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Fibrosis, Liver Markers Improve in
F4 NASH With Once-Weekly Efruxifermin
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EASL International Liver Congress, June 23-26, 2021
Mark Mascolini
Efruxifermin, a long-acting analog of fibroblast growth factor 21 (FGF21), reduced markers of fibrosis and liver injury-and sometimes resolved nonalcoholic steatohepatitis (NASH)-in a 16-week study of people with compensated cirrhosis [1]. One of 20 people taking efruxifermin left the study because of gastrointestinal problems.
FGF21 is a natural hormone involved in glucose, lipid, and energy metabolism [2]. Researchers have engineered variants of this natural hormone that extend its half-life to 3 to 4 days, reduce aggregation and in vivo degradation, reduce extreme C-terminal degradation, and improve binding affinity to β-klotho [2].
In a phase 2a placebo-controlled trial of people with NASH F1-F3 fibrosis [3], all three 20-person efruxifermin dose groups (28, 50, and 70 mg subcutaneously once weekly) met the primary endpoint of absolute change from baseline liver fat at week 12 measured by magnetic resonance imaging-proton-density fat fraction (MRI-PDFF) [4]. Absolute reductions in liver fat were 12.3% with 28 mg of efruxifermin, 13.4% with 50 mg, and 14.1% with 70 mg (P < 0.001 for all vs placebo). Liver fibrosis improved by 2 or more stages in 55% of 40 people receiving efruxifermin and in 68% of 22 efruxifermin recipients with baseline F2-F3 fibrosis.
The phase 2a trial plan built in an expansion group with compensated cirrhosis (F4 fibrosis) and Child-Pugh class A (least severe cirrhosis). Researchers randomized 20 people to receive 50 mg of subcutaneous efruxifermin weekly for 16 weeks and 10 to receive placebo shots.
Age averaged 61 years in the efruxifermin group and 57 in the placebo group, weight 98 and 119 kg, alanine aminotransferase (ALT) 31.7 and 32.7 U/L, aspartate aminotransferase (AST) 31.4 and 28.9 U/L, and liver stiffness 22.1 and 25.8 kPa. Women made up 80% of the efruxifermin group and 30% of the placebo group. Half of each group had type 2 diabetes, and triglycerides averaged 134.6 mg/dL in the efruxifermin arm and 121.7 mg/dL in the placebo arm. Average baseline ELF score was similar with efruxifermin and placebo (10.4 and 9.7), as were Pro-C3 values (25.6 and 22.6 ug/L). (ELF, or enhanced liver fibrosis, score correlates well with fibrosis stage in chronic liver disease. PRO-C3 is a collagen marker of liver fibrosis.)
A single pathologist blinded to treatment assignment read all baseline and end-of-treatment biopsies. Among people with biopsies read at baseline and after 16 weeks of treatment, fibrosis improved at least 1 stage in 4 of 12 people (33%) randomized to efruxifermin and in none of 5 randomized to placebo. NASH resolved in 3 of 12 people (25%) receiving efruxifermin and in none of 5 getting placebo. Seven of 12 people (58%) in the efruxifermin arm and 1 of 5 (20%) getting placebo had a 2 point or greater reduction in nonalcoholic fatty liver disease (NAFLD) activity score.
Comparisons of fibrosis markers and liver injury markers involved all 30 trial participants at week 16. FibroScan-measured liver stiffness (kPa) dropped by an average 5.7% from the baseline value in the efruxifermin group (P < 0.01) versus 1.9% with placebo. PRO-C3 fell 9.0% with efruxifermin versus 3.4% with placebo (P < 0.05 efruxifermin vs placebo). ELF score dwindled 0.4% with efruxifermin and rose 0.3% with placebo (P < 0.01 efruxifermin vs placebo). ALT fell by an average 10.3% with efruxifermin and 1.3% with placebo (P < 0.01 efruxifermin vs placebo), while AST dropped 9.6% and 4.5% (P < 0.001 efruxifermin vs placebo).
Changes in triglycerides, non-HDL cholesterol, HDL cholesterol, and LDL cholesterol suggest improved metabolic health through 16 weeks of efruxifermin therapy. Changes in HbA1c, adiponectin, C-peptide, and body weight with efruxifermin suggest improved glucose metabolism with this investigational agent.
One of 20 people randomized to efruxifermin left the study because of abdominal distension, constipation, diarrhea, and pruritus. No one receiving efruxifermin or placebo had a serious adverse event. In the efruxifermin group the most frequent drug-related adverse events were diarrhea (8 people, 40%), nausea (7 people, 35%), and injection site reactions (6 people, 30%).
Overall findings in these people with F4 NASH, who run the greatest risk of progression to end-stage liver disease, proved generally consistent with the main study results in people with F1-F3 fibrosis [3,4].
References
1. Harrison S, Ruane P, Freilich B, et al. Efruxifermin (EFX) improved markers of fibrosis, liver injury and metabolism in F4 NASH patients with compensated cirrhosis. EASL International Liver Congress, June 23-26, 2021. Abstract LBO-2800.
2. Stanislaus S, Hecht R, Yie J, et al. A novel Fc-FGF21 with improved resistance to proteolysis, increased affinity toward β-klotho, and enhanced efficacy in mice and cynomolgus monkeys. Endocrinology. 2017;158:1314-1327. doi: 10.1210/en.2016-1917.
3. ClinicalTrials.gov. A study of efruxifermin in subjects with histologically confirmed nonalcoholic steatohepatitis (NASH). ClinicalTrials.gov identifier NCT03976401. https://clinicaltrials.gov/ct2/show/NCT03976401
4. akero. Press release. All AKR-001 dose groups met week 12 efficacy endpoints in NASH phase 2a BALANCED study. March 31, 2020. https://ir.akerotx.com/news-releases/news-release-details/all-akr-001-dose-groups-met-week-12-efficacy-endpoints-nash
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