Hepion Pharmaceuticals, Inc. (NASDAQ:HEPA), a clinical stage
biopharmaceutical company focused on Artificial Intelligence
(“AI”)-driven therapeutic drug development for the treatment of
non-alcoholic steatohepatitis (“NASH”) and liver disease, today
announced additional efficacy data from its Phase 2a AMBITION
clinical trial.
AMBITION, a multicenter, randomized, placebo
controlled, single-blind Phase 2a trial, enrolled 43 NASH patients.
The trial was designed to investigate once daily oral
administration of CRV431 at doses of 75 mg (n=12) and 225 mg (n=17)
administered as soft gelatin capsules to presumed F2 and F3 NASH
subjects for 28 days, followed by a 14-day observation period for
safety.
As previously reported, all primary endpoints of
the AMBITION NASH trial (safety, tolerability and pharmacokinetics)
were met.
Today, Hepion reports additional data on
biomarkers, alanine aminotransferase (“ALT”) and N-terminal type
III collagen pro-peptide (“Pro-C3”), as well as advanced
pharmacologic and bioinformatic analyses that indicate CRV431
efficacy in treating NASH patients.
Once-daily 225 mg dosing of CRV431 decreased
mean Pro-C3 levels by 7.9% (-2.1 ng/ml) and 22.4% (-11.6 ng/ml) at
days 28 and 42, respectively, in subjects stratified for baseline
Pro-C3 levels greater than 17.5 ng/mL (n=7). Pro-C3 levels greater
than 15-20 ng/ml are generally accepted to represent active NASH
disease activity and the primary patient population for treatment
by many NASH drug candidates. In contrast to the 225 mg CRV431
cohort, placebo treatment similarly stratified by baseline Pro-C3
greater than 17.5 ng/mL (n=9) resulted in a mean increase of 3.5%
(0.7 ng/ml) and a mean decrease of 4.7% (-1.6 ng/ml) at days 28 and
42, respectively. The same Pro-C3 baseline stratification for the
75 mg CRV431 dose (n=11) resulted in a mean decrease in Pro-C3 of
9.1% by Day 42, indicating a dose-dependent effect. When stratified
for baseline Pro-C3 levels greater than 15.0 ng/mL, 225 mg once
daily CRV431 (n=9) reduced mean levels by 4.1% and 14.3% at days 14
and 28 days, respectively, compared to a mean increase of 1.5% and
a decrease of 8.8% in the placebo group (n=9) at days 28 and 42,
respectively. The reductions in Pro-C3 produced by CRV431 treatment
mirror the previously reported dose-dependent declines in ALT.
Importantly, more detailed analyses of the
AMBITION trial data using Hepion’s proprietary AI-POWR™ platform
provided further evidence of CRV431 efficacy in the treatment of
NASH. First, pharmacokinetic-pharmacodynamic (“PK-PD”) analyses
were able to generate robust models that could predict whether
individual patients would show reductions in ALT and Pro-C3 based
on CRV431 exposure, baseline ALT, Pro-C3, and other demographic and
clinical measurements. Second, analysis of full-genome, ribonucleic
acid (RNA) sequencing data (“transcriptomics”) from the patients
revealed that CRV431 treatment produced changes in gene expression
that were consistent with anti-fibrotic effects. Labelled as a
collagen-related gene regulatory network, the CRV431-induced
changes in gene expression included six key collagen isoforms, and
many other structural and enzymatic constituents of the fibrotic
matrix. In similarity to the PK-PD models for ALT and Pro-C3,
supervised machine learning analyses were able to categorize
patients as responders or non-responders based on their
transcriptome responses to CRV431 treatment.
“The decline in Pro-C3 that was observed in the
AMBITION trial puts us well within the range of NASH data published
by other companies with later-stage NASH drug candidates,” said
Hepion’s Chief Medical Officer, Todd Hobbs MD. “But notably, these
declines in Pro-C3 with CRV431 occurred in only 4 weeks, compared
to declines with other agents, where the changes occurred over
several months.”
“These biomarker findings offer us two important
insights. First, CRV431 has sustained effects, as evidenced by the
Pro-C3 changes at day 42. The long terminal half-life of CRV431 can
explain these findings and, in fact, circulating blood
concentrations of CRV431 are present at day 42, even though drug
administration stopped on day 28,” said Hepion’s Senior VP,
Clinical Pharmacology & Analytics, Patrick Mayo, PhD.
“Second, the most recent data generated from our
AMBITION trial has allowed us to put our machine learning and
proprietary AI-POWR™ to work,” continued Dr. Mayo. “We have been
able to construct models that may predict a priori who will respond
to CRV431. In this context, we believe that we can predict how much
of a reduction in ALT and Pro-C3 may be expected in any given
subject, even as early as the first administered dose of CRV431.
Indeed, we demonstrated that this works very elegantly in
predicting ALT and Pro-C3 responses of subjects in the AMBITION
trial with a high degree of accuracy. The PK-PD modeling also
demonstrated great accuracy in predicting clinical response, as
indicated by modeling diagnostics including predicted versus
observed plots. Moreover, we have used our transcriptomics to
investigate and construct a network of genes that gave us a very
consistent picture of antifibrotic effects when CRV431 was tested
in the latest clinical program. Interestingly, we also looked at
these same genes in our preclinical animal models, our cellular
assays, and our studies of human liver slices, and we observed the
same findings with the collagen-related gene network.”
“These powerful tools allow us to investigate
CRV431 in silico which should allow us to simulate future trials
before conducting them in the clinic. The more data we feed into
our AI, the more the AI will learn. This, in turn, should enable us
to be very precise in this very heterogenous NASH disease. Our AI,
therefore, is a very powerful and important tool. The Phase 2a
study provided a treasure-trove of information that has allowed us
to fine-tune our AI and adjust the design of our planned Phase 2b
study,” concluded Dr. Mayo.
Robert Foster, PharmD, PhD, Hepion’s CEO,
commented, “Dr. Mayo and his team are conducting truly
ground-breaking work. Many of us at Hepion have been working on
cyclophilin inhibitor drug development for the better part of three
decades. But, any kind of drug development is inherently risky,
especially when relying solely on traditional tools. We believe we
may now be able to mitigate a great deal of development risk with
the AI and machine learning tools developed and utilized by our
clinical pharmacology group. The fact that our team has been able
to identify early changes in important biomarkers and in collagen
genes, while developing predictive responder analyses, should help
propel us in the NASH drug development space. Ultimately, our goal
is to employ our models to optimize trial design, efficiency, cost,
and outcomes, while mitigating development risk. In many ways, we
believe that what we are doing is unprecedented in NASH drug
development. We are confident that the AMBITION trial and our
detailed analyses set the stage for success in the upcoming and
larger Phase 2b program called, ASCEND-NASH.”
The full AMBITION analysis will be presented by
Stephen Harrison, MD, at the upcoming AASLD “The Liver Meeting,” in
early November 2021.
Conference Call & Webcast
Details
Hepion is pleased to invite all interested
parties to participate in a conference call today at 8:30 a.m. ET,
during which both the Phase 2a AMBITION trial data and the design
of the planned Phase 2b ASCEND-NASH trial will be discussed. To
participate telephonically, please dial (855) 493-3481 (U.S.) or
(929) 517-0949 (international), conference ID 3568976,
approximately 10 minutes prior to the start time. A live,
listen-only webcast of the conference call, which will include
accompanying slides, can be accessed by visiting the “Events” page
of the “Investors” section at www.hepionpharma.com. An archive of
the webcast will be available for approximately 90 days following
the conclusion of the conference call.
About Hepion Pharmaceuticals
The Company's lead drug candidate, CRV431, is a
potent inhibitor of cyclophilins, which are involved in many
disease processes. CRV431 is currently in clinical-phase
development for the treatment of NASH, with the potential to play
an important role in the overall treatment of liver disease - from
triggering events through to end-stage disease. CRV431 has been
shown to reduce liver fibrosis and hepatocellular carcinoma tumor
burden in experimental models of NASH; and has demonstrated
antiviral activities towards HBV, HCV, and HDV through several
mechanisms, in nonclinical studies.
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 CRV431, potentially shortening development timelines and
increasing the delta between placebo and treatment groups. In
addition to using AI-POWR™ to drive its ongoing NASH clinical
development program, Hepion will use the platform to identify
additional potential indications for CRV431 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, 2020 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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