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Fc-FGF21 Fusion Protein Cuts Liver Fat,
Improves Fibrosis in 4-Arm NASH Trial
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AASLD The Liver Meeting Digital Experience, November 13-16, 2020
Mark Mascolini
Efruxifermin (EFX), a once-weekly subcutaneous fibroblast growth factor-21 (FGF21) analog, cut liver fat and improved fibrosis stage in a 16-week 4-arm randomized comparison with placebo in 80 people with nonalcoholic steatohepatitis (NASH) [1]. NASH resolved in about half of study participants biopsied by week 16.
Based on a fusion polypeptide of human IgG1 Fc and FGF21, EFX aims to control NASH by lowering liver fat, inflammation, and fibrosis while restoring healthy lipid metabolism in the liver [2]. By improving lipid function, EFX targets cardiovascular disease, the leading cause of death in people with NASH.
Conducted by US clinical researchers and Akero Therapeutics, this phase 2a trial randomized 80 people with biopsy-confirmed NASH to 28, 50, or 70 mg of subcutaneous EFX weekly or to placebo for 16 weeks. Participants had at least 10% liver fat, a nonalcoholic fatty liver disease (NAFLD) Activity Score of 4 or more, and fibrosis stage F1-3. People with at least a 30% relative drop in liver fat by week 12 underwent end-of-study biopsy to assess changes in fibrosis and NAFLD Activity Score.
While 21 participants received placebo, 19 got 28 mg of EFX subcutaneously once weekly, 20 got 50 mg, and 20 got 70 mg. Average age stood in the low 50s in all four trial arms, and 34 of 80 participants (42.5%) were men. MRI-PDFF-measured liver fat content ranged from 18.3% to 21.4% across the 4 study groups, NAFLD Activity Score from 5.1 to 5.6, and percentage with F2-3 fibrosis from 62% to 65%.
At week 12 all 3 EFX groups had a 12% or greater average absolute reduction in liver fat from baseline, compared with 0% in the placebo group (P < 0.001 for all three EFX groups versus placebo). Proportions with at least a 50% relative reduction in liver fat at week 12 were 69% (n = 16) with 28 mg of EFX, 100% (n = 17) with 50 mg, 93% (n = 19) with 70 mg, and 5% (n = 20) with placebo (all differences between EFX and placebo statistically significant). Respective proportions with at least a 70% relative drop liver fat at week 12 were 50%, 53%, 80%, and 5% (all differences from placebo significant). Proportions with normalized liver fat content by week 12 were 25% with 28 mg of EFX, 53% with 50 mg, 67% with 70 mg, and 5% with placebo (all differences from placebo statistically significant).
Thirteen people getting 28 mg of EFX, 13 getting 50 mg, 14 getting 70 mg, and 2 on placebo had at least a 30% relative reduction in liver fat by week 12 and so became eligible for end-of-study (16-week) assessment of fibrosis and NAFLD Activity Score. At that point 6 of 13 (46%) in the 28-mg EFX group, 7 of 13 (54%) in the 50-mg group, 6 of 14 (43%) in the 70-mg group, and 1 of 2 (50%) in the placebo group had NASH resolution without worsening fibrosis. For the combined EFX arms, 48% had NASH resolution at week 16.
At week 16 fibrosis improved by at least 1 stage without NASH worsening in 6 of 13 people (46%) getting 28 mg of EFX, 8 of 13 (62%) getting 50 mg, 5 of 14 (36%) getting 70 mg, and 0 of 2 getting placebo. Among all 40 EFX-treated people, 55% had improved fibrosis at week 16, 35% had no change, and 10% had worse fibrosis. Among 22 EFX-treated participants with baseline F2-F3 fibrosis, 68% had a 1- or 2-stage fibrosis improvement at week 16, 23% had no change, and 9% had worse fibrosis.
By treatment week 8, both alanine aminotransferase (ALT) and aspartate aminotransferase (AST) dropped about 40% from baseline values in all three EFX arms while remaining unchanged in the placebo group. ALT and AST maintained those levels in all four groups through week 16.
After 12 weeks ALT absolute change from baseline fell 24 U/L in the 28-mg EFX group, 30 U/L in the 50-mg group, 32 U/L in the 70-mg group, and 5.9 U/L in the placebo group. Respective week-16 absolute changes in HbA1c, a diabetes marker, were -0.1%, -0.4%, -0.5%, and +0.1%. "Good" high-density lipoprotein cholesterol rose by 34%, 39%, 41%, and 4% from baseline to week 16. Over that period triglycerides fell 39%, 48%, and 46% in the 3 EFX groups and rose 6% in the placebo group. Through 16 weeks average "bad" low-density lipoprotein cholesterol fell 16%, 2%, and 6% in the 3 EFX arms and did not change in the placebo arm.
Two people receiving 28 mg of EFX, 4 receiving 70 mg of EFX, and 1 receiving placebo had a treatment-emergent adverse event leading them to stop treatment. One person in the 28-mg EFX group and 1 in the 70-mg group had a serious adverse event. Transient mild or moderate gastrointestinal distress was the most frequent adverse event.
EFX joins lanifibranor [3] as one of the first two agents that both improved fibrosis and resolved NASH in a randomized trial.
References
1. Harrison SA, Ruane PJ, Freilich BL, et al. Efruxifermin (EFX), a long-acting Fc-FGF21 fusion protein, administered for 16 weeks to patients with NASH substantially reduces liver fat and ALT, and improves liver histology: analysis of a randomized, placebo-controlled, phase 2a study (BALANCED). AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 8.
2. Akero. Efruxifermin (EFX): a multi-modal drug. https://akerotx.com/efruxifermin/
3. Francque S, Bedossa P, Ratziu V, et al. The panPPAR agonist lanifibranor induces both resolution of NASH and regression of fibrosis after 24 weeks of treatment in non-cirrhotic NASH: results of the native phase 2b trial. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 12. (Reported separately by NATATP at the AAFLD Liver Meeting.)
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