Source of Orforglipron

{{Infobox compound | name = Orforglipron | subtitle = Investigational | Development code = LY3502970 | Class = Small-molecule [[GLP-1 receptor agonist]] | Route = Oral, once daily | Status = Phase 3; not approved <!-- Contrast with oral peptide --> | Bioavailability = Not limited by proteolysis | Food restriction = None required | Compare = [[Oral semaglutide]], ≈0.4–1% with fasting conditions }} {{medical|talk=Investigational status}} '''Orforglipron''' (development code '''LY3502970''') is an investigational orally administered non-peptide agonist of the [[GLP-1 receptor]]. It is not a peptide and is not subject to proteolysis, so it requires neither an absorption enhancer nor the strict fasting conditions that govern [[Oral semaglutide|oral semaglutide]].{{r|kawai2020}} Small-molecule agonism at a class B G-protein-coupled receptor was long considered difficult, because the natural ligand engages a large surface across two receptor domains.{{r|graaf2016}} Orforglipron binds a pocket near the extracellular face of the transmembrane bundle and stabilises an active conformation without reproducing the peptide's binding mode.{{r|kawai2020}} Reported phase 2 results include glycated-haemoglobin reductions of up to about 2.1 percentage points in type 2 diabetes and weight reduction of up to about 14.7% at 36 weeks in obesity without diabetes. It is not approved in any jurisdiction.{{r|frias2023orfo}} == Molecular basis == The receptor's orthosteric peptide site is a poor target for a small molecule: the natural ligand contacts both the extracellular domain and the transmembrane bundle across a large interface, and a molecule of a few hundred daltons cannot reproduce that. Orforglipron instead occupies a pocket accessible from the extracellular face of the bundle and acts as an agonist by stabilising the same active receptor conformation by a different route.{{r|kawai2020}} A consequence is species selectivity. The pocket differs between human and rodent receptors sufficiently that activity does not translate, and preclinical work required humanised receptor models — a practical complication of small-molecule work at this target that peptide agonists do not face. Signalling profile differs from that of the peptide agonists, with a reported preference for cAMP accumulation over β-arrestin recruitment. Whether that difference has clinical consequences is unknown; see [[Receptor bias]].{{r|kawai2020}} == Reported clinical findings == | Trial setting | Duration | Reported result | |---|---|---| | Type 2 diabetes, phase 2 | 26 weeks | HbA1c −2.1 percentage points at highest dose | | Obesity without diabetes, phase 2 | 36 weeks | −14.7% weight at highest dose vs −2.3% placebo | Gastrointestinal adverse events were dose-related and qualitatively similar to those of injected agonists, which argues that they are a receptor-level rather than a route-level phenomenon.{{r|frias2023orfo,drucker2018}} Because the compound is not a peptide, it is subject to cytochrome-mediated metabolism and to the drug-interaction considerations that entails — a difference from the peptide agonists, which have essentially no cytochrome-mediated interactions. Interaction data are part of the phase 3 programme. == Significance for the field == An orally active agonist without food restrictions changes the practical economics of the class in three ways. Manufacture is by conventional small-molecule chemistry rather than by [[Solid-phase peptide synthesis|solid-phase peptide synthesis]], which is cheaper at scale and is not constrained by peptide manufacturing capacity. Distribution requires no [[Cold chain|cold chain]]. And the administration burden falls to that of an ordinary tablet.{{r|frias2023orfo}} Whether efficacy matches that of the injected peptides at their higher doses is the open question. The phase 2 figures are broadly comparable with [[Semaglutide|semaglutide]] 2.4 mg and below those reported for [[Tirzepatide|tirzepatide]] 15 mg, but cross-trial comparison of this kind is unreliable and the phase 3 programme is the proper test. Orforglipron is a small molecule and does not appear in peptide research-chemical supply in the way the injectable analogues do; material offered under the name would be characterised by small-molecule methods rather than by the peptide battery this wiki mostly describes. == References == {{reflist}} <ref name="kawai2020">Kawai T, Sun B, Yoshino H, et al. "Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist." ''Proceedings of the National Academy of Sciences'' 117(47):29959–29967 (2020). DOI:10.1073/pnas.2014879117. PMID 33177239.</ref> <ref name="frias2023orfo">Frías JP, Hsia S, Eyde S, et al. "Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a phase 2 randomised trial." ''The Lancet'' 402(10400):472–483 (2023). PMID 37369232.</ref> <ref name="drucker2018">Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." ''Cell Metabolism'' 27(4):740–756 (2018). PMID 29617641.</ref> <ref name="graaf2016">de Graaf C, Donnelly D, Wootten D, et al. "Glucagon-like peptide-1 and its class B G protein-coupled receptors." ''Pharmacological Reviews'' 68(4):954–1013 (2016). PMID 27630114.</ref> == See also == * [[GLP-1 receptor agonist]] * [[Oral semaglutide]] * [[GLP-1 receptor]] * [[Receptor bias]] * [[Semaglutide]] {{DEFAULTSORT:Orforglipron}} [[Category:Small-molecule incretin agonists]] [[Category:Compounds and pharmacology]] [[Category:Articles describing unapproved compounds]]