In an announcement short on details and trying to put a positive spin on things, San Diego-based Conatus Pharmaceuticalsindicated its emricasan failed its Phase IIb ENCORE-NF clinical trial in patients with NASH.
Nonalcoholic steatohepatitis (NASH) is a liver disease caused by a buildup of fat in the liver, which causes liver inflammation and scarring. It is similar to cirrhosis of the liver, but occurs in people who drink little or no alcohol. There are no currently approved treatments except for lifestyle changes. It is related to obesity and diabetes.
The ENCORE-NF trial enrolled and treated 318 patients with biopsy-confirmed NASH fibrosis stages F1-F3 at baseline. The patients were randomized equally to receive 5 mg of emricasan, 50 mg of emricasan, or placebo twice a day for 72 weeks.
The primary endpoint of the trial was greater or equal to 1 CRN fibrosis stage improvement with no worsening of steatohepatitis compared with placebo at week 72. The trial failed to meet the endpoint. The response rates were 11.2 percent for the 5 mg dose, 12.3 percent for the 50 mg cohort and 19 percent for the placebo groups.
Statistically significant decreases in ALT and Caspase 3/7 were observed in the emricasan cohorts.
“Although emricasan did not have the desired effect in these earlier-stage NASH fibrosis patients, we believe its demonstrated biomarker activity across a broad spectrum of liver disease warrants continued evaluation in more advanced-stage NASH cirrhosis patients,” stated Steven J. Mento, president, chief executive officer and co-founder of Conatus. “We look forward to seeing the additional data readouts expected over the coming months and reviewing the totality of these results with our collaborators at Novartis to determine the most appropriate path forward.”
This is not the first trial for NASH emricasan has failed but showed some positive trends. On December 5, 2018, the company announced top-line results from its Phase IIb ENCORE-PH trial in NASH cirrhosis patients at high risk of decompensation. The primary endpoint was change in mean hepatic venous pressure gradient (HVPG) from baseline to Week 24 in any of the three dosing groups compared to placebo.
Although the overall trial population showed consistently favorable trends compared to placebo, none met the primary endpoint.
Mento at that time said, “Based on previous discussions with regulators, we expect that separate registration trials would be needed in compensated and decompensated NASH cirrhosis. This trial purposely enrolled mostly compensated patients, and we are encouraged by the treatment effect shown in this population in these top-line results.”
And on April 4, 2018, Conatus announced top-line results from its exploratory Phase IIb POLT-HCV-SVR proof-of-concept clinical trial of emricasan in liver transplant patients with fibrosis or cirrhosis. Again, the trial failed to meet its primary endpoint. The company indicated at the time that “the emricasan treatment effect in the subgroup of patients where the histology endpoint is most relevant, patients with advanced fibrosis and early cirrhosis, supports further evaluation.”
The drug is part of a deal with Novartis. In 2016, Novartis paid Conatus $50 million upfront to license the drug. There is yet another Phase II trial expected to readout later this year.
Stephen Willey, an analyst with Stifel, wrote in a note to clients, “The failure … further limits our ability to generate any lingering enthusiasm for remaining full year 2019 milestones. The limited efficacy details provided by management actually suggested a directional detriment in emricasan-treated patients … the lack of any clinical consequences associated with these benefits is consistent with every other emricasan study reported to date.”
Investors weren’t enthused either, with shares cratering more than 55 percent in premarket trading.