Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL) announced today
that it has dosed the first patient in its second Phase 3 clinical
trial, MAESTRO-NAFLD-1 with its first-in-class, once daily, oral
thyroid hormone receptor-beta selective agonist, resmetirom
(MGL-3196). Madrigal initiated its first Phase 3 clinical
program, MAESTRO-NASH, in NASH patients with advanced liver
fibrosis (stages F2 and F3) in March 2019. The primary endpoint for
that trial, after one year of treatment, is resolution of NASH; key
secondary endpoints include LDL-cholesterol lowering and reduction
in liver fibrosis. Additionally, clinical benefit in reducing
progression to more advanced liver disease, including cirrhosis, is
a long-term goal of MAESTRO-NASH. [clinicaltrials.gov/NCT03900429]
MAESTRO-NAFLD-1 is a 52-week Phase 3, double-blind,
placebo-controlled clinical study in 700 patients designed to
evaluate the safety and biomarkers in resmetirom as compared with
placebo treated patients in a broad segment of patients with NASH
and to support registration for the treatment of NASH. The primary
endpoint of the study is safety. MAESTRO-NAFLD-1 is also expected
to provide additional data regarding clinically relevant efficacy
endpoints including lowering of atherogenic lipids and
lipoproteins. 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. Reduction of liver enzymes, fibroscan scores, and other
NASH and lipid biomarkers will be assessed.
MAESTRO-NAFLD-1 is expected to enroll 700 patients with
biopsy-proven or presumed NASH, many of whom screened for
MAESTRO-NASH, all with documented metabolic risk factors and fatty
liver disease on MRI-PDFF and fibroscan, but who screen failed
MAESTRO-NASH because fibroscan or biopsy prerequisites were not
met. Unlike MAESTRO-NASH, only non-invasive serial evaluations are
included. Patients will be randomized 1:1:1 to receive a
single oral daily dose of placebo, resmetirom 80 mg or resmetirom
100 mg. Up to 100 patients will be randomized to an open
label arm and receive resmetirom 100 mg. Treatment duration
in MAESTRO-NAFLD-1 is 52 weeks.
[clinicaltrials.gov/NCT04197479]
“The initiation of this second Phase 3 NASH safety and biomarker
study is an important next step in establishing the broad
therapeutic benefits of resmetirom and its unique potential
among NASH drugs in development to decrease
cardiovascular risk through the reduction of hepatic fat and
multiple atherogenic lipids including LDL-cholesterol,” stated
Dr. Rebecca Taub, M.D., Chief Medical Officer and President of
R & D of Madrigal. “It is well-established that
NAFLD/NASH patients are at significantly increased risk of
cardiovascular morbidity and mortality. Based on treatment
effects on NASH and the cardiovascular risk reducing profile of
resmetirom to date, we believe results from our Phase 3 program
have the potential to support a highly favorable therapeutic
benefits for resmetirom in patients with biopsy confirmed
advanced NASH and, ultimately, in patients diagnosed with NASH
based on noninvasive tests.”
Dr. Stephen Harrison, M.D., Principal Investigator of the
study, Medical Director for Pinnacle Clinical
Research, San Antonio, Texas, and Visiting Professor of
Hepatology, Oxford University, commented, “The NASH community
is in great need of establishing clinically relevant, noninvasive
biomarkers capable of providing accurate and reproducible
assessments of hepatic fat content and the formation of fibrotic
tissue in the liver. I believe results from MAESTRO-NAFLD-1, along
with results from MAESTRO-NASH, have the potential to add important
insights about the predictive value of noninvasive tests.”
“Because the leading cause of death for patients with NASH and
NAFLD is cardiovascular disease (CVD), I believe our most effective
approach to the treatment of these patients is to aggressively
assess and manage their CVD risk factors. Resmetirom has the
potential to offer patients and the physicians who treat them a
potentially safe and effective way to reduce the broad array of
atherogenic lipids and lipoproteins in addition to reducing fatty
liver, a potentially independent cardiovascular risk factor,”
stated Seth Baum, MD, FACC, FAHA, FASPC, Immediate Past President,
American Society for Preventive Cardiology, Excel Medical Clinical
Trials, LLC Founder, FNLA (Fellow National Lipid Association),
Chief Medical Officer, Clinical Affiliate Professor of Biomedical
Science at Charles E. Schmidt College of Medicine. [see: Seth
Baum AASLD 2019 Presentation]
About NASH Non-alcoholic Steatohepatitis
(NASH) is a common liver disease in the United States and
worldwide, unrelated to alcohol use, that is characterized by a
build-up of fat in the liver, inflammation, damage (ballooning) of
hepatocytes and increasing fibrosis. Although people
with NASH may feel well and often do not know they have
the disease, NASH can lead to permanent damage, including
cirrhosis and impaired liver function in a high percentage of
patients. Patients with NASH are at heightened
cardiovascular risk. Patients across the spectrum of non-alcoholic
fatty liver disease (NAFLD) die more frequently from cardiovascular
events than from their liver disease. Multiple factors may
contribute to this risk, including elevated levels of LDL-C and
excess liver fat. A significant segment of this large group of
patients may also suffer from diabetes and metabolic syndrome, and
have lipid levels that are above target despite treatment with
established therapies. These patients may benefit from therapy to
lower their lipid levels, including excess liver fat. About
Resmetirom (MGL-3196) Among its many functions in
the human body, thyroid hormone, through activation of its beta
receptor, plays a central role in controlling lipid metabolism,
impacting a range of health parameters from levels of serum
cholesterol and triglycerides to the pathological buildup of fat in
the liver. Attempts to exploit this pathway for therapeutic
purposes in cardio-metabolic and liver diseases have been hampered
by the lack of selectivity of older compounds for the thyroid
hormone receptor (THR)-β, chemically-related toxicities and
undesirable distribution in the body. 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. Madrigal believes that
resmetirom is the first orally administered, small-molecule,
liver-directed, truly β-selective THR agonist. Based in part on the
positive Phase 2 clinical study results in patients
with NASH [see: Madrigal Pharmaceuticals Announces Lancet
Publication of Positive Phase 2 Results for resmetirom], in March
2019, Madrigal initiated MAESTRO-NASH, a Phase 3 multinational,
double-blind, randomized, placebo-controlled study of resmetirom in
patients with non-alcoholic steatohepatitis (NASH) and fibrosis to
resolve NASH and reduce progression to cirrhosis and/or
hepatic decompensation [Madrigal Pharmaceuticals Initiates Phase 3
MAESTRO-NASH
Study and clinicaltrials.gov/NCT03900429].
About the Phase 3 Registration Program for
the Treatment of NASHThe 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 will be fibrosis improvement of at least
one stage, with no worsening of NASH, and lowering of
LDL-cholesterol. In the NASH Phase 2 study and a second positive
Phase 2 clinical study in patients with heterozygous familial
hypercholesterolemia [Madrigal Pharmaceuticals Phase 2 HeFH
Results], significant reductions in multiple atherogenic lipids
were observed.
A second 52-week Phase 3 multi-center,
double-blind, randomized, placebo-controlled study of resmetirom,
MAESTRO-NAFLD-1, 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 was
initiated in December 2019. 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. NASH or
presumed NASH is documented using non-invasive techniques or
historical liver biopsy. 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 using noninvasive measures. 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 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. 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. Such statements contain words such
as “expect,” “could,” “may,” “might,” “will,” “be, “predict,”
“project,” “intend,” “believe,” “estimate,” "continue," "future,”
or the negative thereof or comparable terminology and the use of
future dates. Forward-looking statements reflect management's
current knowledge, assumptions, judgment and expectations regarding
future performance or events. Such forward-looking statements
include but are not limited to statements or references concerning:
our primary and secondary study endpoints and their achievement
potential; optimal dosing levels for resmetirom; projections
regarding potential future NASH resolution, fibrosis
treatment, cardiovascular effects and lipid treatment; the
achievement of enrollment objectives concerning patient number
and/or timing; and potential NASH or NAFLD patient risk
profile benefits. Although management believes that the
expectations reflected in such statements are reasonable, they 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, the
company's clinical development of resmetirom, enrollment
uncertainties, outcomes or trends from competitive studies, the
risks of achieving potential benefits in a study that includes
substantially more patients than our prior study, 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 Part I, Item 1A of
our Annual Report on Form 10-K for the year ended December 31,
2018, 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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