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Fibrosis can serve as surrogate endpoint for clinical trials of NASH

AMSTERDAM — Baseline enhanced liver fibrosis score and change from that baseline independently predicted progression of nonalcoholic steatohepatitis in those with advanced fibrosis, according to a prospective study presented at the International Liver Congress.

“In nonalcoholic steatohepatitis, advanced fibrosis is the most important histological determinant of clinical outcomes. The impact of changes in histology on disease progression today has been poorly characterized and data on outcomes in advanced NASH-related fibrosis are limited,” Arun J. Sanyal, MD, FAASLD, from Virginia Commonwealth University, said during his presentation.

Sanyal presented a study assessing the association between histologic features and disease progression in patients with NASH and advanced fibrosis in a clinical trial setting. The study included patients with bridging fibrosis (n = 219) or cirrhosis (n = 258) originally randomized to various doses of simtuzumab (Gilead Sciences). The dosing trial terminated due to lack of efficacy and the treatment groups were pooled for analysis.

Median follow-up was 24.9 months and in that timeframe, 21.5% of patients (n = 47) progressed to cirrhosis. Of those, 42 (89%) showed histologic progression and five (11%) had clinical events.

Sanyal showed that baseline hepatic collagen had a hazard ratio of 3.28 (95% CI, 2.31-4.55) and its change from baseline had a HR of 2.99 (95% CI, 2.36-3.78). Additionally, enhanced liver fibrosis (ELF) at baseline carried a HR of 3.13 (95% CI, 2.31-4.22) and its change a HR of 1.59 (95% CI, 1.18-2.13).

“Greater hepatic collagen and ELF at baseline and worsening over time increased the risk of disease progression,” Sanyal said. “No patient with Ishak stage improvement had clinical deterioration.”

Conversely, baseline NASH activity score (NAS) only had a HR of 1.59 (95% CI, 0.83-3.04) and change over time a HR of 0.89 (95% CI, 0.44-1.8).

Through follow-up, 19% of patients (n = 49) had liver-related clinical event such as ascites, encephalopathy and varices. The likelihood of these events occurring was linked to Ishak stage, hepatic collagen and ELF with the worsening of Ishak stage carrying a HR of 9.63 (95% CI, 1.33-69.81).

“That’s almost a 10-fold increase,” Sanyal said. “If it regressed, you dramatically decreased the likelihood you’d have an event.”

Over 2 years, about 25% of patients with NASH and bridging fibrosis progress to cirrhosis and about 20% of cirrhotic patients have liver related events in the clinical trial setting, Sanyal summarized.

“The primary determinant of disease progression is fibrosis and its change over time. The overall NAS its change from baseline is not significant,” Sanyal said. “These data support the use of fibrosis change as an acceptable surrogate endpoint for use in clinical trials of NASH.” – by Katrina Altersitz

References:

Sanyal A. GS-004. Presented at: International Liver Congress; April 19-24, 2017; Amsterdam.

Disclosure: This study was supported by Gilead Sciences.