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Use of the long-acting FGF21 analog efruxifermin led to statistically significant improvements in fibrosis and resolution of nonalcoholic steatohepatitis (NASH) compared with placebo, the phase IIb randomized trial showed.

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 met the primary endpoint of fibrosis improvement by at least one stage without any worsening of NASH at 24 weeks, as compared with 20% of those who received placebo (P<0.05 for both), reported Stephen Harrison, MD, of Pinnacle Clinical Research in San Antonio.

Also at 24 weeks, significantly more patients who received efruxifermin achieved NASH resolution with no worsening of fibrosis -- 76% and 47% vs 15% with placebo (P<0.001 and P<0.01, respectively), while the composite endpoint of NASH resolution and fibrosis improvement also achieved significance (41% and 29% vs 5%, respectively; P<0.001 and P<0.01), Harrison said in his late-breaking presentation at the annual Liver Meeting sponsored by the American Association for the Study of Liver Diseases.

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

More efruxifermin patients 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 28-mg dose compared with -6% with placebo (P<0.001 for both), and relative reductions in liver fat thresholds of at least 50% (77% and 63% vs 2%, respectively; P<0.001), which showed the "potential to eliminate the underlying disease driver," Harrison said.

More statistically significant reductions were also seen among both efruxifermin dose groups for non-invasive markers, including Pro-C3, Enhanced Liver Fibrosis (ELF) score, and liver stiffness by FibroScan, which reflected histological improvement in fibrosis.

When looking at liver injury markers, both the 50-mg and 28-mg doses of efruxifermin resulted in 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 (LS mean change -49% and -39% vs -2%, respectively) from baseline to 24 weeks.

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

Moreover, "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, significant weight loss (2.6% of total body weight) was seen with the 50-mg efruxifermin dose by week 24 (-2.9 vs -0.6 kg with placebo).

"These findings are remarkable, considering that fat is the driver of progression to fibrosis and cirrhosis," Jamile Wakim-Fleming, MD, director of the Fatty Liver Disease Program of the Cleveland Clinic in Ohio, told 番茄社区.

"EFX seemed to halt the progression, even reverse fatty inflammation in the liver," said Wakim-Fleming, who was not involved in this study. "Considering the fact that there is not yet any medication FDA approved for the treatment of NASH, the hope is that this safe and well-tolerated medication will pass its phase III trial to assist patients in healing and hopefully help cure non-alcoholic fatty liver disease."

"The fact that EFX did not decrease weight by more than 2.6% is a bit disappointing, but its effect on NASH is long awaited and I believe that 24 weeks is not long enough to show significant weight loss, but this may occur with time," added Wakim-Fleming.

In the prior phase IIa randomized , efruxifermin was found to significantly reduce liver fat content, body weight, ALT/AST levels, triglycerides, and other non-invasive histological markers, showing an "encouraging trend toward fibrosis improvement and NASH resolution."

The multicenter, double-blind HARMONY trial randomized 128 patients with NASH and fibrosis stages 2-3 to a once-weekly dose of 50 mg or 28 mg 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.

Mean patient age was 52-57 years, and 53-69% were women. At baseline, mean body mass index was 37-39, and mean NAS was 5.1-5.6. Over two-thirds had type 2 diabetes, and 63-70% had stage 3 fibrosis.

Both the 50-mg and 28-mg efruxifermin doses were well tolerated, said Harrison. Frequent treatment-emergent adverse events included diarrhea (33% and 35%, respectively, vs 14% with placebo) and nausea (33% and 25% vs 12%, respectively). One drug-related serious adverse event of esophagitis occurred in the 50-mg group, as did three non-drug-related serious 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 esophagitis/vomiting and nausea.

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