Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a biopharmaceutical
company focused on delivering novel therapeutics for nonalcoholic
steatohepatitis (NASH), today announced that the U.S. Food and Drug
Administration (FDA) has granted accelerated approval for Rezdiffra
(resmetirom) in conjunction with diet and exercise for the
treatment of adults with noncirrhotic NASH with moderate to
advanced liver fibrosis (consistent with stages F2 to F3 fibrosis).
Continued approval for this indication may be contingent upon
verification and description of clinical benefit in ongoing
confirmatory trials.
Bill Sibold, Chief Executive Officer of Madrigal, stated, “NASH
with moderate to advanced liver fibrosis is a serious and
progressive liver disease that, until now, has not had an
FDA-approved therapy. The accelerated approval of Rezdiffra is a
culmination of more than 15 years of research from our founder Dr.
Becky Taub and a small R&D team that took on one of the biggest
challenges in drug development. This is a historic moment for the
NASH field and represents the best of what our industry is capable
of. We’re excited to deliver Rezdiffra to patients in need.”
Becky Taub, M.D., the Founder, Chief Medical Officer and
President of Research & Development of Madrigal, stated,
“Madrigal would like to thank the many patients who made the
accelerated approval of Rezdiffra possible by participating in our
clinical studies. We believe Rezdiffra will change the treatment
paradigm for NASH with moderate to advanced liver fibrosis, giving
physicians a liver-directed therapy to help improve fibrosis and
resolve NASH before their patients progress to cirrhosis.”
Wayne Eskridge, Co-Founder and Chief Executive Officer of the
Fatty Liver Foundation, stated, “This is a day of celebration for
patients with NASH who have been waiting many years for the first
approved therapy. I believe this approval milestone will bring new
energy and momentum to the NASH community, accelerating our efforts
to improve disease education, build care pathways, and expand
investment in NASH research.”
Rezdiffra is a once-daily, oral THR-β agonist designed to target
key underlying causes of NASH. The accelerated approval of
Rezdiffra was based on results from the Phase 3 MAESTRO-NASH trial,
which was recently published in the New England Journal of
Medicine. MAESTRO-NASH is an ongoing pivotal, multicenter,
randomized, double-blind, placebo-controlled trial that enrolled
1,759 patients with biopsy-confirmed NASH. Following 52 weeks of
treatment, both 100 mg and 80 mg doses of Rezdiffra demonstrated
statistically significant improvement compared to placebo on two
primary endpoints: NASH resolution (including a reduction in the
nonalcoholic fatty liver disease [NAFLD] activity score by ≥2
points) with no worsening of fibrosis, and an improvement in
fibrosis by at least one stage with no worsening of the NAFLD
activity score. Fibrosis improvement and NASH resolution were
consistent regardless of age, gender, type 2 diabetes status, or
fibrosis stage.
The Rezdiffra prescribing information does not include a liver
biopsy requirement for diagnosis. The recommended dosage of
Rezdiffra is based on actual body weight. For patients weighing
<100 kg (220 lbs.), the recommended dosage is 80 mg orally once
daily. For patients weighing ≥100 kg (220 lbs.), the recommended
dosage is 100 mg orally once daily.
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, “The approval of
the first medication for NASH is a true game-changer for healthcare
providers, the research community and, most importantly, patients
living with this serious liver condition. Based on the robust
efficacy and safety data generated in two large Phase 3 MAESTRO
studies, I believe Rezdiffra will become the foundational therapy
for patients with NASH with moderate to advanced liver
fibrosis.”
Dr. Harrison continued, “Importantly, we continue to study
Rezdiffra to determine if the positive results observed in the
MAESTRO studies will lead to reduced risk of progression to
cirrhosis, liver failure, need for liver transplant and premature
mortality.”
MAESTRO-NASH remains ongoing as an outcomes study designed to
generate confirmatory data that, if positive, will help verify
clinical benefit and may support full approval. A second ongoing
outcomes trial is evaluating progression to liver decompensation
events in patients with well-compensated NASH cirrhosis treated
with Rezdiffra versus placebo.
Rezdiffra should not be used in patients with decompensated
cirrhosis. The most common adverse reactions reported in patients
treated with Rezdiffra included diarrhea, nausea, pruritis,
abdominal pain, vomiting, constipation, and dizziness. Diarrhea and
nausea typically began early in treatment initiation and were mild
to moderate in severity. A separate, noninvasive Phase 3 trial,
MAESTRO-NAFLD-1, evaluated the safety and tolerability of Rezdiffra
and contributed to the safety database supporting regulatory
benefit-risk assessment.
Rezdiffra is expected to be available to patients in the U.S. in
April and will be distributed through a limited specialty pharmacy
network. Madrigal is committed to helping appropriate patients who
may benefit from Rezdiffra access the medication through the
Madrigal Patient Support program. This program is designed to help
patients navigate insurance and affordability challenges and
provide co-pay support for eligible patients. Madrigal has also
established a patient assistance program (PAP) to help patients
with no insurance access Rezdiffra.
Conference Call and Webcast
Madrigal will host a conference call and webcast today at 5:15
PM ET to discuss the accelerated approval of Rezdiffra. To access
the webcast of the call with slides please visit the Investors
section of Madrigal’s website or click here. An archived webcast
will be available on the Madrigal website after the event.
Phase 3 MAESTRO-NASH Trial Results
MAESTRO-NASH is an ongoing Phase 3 trial that enrolled 1759
patients with biopsy-confirmed NASH. Patients were randomly
assigned in a 1:1:1 ratio to receive once-daily Rezdiffra at a dose
of 80 mg or 100 mg or placebo. The two primary endpoints at week 52
were NASH resolution with no worsening of fibrosis and an
improvement in fibrosis by at least one stage with no worsening of
the NAFLD activity score. The key secondary endpoint was the
percent change from baseline in LDL cholesterol at week 24.
Rezdiffra achieved both primary endpoints and the key secondary
endpoint of the MAESTRO-NASH trial. Additionally, Rezdiffra
improved liver enzymes, fibrosis biomarkers and imaging tests as
compared with placebo. The primary results of the trial were
published in the New England Journal of Medicine in February
2024.
Patients enrolled in the MAESTRO-NASH trial 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 and hepatic decompensation
events, as well as all-cause mortality. The 54-month outcomes
portion of the trial is designed to generate confirmatory data
that, if positive, will help verify Rezdiffra’s clinical benefit
and may support full approval.
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 moderate to advanced liver
fibrosis (consistent with stages F2 to F3 fibrosis), 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 moderate to advanced liver fibrosis.
Madrigal plans to focus on approximately 315,000 diagnosed patients
with NASH with moderate to advanced liver fibrosis under the care
of the liver specialist physicians during the launch of
Rezdiffra.
NASH is also known as metabolic dysfunction associated
steatohepatitis (MASH). In 2023, global liver disease medical
societies and patient groups came together to rename the disease,
with the goal of establishing an affirmative, non-stigmatizing name
and diagnosis. Nonalcoholic fatty liver disease (NAFLD) was renamed
metabolic dysfunction-associated steatotic liver disease (MASLD),
NASH was renamed MASH, and an overarching term, steatotic liver
disease (SLD), was established to capture multiple types of liver
diseases associated with fat buildup in the liver. In addition to
liver disease, patients with MASH have at least one related
comorbid condition (e.g., obesity, hypertension, dyslipidemia, or
type 2 diabetes).
About Rezdiffra
What is Rezdiffra?
Rezdiffra is a prescribed medicine used along with diet and
exercise to treat adults with nonalcoholic steatohepatitis (NASH)
with moderate to advanced liver scarring (fibrosis), but not with
cirrhosis of the liver.
It is not known if Rezdiffra is safe and effective in children
(under 18 years old).
This indication is approved based on improvement of NASH and
liver scarring (fibrosis). There are ongoing studies to confirm the
clinical benefit of Rezdiffra.
Before you take Rezdiffra, tell your healthcare provider about
all of your medical conditions, including if you:
- have any liver problems other than NASH.
- have gallbladder problems or have been told you have
gallbladder problems, including gallstones.
- are pregnant or plan to become pregnant. It is not known if
Rezdiffra will harm your unborn baby.
- are breastfeeding or plan to breastfeed. It is not known if
Rezdiffra passes into your breast milk. Talk to your healthcare
provider about the best way to feed your baby if you take
Rezdiffra.
Tell your healthcare provider about all the medicines you take,
including prescription and over-the-counter medicines, vitamins,
and herbal supplements.
- Rezdiffra and other medicines may affect each other, causing
side effects. Rezdiffra may affect the way other medicines work,
and other medicines may affect how Rezdiffra works.
- Especially tell your healthcare provider if you take medicines
that contain gemfibrozil to help lower your triglycerides, or
cyclosporine to suppress your immune system, because Rezdiffra is
not recommended in patients taking these medicines.
- Tell your healthcare provider if you are taking medicines such
as clopidogrel to thin your blood or statin medicines to help lower
your cholesterol.
- Know the medicines you take. Keep a list of them to show your
healthcare provider and pharmacist when you get a new
medicine.
What are the possible side effects of Rezdiffra?
Rezdiffra may cause serious side effects, including:
- liver injury (hepatotoxicity). Stop taking Rezdiffra and call
your healthcare provider right away if you develop the following
signs or symptoms of hepatotoxicity: tiredness, nausea, vomiting,
fever, rash, your skin or the white part of your eyes turns yellow
(jaundice), pain or tenderness in the upper middle or upper right
area of your stomach
(abdomen).
- gallbladder problems. Gallbladder problems such as gallstones,
inflammation of the gallbladder, or inflammation of the pancreas
from gallstones can occur with NASH and may occur if you take
Rezdiffra. Call your healthcare provider right away if you develop
any signs or symptoms of these conditions including nausea,
vomiting, fever, or pain in your stomach area (abdomen) that is
severe and will not go away. The pain may be felt going from your
abdomen to your back and the pain may happen with or without
vomiting.
The most common side effects of Rezdiffra include: diarrhea,
nausea, itching, stomach (abdominal) pain, vomiting, dizziness,
constipation.
These are not all the possible side effects of Rezdiffra. For
more information, ask your healthcare provider or pharmacist.
Call your doctor for medical advice about side effects. You may
report side effects to FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch. You may also report side effects to Madrigal
at 1-800-905-0324.
Please see the full Prescribing Information, including Patient
Information, for Rezdiffra.
About Madrigal Pharmaceuticals
Madrigal Pharmaceuticals, Inc. (Nasdaq: MDGL) is a
biopharmaceutical company pursuing novel therapeutics for
nonalcoholic steatohepatitis (NASH), a liver disease with high
unmet medical need. Madrigal’s medication, Rezdiffra (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 presentation 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; and statements regarding: Rezdiffra
(resmetirom) and its expected use for treating NASH with moderate
to advanced fibrosis; the initiation of the commercial launch of
Rezdiffra, including statements regarding commercial insurance and
the anticipated time to fill prescriptions; estimates of patients
diagnosed with NASH and market opportunities; the relationship
between NASH progression and adverse patient outcomes; the
estimated clinical burden of uncontrolled NASH; analyses for
patients with NASH with moderate to advanced fibrosis concerning
potential progression to cirrhosis, decompensated cirrhosis, liver
transplant or death; cardiovascular risks, comorbidities and
outcomes; health economics assessments or projections; indicating
Rezdiffra has been shown to improve the fibrosis that is associated
with progression to cirrhosis and its complications and resolve the
underlying inflammation that drives the disease; projections or
objectives for obtaining full approval for Rezdiffra (resmetirom),
including those concerning potential clinical benefit to support
potential full approval; regarding post-approval requirements and
commitments; reduced risk of progression to cirrhosis, liver
failure, need for liver transplant and premature mortality;
treatment paradigm; improved liver enzymes, fibrosis biomarkers and
imaging tests; the potential efficacy and safety of Rezdiffra
(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, the
timing and results associated with the future development of
Rezdiffra (resmetirom), the timing and completion of projected
future clinical milestone events, including enrollment, additional
studies, the potential to support an additional indication for
Rezdiffra (resmetirom) in patients with well-compensated NASH
cirrhosis; optimal dosing levels for Rezdiffra (resmetirom);
potential NASH or NAFLD and potential patient benefits with
Rezdiffra (resmetirom), including future NASH resolution, safety,
fibrosis treatment, cardiovascular effects, lipid treatment, and/or
biomarker effects with Rezdiffra (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,”
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; the challenges with the
commercial launch of a new product, particularly for a company that
does not have commercial experience; 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
Rezdiffra’s (resmetirom’s) mechanism of action; enrollment and
trial conclusion uncertainties; market demand for and acceptance of
our product; 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; the timing and outcomes of clinical studies
of Rezdiffra (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 sections appearing in Part I, Item 1A of its Annual
Report on Form 10-K for the year ended December 31, 2023, filed
with the SEC on February 28, 2024, 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
A photo accompanying this announcement is available at
https://www.globenewswire.com/NewsRoom/AttachmentNg/699742ee-b5cf-4bac-8fe0-131c989b4210
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