MBX-2982 / Gilead - LARVOL DELTA

HG043, a potent thienopyrimidine GPR119 agonist, demonstrates enhanced anti-diabetic and anti-obesity effects in preclinical models. (PubMed, Biomed Pharmacother) - "We investigated the anti-diabetic and anti-obesity effects of HG043, a novel and potent thienopyrimidine-based GPR119 agonist, by comparing its pharmacological activities to those of MBX-2982 (a known GPR119 agonist) and sibutramine (an appetite suppressant) in both in vitro and in vivo models. Furthermore, HG043 demonstrated synergistic glucose-lowering effects when combined with metformin or sitagliptin. These findings suggest that HG043 may serve as a promising therapeutic option for the treatment of type 2 diabetes with obesity patients."

Journal • Preclinical • Diabetes • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

A Randomized-Controlled, Double-Masked Cross-Over Study of a GPR119 Agonist on Glucagon Counterregulation during Hypoglycemia in Type 1 Diabetes. (PubMed, Diabetes) - "MBX-2982 did not alter epinephrine, norepinephrine, pancreatic polypeptide, free fatty acid, or endogenous glucose production responses to hypoglycemia compared to placebo. In conclusion, GPR119 activation with MBX-2982 did not improve counterregulatory responses to hypoglycemia in people with type 1 diabetes. Increases in GLP-1 during the MMT are consistent with GPR119 target engagement and the expected pharmacodynamic response from L-cells."

Journal • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus • PPY

PHROG: GPR119 Agonist for Hypoglycemia in Type 1 Diabetes (clinicaltrials.gov) - P2 | N=110 | Completed | Sponsor: AdventHealth Translational Research Institute | Active, not recruiting ➔ Completed | N=67 ➔ 110

Enrollment change • Trial completion • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus

A Randomized Study of a GPR119 Agonist on Glucagon Counterregulation during Hypoglycemia in Type 1 Diabetes Mellitus (T1DM) (ADA 2024) - "GPR119 activation with MBX-2982 did not improve glucagon counterregulatory responses to hypoglycemia in participants with T1D. The significant increases in fasting GLP-1 and responses during the MMT are consistent with GPR119 target engagement and the expected pharmacodynamic response from L-cells."

Clinical • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus

PHROG: Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=67 | Active, not recruiting | Sponsor: AdventHealth Translational Research Institute | Trial completion date: Dec 2023 ➔ Jun 2024

Trial completion date • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus

PHROG: Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=67 | Active, not recruiting | Sponsor: AdventHealth Translational Research Institute | Recruiting ➔ Active, not recruiting | N=29 ➔ 67 | Trial completion date: Jun 2023 ➔ Dec 2023 | Trial primary completion date: Jun 2023 ➔ Nov 2022

Enrollment change • Enrollment closed • Trial completion date • Trial primary completion date • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus

GPR119 Agonist PRM A Increases Glucagon Response to Hypoglycemia in Rats (ADA 2023) - "The Gcg AUC during the ITT was nearly 50% greater with all doses of PRM A (p<0.05 vs V) and the peak Gcg CRR was shifted earlier (p<0.01 vs V). MBX-2982 pre-treated rats, relative to V, trended to a higher peak (49±14 vs 26±10 pM) and AUC Gcg (7292±2039 vs 6855±1306 pM*h), but neither difference was significant, whereas the differences for PRM A were strongly significant for time and treatment.In summary, PRM A, a potent GPR119 agonist, tripled peak Gcg CRR during an ITT in healthy rats, affirming that the target of GPR119 holds promise as a novel means to mitigate the dangerous risk of hypoglycemia for individuals with T1D."

Late-breaking abstract • Preclinical • Hypoglycemia • Metabolic Disorders • Severe Hypoglycemia • GCG

Activation and signaling mechanism revealed by GPR119-G complex structures. (PubMed, Nat Commun) - "Here we present the cryo-electron microscopy (cryo-EM) structures of the human GPR119-G signaling complexes bound to AR231453 and MBX-2982, two representative agonists reported for GPR119...Disruption of the salt bridge eliminates the cAMP production of GPR119, indicating an important role of Gβ in GPR119-mediated signaling. Our structures, together with mutagenesis studies, illustrate the conserved binding mode of the chemically different agonists, and provide insights into the conformational changes in receptor activation and G protein coupling."

Journal • Metabolic Disorders

PHROG: Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=29 | Recruiting | Sponsor: AdventHealth Translational Research Institute | Trial completion date: Sep 2022 ➔ Jun 2023 | Trial primary completion date: Sep 2022 ➔ Jun 2023

Trial completion date • Trial primary completion date • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus

PHROG: Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus (clinicaltrials.gov) - P2 | N=29 | Recruiting | Sponsor: AdventHealth Translational Research Institute | Trial completion date: Jun 2022 ➔ Sep 2022 | Trial primary completion date: Jun 2022 ➔ Sep 2022

Trial completion date • Trial primary completion date • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus

PHROG: Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus (clinicaltrials.gov) - P2; N=29; Recruiting; Sponsor: AdventHealth Translational Research Institute; Trial completion date: Dec 2021 ➔ Jun 2022; Trial primary completion date: Dec 2021 ➔ Jun 2022

Trial completion date • Trial primary completion date • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus

PHROG: Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus (clinicaltrials.gov) - P2; N=29; Recruiting; Sponsor: Translational Research Institute for Metabolism and Diabetes, Florida; Trial completion date: Mar 2021 ➔ Dec 2021; Trial primary completion date: Mar 2021 ➔ Dec 2021

Clinical • Trial completion date • Trial primary completion date • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus

PHROG: Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus (clinicaltrials.gov) - P2; N=29; Recruiting; Sponsor: Translational Research Institute for Metabolism and Diabetes, Florida; Not yet recruiting ➔ Recruiting; Initiation date: Oct 2020 ➔ Jan 2021

Clinical • Enrollment open • Trial initiation date • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus

PHROG: Study of the Pharmacologic Action of a GPR119 Agonist on Glucagon Counter-regulation During Insulin-induced Hypoglycemia in Type 1 Diabetes Mellitus (clinicaltrials.gov) - P2; N=29; Not yet recruiting; Sponsor: Translational Research Institute for Metabolism and Diabetes, Florida

Clinical • New P2 trial • Diabetes • Hypoglycemia • Metabolic Disorders • Type 1 Diabetes Mellitus

[VIRTUAL] A Novel GPR119 Agonist, DA-1241, Improves Hepatic Inflammation and Fibrosis in ob-NASH Mice (ADA 2020) - "After 10-weeks of treatment, DA-1241 significantly blocked the progression of hepatic inflammation and fibrosis compared to the NASH control (-39% and -64% for NAS and fibrosis score; p0.05). DA-1241 inhibited the differentiation and activation of macrophages and blocked stellate cells activation. Our findings suggest that DA-1241 has a therapeutic potential for NASH, which may be partly attributed to blocking macrophage and stellate cell activation in addition to the inhibition of lipogenesis."

Late-breaking abstract • Preclinical • Metabolic Disorders • Non-alcoholic Steatohepatitis • CCL2 • TIMP1

Study to evaluate the efficacy, safety, tolerability, and pharmacokinetics of MBX-2982 administered daily for 4 weeks as monotherapy in patients with type 2 diabetes (clinicaltrials.gov) - Metabolex / P2, N=100

Diabetes

DS-8500a, an orally available G protein-coupled receptor 119 agonist, upregulates glucagon-like peptide-1 and enhances glucose-dependent insulin secretion and improves glucose homeostasis in type 2 diabetic rats. (PubMed, J Pharmacol Exp Ther) - "In a repeat-dosing study, DS-8500a had statistically significant glucose-lowering effects at OGTT performed at the 1st day and after 2 weeks of treatment in neonatal streptozotocin-treated (nSTZ) rats, and the efficacy levels of DS-8500a in each test were greater than those of GSK1292263 or MBX-2982, which had been clinically tested previously as GPR119 agonists. Single dose of DS-8500a showed dose dependent glucose lowering effects at OGTT in ZF rats. In the repeat dosing study, DS-8500a had statistically significant glucose lowering effects at OGTT performed at the first day and after 2-weeks treatment in nSTZ rats, and the efficacy levels of DS-8500a in each test were greater than those of GSK1292263 or MBX-2982 which had been clinically tested GPR119 agonists."

Journal

Discovery and biological evaluation of novel G protein-coupled receptor 119 agonists for type 2 diabetes. (PubMed, Arch Pharm (Weinheim)) - "In the oral glucose tolerance test, compound II-18 showed even more efficacious activity in lowering blood excursions than MBX-2982 at a fixed dose of 30 mg/kg. Here, we report that compound II-18 with its excellent agonistic activity and its orally effective activity in decreasing blood glucose deviations may serve as a potent GPR119 agonist for the treatment of T2DM."

Journal