ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials

Calle, Roberto A.; Amin, Neeta B.; Carvajal‐Gonzalez, Santos; Ross, Trenton T.; Bergman, Arthur; Aggarwal, Sudeepta; Crowley, Collin; Rinaldi, Anthony; Mancuso, James P.; Aggarwal, Naresh; Somayaji, Veena; Inglot, Małgorzata; Tuthill, Theresa; Kou, Kou; Boucher, Magalie; Tesz, Gregory J.; Dullea, Robert; Bence, Kendra K.; Kim, Albert M.; Pfefferkorn, Jeffrey A.; Esler, William P.

doi:10.1038/s41591-021-01489-1

Cited by 141 publications

(121 citation statements)

References 48 publications

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“…Another instance is PF-05175157, the first-in-human clinical trials ACC inhibitor, contributes to DNL reduction in treatment for T2DM but with concomitant reductions in platelet count ( 112 ). Recently, an exciting result in phase II clinical trial shows that the co-administration of PF-0522134 (a new ACC1 inhibitor in clinical trial) and PF-6865571 (DGAT2 inhibitor) has a strong effect in treating NASH without the side effect of hypertriglyceridemia ( 113 ). However, there are several challenges to address the side-effects of ACCs inhibition in clinical practice.…”

Section: Limitations and Prospectsmentioning

confidence: 99%

Acetyl-CoA Carboxylases and Diseases

Wang

et al. 2022

Front. Oncol.

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Acetyl-CoA carboxylases (ACCs) are enzymes that catalyze the carboxylation of acetyl-CoA to produce malonyl-CoA. In mammals, ACC1 and ACC2 are two members of ACCs. ACC1 localizes in the cytosol and acts as the first and rate-limiting enzyme in the de novo fatty acid synthesis pathway. ACC2 localizes on the outer membrane of mitochondria and produces malonyl-CoA to regulate the activity of carnitine palmitoyltransferase 1 (CPT1) that involves in the β-oxidation of fatty acid. Fatty acid synthesis is central in a myriad of physiological and pathological conditions. ACC1 is the major member of ACCs in mammalian, mountains of documents record the roles of ACC1 in various diseases, such as cancer, diabetes, obesity. Besides, acetyl-CoA and malonyl-CoA are cofactors in protein acetylation and malonylation, respectively, so that the manipulation of acetyl-CoA and malonyl-CoA by ACC1 can also markedly influence the profile of protein post-translational modifications, resulting in alternated biological processes in mammalian cells. In the review, we summarize our understandings of ACCs, including their structural features, regulatory mechanisms, and roles in diseases. ACC1 has emerged as a promising target for diseases treatment, so that the specific inhibitors of ACC1 for diseases treatment are also discussed.

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Section: Limitations and Prospectsmentioning

confidence: 99%

Acetyl-CoA Carboxylases and Diseases

Wang

et al. 2022

Front. Oncol.

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“…In the phase 2b ATLAS trial, 20 mg/d firsocostat + 30 mg/d cilofexor provided significant reductions in NAS scores, liver steatosis, lobular inflammation and hepatocellular ballooning (HCB), and improved liver biochemistry over 48 weeks in patients with septal fibrosis due to NASH [ 23 ]. Clesacostat (2–50 mg/d) has demonstrated good efficacy in terms of reducing liver steatosis, and is being developed in combination with the DGAT2 inhibitor ervogastat to address the frequently observed elevation of serum TAG, a known effect of ACC inhibitors [ 24 ]. Two phase 2 studies are ongoing to determine the optimal doses of both agents for NASH with and without liver fibrosis (NCT04399538, NCT04321031).…”

Section: Lipogenesis Inhibitorsmentioning

confidence: 99%

Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

2022

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Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.

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“…As discussed above, drugs that inhibit DNL are being investigated in the treatment of NASH and may also be beneficial in CHC patients who have been cured. ACC inhibitors halting DNL show potential in improving steatosis and possibly reducing fibrotic progression of NASH [244][245][246] . ACC inhibition has also been shown to improve survival and response to sorafenib therapy in a pre-clinical model of HCC 196 , but has yet to tested in clinical trials of either HCV-associated or non-HCV associated HCC.…”

Section: Strategies Aimed At Reversing Metabolic Dysfunction and Canc...mentioning

confidence: 99%

Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions

Leslie

Geh

Elsharkawy

et al. 2022

Journal of Hepatology

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ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials

Cited by 141 publications

References 48 publications

Acetyl-CoA Carboxylases and Diseases

Acetyl-CoA Carboxylases and Diseases

Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

Metabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions

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