Analyst Notes: Improvements in fibrosis key to long-term success in NASH

Nonalcoholic steatohepatitis (NASH) progresses from nonalcoholic fatty liver disease (NAFLD) and is defined as the presence of hepatic steatosis with inflammation and hepatocyte injury. In the US, the prevalence of NAFLD is estimated between 10 percent to 46 percent of the population, and the prevalence of NASH is 3 percent to 5 percent (10 percent to 30 percent of NAFLD patients progress to NASH). The prevalence of NAFLD has doubled during the last 20 years and is now the leading cause of liver disease in many developed countries. Cirrhosis resulting from NASH has become the second leading cause for liver transplantation in the US. Due to the lack of approved treatments, NASH has become an exciting and dynamic space for drug development. Currently, there are four therapies in Phase III development, two of which have entered the pipeline in the past year; Tobira Therapeutics/Allergan's dual chemokine receptor antagonist cenicriviroc (CVC) and Gilead Sciences' MAP kinase inhibitor selonsertib.

Insights, Analysis & Opinion

Key opinion leaders (KOLs) interviewed by FirstWord for a new report, Nonalcoholic Steatohepatitis (NASH): Disease Outlook, weighed up cenicriviroc and selonsertib's prospects in NASH and have so far expressed cautious optimism.

In July 2016, Tobira/Allergan's cenicriviroc demonstrated fibrosis improvement in the Phase IIb CENTAUR study. Overall, the KOLs interviewed by FirstWord were pleasantly surprised by the results of CENTAUR and were encouraged by the improvement of fibrosis as they consider this to be more predictive of long-term outcomes. While the results were welcomed, some KOLs cautioned that these findings are preliminary and will need to be validated in further studies. In 2017, the AURORA Phase III study was initiated to investigate cenicriviroc versus placebo in NASH patients with stage 2 to 3 liver fibrosis; the majority of KOLs perceive the AURORA study to be a promising trial with a design that is in line with the other Phase III NASH studies.

"Fibrosis is the key because that’s what gets patients into trouble, so if you can’t make headway on that you’ve got a problem." - US Key Opinion Leader

In October 2016, Gilead also published data showing improvements in fibrosis from its Phase II study investigating selonsertib in combination with simtuzumab in NASH patients with moderate to severe (F2-F3) liver fibrosis. The KOLs expressed enthusiasm for the antifibrotic activity reported in this study, particularly given the short duration of the trial, but again cautioned that the results are still very preliminary. Experts noted the patient numbers were small and that larger, more rigorous trials are needed to confirm the findings of this study.

The experts would have ideally liked to see monotherapy data for selonsertib and they look forward to the inclusion of a placebo arm in Phase III studies. Indeed, in February 2017, Gilead initiated two Phase III studies (STELLAR 3 and 4) of selonsertib versus placebo in adults with either stage 3 fibrosis or stage 4 fibrosis with cirrhosis, respectively. The KOLs view the design of the STELLAR trials to be satisfactory and in line with competitor studies.

Overall, KOLs interviewed by FirstWord emphasised that it is difficult to compare the antifibrotic activity of cenicriviroc and selonsertib with other Phase III agents such as Intercept Pharmaceuticals' obeticholic acid given the differences in study design between trials. While fibrosis improvements are ideally desired in the long-term, KOLs agreed that demonstrating an improvement in fibrosis will not likely be required for regulatory approval; arresting fibrosis or NASH resolution is likely sufficient.

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