- Continued Directional Improvements in Key Measures of Liver Function after Six Months -
- First Drug to Demonstrate Liver Function Benefit in Patients with NASH Cirrhosis -
- Conference Call and Webcast Presentation at 8:00 a.m. ET on Thursday, May 5 -
SAN DIEGO, May 04, 2016 (GLOBE NEWSWIRE) -- Conatus Pharmaceuticals Inc. (NASDAQ:CNAT) today announced positive top-line results from the three-month, open-label second stage of the company’s multicenter Phase 2 clinical trial of emricasan, a first-in-class, orally active pan-caspase inhibitor, in patients with liver cirrhosis. Top-line results from the three-month placebo-controlled first stage of the trial were released in January. In the second stage, patients on emricasan in the first stage continued treatment for another three months, and patients on placebo in the first stage switched over to emricasan for three months.
- Key measures of liver function showed continued directional improvements after the second three months of treatment on emricasan in the overall patient population following previously reported favorable trends with emricasan vs. placebo after the first three months.
- Key measures of liver function showed continued directional improvements after the second three months of treatment on emricasan in a subgroup of patients with baseline Model for End-stage Liver Disease (MELD)1 scores ≥15, a prerequisite for a patient receiving a liver transplant, following previously reported statistically significant emricasan treatment effects vs. placebo after the first three months.
- Regardless of baseline MELD score, patients whose cirrhosis was caused by nonalcoholic steatohepatitis (NASH) achieved statistically significant treatment effects vs. placebo on key measures of liver function after the first three months – making emricasan the first drug to demonstrate liver function benefit in patients with NASH cirrhosis. Directional improvements continued after the second three months of treatment.
- A conference call and webcast are scheduled for 8:00 a.m. ET on Thursday, May 5, as detailed below, to discuss both the Liver Cirrhosis clinical trial results and first quarter 2016 financial results to be released before the call.
Continued Directional Improvements in Overall Patient Population
Two clinically relevant measures of liver function and prognosis, MELD score and Child-Pugh-Turcotte (Child-Pugh)2 score, along with other key liver function parameters which demonstrated favorable trends in emricasan treatment effects vs. placebo (improvement in the emricasan group vs. progression in the placebo group) in the overall patient population after three months of treatment showed continued directional improvement after six months of treatment.
| Overall Patient Population | Placebo (N=42) | Emricasan (N=44) | Month 3 p-value* | |||
| Baseline | Change at Month 3† | Baseline | Change at Month 3† | Change at Month 6† | ||
| MELD score | 12.9 | +0.1 | 12.8 | ‒0.1 | ‒0.3 | 0.466 |
| Child-Pugh score | 6.9 | +0.1 | 6.9 | ‒0.2 | ‒0.3 | 0.124 |
| Total bilirubin (mg/dL) | 2.59 | +0.07 | 2.25 | ‒0.05 | ‒0.05 | 0.209 |
| INR | 1.31 | +0.02 | 1.33 | ‒0.02 | ‒0.04 | 0.117 |
| Albumin (g/dL) | 3.48 | +0.06 | 3.46 | +0.02 | +0.06 | 0.440 |
| *p-values for treatment effect at Month 3, based on adjusted LSMeans from the primary ANCOVA model with baseline value and treatment group; not adjusted for multiple testing. †Based on last observation carried forward. | ||||||
Key Exploratory Subgroup Results
Statistically significant emricasan treatment effects vs. placebo (improvement in the emricasan group vs. progression in the placebo group) after the first three months in a subgroup of patients with baseline MELD scores ≥15 showed continued directional improvements after the second three months.
| Baseline MELD Score ≥15 Patient Population | Placebo (N=10) | Emricasan (N=9) | Month 3 p-value* | |||
| Baseline | Change at Month 3† | Baseline | Change at Month 3† | Change at Month 6† | ||
| MELD score | 16.3 | +0.6 | 16.0 | ‒1.6 | ‒2.8 | 0.003 |
| Child-Pugh score | 8.2 | +0.6 | 7.8 | ‒0.6 | ‒0.7 | 0.003 |
| Total bilirubin (mg/dL) | 4.30 | ‒0.06 | 3.17 | ‒0.55 | ‒0.65 | 0.029 |
| INR | 1.45 | +0.06 | 1.54 | ‒0.14 | ‒0.21 | <0.001 |
| Albumin (g/dL) | 3.19 | +0.05 | 3.41 | +0.07 | +0.10 | 0.779 |
| *p-values for treatment effect at Month 3, based on adjusted LSMeans from the secondary ANCOVA model with baseline value, treatment group, baseline MELD category, etiology, treatment and MELD category interaction, and treatment and etiology interaction; not adjusted for multiple testing. †Based on last observation carried forward. | ||||||
In patients whose liver cirrhosis was caused by NASH, statistically significant emricasan treatment effects vs. placebo (slower progression in the emricasan group than in the placebo group) on measures of liver function after the first three months showed continued directional improvement after the second three months.
| NASH Patient Population | Placebo (N=9) | Emricasan (N=11) | Month 3 p-value* | |||
| Baseline | Change at Month 3† | Baseline | Change at Month 3† | Change at Month 6† | ||
| MELD score | 12.8 | +1.0 | 13.0 | +0.3 | +0.1 | 0.029 |
| Child-Pugh score | 6.9 | +0.4 | 7.3 | ‒0.3 | ‒0.1 | 0.030 |
| Total bilirubin (mg/dL) | 2.26 | +0.39 | 2.68 | +0.09 | ‒0.03 | 0.265 |
| INR | 1.27 | +0.07 | 1.25 | +0.01 | 0.00 | 0.017 |
| Albumin (g/dL) | 3.60 | +0.11 | 3.39 | +0.05 | +0.03 | 0.645 |
| *p-values for treatment effect at Month 3, based on adjusted LSMeans from the secondary ANCOVA model with baseline value, treatment group, baseline MELD category, etiology, treatment and MELD category interaction, and treatment and etiology interaction; not adjusted for multiple testing. †Based on last observation carried forward. | ||||||
Consistent with the company’s previous 15 clinical trials, emricasan was generally well-tolerated in 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.
“We were highly encouraged after the first three months of treatment, in patients with cirrhosis and impaired hepatic function, by the favorable overall trends in two clinically relevant measures of liver function and prognosis – MELD and Child Pugh scores – which clearly were driven by statistically significant improvements in the high baseline MELD score subgroup,” said David T. Hagerty, M.D., Executive Vice President of Clinical Development at Conatus. “The continued directional improvements in these measures of liver function after six months of treatment confirm the sustained activity of emricasan and support continued development in patients with cirrhosis. The statistically significant treatment effects in the NASH patient subgroup, which applied regardless of baseline MELD scores, offer a greater range of options for future clinical trials in patients with NASH cirrhosis.”
“We are pleased to confirm and extend the positive results from our Phase 2 Liver Cirrhosis trial,” said Conatus co-founder, President and Chief Executive Officer Steven J. Mento, Ph.D., “with favorable trends in measures of liver function in the overall patient population and significant treatment effects in the high-MELD population after three months, both with continued directional improvements after six months and a reassuring safety and tolerability profile consistent with our prior experience. Our Portal Hypertension trial and Liver Cirrhosis trial have demonstrated emricasan’s rapid and meaningful activity against all three potentially acceptable validated surrogate endpoints identified by the FDA (U.S. Food and Drug Administration) for clinical trials in patients with liver cirrhosis. The subgroup analysis of NASH patients in the Liver Cirrhosis trial provided the first ever demonstration in NASH cirrhosis of liver function benefit in response to drug treatment. We believe this benefit, along with our Fast Track designation by the FDA in NASH cirrhosis, provides strong support to focus on an initial registration of emricasan in NASH cirrhosis. We intend to discuss these results and plans for the ENCORE-LF clinical trial in patients with NASH cirrhosis with regulatory authorities in the coming months as we advance toward trial initiation in early 2017.”
Liver Cirrhosis Trial
The double-blind, placebo-controlled Phase 2 Liver Cirrhosis clinical trial was conducted at 26 U.S. sites and enrolled 86 patients with liver cirrhosis due to different etiologies, mild to moderate liver impairment and baseline MELD scores of 11 to 18. In the double-blind and placebo-controlled stage, patients were randomized 1:1 to receive either 25 mg of emricasan or placebo orally twice daily for three months. The primary endpoint was change from baseline in cCK18 at three months. Secondary endpoints included changes from baseline in MELD and Child-Pugh scores, which include laboratory parameters associated with liver synthetic and excretory function, such as serum albumin levels, international normalized ratio (INR) and total bilirubin levels. In the open-label stage, all patients either on emricasan or placebo received emricasan for an additional three months.
Among the 86 subjects enrolled and dosed, liver cirrhosis etiologies included alcohol (38%), hepatitis C virus, or HCV (29%), NASH (23%), and other causes (9%). Baseline MELD scores were ≤14 in 78% of enrolled subjects and ≥15 in 22% of enrolled subjects. Baseline Child-Pugh status was A (Child-Pugh score of 5-6) in 43% of subjects and B (Child-Pugh score of 7-9) in 56% of subjects.
Conference Call/Webcast/Presentation
Conatus will host a conference call and webcast at 8:00 a.m. Eastern Time on Thursday, May 5, to discuss results from the Liver Cirrhosis trial and first quarter 2016 financial results scheduled to be announced before the call. To access the conference call, please dial 877-312-5857 (domestic) or 970-315-0455 (international) at least five minutes prior to the start time and refer to conference ID 1360910. An associated presentation and live and archived webcast of the call will be available in the Investors section of the company’s website at http://ir.conatuspharma.com/events.cfm.
About Emricasan Clinical Development
To date, emricasan has been studied in over 650 subjects in sixteen clinical trials across a broad range of liver disease etiologies and stages of progression. In multiple clinical trials, emricasan has demonstrated statistically significant, rapid and sustained reductions in elevated levels of key biomarkers of inflammation and apoptosis that are implicated in the severity and progression of liver disease. Importantly, these key biomarkers are known to be elevated and to have prognostic value in multiple hepatic indications that Conatus is currently pursuing. The company also is evaluating emricasan’s potential longer-term effects on liver structure in its ongoing Phase 2b clinical trial in post-orthotopic liver transplant (POLT) recipients who have reestablished liver fibrosis or cirrhosis post-transplant as a result of recurrent HCV infection and have successfully achieved a sustained viral response following HCV antiviral therapy (POLT-HCV-SVR). In November 2015, the company announced plans to conduct multiple clinical trials covering various liver cirrhosis patient populations for different chronic dosing periods using different endpoints – the EmricasaN, a Caspase inhibitOR, for Evaluation, or ENCORE trials – as a strategy for initial registration of emricasan as a potential treatment for patients with liver cirrhosis. In January 2016, Conatus announced the initiation of ENCORE-NF, the first of the ENCORE trials, a randomized, double-blind, placebo-controlled, Phase 2b clinical trial in patients with biopsy-confirmed NASH and stage 1 to 3 fibrosis using the NASH Clinical Research Network (CRN) Histologic Scoring System.
About Conatus Pharmaceuticals
Conatus is a biotechnology company focused on the development and commercialization of novel medicines to treat liver disease. Conatus is developing its lead compound, emricasan, for the treatment of patients with chronic liver disease. Emricasan is a first-in-class, orally active pan-caspase inhibitor designed to reduce the activity of enzymes that mediate inflammation and apoptosis. Conatus believes that by reducing the activity of these enzymes, emricasan has the potential to interrupt the disease progression across the spectrum of liver disease. For additional information, please visit www.conatuspharma.com.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended. All statements other than statements of historical facts contained in this press release are forward looking statements, including statements regarding: emricasan as the first drug to demonstrate liver function benefit in patients with NASH cirrhosis; the Liver Cirrhosis trial results as support for continued development of emricasan in patients with liver cirrhosis; the ability of the Liver Cirrhosis trial results to offer a greater range of options for future clinical trials in patients with NASH cirrhosis; the support to focus on an initial registration of emricasan in NASH cirrhosis provided by the subgroup analysis of NASH patients in the Liver Cirrhosis trial; plans to discuss the Liver Cirrhosis trial results and plans for the ENCORE-LF clinical trial in patients with NASH cirrhosis with regulatory authorities and advance toward trial initiation in early 2017; plans to conduct multiple clinical trials covering various liver cirrhosis patient populations for different chronic dosing periods using different endpoints as a strategy for initial registration of emricasan as a potential treatment for patients with liver cirrhosis; and emricasan’s potential to interrupt the disease progression across the spectrum of liver disease. In some cases, you can identify forward-looking statements by terms such as “may,” “will,” “should,” “expect,” “plan,” “anticipate,” “could,” “intend,” “target,” “project,” “contemplates,” “believes,” “estimates,” “predicts,” “potential” or “continue” or the negative of these terms or other similar expressions. These forward-looking statements speak only as of the date of this press release and are subject to a number of risks, uncertainties and assumptions, including: Conatus’ ability to initiate and successfully complete current and future clinical trials; the potential that further analysis of the data described herein or additional data may yield different results; Conatus’ ability to develop and implement a registration strategy and pathway for emricasan; FDA’s and other regulatory agencies’ interactions and guidance relating to the development of emricasan; Conatus’ dependence on its ability to obtain regulatory approval for, and then successfully commercialize, emricasan, which is Conatus’ only drug candidate; Conatus’ reliance on third parties to conduct its clinical trials, enroll subjects, manufacture its preclinical and clinical drug supplies and manufacture commercial supplies of emricasan, if approved; the potential that earlier clinical trials may not be predictive of future results; potential adverse side effects or other safety risks associated with emricasan that could delay or preclude its approval; results of future clinical trials of emricasan; the potential for competing products to limit the clinical trial enrollment opportunities for emricasan in certain indications; the uncertainty of the FDA’s and other regulatory agencies’ approval processes and other regulatory requirements; Conatus’ ability to fully comply with numerous federal, state and local laws and regulatory requirements applicable to it; Conatus’ ability to obtain additional financing in order to complete the development and commercialization of emricasan; and those risks described in Conatus’ prior press releases and in the periodic reports it files with the Securities and Exchange Commission. The events and circumstances reflected in Conatus’ forward-looking statements may not be achieved or occur and actual results could differ materially from those projected in the forward-looking statements. Except as required by applicable law, Conatus does not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise.
1 MELD score is a numerical value ranging from 6 (less ill) to 40 (gravely ill) calculated by a formula using three routine serum biomarkers: total bilirubin, creatinine, and INR, and used to position patients on the liver transplant waiting list. Biomarker values below 1 are rounded to 1 to avoid negative values in the MELD formula. Scores of 15 or greater are required for listing eligibility.
2 Child-Pugh score is a numerical value ranging from 5 (least severe) to 15 (most severe) calculated by totaling the individual scores on a 1-3 scale for three routine serum biomarkers: bilirubin, INR, and albumin; and two clinical factors: encephalopathy and ascites. Scores of 5-6 are classified as Child-Pugh A (mild liver impairment); scores of 7-9 are classified as Child-Pugh B (moderate liver impairment); scores of 10-15 are classified as Child-Pugh C (severe liver impairment).