-- Statistically significantly more NASH resolution
in MGL-3196 as compared with placebo in a Phase 2 clinical trial
support MGL-3196 as a first- and potentially best-in class thyroid
hormone receptor (THR) β-selective agonist for treating patients
with NASH
Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL) today announced the
oral presentation of statistically significant results from a
double-blind, placebo-controlled 36-week Phase 2 clinical trial in
patients with biopsy-proven non-alcoholic steatohepatitis (NASH).
These results were presented during a Presidential Plenary Session
at The Liver Meeting® 2018 during the American Association for the
Study of Liver Diseases 2018 Annual Meeting being held in San
Francisco.
“Statistically significantly greater resolution of
NASH in MGL-3196 treated compared with placebo patients provides
evidence for efficacy in an accepted registrational endpoint for
Phase 3 development in NASH,” stated Dr. Stephen Harrison, M.D.,
Principal Investigator of the study, as well as Medical Director
for Pinnacle Clinical Research, San Antonio, Texas, and Visiting
Professor of Hepatology, Oxford University.
Dr. Harrison, who presented the results, added,
“The correlation of NASH resolution with reduction in liver fat on
MRI-PDFF adds to the growing database indicating the importance of
hepatic fat reduction in the effective treatment of NASH.”
In this 36-week serial liver biopsy Phase 2 study in patients
with NASH, fibrosis stage 1-3, there was:
- sustained highly statistically significant reduction in liver
fat based on MRI-PDFF in MGL-3196 treated as compared with placebo
patients;
- sustained statistically significant lowering of multiple
atherogenic lipids including LDL-C, ApoB, triglycerides, ApoCIII
and lipoprotein(a);
- lowering and normalization of liver enzymes;
- statistically significant resolution of NASH that is correlated
with reduction in liver fat on MRI-PDFF and provides evidence for
efficacy at an approvable endpoint for Phase 3 development in
NASH.
To view the MGL-3196 AASLD Plenary Presentation by Dr. Harrison
go to:
https://www.madrigalpharma.com/wp-content/uploads/2018/11/MGL-3196-Plenary-presentation-Nov-10-NASDAQ.pdf“These
highly significant and sustained potential benefits demonstrated in
our Phase 2 clinical trial in patients with NASH, combined with the
significant results MGL-3196 achieved in our Phase 2 clinical trial
in patients with heterozygous familial hypercholesterolemia,
further support our confidence in the broad therapeutic benefits of
MGL-3196,” stated Paul Friedman, M.D., Chief Executive Officer of
Madrigal.
“The key findings in this Phase 2 clinical trial are that once
daily oral doses of MGL-3196 were effective in reducing and
resolving NASH, and were well tolerated, which gives us confidence
that these results will be confirmed in our planned registration
study.” Becky Taub, M.D., CMO and Executive VP, Research
& Development of Madrigal stated, “Additionally, we are
encouraged by the lipid lowering results in NASH patients and
believe that MGL-3196 could provide a safe additional
LDL-cholesterol and atherogenic lipid lowering therapy for patients
at increased CV risk, particularly those with metabolic risk
factors, such as increased blood pressure, high blood sugar, excess
body fat and abnormal cholesterol and/or triglyceride levels who
require better lipid control. This patient group includes patients
with type 2 diabetes, nonalcoholic fatty liver disease and early
stages of NASH fibrosis.”
Live Webcast Information Madrigal will host an
investor meeting to discuss these Phase 2 results in
NASH, which will be webcast live today at 7:00 p.m. PT / 10:00
p.m. ET. To access the webcast please go to:
http://www.madrigalpharma.com/newsroom/presentations/ in the
“Events and Presentations” section of the Madrigal website.
Webcast
link: https://edge.media-server.com/m6/p/ugohg5f8
A dial-in number is also available should you be unable to
access the live webcast:Toll-free 833-660-2754Toll
409-350-3497Conference ID: 2277179
If you are unable to listen to the webcast live, a replay will
be available on the website under
http://www.madrigalpharma.com/newsroom/presentations/.
Clinical Program Summaries for MGL-3196
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.
In October 2016, the first patient was treated in the ongoing
Phase 2 trial of MGL-3196 for the treatment of NASH. The
randomized, double-blind, placebo-controlled, multi- center Phase 2
study enrolled 125 patients 18 years of age and older with liver
biopsy- confirmed NASH and included approximately 25 clinical sites
in the United States. Patients were randomized to receive either
MGL-3196 or placebo in a 2:1 ratio.
The primary endpoint of the study was the reduction of liver fat
at 12 weeks compared with baseline (relative change), assessed by
MRI-PDFF. Key secondary endpoints at 36 weeks included: reduction
in liver fat compared with baseline (relative change), also
assessed by MRI-PDFF; a two-point reduction in NAS (NALFD activity
score) on biopsy; resolution of NASH on biopsy; and, safety and
tolerability based on adverse events and changes in laboratory
values.
The primary endpoint of the study at 12 weeks was achieved.
Liver fat was reduced by 36.3% in all MGL-3196 treated patients and
42.0% in a pre-specified group of high exposure MGL-3196 treated
patients, as compared with 9.6% median reduction in liver fat in
placebo treated patients. These results were statistically
significant (p<0.0001) for both MGL-3196 treatment groups.
Further, 75% of the high-exposure MGL-3196 treated patients showed
liver fat reductions of ≥30%.
At 36 weeks, MGL-3196 achieved multiple key secondary endpoints
including a sustained highly significant (p<0.001) reduction in
liver fat compared to placebo as measured by MRI-PDFF; mean
relative fat reduction for MGL-3196 was 37% versus 8.9% for
placebo. MGL-3196 was associated with a greater percentage of
subjects with a 2-point improvement in NAS (56% vs 32% in MGL-3196
compared with placebo subjects, p=0.02). NASH resolution (NR) was
seen in 27% of MGL-3196 compared with 6% of placebo subjects,
p=0.02. MGL-3196 patients with ≥ 30% fat reduction on Week 12
MRI-PDFF demonstrated a higher percentage of 2-point improvement in
NAS (70%, p=0.001) and NR (39%, p=0.001) compared with placebo,
demonstrating a strong relationship between early reduction in
liver fat as demonstrated by week 12 MRI-PDFF and NASH improvement
on liver biopsy at Week 36.
At Week 36, MGL-3196 treated patients showed sustained reduction
of fibrosis biomarkers. In MGL-3196 patients with NASH resolution,
fibrosis also resolved in 50% of patients and was decreased
statistically significantly relative to all placebo patients. There
were statistically significant reductions in liver enzymes in
MGL-3196 treated patients compared to placebo treated patients;
reductions of greater magnitude were achieved with longer duration
of MGL-3196 treatment. Statistically significantly more MGL-3196
treated patients than placebo treated patients had normalization of
ALT (alanine transaminase).
Similar to week 12, at week 36 there were sustained,
statistically significant reductions in low-density lipoprotein
cholesterol (LDL-C), triglycerides, ApoB and lipoprotein(a).
MGL-3196 was well tolerated in this trial with mostly mild and a
few moderate AEs which were balanced between drug treated and
placebo patients. There was an increase in incidence of mild loose
stools in MGL-3196-treated, often a single episode, at the start of
treatment and incidence of loose stools was not increased later in
the study.
Based on liver enzyme inclusion criteria, some patients are
receiving extended treatment beyond 36 weeks for up to 36
additional weeks. All patients in this extension study have
received MGL-3196 and only non-invasive assessments are made,
including serial MRI-PDFF, safety labs, and circulating biomarkers.
Additional information about the study [NCT02912260] can be
obtained at www.ClinicalTrials.gov.
HeFH Heterozygous familial hypercholesterolemia
(HeFH), and a much rarer form called homozygous familial
hypercholesterolemia (HoFH), are severe genetic dyslipidemias
typically caused by inactivating mutations in the LDL receptor.
Both forms of FH lead to early onset cardiovascular disease. HeFH,
the most common dominantly inherited disease, is present in up to 1
in 200 people; the disease is found in higher frequencies in
certain more genetically homogenous populations. Treatments exist
for both HeFH and HoFH but many patients (as many as 40 percent of
HeFH patients) are not able to reach their cholesterol (LDL-C)
reduction goals on these therapies, reflecting the lifetime burden
of cholesterol buildup in their bodies. Based on evidence of
impressive LDL cholesterol lowering in Phase 1, and data suggesting
that MGL-3196 has a mechanism of action that is different from and
complementary to statins, Madrigal initiated a Phase 2
proof-of-concept trial in HeFH in February 2017 and enrolled 116
patients.
In this Phase 2 HeFH trial, patients who were not at their LDL-C
goal were randomized in a 2:1 ratio to receive either MGL-3196 or
placebo, in addition to their current cholesterol lowering regimen,
which included approximately 75% taking high intensity statins
(20/40 mg rosuvastatin or 80 mg atorvastatin), and about 2/3 of
patients also taking ezetimibe. MGL-3196 treated patients (placebo
corrected) achieved highly significant (p< 0.0001) LDL-C
lowering of 18.8%, and 21% LDL-C lowering in those on an optimal
dose of MGL-3196. LDL-C lowering was 28.5% in MGL-3196 treated
compared to placebo in a prespecified group of patients who did not
tolerate high intensity statin doses. Highly significant reductions
(p<0.0001) relative to placebo were also observed with ApoB,
triglycerides (TG) (25-31%), apolipoprotein CIII (Apo CIII) and
Lp(a) (25-40%) in all MGL-3196 treated patients and prespecified
subgroups, irrespective of statin treatment.
MGL-3196 was well-tolerated with primarily mild and some
moderate AEs, the numbers of which were balanced between placebo
and drug-treatment groups.
About MGL-3196 MGl-3196 is a first- and
potentially best-in class thyroid hormone receptor (THR)
β-selective agonist for treating patients with NASH and
dyslipimdemias.
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 MGL-3196 is the first orally
administered, small-molecule, liver- directed, truly β-selective
THR agonist.
The discovery of MGL-3196 utilized a novel in vitro functional
assay to demonstrate and confirm high β-selectivity (28 fold). In
contrast, other thyroid agonists were not β-selective in this assay
or in a relevant in vivo heart assay. Additional selectivity of
MGL-3196 was conferred by highly specific uptake into the liver and
the avoidance of any systemic thyroid receptor effects. Both
preclinical and clinical data have confirmed the high liver uptake
and safety of MGL-3196 and its ability to avoid activity
at the systemic THR-α receptor as well as no increased heart
rate and/or osteoporosis observed. Long-term animal studies
have been completed that support Phase 3 development.
MGL-3196 has been tested in over 160 subjects in Phase 1 studies
and 150 patients in Phase 2 studies with results suggesting that
MGL-3196 provides a broad array of therapeutically beneficial
effects including improving components of both metabolic syndrome,
such as insulin resistance and dyslipidemia, and fatty liver
disease including lipotoxicity and inflammation.
About Madrigal Madrigal Pharmaceuticals, Inc.
(Nasdaq: MDGL) is a clinical-stage biopharmaceutical company
pursuing novel therapeutics that target a specific thyroid hormone
receptor (THR) 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. The company’s lead product
candidate is MGL-3196, a first-in-class, orally administered,
small-molecule, liver-directed, THR β-selective agonist. Madrigal
has recently completed two successful Phase 2 clinical trials in
non-alcoholic steatohepatitis (NASH) and heterozygous familial
hypercholesterolemia (HeFH) that confirmed the potential of
MGL-3196 to reduce liver fat, lower multiple atherogenic lipids and
resolve NASH. Based on this clinical evidence and a favorable
safety profile, Madrigal plans to initiate a Phase 3 clinical
program in NASH. 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,” “will,” “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. 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 MGL-3196, the timing and outcomes of clinical
studies of MGL-3196, 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.
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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