Madrigal Pharmaceuticals, Inc. (NASDAQ:MDGL), a clinical-stage
biopharmaceutical company pursuing novel therapeutics for
nonalcoholic steatohepatitis (NASH), today presents resmetirom
Phase 3 MAESTRO-NASH data at the opening general session of the
European Association for the Study of the Liver Congress (EASL
2023).
In December 2022, Madrigal announced that MAESTRO-NASH achieved
both liver histological improvement endpoints that FDA proposed as
reasonably likely to predict clinical benefit to support
accelerated approval for the treatment NASH with liver fibrosis
including: 1- NASH resolution (ballooning 0, inflammation 0,1 with
≥2 point improvement in NAFLD activity score (NAS) and no worsening
of fibrosis) 2- ≥1-stage reduction in fibrosis with no worsening of
NAS.
Primary Endpoint (mITT*) |
Resmetirom80 mg(n=316) |
p-value |
Resmetirom100 mg(n=321) |
p-value |
Placebo(n=318) |
NASH resolution (ballooning 0, inflammation 0,1) with ≥2-point
reduction in NAS and no worsening of fibrosis |
26% |
<0.0001 |
30% |
<0.0001 |
10% |
≥1-stage improvement in fibrosis with no worsening of NAS |
24% |
0.0002 |
26% |
<0.0001 |
14% |
* In the modified intent-to-treat (mITT) population, patients
without a Week 52 biopsy are deemed nonresponders
New MAESTRO-NASH data being presented at EASL 2023 demonstrate
that resmetirom helped patients with NASH achieve significant
improvements vs placebo in liver fat, liver stiffness, liver
enzymes, liver volume, spleen volume, and multiple atherogenic
lipids/lipoproteins.
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 selection of
the MAESTRO-NASH primary results as the first abstract at this
year’s EASL Congress reflects the hepatology community’s strong
interest in resmetirom as the potential first approved medication
for the treatment of NASH with fibrosis. The new data being
presented at EASL build on the impressive topline efficacy findings
for both NASH and fibrosis reported last December, reinforce the
safety and tolerability profile of resmetirom, and provide
important insights for community clinicians seeking to understand
the effects of resmetirom on the noninvasive tests that are used to
manage patients in real world clinical practice.”
Becky Taub, M.D., Chief Medical Officer and President of
Research & Development of Madrigal, stated, “It is encouraging
to see such a broad and consistent treatment response with
resmetirom across both histologic and noninvasive measures of
efficacy, and across multiple patient subgroups. These data
reinforce our conviction in the potential of resmetirom to become
the first foundational treatment for patients with at-risk
NASH.”
MAESTRO-NASH Results Being Presented at EASL
2023
In addition to achieving the two primary endpoints, resmetirom
met multiple secondary biopsy endpoints in the MAESTRO-NASH trial,
including:
- 2-stage fibrosis improvement in the mITT population (resmetirom
80 mg, 8%; resmetirom 100 mg, 10%; placebo, 3%, p<0.0001);
- NASH resolution AND ≥1-stage improvement in fibrosis in the
mITT population (resmetirom 80 mg, 14%; resmetirom 100 mg, 16%;
placebo, 5%, p<0.0001);
- NASH resolution with ≥2-point reduction in NAS and no worsening
of fibrosis in patients with both a baseline and Week 52 biopsy
(resmetirom 80 mg, 32%; resmetirom 100 mg, 39%; placebo, 11%,
p<0.0001);
- ≥1-stage fibrosis improvement with no worsening of NAS in
patients with both a baseline and Week 52 biopsy (resmetirom 80 mg,
30%; resmetirom 100 mg, 34%; placebo, 16%, p<0.0001); and
- NASH resolution OR ≥1-stage fibrosis improvement in patients
with both a baseline and Week 52 biopsy (resmetirom 80 mg, 42%;
resmetirom 100 mg, 50%; placebo, 19%, p<0.0001).
Improvements in fibrosis and NASH resolution were observed
across all key subgroups, including:
- Baseline fibrosis stage (F2 or F3)
- NAS (<6, ≥6)
- type 2 diabetes status
- Age (<65, ≥65)
- Sex
No meaningful differences in fibrosis or NASH resolution
responses were observed based on treatment with common concomitant
medications (GLP-1 therapy, 14%; thyroxine, 13%; and statins, 50%
of patients in each arm) or in patients with ≥5% weight loss.
Resmetirom-treated patients showed improvement in all NAS
components and fibrosis, with significantly less worsening in
fibrosis stage compared with placebo. In patients with F1B or F2
fibrosis at baseline:
- 31% improved, 51% had no change, and 18% worsened in the 80 mg
group;
- 33% improved, 48% had no change, and 19% worsened in the
resmetirom 100 mg group; and
- 15% improved, 51% had no change, and 34% worsened in the
placebo group.
Patients treated with resmetirom achieved significant reductions
relative to placebo in key noninvasive tests, including:
- Magnetic resonance imaging-proton density fat fraction
(MRI-PDFF), with reductions at week 52 of -42% for resmetirom 80 mg
and -51% for resmetirom 100 mg vs -10% for placebo;
- ALT, AST, and GGT in patients with ALT ≥30 IU at baseline;
and
- Liver stiffness measured by FibroScan vibration-controlled
transient elastography (VCTE), both in mean change from baseline
and in responder analyses examining 25% improvement and 25%
worsening of kPa.
Safety and tolerability analyses of the MAESTRO-NASH data
demonstrate that study discontinuations in the 100 mg arm were
increased relative to placebo only during the first few weeks of
treatment and were similar in all treatment groups for the
remaining period of the first 52 weeks. Most adverse event-related
discontinuations in the resmetirom 100 mg arm were GI-related:
diarrhea was reported in 34% of patients treated with resmetirom
100 mg and in 16% of patients on placebo. Episodes were mild or
moderate, and median duration of diarrhea was approximately two
weeks. There were no adjudicated cases of drug-induced liver injury
in the MAESTRO-NASH trial.
Separate from the general session presentation, Madrigal is
presenting a late-breaker poster at EASL 2023 featuring the first
analysis of the MAESTRO-NASH biopsy results using artificial
intelligence (AI). Second harmonic generation slide reading
technology (HistoIndex) was employed to measure fibrosis change in
768 sets of paired biopsies from MAESTRO-NASH. The results showed
highly statistically significant reduction in fibrosis in both
resmetirom 80 and 100 mg groups relative to placebo. The authors
concluded that AI-based measurements of fibrosis change using
either a continuous or categorical scale demonstrated a clear
improvement and less worsening in fibrosis in resmetirom-treated
patients as compared with placebo after 52 weeks of treatment.
Investor Event and Webcast
Madrigal will host an investor event in Vienna with webcast on
Saturday, June 24 at 6:30 PM CEST / 12:30 PM ET. Investors and
analysts can click here to register for the live event in Vienna.
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.
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
subpart H portion of the study 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.
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 3 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 of the subpart H submission to FDA
for accelerated approval of resmetirom for treatment of NASH.
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 a cost-effective specialty
therapy for NASH patients with significant liver fibrosis; 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, 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, generally and in relation to COVID-19 related
measures and individual precautionary measures that may be
implemented or continued for an uncertain period of time; 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
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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