Molecular metabolism · 2026
Nisotirostide (LY3457263), a novel NPY2 receptor agonist for type 2 diabetes and obesity: From discovery to clinical proof of concept.
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Briere Daniel A, Leohr Jennifer K, Linnebjerg Helle, Muppidi Avinash, Antonellis Meghan, Antonellis Patrick, Suter Todd M, Smith LaBell Elizabeth, Lopes Daniel, Dogra Mridula, Coskun Tamer, Alsina-Fernandez Jorge, Mather Kieren J
Аннотация
BACKGROUND/OBJECTIVE: Nisotirostide 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).
METHODS: Nisotirostide 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.
RESULTS: Nisotirostide 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.
CONCLUSION: Nisotirostide 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.
GOV NUMBER: NCT04641312.
METHODS: Nisotirostide 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.
RESULTS: Nisotirostide 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.
CONCLUSION: Nisotirostide 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.
GOV NUMBER: NCT04641312.