Hepion Pharmaceuticals, Inc. (NASDAQ:HEPA), a clinical stage
biopharmaceutical company focused on artificial Intelligence
(“AI”)-assisted therapeutic drug development for the treatment of
non-alcoholic steatohepatitis (“NASH”), fibrotic diseases,
hepatocellular carcinoma (“HCC”), and other chronic diseases, today
announced positive topline results from its recently completed
Phase 2 ALTITUDE-NASH clinical trial.
ALTITUDE-NASH met its primary endpoint by
demonstrating improved physiologic liver function and was well
tolerated after four months of treatment in subjects with stage 3
or greater fibrosis based on the AGILE 3+ criteria. All additional
secondary endpoints were also met, including reductions in the
liver injury biomarkers, alanine and aspartate transaminases (“ALT”
and “AST”); and multiple fibrosis-associated biomarkers, including
ProC3 (procollagen 3 C-terminal peptide), PIIINP (procollagen 3
N-terminal peptide), TIMP1 (tissue inhibitor of
metalloproteinase-1), hyaluronic acid, and enhanced liver fibrosis
(“ELF”) scores (composite of PIIINP, TIMP1, and hyaluronic acid).
These observations build on similar findings from a shorter Phase
2a trial and reinforce rencofilstat’s direct antifibrotic mode of
action and increase the confidence for reductions in fibrosis in
Hepion’s ongoing Phase 2b ASCEND-NASH paired biopsy trial.
“We are thrilled that the ALTITUDE-NASH trial
met both its primary efficacy and safety endpoints, in particular
with the 225 mg rencofilstat dose showing the greatest benefit to
liver function and multiple NASH-associated biomarkers,” said Todd
Hobbs, MD, Hepion’s Chief Medical Officer. “This trial was designed
to inform us on how well rencofilstat improves hepatic function in
those with significant impairment and risk for complications from
their advanced NASH. Further, it provided an opportunity to
evaluate data generated from different doses of rencofilstat. I am
very pleased with the research team and the ALTITUDE-NASH sites
that quickly recruited this study. Our improved understanding of
which subjects best respond to rencofilstat can be immediately
applied to increase the likelihood of success of our larger and
longer ASCEND-NASH paired biopsy trial.”
Primary Endpoint: Four Measures of Liver
Impairment Significantly Improved Compared to Baseline with Four
Months Rencofilstat 225 mg Treatment
The HepQuant SHUNT Test was used in this study
under an U.S. Food and Drug Administration (“FDA”)-issued
Investigational Device Exemption (IDE). The SHUNT Test is a
minimally invasive test that tracks changes in the degree of liver
function impairment and was used to determine four key measures:
HepQuant DSI™ (Disease Severity Index) score, which primarily
reflects hepatocyte function; SHUNT, which reflects the impact of
micro-architectural changes, such as fibrosis on blood flow through
the liver; HepQuant HR™ (Hepatic Reserve); and RISK ACE, which
reflects the annual risk of a patient developing an adverse
clinical outcome (Table 1). Rencofilstat met the primary endpoint
and lowered mean DSI score in all doses, with rencofilstat 225 mg
treatment over 4 months resulting in statistically significant
decreases in DSI (mean Δ = -1.62 units; p<0.05), SHUNT% (mean Δ
= -2.8%; p<0.05), HR% (mean Δ = 3.9%; p<0.01), and RISK ACE
(mean Δ = -1.2 events per 100 patient-years; p<0.001) compared
to baseline; and 61% of subjects in the 225 mg rencofilstat arm had
a DSI improvement of >2.0 points (p<0.05). In HepQuant’s
research, improvements from baseline, especially for high DSI
scores that decrease by 2.0 points or more, are associated with
clinically significant reductions in risk for liver related
complications, including esophageal varices and encephalopathy.
Table 1: HepQuant Test Results
in All Subjects with Paired Data (n=61)
|
All Doses |
75 mg |
150 mg |
225 mg |
|
|
|
|
|
|
% of Subjects with a 2-point or Greater Decrease in
DSI |
|
32.8 (20/61) |
26.1 (6/23) |
15.0 (3/20) |
61.1 (11/18)§ |
|
|
|
|
|
|
Mean Difference from Baseline to Day 120 |
BMI
(kg.m-2) |
-0.04 |
0.21 |
-0.09 |
-0.31 |
DSI (score) |
-0.55 |
-0.41 |
0.24 |
-1.62* |
SHUNT (%) |
-1.7* |
-2.1 |
-0.2 |
-2.8* |
HR (%) |
1.3 |
1.4 |
-1.1 |
3.9** |
RISK ACE (Events per 100 patient-years) |
-1.2*** |
-1.5 |
-0.8*** |
-1.2*** |
*p < 0.05; **p
< 0.01; ***p < 0.001; paired t-test, no correction for
multiple comparisons§Chi-Square p < 0.05
In subjects with the most advanced functional
impairment, four measures of liver impairment significantly
improved compared to baseline with rencofilstat treatment for 4
months, independent of dose.
To address the potential of rencofilstat for
patients with the most advanced functional impairment and greatest
risk of disease progression, an analysis was conducted on the 34
subjects with DSI>17 or SHUNT%>25 as research indicates these
subjects are at high risk for hepatic complications (Table 2). In
this subgroup, independent of rencofilstat dose, statistically
significant decreases at Day 120 compared to baseline were again
observed for DSI score (mean Δ = -1.30 units; p<0.05), SHUNT%
(mean Δ = -3.4%; p<0.01), HR% (mean Δ = 2.9%; p<0.05), and
RISK ACE (mean Δ = -1.6 events per 100 patient-years; p<0.01).
The large reduction in SHUNT% suggests alleviation of
micro-architectural defects as anticipated from an antifibrotic
agent and suggests that rencofilstat may be most effective in
patients with more severe liver impairment.
Table 2: HepQuant Test Results
in Functionally Impaired Subjects with Paired Data (n=34)
|
All Doses |
75 mg |
150 mg |
225 mg |
|
|
|
|
|
|
% of Subjects with a 2-point or Greater Decrease in
DSI |
|
41.2 (14/34) |
50.0 (6/12) |
16.7 (2/12) |
60.0 (6/10) |
|
|
|
|
|
|
Absolute Change from Baseline to Day 120 |
BMI (kg
m-2) |
0.17 |
0.16 |
0.35 |
0.00 |
DSI (score) |
-1.30* |
-2.05 |
-0.17 |
-1.76* |
SHUNT (%) |
-3.4** |
-5.8* |
-1.0 |
-3.4 |
HR (%) |
2.9* |
4.6 |
-0.4 |
5.0* |
RISK ACE& (Events per
100 patient-years) |
-1.6** |
-2.3 |
-1.0** |
-1.5*** |
*p < 0.05; **p
< 0.01; ***p < 0.001; paired t-test, no correction for
multiple comparisons
Secondary Endpoints: Fibrosis- and
Injury-Associated Biomarkers Improved with all Doses of
Rencofilstat, with the Greatest Reductions Observed with the 225 mg
Arm
Multiple biomarkers related to fibrosis were
improved following four months of treatment with rencofilstat:
ProC3, PIIINP, TIMP1, and hyaluronic acid. ELF scores were
similarly improved by rencofilstat. Robust reductions in ALT and
AST were also observed with all doses of rencofilstat, with the
greatest reductions seen in the 225 mg rencofilstat dosing arm.
Incremental dose-response patterns were observed for most of the
biomarkers, and in all cases the largest reductions from baseline
for each of the biomarkers occurred in the 225 mg rencofilstat
group (Table 3).
Table 3: Percent Change from
Baseline in Key NASH Biomarkers After Four Months Treatment with
Rencofilstat
All Subjects: Safety Population |
75
mgrencofilstatn=23 |
150
mgrencofilstatn=21 |
225
mgrencofilstatn=21 |
%Change |
%Change |
%Change |
ALT |
-3.37*,**** |
-13.01*,** |
-21.63*,** |
AST |
4.54*,** |
-8.64*,** |
4.68* |
ProC3 |
-6.47 |
-11.12* |
-9.58*,**** |
PIIINP |
2.75 |
-0.47* |
-5.6* |
TIMP1 |
3.76 |
30.5 |
-3.9 |
Hyaluronic acid |
11.67 |
-13.18* |
-10.67* |
ELF score |
1.03* |
3.85*,** |
-2.51*,** |
*Different from Baseline p < 0.001, Friedman
ANOVA, **Different from 75 mg Dose p< 0.01, ***Different from
150 mg Dose, ****All Doses p < 0.001.
Rencofilstat 225 mg in high-risk population led
to the greatest improvements in NASH biomarkers.
Additional analyses were performed on the
approximate one-third of subjects with elevated baseline ProC3,
which assesses the formation of type III collagen and indicates
both severity and activity of disease. Because Pro-C3 is a measure
of collagen cleavage during active fibrinogenesis, subjects with
high ProC3 levels represent a NASH population with more active
disease, therefore representing an important target population for
many NASH drug candidates. In ALTITUDE-NASH, the greatest magnitude
of effects was observed with 225 mg rencofilstat (Table 4), and
most frequent dose-dependencies were observed in subjects with
baseline ProC3>37.5 ng/ml (Roche, Elecsys). Rencofilstat 225 mg,
and often the 150 mg dose, led to greater improvements than with 75
mg rencofilstat for all the NASH biomarkers in this high-risk
population as well as in the entire study population.
Table 4: Percent Change From
Baseline in NASH Biomarkers in Subjects with ProC3 ≥ 37.5 ng/ml
|
75 mg
rencofilstatn=10 |
150 mg rencofilstatn=7 |
225 mg rencofilstatn=6 |
%Change |
%Change |
%Change |
ALT |
-13.24*,*** |
-32.24* |
-37.78*,** |
AST |
6.73*,**** |
-30.72**** |
-11.34*,** |
ProC3 |
-3.39**** |
-17.05**** |
-16.23*,**** |
PIIINP |
-1.22**** |
-7.36*,** |
-21.48*,** |
TIMP1 |
2.4 |
-6.69* |
-4.77* |
Hyaluronic acid |
-4.56*,**** |
6.99*,** |
-19.66*,** |
ELF score |
-0.95*,**** |
-1.64*,** |
-5.31*,** |
*Different from Baseline p < 0.001, Friedman
ANOVA, **Different from 75 mg Dose p< 0.01,***Different from 150
mg Dose, ****All Doses p < 0.001.
Primary Safety and Tolerability
Endpoints Met with No Serious Adverse Events Attributed to
Rencofilstat
Of the 70 subjects enrolled in the study, 67
completed all study procedures including 120 days oral dosing of
rencofilstat with a 14-day routine safety follow up period.
Rencofilstat was well tolerated, with no trends in adverse events
or safety signals identified. There were no deaths or hepatic
decompensation events recorded in the trial, and a total of five
serious adverse events (SAEs) occurred with four unrelated to study
drug (COVID-19, headache, fibula fracture, COPD) and a single SAE
(biliary acute pancreatitis) classified as possibly related to
study drug in a subject diagnosed with a pancreatic stone as the
likely source for the pancreatitis. Other safety labs, EKGs, and
physical exams did not reveal any safety signals or concerns over
the course of the study.
Study Design and Objectives
ALTITUDE-NASH was designed as a Phase 2,
multi-center, randomized, open label study. F3 NASH subjects were
identified by having a baseline AGILE 3+ screening score of ≥0.53
or historical biopsy obtained within the preceding 6 months. The
AGILE 3+ score is calculated using FibroScan fibrosis score,
laboratory values (AST, ALT, platelets), and clinical parameters
(age, sex, diabetes status). Subjects were randomized
to one of three rencofilstat treatment groups receiving either 75
mg, 150 mg, or 225 mg soft gelatin capsules once daily for a period
of 4 months. The HepQuant Shunt test was administered at baseline,
Day 60, and Day 120 of treatment in addition to serum analyses for
safety and efficacy markers at each study visit. End-of-study liver
biopsies or other measures of structural extracellular matrix
changes were not collected due to the relatively short duration of
treatment. The objectives were to: investigate liver function and
safety; confirm the positive results observed in the 28-day Phase
2a AMBITION clinical trial; and collect additional data to support
Hepion’s AI-based precision medicine program (AI-POWR™) which will
be used to optimize future studies and patient outcomes. This trial
also serves as a bridge to Hepion’s current 12-month Phase 2b
ASCEND-NASH liver biopsy-based trial.
The HepQuant SHUNT procedure was chosen as the
primary endpoint in ALTITUDE-NASH based on its ability to quantify
the severity of hepatic dysfunction and portal-systemic shunting.
Currently under review by FDA, the procedure measures clearance by
the liver of administered doses of an isotopically labeled bile
salt, cholate, which reflects an important physiologic function of
the liver. The test is minimally invasive and is able to
sensitively track changes in the degree of liver function
impairment. This contrasts with liver biopsy results, which are
obtained through a more invasive procedure and only documents liver
pathology, not liver function. Further, according to Gregory T.
Everson, MD, HepQuant’s Founder and Chief Executive Officer, “The
results from HepQuant’s testing platform provide compelling
evidence that those patients at the highest risk of complications
are the ones that responded most consistently and robustly to
treatment with rencofilstat.”
Stephen Harrison, MD, Chairman and Co-Founder of
Summit Clinical Research and Chair of Hepion’s Scientific Advisory
Board, commented, “Use of the AGILE 3+ in screening allowed us to
identify an advanced NASH population in ALTITUDE-NASH at a high
risk for complications associated with the
disease. Improvements in numerous NASH biomarkers in concert
across this population not only affirms the positive results in
this four-month study but also increases my confidence in positive
outcomes in the larger and longer Phase 2b ASCEND-NASH biopsy trial
which is currently recruiting well.”
Patrick Mayo, PhD, Hepion’s Senior Vice
President, Clinical Pharmacology & Analytics, added,
“ALTITUDE-NASH represents a veritable data bonanza, providing us
information on patient responsiveness to rencofilstat in a very
advanced NASH population that will further enhance our AI-POWR™
platform, which should allow us to predict rencofilstat-responders
a priori. This not only enhances and de-risks future studies,
including potential Phase 3 trials, but will ultimately allow
clinicians to provide rencofilstat to patients who they know will
respond. Determining which patient is best suited to receive
rencofilstat could ultimately provide guidance to our eventual
commercial strategy.”
Conference Call Details
Hepion is pleased to invite all interested
parties to participate in a conference call at 8:30 a.m. ET today,
during which the ALTITUDE-NASH topline results will be discussed.
To participate in this conference call, please dial (800) 715-9871
(U.S.) or (646) 307-1963 (international), conference ID 9439742,
approximately 10 minutes prior to the start time. The call will
also be broadcast live and archived on the Company's website at
www.hepionpharma.com under "Events" in the Investors section.
About Hepion
Pharmaceuticals
The Company's lead drug candidate, rencofilstat,
is a potent inhibitor of cyclophilins, which are involved in many
disease processes. Rencofilstat has been shown to reduce liver
fibrosis and hepatocellular carcinoma tumor burden in experimental
disease models and is currently in Phase 2 clinical development for
the treatment of NASH. In November 2021, the FDA granted Fast Track
designation for rencofilstat for the treatment of NASH. That was
followed in June 2022 by the FDA’s granting of Orphan Drug
designation to rencofilstat for the treatment of HCC.
Hepion has created a proprietary AI platform,
called AI-POWR™, which stands for Artificial
Intelligence - Precision
Medicine; Omics (including genomics, proteomics,
metabolomics, transcriptomics, and lipidomics);
World database access; and
Response and clinical outcomes. Hepion intends to
use AI-POWR™ to help identify which NASH patients will best respond
to rencofilstat, potentially shortening development timelines and
increasing the observable differences between placebo and treatment
groups. In addition to using AI-POWR™ to drive its ongoing NASH
clinical development program, Hepion intends to use the platform to
identify additional potential indications for rencofilstat to
expand the company's footprint in the cyclophilin inhibition
therapeutic space.
Forward-Looking Statements
Certain statements in this press release are
forward-looking within the meaning of the Private Securities
Litigation Reform Act of 1995. These statements may be identified
by the use of forward-looking words such as “anticipate,”
“believe,” “forecast,” “estimated,” and “intend,” among others.
These forward-looking statements are based on Hepion
Pharmaceuticals’ current expectations and actual results could
differ materially. There are a number of factors that could cause
actual events to differ materially from those indicated by such
forward-looking statements. These factors include, but are not
limited to, substantial competition; our ability to continue as a
going concern; our need for additional financing; uncertainties of
patent protection and litigation; risks associated with delays,
increased costs and funding shortages caused by the COVID-19
pandemic; uncertainties with respect to lengthy and expensive
clinical trials, that results of earlier studies and trials may not
be predictive of future trial results; uncertainties of government
or third party payer reimbursement; limited sales and marketing
efforts and dependence upon third parties; and risks related to
failure to obtain FDA clearances or approvals and noncompliance
with FDA regulations. As with any drug candidates under
development, there are significant risks in the development,
regulatory approval, and commercialization of new products. There
are no guarantees that future clinical trials discussed in this
press release will be completed or successful, or that any product
will receive regulatory approval for any indication or prove to be
commercially successful. Hepion Pharmaceuticals does not undertake
an obligation to update or revise any forward-looking statement.
Investors should read the risk factors set forth in Hepion
Pharmaceuticals’ Form 10-K for the year ended December 31, 2022,
and other periodic reports filed with the Securities and Exchange
Commission.
For further information, please contact:
Stephen KilmerHepion Pharmaceuticals Investor
RelationsDirect: (646)
274-3580skilmer@hepionpharma.com
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