Efruxifermin in non-alcoholic steatohepatitis: a randomized, double-blind, placebo-controlled, phase 2a trial

Abstract

on-alcoholic fatty liver disease (NAFLD) is associated with obesity, metabolic syndrome, dyslipidemia and type 2 diabetes (T2D). NASH is the progressive form of NAFLD, defined as ≥5% hepatic steatosis with inflammation and hepatocyte injury (that is, ballooning), with or without fibrosis 1 . Despite a predicted global prevalence of 2-12% in adults 2,3 , currently there is no approved treatment. Most clinically evaluated therapeutic mechanisms target the metabolic dysfunction of hepatocytes or suppress inflammation and fibrosis 4 . However, an ideal therapeutic would treat advanced fibrosis and resolve the profibrotic milieu driven by hepatocyte death (apoptosis) associated with chronic steatosis, lipotoxicity and oxidative and endoplasmic reticulum stress.FGF21 is a key regulator of whole-body and individual organ metabolism 5 . It activates a cell membrane co-receptor complex of β-klotho and one of its cognate FGF receptors (FGFRs), FGFR1c, FGFR2c or FGFR3c. FGF21 and its analogs improve metabolic status in preclinical models of obesity, diabetes and NASH 6 , suggesting promise as a therapeutic for NASH. However, many FGF21 analogs have not fulfilled the preclinical promise of FGF21 therapeutics, with disappointing translation into the clinic. Although substantial reductions in serum triglycerides have been seen in patients with T2D and obesity, effects on high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol have been variable, with inconsistent effects on glycemic control and body weight [7][8][9] . Furthermore, in patients with NASH, liver fat reductions have been moderate 10 . Two antibody-based therapeutics that act on the FGF21 co-receptor complex are also in development. Unlike analogs of the FGF21 polypeptide, BFKB8488A (Genentech) and MK3655 (Merck Sharp & Dohme; formerly NGM313 (NGM Biopharmaceuticals)) activate only the FGFR1c/β-klotho co-receptor complex. In patients with NAFLD, the highest adequately tolerated dose of BFKB8488A reduced HFF by 38% after 12 weeks 11 but did not improve markers of glycemic control in patients with T2D 12 . After a single dose, MK3655 improved glycemic control in obese non-diabetic participants with 37% relative reduction in liver fat 36 d after administration; however, significant weight gain was seen 13 .Efruxifermin is a fusion protein of human IgG 1 Fc domain linked to a modified human FGF21 (Fc-FGF21) with balanced in vitro agonist potency at FGFR1c, FGFR2c and FGFR3c 14 . Efruxifermin is longer acting than most FGF21 analogs, with a 3-3.5-d half-life 15 . A study in patients with T2D showed improvements in lipoprotein profiles and glycemic control 15 , which supported investigation of efruxifermin in patients with NASH. This study aimed to test the safety and efficacy of weekly subcutaneous administration for 16 weeks in patients with NASH.

Liver Fibrosis and MAFLD: From Molecular Aspects to Novel Pharmacological Strategies

“…This improvement in hepatic steatosis was accompanied by a reduction in biomarkers of fibrosis and the enhanced liver fibrosis scores. More importantly, 55% of patients achieved stage 1 or greater fibrosis improvement, and half of these patients even met all the exploratory endpoints (92). The major adverse effects of FGF21 analogs is mild gastrointestinal reactions.…”

“…Further research using liver biopsies to assess the effects of 24 weeks of Pegbelfermin treatment on patients with histologically confirmed NASH with stage 3 liver fibrosis (FALCON 1; NCT03486899) or compensated cirrhosis (FALCON 2; NCT03486912) was initiated in 2018 (90). Efruxifermin is an engineered fusion protein formed by linking human IgG1 Fc to modified FGF21, and it has a balanced and long-lasting agonistic effect on FGFR1c, 2c, and 3c (91,92). In the 16-week phase 2a BALANCED study (NCT03976401), Efruxifermin resulted in a significant reduction in the liver fat fraction as measured by MRI (92).…”

“…Efruxifermin is an engineered fusion protein formed by linking human IgG1 Fc to modified FGF21, and it has a balanced and long-lasting agonistic effect on FGFR1c, 2c, and 3c (91,92). In the 16-week phase 2a BALANCED study (NCT03976401), Efruxifermin resulted in a significant reduction in the liver fat fraction as measured by MRI (92). This improvement in hepatic steatosis was accompanied by a reduction in biomarkers of fibrosis and the enhanced liver fibrosis scores.…”

Regulation and Potential Biological Role of Fibroblast Growth Factor 21 in Chronic Kidney Disease

“…The latest research evidence confirms that FGF21 can improve metabolic status with anti-fibrotic effects and has the potential treatment for non-alcoholic steatohepatitis (NASH) (Harrison et al, 2021). A new type of long-acting FGF21 (LAPS-FGF21) has been developed for potential therapeutic effects on obesity.…”

Targeting Gut–Liver Axis for Treatment of Liver Fibrosis and Portal Hypertension

“…In view of this, a handful of drugs using the enterokine pathway are in the clinical pipeline, including Efruxifermin (AKR-001), another FGF21 mimetic. In Phase 2 studies in non-alcoholic steatohepatitis (NASH) patients with F1-F3 fibrosis, Efruxifermin demonstrated effective reduction of liver fat content with 48% of treatment responders achieving an improvement in fibrosis stage [85] (Akero Therapeutics, Inc. NCT03976401, NCT04767529).…”