Verve Therapeutics, Inc., a clinical-stage biotechnology company
pioneering a new approach to the care of cardiovascular disease
with single-course gene editing medicines, today announced first
human proof-of-concept data for in vivo base editing from the
ongoing heart-1 phase 1b clinical trial of VERVE-101. Treatment
with VERVE-101 led to dose-dependent reductions of disease-causing
low-density lipoprotein cholesterol (LDL-C) in people living with
heterozygous familial hypercholesterolemia (HeFH), a
life-threatening inherited disease characterized by lifelong
elevations in blood LDL-C and accelerated atherosclerotic
cardiovascular disease (ASCVD). VERVE-101 is an investigational, in
vivo base editing medicine designed to be a single-course treatment
that inactivates the PCSK9 gene in the liver to durably
lower blood LDL-C.
“Of the more than three million people with HeFH in the U.S. and
Europe, very few are currently at LDL-C goal, due in part to a care
model that requires lifetime therapies. This model puts a strain on
the healthcare system and is failing our patients,” said Deepak L.
Bhatt, M.D., M.P.H., Director of the Mount Sinai Fuster Heart
Hospital and the Dr. Valentin Fuster Professor of Cardiovascular
Medicine at the Icahn School of Medicine in New York. “I am
very encouraged by the initial data from the heart-1 trial that
demonstrated the potential for single-course gene editing as a new
approach to treat patients with HeFH. The data showed that
VERVE-101 could meaningfully and durably lower LDL-C in these
patients. This trial enrolled patients with advanced coronary
disease, and the cardiovascular adverse events were consistent with
what might be expected in this patient population. We’re at an
exciting moment for cardiovascular prevention where the management
of ASCVD may fundamentally change.”
heart-1 Clinical Trial Designheart-1 is an
open-label, phase 1b clinical trial in patients living with HeFH,
established ASCVD and uncontrolled hypercholesterolemia. The trial
is designed to evaluate the safety and tolerability of VERVE-101,
with additional analyses for pharmacokinetics and pharmacodynamic
reductions in blood PCSK9 protein and LDL-C. Single doses of 0.1
mg/kg (n=3), 0.3 mg/kg (n=3), 0.45 mg/kg (n=3), and 0.6 mg/kg (n=1)
of VERVE-101 have been administered via intravenous infusion.
Initial safety data reported are from all ten patients enrolled as
of a data cut-off date of October 16, 2023. One patient who
received a 0.45 mg/kg dose had not reached day 28 as of the data
cut-off date and is not included in the efficacy analysis.
Patients included in both the safety and efficacy analyses have
had a high burden of coronary artery disease, consistent with the
2022 U.S. Food and Drug Administration (FDA) draft guidance for
human genome editing products1 that suggests a first-in-human trial
include patients with severe, advanced disease. Nine patients have
had prior coronary revascularizations with either coronary artery
bypass grafting or coronary stenting procedures and four have had
prior myocardial infarctions. With a mean screening LDL-C of 193
mg/dL, none of the patients were at LDL-C goal on maximally
tolerated oral lipid-lowering therapy.
heart-1 Efficacy Analysis Following a single
infusion of VERVE-101, dose-dependent reductions in pharmacodynamic
measures of blood PCSK9 protein levels were observed, suggesting
successful editing at the intended genomic target. Dose-dependent
LDL-C reductions, a validated measure of clinical efficacy for this
patient population, were observed one month after treatment.
In the interim dataset, six patients were treated at
sub-therapeutic doses (0.1 mg/kg and 0.3 mg/kg) and three patients
were treated at potentially therapeutic doses (0.45 mg/kg and 0.6
mg/kg). The two patients treated with 0.45 mg/kg of VERVE-101 had a
time-averaged blood PCSK9 protein reduction of 59% and 84%. The
patient treated with 0.6 mg/kg of VERVE-101 had a time-averaged
blood PCSK9 protein reduction of 47%.
The two patients treated with 0.45 mg/kg of VERVE-101 had a
time-averaged LDL-C reduction of 39% and 48%. The patient treated
with 0.6 mg/kg of VERVE-101 had a time-averaged LDL-C reduction of
55%. In this single participant in the highest dose cohort, the 55%
reduction in LDL-C was durable out to 180 days, with follow-up
ongoing.
Blood PCSK9 protein and LDL-C reductions are quantified as
percent change from baseline using the time-weighted average from
day 28 through last available follow-up.
heart-1 Safety and TolerabilityThe safety
profile observed in the heart-1 trial supports continued
development of VERVE-101, and the adverse events have been
consistent with the severe, advanced ASCVD patient population
enrolled.
VERVE-101 was well-tolerated in the two lower dose cohorts, with
no treatment-related adverse events observed. In the two higher
dose cohorts, treatment-related adverse events were observed,
including transient, mild or moderate infusion reactions and
transient, asymptomatic increases in liver transaminases with mean
bilirubin levels below the upper limit of normal. All infusion
reactions and liver transaminase elevations resolved without
clinical sequelae.
Two patients experienced serious adverse events, which were each
cardiovascular events in the context of severe underlying ASCVD.
One patient dosed in the 0.3 mg/kg cohort had a fatal cardiac
arrest approximately five weeks after treatment due to underlying
ischemic heart disease, which was determined by the investigator
and independent data and safety monitoring board (DSMB) to be not
related to treatment.
One patient dosed in the 0.45 mg/kg cohort experienced a
myocardial infarction (Grade 3) the day after treatment. The event
was considered potentially related to treatment due to the
proximity to dosing. The event occurred in the setting of unstable
chest pain symptoms prior to dosing that were unreported to
investigators. Coronary angiography taken after the event showed
critical left main equivalent coronary artery disease. The same
patient also experienced non-sustained ventricular tachycardia
(Grade 2) more than four weeks after dosing, which was determined
to be unrelated to treatment.
All safety events were reviewed with the independent DSMB who
recommended continuation of trial enrollment with no protocol
changes required.
“We are excited to have reached this milestone of positive
first-in-human data supporting the significant potential for in
vivo liver gene editing as a treatment for patients with HeFH.
VERVE-101 is the first in vivo base editor to be evaluated in the
clinic,” said Sekar Kathiresan, M.D., co-founder and chief
executive officer of Verve. “This milestone is only possible
because of the incredible patients, families, and physicians who
are participating in our study, and the highly talented team at
Verve in their steadfast commitment to bringing VERVE-101
forward.”
“Our goal is to fundamentally disrupt the chronic care model for
cardiovascular disease and provide a new single-course treatment
option for patients,” said Andrew Bellinger, M.D., Ph.D., chief
scientific officer of Verve. “These data confirm our hypothesis
that a single-course gene editing medicine has the potential to
induce meaningful and durable reductions in LDL-C when administered
at therapeutic doses. Based on the favorable initial findings in
the heart-1 trial, we are continuing to enroll patients in the
potentially therapeutic dose cohorts. And with the recent clearance
of the U.S. investigational new drug (IND) application for
VERVE-101, we look forward to expanding our clinical trial into the
U.S.”
Next StepsThe heart-1 trial is enrolling
patients in the 0.45 mg/kg and 0.6 mg/kg cohorts in the United
Kingdom and New Zealand. With the recent clearance of the IND
application by the FDA for VERVE-101, Verve plans to activate and
open U.S. sites. In 2024, the company plans to select a single dose
from the dose escalation phase, initiate an expansion cohort, and
complete this expansion cohort of the heart-1 clinical trial. In
the first half of 2024, the company plans to initiate a phase 1
clinical trial of VERVE-102, subject to regulatory clearance.
VERVE-102 is an in vivo base editing medicine that aims to
inactivate the PCSK9 gene in a similar way to VERVE-101. VERVE-101
and VERVE-102 share an identical guide RNA targeting PCSK9 as well
as similar messenger RNA expressing an adenine base editor;
however, VERVE-102 is delivered using the company’s proprietary
GalNAc-LNP delivery technology. Following completion of the heart-1
trial and the VERVE-102 trial, Verve plans to initiate a
randomized, placebo-controlled phase 2 clinical trial of either
VERVE-101 or VERVE-102 in 2025.
Conference Call InformationVerve will host a
webcast investor event today, November 12 at 6:30 p.m. ET to review
the heart-1 clinical trial data. The event can be accessed under
Events in the Investors section of the company's website at
www.VerveTx.com. The archived webcast will be available on the
company’s website beginning approximately two hours after the
event.
About heart-1 and HeFHheart-1 is an open-label
phase 1b clinical trial designed to enroll adult patients with
heterozygous familial hypercholesterolemia (HeFH) who have
established atherosclerotic cardiovascular disease (ASCVD) to
evaluate the safety and tolerability of VERVE-101 administration,
with additional analyses for pharmacokinetics and reductions in
blood PCSK9 protein and low-density lipoprotein cholesterol
(LDL-C).
HeFH is a prevalent and potentially life-threatening subtype of
ASCVD. High cumulative life-long exposure to LDL-C drives the
development of atherosclerotic plaque that results in the hardening
of arteries seen in ASCVD. The relationship between lowering of
cumulative LDL-C exposure and reduction in the risk of ASCVD is
among the best understood relationships in medicine.
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 initial three
programs – VERVE-101, VERVE-102, and VERVE-201 – target genes that
have been extensively validated as pharmacologic targets for
lowering low-density lipoprotein cholesterol (LDL-C), a root cause
of cardiovascular disease. 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 atherosclerotic cardiovascular
disease (ASCVD) patients not at LDL-C goal on oral therapy.
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 ultimately to treat patients with
refractory hypercholesterolemia. For more information, please visit
www.VerveTx.com.
Cautionary Note Regarding Forward Looking
Statements This 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 the safety,
tolerability and potential benefits of VERVE-101; the company’s
timing and ability to enroll patients in its ongoing heart-1 trial
and activate clinical trial sites in the U.S.; the expected timing
of the expansion cohort of VERVE-101; the receipt of regulatory
clearances and timing of initiating the phase 1 clinical trial of
VERVE-102 and phase 2 clinical trial for the company’s PCSK9
program; and the company’s strategic plans and prospects. 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 Kosikowski
1ABashlea@1abmedia.com
1 https://www.fda.gov/media/156894/download
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