Shares of Tobira Therapeutics Inc. lost more than half their value Monday, falling 60 percent to close at $4.50 on news that Centaur, a phase IIb study of its experimental non-alcoholic steatohepatitis (NASH) drug cenicriviroc, failed to meet its primary endpoint, knocking two points off a score used to evaluate changes in the condition after a year of treatment. Despite the outcome, Tobira said that success on a secondary and possibly more meaningful endpoint of Centaur, improvement of fibrosis, or liver scarring, could potentially form the basis of a pivotal phase III study in 2017.

Deeper insights into the outcome, which will help clarify how Centaur's result positions the drug against its fiercest competitor, Intercept Pharmaceuticals Inc.'s obeticholic acid, probably won't arrive until the American Association for the Study of Liver Diseases annual meeting in Boston this November. Intercept's shares (NASDAQ:ICPT) moved little on Monday, rising just 30 cents, to close at $158.50.

"The field [of NASH], our understanding of the disease, and therefore the trial designs are evolving very rapidly," study chairman Scott Friedman told BioWorld Today. The outcome "at least for me, forces a rethink, because we had assumed that components of the NAFLD, or NAS [non-alcoholic fatty liver disease activity] score, are driving fibrosis," he said. Instead, patients in the trial saw what he called an "unprecedented" improvement in fibrosis without affecting all the elements of that score.

That disconnect creates a fresh dissonance that Tobira will have to unwind in further analysis of the trial. Nonetheless, a number of things have become clear over the course of multiple studies sponsored by Tobira and its competitors, Intercept Pharmaceuticals Inc. and Genfit SA, said Friedman, chief of the division of liver diseases at Icahn School of Medicine at Mount Sinai.

First, "it's the amount of fibrosis or scar or that ultimately drives outcomes," he said. "So, whatever impact you have on the disease, the most important impact is how much fibrosis is present or how much it responds to therapy." Furthermore, he added, although liver experts had assumed that the worse the components of the NAS, the more likely they are to drive fibrosis, "it has been a somewhat empiric link, and one that has not really been quantified" in terms of whether bloating and death of hepatocytes (called ballooning), inflammation, or fat contribute most. Now, the amount of ballooning seems to be the most critical precursor that drives fibrosis, he said.

WHAT MATTERS MOST

Centaur, which enrolled 289 adults with liver fibrosis, sought to evaluate cenicriviroc's impact on participants' NAS after one year of cenicriviroc treatment vs. placebo, using each person's screening biopsy as the baseline. The endpoint, the same as in Intercept's Flint trial of obeticholic acid, was two-point reduction in NAS score without production of fibrosis. NASH resolution and improvement of fibrosis, or liver scarring, were key secondary endpoints.

Cenicriviroc, often called CVC, is an immunomodulator. It blocks two chemokine receptors, CCR2 and CCR5, which are intricately involved in the inflammatory and fibrogenic pathways in NASH. Between 3 percent and 5 percent of the U.S. population are thought to be impacted by NASH, a severe type of non-alcoholic fatty liver disease (NAFLD), which is characterized by the accumulation of fat in the liver with no other apparent causes. The condition occurs when the accumulation of liver fat is accompanied by inflammation and cellular damage. The inflammation can lead to fibrosis of the liver and eventually progress to cirrhosis, portal hypertension, liver cancer and eventual liver failure.

Twice the number of patients treated with CVC for one year saw an improvement in fibrosis by at least one stage without worsening of steatohepatitis vs. placebo in Tobira's intent-to-treat population (20 percent vs. 10 percent, p=0.02) and CVC showed anti-fibrotic activity across all three stages of fibrosis (F1-F3). However, the study did not meet the other key secondary endpoint, which was complete resolution of steatohepatitis. Patients remain on therapy in a blinded fashion and all study endpoints will be evaluated again at year two of the study with a liver biopsy.

The safety profile of CVC in Centaur was comparable to placebo, with the most commonly reported drug-related clinical adverse events of at least moderate severity in the CVC arm being fatigue (2.8 percent) and diarrhea (2.1 percent).

Tobira CEO Laurent Fischer told BioWorld Today that he thinks people haven't really had a chance to understand the lack of clear FDA guidance in NASH. The NAS score is not considered an approvable endpoint, he said. That distinction accrues to two other endpoints: NASH resolution without worsening of fibrosis or achievement of improvement in fibrosis of at least one stage without worsening of NASH, the endpoint Tobira hit in Centaur.

Company execs plan to meet with regulators later this year to discuss the design of a pivotal phase III study for CVC, a trial that it anticipates would include a similar population to those enrolled in Centaur. It expects to initiate the study in 2017 to confirm CVC's anti-fibrotic activity.