On December 5, 2018, Conatus Pharmaceuticals Inc. (the “Company”)
announced top-line results from the Company’s Phase 2b ENCORE-PH clinical trial of emricasan, the Company’s first-in-class,
orally active pan-caspase inhibitor under development in compensated or early decompensated nonalcoholic steatohepatitis (“NASH”)
cirrhosis patients with severe portal hypertension. The trial’s primary endpoint was change in mean hepatic venous pressure
gradient (HVPG) from baseline to Week 24 in any of three emricasan dosing groups compared with placebo. The total patient population
was composed of two prespecified subgroups – patients with compensated NASH cirrhosis (201 of 263 patients, or 76%) and patients
with early decompensated NASH cirrhosis (62 of 263 patients, or 24%). The trial did not meet its primary endpoint in the overall
trial population but clinically meaningful treatment effects were observed in subsets of the compensated patient subgroup.
In patients with compensated NASH cirrhosis, post hoc analyses demonstrated
consistent improvements in mean HVPG at week 24 over baseline. The magnitude of the improvement in mean HVPG generally increased
as the baseline HVPG levels increased.
Mean HVPG Change from Baseline of Emricasan vs. Placebo*
Overall Compensated and Decompensated Patient Population
|
Mean Baseline HVPG
|
Emricasan 5 mg BID
|
Emricasan 25 mg BID
|
Emricasan 50 mg BID
|
≥12 mmHg
|
-0.3 (p=0.666)
|
-0.5 (p=0.416)
|
-0.6 (p=0.337)
|
Compensated Patient Subpopulation
|
≥12 mmHg
|
-1.0 (p=0.098)
|
-1.1 (p=0.087)
|
-0.7 (p=0.275)
|
≥13 mmHg
|
-1.4 (p=0.047)
|
-1.4 (p=0.040)
|
-1.5 (p=0.037)
|
≥14 mmHg
|
-1.5 (p=0.037)
|
-1.8 (p=0.015)
|
-1.6 (p=0.032)
|
≥15 mmHg
|
-1.4 (p=0.074)
|
-1.6 (p=0.035)
|
-2.0 (p=0.017)
|
≥16 mmHg
|
-2.2 (p=0.010)
|
-2.3 (p=0.006)
|
-2.0 (p=0.023)
|
≥17 mmHg
|
-2.6 (p=0.009)
|
-2.8 (p=0.005)
|
-2.5 (p=0.015)
|
*Post-hoc analyses based on ANOVA model adjusted for baseline
HVPG
Mean HVPG Change from Baseline of Emricasan and Placebo*
Overall Compensated and Decompensated Patient Population
|
|
Mean Baseline HVPG
|
Emricasan 5 mg BID
|
Emricasan 25 mg BID
|
Emricasan 50 mg BID
|
Placebo BID
|
≥12 mmHg
|
-0.5 (N=61)
|
-0.7 (N=62)
|
-0.8 (N=56)
|
-0.2 (N=64)
|
Compensated Patient Subpopulation
|
|
≥12 mmHg
|
-0.8 (n=46)
|
-0.8 (n=47)
|
-0.4 (n=42)
|
+0.2 (n=53)
|
≥13 mmHg
|
-0.9 (n=39)
|
-0.9 (n=46)
|
-1.0 (n=37)
|
+0.5 (n=44)
|
≥14 mmHg
|
-1.0 (n=35)
|
-1.3 (n=38)
|
-1.1 (n=31)
|
+0.5 (n=39)
|
≥15 mmHg
|
-1.2 (n=30)
|
-1.3 (n=35)
|
-1.7 (n=25)
|
+0.3 (n=35)
|
≥16 mmHg
|
-1.6 (n=26)
|
-1.7 (n=30)
|
-1.5 (n=21)
|
+0.5 (n=26)
|
≥17 mmHg
|
-1.7 (n=23)
|
-1.9 (n=25)
|
-1.6 (n=19)
|
+0.9 (n=20)
|
*Post-hoc analyses based on ANOVA model adjusted for baseline
HVPG
In a post hoc analysis, the high-risk subgroup of compensated patients
with HVPG ≥16 mmHg, which is the clinical cutoff to predict decompensation and higher risk of death, at baseline showed a clinically
meaningful ≥2-point improvement in mean HVPG compared with placebo in all three emricasan dosing groups. A trend in responses
predictive of clinical benefit (≥20% reduction in HVPG from baseline) was also observed in the total ≥12 mmHg compensated
patient population with the greatest responses observed in the ≥16 mmHg cohort in the 5 mg BID and 50 mg BID dose groups.
Post Hoc ≥20% Responders (from Baseline) in Compensated NASH
Cirrhosis Subgroup*
Baseline HVPG
|
Emricasan 5 mg BID
|
Emricasan 25 mg BID
|
Emricasan 50 mg BID
|
Placebo BID
|
≥16 mmHg
|
22% (p=0.023)
(7%, 39%)
(n=6/27)
|
13% (p=0.110)
(1%, 26%)
(n=4/30)
|
20% (p=0.013)
(6%, 42%)
(n=5/25)
|
0%
(n=0/26)
|
≥12 mmHg
|
15% (p=0.379) (-7%,19%)
(n=7/46)
|
19% (p=0.162)
(-4%, 23%)
(n=9/47)
|
19% (p=0.176)
(-4%, 24%)
(n=8/42)
|
9%
(n=5/53)
|
*Post-hoc chi-square test for assessing difference in response rates
(95% CI of risk difference)
Consistent with safety results from 17 previously completed clinical
trials, emricasan was generally well-tolerated in the ENCORE-PH clinical trial, and the overall safety profile was similar in the
emricasan and placebo groups. Patients enrolled in the ENCORE-PH clinical trial are continuing treatment or placebo in a six-month
extension period to evaluate longer term safety, liver function and clinical outcomes, and results from the extension are expected
in mid-2019.
* * *
This Current Report on Form 8-K 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 Current Report on Form 8-K are forward-looking statements, including statements regarding the timing of
expected results from the six-month extension of the ENCORE-PH clinical trial. 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 Current
Report on Form 8-K and are subject to a number of risks, uncertainties and assumptions, including: reported top-line results are
based on preliminary analysis of key data and as a result, such top-line results may change following a more comprehensive review
and may not accurately reflect the complete results of the clinical trial; the Company’s ability to successfully enroll patients
in and complete its ongoing clinical trials; Novartis continuing development and commercialization of emricasan; the Company’s
reliance on third parties to conduct its clinical trials, including the enrollment of patients, and manufacture its clinical drug
supplies of emricasan; 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; and those risks described in the Company’s periodic reports
it files with the Securities and Exchange Commission. The events and circumstances reflected in the Company’s 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, the Company 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.