Firsocostat (GS-0976) / Gilead 
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  • ||||||||||  EVALUATION OF MASH DRUG EFFICACY USING LIVER ORGANOIDS BASED ON DRUG TARGET PATHWAYS () -  Oct 15, 2024 - Abstract #AASLD2024AASLD_2302;    
    Then, we administered the following drugs alone or in combination: Resmetirom (10 ?M), Lanifibranor (80 ?M), Firsocostat (20 ?M) and Liraglutide (20 ?M). Although accurately reproducing the lipid metabolism of actual patients is difficult, the organoid model was shown to be more appropriate for evaluating drug efficacy than the existing in vitro 2D cell models.
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    Journal:  Dynamic Liver Chip Based on Well-Coupled Microfluidics: An Accurate NASH Model for Drug Evaluation. (Pubmed Central) -  Oct 2, 2024   
    The subtle time dependence of firsocostat treatment to different progressed stages of NASH was clearly figured out. Therefore, we prospect the liver chip that adopted well-coupled microfluidics could be an accurate and standard liver model in vitro to carry out the antilipemic evaluation and screening, which significantly enlightens the drug evaluation by liver on chip in vitro.
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    Journal:  A microvascularizedin vitroliver model for disease modeling and drug discovery. (Pubmed Central) -  Sep 30, 2024   
    resulted in an activated stellate cells phenotype which could be prevented by the co-administration of SB-431542. The model was implemented on a microtiter plate format comprising 64 chips which enabled the development of a fully automated, multiplexed fibrosis assay with a robust Z' factor suitable for high-throughput applications.
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    68Ga-labeled novel ACC-targeted probes for precise monitoring of acquired drug resistance in melanoma (Hall F) -  Sep 27, 2024 - Abstract #EANM2024EANM_727;    
    Materials and Probes with different lengths of PEG chains were prepared by using the ACC inhibitor ND630 as the lead compound and modifying the metal chelating groups by the coupling design method... A series of 68Ga-labeled ACC-targeting probes were successfully prepared, among which 68Ga-DEACC has the potential to be used to monitor the evolution of fatty acid synthesis resistance, which is worthy of further study, and further probe optimization and evaluation are in progress.
  • ||||||||||  Clinical translatability of the GAN diet-induced obese and biopsy-confirmed mouse model of MASH (Poster Area) -  Apr 2, 2024 - Abstract #EASLILC2024EASL_ILC_1091;    
    agonist, 10 mg/kg, PO, QD), firsocostat (ACC inhibitor, 5 mg/kg, PO, QD), or vehicle for 12 weeks. GAN DIO-MASH mice faithfully reproduce histological outcomes of several compounds profiled in clinical trials for MASH, highlighting clinical translatability and utility of the model in preclinical drug development.
  • ||||||||||  selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead
    Biomarker, Journal:  Digital pathology with artificial intelligence analysis provides insight to the efficacy of anti-fibrotic compounds in human 3D MASH model. (Pubmed Central) -  Mar 16, 2024   
    In contrast, clinical compounds, Firsocostat and Selonsertib, alone and in combination showed strong anti-fibrotic effects on the deposition of collagen fibers, however less pronounced on the secretion of pro-fibrotic biomarkers. In summary, the phenotypic quantification of fibrosis of MASH hLiMTs combined with secretion of pro-fibrotic biomarkers and transcriptomics represents a promising drug discovery tool for assessing anti-fibrotic compounds.
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    Journal:  Repurposing a human acetyl-CoA carboxylase inhibitor firsocostat to treat fungal candidiasis alone and in combination. (Pubmed Central) -  Nov 29, 2023   
    Sequencing spontaneous firsocostat-resistant mutants revealed mutations mapping to C. albicans ACC, confirming that firsocostat has retained its target in C. albicans. Overall, our findings suggest that repurposing firsocostat, either alone or in combination with other antifungal agents, holds promising potential in the development of antifungal drugs and the treatment of candidiasis.
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    ACC1 Inhibition Enhances Treg Gvhd Treatment Efficacy through Regulation of Mitochondrial Fusion and Elongation (SDCC - Halls G-H) -  Nov 3, 2023 - Abstract #ASH2023ASH_6275;    
    In summary, ACC1 inhibition or deletion amplifies murine Treg potency resulting in superior metabolic fitness, and greater efficacy in treating cGVHD mice with established BOS, in part through enhancing mitochondrial fusion. Since ND630 is already under investigation in patients, ACC1 inhibition with ND630 could be readily translatable for clinical trials with a goal of utilizing Tregs with inhibited or deleted ACC1 to improve GVHD therapy.
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    Journal:  VDAC2 malonylation participates in sepsis-induced myocardial dysfunction via mitochondrial-related ferroptosis. (Pubmed Central) -  Jul 11, 2023   
    The study also found that the inhibition of VDAC2 malonylation by synthesizing mitochondria targeting nano material TPP-AAV could further alleviate ferroptosis and myocardial dysfunction following sepsis. In summary, our findings indicated that VDAC2 malonylation plays a crucial role in SIMD and that targeting VDAC2 malonylation could be a potential treatment strategy for SIMD.
  • ||||||||||  selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead
    Evaluation of anti-fibrotic compounds effect in 3D human NASH model using quantitative digital pathology (Poster Area) -  Apr 12, 2023 - Abstract #EASLILC2023EASL_ILC_514;    
    An efficacy study extended the evaluation to include clinical compounds, Firsocostat, Selonsertib, and Resmiteron, and a combination of Firsocostat and Selonsertib. In summary, the use of NASH hLiMTs and FibroNest imaging combined with transcriptomics and functional assays represents a promising drug discovery tool for the evaluation of the efficacy of different modalities of anti-fibrotic drug candidates and their combinatorial treatment.
  • ||||||||||  TLC-3595 / OrsoBio
    TLC-3595, a selective acetyl-CoA carboxylase 2 (ACC2) inhibitor, improves steatosis and fibrosis in murine models of NASH via pleiotropic mechanisms (Poster Area) -  Apr 12, 2023 - Abstract #EASLILC2023EASL_ILC_507;    
    In summary, the use of NASH hLiMTs and FibroNest imaging combined with transcriptomics and functional assays represents a promising drug discovery tool for the evaluation of the efficacy of different modalities of anti-fibrotic drug candidates and their combinatorial treatment. High-fat diet (HFD)-fed, diet-induced obese (DIO) mice, Fatty Liver Shionogi-Lepob/Lepob (FLS-ob/ob) mice, or choline-deficient, L-amino acid-defined HFD (CDAHFD)-fed mice were treated with TLC-3595 (5-60 mg/kg BID) or the nonselective, liver-targeted ACC inhibitor firsocostat (FIR, 0.5-1.5 mg/kg BID) for 4
  • ||||||||||  Firsocostat (GS-0976) / Gilead, cilofexor/firsocostat (GS-9674/GS-0976) / Gilead, cilofexor (GS-9674) / Gilead
    Trial completion date, Trial primary completion date:  Study of Semaglutide, and Cilofexor/Firsocostat, Alone and in Combination, in Adults With Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH) (clinicaltrials.gov) -  Mar 30, 2023   
    P2,  N=440, Recruiting, 
    High-fat diet (HFD)-fed, diet-induced obese (DIO) mice, Fatty Liver Shionogi-Lepob/Lepob (FLS-ob/ob) mice, or choline-deficient, L-amino acid-defined HFD (CDAHFD)-fed mice were treated with TLC-3595 (5-60 mg/kg BID) or the nonselective, liver-targeted ACC inhibitor firsocostat (FIR, 0.5-1.5 mg/kg BID) for 4 Trial completion date: Mar 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Nov 2024
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    Preclinical, Journal:  Obesity promotes lipid accumulation in mouse cartilage-A potential role of acetyl-CoA carboxylase (ACC) mediated chondrocyte de novo lipogenesis. (Pubmed Central) -  Nov 19, 2022   
    In vitro, chondrocytes upregulated de novo lipogenesis when cultured under high-glucose, high-insulin conditions, and this observation was associated with the activation of ACC, which was attenuated by the addition of ND-630. This study provides the first evidence that lipid deposition is increased in cartilage with obesity and that this is associated with the upregulation of ACC-mediated de novo lipogenesis. This was supported by our observation that ACC inhibition ameliorated lipid accumulation in chondrocytes, thereby suggesting that ACC could potentially be targeted to treat obesity-associated OA.
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    Journal:  Acetyl Co-A Carboxylase Inhibition Halts Hyperglycemia Induced Upregulation of De Novo Lipogenesis in Podocytes and Proximal Tubular Cells. (Pubmed Central) -  Oct 28, 2022   
    Knocking out of the ACC coding Acaca and Acacb genes by CRISPR/cas9, downregulation of Acaca and Acacb by specific antisense LNA GapmeRs and inhibition of ACC by firsocostat similarly halted/mitigated upregulation of DNL and decreased markers of fibrosis and programmed cell death in podocytes and various tubular cells. ACC inhibition is a potential therapeutic target to mitigate or halt hyperglycemia-induced upregulation of DNL in podocytes and tubular cells.
  • ||||||||||  selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead
    MODELLING BIOLOGICAL MECHANISMS OF A PNPLA3 POLYMORPHISM IN A 3D HUMAN LIVER MICROTISSUE FOR NASH PROGRESSION AND DRUG EFFICACY () -  Oct 23, 2022 - Abstract #AASLD2022AASLD_1355;    
    Stimulated human ex-vivo liver microtissues recapitulate human hallmarks of NASH and represent a valuable model for the identification of novel pharmacological strategies and selection of candidates. We furthermore demonstrate the worsening effect of PNPLA3 (I148M) in NASH by generating a new model of study with a defined genetic background for a better efficiency of drug candidates selection and personalized medicine application.
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    RECAPITULATING INSULIN RESISTANCE IN A 3D HUMAN LIVER MODEL FOR EFFICACY TESTING OF DRUG CANDIDATES () -  Oct 23, 2022 - Abstract #AASLD2022AASLD_1350;    
    he presented 3D human liver model replicates the features of glucose and lipid handling in a highly scalable format and its application for efficacy testing of anti-steatotic and anti-diabetic compounds. It constitutes one of the three central elements for building a multi-tissue MPS besides pancreatic islets and adipose microtissues to study human glucose and lipid homeostasis.
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    Biomarker, Journal:  Elevated de novo lipogenesis, slow liver triglyceride turnover and clinical correlations in nonalcoholic steatohepatitis patients. (Pubmed Central) -  Oct 5, 2022   
    Finally, we found treatment with the acetyl-CoA carboxylase inhibitor firsocostat reduced hepatic DNL at 4 and 12 weeks, using a correction model for residual label that accounts for hepatic triglyceride turnover. Taken together, these data support an important pathophysiological role for elevated hepatic DNL in NASH, and demonstrate that response to pharmacological agents targeting DNL can be correlated with pre-treatment DNL.
  • ||||||||||  Firsocostat (GS-0976) / Gilead
    Recapitulating insulin resistance in a 3D human liver model for efficacy testing of drug candidates (Poster Area) -  May 12, 2022 - Abstract #EASLILC2022EASL_ILC_2221;    
    The presented 3D human liver model replicates the features of glucose and lipid handling in a highly scalable format and its application for efficacy testing of anti-steatotic and anti-diabetic compounds. It constitutes one of the three central elements for building a multi-tissue MPS besides pancreatic islets and adipose microtissues to study human glucose and lipid homeostasis.
  • ||||||||||  selonsertib (GS-4997) / Gilead, Firsocostat (GS-0976) / Gilead
    3D human NASH model as a screening-based discovery approach for selecting and prioritizing drug candidates (Poster Area) -  May 12, 2022 - Abstract #EASLILC2022EASL_ILC_1784;    
    It constitutes one of the three central elements for building a multi-tissue MPS besides pancreatic islets and adipose microtissues to study human glucose and lipid homeostasis. In summary, this high-throughput and compatible 3D human NASH model represents a promising approach for NASH drug candidate efficacy selection early within the drug discovery process.
  • ||||||||||  Firsocostat (GS-0976) / Gilead, cilofexor (GS-9674) / Gilead
    The MRI and AST (MAST) score is correlated with noninvasive and histologic markers of fibrosis in patients with advanced fibrosis due to NASH (Poster Area) -  Mar 16, 2022 - Abstract #EASLILC2022EASL_ILC_1227;    
    Our aims were to evaluate the effects of cilofexor (CILO) and firsocostat (FIR) on MAST, and associations between treatmentinduced changes in MAST with histologic and noninvasive test (NIT) responses in patients with advanced fibrosis due to NASH. In patients with advanced fibrosis due to NASH, the MAST Risk score is correlated with noninvasive and histologic measures of fibrosis and may be a useful marker of treatment response beyond conventional histologic methods.