retatrutide]] * [[Glucagon]] * [[Dual incretin agonist]] * [[Efinopegdutide]] * [[Tirzepatide]] {{DEFAULTSORT:Survodutide}} [[Category:Dual and triple agonists]] [[Category:Peptide drugs]] [[Category:Articles describing unapproved compounds]]