Conatus Pharmaceuticals Inc. often gets listed alongside the 10 or more companies developing drugs for non-alcoholic steatohepatitis (NASH), but it consistently points out that its lead candidate, emricasan, is intended to treat a wide range of liver disease including cirrhosis and the remaining liver damage in patients who've been cured of hepatitis C.

At the American Association for the Study of Liver Diseases (AASLD) conference Nov. 13-17, the San Diego company presented data for emricasan in portal hypertension and other liver indications. The firm now is embarking on a series of Phase IIb ENCORE trials to test its drug, a first-in-class, orally active pan-caspase protease inhibitor, across the spectrum of liver disease ranging from early-stage to late-stage indications, CEO Steve Mento said in an interview.

Mento noted that AASLD two years ago was focused on the coming wave of new direct-acting antiviral therapies for HCV, while last year's meeting included significant buzz about NASH, as several programs appeared headed toward pivotal trials in the unmet medical need ([A#00141117003]). Intercept Pharmaceuticals Inc. and Genfit SA have since initiated or announced Phase III programs for NASH (see related story,[A#00151130011]).

Now, Mento perceives the attention of liver disease stakeholders as turning to cirrhosis and the various disease pathways that lead to that complication. If he's right, that might suggest a significant interest in Conatus' development plans for emricasan ([A#00150330004]).

"This year [at AASLD] is kind of a tweener, [with] not a whole lot of interest in the NASH space per se, but a lot of different interest in the HCV space, as a lot of the manufacturers of new antivirals are focused on trying to get good, robust responses in the sickest patients, either post-transplant patients or pre-transplant patients with cirrhosis," the exec pointed out. "I think that's particularly interesting and strategically a really good fit for where Conatus has been and where we're going."

Heading into the San Francisco meeting, Conatus was engaged in a pair of Phase II studies of emricasan: one in post-orthotopic liver transplant (POLT) recipients with liver fibrosis or cirrhosis post-transplant as a result of recurrent HCV infection (who have successfully achieved a sustained virologic response (SVR) on antiviral therapy), and another in patients with liver cirrhosis and Model for End-stage Liver Disease (MELD) scores of 11 to 18.

"We've talked about emricasan as being a drug that has the potential to provide therapeutic benefit to patients at all levels of liver disease, very early disease through later-stage disease." – Conatus CEO Steve Mento

ENCORE will consist of five studies slated to begin over the next 15 months, Mento said, one evaluating the drug for reduction of hepatic venous pressure gradient (HVPG) in 160 patients with compensated or recently decompensated cirrhosis. In this study, patients will have severe portal hypertension due either to NASH or to HCV, despite having achieved SVR.

A second study will look at severe portal hypertension in patients with compensated or recently decompensated cirrhosis due to alcohol. Both studies will dose emricasan for six months. Patients who complete either of those studies also will be enrolled in an 18-month extension study to assess safety, efficacy, clinical outcomes and health-related quality of life.

Mento said Conatus should begin reporting data from the ENCORE trials in early 2018. Getting later starts will be ENCORE studies that test emricasan for long-term liver function and then for reducing fibrosis and steatohepatitis in NASH patients who have fibrosis but not cirrhosis. Conatus thinks the trials could inform the design of a Phase III program for emricasan, but if the efficacy and safety data are robust enough, might be sufficient for consideration of accelerated approval, Mento said.

"We've talked about emricasan as being a drug that has the potential to provide therapeutic benefit to patients at all levels of liver disease, very early disease through later-stage disease," he said. "And where we've focused most recently is on the later-stage patients, so cirrhosis is where we're going. [We're] not just looking at portal hypertension."

"If you look at the mechanism of action of this drug, it has the potential and we've just shown that potential in a clinical trial to provide a very short-term benefit: decreasing portal pressure, which is basically responsible for most of the consequences associated with cirrhosis, the variceal bleeding, the encephalopathy, the decreases in liver function," the exec added. "So that's a measureable short-term effect, but it’s not an effect where you're going to give emricasan for a month and then take it away. It's something that predicts that the longer you're on the drug, the better your outcome is going to be."

Safety Concerns About Chronic Therapy

The potential of emricasan as a chronic therapy necessitates the 18-month extension study. In a Nov. 17 note, JMP Securities analyst Liisa Bayko maintained a "market outperform" rating for Conatus stock, but lowered her target price from $10 a share to $6 due to safety concerns about chronic administration. She added that conference attendees were impressed with Phase II data demonstrating that emricasan produces a clinically meaningful 17% reduction in HVPF, which is an important measure of portal hypertension.

Emricasan inhibits both apoptotic and inflammatory caspases. "Experts at the Liver Meeting continued to express concerns over the chronic use of emricasan due to the theoretical risk of malignancies with an anti-apoptotic drug in cirrhotics (at risk for liver cancer)," Bayko wrote.

"We've got what we think is very comprehensive approach to looking at these three opportunities to help patients, the more rapid short-term opportunity in portal hypertension, the medium-term opportunity of liver function … and then in the two fibrosis studies, looking histologically for structural improvement in the post-transplant HCV and in the NASH fibrosis population," Mento said.

Conatus' Liver Focus Goes Well Beyond NASH

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