Efruxifermin in non-alcoholic steatohepatitis (vol 8, pg 1058, 2023)

Non-alcoholic fatty liver disease (NAFLD) has emerged as one of the commonest causes of liver-related mortality and morbidity, with a predicted global prevalence of 30%.1Younossi ZM Golabi P Paik JM Henry A Van Dongen C Henry L The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review.Hepatology. 2023; 77: 1335-1347Crossref PubMed Scopus (104) Google Scholar This finding has fuelled extensive therapeutic research; however, there are no currently licensed therapies for NAFLD, with weight loss and lifestyle interventions as the mainstay of treatment. In The Lancet Gastroenterology & Hepatology, Stephen A Harrison and colleagues2Harrison SA Frias JP Neff G et al.Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial.Lancet Gastroenterol Hepatol. 2023; (published online Oct 3.)https://doi.org/10.1016/S2468-1253(23)00272-8Google Scholar present a 96-week multicentre, randomised, double-blind, placebo-controlled, phase 2b study of efruxifermin in non-alcoholic steatohepatitis (NASH). Efruxifermin is a fibroblast growth factor 21 (FGF21) fusion protein that has been modified to mimic native FGF21, an important regulator of metabolism, alongside protein, lipid, and glucose homoeostasis. 128 patients (mean age 54·7 years [SD 10·4]; 79 [62%] female and 49 [38%] male) were randomly assigned to placebo (n=43), efruxifermin 28 mg (n=42), or efruxifermin 50 mg (n=43) subcutaneously once weekly. The study met its primary endpoint of improvement in fibrosis of at least 1 stage with no worsening of NASH on liver biopsy after 24 weeks in the liver biopsy analysis set (LBAS); 15 (39%) of 38 patients on efruxifermin 28 mg and 14 (41%) of 34 on efruxifermin 50 mg reached the primary endpoint, compared with eight (20%) on placebo (p=0·025 for 28 mg vs placebo; p=0·036 for 50 mg vs placebo). This finding is important given the link between fibrosis stage and all-case mortality, liver-related mortality, and morbidity in patients with NAFLD.3Taylor RS Taylor RJ Bayliss S et al.Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis.Gastroenterology. 2020; 158: 1611-1625Summary Full Text Full Text PDF PubMed Google Scholar The key secondary endpoint of NASH resolution without worsening of fibrosis was met by 18 (47%) patients on efruxifermin 28 mg (p=0·002 vs placebo) and 26 (76%) on efruxifermin 50 mg (p<0·001 vs placebo), compared with six (15%) on placebo. The efficacy signal was lower when all patients, as opposed to just those who had paired biopsies, were included, although there was still a signal at the higher dose. Efruxifermin improved liver fat content, lipid and glycaemic profiles, bodyweight, and non-invasive liver fibrosis biomarkers. This well conducted study builds on trials of other FGF21 assets in the setting of NASH.4Loomba R Sanyal AJ Nakajima A Neuschwander-Tetri BA Goodman ZD Harrison SA et al.Pegbelfermin in patients with nonalcoholic steatohepatitis and stage 3 fibrosis (FALCON 1): a randomized phase 2b study.Clin Gastroenterol Hepatol. 2023; (published online April 23.)https://doi.org/10.1016/j.cgh.2023.04.011Summary Full Text Full Text PDF Scopus (2) Google Scholar, 5Loomba R Sanyal AJ Kowdley KV Bhatt DL Alkhouri N Frias JP et al.Randomized, controlled trial of the FGF21 analogue pegozafermin in NASH.N Engl J Med. 2023; (published online June 24.)https://doi.org/10.1056/NEJMoa2304286Crossref PubMed Google Scholar One of the first FGF21 compounds to be tested, pegbelfermin, did not lead to significant improvements in liver fibrosis,4Loomba R Sanyal AJ Nakajima A Neuschwander-Tetri BA Goodman ZD Harrison SA et al.Pegbelfermin in patients with nonalcoholic steatohepatitis and stage 3 fibrosis (FALCON 1): a randomized phase 2b study.Clin Gastroenterol Hepatol. 2023; (published online April 23.)https://doi.org/10.1016/j.cgh.2023.04.011Summary Full Text Full Text PDF Scopus (2) Google Scholar which was speculated to reflect tachyphylaxis. At the lower dose of efruxifermin, liver enzymes increased by week 24 in the setting of increasing anti-drug antibodies (83% of patients), raising a question about durability of effect at that dose. In the recent study of pegozafermin,5Loomba R Sanyal AJ Kowdley KV Bhatt DL Alkhouri N Frias JP et al.Randomized, controlled trial of the FGF21 analogue pegozafermin in NASH.N Engl J Med. 2023; (published online June 24.)https://doi.org/10.1056/NEJMoa2304286Crossref PubMed Google Scholar 22–27% of patients with NASH reached the primary endpoint and there were no features to suggest increased anti-drug antibodies or liver enzymes. By comparison, pegozafermin is a long-acting glycol PEGylated FGF21 analogue that has a prolonged half-life compared with efruxifermin, which has a predicted half-life of 3 days. Longer term data on durability of effect on liver histology will be of interest for all FGF21 assets, as will comparison with effects seen with other therapeutics, such as thyroid hormone receptor beta-agonists and GLP-1 analogues.6Harrison SA, Bedossa P, Guy C, et al. Primary results from MAESTRO-NASH a pivotal phase 3 52-week serial liver biopsy study in 966 patients with NASH and fibrosis. The International Liver Congress; 21–24 June 2023; Vienna, Austria (abstr).Google Scholar, 7Harrison SA Bashir MR Guy CD et al.Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial.Lancet. 2019; 394: 2012-2024Summary Full Text Full Text PDF PubMed Scopus (323) Google Scholar, 8Newsome PN Buchholtz K Cusi K et al.A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis.N Engl J Med. 2021; 384: 1113-1124Crossref PubMed Scopus (602) Google Scholar, 9Newsome PN Ambery P Incretins (GLP1 r agonists and dual, triple agonists) and the liver.J Hepatol. 2023; (published online August 9.)https://doi.org/10.1016/j.jhep.2023.07.033Summary Full Text Full Text PDF Google Scholar Treatment with efruxifermin led to an improvement in non-invasive tests of fibrosis, including both the enhanced liver fibrosis test and liver stiffness. Consistent with other studies, there appeared to be modest association at a patient level between non-invasive tests and improvement in histology. This finding raises questions as to which parameter is of greater use in predicting clinical outcomes and how they should be used in clinical practice as and when drugs are approved. Choice of therapy will inevitably be an integrated decision based on magnitude of efficacy in liver disease, impact on broader cardio-metabolic parameters, side-effect profile, and cost (table). The overall tolerability of efruxifermin was similar to other FGF21 analogues, with mild-to-moderate gastrointestinal symptoms being the most common adverse events. Although there were no significant safety concerns with efruxifermin, an increase in markers of bone turnover was noted at week 24. The significance of those changes is unclear and will require long-term follow-up.TableSummary of recent major clinical trials for treatment of NASH and fibrosis stage (F1–F3)Intervention or mechanism of actionPrimary endpoint(s)Effect on liver enzymesEffect on non-invasive tests on fat content or fibrosisEffect of cardio-metabolic factorsAdverse eventsPhase 2b HARMONY2Harrison SA Frias JP Neff G et al.Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial.Lancet Gastroenterol Hepatol. 2023; (published online Oct 3.)https://doi.org/10.1016/S2468-1253(23)00272-8Google ScholarEfruxifermin (FGF21 analogue)Met primary endpoint of ≥ 1 stage reduction in fibrosis with no worsening of NASH; met secondary endpoint of resolution of NASHImprovement in ALT and ASTImproved liver fat content and fibrosis markers; reduction in markers of collagen synthesisImproved lipid and glycaemic profiles; reduction in bodyweightGastrointestinal upset (nausea and diarrhoea); high bone turnover and elevated levels of anti-drug antibodies (significance unclear, requires long-term follow-up)Phase 2b FALCON4Loomba R Sanyal AJ Nakajima A Neuschwander-Tetri BA Goodman ZD Harrison SA et al.Pegbelfermin in patients with nonalcoholic steatohepatitis and stage 3 fibrosis (FALCON 1): a randomized phase 2b study.Clin Gastroenterol Hepatol. 2023; (published online April 23.)https://doi.org/10.1016/j.cgh.2023.04.011Summary Full Text Full Text PDF Scopus (2) Google ScholarPegbelfermin (FGF21 analogue)Failed to meet primary endpoint of ≥ 1 reduction in fibrosis score without NASH worsening or NASH improvement without worseningImprovement in ALT and ASTRelative reductions in liver fat (not statistically significant); no improvement in fibrosis and non-invasive tests (ALT/fibrosis)Modest bodyweight increase (not statistically significant); no change to HbA1c and lipid profileGastrointestinal upset (nausea and diarrhoea)Phase 2b ENLIVEN5Loomba R Sanyal AJ Kowdley KV Bhatt DL Alkhouri N Frias JP et al.Randomized, controlled trial of the FGF21 analogue pegozafermin in NASH.N Engl J Med. 2023; (published online June 24.)https://doi.org/10.1056/NEJMoa2304286Crossref PubMed Google ScholarPegozafermin (FGF21 analogue)Met both primary endpoints (NASH resolution with no worsening of fibrosis, and ≥ 1 stage reduction in fibrosis with no worsening of NASH)Improvement in ALT and ASTImproved liver fat content and fibrosis markersImproved lipid and glycaemic profiles; no effect on bodyweightGastrointestinal upset (nausea and diarrhoea); increased appetitePhase 3 MAESTRO-NASH6Harrison SA, Bedossa P, Guy C, et al. Primary results from MAESTRO-NASH a pivotal phase 3 52-week serial liver biopsy study in 966 patients with NASH and fibrosis. The International Liver Congress; 21–24 June 2023; Vienna, Austria (abstr).Google ScholarResmetirom (THR-β agonist)Met both primary endpoints (NASH resolution with no worsening of fibrosis, and ≥ 1 stage reduction in fibrosis with no worsening of NASH)Improvement in ALT, AST, and GGTImprovement in liver stiffness; reduction in hepatic fatImproved lipid and glycaemic profilesGastrointestinal upset (predominantly diarrhoea)Phase 2b SEMA-NASH9Newsome PN Ambery P Incretins (GLP1 r agonists and dual, triple agonists) and the liver.J Hepatol. 2023; (published online August 9.)https://doi.org/10.1016/j.jhep.2023.07.033Summary Full Text Full Text PDF Google ScholarSemaglutide (GLP-1)Met resolution of NASH; did not meet confirmatory secondary endpoint of fibrosis improvementImprovement in ALT, AST, and GGTReduction in hepatic steatosis and hepatic fat volume; reduction in serum enhanced liver fibrosis and liver stiffnessDose-dependent reduction in bodyweight; improvement in HbA1c, triglycerides, and VLDL cholesterolGastrointestinal upset (nausea and diarrhoea); increase in amylase and lipaseALT=alanine aminotransferase. AST=aspartate aminotransferase. FGF21=fibroblast growth factor 21. GGT=gamma glutamyl transferase. HbA1c=glycated haemoglobin A1c. NASH=non-alcoholic steatohepatitis. Open table in a new tab ALT=alanine aminotransferase. AST=aspartate aminotransferase. FGF21=fibroblast growth factor 21. GGT=gamma glutamyl transferase. HbA1c=glycated haemoglobin A1c. NASH=non-alcoholic steatohepatitis. In this study of 128 adult US patients, most (92%) were White, indicating an under-representation of other ethnic groups. This observation is important given that genetic factors are known to affect both the prevalence and phenotype in patients with NAFLD.10Jonas W Schurmann A Genetic and epigenetic factors determining NAFLD risk.Mol Metab. 2021; 50101111Crossref PubMed Scopus (54) Google Scholar Notably, 13% of patients were taking GLP-1 receptor agonists and 15% of patients were taking SGLT-2 inhibitors at baseline. Reassuringly, it would appear that concomitant usage did not interfere with likelihood of meeting the primary endpoint, suggesting there is an additive effect. Larger studies to understand efficacy with and without these concomitant medications will be of great interest given their growing usage for type 2 diabetes and obesity. In summary, this study adds to the case for FGF21 analogues as treatment for NASH and moves us closer to effective therapies for patients. PNN discloses the following financial relationships on behalf of the University of Birmingham with a commercial interest: grant or research support from Novo Nordisk and consulting fees from Astra Zeneca, Boehringer Ingelheim, BMS, Gilead, GSK, Intercept, Madrigal, Novo Nordisk, Pfizer and Sun Pharma. SM declares no competing interests. Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trialEfruxifermin improved liver fibrosis and resolved NASH over 24 weeks in patients with F2 or F3 fibrosis, with acceptable tolerability, supporting further assessment in phase 3 trials. Full-Text PDF