Verve Therapeutics, a clinical-stage biotechnology company
pioneering a new approach to the care of cardiovascular disease
with single-course gene editing medicines, today announced updates
from the Heart-1 Phase 1b clinical trial of VERVE-101 and clearance
of its Clinical Trial Applications (CTAs) by the U.K. Medicines and
Healthcare products Regulatory Agency (MHRA) and Health Canada for
VERVE-102, with the Heart-2 Phase 1b clinical trial expected to
initiate in the second quarter of this year.
VERVE-101 is being evaluated in the Heart-1 Phase 1b clinical
trial with trial endpoints of safety and tolerability as well as
changes in blood PCSK9 protein and low-density lipoprotein
cholesterol (LDL-C) levels in patients living with heterozygous
familial hypercholesterolemia (HeFH), established atherosclerotic
cardiovascular disease (ASCVD), and uncontrolled
hypercholesterolemia. Six participants have been dosed at 0.45
mg/kg of VERVE-101, with a total of 13 participants dosed in the
study. For the first five participants in the 0.45 mg/kg cohort
with follow-up to at least 28 days, VERVE-101 demonstrated
time-averaged LDL-C reductions ranging from 21% to 73%, and
averaging 46% (as of a data cut-off date of March 18, 2024). In the
two patients with the longest follow-up in the 0.45 mg/kg or 0.6
mg/kg cohorts, LDL-C lowering has been durable out to 270 days,
with follow-up ongoing.
However, the sixth participant treated in the 0.45 mg/kg cohort
experienced a Grade 3 drug-induced transient increase in serum
alanine aminotransferase (ALT) as well as a serious adverse event
of Grade 3 drug-induced thrombocytopenia within the first four days
after dosing. The participant did not experience any bleeding or
other symptoms related to the laboratory abnormalities, and the
abnormalities resolved fully within a few days.
In light of such observed laboratory abnormalities associated
with VERVE-101, Verve, in consultation with the study’s independent
data and safety monitoring board (DSMB), has decided to pause
enrollment in the Heart-1 clinical trial. Verve is conducting an
investigation into the laboratory abnormalities and based on those
results, expects to work with regulatory authorities to define a
path forward for VERVE-101. These safety events were reported to
the U.S. Food and Drug Administration (FDA), MHRA, and the New
Zealand Medicines and Medical Devices Safety Authority (Medsafe).
The VERVE-101 Investigational New Drug Application (IND) and other
CTAs remain active.
Verve is now prioritizing the development of VERVE-102 and the
initiation of the Heart-2 clinical trial. VERVE-102 uses the same
base editor and guide RNA for PCSK9 but a different lipid
nanoparticle (LNP) delivery system than VERVE-101. VERVE-102 has
two principal differences from VERVE-101. First, VERVE-102 includes
a different ionizable lipid from VERVE-101. VERVE-102’s ionizable
lipid has already been used in third-party clinical trials of gene
editing product candidates and has been well-tolerated in these
trials. Second, the incorporation of GalNAc allows the LNP in
VERVE-102 to access liver cells using either the asialoglycoprotein
receptor (ASGPR) or the low-density lipoprotein receptor (LDLR).
Verve has received regulatory clearances for the Heart-2 clinical
trial in the U.K. and Canada and plans to initiate the Heart-2
clinical trial in patients with HeFH or premature coronary artery
disease in the second quarter of 2024.
“The Heart-1 clinical trial continues to support
proof-of-concept for in vivo base editing of the PCSK9 gene in the
liver, with a meaningful and durable lowering of LDL-C,” said Sekar
Kathiresan, M.D., co-founder and chief executive officer of Verve.
“However, at potentially therapeutic dose levels of VERVE-101, we
have observed certain asymptomatic laboratory abnormalities, which
we believe are attributable to the LNP delivery system. The safety
of patients in our clinical trials is of the utmost importance. We
plan to further investigate the laboratory abnormalities observed
in the Heart-1 clinical trial in order to inform the next steps for
VERVE-101. At this time, we are prioritizing the initiation of the
Heart-2 clinical trial of VERVE-102 due to its proximity to the
clinic and its use of a different LNP that incorporates an
ionizable lipid which has been well-tolerated in third-party
clinical trials. We are grateful to our study participants and to
our investigators, who share our belief in the promise of
single-course gene editing medicines for the treatment of
cardiovascular disease. We look forward to initiating the Heart-2
clinical trial in the second quarter of this year.”
About VERVE-101VERVE-101 is a novel,
investigational gene editing medicine designed to be a single
course treatment that permanently turns off
the PCSK9 gene in the liver to reduce disease-driving
low-density lipoprotein cholesterol (LDL-C). VERVE-101 is being
developed initially as a treatment for patients with heterozygous
familial hypercholesterolemia (HeFH), a prevalent and potentially
life-threatening subtype of atherosclerotic cardiovascular disease
(ASCVD). VERVE-101 consists of messenger RNA expressing an adenine
base editor and an optimized guide RNA targeting
the PCSK9 gene packaged in an engineered lipid
nanoparticle.
About VERVE-102VERVE-102 is a novel,
investigational gene editing medicine designed to be a single
course treatment that permanently turns off
the PCSK9 gene in the liver to reduce disease-driving
low-density lipoprotein cholesterol (LDL-C), similar to VERVE-101.
VERVE-102 is being developed initially as a treatment for patients
with heterozygous familial hypercholesterolemia (HeFH) or premature
coronary artery disease (CAD). VERVE-102 consists of messenger RNA
expressing an adenine base editor and an optimized guide RNA
targeting the PCSK9 gene, identical to VERVE-101.
However, VERVE-102 uses a different delivery system than VERVE-101,
which includes a different ionizable lipid and Verve’s proprietary
GalNAc liver-targeting ligand.
About Heart-1Heart-1 is an open-label Phase 1b
clinical trial designed to enroll adult patients with heterozygous
familial hypercholesterolemia (HeFH), established atherosclerotic
cardiovascular disease (ASCVD) and uncontrolled
hypercholesterolemia to evaluate the safety and tolerability of
VERVE-101 administration, with additional analyses for
pharmacokinetics and changes in blood PCSK9 protein and low-density
lipoprotein cholesterol (LDL-C) levels. The single ascending dose
portion of the trial has consisted of four dose levels: 0.1 mg/kg
[n=3], 0.3 mg/kg [n=3], 0.45 mg/kg [n=6], and 0.6 mg/kg [n=1].
About Heart-2Heart-2 is an open-label Phase 1b
clinical trial designed to enroll adult patients with heterozygous
familial hypercholesterolemia (HeFH) or premature coronary artery
disease (CAD) who require additional lowering of low-density
lipoprotein cholesterol (LDL-C) to evaluate the safety and
tolerability of VERVE-102 administration, with additional analyses
for pharmacokinetics and changes in blood PCSK9 protein and LDL-C
levels. Initiation of the Heart-2 clinical trial is expected in the
second quarter of 2024.
About Verve Therapeutics Verve
Therapeutics, Inc. (Nasdaq: VERV) is a clinical-stage genetic
medicines company pioneering a new approach to the care of
cardiovascular disease, potentially transforming treatment from
chronic management to single-course gene editing medicines. The
company’s lead programs – VERVE-101, VERVE-102, and VERVE-201 –
target genes that have been extensively validated as targets for
lowering low-density lipoprotein cholesterol (LDL-C), a root cause
of atherosclerotic cardiovascular disease (ASCVD). VERVE-101 and
VERVE-102 are designed to permanently turn off
the PCSK9 gene in the liver and are being developed
initially for heterozygous familial hypercholesterolemia (HeFH) and
ultimately to treat patients with established ASCVD who continue to
be impacted by high LDL-C levels. VERVE-201 is designed to
permanently turn off the ANGPTL3 gene in the liver and is
initially being developed for homozygous familial
hypercholesterolemia (HoFH) and for refractory hypercholesterolemia
where patients still have high LDL-C despite treatment with
maximally-tolerated standard of care therapies. For more
information, please visit www.VerveTx.com.
Cautionary Note Regarding Forward Looking
StatementsThis press release contains “forward-looking
statements” within the meaning of the Private Securities Litigation
Reform Act of 1995 that involve substantial risks and
uncertainties, including statements regarding expectations for the
company’s Heart-1 clinical trial, including the company’s
assessment of the laboratory abnormalities observed in the trial
and the company’s interactions with regulatory authorities
regarding VERVE-101; the expected timing of initiating the clinical
trial of VERVE-102; and the potential advantages and therapeutic
potential of the company’s PCSK9 program. All statements, other
than statements of historical facts, contained in this press
release, including statements regarding the company’s strategy,
future operations, future financial position, prospects, plans and
objectives of management, are forward-looking statements. The words
“anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,”
“intend,” “may,” “plan,” “potential,” “predict,” “project,”
“should,” “target,” “will,” “would” and similar expressions are
intended to identify forward-looking statements, although not all
forward-looking statements contain these identifying words. Any
forward-looking statements are based on management’s current
expectations of future events and are subject to a number of risks
and uncertainties that could cause actual results to differ
materially and adversely from those set forth in, or implied by,
such forward-looking statements. These risks and uncertainties
include, but are not limited to, risks associated with the
company’s limited operating history; the company’s ability to
timely submit and receive approvals of regulatory applications for
its product candidates; advance its product candidates in clinical
trials; initiate, enroll and complete its ongoing and future
clinical trials on the timeline expected or at all; correctly
estimate the potential patient population and/or market for the
company’s product candidates; replicate in clinical trials positive
results found in preclinical studies and/or earlier-stage clinical
trials of VERVE-101, VERVE-102, and VERVE-201; advance the
development of its product candidates under the timelines it
anticipates in current and future clinical trials; obtain, maintain
or protect intellectual property rights related to its product
candidates; manage expenses; and raise the substantial additional
capital needed to achieve its business objectives. For a discussion
of other risks and uncertainties, and other important factors, any
of which could cause the company’s actual results to differ from
those contained in the forward-looking statements, see the “Risk
Factors” section, as well as discussions of potential risks,
uncertainties and other important factors, in the company’s most
recent filings with the Securities and Exchange Commission and in
other filings that the company makes with the Securities and
Exchange Commission in the future. In addition, the forward-looking
statements included in this press release represent the company’s
views as of the date hereof and should not be relied upon as
representing the company’s views as of any date subsequent to the
date hereof. The company anticipates that subsequent events and
developments will cause the company’s views to change. However,
while the company may elect to update these forward-looking
statements at some point in the future, the company specifically
disclaims any obligation to do so.
Investor ContactJen RobinsonVerve Therapeutics,
Inc.jrobinson@vervetx.com
Media ContactAshlea
Kosikowski1ABashlea@1abmedia.com
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