Conatus Announces Initial Baseline Data From Phase 2b POLT-HCV-SVR Clinical Trial of Emricasan Confirming Activity of Relevant Mechanisms and Opportunity for Histological Improvement

Conatus Pharmaceuticals Inc.

today announced pre-treatment biomarker and histology data from the first 16 patients enrolled in the company's Phase 2b clinical trial of its lead drug candidate, emricasan, in post-orthotopic liver transplant (POLT) recipients. These patients have reestablished liver fibrosis or cirrhosis post-transplant as a result of recurrent hepatitis C virus (HCV) infection and have successfully achieved a sustained viral response (SVR) following HCV antiviral therapy (POLT-HCV-SVR). Among the first 16 patients enrolled, more than 85% achieved SVRs using recently approved oral HCV antiviral treatments. The excitement generated by these new treatments altered enrollment patterns during the early stage of the POLT-HCV-SVR trial, and their rapid market penetration is now expanding the trial-eligible population. The double-blind, placebo-controlled trial was initiated in May 2014 in patients with Ishak Fibrosis Scores of 2 to 4 (mid- to advanced-stage fibrosis). Consistent with the company's initial registration focus on the development of a treatment for cirrhosis, the trial was expanded in early 2015 to include patients with Ishak 5 (early-stage cirrhosis) and is currently expanding to Ishak 6 (advanced-stage cirrhosis). Patients are being randomized 2:1 to receive either 25 mg of emricasan or placebo orally twice daily for 24 months and will be followed for another month post-treatment. The primary endpoint in this exploratory proof-of-concept trial is the change in the Ishak Fibrosis Score compared with placebo. The trial will also evaluate histological markers of inflammation, key serum biomarkers, and the safety and tolerability of emricasan in the target patient population. Enrollment of approximately 60 total planned patients is on track for release of final top-line results in the first half of 2018. "Our POLT-HCV-SVR trial is enrolling a growing but largely unstudied patient population of liver transplant recipients whose underlying HCV infection has been successfully treated primarily with recently approved antiviral drugs," said Conatus co-founder, President and Chief Executive Officer, Steven J. Mento, Ph.D. "While fibrosis may slowly improve in some patients after sustained viral response is achieved, the consequences among those with advancing fibrosis and cirrhosis with accompanying portal hypertension remain relatively unaffected even up to five years after SVR. There is a significant unmet medical need particularly in patients with cirrhosis due to HCV who have achieved SVR, because these patients remain at high risk for decompensation, including variceal bleeding. We have followed the recommendation of our Data Monitoring Committee to keep results blinded to maintain the integrity of the final data analysis. The initial pre-treatment biomarker data confirm that the underlying mechanisms addressed by emricasan are active, and baseline biopsy data confirm that the target population may be suitable for demonstrating potential histology benefits of treatment with emricasan." The initial baseline data analysis included the first 16 patients (approximately 27% of the total planned enrollment) to meet all trial inclusion and exclusion requirements and enroll in the trial. Among those first 16 patients, 3 patients (19%) had baseline Ishak Fibrosis Scores of 2, 12 patients (75%) had baseline Ishak Fibrosis Scores of 3 or 4, and 1 patient (6%) had a baseline Ishak Fibrosis Score of 5 and none had an Ishak Fibrosis Score of 6. The proportion of cirrhosis patients enrolling in this trial is expected to increase during the remainder of the trial. Baseline serum levels of caspase-cleaved cytokeratin 18 (cCK18) and caspase 3/7 were elevated in these subjects. Both cCK18 and caspase 3/7 are biomarkers of apoptosis activity and mechanism-specific indicators for emricasan. The biomarker elevations also were generally consistent with histology, with the highest levels of both cCK18 and caspase 3/7 observed in patients with Ishak 4, intermediate levels observed in patients with Ishak 3, and the lowest levels observed in patients with Ishak 2. Patients with Ishak 5 or 6 were not included in this analysis due to their recent inclusion and resulting low number at the cutoff date. The company concluded from the pre-treatment analyses of biomarkers and histology that: 1) the underlying mechanisms of action relevant to emricasan were active and, 2) POLT subjects who have fibrosis or cirrhosis due to HCV and achieved SVR are an appropriate patient population in which to evaluate potential treatment effects of emricasan. The POLT-HCV-SVR trial may provide long-term safety data that could be supportive of the company's planned initial registration of emricasan for patients with cirrhosis. In addition, the U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to emricasan in late 2013 for the treatment of liver transplant recipients with reestablished fibrosis to delay the progression to cirrhosis and end-stage liver disease.