adomeglivant (LY2409021) / Eli Lilly - LARVOL DELTA

The Inferential Binding Sites of GCGR for Small Molecules Using Protein Dynamic Conformations and Crystal Structures. (PubMed, Int J Mol Sci) - "Currently, six small molecules (Bay 27-9955, MK-0893, MK-3577, LY2409021, PF-06291874, and LGD-6972) have been tested or are undergoing clinical trials, but only the binding site of MK-0893 has been resolved. Additionally, LGD-6972 exhibited relatively stable binding in Pocket 5. We also conducted structural modifications of LGD-6972 based on the results of MD simulations and predicted its analogues' bioavailability, providing a reference for the study of GCGR small molecules."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Elevated FGF21 levels after total pancreatectomy and in response to single-dose glucagon receptor antagonist administration in humans (EASD 2023) - P=N/A | "Our results suggest that both chronic glucagon depletion and acute antagonism of the glucagon receptor mediate an increase in FGF21 levels in humans, pointing to direct or indirect effects of glucagon as important regulators of FGF21 secretion."

Metabolic Disorders • FGF21

Exercise Training Decreases ß-Cell Senescence in Mice and Humans (ADA 2023) - "Exercised mice treated with a glucagon antagonist (adomeglivant) blocked AMPK phosphorylation and increased p21Cip1 and p16Ink4...Treatment of human donor islets with serum obtained pre- and post-exercise training for 10 weeks in people with T2D showed that training activated AMPK and decreased senescence markers. These findings demonstrate that exercise training decreases β-cell senescence and suggest that this important response to exercise occurs through circulating factors mediating an AMPK-dependent pathway."

Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • CDKN1A • CDKN2A • IR

Elevated FGF21 Levels after Total Pancreatectomy and in Response to Single-Dose Glucagon Receptor Antagonism in Humans (ADA 2023) - "In the control subjects, administration of LY2409021 significantly increased mean fasting levels of FGF21 (216 ± 117 vs 108 ± 58 pg/mL, P=0.004) whereas fasting FGF21 levels in the pancreatectomized patients were unaffected by LY2409021. In both groups, FGF21 levels increased in response to the OGTT, with no significant treatment effect of LY2409021.Our results suggest that both chronic glucagon depletion and acute antagonism of the glucagon receptor mediate an increase in FGF21 levels in humans, pointing to direct or indirect effects of glucagon as important regulators of FGF21 secretion."

Metabolic Disorders • FGF21

The Glucagon Receptor Antagonist LY2409021 does not affect gastrointestinal-mediated glucose disposal or the incretin effect in individuals with and without type 2 diabetes. (PubMed, Eur J Endocrinol) - "Glucagon receptor antagonism with LY2409021 had no effect on the impaired GIGD or the impaired incretin effect in patients with T2D and did also not affect these parameters in the controls. Surprisingly, we observed reduced oral glucose tolerance with LY2409021 which may be specific for this glucagon receptor antagonist."

Journal • Diabetes • Gastrointestinal Disorder • Metabolic Disorders • Type 2 Diabetes Mellitus

The Glucagon Receptor Antagonist LY2409021 has No Effect on Postprandial Glucose in Type 2 Diabetes. (PubMed, Eur J Endocrinol) - "LY2409021 lowered fasting plasma glucose concentrations but did not improve postprandial glucose tolerance after a meal in patients with T2D and controls. The metabolic consequences of postprandial hyperglucagonemia are difficult to evaluate using LY2409021 because of its antagonizing effects on the incretin receptors."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

PX-GRA: Delineation of the Diabetogenic Role of Extrapancreatic Glucagon in Totally Pancreatectomised Patients Using Glucagon Receptor Antagonism (clinicaltrials.gov) - P=N/A; N=20; Enrolling by invitation; Sponsor: University Hospital, Gentofte, Copenhagen; Trial completion date: Jul 2020 ➔ Jul 2021

Clinical • Trial completion date • Diabetes • Metabolic Disorders

The Role of Glucagon in the Acute Therapeutic Effects of SGLT2 Inhibition. (PubMed, Diabetes) - "LY2409021 reduced EGP significantly, but gave rise to a paradoxical increase in postprandial PG excursion, which was annulled by empagliflozin during their combination (empagliflozin+LY2409021). In conclusion, our findings do not support that an SGLT2i-induced glucagonotropic effect is of importance for the glucose-lowering property of SGLT2 inhibition."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Design, synthesis and structure activity relationships of indazole and indole derivatives as potent glucagon receptor antagonists. (PubMed, Bioorg Med Chem Lett) - "A novel series of indazole/indole derivatives were discovered as glucagon receptor (GCGR) antagonists through scaffold hopping based on two literature leads: MK-0893 and LY-2409021. Further structure-activity relationship (SAR) exploration and optimization led to the discovery of multiple potent GCGR antagonists with excellent pharmacokinetic properties in mice and rats, including low systemic clearance, long elimination half-life, and good oral bioavailability. These potent GCGR antagonists could be used for potential treatment of type II diabetes."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A Study of LY2409021 in Patients With Type 2 Diabetes -

Eli Lilly; P2, N=260; Not yet recruiting

Single doses of the glucagon receptor antagonist LY2409021 reduce blood glucose in healthy subjects and patients with type 2 diabetes mellitus (EASD 2011) - Presentation Time: Sep 14, 12:30 - 1:30 PM; P1, N=NA; LY reduced fasting serum insulin, with LS mean changes vs. pbo (p≤.02) observed at higher dose levels (250 and 500mg in HS at 24-h, and 200mg [24-h] and 500mg [48-h] in T2DM)

P1 data • Diabetes

Glucagon receptor antagonist LY2409021 does not impede recovery from insulin induced hypoglycemia in patients with T2DM (ADA 2012) - Presentation time: 6/9/2012 11:30:00 AM; P=NA, N=13; With LY2409021 (LY) vs. PB, the LS mean insulin load required to achieve hypoglycemia was 1920 pmol/kg vs. 2170 pmol/kg; Mean time to recovery from hypoglycemia to a blood glucose ≥63 mg/dL was similar between LY and PB, and among pts taking Met and not taking Met

Clinical data • Diabetes

A Study of LY2409021 in Healthy Participants (clinicaltrials.gov) - P1; N=16; Completed; Sponsor: Eli Lilly and Company; Recruiting -> Completed

Trial completion • Biosimilar

A study on the effects of LY2409021 on the electrical impulses of the heart (clinicaltrials.gov) - P1, N=68; Recruiting -> Active, not recruiting

Enrollment closed • Diabetes

A Study of LY2409021 on Blood Pressure and Pulse Rate in Participants With Type 2 Diabetes Mellitus (clinicaltrials.gov) - P2; N=260; Active, not recruiting; Sponsor: Eli Lilly and Company; Recruiting -> Active, not recruiting

Enrollment closed • Biosimilar • Diabetes

12-week treatment with glucagon receptor antagonist LY2409021 significantly lowers HbA1c and is well tolerated in patients with type 2 diabetes mellitus (EASD 2012) - Presentation time: Wed, Oct 03, 2012, 3:15 PM - 3:30 PM; P2, N=87; NCT00871572 ; No significant changes in triglycerides, LDL- or HDL-cholesterol, weight, or blood pressure were observed; Dose-dependent increases in fasting glucagon, ALT, AST, and total GLP-1 were observed and these returned to baseline on washout of LY2409021

P2 data • Diabetes

PX-GRA: Delineation of the Diabetogenic Role of Extrapancreatic Glucagon in Totally Pancreatectomised Patients Using Glucagon Receptor Antagonism (clinicaltrials.gov) - P=N/A; N=20; Enrolling by invitation; Sponsor: University Hospital, Gentofte, Copenhagen; Initiation date: May 2015 ➔ May 2016; Trial primary completion date: Nov 2016 ➔ Aug 2017

Trial initiation date • Trial primary completion date • Biosimilar • Diabetes • Gastrointestinal Cancer • Pancreatic Cancer

A Study of LY2409021 Formulations in Healthy Participants (clinicaltrials.gov) - P1; N=72; Not yet recruiting; Sponsor: Eli Lilly and Company

New P1 trial • Biosimilar

PX-GRA: Delineation of the Diabetogenic Role of Extrapancreatic Glucagon in Totally Pancreatectomised Patients Using Glucagon Receptor Antagonism (clinicaltrials.gov) - P=N/A; N=20; Enrolling by invitation; Sponsor: University Hospital, Gentofte, Copenhagen; Trial completion date: Sep 2019 ➔ Jul 2020

Clinical • Trial completion date

PX-GRA: Delineation of the Diabetogenic Role of Extrapancreatic Glucagon in Totally Pancreatectomised Patients Using Glucagon Receptor Antagonism (clinicaltrials.gov) - P=N/A; N=20; Enrolling by invitation; Sponsor: University Hospital, Gentofte, Copenhagen; Trial completion date: Dec 2017 ➔ Sep 2019; Trial primary completion date: Oct 2017 ➔ Sep 2019

Clinical • Trial completion date • Trial primary completion date

Glucagon Receptor Antagonism Increases Plasma Amino Acids and Glucagon (ADA 2019) - "...In a double-blinded, cross-over study, blood was sampled from 10 overnight fasted patients with T2D (BMI [mean±SD]: 33.0±5.4 kg/m2; HbA1c: 46.2±6.1 mmol/mol, 6.4±0.6%) and 10 matched healthy controls (BMI: 31.7±4.2 kg/m2; HbA1c: 33.9±3.0 mmol/mol, 5.3±0.3%) after a single-dose of the glucagon receptor antagonist (GRA) LY2409021 or placebo...Total AA concentrations were increased by GRA compared to placebo by 1.4 fold in T2D and 1.3 fold in controls (P≤0.001) with threonine, proline and the glucagonotropic AAs alanine and tyrosine exhibiting the greatest increases in T2D (1.6-2 fold) and controls (1.4-1.5 fold). GRA also increased plasma glucagon concentrations by more than 3-fold (P≤0.0001), and the glucagonotropic AAs alanine (R2 0.24, P=0.0012) and tyrosine (R2 0.30, P=0.0002) were correlated to glucagon.In conclusion, acute inhibition of glucagon receptor signaling by GRA causes hyperaminoacidemia linked to hyperglucagonemia,..."

Glucagon Receptor Antagonism Increases Plasma Amino Acids and Glucagon (ADA 2019) - "...In a double-blinded, cross-over study, blood was sampled from 10 overnight fasted patients with T2D (BMI [mean±SD]: 33.0±5.4 kg/m2; HbA1c: 46.2±6.1 mmol/mol, 6.4±0.6%) and 10 matched healthy controls (BMI: 31.7±4.2 kg/m2; HbA1c: 33.9±3.0 mmol/mol, 5.3±0.3%) after a single-dose of the glucagon receptor antagonist (GRA) LY2409021 or placebo...Total AA concentrations were increased by GRA compared to placebo by 1.4 fold in T2D and 1.3 fold in controls (P≤0.001) with threonine, proline and the glucagonotropic AAs alanine and tyrosine exhibiting the greatest increases in T2D (1.6-2 fold) and controls (1.4-1.5 fold). GRA also increased plasma glucagon concentrations by more than 3-fold (P≤0.0001), and the glucagonotropic AAs alanine (R2 0.24, P=0.0012) and tyrosine (R2 0.30, P=0.0002) were correlated to glucagon.In conclusion, acute inhibition of glucagon receptor signaling by GRA causes hyperaminoacidemia linked to hyperglucagonemia,..."

The Physiological Effects of Extrapancreatic Glucagon in Totally Pancreatectomized Patients Evaluated Using Glucagon Receptor Antagonism (ADA 2019) - "...Before the tests, subjects ingested 300 mg of the GRA, LY2409021 (Eli Lilly and Company), and placebo, respectively...In the PX patients, equal fasting glucagon concentrations (3.2±0.7 vs. 4.7±1.9 pmol/l, P=0.373) and similarly exaggerated plasma glucagon responses to OGTT were observed with the GRA and placebo (bsAUC: 1,636±573 vs. 1,034±542 pmol/l×min, P=0.113). In this study, antagonizing the glucagon receptor in totally pancreatectomized patients did not influence fasting or post-OGTT glucose levels."

Clinical

Non-conventional glucagon and GLP-1 receptor agonist and antagonist interplay at the GLP-1 receptor revealed in high-throughput FRET assays for cAMP. (PubMed, J Biol Chem) - "...This analysis established that glucagon is a nonconventional GLP-1R agonist, an effect inhibited by the GLP-1R orthosteric antagonist exendin(9-39) (Ex(9-39)). The GluR allosteric inhibitors LY2409021 and MK 0893 antagonized glucagon and GLP-1 action at the GLP-1R, whereas des-His-[Glu]glucagon antagonized glucagon action at the GluR, while having minimal inhibitory action versus glucagon or GLP-1 at the GLP-1R...Collectively, these findings provide a new triagonist strategy with which to target the GluR, GLP-1R, and NPY2R. They also provide an impetus to reevaluate prior studies in which GluR and GLP-1R agonists and antagonists were assumed not to exert promiscuous actions at other GPCRs."

Journal