Fibrosis Belongs at Center of MASH End Points: Zobair M. Younossi, MD

Fibrosis stage, not resolution of steatohepatitis, should serve as the primary end point in metabolic dysfunction–associated steatohepatitis (MASH) clinical trials, according to Zobair M. Younossi, MD, chairman of The Global NASH Council, discussing data presented at the European Association for the Study of the Liver Congress.

Why Fibrosis Outperforms Steatohepatitis Resolution as an End Point

Regulators built early MASH trial end points around 2 surrogates: resolution of steatohepatitis without worsening fibrosis or improvement in fibrosis by 1 stage without worsening steatohepatitis. Both were intended to stand in for the outcome that matters most: liver-related mortality. Younossi's analysis found that steatohepatitis and its individual components, including ballooning degeneration and lobular inflammation, predict the development of fibrosis but lose their association with mortality once the fibrosis stage is added to the model.

"It's actually fibrosis stage that determines mortality," Younossi said. He added that this holds even when fibrosis is assessed through noninvasive tests (NITs) rather than biopsy. In Younossi's cohort, swapping biopsy-confirmed fibrosis stage for NITs such as transient elastography or the enhanced liver fibrosis test produced the same predictive relationship with outcomes, a finding he said supports fibrosis as what he called the "best integrator" of disease severity and risk.

What This Means for Trial Sponsors and Regulators

Younossi framed the distinction as one of purpose rather than competing merit. Steatohepatitis remains important evidence that a drug is engaging the underlying disease process, since it sits earlier in the pathogenic pathway and drives fibrosis development. But for demonstrating that a drug improves patient outcomes, he said fibrosis is the more appropriate primary end point, with steatohepatitis serving as a secondary measure.

He also pointed to a practical limitation of steatohepatitis as a primary end point: its diagnosis depends on liver biopsy interpretation, which is subject to substantial variability between pathologists reading the same sample. Fibrosis-based NITs avoid that variability while still tracking patient outcomes, reinforcing their value alongside biopsy-based staging.

Younossi's recommendation is that MASH trials center their primary end point on fibrosis, assessed invasively or through validated noninvasive measures, while retaining steatohepatitis resolution as a secondary end point that confirms a drug is engaging the disease process those trials are designed to treat.