HuaTangNing (dorzagliatin) / Hua Medicine - LARVOL DELTA

Hua Medicine…announced that the Department of Health of the Hong Kong Special Administrative Region of China accepted a New Drug Application (NDA) for dorzagliatin, the world’s first glucokinase activator (GKA) approved for the treatment of Type 2 diabetes (T2D). (The Globe and Mail) - "Results from two Phase III registration trials in China demonstrated that dorzagliatin significantly and sustainably lowered HbA1c levels, improved pancreatic β-cell function, and reduced insulin resistance, all while showing strong safety and tolerability."

Filing • Type 2 Diabetes Mellitus

Genotype-Phenotype Discrepancies in Family Members With a Novel Glucokinase Mutation: Insights Into GCK-MODY and Its Interplay With Insulin Resistance. (PubMed, Diabetes) - "Both dorzagliatin and liraglutide improved glucose tolerance and insulin secretion in mutant mice. We found that GCK-Q26L is a pathogenic mutation leading to GCK-MODY, with severity modulated by polygenic risk score for insulin resistance and type 2 diabetes. These findings not only expand the list of GCK-MODY causing mutations but also highlight the importance of polygenic backgrounds in the clinical presentation and management of monogenic diabetes."

Journal • Diabetes • Dyslipidemia • Metabolic Disorders • Type 2 Diabetes Mellitus

Dorzagliatin enhances GLP-1 secretion by restoring the function of intestinal L-cells (EASD 2025) - "Our study reveals the unique ability of dorzagliatin to promote the synthesis of GLP-1 in intestinal L-cells, while TTP399 lacks this effect. The observed upregulation of Gcg and Pcsk1 genes and increased L-cell abundance further demonstrate the role of dorzagliatin in restoring L-cell function, underscoring its superior therapeutic potential for T2D compared with other GKA, such as TTP399."

Late-breaking abstract • Diabetes • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus • GCG • PCSK1

Effects of Dorzagliatin, a Glucokinase Activator, on α- and β-Cell Function in Individuals With Impaired and Normal Glucose Tolerance. (PubMed, Diabetes) - "With increasing glucose, plasma glucagon and total GLP-1 levels declined progressively. A modest to moderate positive correlation between glucagon and total GLP-1 was observed under both dorzagliatin and placebo treatments."

Journal • Diabetes • Metabolic Disorders

Business Highlights and Operational Progress (The Manila Times) - "Effective from January 1, 2025, the Company terminated its exclusive promotion service agreement with Bayer and fully took over the commercialization of HuaTangNing in China. During the Reporting Period, with unit prices remaining consistent with the same period in 2024, sales of HuaTangNing reached 1,764,000 packs, a year-on-year increase of 108%. Net sales reached RMB217.4 million, a year-on-year increase of 112%."

Commercial • Type 2 Diabetes Mellitus

An innovative method for simultaneous separation and determination of monosaccharide and sugar alcohol isomers associated with glycometabolism in beagle plasma using gas chromatography-mass spectrometry. (PubMed, Anal Chim Acta) - "This method solves the problems of multiple peaks after derivatization and frequent co-elution of analytes in previous analytical methods, significantly enhances derivatization efficiency of ketoses, which provides a promising approach for simultaneous analysis of aldose, ketose, and sugar alcohol. It offers new insights into a more comprehensive research on glycometabolism rather than merely focusing on glucose."

Journal • Metabolic Disorders

In Vivo PK-PD and Drug-Drug Interaction Study of Dorzagliatin for the Management of PI3Kα Inhibitor-Induced Hyperglycemia. (PubMed, Pharmaceuticals (Basel)) - "Objectives: The anticancer effects of PI3Kα inhibitors (PI3Ki) are constrained by their hyperglycemic side effects, while the efficacy of conventional hypoglycemic agents, such as insulin, metformin, and SGLT-2 inhibitors, in mitigating PI3Ki-induced hyperglycemia remains suboptimal. Our findings indicate that the drug-drug interactions (DDIs) between dorzagliatin and multiple PI3Ki (including WX390 and BYL719) may partially account for the enhanced antitumor efficacy observed in the combination therapy group compared to PI3Ki monotherapy. This interaction may be explained by the inhibition of P-glycoprotein (P-gp) and the pharmacological mechanism of dorzagliatin regarding the activation of insulin regulation."

Journal • PK/PD data • Preclinical • Diabetes • Oncology • PIK3CA

Factors influencing the initial glycemic efficacy of dorzagliatin, a novel glucokinase activator, in type 2 diabetes. (PubMed, Endocrine) - "Blood glucose levels of T2DM patients during dorzagliatin initial treatment are positively correlated with diabetes duration, suggesting greater efficacy of dorzagliatin in patients with shorter disease duration. Metformin may enhance the glucose-lowering efficacy of dorzagliatin but also increase the risk of hypoglycemia. Furthermore, factors like baseline FPG, TC and AST also influence outcomes."

Journal • Diabetes • Hypoglycemia • Metabolic Disorders • Type 2 Diabetes Mellitus

Interim Analysis of a Real-World Study—Glucokinase Activator Dorzagliatin Demonstrates Improved Glycemic Homeostasis and β-Cell Function in T2DM (ADA 2025) - "Dorzagliatin significantly improves glycemic homeostasis and β-cell function in patients with T2DM. These findings support the therapeutic potential of GKAs in diabetes management. Longer-term follow-up will further elucidate its clinical utility."

Clinical • Late-breaking abstract • Real-world • Real-world evidence • Metabolic Disorders • Type 2 Diabetes Mellitus

Dorzagliatin Enhances Alpha–to–Beta Cell Glucagon-Like Peptide 1 Paracrine Signaling to Improve Beta-Cell Function in Type 2 Diabetes (ADA 2025) - "Dorzagliatin augments β-cell function primarily by stimulating α→β paracrine GLP-1. These findings clarify its mechanism and suggest potential synergy with GLP-1-based strategies in T2D."

Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Long-Term Administration of Dorzagliatin Combined with Sitagliptin for the Management of Glucose Homeostasis in High-Fat Diet–Induced Obesity Mice (ADA 2025) - "DIO mice have impaired GLP-1 secretion, elevated glucose, insulin and glucagon levels. Following 30 days of treatment, glucose levels were improved with increased secretion of insulin, the combination of GKA and DPP4i was superior to dorzagliatin alone with the improved GLP-1 secretion. Those data indicated that, in addition to increased insulin secretion by GKA, the enhanced GLP-1 secretion also played a significant role in improving glucose homeostasis, and the addition of DPP4i amplified these effects."

Preclinical • Diabetes • Metabolic Disorders • Obesity

Sex-Dependent Additive Effects of Dorzagliatin and Incretin on Insulin Secretion in a Novel Mouse Model of GCK-MODY (ADA 2025) - "Combined treatment with GKA and incretin may thus be useful in GCK-MODY or GCK-PNDM, and possibly in more common forms of type 2 diabetes."

Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Dorzagliatin Increases Hepatic UDP Glucose Flux via the Direct Pathway in Type 2 Diabetes—New Glucokinase Activator for Type 2 Diabetes? (ADA 2025) - "The initial data suggest that dorzagliatin increases total UDP-glucose flux through the direct pathway of glycogen synthesis, implying an increase in hepatic GKA in people with T2D. Future larger clinical trials are required to test long term glucose control with this new drug for T2D."

Diabetes • Hypoglycemia • Metabolic Disorders • Type 2 Diabetes Mellitus

Effects of Dorzagliatin, Insulin Glargine, and Metformin on Nocturnal Endogenous Glucose Production in Type 2 Diabetes (ADA 2025) - "Both DG and IG lowered nocturnal EGP by reducing rates of GGL overnight with a smaller contribution of GNG. M used as monotherapy did not provide adequate lowering of nocturnal EGP. These drugs used in combination may target GGL and GNG overnight thereby reducing nighttime EGP."

Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Dorzagliatin in Pancreatic Insufficient Cystic Fibrosis (clinicaltrials.gov) - P1 | N=15 | Not yet recruiting | Sponsor: University of Pennsylvania

New P1 trial • Cystic Fibrosis • Diabetes • Genetic Disorders • Immunology • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases

RESENSE: Glucokinase Activator in Monogenic Diabetes (clinicaltrials.gov) - P2 | N=44 | Not yet recruiting | Sponsor: Chinese University of Hong Kong

New P2 trial • Diabetes • Metabolic Disorders

Effects of Modulators of Gluconeogenesis, Glycogenolysis and Glucokinase Activity (clinicaltrials.gov) - P3 | N=100 | Active, not recruiting | Sponsor: University of Alabama at Birmingham | Recruiting ➔ Active, not recruiting

Enrollment closed • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

A functional and mechanistic explanation for the unique clinical success of the glucokinase activator dorzagliatin for treatment of type 2 diabetes. (PubMed, Diabetes) - "In contrast, dorzagliatin only binds favorably to the closed form of glucokinase, interacting primarily with R63, and causing a low energy barrier for the open-to-close transition. This provides the molecular rationale for the clinical success of dorzagliatin which can guide the future development of next-generation allosteric activators of GK."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Therapeutic Management of PI3Kα Inhibitor-Induced Hyperglycemia with a Novel Glucokinase Activator: Advancing the Frontier of PI3Kα Inhibitor Therapy. (PubMed, Mol Metab) - P1/2 | "Dorzagliatin shows promise for managing PI3Ki-associated hyperglycemia, thereby enhancing its therapeutic efficacy. The activation of liver glycogen kinase and insulin regulation may be key mechanisms underlying its therapeutic benefits."

Journal • Cervical Cancer • Diabetes • Oncology • Ovarian Cancer • Solid Tumor • IR • PIK3CA

Inclusive Drug Designing of Novel Indole Derivatives using Rationale, Pharmacophore Mapping and Molecular Docking. (PubMed, Antiinflamm Antiallergy Agents Med Chem) - "The novel-designed lead molecules demonstrate an enhanced pharmacokinetic profile, superior binding affinity, and minimal toxicity, based on computational study. These attributes make them promising candidates for further optimization as glucokinase activators."

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

SENSITISE-3: Chronic Dorzagliatin on Insulin and Incretin Function in Intermediate Hyperglycemia and Type 2 Diabetes (clinicaltrials.gov) - P=N/A | N=30 | Not yet recruiting | Sponsor: Elaine Chow | Initiation date: Nov 2024 ➔ Apr 2025

Trial initiation date • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Research of the efficacy and safety of dorzagliatin on latent autoimmune diabetes in adults(LADA) (ChiCTR) - P=N/A | N=60 | Sponsor: The First Affiliated Hospital of Bengbu Medical University; The First Affiliated Hospital of Bengbu Medical University

New trial • Diabetes • Immunology • Metabolic Disorders

Application of Dorzagliatin in peritoneal dialysis patients with type 2 diabetes mellitus: A case report. (PubMed, World J Diabetes) - "To our knowledge, this report is the first to use Dorzagliatin to treat type 2 diabetes peritoneal dialysis patients with challenging glucose control. Dorzagliatin, a novel glucokinase activator primarily metabolized by the liver, exhibits no pharmacokinetic differences among patients with varying degrees of chronic kidney disease. It has a high plasma protein binding rate and may not be cleared by peritoneal dialysis, potentially offering a new glycemic control option for Type 2 diabetic patients on peritoneal dialysis."

Journal • Cardiovascular • Chronic Kidney Disease • Diabetes • Hypertension • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Evaluating the Overall Safety of Glucokinase Activators in Patients with Type 2 Diabetes Mellitus. (PubMed, Diabetes Metab Syndr Obes) - "Among the 17 RCTs, dorzagliatin, AZD1656 and MK-0941 in three trials (1,541 patients), five trials (885 patients), and three trials (798 patients), respectively. The results of our meta-analysis indicated that GKAs were associated with a higher risk of any AEs, mild AEs, hyperlipidemia, and hyperuricemia. Further subgroup analyses revealed that the increased occurrence of hyperlipidemia, and hyperuricemia mainly originated from dorzagliatin treatment."

Journal • Review • Diabetes • Dyslipidemia • Metabolic Disorders • Type 2 Diabetes Mellitus

Sex-dependent additive effects of dorzagliatin and incretin on insulin secretion in a novel mouse model of GCK -MODY. (PubMed, bioRxiv) - "The GLP-1 receptor agonist exendin-4 improved glucose tolerance in male Gck KI/+ mice, an action potentiated by dorzagliatin, in male but not female mice. We use these mice to explore the effects of the glucokinase activator, dorzagliatin, and incretin on insulin secretion Whereas heterozygous mutant mice are mildly hyperglycemic, homozygotes have frank diabetes but survive to adulthood. Dorzagliatin potentiates the effects of GLP-1 receptor activation sex-dependently in heterozygotes Combined use of these drugs may be useful in some forms of GCK diabetes."

Journal • Preclinical • Diabetes • Metabolic Disorders • Renal Disease • Type 2 Diabetes Mellitus