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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.

Resmetirom (MGL‐3196), a selective thyroid hormone receptor‐β agonist, was evaluated in a 36‐week paired liver biopsy study (NCT02912260) in adults with biopsy‐confirmed nonalcoholic steatohepatitis (NASH). The primary endpoint was relative liver fat reduction as assessed by MRI–proton density fat fraction (MRI‐PDFF), and secondary endpoints included histopathology. Subsequently, a 36‐week active treatment open‐label extension (OLE) study was conducted in 31 consenting patients (including 14 former placebo patients) with persistently mild to markedly elevated liver enzymes at the end of the main study. In patients treated with resmetirom (80 or 100 mg orally per day), MRI‐PDFF reduction at OLE week 36 was −11.1% (1.5%) mean reduction (standard error [SE]; P < 0.0001) and −52.3% (4.4%) mean relative reduction, P < 0.0001. Low‐density lipoprotein (LDL) cholesterol (−26.1% [4.5%], P < 0.0001), apolipoprotein B (−23.8% [3.0%], P < 0.0001), and triglycerides (−19.6% [5.4%], P = 0.0012; −46.1 [14.5] mg/dL, P = 0.0031) were reduced from baseline. Markers of fibrosis were reduced, including liver stiffness assessed by transient elastography (−2.1 [0.8] mean kilopascals [SE], P = 0.015) and N‐terminal type III collagen pro‐peptide (PRO‐C3) (−9.8 [2.3] ng/mL, P = 0.0004 (baseline ≥ 10 ng/mL). In the main and OLE studies, PRO‐C3/C3M (matrix metalloproteinase‐degraded C3), a marker of net fibrosis formation, was reduced in resmetirom‐treated patients (−0.76 [−1.27, −0.24], P = 0.0044 and −0.68, P < 0.0001, respectively). Resmetirom was well tolerated, with few, nonserious adverse events. Conclusion: The results of this 36‐week OLE study support the efficacy and safety of resmetirom at daily doses of 80 mg and 100 mg, used in the ongoing phase 3 NASH study, MAESTRO‐NASH (NCT03900429). The OLE study demonstrates a potential for noninvasive assessments to monitor the response to resmetirom from an individual patient with NASH.

In a phase 2 study of patients with symptomatic celiac disease and histologic evidence of significant duodenal mucosal injury, latiglutenase did not improve histologic and symptom scores when compared with placebo. There were no significant differences in change from baseline between groups. ClinicalTrials.gov no: NCT01917630.

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NOTE. The primary investigators listed are those who enrolled at least 1 patient. NC, not contactable.