Firsocostat (GS-0976) / Nimbus Therap, Gilead, Schrodinger - LARVOL DELTA

ACC1 Inhibition Enhances Treg Gvhd Treatment Efficacy through Regulation of Mitochondrial Fusion and Elongation (ASH 2023) - "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."

Clinical • Chronic Graft versus Host Disease • Graft versus Host Disease • Immunology • Pulmonary Disease • Respiratory Diseases • ACACA • CD4 • CPT1A

Precise monitoring of acquired drug resistance in melanoma by ACC-targeted PET imaging (EANM 2025) - "Materials and Methods A series of novel ACC-targeting probes were designed by coupling method using the inhibitor ND630 as the lead compound. 68Ga-DEACC PET imaging results showed that tumor uptake was significantly higher in the resistant group than in the sensitive group after treatment with vemurafenib, suggesting that ACC-targeted PET imaging can Precise monitoring of acquired drug resistance in melanoma. Conclusion 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."

Melanoma • Solid Tumor • BRAF

THE LIPID SYNTHESIS INHIBITORS ACC (FIRSOCOSAT) AND DGAT2 (ERVOGASTAT) REDUCE TRIGLYCERIDE CONTENT INDEPENDENTLY, BUT ONLY ERVOGASTAT ALSO REDUCES FIBROSIS BIOMARKERS IN HUMAN LIVER SPHEROIDS (AASLD 2025) - "The DGAT2 inhibitor Ervogastat and ACC inhibitor Firsocostat did not show any significant elevation of LDH secretion. We show a robust platform for MASH drug candidates and identify the DGAT2 inhibitor as a clinical candidate improving steatosis and fibrosis in human liver spheroid model. This data show that supressing steatosis would result in fibrosis prevention."

Biomarker • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

A RANDOMIZED, PLACEBO-CONTROLLED, PHASE 2 STUDY OF THE SAFETY AND EFFICACY OF COMBINATION TREATMENT WITH SEMAGLUTIDE, CILOFEXOR AND FIRSOCOSTAT IN PATIENTS WITH COMPENSATED CIRRHOSIS DUE TO METABOLIC DYSFUNCTION-ASSOCIATED STEATOHEPATITIS (WAYFIND) (AASLD 2025) - P2 | "SEMA+CILO/FIR did not achieve the primary endpoint of fibrosis improvement compared with PBO based on pathologist review. However, SEMA-containing regimens achieved MASH resolution and CILO/FIR achieved fibrosis improvement compared with PBO. Interestingly, PathAI showed clinical benefit with SEMA+CILO/FIR, suggesting that combination therapies should be explored for MASH."

Clinical • P2 data • Constipation • Fibrosis • Gastroenterology • Gastrointestinal Disorder • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Acetyl-CoA Carboxylase Inhibitors for Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. (PubMed, Pharmaceuticals (Basel)) - "Interventions included firsocostat, clesacostat, and combined regimens with semaglutide, selonsertib, and cilofexor or ervogastat. Dual ACC 1/2 inhibitors reduce hepatic steatosis and ALT levels but do not improve fibrosis. Their consistent association with hypertriglyceridemia raises concerns regarding potential long-term cardiometabolic risks, particularly in NAFLD patients with metabolic dysfunction."

Journal • Retrospective data • Review • Dyslipidemia • Fibrosis • Hepatology • Hypertriglyceridemia • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease

ND-630, an acetyl-CoA carboxylase inhibitor, prevents renal fibrosis in adenine-induced CKD mice. (PubMed, Naunyn Schmiedebergs Arch Pharmacol) - "Additionally, ND-630 protected against oxidative stress, decreased inflammatory cytokines levels, and antagonized TGF-β1/Smad signaling activation in CKD kidneys. ND-630 demonstrates nephroprotective effects in adenine-induced CKD mice by inhibiting ACC1-mediated lipid accumulation, suppressing oxidative stress and inflammation, and antagonizing TGF-β1/Smad signaling."

Journal • Preclinical • Chronic Kidney Disease • Fibrosis • Immunology • Inflammation • Nephrology • Oncology • Renal Disease • ACACA • CAT • IL6 • NOX4 • SOD2 • TGFB1 • TNFA • VIM

Gilead culls Novo-partnered MASH candidate (FierceBiotech) - "The...dropped program was evaluating two Gilead assets, cilofexor and firsocostat, either alone or with Novo's semaglutide for the treatment of MASH, a serious liver disease that used be called nonalcoholic steatohepatitis (NASH). A phase 2 trial with 457 patients wrapped up in December 2024, but Gilead has yet to publicly disclose any data from the study...With the Novo collaboration dropped, Gilead’s fibrotic disease pipeline is now entirely empty."

Discontinued • Metabolic Dysfunction-Associated Steatohepatitis

Gilead culls Novo-partnered MASH candidate… (FierceBiotech) - "After the recent approval and launch of twice-yearly HIV prophylactic Yeztugo, Gilead is cleaning up its R&D pipeline. The Bay Area company has dropped...a Novo Nordisk-partnered combination treatment for metabolic dysfunction-associated steatohepatitis (MASH)....The...dropped program was evaluating two Gilead assets, cilofexor and firsocostat, either alone or with Novo's semaglutide for the treatment of MASH, a serious liver disease that used be called nonalcoholic steatohepatitis (NASH). A phase 2 trial with 457 patients wrapped up in December 2024, but Gilead has yet to publicly disclose any data from the study."

Pipeline update • Metabolic Dysfunction-Associated Steatohepatitis

Fetuin-A increases thrombosis risk in non-alcoholic fatty liver disease by binding to TLR-4 on platelets. (PubMed, Cardiovasc Res) - "Fetuin-A emerges as a positive regulator of platelet hyperreactivity in NAFLD. Acting via TLR-4-dependent signalling pathways, plasma fetuin-A directly amplifies platelet activation and promotes in vivo thrombosis. Firsocostat, rosuvastatin, and pioglitazone abrogate these enhancing effects by reducing fetuin-A levels. The fetuin-A-inhibiting antibody presents potential therapeutic advantages to prevent thrombotic complications in NAFLD."

Journal • Addiction (Opioid and Alcohol) • Cardiovascular • Hematological Disorders • Hepatology • Metabolic Dysfunction-Associated Steatotic Liver Disease • Thrombosis • AHSG • MYD88 • TLR4

Precise monitoring of acquired drug resistance in melanoma by ACC-targeted PET imaging (SNMMI 2025) - " A series of novel ACC-targeting probes were designed by coupling method using the inhibitor ND630 as the lead compound. A total of four probes were designed and synthesized, and the targeted compounds were characterized by MS and NMR. The chemical purity of all the target compounds was higher than 98% by analytic-HPLC. The 68Ga labeling was successfully performed by conventional metal labeling methods, and the labeling rate of all four probes was more than 60% (n = 3, uncorrected for decay) and the radiochemical purity was > 98%."

Melanoma • Oncology • Solid Tumor • BRAF

Comparison of Pharmacological Therapies for Metabolic Dysfunction-Associated Steatohepatitis: Systematic Review and Network Meta-analysis (APASL 2025) - "For the co-primary endpoint of fibrosis improvement without MASH resolution, pegozafermin, cilofexor + firsocostat, survodutide, obeticholic acid, tirzepatide, and resmetirom were significantly better than placebo in improving ≥ 1 fibrosis stage without worsening MASH. Pegozafermin (SUCRA: 90.18), cilofexor plus firsocostat (SUCRA: 82.82), and cilofexor plus selonsertib (SUCRA: 79.62) were ranked the most effective interventions. For the co-primary endpoint of MASH resolution without worsening fibrosis, pegozafermin, survodutide, tirzepatide, efruxifermin, liraglutide, vitamin E + pioglitazone, resmetirom, semaglutide, pioglitazone, and lanifibranor were significantly better than placebo... This study provides updated rank-order efficacy of MASH pharmacological therapies for fibrosis regression and MASH resolution. These data are helpful to inform practice and clinical trial design."

Retrospective data • Review • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

Pharmacokinetics and Safety of Fenofibrate in Participants with Mild Hepatic Impairment or with Advanced Fibrosis due to Metabolic-Associated Fatty Liver Disease. (PubMed, J Clin Pharmacol) - "In the phase 2a study, participants with hypertriglyceridemia and advanced fibrosis due to MAFLD were randomly assigned (1:1) fenofibrate 48 mg (n = 15) or fenofibrate 145 mg (n = 16) combined with firsocostat 20 mg, taken orally once daily for 24 weeks. In the phase 2a study, three participants had grade 3 hypertriglyceridemia. Fenofibrate was well tolerated, and modest differences were observed in fenofibric acid exposure in participants with mild hepatic impairment or advanced fibrosis due to MAFLD."

Journal • PK/PD data • Dyslipidemia • Fibrosis • Hepatology • Hypertriglyceridemia • Immunology • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Comparison of pharmacological therapies in metabolic dysfunction-associated steatohepatitis for fibrosis regression and MASH resolution: Systematic review and network meta-analysis. (PubMed, Hepatology) - "This study provides updated rank-order efficacy of MASH pharmacological therapies for fibrosis regression and MASH resolution. These data are helpful to inform practice and clinical trial design."

Journal • Retrospective data • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis

LncRNA CRCMSL interferes in phospholipid unsaturation to suppress colorectal cancer progression via reducing membrane fluidity. (PubMed, J Adv Res) - "Our study illustrated a novel mechanism of CRCMSL-ACC1 axis-associated fatty acid metabolism in CRC progression, providing laboratory evidence for the development of targeted therapies for patients with advanced CRC."

Journal • Colorectal Cancer • Metabolic Disorders • Oncology • Solid Tumor • SCD

UHRF1 promotes calcium oxalate-induced renal fibrosis by renal lipid deposition via bridging AMPK dephosphorylation. (PubMed, Cell Biol Toxicol) - "This study revealed that UHRF1 promotes CaOx -induced renal fibrosis by enhancing lipid accumulation and suppressing FAO via inhibiting the AMPK pathway. These findings underscore the feasible therapeutic implications of targeting UHRF1 to prevent renal fibrosis due to stones."

Journal • Chronic Kidney Disease • Fibrosis • Immunology • Metabolic Disorders • Nephrology • Renal Calculi • Renal Disease • Targeted Protein Degradation • ACACA • AMPK • UHRF1

Study of Semaglutide, and Cilofexor/Firsocostat, Alone and in Combination, in Adults With Cirrhosis Due to Nonalcoholic Steatohepatitis (NASH) (clinicaltrials.gov) - P2 | N=457 | Completed | Sponsor: Gilead Sciences | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Hepatology • Immunology • Metabolic Dysfunction-Associated Steatohepatitis

Regulation of Rice Grain Weight by Fatty Acid Composition: Unveiling the Mechanistic Roles of OsLIN6 by OsARF12. (PubMed, J Agric Food Chem) - "Field trials showed that 1000-grain weight was significantly reduced when treated with the fatty acid synthesis inhibitor, Firsocostat S enantiomer (FSE), at the heading and flowering stages...Importantly, OsARF12 was shown to bind to the OsLIN6 promoter and activate its expression. In summary, this study highlights the crucial role of the fatty acid synthesis gene, OsLIN6, which was regulated by OsARF12, in rice grain weight determination, thus establishing the molecular link between fatty acid synthesis and auxin signaling."

Journal

COMPARATIVE EFFICACY OF PHARMACOLOGIC THERAPIES FOR MASH IN REDUCING LIVER FAT CONTENT: SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS (AASLD 2024) - "By comparison of absolute MRI-PDFF decline at 24 weeks, aldafermin (SUCRA: 83.65), pegozafermin (SUCRA: 83.46), and pioglitazone (SUCRA: 71.67) were the most efficacious interventions. Efinopegdutide (SUCRA: 67.02), semaglutide + firsocostat (SUCRA: 62.43), and pegbelfermin (SUCRA: 61.68) were the most efficacious interventions for achieving ≥30% decline in MRI-PDFF at 24 weeks...Efruxifermin, aldafermin and pegozafermin were the most efficacious for MRI-PDFF decline at 12 weeks by both the absolute decline and achieving ≥30% decline in MRI-PDFF. At 48 weeks, Cilofexor + firsocostat, selonternib + firsocostat and cilofexor were most efficacious in absolute reduction in MRI-PDFF, while semglutide, tropifexor and tropifexor + cenicriviroc were most efficacious in achieving ≥30% decline in MRI-PDFF... This study provides an updated, relative rank-order efficacy of therapies for MASH in reducing hepatic fat as assessed by MRI-PDFF. These data may help inform the design and..."

Retrospective data • Review • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • FGF21

Characterization of six clinical drugs and dietary intervention in the non-obese CDAA-HFD mouse model of MASH and progressive fibrosis. (PubMed, Am J Physiol Gastrointest Liver Physiol) - "To validate the CDAA-HFD mouse, we evaluated disease progression and responsiveness to dietary and pharmacological interventions with semaglutide, lanifibranor, elafibranor, obeticholic acid (OCA), firsocostat and resmetirom.Disease phenotyping was performed in C57BL/6J mice fed CDAA-HFD for 3-20 weeks and ranked using the MASLD Human Proximity Score (MHPS). CDAA-HFD mice are suitable for profiling drug candidates directly targeting hepatic lipid metabolism, inflammation, and fibrosis. The timing of pharmacological intervention is critical for determining antifibrotic drug efficacy in the model."

Journal • Preclinical • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Oncology

ACC2: A NOVEL BIOMARKER FOR METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE-INDUCED HEPATOCELLULAR CARCINOMA WITH SEVERE STEATOSIS (AASLD 2024) - "This result aligns with findings from studies using an ACC inhibitor (GS-0976) in NASH (Loomba et al., 2018). The transcriptomic analyses in this study suggest that AAC2 inhibitors could be evaluated in combination with tyrosine kinase inhibitors and/or immunotherapy treatment for MASLD-HCC in patients with severe steatosis."

Biomarker • IO biomarker • Fibrosis • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • Oncology • Solid Tumor • ACACA • ACACB • FASN • NAT2

EVALUATION OF MASH DRUG EFFICACY USING LIVER ORGANOIDS BASED ON DRUG TARGET PATHWAYS (AASLD 2024) - "Then, we administered the following drugs alone or in combination: Resmetirom (10 μM), Lanifibranor (80 μM), Firsocostat (20 μM) and Liraglutide (20 μM). 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."

Clinical • Fibrosis • Hepatology • Immunology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • FGF19 • FGF21 • IL6

HIGHLY SENSITIVE METABOLIC FLUX ANALYSIS USING 14C-MICROTRACERS COMBINED WITH ACCELERATOR MASS SPECTROMETRY - A PROOF OF CONCEPT STUDY ON DE NOVO LIPOGENESIS (AASLD 2024) - " De novo lipogenesis activity was assessed in Ldlr-/-.Leiden MASLD mice fed a standard chow or a MASH-inducing high-fat diet (HFD) with/without the DNL inhibitor firsocostat (ACCi), as well as in an ex vivo porcine liver perfusion model... We show here that this 14C microtracer approach combined with AMS analysis can be used for assessment of metabolic fluxes in various experimental models at much lower amounts of tracer used than in conventional tracer methodologies. This allows study of metabolic pathways without disrupting the pathway of interest by adding large quantities of precursor and opens up opportunities to study the activity of other (metabolic) pathways in which only very small amounts of product are produced."

Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Dynamic Liver Chip Based on Well-Coupled Microfluidics: An Accurate NASH Model for Drug Evaluation. (PubMed, Anal Chem) - "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."

Journal • Addiction (Opioid and Alcohol) • Hepatitis C • Hepatology • Metabolic Dysfunction-Associated Steatohepatitis

A microvascularizedin vitroliver model for disease modeling and drug discovery. (PubMed, Biofabrication) - "Steatosis was induced by exogenous administration of fatty acids which could be prevented by co-administration of firsocostat. Administration of TGF-β 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."

Journal • Fibrosis • Hepatology • Immunology • TGFB1

68Ga-labeled novel ACC-targeted probes for precise monitoring of acquired drug resistance in melanoma (EANM 2024) - "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."

Melanoma • Oncology • Solid Tumor • BRAF