Investors wanted but didn't get details from Conatus Pharmaceuticals Inc. about next clinical moves, though the firm offered color Thursday on positive phase II data disclosed the previous day with emricasan, an oral pan-caspase inhibitor, in severe portal hypertension (PH) with cirrhosis.

The drug, undergoing development across the spectrum of liver disease, met its primary endpoints against cirrhotic PH of a clinically meaningful and statistically significant change from baseline in the hepatic venous pressure gradient (HVPG, which measures pressure in the portal vein), and a statistically significant change from baseline in cleaved cytokeratin 18 (cCK18), a biomarker of the cell death that contributes to chronic inflammation.

CEO Steven Mento said the firm believes it will have a registration strategy for emricasan in place by the end of the year. "We do believe that HVPG can be a primary endpoint and a component in those studies, and we do believe that those studies need not be restricted only to nonalcoholic steatohepatitis [NASH] patients, that mixed etiologies are possible," he said. "So, when we talk about phase IIb studies, we're talking about the kinds of studies that would certainly support registration activity for this drug in patients with cirrhosis."

Mento said using HVPG as a primary endpoint in further experiments "opens the door for using those studies in a registration strategy as we see fit. We think we have the information in hand now to plan the studies that we would move forward with," he said, adding that the firm "already had a meeting with the FDA in May, and a lot of the analysis that we've done on this study and how we've looked at these patient populations is a direct result of the comments" by the agency back then.

Pressed regarding patient numbers and dosing duration in registration trials, Mento called those "two good questions that we're still pondering." Conatus wants to show long-term liver improvements, and has two other studies ongoing with emricasan. "We've got to complete a database that would allow for chronic administration," he said, and extended therapy could end up pushing livers toward more normal states than available therapies do. "Beta blockers give you symptomatic relief early on and there has been good correlation with their use in the severe hypertension [patients] and improved clinical outcomes, but those patients still have cirrhosis," he said.

Piper Jaffray analyst Charles Duncan found the latest data "intriguing proof-of-mechanism" but said in a research report that he remains "wary of investor over-interpretation due to the small, short study design and our speculation around the predictive value of study endpoints." As a "cautionary example," he pointed to Novato, Calif.-based Raptor Pharmaceuticals Inc.'s phase IIb failure earlier this month with RP103 (cysteamine bitartrate delayed-release capsules) in pediatric non-alcoholic fatty liver disease, an outcome that happened "despite clear biomarker improvement."

NASH SPLASH? RASH: ANALYST

The open-label PH trial was conducted by Conatus, of San Diego, at nine U.S. sites, enrolling 23 patients (22 evaluable) with PH and compensated liver cirrhosis that was predominantly due to NASH or hepatitis C virus (HCV), including patients with active HCV infection and patients who had a sustained viral response to antiviral therapy.

PH, or elevated blood pressure in the major vein that feeds into the liver, was confirmed by HVPG measurement of greater than 5 mmHg at baseline, and measured again after treatment with 25 mg of emricasan given twice daily for 28 days. Patients were divided according to the HVPG therapeutic threshold of 12 mmHg, which indicates more severe PH. Reducing the HVPG to below 12 mmHg or reducing HVPG by 10 percent or greater or 20 percent or greater has been strongly associated with clinical benefit in that patient population, Conatus said. The HVPG endpoint was analyzed in patients with baseline HVPG values 12 mmHg or greater (N = 12), patients with baseline HVPG values of less than 12 mmHg (N = 10), and all evaluable patients. HVPG measurement was standardized, and tracings were evaluated by a single expert reader not otherwise involved in the PH trial.

HVPG decreased by a mean of 3.7 mmHg from the mean baseline of 20.6 mmHg in the higher baseline HVPG group (p < 0.003), with eight of 12 achieving a 10 percent or greater decrease, four of 12 achieving a 20 percent or greater decrease, and two of 12 achieving reductions below 12 mmHg. The changes from baseline HVPG were not statistically significant in the lower baseline HVPG group (+1.9 mmHg mean increase from mean baseline of 8.1 mmHg; p = 0.12) or the total evaluable patient population (-1.1 mmHg from mean baseline of 15.2 mmHg; p = 0.26). The cCK18 endpoint, analyzed in the total evaluable patient population, showed a statistically significant reduction (p < 0.03) from baseline.

As in previous experiments, emricasan was safe and well tolerated in the PH study, with no dose-limiting toxicities and no drug-related serious adverse events. Detailed results are expected to be presented in a scientific forum. Data on secondary endpoints will be reported later, too, but are consistent with the findings disclosed so far, the company said.

Piper Jaffray's Duncan was "cautious of read-through to a larger trial for several reasons. The first is replicability in a sufficiently powered study. Was the HVPG decrease in 12 patients a signal or noise? The second is translation from biomarkers or surrogate improvements to meaningful impact on hepatic decompensation and long-term liver structure and function," with Raptor's experiment supplying what Duncan called a "provocative point of comparison."

Michael Yee, with RBC Capital Markets, found the Conatus phase II results "interesting, having hit statistical significance on a surrogate endpoint in 'high risk/severe' patients," and he wrote in a research report that the drug "could be promising, given a serious unmet need like cirrhosis, and particularly noting this is for a $97 million market cap company (pre-data) with a drug that is off the radar for most investors." But the early data plus the size and duration of the trial make emricasan not yet a definitive player in the busy NASH field, according to Yee.

"As we've said with other NASH options, many thought leaders agree that NASH and cirrhosis are complicated situations and many mechanisms could work in combination or in synergy," he added.

Conatus shares (NASDAQ:CNAT) closed Thursday at $5.84, up 10 cents.