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Background and Aims Advanced fibrosis attributable to NASH is a leading cause of end‐stage liver disease. Approach and Results In this phase 2b trial, 392 patients with bridging fibrosis or compensated cirrhosis (F3‐F4) were randomized to receive placebo, selonsertib 18 mg, cilofexor 30 mg, or firsocostat 20 mg, alone or in two‐drug combinations, once‐daily for 48 weeks. The primary endpoint was a ≥1‐stage improvement in fibrosis without worsening of NASH between baseline and 48 weeks based on central pathologist review. Exploratory endpoints included changes in NAFLD Activity Score (NAS), liver histology assessed using a machine learning (ML) approach, liver biochemistry, and noninvasive markers. The majority had cirrhosis (56%) and NAS ≥5 (83%). The primary endpoint was achieved in 11% of placebo‐treated patients versus cilofexor/firsocostat (21%; P = 0.17), cilofexor/selonsertib (19%; P = 0.26), firsocostat/selonsertib (15%; P = 0.62), firsocostat (12%; P = 0.94), and cilofexor (12%; P = 0.96). Changes in hepatic collagen by morphometry were not significant, but cilofexor/firsocostat led to a significant decrease in ML NASH CRN fibrosis score (P = 0.040) and a shift in biopsy area from F3‐F4 to ≤F2 fibrosis patterns. Compared to placebo, significantly higher proportions of cilofexor/firsocostat patients had a ≥2‐point NAS reduction; reductions in steatosis, lobular inflammation, and ballooning; and significant improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, cytokeratin‐18, insulin, estimated glomerular filtration rate, ELF score, and liver stiffness by transient elastography (all P ≤ 0.05). Pruritus occurred in 20%‐29% of cilofexor versus 15% of placebo‐treated patients. Conclusions In patients with bridging fibrosis and cirrhosis, 48 weeks of cilofexor/firsocostat was well tolerated, led to improvements in NASH activity, and may have an antifibrotic effect. This combination offers potential for fibrosis regression with longer‐term therapy in patients with advanced fibrosis attributable to NASH.

N ASH affects more 80 million people worldwide and represents one of our most urgent and neglected global health crises, with broad implications on public health. 1,2 It is associated with increased risks of cirrhosis, hepatic decompensation, hepatocellular carcinoma, liver transplantation, and death. The prevalence of NASH and NASH-related end-stage liver disease are predicted to increase significantly over the next decade. 3 There are currently no approved therapies for NASH.NASH is characterized histologically by hepatocellular injury, inflammation, steatosis, and may be accompanied by fibrosis, an important predictor of disease progression and mortality. [4][5][6][7] At present, the US Food and Drug Administration and European Medicines Agency support the use of the histologic end points of fibrosis improvement and NASH resolution for accelerated or conditional approval. 8,9 The pathogenesis of NASH is incompletely understood, although several hypotheses have been proposed. 10 Developing therapeutics for NASH poses a vexing challenge for clinicians and researchers, as none of the agents tested to date has been able to demonstrate concurrent histologic improvement in both fibrosis and NASH resolution. [11][12][13][14][15][16] Aldafermin (also known as NGM282 or M70) is an engineered, non-tumorigenic analog of the human gut hormone, fibroblast growth factor 19 (FGF19). [17][18][19] FGF19 plays a central role in regulating bile acid, carbohydrate, and energy metabolism. 20,21 Physiologically, FGF19 is secreted from the ileum in response to farnesoid X receptor activation, leading to the postulation that the effect of farnesoid X receptor agonists may be largely dependent on the induction of its target gene, FGF19. Aldafermin acts on 2 receptor complexes, FGFR1c-KLB and FGFR4-KLB. Activation of the FGFR1c-KLB receptor leads to reduction in liver steatosis and improvement in insulin sensitivity in patients. 22,23 Activation of the FGFR4-KLB receptor potently suppresses the expression of CYP7A1, which encodes the first and ratelimiting enzyme in the de novo synthesis of bile acids. 17,24 Emerging evidence reveals bile acids as an important risk factor for chronic liver diseases including NASH 25 ; accumulation of bile acids induces hepatic stellate cell activation, mitochondrial dysfunction and endoplasmic reticulum stress, leading to cell death, inflammation and liver injury. 26,27 Given aldafermin's mechanism of action, reducing bile acid burden may contribute to additional antiinflammatory and anti-fibrotic benefits beyond those associated with liver fat reduction.We have previously shown that a 12-week treatment with aldafermin produced reductions in liver fat content (LFC) and liver enzymes, and in an open-label study, improvements in liver histology. 28,29 In the current study, we investigated the efficacy and safety of longer treatment with aldafermin 1 mg compared with placebo in patients with biopsy-proven NASH and stage 2 or stage 3 liver fibrosis.

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