ArticleMolecular metabolism2026
Nisotirostide (LY3457263), a novel NPY2 receptor agonist for type 2 diabetes and obesity: From discovery to clinical proof of concept.
Article in Molecular metabolism, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It reports registered trial NCT04641312. Not yet cited in PubMed.
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A Single Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of LY3457263 in Healthy Participants and in Patients With Type 2 Diabetes
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13 authors.
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Abstract
BACKGROUND/
objectivesNisotirostide is a novel selective NPY2 receptor agonist under development as adjunctive therapy for people with type 2 diabetes (T2D) on glucagon-like peptide-1 receptor agonists (GLP-1 RA).
methodsNisotirostide binding affinity and potency were determined against human NPY2 receptor. Effects of nisotirostide on body weight, food intake, body composition, glucose, and insulin were evaluated in mouse models. A Phase 1 study in healthy participants and participants with T2D on 1.5 mg once-weekly dose of dulaglutide evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics, following a single subcutaneous dose of nisotirostide ranging from 0.025 to 1 mg.
resultsNisotirostide potently and selectively activated NPY2 receptor signaling in vitro. In mice, nisotirostide reduced body weight by up to 12% as monotherapy and up to 31% when combined with GLP-1 RA, demonstrating synergism. Nisotirostide-treated mice showed improved glucose control, independent of weight loss. In Phase 1 clinical study (N = 65), PK of nisotirostide supported a once-weekly dosing regimen. A 1 mg dose of nisotirostide in monotherapy reduced mean body weight by 0.75 kg versus placebo (ns); when added to dulaglutide, up to 2.58 kg reduction was observed versus dulaglutide alone (p < 0.05). Gastrointestinal adverse events, such as nausea and vomiting, were the most commonly reported with nisotirostide; these were dose-dependent and mild-to-moderate in severity.
conclusionsNisotirostide demonstrated potent, selective NPY2R agonism with a PK profile supporting once-weekly dosing. Preclinical metabolic benefits, including weight-independent glucose improvements, translated clinically, and a manageable tolerability profile supports further development as adjunctive GLP-1 RA therapy for T2D and obesity. CLINICALTRIALS: gov number: NCT04641312.
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