Efruxifermin led to resolution of NASH and improvement of fibrosis in a mid-term trial

Use of long-acting FGF21 analog efruxifermin resulted in statistically significant improvements in fibrosis and resolution of non-alcoholic steatohepatitis (NASH) compared to placebo, the trial showed. randomized Phase IIb HARMONY.

Among patients with pre-cirrhotic NASH and stage ≥ 1 fibrosis, 41% of those who received efruxifermin 50 mg and 39% of those who received efruxifermin 28 mg achieved the primary endpoint of improvement in fibrosis by at least one stage without NASH worsening at 24 weeks, compared to 20% of those who received placebo (P

Also at 24 weeks, significantly more patients who received efruxifermine achieved resolution of NASH without worsening fibrosis – 76% and 47% compared to 15% with placebo (PPPPliver meeting sponsored by the American Association for the Study of Liver Diseases.

“These data support the initiation of EFX [efruxifermin] phase III program,” he noted.

More patients on efruxifermin also achieved improvements in liver fat content, with a mean relative percent change from baseline of -64% with the 50 mg dose and -52% with the of 28 mg, versus -6% with placebo (PP

More statistically significant reductions were also observed in both efruxifermin dose groups for non-invasive markers including Pro-C3, Improved Liver Fibrosis (ELF) Score and Liver Stiffness by FibroScan, which which reflected histological improvement of the fibrosis.

With respect to markers of liver injury, the 50 mg and 28 mg doses of efruxifermin produced more “rapid and sustained” improvements in alanine aminotransferase (ALT) levels (least squares [LS] mean change -47% and -38% vs -4% with placebo) and aspartate aminotransferase (AST) levels (mean LS change -49% and -39% vs -2%, respectively) between baseline and 24 weeks.

Other improvements were also seen in the lipoprotein profile with efruxifermin, including triglycerides, low-density lipoprotein/high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol.

Additionally, “clinically meaningful improvements” were observed in glycemic control and insulin sensitivity in the treatment groups, as evidenced by greater reductions in HbA1c and C-peptide levels.

Finally, a significant weight loss (2.6% of total body weight) was observed with the 50 mg dose of efruxifermin at week 24 (-2.9 against -0.6 kg with the placebo).

“These results are remarkable, given that fat is the driver of progression to fibrosis and cirrhosis,” said Jamile Wakim-Fleming, MD, director of the Fatty Liver Disease Program at Cleveland Clinic in Ohio. MedPage today.

“EFX seemed to halt the progression and even reverse fatty inflammation in the liver,” said Wakim-Fleming, who was not involved in this study. “Given that there is no FDA-approved drug yet for the treatment of NASH, the hope is that this safe and well-tolerated drug will pass its Phase III trial to help patients recover. and hopefully help cure non-alcoholic fatty liver disease.”

“The fact that EFX did not decrease weight by more than 2.6% is a little disappointing, but its effect on NASH is long overdue and I think 24 weeks is not long enough to show loss significant weight loss, but that can happen over time,” added Wakim-Fleming.

In the previous phase IIa randomized BALANCED trial, efruxifermin was found to significantly reduce liver fat content, body weight, ALT/AST levels, triglycerides and other histological markers non-invasive, showing an “encouraging trend towards improvement of fibrosis and resolution of NASH”.

The multicenter, double-blind HARMONY trial randomized 128 patients with NASH and fibrosis stages 2-3 to receive a weekly dose of 50 mg or 28 mg of efruxifermin or placebo for 24 weeks. Those included had a NAFLD (non-alcoholic fatty liver disease) activity score (NAS) of at least 4 (out of 8) and a minimum liver fat level of at least 8% on MRI proton density fat fraction .

The mean age of the patients was 52 to 57 years old and 53 to 69% were women. At baseline, the average body mass index was 37-39 and the average SSIN was 5.1-5.6. More than two-thirds had type 2 diabetes and 63-70% had stage 3 fibrosis.

Efruxifermin doses of 50 mg and 28 mg were well tolerated, Harrison said. Common treatment-emergent adverse events included diarrhea (33% and 35%, respectively, versus 14% with placebo) and nausea (33% and 25%, versus 12%, respectively). One serious drug-related adverse event of esophagitis occurred in the 50 mg group, as did three serious non-drug-related adverse events – COVID-19, edema, and pancreatitis.

Four patients discontinued treatment: two in the 28 mg group due to increased appetite/weight gain and diarrhea, and two in the 50 mg group due to oesophagitis/vomiting and of nausea.

  • Zaina Hamza is a writer for MedPage Today, covering gastroenterology and infectious diseases. She is based in Chicago.

Disclosures

Harrison reported multiple industry relationships, including with Akero Therapeutics, the drug’s maker.

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