NGM Biopharmaceuticals, Inc. (NGM) (Nasdaq: NGM), a biotechnology
company focused on discovering and developing transformative
therapeutics for patients, today reported results from the 24-week
Phase 2b ALPINE 2/3 study evaluating aldafermin in 171 patients
with biopsy-confirmed non-alcoholic steatohepatitis (NASH) with
stage 2 or 3 liver fibrosis (F2/F3). The trial was an equally
randomized, double-blind, placebo-controlled study that assessed
the efficacy, safety and tolerability of 0.3 mg, 1 mg and 3 mg
doses of aldafermin once-daily subcutaneous injections compared to
placebo. The study did not meet its primary endpoint evaluating a
dose response showing improvement in liver fibrosis by >1 stage
with no worsening of NASH at week 24 (p=0.55), analyzed using a
dose response-driven statistical analysis plan (Multiple Comparison
Procedure Modeling, or MCP-Mod). The study did achieve statistical
significance versus placebo on certain secondary endpoints,
including NASH resolution (at the 3 mg dose) and multiple
non-invasive measures of NASH, including liver fat content
reduction by MRI-PDFF, ALT, AST and Pro-C3 (at the 1 mg and 3 mg
doses).
“These results are certainly disappointing, particularly given
the dire unmet need in this patient population. The lack of
significant fibrosis improvement was unexpected given the
consistency of histology findings previously seen with aldafermin
in our adaptive four-cohort Phase 2 study,” said David J.
Woodhouse, Ph.D., Chief Executive Officer at NGM. “However, in line
with the data from that study, ALPINE 2/3 achieved statistical
significance on multiple non-invasive measures of NASH at the two
higher doses. That said, given the failure to meet the primary
endpoint, we have decided to shift resources that had previously
been reserved for a Phase 3 F2/F3 NASH development program toward
advancing our other programs.”
Dr. Woodhouse further commented, “NGM is a markedly different
company than when we initiated ALPINE 2/3 in May 2019, when our
clinical-stage pipeline consisted primarily of liver and metabolic
programs. Over the past two years, we have steadily expanded that
pipeline with programs generated from our productive in-house
discovery engine, and today we are also an ophthalmology and
oncology company with four Phase 2 programs underway. We look
forward to advancing our clinical programs and moving additional
programs into the clinic, supported by our cash balance that was in
excess of $400 million at the end of the first quarter.”
NGM’s disclosed pipeline includes: NGM621, an anti-complement C3
antibody, currently in Phase 2 development for the treatment of
geographic atrophy; NGM120, a GFRAL antagonistic antibody in Phase
2 development for the treatment of metastatic
pancreatic cancer and cancer-related cachexia; and NGM707 and
NGM438, anti-ILT2/ILT4 and LAIR1 myeloid checkpoint candidates,
respectively, both of which are anticipated to begin Phase 1
studies for the treatment of advanced solid tumors this
year. Additionally, Merck continues to progress a global Phase
2b study of MK-3655, an FGFR1c/KLB agonistic antibody for the
treatment of NASH, which was discovered by NGM under its
collaboration with Merck.
ALPINE 2/3 Topline Findings – Secondary Analyses of Key
Histology Measures
Summary of ALPINE 2/3 Histology Data (pairwise) ± |
|
Placebo(n=36) |
Aldafermin 0.3 mg(n=36) |
Aldafermin 1 mg(n=34) |
Aldafermin 3 mg(n=37) |
Fibrosis Improvement ≥1 Stage with No Worsening of NASH1 |
19% |
31% |
15% |
30% |
NASH Resolution with No Worsening of Fibrosis2 |
6% |
11% |
18% |
22%* |
Fibrosis Improvement and NASH Resolution3 |
3% |
11% |
9% |
14% |
*p<0.05± Analyzed using a pre-specified, pairwise statistical
analysis plan; per protocol includes only those patients who
completed both baseline and week 24 biopsies (n=143)
1 Defined as patients who have an improvement in liver fibrosis
by ≥1 stage with no worsening of NASH (no worsening of steatosis,
lobular inflammation or hepatocyte ballooning grade) from baseline
to W242 Defined as patients having a NAS score of 0 or 1 for
inflammation and 0 for ballooning, with no worsening of fibrosis
(no progression of NASH CRN fibrosis stage) from baseline to W24;
NAS refers to the non-alcoholic fatty liver disease (NAFLD)
activity score, which is comprised of three components: steatosis,
lobular inflammation and hepatocellular ballooning3 Defined as
patients who have an improvement in liver fibrosis by ≥1 stage AND
have a NAS score of 0 or 1 for inflammation and 0 for ballooning
and no worsening of steatosis at W24
“We want to thank our clinical development team, all of the
clinical trial investigators, clinical site staff and, most
importantly, the patients who participated in ALPINE 2/3. Clearly,
NASH continues to be an area of high unmet need, while proving to
be a difficult area for clinical development,” said Hsiao D. Lieu,
M.D., Chief Medical Officer at NGM. “We are obviously disappointed
by the outcome on fibrosis improvement in ALPINE 2/3. We plan to
continue enrollment in our ongoing 48-week Phase 2b ALPINE 4 study
to understand the profile of aldafermin in patients with F4 NASH
and compensated cirrhosis, which is a disease with a particularly
acute unmet need.”
ALPINE 2/3 Topline Non-Invasive Biomarker
Findings
Summary of ALPINE 2/3 Non-Invasive Biomarker Data+ |
Relative Change from Baseline in Patients’: |
Placebo(n=43) |
Aldafermin 0.3 mg(n=43) |
Aldafermin 1 mg(n=42) |
Aldafermin 3 mg(n=43) |
Liver Fat Content (LFC) by MRI-PDFF |
-15% |
-25% |
-38%*** |
-59%*** |
Alanine Aminotransferase (ALT) |
-8% |
-25% |
-40%*** |
-51%*** |
Aspartate Aminotransferase (AST) |
-6% |
-18% |
-30%** |
-39%*** |
Pro-C3 |
+4% |
-7%* |
-9%* |
-26%*** |
*p<0.05; **p<0.01; ***p<0.001+ Analyzed using a
pre-specified pairwise statistical analysis plan; intent-to-treat
(ITT) population (n=171)
ALPINE 2/3 Safety and Tolerability Findings
In the 24-week study (n=171), the overall safety profile of
aldafermin was consistent with prior studies and similar to that of
placebo. Patients treated with aldafermin at all three doses
studied in the trial demonstrated a comparable frequency of adverse
events versus placebo:
- any treatment-emergent adverse events (TEAEs) for placebo, 0.3
mg, 1 mg and 3 mg aldafermin were 84%, 70%, 83% and 88%,
respectively;
- serious adverse events (SAEs) for placebo, 0.3 mg, 1 mg and 3
mg aldafermin were 7%, 2%, 10% and 2%, respectively. None of the
reported SAEs were deemed related to treatment by the site
investigator;
- drug-related TEAEs leading to discontinuation for placebo, 0.3
mg, 1 mg and 3 mg aldafermin were 5%, 2%, 2% and 2%, respectively;
and
- there was one fatal adverse event in the 1 mg aldafermin arm,
which occurred 30 days after the last confirmed aldafermin dose and
was determined unrelated to treatment by the site
investigator.
As expected, given aldafermin’s mechanism of action as a potent
inhibitor of the classical bile acid synthesis pathway, a mean
LDL-cholesterol increase was observed, which was fully mitigated by
concomitant statin use.
Conference Call / Webcast Details
NGM will host a conference call and webcast with slide
presentation at 8:30 a.m. ET (5:30 a.m. PT) today. The live
conference call details are as follows: domestic (844) 873-0551;
international (602) 563-8472; and Passcode: 9393531. To access the
live webcast and slides, please visit the “Investors & Media”
section of NGM’s website at https://ir.ngmbio.com/. The
webcast will be archived for 30 days. Archived conference call
details are as follows: domestic (855) 859-2056; international
(404) 537-3406; and Passcode: 9393531. The archived conference call
will be available for 30 days.
Design of Phase 2b ALPINE 2/3 Study
ALPINE 2/3 was a multi-center, double-blind, randomized,
placebo-controlled Phase 2b study that evaluated the efficacy,
safety and tolerability of 0.3 mg, 1 mg and 3 mg once-daily
subcutaneous injections of aldafermin over 24 weeks of treatment.
The study enrolled 171 patients with biopsy-confirmed NASH with
F2-F3 liver fibrosis who were randomized 1:1:1:1 to receive
aldafermin 0.3 mg (n=43), aldafermin 1 mg (n=42), aldafermin 3 mg
(n=43) or placebo (n=43). The primary objective of the study was to
evaluate a dose-response showing fibrosis improvement >1 stage
with no worsening of NASH at week 24. Secondary endpoints included
NASH resolution, fibrosis improvement and NASH resolution, and
relative changes in LFC, ALT, AST and biomarkers of fibrosis at
week 24. Patients were also evaluated at week 30 following six
weeks off treatment for safety and non-invasive measures.
The primary endpoint, improvement in liver fibrosis ≥1 stage and
no worsening of steatohepatitis at week 24, was evaluated using the
MCP‑Mod (Multiple Comparison Procedure-Modeling) approach to assess
the dose response relationship in the ITT population. All remaining
analyses of the primary endpoint and of all secondary endpoints
were evaluated using a pre-specified pairwise approach and used the
Cochran-Mantel-Haenszel test. Continuous efficacy endpoints were
analyzed using analysis of covariance. Per protocol, patient liver
biopsies were performed at baseline screening and after 24 weeks of
treatment (n=143) and were read using the NASH CRN criteria by one
central, independent hepatopathologist who was blinded to patient
and treatment assignment.
Design of Ongoing Phase 2b ALPINE 4 Study
ALPINE 4 is a multi-center, double-blind, randomized,
placebo-controlled Phase 2b study evaluating the efficacy, safety
and tolerability of 0.3 mg, 1 mg and 3 mg once-daily subcutaneous
injections of aldafermin over 48 weeks of treatment. The study is
designed to enroll 160 patients with biopsy-confirmed NASH with F4
liver fibrosis and compensated cirrhosis. The primary endpoint is
to evaluate a dose-response showing fibrosis improvement >1
stage with no worsening of NASH at week 48. Secondary endpoints
include relative changes in ALT, AST, biomarkers of fibrosis and
Liver Stiffness Measure at week 48. Patients will also be evaluated
at week 54 following six weeks off treatment for safety and
non-invasive measures.
About Aldafermin
Aldafermin is an engineered analog of the human hormone FGF19
that is dosed once daily as a subcutaneous injection. NGM has
evaluated this wholly-owned therapeutic in over 650 healthy
volunteers and patients across multiple liver and metabolic
diseases, including more than 375 patients with NASH.
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,
ocular 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. All of our therapeutics have been
generated by our in-house discovery engine; today, we have six
active clinical-stage programs, including four in Phase 2 or 2b
studies, across three therapeutics areas. 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 “plans,” “will,” “toward,” “look forward,”
“continuing,” “anticipated,” “designed to,” “potential,” “aspire,”
“continue,” 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 NGM advancing its other ongoing
clinical programs and moving additional programs into the clinic;
the therapeutic potential of NGM621, NGM120, NGM707, NGM438 and
MK-3655, and of aldafermin in F4 NASH patients; the anticipated
initiation this year of Phase 1 studies for NGM707 and NGM438 for
the treatment of advanced solid tumors; the continuation by Merck
of the Phase 2b study of MK-3655; NGM’s plan to continue enrollment
in its Phase 2b ALPINE 4 study of aldafermin and the design of the
ALPINE 4 study; NGM’s aspiration to operate one of the most
productive R&D engines in the biopharmaceutical industry and to
deliver first-in-class medicines to patients; and other statements
that are not historical fact. 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
biopharmaceutical product development process and the uncertainty
of clinical success, including risks related to failure or delays
in successfully initiating, enrolling or completing clinical
studies; the risks that results obtained in clinical trials to date
may not be inductive of results obtained in ongoing or future
trials, including the risk that NGM’s ALPINE 4 study of aldafermin,
or Merck’s ongoing or future clinical studies of MK-3655, may show
that aldafermin and/or MK-3655 are not tolerable and effective
treatments for patients with NASH, particularly in light of the
failure to achieve the primary endpoint in the ALPINE 2/3 study of
aldafermin, and the risk that NGM’s other product candidates may
also not be tolerable and effective treatments in their planned
indications; the risks that Merck may elect not to extend the
research phase of NGM’s collaboration with Merck, and may otherwise
be unable to reach agreement with Merck on the terms of a modified
collaboration and, regardless of whether NGM and Merck reach
agreement on the terms of a modified collaboration, Merck will not
provide research funding for certain of NGM’s product candidates,
and NGM’s collaboration with Merck otherwise involves numerous
other risks, any of which could materially and adversely affect
NGM’s business and financial condition; the ongoing COVID-19
pandemic, which has adversely affected, and could materially and
adversely affect in the future, NGM’s business and operations,
including NGM’s clinical trials; the time-consuming and uncertain
regulatory approval process; NGM’s reliance on third-party
manufacturers for its product candidates; the sufficiency of NGM’s
cash resources and need for additional capital; and other risks and
uncertainties affecting NGM and its development programs, including
those discussed in the section titled “Risk Factors” in NGM’s
quarterly report on Form 10-Q for the quarter ended March 31, 2021
filed with the United States Securities and Exchange Commission
(SEC) on May 6, 2021 and future filings and reports that NGM makes
from time to time with the SEC. 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 Schwartzir@ngmbio.com |
Media Contact:Liz Melonemedia@ngmbio.com |
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