CymaBay scraps key NASH, PSC programs after lead drug triggers safety alarms — share price implodes
When CymaBay Therapeutics recently acknowledged defeat in a 12-week readout of its Phase II trial of seladelpar, the biotech grasped at “significant improvements in biochemical markers of liver injury” as a reason to remain hopeful about the 52-week biopsy results. But that hope is now dashed.
Not only did the drug fail to reduce liver fat, it also appeared to cause cell injury.
These “atypical histological findings” — including cases of suspected interface hepatitis — observed in patients who responded to their drug forced CymaBay to slam the brakes to its seladelpar clinical program, terminating the Phase IIb study in NASH in question and a Phase IIa in primary sclerosing cholangitis (PSC) as well as putting all studies in primary biliary cholangitis on hold.
“We are very disappointed in having to halt the development of seladelpar at this time but patient safety and care is paramount,” CEO Sujal Shah said in a statement.
SVB Leerink analysts called it “a worst case scenario elevating safety issues that are unlikely to be resolved in the near future, in our opinion.”
“The risk/reward clearly favors significant risk, even as we await additional information and clarity from CBAY,” they wrote in a note. “Our model is currently under review.”
But CymaBay’s good day turned out to be a good one for Intercept, which has just clinched priority review and a March 26, 2020 PDUFA for their NASH drug obeticholic acid (OCA).
From Baird’s Brian Skorney:
This follows a long history of PPAR agonists blowing up (muraglitazar, troglitazone) and highlights what we believe is an underappreciation of the risks of clinical development in the NASH space. OCA remains the only medication, to date, that has shown a fibrotic benefit in a prospectively defined controlled study, and its done it twice. We continue to believe OCA is likely to be the only game in town for NASH for the foreseeable future.
Safety issues have previously ben raised in the PPAR agonist class. This family of drugs activate proteins called peroxisome proliferator-activated receptors, which regulate gene expression and are believed to play a role in bile acid synthesis, inflammation, fibrosis and lipid metabolism.
Back in 2007 GlaxoSmithKline abandoned its own effort in the field — a collaboration with Ligand Pharmaceuticals — after their agent led to the formation of tumors in animal tests. (The compound, GW501516, subsequently took on a second life as an illegal performance-enhancing drug for athletes).
France’s Genfit and Inventiva are also working on their own PPAR agonists for NASH. Genfit $GNFT took a smaller toll on CymaBay’s termination news than it did following CymaBay’s initial readout, sliding 3.35% to $14.72. Almost a year ago the drugmaker touted that their elafibranor induced a statistically significant decrease in serum alkaline phosphatase (ALP) levels for PBC patients, and earlier this year it won orphan status for that indication.
While the market eagerly awaits Phase III results from Genfit, it has also secured a deal with Terns Pharmaceuticals to bring the therapy to China.
On CymaBay’s part, execs said they are investigating the surprise findings, which involved 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.”