Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), announced today that,
based on data from studies with MGL-3196 (resmetirom), three
posters and an oral presentation of these data will be presented at
The Liver Meeting Digital Experience™, The American Association for
the Study of Liver Diseases Meeting in November 2020. Resmetirom is
the first orally administered, small-molecule, liver-directed,
truly β-selective thyroid hormone receptor (THR) agonist and is
currently in Phase 3 development for the treatment of NASH patients
both with biopsy-confirmed fibrosis stage 2-3 (ClinicalTrials.gov
NCT03900429) and in presumed NASH subjects diagnosed non-invasively
(ClinicalTrials.gov/NCT04197479).
Madrigal, a Silver Level Sponsor of The Liver Meeting Digital
Experience™, is looking forward to Dr. Stephen Harrison’s oral
presentation as well as three poster presentations to registered
attendees with access via The Liver Meeting Digital Experience™
website, beginning on Friday November 13, 2020, at 9:00AM ET:
- Friday, November 13, 2020, from 4:30-5:00 PM ET, Dr. Stephen
Harrison, M.D., Medical Director for Pinnacle Clinical Research,
San Antonio, Texas, and Visiting Professor of Hepatology, Oxford
University, and Principal Investigator of the MAESTRO studies, will
make a presentation in Madrigal’s product theater titled:
“Resmetirom for the Treatment of NASH: Early Data from the Phase 3
MAESTRO Clinical Trials.”
Dr. Harrison commented, “In the MAESTRO-NASH study, using a
series of readily available tests such as fibroscan, MRI-PDFF and
PRO-C3 in patients with metabolic risk factors (diabetes, obesity,
dyslipidemia and hypertension) we have demonstrated that, in
recruiting a clinical trial, NASH with advanced fibrosis (F2-F3)
may be confirmed on liver biopsy with an increasing level of
confidence. Interestingly, the PRO-C3 biomarker, a measure of
production of liver collagen that is correlated with liver fibrosis
on biopsy, is also statistically significantly correlated with the
level of inflammatory activity in the NASH liver.”
“We remain confident in achieving the primary and key secondary
endpoints in both of our studies. Open label MAESTRO-NAFLD-1 data,
using non-invasive measures, predict a favorable probability of
demonstrating primary and key secondary liver biopsy and lipid
endpoints in the ongoing MAESTRO-NASH serial liver biopsy
registration study,” stated Paul Friedman, M.D., Madrigal’s Chief
Executive Officer.
Becky Taub, M.D., Chief Medical Officer and President of
Research & Development of Madrigal, stated, “The data from the
ongoing open label arm of MAESTRO-NAFLD-1 confirm the robust
effects of a 100 mg dose of resmetirom with direct actions in the
liver at 16 weeks to statistically significantly reduce, compared
to baseline, both hepatic fat on serial MRI-PDFF as well as
meaningfully reduce a measure of liver fibrosis assessed by serial
MRE. MRI-PDFF reduction was 53% overall and up to 62% in key
subgroups. Marked lowering (p<0.0001) of multiple atherogenic
lipids and lipoproteins was also observed, including LDL-C and
apolipoprotein B >22%, triglycerides >25% and lipoprotein (a)
>30%. These data at a dose used in the ongoing serial liver
biopsy study, MAESTRO-NASH, predict that a high percentage of
MAESTRO-NASH patients will achieve a level of liver fat reduction
that has been shown, with this mechanism of action, to be
associated with improvement in NASH and liver fibrosis on liver
biopsy.”
POSTER PRESENTATIONS
- ALGORITHM FOR PREDICTING ADVANCED NASH FIBROSIS ON
SCREENING BIOPSY IN RESMETIROM PHASE 3 MAESTRO-NASH CLINICAL
TRIALDr. Stephen A Harrison1, Dr. Rebecca
A. Taub2, Prof. Morten Asser Karsdal3, John Franc2, Dr. Mustafa R
Bashir4, Mr. Jordan Mark Barbone2, Dr. Guy Neff5, Dr. Nadege T
Gunn1 and Dr. Sam Moussa6, (1) Pinnacle Clinical Research, (2)
Madrigal Pharmaceuticals, (3) Biomarkers & Research, Nordic
Bioscience, (4) Department of Radiology, Duke University Medical
Center, (5) Covenant Research, LLC, (6) Medical, Adobe
GastroenterologyMAESTRO-NASH is a Phase 3 double-blind
placebo-controlled serial liver biopsy study to evaluate resmetirom
for the treatment of NASH with F2 or F3 fibrosis and an exploratory
F1 arm. Data was assessed for the power of the screening paradigm
to predict eligible NASH with fibrosis on liver biopsy. These data
suggest that PRO-C3 is a marker not only of fibrosis stage in NASH
but also of the level of NASH activity (inflammation and
ballooning) in the NASH liver. In the absence of a liver biopsy,
elevated PRO-C3 in the setting of metabolic syndrome (or FIBC3
(PRO-C3 [age, BMI, platelets, T2D]), fibroscan and MRI-PDFF may
predict advanced NASH.
- TREATMENT WITH RESMETIROM IN PHASE 3 MAESTRO-NAFLD-1
NASH STUDY OPEN LABEL ARM: EFFECTS ON BIOMARKERS AND
IMAGINGDr. Stephen A Harrison, Pinnacle Clinical Research,
Dr. Naim Alkhouri, Arizona Liver Health, Dr. Rebecca A. Taub,
Madrigal Pharmaceuticals, Dr. Guy Neff, Covenant Research, LLC, Dr.
Seth J Baum, Excel Medical Clinical Trials and Dr. Mustafa R
Bashir, Department of Radiology, Duke University Medical CenterData
from the ongoing Open Label Arm of Madrigal’s MAESTRO-NAFLD-1 trial
will be presented. In this 52 week Phase 3 open label study, NASH
patients identified using non-invasive imaging and biomarkers were
treated with resmetirom 100 mg and demonstrated rapid reduction in
hepatic fat, biomarkers and atherogenic lipids after 12-16 weeks of
treatment, potentially supporting use of non-invasive tests to
monitor individual NASH patient response to resmetirom
treatment.
|
Baseline MRI-PDFF(%) |
Relative % change at Week 16 |
p- value |
MRE, Baseline (>2.9, F1-F3) (kpa) |
Change(absolute, kPa) |
p- value |
Open label cohort |
17.6 |
53% |
<0.0001 |
3.5 |
-0.34 |
0.003 |
- IMPROVEMENT OF HEALTH-RELATED QUALITY OF LIFE IS
ASSOCIATED WITH IMPROVEMENT OF FAT FRACTION BY
MRI-PDFF IN PATIENTS WITH NONALCOHOLIC
STEATOHEPATITIS TREATED WITH RESMETIROMDr. Zobair
M. Younossi, MD, MPH, FAASLD1, Maria Stepanova2, Dr. Rebecca A.
Taub3, Mr. Jordan Mark Barbone3, Dr. Sam Moussa4and Dr. Stephen A
Harrison5, (1) Center for Liver Disease, Department of Medicine,
Inova Health System, (2) Center for Outcomes Research in Liver
Diseases, Washington, DC, United States, (3) Madrigal
Pharmaceuticals, (4) Medical, Adobe Gastroenterology, (5) Pinnacle
Clinical ResearchA review of patient reported outcome data from
resmetirom’s Phase 2 NASH study demonstrates that NASH patients
treated with resmetirom who had liver fat reduction also improved
some quality of life measures, particularly physical components
such as bodily pain. Ongoing Phase 3 studies will assess long-term
sustainability of quality of life improvements with resmetirom
treatment.
About Resmetirom (MGL-3196) Thyroid hormone,
through activation of its β-receptor in hepatocytes, plays a
central role in liver function impacting a range of health
parameters from levels of serum cholesterol and triglycerides to
the pathological buildup of fat in the liver. Thyroid hormone
receptor (THR)-β action in the liver is key to proper function of
the liver, including regulation of mitochondrial activity such as
breakdown of liver fat and control of the level of normal, healthy
mitochondria. Patients with NASH have reduced levels of thyroid
hormone activity in the liver with resultant impaired hepatic
function, in part due to the inflamed state of the liver that
causes degradation of thyroid hormone.
To exploit the thyroid hormone receptor (THR)-β pathway for
therapeutic purposes in cardio-metabolic and liver diseases, it is
important to avoid activity at the THR- receptor, the predominant
systemic receptor for thyroid hormone that is responsible for
activity outside the liver including in heart and bone. The lack of
selectivity of older thyromimetic compounds, chemically-related
toxicities and undesirable distribution in the body led to safety
concerns. Madrigal recognized that greater selectivity for thyroid
hormone receptor (THR)-β and liver targeting might overcome these
challenges and deliver the full therapeutic potential of THR-β
agonism. Resmetirom has been shown to be highly selective based on
1) THR- β receptor functional selectivity based on both in vitro
and in vivo assays 2) specific uptake into the liver, its site of
action, virtually avoiding any uptake into tissues outside the
liver. In short and long term human and animal studies, resmetirom
has been confirmed to be safe and devoid of activity at the THR-
receptor and without impact on bone or cardiac parameters.
Resmetirom does not impact the thyroid axis hormones, including the
central thyroid axis. Madrigal believes that resmetirom is the
first orally administered, small-molecule, liver-directed, truly
β-selective THR agonist.
About the Phase 3 Registration Program for the Treatment
of NASH (Non-alcoholic steatohepatitis)Analyses from the
resmetirom Phase 2 NASH study demonstrate that the magnitude of
liver fat reduction accurately predicts NASH resolution and liver
fibrosis reduction and, specifically, that the resmetirom doses
being used in Madrigal’s Phase 3 MAESTRO-NASH trial could achieve
the level of fat reduction predictive of NASH resolution and
fibrosis reduction [Madrigal COVID and ABSTRACT Press
Release_20200414].
Madrigal has also reported, including in presentations by NASH
experts at The Digital International Liver Congress™ 2020 (EASL),
secondary analyses of data from our Phase 2 NASH study which
demonstrate that liver fat reduction at three months after starting
treatment has clear predictive power for NASH resolution and
fibrosis reduction on subsequent liver biopsy. Data from these
analyses demonstrate that resmetirom robustly and statistically
significantly (p<0.001) reduces markers of net collagen
deposition in the liver, supporting the anti-fibrotic action of
resmetirom. The related presentations by NASH experts at EASL are
available here: EASL Presentations by NASH Experts August 2020.
The Phase 3 MAESTRO-NASH trial is expected to enroll 900
patients with biopsy-proven NASH (fibrosis stage 2 or 3),
randomized 1:1:1 to receive resmetirom 80 mg once a day, 100 mg
once a day, or placebo. After 52 weeks of treatment a second biopsy
is performed. The primary surrogate endpoint on biopsy will
be NASH resolution, with at least a 2-point reduction in
NAS (NASH Activity Score), and with no worsening of fibrosis. Two
key secondary endpoints are liver fibrosis improvement of at least
one stage, with no worsening of NASH, and lowering of
LDL-cholesterol [ClinicalTrials.gov/NCT03900429].
A second 52-week Phase 3 multi-center, double-blind, randomized,
placebo-controlled study of resmetirom, MAESTRO-NAFLD-1, was
initiated in December 2019 targeting 700 patients with
non-alcoholic fatty liver disease (NAFLD), presumed NASH,
randomized 1:1:1 to receive resmetirom 80 mg once a day, 100 mg
once a day, or placebo. MAESTRO-NAFLD-1 also includes a 100 mg
resmetirom open label arm in up to 100 patients. Unlike
MAESTRO-NASH, MAESTRO-NAFLD-1 is a non-biopsy study and represents
a “real-life” NASH study. NASH or presumed NASH is documented using
historical liver biopsy or non-invasive techniques including
fibroscan and MRI-PDFF. Using non-invasive measures,
MAESTRO-NAFLD-1 is designed to provide incremental safety
information to support the NASH indication as well as provide
additional data regarding clinically relevant key secondary
efficacy endpoints to better characterize the potential clinical
benefits of resmetirom on cardiovascular and liver related
endpoints. These key secondary endpoints include LDL-cholesterol,
apolipoprotein B and triglyceride (TG) lowering; reduction of liver
fat as determined by magnetic resonance imaging, proton density fat
fraction (MRI-PDFF); and reduction of PRO-C3, a NASH fibrosis
biomarker. [ClinicalTrials.gov/NCT04197479] Additional secondary
and exploratory endpoints will be assessed including reduction in
liver enzymes, fibroscan scores and other fibrosis and inflammatory
biomarkers.These and other data, including safety parameters, form
the basis for potential subpart H submission to FDA for
accelerated approval for the treatment of NASH. The original 900
patients in the MAESTRO-NASH study will continue on therapy after
the initial 52-week treatment period; up to another 1,100 patients
are to be added using the same randomization plan and the study is
expected to continue for up to 54 months to accrue and measure
clinical events, most relevantly progression to
cirrhosis.
About Resmetirom’s Potential to Confer Cardiovascular
Risk Reduction in NASH patientsAdditionally, resmetirom
lowers multiple atherogenic lipids, including LDL cholesterol,
apolipoprotein B, triglycerides, and lipoprotein (a), as
demonstrated in Phase 2, a key differentiating factor compared with
other NASH therapeutics. The magnitude of reduction of these lipids
support a potential indication for treatment of hyperlipidemia in
NASH patients and predicts a potential for benefit on
cardiovascular (CV) events in NASH patients who die most frequently
of CV, not liver disease.
Because of their diabetes, dyslipidemia, hypertension, obesity
in concert with an inflamed, fatty liver, NASH patients,
particularly those with advanced fibrosis, are at a substantially
increased CV risk compared to the general population. Resmetirom’s
ability to decrease liver fat, which is an independent risk factor
for CV events, and resmetirom’s effect to reduce atherogenic lipids
are being further evaluated in several key secondary endpoints in
both MAESTRO Phase 3 clinical studies.
About Madrigal Pharmaceuticals Madrigal
Pharmaceuticals, Inc. (Nasdaq Global Select: MDGL) is a
clinical-stage biopharmaceutical company pursuing novel
therapeutics that target a specific thyroid hormone receptor
pathway in the liver, which is a key regulatory mechanism common to
a spectrum of cardio-metabolic and fatty liver diseases with high
unmet medical need. Madrigal’s lead candidate, resmetirom, is a
first-in- class, orally administered, small-molecule,
liver-directed, thyroid hormone receptor (THR)-β selective agonist
that is in currently in two Phase 3 clinical studies, MAESTRO-NASH
and MAESTRO-NAFLD-1, designed to demonstrate multiple benefits
across a broad spectrum of NASH (non-alcoholic steatohepatitis) and
NAFLD (non-alcoholic fatty liver disease) patients. For more
information, visit www.madrigalpharma.com.
Forward-Looking Statements This communication
contains “forward-looking statements” made pursuant to the safe
harbor provisions of the Private Securities Litigation Reform Act
of 1995, that are based on our beliefs and assumptions and on
information currently available to us, but are subject to factors
beyond our control. Forward-looking statements include but are not
limited to statements or references concerning: our clinical
trials; research and development activities; the timing and results
associated with the future development of our lead product
candidate, MGL-3196 (resmetirom); our primary and secondary study
endpoints for resmetirom and the potential for achieving such
endpoints and projections; optimal dosing levels for resmetirom;
projections regarding potential future NASH resolution, safety,
fibrosis treatment, cardiovascular effects, lipid treatment or
biomarker effects with resmetirom; the predictive power of liver
fat reduction on NASH resolution with fibrosis reduction or
improvement; the predictive power of readily available non-invasive
imaging and biomarkers, such as fibroscan, MRI-PDFF and PRO-C3; the
achievement of enrollment objectives concerning patient number,
safety database and/or timing for our studies; potential NASH or
NAFLD patient risk profile benefits with resmetirom; and our
possible or assumed future results of operations and expenses,
business strategies and plans, capital needs and financing plans,
trends, market sizing, competitive position, industry environment
and potential growth opportunities, among other things.
Forward-looking statements: reflect management’s current knowledge,
assumptions, judgment and expectations regarding future performance
or events; include all statements that are not historical facts;
and can be identified by terms such as “anticipates,” “be,”
“believes,” “continue,” “could,” “demonstrates,” ”design,”
“estimates,” “expects,” “forecasts,” “future,” “goal,” “hopeful,”
“intends,” “may,” “might,” “plans,” “potential,” “predicts,”
”predictive,” “projects,” “seeks,” “should,” “will,””will achieve,”
“would” or similar expressions and the negatives of those terms.
Although management presently believes that the expectations
reflected in such forward-looking statements are reasonable, it can
give no assurance that such expectations will prove to be correct
and you should be aware that actual results could differ materially
from those contained in the forward-looking statements.
Forward-looking statements are subject to a number of risks and
uncertainties including, but not limited to: our clinical
development of resmetirom; enrollment uncertainties, generally and
in relation to COVID-19 shelter-in-place and social distancing
measures and individual precautionary measures that may be
implemented or continued for an uncertain period of time; outcomes
or trends from competitive studies; the risks of achieving
potential benefits in studies that includes substantially more
patients than our prior studies; the timing and outcomes of
clinical studies of resmetirom; and the uncertainties inherent in
clinical testing. Undue reliance should not be placed on forward-
looking statements, which speak only as of the date they are made.
Madrigal undertakes no obligation to update any forward-looking
statements to reflect new information, events or circumstances
after the date they are made, or to reflect the occurrence of
unanticipated events. Please refer to Madrigal's filings with the
U.S. Securities and Exchange Commission for more detailed
information regarding these risks and uncertainties and other
factors that may cause actual results to differ materially from
those expressed or implied. We specifically discuss these risks and
uncertainties in greater detail in the section entitled "Risk
Factors" in our Annual Report on Form 10-K for the year ended
December 31, 2019 and our Quarterly Report on Form 10-Q for the
period ended June 30, 2020, as well as in our other filings with
the SEC.
Investor Contact: Marc Schneebaum, Madrigal
Pharmaceuticals, Inc. IR@madrigalpharma.com
Media Contact: Mike Beyer, Sam Brown Inc.
mikebeyer@sambrown.com 312 961 2502
A photo accompanying this announcement is available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/ddef7e87-55ed-4683-9a20-04a4b83cd5ba
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