Beam Therapeutics Presents Preclinical Data Highlighting Utility of BEAM-302 to Correct an Alpha-1 Antitrypsin (AAT) Deficiency Disease-Causing Mutation
September 07 2023 - 10:00AM
Beam Therapeutics Inc. (Nasdaq: BEAM), a biotechnology company
developing precision genetic medicines through base editing, today
reported new preclinical data demonstrating the ability of its in
vivo drug candidate, BEAM-302, to directly correct the PiZ
mutation, the primary disease-causing mutation associated with
severe alpha-1 antitrypsin deficiency (AATD). The data are featured
in an oral presentation titled “BEAM-302: Targeting AATD Liver and
Lung Disease with Base Editing” at the Alpha-1 Antitrypsin
Deficiency 2023 Meeting in Naples, Italy.
“AATD, one of the most common genetic conditions, predominantly
results in lung and liver disease, and we believe base editing is
uniquely suited to address the underlying drivers of disease
progression in both organs,” said Giuseppe Ciaramella, Ph.D.,
president of Beam. “In today’s presentation, we shared – for the
first time – a full summary of preclinical in vivo data for
BEAM-302, our lead candidate for the potential treatment of AATD.
In two rodent models of AATD, one-time treatment at clinically
relevant dose levels of BEAM-302 led to significant increases in
circulating total corrected AAT and corresponding reductions in
circulating mutant PiZ AAT. These data support the continued
advancement of BEAM-302 as a potential treatment option for
AATD-related lung and liver disease, and we remain focused on the
planned submission of our regulatory application in the first
quarter of next year.”
AATD is caused by mutations in the SERPINA1 gene, with >95%
of severe clinical cases homozygous for the PiZ mutation (known as
the PiZZ genotype). BEAM-302 is a liver-targeting
lipid-nanoparticle (LNP) formulation of base editing reagents
designed to precisely correct the PiZ mutation, a single-letter
genetic error. A one-time A-to-G correction of the PiZ mutation
with Beam’s adenine base editor has the potential to simultaneously
reduce the aggregation of mutant, misfolded AAT protein that causes
toxicity to the liver and increase circulating levels of corrected
and functional AAT protein, thus addressing the underlying
pathophysiology of both the lung and liver disease. Correction is
expected to be durable based on preclinical evidence to date.
Importantly, because the native AAT gene would be corrected in its
normal genetic location, AAT levels would be anticipated to
increase in response to inflammation or infection, an important
aspect of normal AAT function, which does not occur with currently
approved protein replacement therapies.
BEAM-302 was evaluated in two preclinical species: an NSG-PiZ
mouse model of AATD carrying multiple copies of the human PiZ
allele and a novel humanized PiZ rat model developed by Beam
scientists in which the normal rat AAT is replaced with human
mutated PiZ AAT.
- Treatment with a single dose of BEAM-302 induced dose-dependent
correction of the PiZ mutation. Clinically relevant doses up to
1mpk resulted in correction of up to 39% and 49% of liver DNA in
rats and mice, respectively.
- Relative to pre-dose values, editing with BEAM-302 yielded
two-times higher levels of total serum AAT and a 70% decrease in
serum Z-AAT in rats. Editing with BEAM-302 yielded four-times
higher levels of total serum AAT, and a 90% decrease in serum Z-AAT
in mice.
- Relative to pre-dose values, editing with BEAM-302 yielded two-
and three-times higher functional AAT in rats and mice,
respectively, as indicated by the increased capacity of serum
samples to inhibit human neutrophil elastase.
- Experiments with research-grade BEAM-302 demonstrated a
reduction in toxic liver aggregates, also referred to as liver
polymers.
These findings support the potential of BEAM-302 to efficiently
correct the disease-causal PiZ mutation after a single dose and
potentially address both the liver and lung disease associated with
AATD.
Beam plans to submit a regulatory application for authorization
to initiate clinical trials of BEAM-302 in the first quarter of
2024.
About Alpha-1 Antitrypsin Deficiency (AATD)AATD
is an inherited genetic disorder that causes early onset emphysema
and liver disease. A severe form of AATD arises when a patient has
the p.Glu366Lys point mutation in both copies of the SERPINA1 gene,
which results in the expression of the pathogenic PiZ variant of
alpha-1 antitrypsin (Z-AAT) that misfolds and aggregates inside
liver cells causing liver damage, rather than being secreted. The
inability of liver cells to secrete Z-AAT results in roughly
10%-15% of the normal level of circulating AAT, which is a potent
inhibitor of proteases such as neutrophil elastase. As a
consequence, the lung is left unprotected from neutrophil elastase,
resulting in progressive, destructive changes in the lung, such as
emphysema, which can result in the need for lung transplants. The
Z-AAT protein that accumulates in the liver, causes liver
inflammation and cirrhosis, which can ultimately result in liver
failure or cancer requiring patients to undergo a liver transplant.
In addition, circulating Z-AAT aggregates (called circulating Z
polymers) have increasingly been recognized as a factor
contributing to disease severity in both the lungs as well as the
liver. It is estimated that approximately 60,000 individuals in the
United States have two copies of the Z allele, known as the PiZZ
genotype. There are currently no curative treatments approved for
patients with AATD.
About Beam TherapeuticsBeam Therapeutics
(Nasdaq: BEAM) is a biotechnology company committed to establishing
the leading, fully integrated platform for precision genetic
medicines. To achieve this vision, Beam has assembled a platform
that includes a suite of gene editing and delivery technologies and
is in the process of building internal manufacturing capabilities.
Beam’s suite of gene editing technologies is anchored by base
editing, a proprietary technology that is designed to enable
precise, predictable and efficient single base changes, at targeted
genomic sequences, without making double-stranded breaks in the
DNA. This has the potential to enable a wide range of therapeutic
editing strategies that Beam is using to advance a diversified
portfolio of base editing programs. Beam is a values-driven
organization committed to its people, cutting-edge science, and a
vision of providing life-long cures to patients suffering from
serious diseases.
Cautionary Note Regarding Forward-Looking
StatementsThis press release contains forward-looking
statements within the meaning of the Private Securities Litigation
Reform Act of 1995. Investors are cautioned not to place undue
reliance on these forward-looking statements, including, but not
limited to, statements related to: the therapeutic applications and
potential of our technology, including with respect to AATD; our
plans, and anticipated timing, to submit a regulatory application
for authorization to initiate clinical trials of BEAM-302; and our
ability to develop life-long, curative, precision genetic medicines
for patients through base editing. Each forward-looking statement
is subject to important risks and uncertainties that could cause
actual results to differ materially from those expressed or implied
in such statement, including, without limitation, risks and
uncertainties related to: our ability to develop, obtain regulatory
approval for, and commercialize our product candidates, which may
take longer or cost more than planned; our ability to raise
additional funding, which may not be available; our ability to
obtain, maintain and enforce patent and other intellectual property
protection for our product candidates; the potential impact of
pandemics and other health emergencies, including their impact on
the global supply chain; the uncertainty that our product
candidates will receive regulatory approval necessary to initiate
human clinical studies; that preclinical testing of our product
candidates and preliminary or interim data from preclinical studies
and clinical trials may not be predictive of the results or success
of ongoing or later clinical trials; that initiation and enrollment
of, and anticipated timing to advance, our clinical trials may take
longer than expected; that our product candidates may experience
manufacturing or supply interruptions or failures; risks related to
competitive products; and the other risks and uncertainties
identified under the headings “Risk Factors Summary” and “Risk
Factors” in our Annual Report on Form 10-K for the year ended
December 31, 2022, our Quarterly Report on Form 10-Q for the
quarter ended March 31, 2023, our Quarterly Report on Form 10-Q for
the quarter ended June 30, 2023, and in any subsequent filings with
the Securities and Exchange Commission. These forward-looking
statements speak only as of the date of this press release. Factors
or events that could cause our actual results to differ may emerge
from time to time, and it is not possible for us to predict all of
them. We undertake no obligation to update any forward-looking
statement, whether as a result of new information, future
developments or otherwise, except as may be required by applicable
law.
Contacts: Investors:Chelcie ListerTHRUST
Strategic Communicationschelcie@thrustsc.com
Media:Dan Budwick1ABdan@1abmedia.com
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