Aldafermin fails to significantly improve fibrosis on liver biopsy in NASH
Click Here to Manage Email Alerts
Aldafermin did not reach statistical significance on dose-dependent improvement in fibrosis on liver biopsy in patients with nonalcoholic steatohepatitis, according to a presentation at The Liver Meeting Digital Experience.
“The primary endpoint was not met — a dose response in the fibrosis endpoint was not detected. However, clinically significant improvements in several histologic endpoints were seen to include NASH resolution, the composite endpoint of fibrosis improvement and NASH resolution and [nonalcoholic fatty liver disease] activity reduction of at least two points,” Stephen A. Harrison, MD, medical director at Pinnacle Clinical Research in San Antonio, Texas, said during the presentation. “Furthermore, dose dependence improvements in noninvasive endpoints were seen to include liver fat content, ALT, AST, C4, bile acids and PRO- C3. There was a favorable tolerability profile. Aldafermin appears to be well tolerated up to 24 weeks.”
Placebo vs. aldafermin
Harrison, also honorary chair at the University of Oxford, and colleagues randomly assigned 171 patients with NASH to receive placebo (n = 43), aldafermin 0.3 mg (n = 43), 1 mg (n = 42), or 3 mg (n = 43) subcutaneous daily. At baseline and week 24, patients underwent liver biopsies. Dose response in fibrosis improvement of 1-stage or greater by NASH Clinical Research Network criteria with no worsening of NASH served as the primary endpoint. Other endpoints included resolution of NASH with no worsening of fibrosis, liver fat content and serum markers. The primary analysis was conducted in the intention-to-treat population using MCP-MOD procedure.
The trial groups were similar with regard to demographic and baseline characteristics. Harrison said overall, 49% of patients had type 2 diabetes and 64% had stage 2 fibrosis. The proportion of patients who achieved a fibrosis improvement of 1-stage or greater without NASH worsening at week 24 was 19% in the placebo group, 31% in 0.3 mg group, 15% in the 1 mg group and 30% in the 3 mg group. In 6%, 11%, 18% and 22% of patients, Harrison and colleagues observed NASH resolution with no worsening of fibrosis.
No serious adverse events
According to Harrison, treatment with aldafermin led to significant, dose-dependent decreases in liver fat content, with 15% in the placebo group, 25% in the 0.3 mg group, 38% in the 1 mg group and 59% in the 3 mg group. In addition, there were significant reductions in ALT (8%, 25%, 40%, 51%), AST (6%, 18%, 30%, 39%) and the fibrogenesis biomarker Pro-C3 (4%, 7%, 9%, 26%).
Investigators noted mild to moderate adverse events. There was a balance in the incidences of serious adverse events and treatment discontinuation due to adverse events between arms. The serious adverse events were unrelated to aldafermin.
“All serious adverse events were unrelated to treatment,” Harrison said. “[Gastrointestinal] symptoms were more frequent in the 3 mg group. Injection site erythema — mostly mild — was also associated with aldafermin. Aldafermin-induced LDL cholesterol elevations were safely and effectively managed by rosuvastatin.”