Most of the time, when your lead product fails to meet the primary end point of a clinical trial it is a disaster. Even if secondary end points are met, many critics will not be convinced that potential remains. But this is not necessarily the case for Tobira Therapeutics and their lead non-alcoholic steatohepatitis (NASH) candidate, the dual chemokine receptor agonist cenicriviroc. On Monday July 25, Tobira released the results of the placebo-controlled Phase II CENTAUR trial. The prespecified end point of a reduction in NAFLD Activity Score of two points was not met after 1 year. Back to the drawing board, right? Wrong. Cenicriviroc recipients were twice as likely as placebo recipients to improve at least one fibrosis stage without worsening of NASH (20% versus 10%; p=0.02). These results should actually provide hope to the developers, investors, physicians, and patients alike.
Understanding of the pathophysiology, natural history, and treatment responses in NAFLD/NASH is evolving so quickly that initially well designed trials have become suboptimal over the study period as new research shifts the goalposts. Fibrosis is now recognised as an independent predictor of liver-related outcomes, the need for transplantation, and overall mortality, and is generally accepted as the most clinical meaningful end point for assessing novel therapies based on current knowledge.
Similarly, Genfit’s elafibranor failed its Phase II GOLDEN-505 trial. However, during the study period, academics, industry representatives, and regulators worked together to determine better end points for assessing drug candidates for NASH, factoring in the importance of fibrosis. A post hoc analysis of data from GOLDEN-505 based on the new end points showed a significant benefit with elafibranor, and there is a general consensus among thought leaders that this drug will provide clinically meaningful benefits and get to market. Genfit have commenced elafibranor’s Phase III program. Meanwhile, Tobira is convinced that cenicriviroc is still worth pursuing: the company is meeting with the FDA late this year to discuss plans for Phase III investigations. Overall, I believe that cenicriviroc is likely to live to fight another day. Unless the goalpost move again, of course.
In-depth analysis of NASH, with accompanying epidemiology driven sales forecast models, are presented in Decision Resources Group’s NASH Insights, available here.