NGM Biopharmaceuticals, Inc. (NGM) (Nasdaq: NGM), a biotechnology
company focused on discovering and developing transformative
therapeutics for patients, today announced that final data from its
24-week Phase 2 study (Cohort 4) of aldafermin 1 mg in patients
with non-alcoholic steatohepatitis (NASH) were featured in a
late-breaker oral plenary presentation today (LBO-01) at The
Digital International Liver Congress™ (ILC) 2020. The
presentation included a new analysis of Cohort 4 data from NASH
patients with stage 3 liver fibrosis (F3) demonstrating that 1 mg
aldafermin had a potent anti-fibrotic effect in these patients with
more advanced disease. NGM also announced today that it has
completed enrollment in its ongoing Phase 2b ALPINE 2/3 study of
0.3 mg, 1 mg and 3 mg aldafermin versus placebo in patients with
biopsy-confirmed NASH with stage 2 (F2) and F3 liver fibrosis. The
primary objective of the ALPINE 2/3 study is to evaluate a dose
response showing an improvement in liver fibrosis by ≥ 1 stage with
no worsening of steatohepatitis at Week 24. NGM expects to report
topline findings from the study in the second quarter of 2021.
Efficacy data from a new secondary analysis of patients with
advanced liver fibrosis enrolled in the 24-week Phase 2 study
(Cohort 4) were included in the aldafermin presentation at Digital
ILC. In this patient population, 30% of patients with F3 liver
fibrosis treated with aldafermin 1 mg achieved fibrosis improvement
>1 stage without worsening of NASH compared to 0% in the placebo
arm. A responder analysis conducted in patients with F3 liver
fibrosis who achieved ≥30% LFC reductions showed that 46% of
patients treated with aldafermin 1 mg had fibrosis improvement of
≥1 stage without worsening of NASH compared to 0% of placebo
patients.
"We are delighted to present the comprehensive and promising
results from the 24-week Phase 2 Cohort 4 study of aldafermin 1 mg
in patients with NASH. The four successive cohorts of this Phase 2
study have enabled NGM Bio to amass a robust body of evidence that
has consistently demonstrated aldafermin’s potential as a
transformative agent for patients with NASH and established liver
fibrosis,” said Stephen A. Harrison, M.D., Medical Director at
Pinnacle Clinical Research, Visiting Professor of Hepatology at
University of Oxford, UK and principal investigator of the study,
who gave the aldafermin presentation at Digital ILC.
Phase 2 24-Week Cohort 4 Key Efficacy
Findings
In February 2020, NGM announced positive preliminary topline
results from the 24-week double-blind, randomized,
placebo-controlled Phase 2 clinical study (Cohort 4) of aldafermin,
which enrolled patients with biopsy-confirmed NASH and stage 2 and
3 (F2-F3) liver fibrosis. Cohort 4 was the final reported cohort
from NGM’s adaptive Phase 2 clinical study of aldafermin in
NASH.
Cohort 4 was statistically powered to demonstrate the effect of
1 mg aldafermin treatment versus placebo on the primary endpoint of
change in absolute LFC, which achieved statistical significance. In
addition, the study assessed secondary and exploratory endpoints of
liver histology and biomarkers of disease activity. The histology
results revealed that treatment with aldafermin led to clinically
meaningful improvements at 24 weeks versus placebo in fibrosis
improvement of ≥1 stage with no worsening of NASH (38% of
aldafermin-treated patients vs. 18% placebo) and in resolution of
NASH with no worsening of liver fibrosis (24% of aldafermin-treated
patients vs. 9% placebo). The study also demonstrated a
statistically significant impact on the combined endpoint of both
fibrosis improvement and resolution of NASH (22% in
aldafermin-treated patients vs. 0%
placebo).
Summary of Cohort 4 Histology Data1 |
Proportion of Patients Achieving Endpoints |
Aldafermin1 mg (n=50) |
Placebo(n=22) |
Fibrosis improvement (>1 stage) with no worsening of NASH2 |
38% |
18 |
% |
Resolution of NASH with no worsening of liver fibrosis3 |
24% |
9 |
% |
Fibrosis Improvement and resolution of NASH4 |
22%* |
0 |
% |
NAS reduction of >2 points with no worsening of liver
fibrosis |
62%*** |
9 |
% |
*<0.05; ***p<0.001
1 Per protocol, analyzed using the “liver histologic
population,” defined as the subset of enrolled patients who had
valid, non-missing biopsy data at both baseline and week 24 (n=72)2
Defined as patients having an improvement in liver fibrosis ≥1
stage and having no worsening of hepatocellular ballooning, no
worsening of lobular inflammation and no worsening of steatosis
from baseline to week 243 Defined as patients having a
non-alcoholic fatty liver disease (NAFLD) activity score (NAS) of 0
or 1 for lobular inflammation and 0 for hepatocellular ballooning,
with no worsening of fibrosis (no progression of NASH fibrosis
stage) from baseline to week 24 (as defined by Clinical Research
Network criteria)4 Defined as patients having an improvement in
liver fibrosis ≥1 stage and having a NAS of 0 or 1 for lobular
inflammation and 0 for hepatocellular ballooning at week 24
“As NASH progresses, there is a critical need for a powerful,
well-tolerated agent that can rapidly reverse liver fibrosis and
resolve NASH to prevent the development of cirrhosis and its
complications. In addition to histological efficacy data from
earlier Phase 2 cohorts across the spectrum of noncirrhotic NASH,
this new analysis suggests that aldafermin also has potential to be
an important cornerstone of chronic therapy in more advanced NASH
fibrosis,” said Hsiao D. Lieu, M.D., Chief Medical Officer at NGM
Bio. “These new findings, along with the existing comprehensive
Phase 2 efficacy and safety data generated in over 250 NASH
subjects, will help further inform and advance our ongoing planning
for the aldafermin Phase 3 study.”
Phase 2 24-Week Cohort 4 Key Safety and Tolerability
Findings
Aldafermin had an overall adverse event profile that was similar
to that of placebo, with no meaningful difference in
gastrointestinal or pruritus adverse events in aldafermin compared
to placebo. Serious adverse events were also similar to placebo
(aldafermin 4% versus 12% placebo), with all serious adverse events
determined not to be related to treatment by the site investigator.
Aldafermin was generally well tolerated and there were no study
withdrawals due to adverse events in the aldafermin arm as compared
to one withdrawal due to an adverse event in the placebo arm.
A new analysis of lipid data presented at Digital ILC found that
the statin use algorithm applied to optimize the lipid management
of both aldafermin and placebo patients in Cohort 4 was associated
with an overall reduction in the 10-year atherosclerotic
cardiovascular disease (ASCVD) risk score for patients
participating in the study. The analysis found that the 10-year
ASCVD risk score declined from a baseline of 15% to 12% in patients
treated with aldafermin at week 24 (compared to a decline from
baseline of 12% to 11% in the placebo arm). Over the course
of the study, the concomitant use of aldafermin and rosuvastatin
led to a mean LDL-C decline of 19 mg/dL in the treatment group
versus a mean decline of 16 mg/dL in the placebo group. As noted in
the Cohort 4 publication in Gastroenterology, triglycerides
declined 62 mg/dL in the aldafermin treatment arm vs. 29 mg/dL in
placebo. Moreover, the numbers and size of lipoprotein particles
did not differ between groups at the end of treatment at week 24.
Additional new safety data presented from Cohort 4 showed no
effect on blood pressure or heart rate in NASH patients in the
treatment arm.
Phase 2 24-Week Cohort 4 Study Design
Cohort 4 was a multi-center, double-blind, randomized,
placebo-controlled Phase 2 study evaluating the efficacy, safety
and tolerability of 1 mg once-daily subcutaneous injections of
aldafermin over 24 weeks of treatment. The study enrolled 78
patients with biopsy-confirmed NASH with F2-F3 liver fibrosis who
were randomized 2:1 to receive once-daily aldafermin 1 mg (n=53) or
placebo (n=25). The primary endpoint was the treatment effect on
absolute LFC as measured by magnetic resonance imaging-estimated
proton density fat fraction, or MRI-PDFF, compared to placebo at 24
weeks, with a ≥5% absolute LFC reduction identified as clinically
meaningful. Secondary and exploratory endpoints included relative
changes in LFC, biomarkers of liver function and effect on liver
histology. Patients were also evaluated at week 30 following six
weeks off treatment for safety and non-invasive measures.
Liver biopsies were performed at screening and at the end of 24
weeks of treatment and were read using the NASH CRN criteria by one
central, independent hepatopathologist who was blinded to patient
and treatment assignment. As per protocol, liver biopsy data were
analyzed using the “liver histologic population," which was defined
as the subset of enrolled patients who had valid, non-missing
biopsy data at both baseline and week 24 (n=72). Six patients
(three in the aldafermin arm and three in the placebo arm) withdrew
prior to the week 24 biopsy for reasons not due to adverse events
related to treatment.
Background on the Aldafermin Phase 2 Study
The adaptive Phase 2 aldafermin study included four successive
cohorts:
- Cohort 1: a 12‐week, multi-center, double-blind,
randomized, placebo-controlled study that assessed the efficacy and
safety of aldafermin 3 mg and 6 mg once daily through non-invasive
measures only;
- Cohort 2: a 12-week, single-blind study that assessed the
efficacy and safety of aldafermin 0.3 mg, 1 mg and 3 mg once daily,
with the 3 mg dose group including histology endpoints;
- Cohort 3: a 12-week, single-blind study that assessed the
efficacy and safety of aldafermin 1 mg once daily, including
non-invasive and histology endpoints; and
- Cohort 4: a 24-week, multi-center, double-blind,
randomized, placebo-controlled study that assessed the efficacy and
safety of aldafermin 1 mg once daily, including non-invasive and
histology endpoints.
Key eligibility criteria were similar across study cohorts and
included adult patients with biopsy-confirmed NASH, NAS ≥4 (with at
least one point in each NAS component of steatosis, lobular
inflammation and hepatocellular ballooning), presence of liver
fibrosis and ≥8% LFC as measured by MRI-PDFF. Cohorts 1, 2 and 3
enrolled patients with fibrosis stages F1-F3; Cohort 4 enrolled
only patients with fibrosis stages F2-F3. Results from Cohort 1
were presented at the International Liver Congress™ in 2017 and
published in The Lancet in 2018. Data from Cohorts 2 and 3 were
presented at the International Liver Congress in 2018 and The Liver
Meeting® in 2018 and published in Hepatology in 2019. Results
from Cohort 4 were presented at the Digital International Liver
Congress 2020 and published in Gastroenterology in 2020.
About Aldafermin
Aldafermin (formerly NGM282) is an engineered variant of the
human hormone FGF19 that is dosed once daily as a subcutaneous
injection and has generated robust preclinical and clinical
evidence supporting its ability to reduce liver fat content,
improve liver function, reverse fibrosis and resolve NASH by
targeting multiple pathogenic pathways of liver disease. NGM
has evaluated this wholly-owned therapeutic in over 500 healthy
volunteers and patients across multiple liver and metabolic
diseases, including more than 200 NASH patients.
About NGM Biopharmaceuticals, Inc.
NGM is a biopharmaceutical company focused on discovering and
developing novel therapeutics based on scientific understanding of
key biological pathways underlying liver and metabolic diseases,
retinal diseases and cancer. We leverage our biology-centric drug
discovery approach to uncover novel mechanisms of action and
generate proprietary insights that enable us to move rapidly
into proof-of-concept studies and deliver
potential first-in-class medicines to patients. At NGM,
we aspire to operate one of the most productive research and
development engines in the biopharmaceutical industry, with
multiple programs in clinical development. Visit us
at www.ngmbio.com for more information.
Forward Looking Statements
Statements contained in this press release regarding matters
that are not historical facts are “forward-looking statements”
within the meaning of the Private Securities Litigation Reform Act
of 1995. Words such as “promising,” “suggests,” “aspire,”
“advance,” “potential,” “expects,” “anticipates,” “planning” and
similar expressions (as well as other words or expressions
referencing future events, conditions or circumstances) are
intended to identify forward-looking statements. These statements
include those related to the potential of aldafermin as a
transformative agent or a cornerstone therapy for patients with
NASH and established liver fibrosis; the potential of NGM’s drug
discovery approach to deliver first-in-class medicines; the
continued progress of, and the timing of enrollment and results of,
NGM’s clinical trials, including timing of topline results of the
ALPINE 2/3 study; NGM’s ability to advance aldafermin into Phase 3
clinical development for NASH patients; and the safety,
tolerability and efficacy of aldafermin. Because such statements
deal with future events and are based on NGM’s current
expectations, they are subject to various risks and uncertainties,
and actual results, performance or achievements of NGM could differ
materially from those described in or implied by the statements in
this press release. These forward-looking statements are subject to
risks and uncertainties, including, without limitation, risks and
uncertainties associated with the costly and time-consuming
pharmaceutical product development process and the uncertainty of
clinical success, including risks related to failure or delays in
successfully enrolling or completing clinical studies, the risk
that the results obtained to date in NGM’s clinical trials may not
be indicative of results obtained in subsequent pivotal or other
late-stage trials, and the risk that NGM’s ongoing or future
clinical studies in humans may show that aldafermin is not a
tolerable and effective treatment for NASH patients; the ongoing
COVID-19 pandemic, which has adversely affected, and could
materially and adversely affect in the future, our business and
operations; the time-consuming and uncertain regulatory approval
process; NGM’s reliance on third-party manufacturers for aldafermin
and its other product candidates; the sufficiency of NGM’s cash,
cash equivalents and short-term marketable securities and need for
additional capital; and other risks and uncertainties affecting NGM
and its development programs, as well as those discussed in the
sections titled “Risk Factors” and “Management’s Discussion and
Analysis of Financial Condition and Results of Operations” in our
quarterly report on Form 10-Q for the quarter ended June 30, 2020
and future filings and reports that NGM makes from time to time
with the United States Securities and Exchange Commission. Except
as required by law, NGM assumes no obligation to update these
forward-looking statements, or to update the reasons if actual
results differ materially from those anticipated in the
forward-looking statements.
Investor Contact: Alex Schwartz
ir@ngmbio.com |
Media Contact: Liz Melone
media@ngmbio.com |
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