CymaBay Therapeutics is pulling the plug on midphase studies of its liver disease drug in nonalcoholic steatohepatitis (NASH) and primary sclerosing cholangitis (PSC) and after biopsies found liver damage in some patients. The company’s stock nose-dived more than 75% Monday.
The California biotech was developing the drug, seladelpar, for primary biliary cholangitis (PBC) as well as for NASH and PSC. The phase 2b study pitted three doses of the PPAR-delta agonist against placebo in 181 patients with NASH and a liver fat content higher than 10%. The company is calling off the NASH study and a phase 2 study in PSC after liver biopsies found that some patients had inflamed and destroyed liver cells, a condition known as interface hepatitis.
CymaBay is hitting pause on all PBC studies as looks to unravel these “atypical” findings.
“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,” said Sujal Shah, president and CEO of CymaBay, in a statement. “These findings were also unexpected based on our preclinical and clinical experience with seladelpar to date.”
Cantor Fitzgerald analysts were “surprised” by the move, as “Seladelpar is the sole asset we believe investors assign credit to for CBAY.” The company has two other programs in its pipeline, but neither is in an active clinical study.
The move comes five months after the company unveiled 12-week data for the study showing it had missed its primary endpoint of reducing liver fat. The company persevered with the study thanks to “robust and clinically meaningful” reductions in several liver enzyme levels.
Seladelpar is an agonist of peroxisome proliferator-activated receptor delta (PPAR-delta), a type of protein found inside cells that play a role in, among other things, cellular metabolism. It is expressed in many types of liver cells and was thought to be an avenue to affect pathways around inflammation, fibrosis and fat metabolism.
“NASH is a complex, multifactorial disease that can lead to liver injury and fibrosis. These data demonstrated a notable decrease in biochemical markers of liver injury despite lack of overall improvement in liver fat,” said Stephen Harrison, M.D., the principal coordinating investigator of the study, at the time. The liver injury seen after 52 weeks is the nail in the coffin for seladelpar’s journey in NASH.
It might affect the path of other PPAR-targeting meds, the Cantor Fitzgerald analysts wrote: “Is this a PPAR issue, a PPAR-delta issue or a seladelpar issue? ... We think this may result in more scrutiny from the FDA around the PPAR class depending on the details of what exactly was seen on these biopsies. We note that PPAR’s as a class already have a longstanding partial FDA clinical hold around carcinogenicity suggesting FDA caution with this class safety historically.”
Genfit, the French biotech whose drug, elafibranor, hits two PPAR receptors, alpha and delta, saw its stock dip 3%, while Inventiva, whose lanifibranor targets PPAR alpha, delta and gamma, also had a slight dip of nearly 2%. Genfit expects to report top-line data from the phase 3 study of elafibranor by the end of the year, while Inventiva’s phase 2b study of lanifibranor is slated to readout by mid-2020.