Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL) announced today that
it has already exceeded the originally targeted enrollment of 700
patients in its MAESTRO NAFLD-1 clinical trial of resmetirom in
patients with NASH and fibrosis that is diagnosed using
non-invasive assessments. Resmetirom is the first orally
administered, small-molecule, liver-directed, truly β-selective
thyroid hormone receptor (THR) agonist currently in Phase 3
development for the treatment of NASH patients with fibrosis stage
2-3 (ClinicalTrials.gov NCT03900429 and
ClinicalTrials.gov/NCT04197479).
MAESTRO-NAFLD-1, was originally planned to enroll
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, and included an 100 mg
resmetirom open label arm in up to 100 patients.
MAESTRO-NAFLD-1 enrollment has already exceeded the enrollment
targets in the three double-blinded arms and in the open label arm.
Although new screening of patients for the double-blind arms has
ended, eligible patients who have already screened for the study
will continue to enroll over the next few weeks.
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 commented, “MAESTRO-NAFLD-1 has
exceeded expectations in terms of enrollment, even during the COVID
pandemic, that attests to the high prevalence of NASH and the
enthusiasm of patients and investigators to participate in a Phase
3 clinical trial in which the NASH diagnosis is made without a
liver biopsy. The ultimate goals of the biomarker tests and liver
imaging, which have expanded rapidly in the past few years, are to
diagnose NASH with fibrosis non-invasively in order to identify
patients with high risk fatty liver disease.”
“We are pleased to have achieved our target
enrollment in the MAESTRO-NAFLD-1 trial,” stated Paul Friedman,
M.D., Madrigal’s Chief Executive Officer. “We plan to
complete enrollment in the double-blind arms of this study near the
beginning of October to enable us to report topline 52-week data by
the end of next year as planned. We intend to present data from the
ongoing open label arm before the end of 2020.”
Becky Taub, M.D., Chief Medical Officer and
President of Research & Development of Madrigal, stated, “We
are encouraged by patient participation in our Phase 3 MAESTRO-NASH
and MAESTRO-NAFLD-1 studies of resmetirom, a once daily oral
medication. We recently began and will continue to enroll
patients with compensated NASH cirrhosis into the open label arm of
MAESTRO-NAFLD-1 to collect exploratory efficacy and safety data in
this important population. We believe the data from
additional enrolled NASH patients in the double-blind arms and
patients with NASH cirrhosis will reinforce the safety and efficacy
of resmetirom and provide an even more robust safety data base for
our Phase 3 NASH program.”
Dr. Taub continued, “As we have recently reported,
including in presentations by NASH experts over the past week at
the Digital International Liver Congress™ 2020 (EASL), secondary
analyses of data from our Phase 2 NASH study 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. Further, once daily oral 80 mg and
100 mg Phase 3 doses of resmetirom deliver at least 50% reduction
in liver fat, and, based on secondary analyses of Phase 2 data, are
associated with a statistically significant reduction in all
components of NASH, including 64% NASH resolution (p<0.0001), of
which >60% had fibrosis reduction. Finally, 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.”
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-α 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-α 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].
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 in 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: 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 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,” “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
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