Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL) announced today the
online publication in The Lancet of the resmetirom (MGL-3196) Phase
2 multi-center, randomized, double-blind, placebo-controlled
clinical trial in patients with non-alcoholic steatohepatitis
(NASH). See The Lancet publication - Madrigal Phase 2 NASH
Study
The 36-week Phase 2 NASH study in 125 patients, and a 36-week
extension study in 31 of those patients (described below), are
highly supportive of MAESTRO-NASH, an ongoing international Phase 3
registrational clinical trial of resmetirom in patients with NASH
and liver fibrosis, that is powered at >90% to achieve the
primary endpoint of NASH resolution and key secondary endpoints of
LDL cholesterol lowering and reduction in liver fibrosis.
Additional information about Madrigal’s Phase 3 study in patients
with NASH can be obtained at Madrigal Pharmaceuticals Initiates
Phase 3 MAESTRO-NASH Study and www.clinicaltrials.gov
[NCT03900429]
Stephen Harrison, M.D., Principal Investigator of the resmetirom
Phase 2 study, and Medical Director for Pinnacle Clinical Research,
San Antonio, Texas, and Visiting Professor of Hepatology, Oxford
University, and primary author of The Lancet paper
stated, “In this trial, resmetirom as compared with placebo
demonstrated statistically significant and meaningful reduction of
hepatic fat at 12 weeks, the primary endpoint of the study, and
this reduction was sustained over 36 weeks. Statistically
significant reduction and resolution of NASH on liver biopsy,
lowering and normalizing elevated liver enzymes, and reductions of
markers of fibrosis were also observed. A strong association was
observed between reduction in hepatic fat by resmetirom and
improvement in the inflammatory components of NASH, ballooning and
inflammation.”
“MRI-PDFF is a noninvasive imaging biomarker that provides an
accurate and reproducible assessment of hepatic fat content. It has
been shown to correlate with the liver biopsy steatosis score and
can be used to assess the change in hepatic fat content over time.
This study shows the potential value of MRI-PDFF for assessing
early treatment response in patients with NASH,” stated Mustafa R.
Bashir M.D., Associate Professor of Radiology and Associate
Professor in the Department of Medicine Duke University,
Gastroenterology, Director MRI, Director, Center for Advanced
Magnetic Resonance Imaging, Bashir Lab for Liver Imaging Research,
and a coauthor of The Lancet paper.
“Liver biopsy is an invasive technique with associated
morbidity. A goal of the NASH field is to find noninvasive tests
that predict outcome of NASH treatments to avoid use of serial
liver biopsies. In addition to improving the understanding of the
pharmacology and safety of resmetirom in patients with NASH, this
study provides results of serial non-invasive imaging of liver fat
content, serial biomarkers of liver injury and fibrosis, and serial
liver biopsies at baseline and after 36 weeks of treatment,
providing the potential to demonstrate associations between changes
in non-invasive measures and liver histology,” stated Rebecca Taub,
M.D., Chief Medical Officer and President of Research &
Development at Madrigal.
Based in part on the results of this study, a multi-center,
double-blind, randomized, placebo-controlled Phase 3 registration
study, MAESTRO-NASH, is currently enrolling 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.
Summary of key results featured in The Lancet and the
36-week extension study presented today by Dr. Stephen Harrison as
an oral presentation at AASLD The Phase 2 clinical trial
was designed to determine the effect of resmetirom compared to
placebo on hepatic fat at week 12 (the primary endpoint) and week
36 in patients with liver biopsy confirmed NASH and stage 1-3
fibrosis. Steatosis was assessed by MRI-PDFF, a sensitive measure
of hepatic fat. Secondary objectives were to assess safety and
tolerability and to assess the impact of resmetirom on liver
histology, serum lipids, liver enzymes and biomarkers of
fibrosis after 36 weeks of treatment. 348 patients were
screened and 84 were randomized to resmetirom and 41 to placebo at
18 sites in the US. Resmetirom-treated patients (n=78) demonstrated
a relative reduction (%) of hepatic fat compared with placebo
(n=38) at week 12 (–32.9% resmetirom vs –10.4% placebo; least
squares mean difference –22.5%, 95% CI –32.9 to –12.2; p<0·0001)
and week 36 (–37.3% resmetirom [n=74] vs –8.5 placebo [n=34];
–28.8%, –42.0 to –15.7; p<0·0001). NASH resolution without
worsening of fibrosis occurred in 24.7% of resmetirom treated as
compared with 6.5% of placebo treated patients (p=0.024) and in
resmetirom treated patients who had at least 30% reduction in liver
fat at week 12, NASH resolution at 36 weeks occurred in 37%
(p=0.0026).
A 36-week extension study was conducted in patients completing
the 36-week main Phase 2 study who had at least some remaining
elevation of liver enzymes. The treatment code was unknown at the
time of entry of 31 patients into the 36-week non-invasive
extension study in which all patients received active treatment
with 80 or 100 mg of resmetirom. Twenty-nine patients completed all
36 weeks. Endpoints of the extension study were non-invasive.
Statistically significant reductions were observed in hepatic fat
(64% at the 100 mg dose), atherogenic lipids, fibrosis markers,
serial fibroscan liver stiffness, and liver enzymes, suggesting
that non-invasive biomarkers and imaging indicative of improvement
in NASH with fibrosis could ultimately be used to monitor response
to treatment.
Safety in the Phase 2 NASH clinical trial and overall
resmetirom development programResmetirom was well
tolerated and appeared safe in more than 400 treated patients and
healthy volunteers. There was a low incidence of severe and serious
adverse events in the NASH Phase 2 clinical trial, none related to
resmetirom. There was no imbalance in severe or moderate AEs with
resmetirom treatment compared to placebo. There was an increase in
the incidence of mild transient gastrointestinal side effects
including loose stools and mild nausea, typically a single instance
at the initiation of dosing; these were not observed in the NASH
Phase 2 extension study. More than 50 healthy volunteers have
received 1-2 weeks of 100 mg doses of resmetirom without increase
in incidence of diarrhea or nausea (<2%).
Safety data in more than 150 patients treated at the top dose
being used in Phase 3, 100 mg, for up to 1.5 years demonstrate that
there is no effect of resmetirom on thyroid axis hormones, and no
symptoms, clinical signs or incidence of either hyperthyroidism or
hypothyroidism.
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 [Madrigal
Pharmaceuticals 36-week Phase 2 NASH Results], 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
www.clinicaltrials.gov [NCT03900429]]. Additionally, in
both 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. Madrigal
is planning a non-invasive Phase 3 study in biopsy proven NASH
patients and patients with presumed NASH to further assess safety
as well as effects on LDL-cholesterol, other atherogenic lipids,
MRI-PDFF, liver enzymes, biomarkers of fibrosis and fibroscans to
better characterize potential clinical benefits of resmetirom on
cardiovascular and liver related endpoints using these noninvasive
measures. 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, 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. These and other data, including safety
parameters, would form the basis of a subpart H submission to FDA
for accelerated approval. The original 900 patients continue on
therapy; up to another 1,100 patients are to be added using the
same randomization plan and the study is continued 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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