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• W4328103790 abstract "Sanyal AJ, Lopez P, Lawitz EJ, et al. Tropifexor for nonalcoholic steatohepatitis: an adaptive, randomized, placebo-controlled phase 2a/b trial. Nat Med 2023;29:392–400. Nonalcoholic steatohepatitis (NASH) is quickly becoming the most common indication for liver transplantation, yet there are no therapies approved to treat NASH. The future is bright; robust efforts understanding the molecular pathogenesis of NASH over the past 2 decades paved the way for several targeted NASH treatments. For example, the Farnesoid X receptor (FXR) regulates bile acid and glucose homeostasis, and, in preclinical and clinical studies, FXR agonists can decrease hepatic fibrosis. Recent data from the double-blinded, multicenter phase IIa/b FLIGHT-FXR trial advance the idea of FXR agonism to treat NASH. Patients with F2–F3 NASH were treated with placebo or tropifexor (TXR), a high-potency non-bile acid oral FXR agonist with ascending doses (10–200 μg/d) for 12–48 weeks. Primary end points revealed significant mean improvements in alanine aminotransferase and hepatic fat fraction of ≤–23 U/L and –39% in the 200-μg, 48-week TXR-treated group versus placebo (–8.3 U/L and –11%, respectively). No histological improvements were detected, and the most common adverse events were significantly increased low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, and pruritus (≤69% in the highest dose group). The data reflect some advances when compared with the multicenter, randomized, placebo-controlled phase III REGENERATE trial (PMID: 31813633), which showed the effect of an earlier-generation FXR agonist, obeticholic acid (OCA), on histological and biochemical outcomes in patients also with F2–F3 NASH. In that trial, 18 months of treatment with OCA decreased histological fibrosis, without improving NASH resolution when compared with placebo-treated patients. OCA also reduced alanine aminotransferase (≤–36 U/L or –30% from baseline in the higher dose group). No hepatic fat fraction (HFF) measurements were demonstrated in this trial, but improvements in histological steatosis were not different between groups. The most common adverse events were similar to TXR: increased low-density lipoprotein cholesterol, lower high-density lipoprotein cholesterol, and pruritus (≤51% of patients in the high-dose groups). Activating FXR agonism is a clinically efficacious target pathway with potential caveats. In rigorously run clinical trials, OCA and TXR were generally safe, and they decreased serum transaminases, a biomarker of hepatocellular disruption. Whereas only REGNERATE showed FXR agonism can decrease histological fibrosis, the FLIGHT-FXR trial, which used the more potent, non–bile acid structure of TXR, showed a robust HFF decreased in response to TXR. However, altering the FXR agonist structure has not mitigated some concerns surrounding FXR agonist-induced pruritus and dyslipidemia, which will shape the clinical contexts in which FXR agonism is deployed. The FLIGHT-FXR trial reveals that structurally distinct pharmacologic FXR agonism can maintain clinical efficacy, which affords future avenues to better address its FXR targeting effects. As those advances continue to develop, the exciting future for NASH treatment is now upon us, and FXR agonism shows promise to be a part of this paradigm." @default.
• W4328103790 created "2023-03-22" @default.
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• W4328103790 date "2023-08-01" @default.
• W4328103790 modified "2023-09-30" @default.
• W4328103790 title "Next-Generation Farnesoid X Receptor Agonists in NASH Treatment: Are We There Yet?" @default.
• W4328103790 doi "https://doi.org/10.1053/j.gastro.2023.03.213" @default.
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