CymaBay's seladelpar fails to hit main goal in mid-stage NASH study; shares more than halve

Shares in CymaBay Therapeutics fell as much as 55 percent Tuesday after the company reported that in a Phase IIb study, reductions in liver fat with the experimental drug seladelpar were "minimal" and not significant compared to placebo in patients with non-alcoholic steatohepatitis (NASH). The selective PPAR delta agonist is currently under development for NASH and primary biliary cholangitis. 

The study randomised 181 patients with biopsy-confirmed NASH and a liver fat content (LFC) greater than 10 percent to receive either placebo or seladelpar at one of three once-daily doses. The primary endpoint of the trial was the relative change in LFC at week 12 versus baseline as measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF), while key secondary endpoints include histological improvement in NASH and fibrosis from baseline at week 52 and MRI-PDFF measurements at 26 weeks and 52 weeks.  

Top-line results showed that for the trial's main goal, the relative reduction in LFC from baseline to 12 weeks was 20.8 percent for placebo, which was greater than that seen for all doses of CymaBay's drug. In the seladelpar low-, mid- and high-dose groups, the relative reductions in LFC from baseline to 12 weeks were 9.8 percent, 14.2 percent and 13 percent, respectively. 

The proportions of patients with an at least 30-percent reduction in LFC at week 12 in the low-, mid- and high-dose groups were 24 percent, 25.5 percent and 18.8 percent, respectively, compared with 30.8 percent for placebo. Meanwhile, seladelpar was associated with significant improvements in biochemical markers of liver injury, namely alanine aminotransferase, aspartate aminotransferase (AST, gamma glutamyl transferase (GGT) and alkaline phosphatase, in all three dose groups versus placebo at 12 weeks. 

"While the reductions in liver fat were minimal, we remain encouraged by the significant improvements in biochemical markers of liver injury that we observed at week 12," commented CymaBay chief medical officer Pol Boudes, continuing "the 52-week liver biopsy data will allow us to understand whether the improvement in liver injury markers will translate into histological improvement." 

Commenting on the news, RBC Capital Markets analyst Brian Abrahams remarked "seladelpar could still possibly have an effect on fibrosis longer-term," continuing "nonetheless, we believe these data do clearly reflect the underappreciated complexity and challenges in NASH." 

Additionally, Jefferies analyst Jared Holz noted "investors have not been impressed with current data" in NASH this year. Gilead Sciences' investigational NASH therapy selonsertib missed the main goal of a Phase III study, while analysts questioned the risk of side effects for Intercept Pharmaceuticals' Ocaliva (obeticholic acid) even though the drug was shown to significantly improve fibrosis with no worsening of NASH after 18 months in a late-stage trial.  

Earlier this month, the FDA issued draft guidance detailing its recommendations for developing treatments for stage 4 NASH, noting that the agency believes that approval should be based on clinical trials using outcomes-based endpoints as opposed to histological endpoints. For related analysis on NASH, see ViewPoints: FDA throws wrench in Intercept's advanced NASH plans

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