In November, CymaBay Therapeutics stopped clinical development of its nonalcoholic steatohepatitis (NASH) hopeful, seladelpar, after biopsies showed signs of liver damage in some patients. Now, the biotech is gearing up to revive the program after a panel of independent experts found no “chemical, biochemical or histological evidence” that the drug caused any liver injury.
The California biotech had been developing seladelpar, a PPAR-delta agonist, for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) as well as for NASH. Its first focus with the resurrected program will be PBC, an autoimmune disease of the liver that causes inflammation and scarring of the bile ducts.
CymaBay had halted all studies of seladelpar after liver biopsies showed some patients in a phase 2b NASH trial had inflamed and destroyed liver cells, a condition known as interface hepatitis.
“The atypical histological findings in the NASH Phase 2b clinical study of seladelpar were observed in patients who demonstrated on-study improvement or stabilization of their biochemical measures of inflammation and liver injury and no liver-related adverse events after 52 weeks of treatment,” Sujal Shah, president and CEO of CymaBay, said at the time.
Translation? The biopsies may have shown liver damage, but other measures, such as liver enzyme levels, did not.
The independent panel, made up of top hepatologists and liver pathologists, agreed. They “unanimously supported re-initiating clinical development of seladelpar pending approval by the FDA,” CymaBay said in a statement announcing that yes, the FDA has lifted the clinical hold for all three seladelpar INDs.
This turnaround could have implications for other PPAR agonists in the field, notably Inventiva’s lanifibranor, which recently posted promising phase 2 results, and elafibranor, which Genfit dumped after it failed a key phase 3 study in May. Elafibranor failed to beat placebo at improving NASH symptoms without making scarring worse.
This class of drugs targets PPAR, a protein found inside cells that plays a role in, among other things, cellular metabolism. Its different forms are expressed in many types of liver cells, and it's thought to be an avenue to affect pathways around inflammation, fibrosis and fat metabolism. Seladelpar activates the delta form of PPAR, while elafibranor targets PPAR-alpha and PPAR-delta. Inventiva’s prospect hits all three: alpha, gamma and delta.
The news also revisits familiar questions about the reliability of liver biopsy as an endpoint for NASH trials. While doctors are increasingly using noninvasive tests, such as blood-based tests and imaging-based ones, to diagnose NASH, clinical R&D hasn’t caught up. Not only is liver biopsy invasive and expensive, it’s also subjective—a pathologist’s findings depend on which part of the liver the sample was taken from and on the pathologist’s own experience. That’s how samples taken from different parts of a person’s liver can turn up vastly different results.
“It’s long been known to be a challenge with liver biopsy in liver diseases including NASH and it creates problems when we’re trying to evaluate new therapies when we can’t trust a gold standard,” Rob Myers, vice president and clinical fibrosis research lead at Gilead Sciences, said in a previous interview.
Gilead has seen its fair share of failures in NASH, with selonsertib flunking not one, but two, phase 3 studies in 2019. An analysis of the nearly 1,700 patients who took part in the studies found that their scores on noninvasive tests—such as a blood test for liver scarring or an ultrasound-based test for liver stiffness—reflected the state of their disease better than a liver biopsy did.
If the scores worsened, so did the risk of a patient’s fibrosis getting worse and progressing to cirrhosis, Myers said. If they improved, so did the other parameters, including tests of liver function, liver stiffness, markers of metabolism and noninvasive tests of fibrosis. But if a patient's disease appeared to have improved according to a biopsy, it did not improve based on the other tests.