Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a clinical-stage
biopharmaceutical company pursuing novel therapeutics for
nonalcoholic steatohepatitis (NASH), today announced that the U.S.
Food and Drug Administration (FDA) has accepted for review its New
Drug Application (NDA) for resmetirom for the treatment of adult
patients with NASH with liver fibrosis. The FDA has granted
Priority Review and assigned a Prescription Drug User Fee Act date
for resmetirom of March 14, 2024, the target date by which the FDA
intends to complete its review and take action on the NDA. The
Agency noted that it is not currently planning to hold an advisory
committee meeting to discuss the application.
Resmetirom is a once daily, oral, thyroid hormone receptor
(THR)-β selective agonist designed to target key underlying causes
of NASH in the liver. The clinical development program for
resmetirom is comprised of 18 clinical studies supporting the NDA:
twelve Phase 1 studies, two Phase 2 studies, and four Phase 3
studies. Madrigal is seeking approval of resmetirom for the
treatment of patients with NASH and liver fibrosis under the FDA’s
accelerated approval pathway.
Bill Sibold, Chief Executive Officer of Madrigal, stated, “NASH
with liver fibrosis represents a significant unmet need in
healthcare today: the disease has a serious impact on patients and,
without treatment, it can lead to increased risk of cirrhosis,
liver failure, liver cancer, and premature mortality. Resmetirom is
a liver-directed therapy that has demonstrated the potential to
treat the liver fibrosis that is associated with these negative
outcomes, while resolving the underlying steatohepatitis that
drives the disease. The FDA’s acceptance of our NDA with priority
review is an important step forward as we pursue our goal of
delivering the first approved treatment to patients with NASH with
liver fibrosis.”
The FDA grants Priority Review to applications for medicines
that, if approved, would be significant improvements in the safety
or effectiveness of the treatment, diagnosis, or prevention of
serious conditions. A Priority Review designation means FDA’s goal
is to take action on an application within 6 months (compared to 10
months under standard review).
Becky Taub, M.D., Chief Medical Officer and President of
Research & Development of Madrigal, stated, “We believe that we
have delivered a compelling data package to support the FDA’s
benefit-risk evaluation of resmetirom for the treatment of NASH
with liver fibrosis. The NDA is supported by the positive efficacy
results observed in our pivotal Phase 3 trial, the large safety
database we have established through the MAESTRO program, and two
ongoing outcomes studies that are designed to verify clinical
benefit following a potential accelerated approval. We look forward
to beginning this critical next phase of the review process.”
About the Resmetirom Phase 3 Registration Program for
the Treatment of NASH
Resmetirom is a once daily, oral, thyroid hormone receptor
(THR)-β selective agonist designed to target key underlying causes
of NASH in the liver.
Madrigal is currently conducting four Phase 3 clinical trials to
demonstrate the safety and efficacy of resmetirom for the treatment
of NASH: MAESTRO-NASH, MAESTRO-NAFLD-1, MAESTRO-NAFLD-OLE, and
MAESTRO-NASH-OUTCOMES.
MAESTRO-NASH is a multicenter, randomized, double-blind,
placebo-controlled Phase 3 study of resmetirom in patients with
liver biopsy-confirmed NASH. The portion of the study designed to
support a subpart H approval enrolled more than 1,000 patients with
biopsy-proven NASH with fibrosis, randomized 1:1:1 to receive
once-daily resmetirom 80 mg, resmetirom 100 mg, or placebo. The
dual primary surrogate endpoints on biopsy were NASH resolution
with ≥2-point reduction in NAS (NAFLD Activity Score), and with no
worsening of fibrosis OR a 1-point decrease in fibrosis with no
worsening of NAS after 52 weeks of treatment. Achievement of either
primary endpoint was considered a successful trial outcome.
In December 2022, Madrigal announced that both daily oral doses
of resmetirom achieved both MAESTRO-NASH primary liver biopsy
endpoints. Multiple secondary endpoints were also achieved,
including statistically significant reductions by resmetirom as
compared with placebo in atherogenic lipids and lipoproteins, liver
enzymes, fibrosis biomarkers, and imaging tests.
Resmetirom was generally safe and well-tolerated at both the 80
mg and 100 mg doses. Consistent with previous Phase 2 and Phase 3
data, the most common adverse event reported with greater frequency
in the resmetirom groups versus placebo was an excess of generally
mild and transient diarrhea and nausea at the beginning of
therapy.
Patients enrolled in MAESTRO-NASH (approximately 1,750 total
enrollment) continue on therapy after the initial 52-week treatment
period for up to 54 months to accrue and measure hepatic clinical
outcome events including progression to cirrhosis on biopsy (52
weeks and 54 months) and hepatic decompensation events, as well as
all-cause mortality. This portion of the study is designed to
generate confirmatory data that, if positive, will help verify
resmetirom’s clinical benefit and support full approval.
MAESTRO-NAFLD-1 was a 52-week multicenter, randomized,
placebo-controlled, double-blind Phase 3 study of resmetirom in
~1,200 patients with NAFLD, presumed NASH. MAESTRO-NAFLD-1 might be
considered a “real-world” NASH study in that diagnosis was based on
noninvasive measures rather than liver biopsy. The primary endpoint
was to evaluate the safety and tolerability of resmetirom.
Patients in the MAESTRO-NAFLD-1 study were randomized 1:1:1:1 to
receive once-daily resmetirom 80 mg, resmetirom 100 mg, or placebo
in double-blind arms or resmetirom 100 mg in an open-label arm.
Using noninvasive measures, MAESTRO-NAFLD-1 was 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.
The primary safety endpoint of MAESTRO-NAFLD-1 and key secondary
endpoints were achieved: resmetirom was safe, well-tolerated and
provided statistically significant improvements in LDL-C,
apolipoprotein B, triglycerides, and liver fat as measured by
MRI-PDFF.
An additional open-label active treatment arm in 180 patients
with early (well-compensated) NASH cirrhosis was conducted.
Resmetirom was safe and well tolerated in the MAESTRO-NAFLD-1
open-label cohort of patients with well-compensated NASH cirrhosis.
As observed in patients with noncirrhotic NASH, mild GI adverse
events were seen at the beginning of therapy. Resmetirom reduced
LDL-C, other atherogenic lipids and lipoproteins, and MRI-PDFF in
patients with NASH cirrhosis and also reduced liver and spleen
volume.
A separate 52 week Phase 3 clinical trial, an open-label active
treatment extension study of MAESTRO-NAFLD-1 (MAESTRO-NAFLD-OLE),
in about 700 patients is ongoing.
Data from the 52-week first 1,000 patient portion of
MAESTRO-NASH, together with data from MAESTRO-NAFLD-1,
MAESTRO-NAFLD-OLE, Phase 2 and Phase 1 data, including safety
parameters, form the basis for Madrigal’s subpart H submission to
FDA for accelerated approval of resmetirom for treatment of NASH
with liver fibrosis.
In August 2022, Madrigal initiated MAESTRO-NASH-OUTCOMES, a
randomized double-blind placebo-controlled study in approximately
700 patients with early NASH cirrhosis to allow for noninvasive
monitoring of progression to liver decompensation events. A
positive outcome is expected to support the full approval of
resmetirom for noncirrhotic NASH, potentially accelerating the
timeline to full approval. In addition, this study has the
potential to support an additional indication for resmetirom in
patients with well-compensated NASH cirrhosis.
About NASH
Nonalcoholic steatohepatitis (NASH) is a more advanced form of
nonalcoholic fatty liver disease (NAFLD). NAFLD is estimated to
afflict more than 20% of adults globally, about 30% in the United
States. Of that population, 20% may have NASH.
NASH is a leading cause of liver related mortality and an
increasing burden on healthcare systems globally. Additionally,
patients with NASH, especially those with more advanced metabolic
risk factors (hypertension, concomitant type 2 diabetes), are at
increased risk for adverse cardiovascular events and increased
morbidity and mortality.
In NASH, thyroid hormone beta activity in the liver is impaired,
leading to a reduction in mitochondrial function and beta-oxidation
of fatty acids, which in turn drive inflammation and liver
fibrosis.
Once NASH progresses to significant liver fibrosis (stages F2
and F3) the risk of adverse liver outcomes increases dramatically.
NASH is rapidly becoming the leading cause of liver transplantation
in the U.S. There are currently no FDA-approved therapies available
for the treatment of NASH.
About Madrigal Pharmaceuticals
Madrigal Pharmaceuticals, Inc. (Nasdaq: MDGL) is a
clinical-stage biopharmaceutical company pursuing novel
therapeutics for nonalcoholic steatohepatitis (NASH), a liver
disease with high unmet medical need. Madrigal’s lead candidate,
resmetirom, is a once daily, oral, thyroid hormone receptor (THR)-β
selective agonist designed to target key underlying causes of NASH
in the liver. For more information, visit
www.madrigalpharma.com.
Forward Looking Statements
This communication includes “forward-looking statements” made
pursuant to the safe harbor provisions of the Private Securities
Litigation Reform Act of 1995, that are based on Madrigal’s beliefs
and assumptions and on information currently available to it, but
are subject to factors beyond its control. Forward-looking
statements reflect management’s current knowledge, assumptions,
judgment and expectations regarding future performance or events.
Forward-looking statements include: all statements that are not
historical facts; statements concerning the timing and potential
impact of FDA acceptance and priority review of our NDA; statements
referenced by forward-looking statement identifiers, including the
examples in the paragraph below; resmetirom’s potential to be the
first specialty therapy for NASH patients with significant liver
fibrosis; statements concerning potential accelerated approval; and
statements or references concerning - the potential efficacy and
safety of resmetirom for noncirrhotic NASH patients and cirrhotic
NASH patients, possible or assumed future results of operations and
expenses, business strategies and plans (including ex-US.
Launch/partnering plans), research and development activities, and
the timing and results associated with the future development of
resmetirom, the timing and completion of projected future clinical
milestone events, including enrollment, additional studies,
top-line data and open label projections, plans, objectives, timing
and support for making for making a Subpart H (Accelerated Approval
of New Drugs for Serious or Life-Threatening Illnesses) submission
to FDA, projections or objectives for obtaining accelerated or full
approval for resmetirom, Madrigal’s primary and key secondary study
endpoints for resmetirom and the potential for achieving such
endpoints and projections, demonstrating clinical benefit to
support accelerated approval, the potential to support an
additional indication for resmetirom in patients with
well-compensated NASH cirrhosis, optimal dosing levels for
resmetirom and projections regarding potential NASH or NAFLD and
potential patient benefits with resmetirom, including future NASH
resolution, safety, fibrosis treatment, cardiovascular effects,
lipid treatment, and/or biomarker effects with resmetirom.
Forward-looking statements can be identified by terms such as
“accelerate,” “achieve,” “allow,” “anticipates,” “appear,” “be,”
“believes,” “can,” “confidence,” “continue,” “could,”
“demonstrates,” ”design,” “estimates,” “expectation,” “expects,”
“forecasts,” “future,” “goal,” “help,” “hopeful,” “inform,”
inform,” “intended,” “intends,” “may,” “might,” “on track,”
“planned,” “planning,” “plans,” “positions,” “potential,” “powers,”
“predicts,” ”predictive,” “projects,” “seeks,” “should,” “will,”
“will achieve,” “will be,” “would” or similar expressions and the
negatives of those terms.
Forward-looking statements are subject to a number of risks and
uncertainties including, but not limited to: the assumptions
underlying the forward-looking statements; risks of obtaining and
maintaining regulatory approvals, including, but not limited to,
potential regulatory delays or rejections; risks associated with
meeting the objectives of Madrigal’s clinical studies, including,
but not limited to Madrigal’s ability to achieve enrollment
objectives concerning patient numbers (including an adequate safety
database), outcomes objectives and/or timing objectives for
Madrigal’s studies; any delays or failures in enrollment, and the
occurrence of adverse safety events; risks related to the effects
of resmetirom’s mechanism of action; the achievement of enrollment
objectives concerning patient number, safety database and/or timing
for Madrigal’s studies; enrollment and trial conclusion
uncertainties; market demand for and acceptance of our products;
the potential inability to raise sufficient capital to fund ongoing
operations as currently planned or to obtain financings on terms
similar to those arranged in the past; the ability to service
indebtedness and otherwise comply with debt covenants; outcomes or
trends from competitive studies; future topline data timing or
results; the risks of achieving potential benefits in studies that
includes substantially more patients, and patients with different
disease states, than 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
submissions filed with the U.S. Securities and Exchange Commission,
or SEC, 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. Madrigal
specifically discusses these risks and uncertainties in greater
detail in the section appearing in Part I, Item 1A of its Annual
Report on Form 10-K for the year ended December 31, 2022, filed
with the SEC on February 23, 2023, as amended by our Form 10-K/A
filed with the SEC on March 3, 2023, and as updated from time to
time by Madrigal’s other filings with the SEC.
Investor Contact Alex Howarth, Madrigal
Pharmaceuticals, Inc., IR@madrigalpharma.com
Media ContactChristopher Frates, Madrigal
Pharmaceuticals, Inc., media@madrigalpharma.com
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