Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a clinical-stage
biopharmaceutical company pursuing novel therapeutics for
nonalcoholic steatohepatitis (NASH), initiated a rolling submission
of a New Drug Application (NDA) to the U.S. Food and Drug
Administration (FDA) seeking accelerated approval of resmetirom for
the treatment of NASH with liver fibrosis. Madrigal has submitted
the majority of the NDA to the FDA and plans to submit the
remaining components in July 2023. The company will request a
priority review of the NDA.
Resmetirom was granted Breakthrough Therapy designation in April
2023 for the treatment of patients with NASH with liver fibrosis.
As a result, Madrigal was allowed to submit individual sections of
its NDA as they were completed rather than waiting until the entire
application was complete.
Becky Taub, M.D., Chief Medical Officer and President of
Research & Development of Madrigal, stated, “In the
MAESTRO-NASH biopsy trial, resmetirom achieved both liver
histological improvement endpoints proposed by FDA as reasonably
likely to predict clinical benefit and demonstrated a
well-tolerated safety profile. We believe the positive results from
MAESTRO-NASH support the potential of resmetirom to become a
foundational therapy for NASH with liver fibrosis. The MAESTRO
development program will provide a robust data package to support
the FDA’s review of the resmetirom NDA.”
Paul Friedman, M.D., Chief Executive Officer of Madrigal,
stated, “Madrigal is committed to addressing the needs of patients
who currently have no approved treatments for NASH with liver
fibrosis and the NDA submission for resmetirom is an important
milestone. We look forward to working closely with the FDA as the
review process progresses.”
About the Resmetirom Phase 3 Registration Program for
the Treatment of NASH
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 and was initiated in March 2019. The
portion of the study designed to support a subpart H approval
enrolled more than 1,000 patients with biopsy-proven NASH (at least
half with F3 (advanced) fibrosis, the remainder F2 or F1B (moderate
fibrosis) with a few earlier F1 patients, randomized 1:1:1 to
receive once-daily resmetirom 80 mg, resmetirom 100 mg, or placebo.
After 52 weeks of treatment, a second liver biopsy is performed.
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. Achievement of either primary endpoint was
considered a successful trial outcome. A key secondary endpoint was
lowering of LDL-C.
Patients enrolled in the MAESTRO-NASH study (approximately
1,750) 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, may help verify
resmetirom’s clinical benefit and support full approval.
MAESTRO-NAFLD-1 was initiated in December 2019 and the 52-week
multicenter, randomized, placebo-controlled Phase 3 study of
resmetirom in over 1,200 patients with NAFLD, presumed NASH, has
completed the double-blind arms and an open-label 100 mg arm. An
additional open-label active treatment arm in patients with early
(well-compensated) NASH cirrhosis is ongoing. The primary endpoint
was to evaluate the safety and tolerability of resmetirom. A
separate 52 week Phase 3 clinical trial, an open-label extension
study of MAESTRO-NAFLD-1 (MAESTRO-NAFLD-OLE), is ongoing.
Patients in the 52-week Phase 3 MAESTRO-NAFLD-1 study were
randomized 1:1:1:1 to receive once-daily resmetirom 80 mg,
resmetirom 100 mg, placebo in double-blind arms or resmetirom 100
mg in an open-label arm. MAESTRO-NAFLD-1 (unlike MAESTRO-NASH), did
not include a liver biopsy and represents a “real-life” NASH study.
Patients with three metabolic risk factors were documented with
NASH or NAFLD by historical liver biopsy or noninvasive techniques.
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 and several
key secondary endpoints were met, including LDL-C, apolipoprotein
B, and triglyceride lowering and reduction of liver fat as
determined by MRI-PDFF. Additional secondary and exploratory
endpoints were assessed including reduction in liver enzymes,
FibroScan, and MRE scores, and other NASH biomarkers.
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, will 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). In the United States,
NAFLD is estimated to affect approximately 25% of the population,
and approximately 25% of those will progress from NAFLD to
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.
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 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; statements concerning
the timing of resmetirom’s rolling NDA submission; 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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