Phase II trial updates underpin benefit of efruxifermin for NASH

In individuals with biopsy-confirmed nonalcoholic steatohepatitis (NASH) with fibrosis, the reductions in liver fat content (LFC) with efruxifermin correlated with improvements in markers of liver injury, fibrosis, metabolic parameters, and histologic features, according to updates from the phase IIa BALANCED study presented at ILC 2021.

A long-acting FGF21* analogue, once-weekly efruxifermin, irrespective of dose, has been shown to reduce LFC (as per MRI-PDFF**) vs placebo at 12 weeks in F1–F3 NASH patients. [Hepatology 2020;72;1S;6A] Eighty participants were randomized 1:1:1:1 to receive either efruxifermin 28, 50, or 70 mg, or placebo. Of these, 68 had available MRI-PDFF assessments at baseline and week 12 (n=50 achieved ≥30-percent relative LFC reduction at week 12 [MRI-PDFF responders]). Forty-two of the MRI-PDFF responders comprised the Biopsy Analysis Set (BAS; those with baseline and post-treatment biopsies). [Nat Med 2021;doi:10.1038/s41591-021-01425-3]

Improvements in key markers of liver injury

Of those with MRI-PDFF assessments at baseline and week 12, LFC reduction with efruxifermin significantly correlated with the extent of reduction in serum markers (Spearman correlation coefficient [ρ], 0.532, 0.582, and 0.599 for ALT***, Pro-C3^#, and triglycerides, respectively; p<0.0001 for all). In a subset of patients with type 2 diabetes (n=35), the LFC improvement correlated with improvements in adiponectin (ρ, −0.643; p<0.0001) and Hb_A1c (ρ, 0.606; p=0.0001). [ILC 2021, abstract PO-1762]

Individuals with normalized LFC had a greater likelihood of achieving NASH resolution (odds ratio [OR], 4.08; p=0.0365) or NAFLD Activity Score (NAS) improvement by ≥4 (OR, 6.43; p=0.0068).

“[These imply that] efruxifermin has the potential to significantly improve all aspects of the pathophysiology of NASH with fibrosis,” said the researchers.

F4 NASH with compensated cirrhosis

In a cohort of F4 NASH patients without decompensation (n=30), efruxifermin 50 mg led to improvements in liver stiffness (absolute change, –5.7 vs –1.9 kPa), Pro-C3 (absolute change, –9.0 vs –3.4 µg/L; p<0.05), ALT (absolute change, –10 vs –1.3 U/L; p<0.01), AST*** (absolute change, –9.6 vs –4.5 U/L), and Enhanced Liver Fibrosis score (absolute change, –0.4 vs 0.3; p<0.01) vs placebo at week 16. [ILC 2021, abstract LBO-2800]

Efruxifermin also improved various markers of glucose and lipid metabolism such as Hb_A1c, adiponectin, triglycerides, low-density lipoprotein-cholesterol, non-high-density lipoprotein-cholesterol (non-HDL-C), and HDL-C (p<0.01 for all).

Of the 12 efruxifermin recipients included for histologic evaluation, four had fibrosis improvement (or reversal of cirrhosis) without NASH worsening, three achieved NASH resolution, while seven had NAS improvement by ≥2^##. Of the five placebo-treated patients, only one achieved NAS improvement by ≥2^##; none achieved the other two endpoints.

“Efruxifermin showed trends to reverse cirrhosis on semiquantitative histopathologic assessment with significant reductions in key noninvasive markers of liver injury and fibrosis, and improved markers of glucose and lipid metabolism [in F4 NASH patients], consistent with the results of the main study in F1–F3 NASH patients,” the researchers explained. These suggest that the benefit of efruxifermin may extend to those who are at the greatest risk of progressing to end-stage liver disease.

ALT: A predictor of NASH resolution?

In a secondary analysis of participants included in the BAS, compared with ALT nonresponders (n=14), ALT responders (n=28) had a higher likelihood of achieving NASH resolution (OR, 2.08) and the composite endpoint of NASH resolution and fibrosis improvement (OR, 2.84). ALT responders with normalized LFC were also more likely to achieve NASH resolution (OR, 2.67). The AUROC^### of ALT decline by ≥17 U/L to predict NASH resolution was 0.74. [ILC 2021, abstract PO-1314]

“[We sought] to examine the utility of a threshold response for ALT in predicting NASH resolution among a treated population [of MRI-PDFF responders],” said the researchers. “[A] decline in serum ALT of at least 17 U/L is a robust marker in predicting NASH resolution for efruxifermin and potentially other metabolic therapies with a potent antisteatotic effect.”

Collectively, findings from these analyses underscore the potential of efruxifermin to modify the course of NASH progression.