Efficacy and Safety of Aldafermin, an Engineered FGF19 Analog, in a Randomized, Double-Blind, Placebo-Controlled Trial of Patients With Nonalcoholic Steatohepatitis

Abstract

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.

FGF21: An Emerging Therapeutic Target for Non-Alcoholic Steatohepatitis and Related Metabolic Diseases

“…In a longer-term 24-week study in NASH patients, daily administration of 1 mg aldafermin led to an approximately 30% placebo-adjusted relative reduction in liver fat while reducing ALT by about 45% from baseline. However, statin co-administration was required in more than 95% of treated subjects to mitigate the increase in LDL-cholesterol, which was also observed previously at higher doses (306). This study confirmed that aldafermin treatment did not improve glycemic control.…”

“…While a similar effect does not appear to have been reported for FGF19, this indirect antifibrotic effect of FGF21 suggests that FGFR4 is unnecessary for inhibition of Kupffer cell-HSC signaling. Third, analogs of FGF21 and FGF19 appear to reduce markers of liver injury (ALT) and fibrosis (Pro-C3) to a similar extent in humans (245,306), consistent with FGFR4 agonism not being required in vivo, while being associated with an undesirable increase in LDL-C.…”

“…The most prevalent and consistent dose-limiting side effects observed across studies of FGF21 analogs in patients with metabolic disease are gastrointestinal (GI), including mild-tomoderate nausea and diarrhea (183,245,246,298,301). These side effects were also seen in trials of the FGF19 analog, aldafermin (31,306). However, preclinical studies of these various endocrine FGF analogs in rodents and monkeys did not reveal GI symptoms, therefore the potential mechanisms underlying adverse GI effects have not been investigated ( Table 2).…”

Immunological mechanisms and therapeutic targets of fatty liver diseases

“…Other agents targeting global metabolic pathways have shown benefit in phase II clinical trials, including analogs of fibroblast growth factor 19 (FGF-19), 326 fibroblast growth factor 21 327 and thyroid hormone receptor β agonizts. 328 In addition to agents targeting global pathways, there are also agents specific to hepatic lipid metabolism.…”

FGF19 and FGF21 for the Treatment of NASH—Two Sides of the Same Coin? Differential and Overlapping Effects of FGF19 and FGF21 From Mice to Human

“…However, no placebo group was included in the trial and the significance of these effect needs to be confirmed. The data was recently confirmed in a 24 weeks trial (78 patients with F2/F3) where fibrosis improvement (>1) and no worsening of NASH was observed in 38% of patients treated with Aldafermin versus only 18% in the placebo group ( 214 ). NASH resolution with no worsening of fibrosis was observed in 24% of patients receiving Aldafermin compared to 9% in the placebo group ( 214 ).…”