CymaBay tees up new phase 3 study for resurrected liver drug as truncated trial shows promise

CymaBay tees up new phase 3 study for resurrected liver drug as truncated trial shows promise

CymaBay Therapeutics is getting its liver disease drug back on track. The treatment beat placebo at lowering a liver enzyme in patients with primary biliary cholangitis (PBC), a rare, progressive disease that can lead to inflammation and scarring in the liver. The data come one year after the company halted all clinical development of the drug, seladelpar, and four months after it resurrected the program.

After three months of treatment, 78% patients taking the higher dose of seladelpar, 10 mg, hit the study’s primary endpoint, compared to just 13% of patients on placebo. That endpoint was a composite measure of a liver enzyme called alkaline phosphatase, or ALP, and bilirubin, both of which can indicate liver disease.

“ALP is a key biomarker of cholestasis,” said CymaBay CEO Sujal Shah, referring to the blockage or reduction of bile flow that can lead to inflammation and destruction of bile ducts in the liver. “When allowed to progress, that inflammation leads to fibrosis and even liver cirrhosis … It has become a surrogate for potentially improving the long-term outcomes for patients with PBC.”

The treatment also beat placebo on a secondary endpoint, with 27% of patients on the high dose hitting normal ALP levels compared to no patients on placebo. It also did better at reducing pruritus, or itching, than placebo did.

The data, presented Monday at the virtual meeting of the American Association for the Study of Liver Diseases, come from what would have been the pivotal trial for seladelpar in PBC. The ENHANCE study sought to test two dose levels of seladelpar against placebo over the course of a year, and it recruited patients whose ALP levels stayed high despite taking the standard of care—ursodeoxycholic acid, or UDCA—for at least one year.

But the study, along with all other trials involving seladelpar, was cut short after some patient biopsies showed signs of liver damage in a separate phase 2 study.

“The endpoint itself is the same measure, but the time point at which it was evaluated was changed from what was intended to be at 12 months down to three months. We had about 55 patients in each treatment group, including placebo, that made it through three months,” Shah said. “Importantly, we modified the timepoint before the study was unblinded to maintain the scientific rigor around assessing it.”

Now, CymaBay is gearing up for a new phase 3 study that is slated to kick off in the first quarter of 2021.

“We are studying effectively the same patient population, the same optimal dose and the same endpoints that we had in ENHANCE,” Shah said. The company plans to see this study through to the 52-week mark and—if the results echo those seen here at three months—file the drug for FDA approval.

CymaBay had been developing seladelpar, a PPAR-delta agonist, for primary sclerosing cholangitis and nonalcoholic steatohepatitis (NASH), as well as for PBC. It halted all studies of the drug in November 2019 after biopsies of some patients in a phase 2b NASH trial showed inflamed and destroyed liver cells, a condition known as interface hepatitis.

While those findings, seen under the microscope, showed liver damage, other measures of inflammation and injury—such as liver enzymes—did not. CymaBay put seladelpar on hold because, as Shah puts it, “it was the only decision we could make at the time. It’s not our job to put patients’ safety at risk.”

“It was a very tough decision to make because it caused us to halt all development, and frankly, put the company in significant peril, if you will,” he said.

Eight months later, an independent panel of top hepatologists and liver pathologists agreed that the “atypical” biopsies didn’t match up with other markers that would indicate liver damage and “unanimously supported re-initiating” development of seladelpar, CymaBay said at the time.

“We shared the details of that investigation and review meeting with the FDA and within three weeks, (the agency) agreed with all conclusions of the investigator and lifted the clinical holds. They agreed the concern that was raised was, in fact, a false alarm,” Shah said.

Now, CymaBay’s priority is getting seladelpar through phase 3 and then, the hope is, to patients as quickly as possible. The FDA approved a new PBC treatment in 2016—Intercept Pharmaceuticals’ Ocaliva, for use alongside UDCA—but CymaBay thinks seladelpar will have the edge. For starters, it works differently. While Ocaliva (obeticholic acid) is an FXR agonist, seladelpar activates PPAR-delta. Cross-trial comparisons are always tricky, but Shah reckons seladelpar can deliver better results without causing itching or making it worse—a side effect seen in Ocaliva trials.

As for seladelpar’s future in NASH, some data from the phase 2 study point to positive effects on inflammation, scarring and NASH resolution, or improvements in liver inflammation or liver cell ballooning. But CymaBay will not be tackling that disease alone.

“It’s a very heterogeneous disease for which we are seeing quite a few compounds fall somewhat short of the mark in terms of overall benefit,” Shah said. “It really points you to starting to think about combinations. We continue to explore that through dialogue and discussions with others in the field, but we won’t advance short of having some collaborative effort that proposes a more meaningful clinical development strategy by putting to complementary mechanisms together—and bringing combined resources.”

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