-- Statistically significant improvement in the relative
decrease in liver fat in patients treated with MGL-3196 compared
with placebo, determined by magnetic resonance imaging-estimated
proton density fat fraction (MRI-PDFF) at 12-weeks, the primary end
point in this Phase 2 proof-of-concept trial–
Madrigal Pharmaceuticals, Inc.
(Nasdaq:MDGL) today announced positive top-line results from a
Phase 2 clinical trial in patients with biopsy-proven non-alcoholic
steatohepatitis (NASH). In this trial, MGL-3196, a first-in-class,
oral, once-daily, liver-directed, thyroid hormone receptor (THR) β
-selective agonist, demonstrated statistically significant results
for the primary endpoint, the percent change in hepatic fat versus
placebo as measured by MRI-PDFF, a non-invasive imaging test.
Recent published data have shown a high correlation of the
reduction of liver fat of 30% or more as measured by MRI-PDFF to
improvement in NASH on liver biopsy.
|
ALL MGL-3196 |
HIGH MGL-3196** |
Placebo |
Numbers of patients |
78 |
44 |
38 |
Relative change in MRI-PDFF (% change from baseline,
median)Significance relative to placebo |
-36.3%p<0.0001 |
-42.0%p<0.0001 |
-9.6% |
Percentage of patients attaining ≥30% liver fat
reductionSignificance relative to placebo |
60.3%p<0.0001 |
75.0%p<0.0001 |
18.4% |
**Prespecified group of patients (44/78) with relatively higher
MGL-3196 drug levels
Statistically significant reductions in ALT and AST were
observed in MGL-3196 treated patients; greater reductions in ALT
and AST, statistically significant relative to placebo, were
observed in the prespecified group of 44/78 patients with
relatively higher MGL-3196 drug levels. In drug-treated relative to
placebo patients, statistically significant improvements were also
seen in multiple secondary endpoints considered to be potentially
clinically relevant in patients with NASH including LDL-C,
triglycerides, apolipoprotein B (ApoB), and Lp(a).
MGL-3196 has been well-tolerated with mostly mild AEs, and a few
moderate AEs, the numbers of which are balanced between placebo and
drug-treatment groups. There are no adverse effects of MGL-3196 on
safety laboratory or vital sign parameters. There have been three
serious adverse effects in the study, all considered unrelated to
MGL-3196.
The on-going study remains blinded. Safety, efficacy of NASH
resolution by biopsy, and repeat MRI-PDFF will be assessed at 36
weeks. Multiple inflammatory and fibrosis serum biomarkers at 12
and 36 weeks are being and will be assessed.
“NASH is a common liver disease in the United States, with a
growing prevalence, for which no FDA approved treatment is yet
available,” said Dr. Stephen Harrison, M.D., Principal Investigator
of the study as well as Medical Director for Pinnacle Clinical
Research, San Antonio, Texas, and Visiting Professor of Hepatology,
Oxford University. “These results suggest that a highly selective
liver-directed, thyroid hormone receptor-β agonist may be able to
effectively and safely treat patients with NASH. Importantly, the
study is designed to allow correlations between efficacy in a
non-invasive imaging test, MRI-PDFF at 12 and 36 weeks, and
improvement in NASH on liver biopsy at 36 weeks.”
Rebecca Taub, M.D., Chief Medical Officer and Executive VP,
Research & Development of Madrigal added, “Results from this
study confirm what we have seen in both our preclinical and earlier
clinical studies and support our long-standing confidence in the
safety and potential therapeutic value of MGL-3196. We fully expect
data at 36 weeks to confirm results seen at 12 weeks, and
potentially show improvement in NASH on liver biopsy. We look
forward to the presentation of the 12-week, Phase 2 results to the
scientific and clinical community, and further development of
MGL-3196 for treatment of patients with NASH.”
Paul Friedman, M.D., Chief Executive Officer of Madrigal,
stated, “We are gratified to see clinical results that strongly
suggest MGL-3196 has the potential to provide clinically meaningful
improvement of NASH by targeting lipotoxicity and inflammation as
well as by reduction of cardiovascular risk by lowering atherogenic
lipids. These pleiotropic actions, coupled with the excellent
safety profile we have seen in this trial, continue to suggest that
MGL-3196 has the potential to address the root causes of the
underlying disease process in NASH.”
Conference Call and Webcast InformationMadrigal
will hold a conference call and webcast this morning at 8:30 a.m.
ET. To access the conference call, please dial 833-660-2754 for
domestic callers or 409-350-3497 for international callers. When
prompted, provide the conference identification number,
5577478.
The conference call will also be webcast live and can be
accessed
at http://www.madrigalpharma.com/newsroom/presentations/ in
the “Events and Presentations” section of the Madrigal website.
If you are unable to participate, a replay of the conference
call will be available on the website under
http://www.madrigalpharma.com/newsroom/presentations/.
About the Phase 2 NASH Study The randomized,
double-blind, placebo-controlled, multi-center Phase 2 study
enrolled 125 patients 18 years of age and older with liver
biopsy-confirmed NASH and included approximately 25 clinical sites
in the United States. Patients were randomized to receive either
placebo or MGL-3196 with twice as many patients receiving MGL-3196
as placebo. The starting dose in 3196-treated patients was 80 mg
once a day. The study employed an adaptive dosing design whereby,
in a blinded fashion, the dose could be adjusted by small amounts
(i.e. 20 mg up or down) or remain at 80 mg in each 3196-treated
patient based on a pharmacokinetic analysis of drug level performed
in each patient at 2 weeks.
The primary endpoint of the study is the reduction of liver fat
at 12 weeks compared with baseline (relative change), assessed by
MRI-PDFF, with efficacy confirmed at the end of the trial (36
weeks) by repeat MRI-PDFF and conventional liver biopsy to examine
histological evidence for the resolution of NASH. A total of 116
patients completed the 12 week MRI-PDFF; the 9 discontinuations
were balanced between placebo and drug treated; 2/9
discontinuations were AE-related.
Other secondary endpoints include changes in clinically relevant
biomarkers at 12 and 36 weeks, improvement in fibrosis by at least
one stage with no worsening of steatohepatitis, and safety and
tolerability. Results at 36-weeks are expected in the second
quarter of 2018. Additional information about the study
[NCT02912260] can be obtained at www.ClinicalTrials.gov.
About MGL-3196 Among its many functions in the
human body, thyroid hormone, through activation of its beta
receptor, plays a central role in controlling lipid metabolism,
impacting a range of health parameters from levels of serum
cholesterol and triglycerides to the pathological buildup of fat in
the liver. Attempts to exploit this pathway for therapeutic
purposes in cardio-metabolic and liver diseases have been hampered
by the lack of selectivity of older compounds for the thyroid
hormone receptor (THR)-β, chemically-related toxicities and
undesirable distribution in the body.
Madrigal recognized that greater selectivity for thyroid hormone
receptor (THR)-β and liver targeting might overcome these
challenges and deliver the full therapeutic potential of THR-β
agonism. Madrigal believes that MGL-3196 is the first orally
administered, small-molecule, liver-directed, truly β-selective THR
agonist. MGL-3196 has demonstrated the potential for a broad array
of therapeutically beneficial effects, improving components of both
metabolic syndrome, such as insulin resistance and dyslipidemia,
and fatty liver disease, including lipotoxicity and inflammation.
These pleiotropic actions, coupled with an excellent safety
profile, suggest that MGL-3196 could be the preferred treatment
option for NASH.
About Madrigal Pharmaceuticals Madrigal
Pharmaceuticals, Inc. (Nasdaq:MDGL) is a clinical-stage
biopharmaceutical company pursuing novel therapeutics that target a
specific thyroid hormone receptor pathway in the liver, which is a
key regulatory mechanism common to a spectrum of cardio-metabolic
and fatty liver diseases with high unmet medical need. Madrigal’s
lead candidate, MGL-3196, is a first-in-class, orally administered,
small-molecule, liver-directed, thyroid hormone receptor
(THR) β-selective agonist that is currently in Phase 2
development for NASH and HeFH. For more information, visit
www.madrigalpharma.com.
Forward-Looking StatementsThis communication
contains “forward-looking statements” made pursuant to the safe
harbor provisions of the Private Securities Litigation Reform Act
of 1995. Such statements contain words such as “expect,” “could,”
“may,” “will,” “believe,” “estimate,” "continue," "future,” or the
negative thereof or comparable terminology and the use of future
dates. Forward-looking statements reflect management's current
knowledge, assumptions, judgment and expectations regarding future
performance or events. Although management believes that the
expectations reflected in such statements are reasonable, they give
no assurance that such expectations will prove to be correct and
you should be aware that actual results could differ materially
from those contained in the forward-looking statements.
Forward-looking statements are subject to a number of risks and
uncertainties including, but not limited to, the company's clinical
development of MGL-3196, the timing and outcomes of clinical
studies of MGL-3196, 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 filings with the U.S. Securities
and Exchange Commission 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.
Investor Contact:Marc Schneebaum,
Madrigal Pharmaceuticals, Inc.IR@madrigalpharma.comMedia
Contact:Mike Beyer, Sam Brown
Inc.mikebeyer@sambrown.com312 961 2502
Madrigal Pharmaceuticals (NASDAQ:MDGL)
Historical Stock Chart
From Mar 2024 to Apr 2024
Madrigal Pharmaceuticals (NASDAQ:MDGL)
Historical Stock Chart
From Apr 2023 to Apr 2024