Tobira Says Secondary Endpoint In NASH Will Carry CVC Into Pivotal Study

The biotech argues that success in reducing fibrosis is more important than the failed primary endpoint measuring NAFLD activity score improvement – and also meets FDA's expectations – but the firm is taking a beating nonetheless.

Tobira Therapeutics Inc.'s CENTAUR trial may have failed on the primary endpoint, but the firm argues that the success on a key secondary endpoint of its Phase IIb study of cenicriviroc in NASH fits FDA's expressed standards for approval.

On July 25, Tobira announced that cenicriviroc (CVC), its dual CCR2/CCR5 inhibitor, missed the primary endpoint of improvement in the non-alcoholic fatty liver disease (NAFLD) activity in the Phase IIb CENTAUR trial, but noted the study did demonstrate a clinically and statistically significant improvement in fibrosis of at least one stage without worsening of non-alcoholic steatohepatitis (NASH) after one year of treatment, a key secondary endpoint. CVC also failed the other key secondary endpoint, complete resolution of steatohepatitis.

"Regulators … have indicated that either of these surrogate endpoints could be used to support a marketing application, [and] that the reduction in the NAFLD activity score, our primary endpoint, was not acceptable as a registrational endpoint," CMO Lefebrve said.

Execs said on an investor call that they would look to confer with FDA about the possibility of designing a pivotal Phase III study based on improvement in fibrosis score, with a hope of initiating a pivotal trial in 2017. Some analysts agreed with the company that success on the fibrosis endpoint was more important for potential patient outcomes than a now-outdated NAFLD score measurement, but investors fled, as Tobira stock crashed from $11.25 at close on July 22 to $4.50 at the end of trading on July 25.

In a same-day note affirming a "buy" rating for Tobira's stock, H.C. Wainwright & Co. analyst Ed Arce said CENTAUR "did achieve a key registrational endpoint." Leerink Partners' analyst Joseph Schwartz took a similar view, maintaining an "outperform" rating for Tobira and saying the improvement seen in fibrosis justifies continued development of CVC into Phase III.

"We view this result as critical as it represents one of two potentially registrational endpoints acceptable to the FDA for accelerated approval [in NASH]," Wainwright's Arce wrote. "Further, CVC showed antifibrotic activity across all three stages of fibrosis (F1-F3), including bridging fibrosis. As related to safety, the rate of adverse events was similar between the placebo and CVC group."

In the 289-patient, placebo-controlled Phase IIb study, significantly more patients treated for one year with CVC saw an improvement in liver fibrosis by at least one stage compared to those treated with placebo (20% vs. 10%, p=0.02) based on a liver biopsy.

CENTAUR study chairman Scott Friedman, chief of the division of liver diseases at Mt. Sinai's Icahn School of Medicine, said in a statement that liver fibrosis is the most important symptomatic feature of NASH, because it is independently associated with outcomes such as long-term overall mortality, liver transplantation and liver-related events.

Predictive Importance Of Fibrosis

On the investor call, Tobira CEO Laurent Fischer said that given the conventional wisdom surrounding NASH, a disease for which no drug is yet FDA-approved, results showing improvement in fibrosis but not statistical significance in NAFLD activity score might be viewed as surprising. He added that the results fit with CVC's mechanism of action, which occurs at the intersection of fibrosis and inflammation.

"To be frank, an improvement in fibrosis without worsening of NASH is a high hurdle and we believe that it is likely to be more meaningful for patients with this disease," Fischer said. "We did not anticipate that we would have such a significant effect on fibrosis after only one year of treatment, which is why we looked at multiple endpoints in this Phase IIb study."

While Tobira will discuss launching a Phase III trial using fibrosis score improvement as the primary endpoint, the patients in CENTAUR will continue to be followed through two years of treatment to see if the results are maintained. Tobira will be seeking to become the third company to enter into Phase III development in NASH, following Intercept Pharmaceuticals Inc. and Genfit SA. (Also see "With 29 Candidates Advancing, NASH Race May Hinge On Long-Duration Data" - Pink Sheet, 25 May, 2015.)

"[Our] findings support the fact that NASH is a complex, multi-factorial heterogeneous disease and that drugs that target different pathways with different mechanisms of action may impact the disease on different parameters," Fischer said. "This highlights the importance of aligning clinical study endpoints with the mechanism of action of investigational agents. And, clearly, what we have demonstrated here is that cenicriviroc has significant antifibrotic activity."

Chief Medical Officer Eric Lefebvre explained that the understanding of NASH and how best to treat has changed dramatically in the two-and-a-half years since the CENTAUR protocol was finalized in early 2014. At the time, there was no formal regulatory guidance for drug development in NASH, he noted.

"Given that, we used improvement in the NAFLD activity score of at least two points as our primary endpoint," Lefebvre said. "Also, based on guidance from experts, we included resolution of steatohepatitis or NASH without worsening of fibrosis and improvement of fibrosis by at least one stage with no worsening of NASH as key secondary endpoints."

"Since then, we've learned quite a bit about this rapidly evolving clinical research and development landscape," he continued. "In fact, as recently as earlier this year, in our communications with regulators, they have indicated that either of these surrogate endpoints could be used to support a marketing application, [as well as] clarifying that the reduction in the NAFLD activity score [NAS], our primary endpoint, was not acceptable as a registrational endpoint."

Limited Value Of NAS Endpoint

In his note, Wainwright analyst Arce asserted that NAFLD score offers "limited predictive value" and should be a secondary endpoint. "The current view on a decrease in NAS is its value is limited by a lack of data linking changes in NAS and its individual component scores (steatosis, lobular inflammation, hepatocyte ballooning), to either progression to advanced fibrosis or clinical outcomes," he wrote. Arce also predicted that NASH, as a multi-factorial disease, is likely to be treated ultimately via combination regimens, with other treatments serving to address different manifestations of metabolic syndrome in the liver.

Lefebvre went as far as to predict that CVC might be able to earn a claim as a disease-modifying drug if its improvement in fibrosis is sustained. "We learned from our data that [CVC's] mechanism is most impactful on the fibrosis endpoint, which will be the focus of our future studies," he said. "We believe that CVC has the potential to play a differentiated role in the management of NASH and liver fibrosis, giving it the potential to have a disease-modifying impact."

At the time Intercept and Genfit were moving their NASH candidates into Phase III, Tobira's Fischer remarked that it was good news for his company and others trailing the top two in the NASH race that FDA had shown a willingness to consider surrogate endpoints for registrational trials in this indication (Also see "Intercept’s Phase III Endpoints May Not Apply To Other Firms’ NASH Programs" - Pink Sheet, 25 May, 2015.).

In May 2015, the exec noted the similarity between the CENTAUR endpoints and those being used by Intercept in its planned Phase III study for obeticholic acid (OCA) in NASH, and commented that FDA's willingness to consider NASH resolution without worsening of fibrosis was helpful because it likely would take longer to demonstrate improvement in fibrosis. The exact opposite has proven true now for Tobira's CVC.