cCK18 is a mechanism-specific biomarker of caspase-driven cell death. Multiple additional liver disease biomarkers achieved statistically significant reductions vs. placebo in the overall patient population after three months of treatment, while others achieved positive trends.
The company believes that the consistent pattern of improvement across these biomarkers in the overall patient population provides strong evidence of a favorable treatment effect with emricasan, the company’s first-in-class, orally-active pan-caspase inhibitor.
Collectively, two key secondary endpoints and clinically relevant measures of liver function, MELD score and Child-Pugh-Turcotte (Child-Pugh)2 score, along with other key liver function parameters, demonstrated favorable trends vs. placebo in the overall patient population after three months of treatment.
Importantly, the trends in the overall patient population were driven by statistically significant improvements in a subgroup of patients with baseline MELD scores =15, the established prerequisite for listing a patient for liver transplant. This pattern of greatest responses in highest need patients is consistent with the results from the company’s Phase 2 Portal Hypertension clinical trial announced in the third quarter of 2015.
Additional analyses of the three-month data showed the following broadly evident treatment effects in this subgroup:
1.6 reduction in mean MELD score with emricasan vs. 0.6 increase with placebo (p=0.003)
Patients achieving at least 2-point reductions in MELD score
6 of 9 with emricasan vs. 2 of 10 with placebo
Patients achieving reductions in MELD score to =14
4 of 9 with emricasan vs. 1 of 10 with placebo
0.6 reduction in mean Child-Pugh score with emricasan vs. 0.6 increase with placebo (p=0.003)
Patients achieving at least 1-point changes in Child-Pugh score
4 of 9 had decreases with emricasan vs. 2 of 10 with placebo
0 of 9 had increases with emricasan vs. 4 of 10 with placebo
Consistent with the company’s previous 15 clinical trials, emricasan was generally well-tolerated in the placebo-controlled stage of the Liver Cirrhosis clinical trial, and the overall safety profile was similar in the emricasan and placebo groups with regard to both serious and other adverse events.
Conatus executive vice president of clinical development David Hagerty said: "The improvement after only three months of treatment in patients with cirrhosis and impaired hepatic function in nearly all of the mechanism-specific and mechanism-independent biomarkers, as well as favorable overall trends driven by statistically significant subgroup improvements in clinically relevant markers of liver function — MELD and Child Pugh scores — is highly encouraging.
"The magnitude of the treatment effect was much more meaningful in patients with high baseline MELD scores. We believe these results, if confirmed and sustained, will be very important clinically. We look forward to the availability of the six-month data from this clinical trial to understand whether longer dosing may also demonstrate a treatment effect as measured by MELD and Child-Pugh in patients with lower baseline MELD scores and the overall patient population."
Conatus co-founder, president and CEO Steven Mento said: "With these latest results, we have now demonstrated emricasan’s ability to cause meaningful improvements in targeted patient populations using all three measures identified by the FDA (U.S. Food and Drug Administration) as potentially acceptable surrogate endpoints for clinical trials in patients with liver cirrhosis.
"The evidence of emricasan’s clinical activity across the spectrum of liver disease continues to build. Over the past year, we have generated clinical data defining acceptable emricasan dosing in patients with all levels of liver function impairment, and confirming that emricasan is active across multiple etiologies of liver disease.
"The two latest clinical trials demonstrate emricasan’s ability to provide statistically significant improvements rapidly in clinically important validated surrogate endpoints of portal hypertension and liver function in the subgroups of patients with highest medical need. These results reinforce our commitment to the further development of emricasan with a focus on an initial registration in liver cirrhosis.
"We believe the planned ENCORE liver cirrhosis and nonalcoholic steatohepatitis (NASH) fibrosis clinical trials announced in November offer the optimal path forward toward that objective. We expect that the upcoming six-month Liver Cirrhosis clinical trial data will allow us to determine, with the continued engagement of the regulatory authorities, whether the ENCORE-LF clinical trial — originally planned as a Phase 2 clinical trial — may be redesigned to qualify as Phase 3. We are advancing well with our plans to initiate the ENCORE clinical trials on a staggered basis through early 2017."