Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a clinical-stage
biopharmaceutical company pursuing novel therapeutics for
nonalcoholic steatohepatitis (NASH), today announced the
publication of the pivotal Phase 3 MAESTRO-NASH trial of resmetirom
in the New England Journal of Medicine.
NASH is a leading cause of liver-related mortality and an
increasing burden on healthcare systems globally. Resmetirom
received Breakthrough Therapy designation from the FDA and is under
review to become the first medicine approved to treat patients with
NASH with liver fibrosis. The FDA granted resmetirom Priority
Review and assigned a Prescription Drug User Fee Act (PDUFA) date
of March 14, 2024, the target date by which FDA intends to complete
its review.
Stephen Harrison, M.D., Chairman for both Pinnacle Clinical
Research and Summit Clinical Research, San Antonio, Texas, Visiting
Professor of Hepatology, Oxford University, and lead Principal
Investigator of the MAESTRO studies, commented, “MAESTRO-NASH is a
landmark study in a disease that has historically been very
challenging for drug development. The publication of detailed
efficacy and safety data in the New England Journal of Medicine
will provide clinicians with valuable information about the
medication that may soon become the first approved therapy for
patients with NASH.”
The MAESTRO-NASH trial evaluates resmetirom treatment vs.
placebo in patients with NASH with significant fibrosis (consistent
with fibrosis stages 2 and 3), a population at elevated risk of
progressing to cirrhosis and other adverse liver outcomes. The
study includes a 52-week biopsy assessment to support accelerated
approval and an ongoing 54-month outcomes study designed to
generate confirmatory data that, if positive, will help verify
resmetirom’s clinical benefit and support full approval.
Based on the results of the 52-week biopsy portion of the trial,
MAESTRO-NASH is the only Phase 3 study in NASH to achieve both
primary endpoints that FDA proposed as reasonably likely to predict
clinical benefit: NASH resolution with no worsening of fibrosis and
fibrosis reduction with no worsening of NAFLD activity score (NAS).
Approximately 50% of patients treated with resmetirom 100 mg with
biopsies at Week 52 showed either NASH resolution or fibrosis
improvement. More than 80% of patients with biopsies at Week 52 had
either fibrosis reversal or no progression of fibrosis.
Becky Taub, M.D., Chief Medical Officer and President of
Research & Development of Madrigal, stated, “Patients with NASH
with significant fibrosis are at increased risk of progressing to
cirrhosis, liver failure, liver cancer and premature death.
Additionally, NASH is the leading cause of liver transplant among
women in the U.S. and may soon be the leading cause overall.
Despite its serious impact on patients and the health system, there
are no approved treatments for the disease. As a liver-directed
therapy that has demonstrated efficacy in both reversing fibrosis
and resolving NASH in a pivotal Phase 3 clinical trial, we believe
resmetirom will change the treatment paradigm for patients with
NASH with significant fibrosis if it receives accelerated approval
from the FDA.”
In addition to the two primary endpoints, multiple secondary
endpoints were achieved in the MAESTRO-NASH study, including
statistically significant reduction from baseline in liver enzymes
(ALT, AST and GGT). Reductions in atherogenic lipids and
lipoproteins, fibrosis biomarkers and imaging tests (MRI-PDFF, CAP
and liver stiffness measures) were observed in resmetirom treatment
arms as compared with placebo. MAESTRO-NASH also included many
biomarker and imaging assessments that may be used in real world
clinical practice to identify appropriate patients for treatment
and monitor response to resmetirom, if approved.
The incidence of serious adverse events was similar across the
treatment groups, 10.9%, 12.7%, and 11.5% in 80 mg, 100 mg and
placebo groups respectively. Transient diarrhea and nausea were
more frequent with resmetirom at the beginning of therapy. No
increase in the incidence of diarrhea and nausea was noted among
resmetirom-treated patients relative to placebo-treated patients
after the first few weeks of treatment. There was no incidence of
drug-induced liver injury. There were no increases in bone
fractures, or fracture risk score with resmetirom or increase in
adverse events related to thyroid hormone effects outside the liver
such as heart rate changes or sex hormone abnormalities.
Bill Sibold, Chief Executive Officer of Madrigal, stated, “The
unprecedented efficacy and safety results from the pivotal
MAESTRO-NASH Phase 3 trial provide Madrigal with a unique
opportunity to establish resmetirom as the foundational therapy for
NASH with significant fibrosis and transform care for patients who
currently have no approved treatment options. Resmetirom is the
only investigational medication to achieve both fibrosis
improvement and NASH resolution endpoints in Phase 3, and we intend
to build on our leadership position in NASH drug development with
two ongoing outcomes trials that carry the potential to confirm
clinical benefit and expand the eligible patient population for
resmetirom to include patients with more advanced disease.”
About the Resmetirom Phase 3 Program
Resmetirom is a once-daily, oral, liver-directed THR-β agonist
designed to target key underlying causes of NASH.
Madrigal is currently conducting multiple Phase 3 clinical
trials to evaluate the safety and efficacy of resmetirom for the
treatment of NASH:
- The pivotal MAESTRO-NASH (Significant
Fibrosis) study includes a 52-week biopsy assessment to
support accelerated approval and an ongoing 54-month outcomes study
designed to generate confirmatory data that, if positive, will help
verify resmetirom’s clinical benefit and support full approval.
Positive topline results from the 52-week biopsy portion of the
trial were reported in December 2022 and the primary results were
published in the New England Journal of Medicine.
- MAESTRO-NASH Outcomes (Compensated Cirrhosis)
evaluates progression to liver decompensation events in patients
with well-compensated NASH cirrhosis treated with resmetirom versus
placebo. A positive outcome is expected to support the full
approval of resmetirom for noncirrhotic NASH and expand the
eligible patient population for resmetirom with an additional
indication in patients with compensated NASH cirrhosis.
- The MAESTRO-NAFLD-1 (Safety) study was
designed to noninvasively evaluate the safety and tolerability of
resmetirom and provide a larger safety database to support
regulatory benefit-risk assessment. Positive topline results from
the study were reported in January 2022 and the primary publication
appeared in Nature Medicine. MAESTRO-NAFLD-OLE, an open-label
active treatment extension of MAESTRO-NAFLD-1, is ongoing to
collect additional safety data in patients with noncirrhotic NASH
and patients with well-compensated NASH cirrhosis.
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.
About NASH
Nonalcoholic steatohepatitis (NASH) is a more advanced form of
nonalcoholic fatty liver disease (NAFLD). 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 patients progress to NASH with significant fibrosis
(consistent with fibrosis stages 2 and 3), the risk of adverse
liver outcomes increases dramatically. NASH is rapidly becoming the
leading cause of liver transplantation in the U.S.
Madrigal estimates that approximately 1.5 million patients have
been diagnosed with NASH in the U.S., of which approximately
525,000 have NASH with significant fibrosis. Madrigal plans to
focus on approximately 315,000 diagnosed patients with NASH with
significant fibrosis under the care of the liver specialist
physicians during the launch of resmetirom.
There are currently no FDA-approved therapies available for the
treatment of NASH.
NASH is also known as “metabolic dysfunction-associated
steatohepatitis (MASH)” following a change in disease nomenclature
introduced by hepatology medical societies in 2023.
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, liver-directed THR-β agonist
designed to target key underlying causes of NASH. 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; the relationship between NASH progression and adverse
patient outcomes; the estimated clinical burden of uncontrolled
NASH; analyses for patients with NASH with significant fibrosis
concerning potential progression to cirrhosis, decompensated
cirrhosis, liver transplant or death, and cardiovascular risks,
comorbidities and outcomes; health economics assessments or
projections; resmetirom’s potential to be the first specialty
therapy for NASH patients with significant liver fibrosis;
projections or objectives for obtaining accelerated or full
approval for resmetirom, including all statements concerning
potential clinical benefit to support accelerated approval and/or
potential 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, Madrigal’s primary and key secondary study endpoints for
resmetirom and the potential for achieving such endpoints and
projections, the potential to support an additional indication for
resmetirom in patients with well-compensated NASH cirrhosis,
optimal dosing levels for resmetirom, 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, and strategies, objectives and
commercial opportunities, including potential prospects or
results..
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,”
“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; our ability to prevent and/or mitigate cyber-attacks,
unauthorized exfiltration of data or other security incidents; 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; the uncertainties inherent in clinical
testing; and uncertainties concerning analyses or assessments
outside of a controlled clinical trial. 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 Tina Ventura, Madrigal
Pharmaceuticals, Inc., IR@madrigalpharma.com
Media ContactChristopher Frates, Madrigal
Pharmaceuticals, Inc., media@madrigalpharma.com
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