Due to the “dynamic nature of the situation,” officials of Cymabay Therapeutics Inc. declined to comment on the stoppage of work with PPAR-delta agonist seladelpar, but in a press release they pointed to “a series of investigative actions [that have begun in order] to better understand these findings.”  

Wall Street didn’t wait, taking 76% off Newark Calif.-based Cymabay’s shares (NASDAQ:CBAY), which ended at $4.22, down by $1.33. The company slated a conference call for late in the day, after the market closed.  

Based on early findings from the phase IIb study in nonalcoholic steatohepatitis (NASH), the company terminated that experiment along with the recently begun phase II effort with the same drug in primary sclerosing cholangitis. Placed on hold were all studies of seladelpar in primary biliary cholangitis (PBC). As a reason Cymabay cited “atypical” histology characterized as an interface hepatitis – also called piecemeal necrosis – presentation, with or without biliary injury. The situation turned up in patients who have shown on-study improvement or stabilization of their inflammation and liver injury, with no liver-related adverse events after 52 weeks of treatment, the firm said. 

Evercore ISI analyst Josh Schimmer said in a report that “another setback makes clinical success for seladelpar unlikely, in our view. This type of histologic finding and dramatic impact across the portfolio is particularly concerning, especially because the phase III PBC [study] is based on a biomarker endpoint. As such, it will be very difficult to make a case that a clinical biomarker should trump a histopathologic liver signal,” he concluded. In June, Cymabay took a hit upon making public the 12-week top-line results from an ongoing 52-week phase IIb dose-ranging, paired liver biopsy study of seladelpar in NASH.

At the time, CEO Sujal Shah told BioWorld that, “in the end, irrespective of fat reduction and even alanine transaminase [ALT], the true endpoint to progress to phase III or even in phase III in the setting of NASH comes from a read on histology. It's either NASH resolution or a reduction in fibrosis. You want to get to the biopsy” and allow histological results to speak. They did. 

Genfit read-through case ‘weak’ 

“This is a worst-case scenario, elevating safety issues that are unlikely to be resolved in the near future,” SVB Leerink analyst Pasha Sarraf wrote in a report. “The risk/reward clearly favors significant risk, even as we await additional information and clarity from [the company]. Our model is currently under review.”

Roth’s Yasmeen Rahimi sounded more circumspect. “These observations [in improving patients] are peculiar since normal presentation of autoimmune hepatitis would be accompanied by elevated ALT/aspartate aminotransferase levels (typically, upwards of 5-10xULN),” she wrote, adding that it’s key “that these findings came from an initial tranche of biopsy reads; with this first cut of 52-week data, we could see a situation where a stringent biopsy grader noticed the histological signals and a methodical overall plan was enacted by Cymabay to accurately identify the source of these findings.” Seladelpar has cleared safety hurdles that include six-month and 12-month toxicity studies in rats and monkeys, respectively; two-year carcinogenicity studies in mice and rats; and nine phase I and three phase II studies, all with no safety signals. “Without knowing what the patients' backgrounds were prior to the study (though normally autoimmune hepatitis would fall under exclusion criteria),” she wrote, “we believe it's not yet possible to definitively say that the observations of autoimmune hepatitis were drug-induced, and are delaying making a call until we know more about the magnitude and severity of the interface hepatitis presentation, as well as Cymabay’s game plan for verifying that the histology is not drug-induced.” 

Meanwhile, shares of Intercept Pharmaceuticals Inc. (NASDAQ:ICPT) closed at $96.34, up $7.45, after trading as high as $99.94. The New York-based firm said the FDA has granted obeticholic acid (OCA) priority review in NASH, with a PDUFA date of March 26, 2020. RBC Capital Markets’ Brian Abrahams noted in a report that Cymabay’s seladelpar was “considered by many to be the most significant potential future competitor in PBC, and also an agent to watch in NASH.” The NDA filing acceptance for OCA “essentially confirms that FDA is on board with Intercept’s strategy of having a different brand for OCA in NASH than in PBC,” he wrote. “Though we do not believe Intercept would have filed without some signals that [the] agency would allow this, we believe there was still some Street skepticism around this potential.” Regulators said OCA will undergo an advisory committee meeting, but Abrahams predicted “an uncontroversial discussion focused on appropriate population and labeling” and did not expect biopsy requirements to be included. 

Also in the space is Lille, France-based Genfit SA with elafibranor, a dual agonist of the PPAR-alpha and PPAR-delta. SVB Leerink’s Sarraf reminded Genfit backers that elafibranor is further along in development than seladelpar “and has more safety information than [the Cymabay candidate] ever had.” Genfit has treated more than 1,000 patients in NASH, compared to about 300 to 400 with seladelpar across all indications. In the phase IIb study called Golden, Genfit treated about 180 patients, and full histology results at 52 weeks turned up no issues, which allowed the firm to proceed to phase III. “Per management, given historical PPAR safety concerns, elafibranor has always been under the microscope, with extensive regulatory scrutiny,” he said. Genfit came through a 36-month data safety monitoring board review of its phase III Resolve-It study and the board recommended continuation of the trial without any modifications. Sarraf called the case for read-through from seladelpar to elafibranor “weak.”

Shares of Genfit (NASDAQ:GNFT) closed Monday at $15.30, up 7 cents. 

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