TVB-3664 / Sagimet Biosci - LARVOL DELTA

Hepatoprotective effects of fatty acid synthase inhibitor TVB-3664 in the GAN diet-induced obese and biopsy-confirmed mouse model of MASH (EASL 2025) - "Background and Aims: Denifanstat, an oral fatty acid synthase (FASN) inhibitor, have recently been demonstrated to improve NAFLD Activity Score (NAS) and fibrosis stage in a phase 2b clinical trial (FASCINATE-2) in patients with metabolic dysfunction-associated steatohepatitis (MASH). TVB-3664 improved metabolic, biochemical and histological markers of steatosis, inflammation and fibrosis/fibrogenesis. In addition, TVB-3664 improved histopathological NAFLD Activity Score, with longer treatment intervention needed for fibrosis stage improvement. The therapeutic effects of TVB-3664 highlight the translatability and applicability of the GAN DIO-MASH mouse model in preclinical drug discovery."

Biopsy • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Obesity • FASN

Fatty acid synthase (FASN) inhibition cooperates with BH3 mimetic drugs to overcome resistance to mitochondrial apoptosis in pancreatic cancer. (PubMed, Neoplasia) - "Computational studies with TVB-3166 and TVB-3664, two analogues of the clinical-grade FASNi TVB-2640 (denifanstat), confirmed their uncompetitive behavior towards NADPH when bound to the FASN ketoacyl reductase domain...Experiments in PDAC PDXs in vivo confirmed the synergistic antitumor activity of TVB-3664 with navitoclax and venetoclax, independent of the nature of the replication stress signature of patient-derived PDAC cells. The discovery that targeted inhibition of FASN is a metabolic perturbation that sensitizes PDAC cells to BH3 mimetics warrants further investigation to overcome resistance to mitochondrial apoptosis in PDAC patients."

Journal • Hepatology • Oncology • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • BCL2 • BCL2L1 • BCL2L2 • FASN

Hepatoprotective effects of fatty acid synthase inhibitor TVB-3664 in the GAN diet-induced obese and biopsy-confirmed mouse model of MASH (EASL-SLD 2025) - "Background and Aims: Denifanstat, an oral fatty acid synthase (FASN) inhibitor, have recently been demonstrated to improve NAFLD Activity Score (NAS) and fibrosis stage in a phase 2b clinical trial (FASCINATE-2) in patients with metabolic dysfunction-associated steatohepatitis (MASH). TVB-3664 improved metabolic, biochemical, and histopathological parameters of MASH including NAFLD Activity Score in the GAN DIO-MASH mouse model. Longer treatment intervention might be required for observing anti-fibrotic action."

Biopsy • Preclinical • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • FASN

FATTY ACID SYNTHASE (FASN) INHIBITOR REDUCES ATHEROSCLEROSIS DEVELOPMENT IN DIET-INDUCED DYSLIPIDAEMIA LDL RECEPTOR KNOCKOUT MICE WITH MASH (AASLD 2024) - " Male Ldlr-/-.Leiden mice were fed with fast-food diet (FFD) for 18 weeks to induce dyslipidaemia, atherosclerosis and MASH features and treated with TVB-3664 (a surrogate FASN inhibitor for denifanstat, 5 mg/kg, PO, QD) for 10 weeks. Denifanstat has shown promise on LDL-C lowering and histological improvements in MASH patients. FASN inhibition not only reduced circulating cholesterol but also decreased the development of atherosclerosis and improved liver histology in a mouse model of dyslipidaemia and MASH. These results suggest that denifanstat could provide benefits in both cardiovascular and liver health and support its future clinical evaluation for long term outcomes in MASH patients."

Preclinical • Atherosclerosis • Cardiovascular • Dyslipidemia • Fibrosis • Immunology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • FASN

Combination of fatty acid synthase (FASN) inhibitor and thyroid hormone receptor beta (THRb) agonist resmetirom shows synergistic improvement of NAFLD activity score (NAS) within 6-weeks in diet-induced obese mice with biopsy-confirmed MASH (EASL-ILC 2024) - " Male C57BL/6J GAN-diet-induced obese mice with histologically confirmed NAS ≥ 5 and fibrosis stage F1-F3 were randomized and treated with either vehicle, TVB-3664 (a surrogate FASN inhibitor for denifanstat, 5 mg/kg, PO, QD) or RES (3 mg/kg, PO, QD) individually or in combination for 6 weeks (n=10-12 for each group). Combination of FASN inhibitor and THRb agonist RES had a synergistic effect on histological improvement of NAS compared to single agents within 6-weeks in a mouse model of MASH. These results suggest that the complementary mechanisms of action of denifanstat (directly decrease lipid synthesis, inflammation and fibrosis) and RES (increase lipid oxidation) combined could provide added benefit and support future clinical evaluation of this combination for MASH."

Biopsy • Late-breaking abstract • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • FASN

Combination of fatty acid synthase (FASN) inhibitor and thyroid hormone receptor beta (THRb) agonist, resmetirom, improved markers of NASH and cardiovascular health in LDL receptor knockout NASH mice (EASL-ILC 2024) - "Denifanstat and resmetirom were also evaluated in vitro in HSCs for direct anti-fibrotic effects Male Ldlr-/- mice were fed with fast-food diet (FFD) for 18 weeks to induce NASH features and treated with either TVB-3664 (a surrogate FASN inhibitor for denifanstat, 5 mg/kg, PO, QD) or THRb agonist resmetirom (MGL-3196, 3 mg/kg, PO, QD) alone or in combination for 10 weeks. Combination of FASN inhibitor and THRb agonist resmetirom showed further ALT/AST improvement and lipid lowering compared to either agent alone in a mouse model of dyslipidaemia and NASH. In vitro, denifanstat, but not resmetirom, directly reduced collagen production. These results suggest that complementary MOAs of denifanstat (DNL inhibition and direct anti-fibrotic effect) and resmetirom (lipid burning) combined could provide added benefit and support future clinical evaluation of this combination for NASH."

Preclinical • Cardiovascular • Dyslipidemia • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Dysfunction-Associated Steatohepatitis • FASN • TGFB1

ARTIFICIAL INTELLIGENCE BASED DIGITAL PATHOLOGY REVEALS FATTY ACID SYNTHASE (FASN) INHIBITOR ALONE OR IN COMBINATION WITH SEMAGLUTIDE IMPROVES FIBROSIS IN DIET-INDUCED OBESE MICE WITH BIOPSY-CONFIRMED NASH AND FIBROSIS (AASLD 2023) - " Male C57BL/6J Gubra-Amylin-NASH (GAN) diet-induced obese mice with histologically-confirmed NAS (≥ 5) and fibrosis stage (F2-F3) were randomized and treated with either TVB-3664 (a surrogate FASN inhibitor for denifanstat, 10 mg/kg, PO, QD) or semaglutide (30 nmol/kg, SC, QD) alone or in combination for 12 weeks (Gubra, Denmark). Combination treatment of FASN inhibitor and semaglutide showed further histological improvement of NAS and fibrosis compared to single agent treatment in a translational mouse model of NASH. These results support future clinical evaluation of denifanstat/GLP-1 combination therapy."

Biopsy • Combination therapy • Preclinical • Fibrosis • Hepatology • Immunology • Inflammation • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Obesity • FASN

Pharmacological induction of membrane lipid poly-unsaturation sensitizes melanoma to ROS inducers and overcomes acquired resistance to targeted therapy. (PubMed, J Exp Clin Cancer Res) - "We conclude that under MAPK inhibition the direct pharmacological inhibition of FASN evokes an exquisite vulnerability to inducers of ROS by increasing membrane lipid poly-unsaturation. The exploitation of this vulnerability by combining MAPK and/or FASN inhibitors with inducers of ROS greatly delays the onset of therapy resistance and increases survival. Our work identifies a clinically actionable combinatorial treatment for therapy-resistant cancer."

Journal • Preclinical • Melanoma • Metabolic Disorders • Oncology • Solid Tumor • BRAF

FASN inhibition targets multiple drivers of NASH by reducing steatosis, inflammation and fibrosis in preclinical models. (PubMed, Sci Rep) - "Three related FASN inhibitors were used; TVB-3664, TVB-3166 and clinical stage TVB-2640 (denifanstat). These results demonstrate that FASN inhibition attenuates inflammatory and fibrotic drivers of NASH by direct inhibition of immune and stellate cells, beyond decreasing fat accumulation in hepatocytes. FASN inhibition therefore provides an opportunity to target three key hallmarks of NASH."

Journal • Preclinical • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Inflammation • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis • Oncology • Solid Tumor • CD4 • COL1A1 • IL1B

Therapeutic efficacy of FASN inhibition in preclinical models of HCC. (PubMed, Hepatology) - "This preclinical study suggests the limited efficacy of targeting FASN as monotherapy for HCC treatment. However, FASN inhibitors could be combined with other drugs for improved effectiveness. These combination therapies could be developed based on the driver oncogenes, supporting precision medicine approaches for HCC treatment."

IO biomarker • Journal • Preclinical • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Non-alcoholic Steatohepatitis • Oncology • Solid Tumor • MET • MYC • PTEN

Loss of wild type KRAS in KRAS lung adenocarcinoma is associated with cancer mortality and confers sensitivity to FASN inhibitors. (PubMed, Lung Cancer) - "LAKR in KRAS cancers may represent an independent negative prognostic factor for patients with KRAS LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRAS and FASN inhibitors in patients with KRAS LAKR is warranted."

Journal • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Overexpression of CD36 promotes tumorigenesis in colorectal cancer (AACR 2018) - "...Cell proliferation was assessed in primary CRC cells established from patient derived xenografts (PDX) treated in combination with Sulfo-N-succinimidyl oleate (SSO), an irreversible inhibitor of CD36, and FASN inhibitor TVB-3664...Furthermore, a decrease in FASN expression is associated with an induction of CD36, suggesting a possible mechanism of resistance to FASN inhibition. Better understanding the role of CD36 may provide new therapeutic approaches for treatment of CRC patients."

IO Biomarker • Colorectal Cancer • Oral Cancer

De novo fatty acid synthesis-driven sphingolipid metabolism promotes metastatic potential of colorectal cancer (AACR 2018) - "Primary CRC cells were established from CRC patient-derived xenograft (PDX) tumors and treated with TVB-3664, a novel FASN inhibitor, or FTY-720, an S1P mimetic that inhibits SPHKs and S1P receptors. Upregulation of the FASN/SPHK/S1P axis promotes CRC progression by enhancing cellular proliferation, adhesion and migration. Therefore, this study provides a strong rationale for further investigation of the interconnection of de novo lipogenesis and sphingolipid metabolism that would potentially lead to identification of new therapeutic targets and strategies for CRC."

IO Biomarker • Colorectal Cancer

Inhibition of Fatty Acid Synthase Upregulates Expression of CD36 to Sustain Proliferation of Colorectal Cancer Cells. (PubMed, Front Oncol) - "Importantly, combinatorial treatment of primary and established colorectal cancer cells with TVB-3664 and sulfosuccinimidyl oleate shows a synergistic effect on cell proliferation. In summary, our study demonstrates that upregulation of CD36 expression is a potential compensatory mechanism for fatty acid synthase inhibition and that inhibition of CD36 can improve the efficacy of fatty acid synthase-targeted therapy."

Journal • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • BIRC5 • CD36 • FASN

De Novo Fatty Acid Synthesis Driven Sphingolipid Metabolism Promotes Metastatic Potential of Colorectal Cancer. (PubMed, Mol Cancer Res) - "This study provides a strong rationale for further investigation of the interconnection of de novo lipogenesis and sphingolipid metabolism that could potentially lead to the identification of new therapeutic targets and strategies for CRC."

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