MBX-2982 / Gilead - LARVOL DELTA

G protein-coupled receptor 119 regulates hepatic lipid homeostasis in zebrafish (Danio rerio). (PubMed, Comp Biochem Physiol B Biochem Mol Biol) - "We demonstrated that pharmacological activation of Gpr119 by the agonist MBX-2982 attenuated HFD-induced hepatic steatosis and liver injury...Collectively, our findings indicate that Gpr119 is a regulator of hepatic lipid homeostasis, functioning to restrict lipid supply and accelerate lipid clearance. This study provides in vivo genetic evidence highlighting the role of Gpr119 in hepatic lipid homeostasis, thereby advancing our physiological understanding of liver function and lipid handling."

Journal • Dyslipidemia • Hepatology • Liver Failure • Metabolic Disorders

GPR119 Exerts Anti-Inflammatory Effects on the Liver of Zebrafish via Mediating Gs/cAMP-Dependent Pathway. (PubMed, Fish Shellfish Immunol) - "Functional analyses demonstrated that activation of GPR119 by the selective agonist MBX-2982 significantly suppressed the expression of pro-inflammatory cytokines in zebrafish hepatocytes...In addition, β-Arrestin-extracellular regulated protein kinases (ERK)-associated signaling was involved in the fine-tuning of CREB-mediated inflammatory regulation. Collectively, these findings identify GPR119 as a critical negative regulator of hepatic inflammation in zebrafish and provide mechanistic insights into its immunomodulatory function, highlighting its potential as a therapeutic target for improving liver health in aquaculture species."

Journal • Inflammation

A Novel Anti-Fibrotic Role of G-Protein-Coupled Receptor 119 in Hepatic Stellate Cells. (PubMed, Biomol Ther (Seoul)) - "Treatment with the GPR119 agonists MBX-2982 and GSK1292263 inhibited HSC activation, suppressed transforming growth factor-β1 (TGFβ1)-induced Smad2/3 phosphorylation, and reduced the expression of fibrogenic genes. MBX-2982 further reduced Smad3 acetylation by disrupting the interaction between Smad3 and p300 and promoting AMPK-dependent proteasomal degradation of p300. These results identify GPR119 as a regulator of HSC activation and highlight GPR119 agonists as promising therapeutic candidates for liver fibrosis."

Journal • Diabetes • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Liver Failure • Metabolic Disorders • Type 2 Diabetes Mellitus • AMPK • SMAD3 • TGFB1

Drug repurposing screen identifies an HRI activating compound that promotes adaptive mitochondrial remodeling in MFN2-deficient cells. (PubMed, Proc Natl Acad Sci U S A) - "This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2-deficient cells. These results demonstrate the potential for pharmacologic ISR activation through the OMA1-DELE1-HRI signaling pathway as a potential strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency."

Journal • Genetic Disorders • Metabolic Disorders • Pain • KIF1B • MFN2

Drug Repurposing Screen Identifies an HRI Activating Compound that Promotes Adaptive Mitochondrial Remodeling in MFN2-deficient Cells. (PubMed, bioRxiv) - "This screen identified the compounds parogrelil and MBX-2982 as potent and selective activators of the ISR through the OMA1-DELE1-HRI signaling axis. Moreover, we show that pharmacologic ISR activation afforded by parogrelil restores mitochondrial tubular morphology, promotes mitochondrial motility, rescues MERCs, and enhances mitochondrial respiration in MFN2 -deficient cells. These results demonstrate the potential for pharmacologic HRI activation as a viable strategy to mitigate mitochondrial dysfunction in CMT2A and other pathologies associated with MFN2 deficiency."

Journal • Genetic Disorders • Metabolic Disorders • Pain • KIF1B • MFN2

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