Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL) today announced
that in response to guidance from regulatory agencies, measures for
COVID-19 at impacted sites have been put in place for its Phase 3
MAESTRO-NASH and MAESTRO-NAFLD-1 studies, allowing both studies to
continue without changes to the protocol. Both MAESTRO studies are
well-established and have been recruiting according to plan. At a
recently conducted Data Monitoring Committee (DMC) meeting it
was recommended that Phase 3 studies proceed without
modification.
“In response to direction from regulatory agencies, a guidance to
allow more flexible processes at sites impacted by COVID-19 was
rapidly put in place to allow patients to progress through the
screening process or continue their enrollment in the study,”
stated Paul Friedman, M.D., Madrigal’s Chief Executive Officer.
“Thus far, except for a slow down in new screening at
impacted sites, the effect has been minimal on patients already in
screening or enrolled in the
studies.”
Dr.
Friedman continued, “The recent DMC meeting gave the go ahead with
no recommended changes to the protocols. We have sufficient drug
supplies in hand to complete both studies without interruption and
sufficient cash available to complete both the non-invasive 52 week
MAESTRO-NAFLD-1 study and the 900 patient 52-week serial biopsy
MAESTRO-NASH study that support the planned subpart H submission to
FDA for accelerated approval.”
Becky Taub, M.D., Chief Medical Officer and President of
Research & Development of Madrigal, stated, “As shown in
our EASL abstract publication now rescheduled for oral presentation
at the end of August, fat reduction as measured by week 12 MRI-PDFF
predicts NASH resolution on biopsy at week 36. This finding,
incorporating data from both placebo and resmetirom treated
patients, was confirmed by two independent blinded central
pathology readers. Higher fat reduction ( >50%) was correlated
with a greater than 60% likelihood of NASH resolution with fibrosis
reduction. Liver fat reductions at 80 mg and 100 mg, the Phase 3
doses, are impressive with relative: absolute fat reductions of
50%: 9.7% and 64%: 15.7%, respectively, as demonstrated in Phase 2.
Available data, including our own, also indicate that liver fat
reduction and NASH resolution are directly associated to a
reduction in fibrosis.
Dr. Stephen Harrison, M.D., Principal Investigator of the
study, and Medical Director for Pinnacle Clinical
Research, San Antonio, Texas, and Visiting Professor of
Hepatology, Oxford University, and Principal Investigator of
the MAESTRO studies commented, “There is significant rationale for
NASH patients to continue in clinical trials during the COVID-19
pandemic. With their high prevalence of diabetes and metabolic
syndrome, NASH patients are at higher risk for developing
life-threatening complications from COVID-19 infection. Controlling
the liver disease and metabolic risk of such patients may help them
survive COVID-19. Moreover, NASH patients in clinical trials
can be well-managed for safety. Because resmetirom is in Phase 3,
supported by substantial safety data and has shown benefit in NASH
and parameters of metabolic syndrome, I believe MAESTRO trials are
well-positioned to maintain enrolled patients in the studies,
continue recruiting at unaffected sites and restart quickly at
affected sites once the pandemic conditions are alleviated.”
He added, “I am particularly excited about the high predictive
power of liver fat reduction on NASH resolution with fibrosis
reduction demonstrated in resmetirom’s Phase 2 study. Moreover,
PRO-C3 is a robust non-invasive biomarker demonstrated to be
strongly correlated with NASH fibrosis. New analyses show that
resmetirom statistically significantly reduces markers (PRO-C3/C3M)
of net collagen deposition in the liver further supporting the
potential anti-fibrotic action of resmetirom.”
EASL (European Association for the Study of the
Liver) Abstract Publication - Magnetic resonance
imaging-proton density fat fraction (MRI-PDFF) to predict treatment
response on NASH liver biopsy: a secondary analysis of the
resmetirom randomized placebo controlled Phase 2 clinical trial.
Loomba, R, Bedossa, P, Guy, C, Taub, R, Bashir, M, Harrison,
SA
Summary and findings:
Resmetirom treatment resulted in significant reduction in
hepatic fat as assessed by MRI-PDFF after 12 and 36 weeks that was
associated with higher rates of NASH resolution compared to placebo
on week 36 liver biopsy assessment. The aim of this secondary
analysis was to examine the potential of early reduction in
MRI-PDFF to predict histologic response in patients with NASH
including both placebo and resmetirom treated patients. The study
cohort was assessed for those who had a ≥ 30, ≥ 40 and ≥ 50 %
decline in MRI-PDFF between baseline and week 12 as predictors of
NASH resolution.
To determine the potential predictive power of liver fat
reduction on NASH resolution, data were analyzed from 107 NASH
patients (n=34 placebo, n=73 resmetirom) with paired baseline/week
36 liver biopsies (read by two blinded central pathologists) and
paired baseline/week 12 MRI-PDFFs. Including the MRI-PDFF/biopsy
data from both MRI-PDFF responders and non-responders (including
placebo patients) the relationship to a NASH resolution response
was assessed.
In patients with NASH resolution, the mean week 12 fat reduction
(MRI-PDFF) was 56%. The predictive accuracy was determined by
calculating the area under the receiver operating characteristic
curve (AUROC) and its 95% confidence intervals (CI)s. The AUROC was
0.89, the optimal MRI-PDFF reduction with best balance of true
positive and false negative rates was 41.5% (p<0.001) with a
sensitivity of 82% (95% confidence interval (CI) 61%, 93%) and
specificity of 83% (95%CI 0.74%, 90%) (Figure), and was similarly
observed by both central readers. Compared to MRI-PDFF
non-responders with <30% fat reduction (n=56), MRI-PDFF
responders (≥30% fat reduction) (n=51) had significantly higher
odds of NASH resolution (40% versus 3.7%) with odds ratio (OR) of
18.0, 95% CI (3.9-82.3), p <0.0001. Additionally, the
percentages with NASH resolution were higher with greater
reductions in liver fat content, ≥ 40% and ≥50% MRI-PDFF reduction
showing an OR of 16.5, and 25.3, respectively, compared to PDFF
non-responders, p<0.0001. In patients with ≥50% fat reduction at
week 12 (placebo=2; resmetirom= 22) 64% had NASH resolution with a
component response driven primarily by ballooning and inflammation
reduction. The positive predictive values of PDFF reduction for
NASH resolution at cutoffs of ≥30%, ≥40%, ≥50% were 40%, 50% and
67%, respectively, and the negative predictive values were >90%
for all three cutoffs. Importantly, the analysis also
confirmed the direct association of NASH resolution to fibrosis
reduction, with fibrosis reduction in 61% of resmetirom treated
patients with NASH resolution. Reductions in other biomarkers (e.g.
ALT) were not strongly associated with NASH resolution or fibrosis
reduction.
In conclusion, the early MRI-PDFF response in resmetirom and
placebo treated patients achieved good sensitivity and specificity
for the identification of patients with NASH resolution and
corresponding fibrosis reduction. Compared with the Phase 2 dose of
60 mg (39% PDFF reduction), the higher doses of resmetirom (80 mg
and 100 mg) being used in the ongoing Phase 3 MAESTRO-NASH
study demonstrated an average PDFF reduction of 50% and 64%,
respectively, that associate with high rates of NASH resolution and
liver fibrosis reduction.
A photo accompanying this announcement is available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/d2656c0a-e309-4d39-aa52-7fc3ff9c5e94
American Association for the Study of Liver Diseases
(AASLD) Emerging Topic Conference 2020---Nuclear Receptors in
Nonalcoholic Fatty Liver Diseases (conference
cancelled), Resmetirom, a beta selective thyroid hormone
receptor agonist, reduces net collagen III deposition in
nonalcoholic Steatohepatitis Harrison SA, Taub R, Barbone JM,
Franc, J, Karsdal, MA
Summary and findings:
Type III collagen is a key component of liver fibrosis in NASH
patients. N-terminal type III collagen pro-peptide (PRO-C3) are
serum markers reflecting formation of type III collagen (pathologic
collagen that is increased in the liver in advanced NASH fibrosis).
Matrix metalloproteinase-degraded collagen III (C3M) degrades
existing collagen III which is present in fibrotic livers. A
reduction in PRO-C3 and/or elevation in C3M levels reflected by the
PRO-C3/C3M ratio may be indicative of an overall decrease in liver
fibrosis. We evaluated the effect of resmetirom treatment on
PRO-C3, C3M and PRO-C3/C3M ratio in the Phase 2 study.
MGL-3196-05 (NCT02912260) was a 36-week multicenter, randomized,
double-blind, placebo-controlled serial MRI-PDFF, paired liver
biopsy Phase 2 study in adults with biopsy-confirmed NASH (NAS ≥4,
F1-F3) and hepatic fat fraction ≥10%, assessed by MRI- PDFF (main
study). Thirty-one patients (including 14 former placebo patients)
received open-label MGL-3196 in the 36-week extension study.
Baseline PRO-C3 and PRO-C3/C3M ratio levels were significantly
correlated with baseline fibrosis stage (Correlation coefficient
(cc)= 0.24, p = 0.001) and ballooning (cc=0.29, p=0.003). PRO-C3
levels declined in patients treated with resmetirom relative to
placebo (p < 0.0001) in the main study [Lancet 394, 2012-2024,
2019]. C3M levels increased slightly with resmetirom treatment,
with no change in placebo. The PRO-C3/C3M ratio declined in
resmetirom compared with placebo treatment in the main study
(resmetirom, -0.24; placebo, 0.42, p<0.001) and significantly
decreased in the extension study, in which all patients were
treated with resmetirom (-0.50, p < 0.0001) (figure).
In conclusion, PRO-C3 levels and PRO-C3/C3M ratios were
correlated to fibrosis stage and NAS components at baseline.
Treatment of NASH patients with resmetirom produced significant
reductions in PRO-C3 levels and PRO-C3/C3M ratio, which may reflect
a net reduction in collagen deposition and fibrosis.
A photo accompanying this announcement is available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/c7bce372-1dda-4e08-8414-a0b6001f1cae
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)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, 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-NAGLD-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, and 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; the
achievement of enrollment objectives concerning patient number,
safety database and/or timing for our studies; the risks attendant
with conducting trials that are substantially larger than our past
trials; potential NASH or NAFLD patient risk profile benefits with
resmetirom; 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,” “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 mandatory lock-down measures and individual
precautionary measures that may be implemented for an uncertain
period of time; 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, 2019, 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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