Wave Life Sciences Announces Proof-of-Concept Preclinical Data for ADAR Editing Program in Alpha-1 Antitrypsin Deficiency
June 02 2021 - 4:52PM
Wave Life Sciences Ltd. (Nasdaq: WVE), a clinical-stage genetic
medicines company committed to delivering life-changing treatments
for people battling devastating diseases, today announced the first
proof-of-concept preclinical data for its ADAR (adenosine
deaminases acting on RNA)-mediated RNA editing (“ADAR editing”)
program in alpha-1 antitrypsin deficiency (AATD). Up to 40 percent
editing of human SERPINA1 Z-allele mRNA in the liver was observed
at a single timepoint, which resulted in a therapeutically
meaningful increase in circulating functional wild-type AAT
protein. This initial in vivo study utilized Wave’s proprietary
transgenic mouse model, which has both the human SERPINA1 Z-allele
as well as human ADAR that is expressed comparably to human cells.
“These findings are a critical contribution to the genetic
medicines field, as they represent the first proof-of-concept in
vivo data for RNA editing using endogenous ADAR enzymes in AATD.
They also reinforce Wave’s leadership position in the RNA editing
field, as we continue to observe meaningful and significant levels
of editing in animal models, including in mice and NHPs, which
paves the way for translating this technology to the clinic,” said
Paul Bolno, President and Chief Executive Officer of Wave Life
Sciences. “Wave’s approach to RNA editing using endogenous ADAR and
our AATD program have advanced quickly, with the team demonstrating
immense creativity and tenacity to reach this important milestone.
We look forward to presenting additional in vivo data in the second
half of this year and continuing our progress towards the
clinic.”
Wave’s AATD program, the first to utilize its ADAR editing
modality, uses GalNAc-conjugated oligonucleotides to correct the
single base mutation in mRNA derived from the SERPINA1 Z allele.
ADAR editing provides a simple and efficient approach to treating
AATD by simultaneously reducing aggregation of mutated, misfolded
alpha-1 antitrypsin protein (Z-AAT) and increasing circulating
levels of wild-type protein (M-AAT), thus having the potential to
address both the lung and liver manifestations of the disease while
avoiding risk from permanent off-target changes to the DNA. Wave is
initially focusing on homozygous “ZZ” patients who have the highest
risk of disease and where RNA editing may result in a heterozygous
“MZ” phenotype, which would result in a substantially lower risk of
disease.
The goals of Wave’s first in vivo proof-of-concept study were:
1) achieve editing of SERPINA1 Z allele mRNA in the liver at levels
that approach the MZ phenotype; 2) restore human M-AAT protein in
serum; and 3) demonstrate functionality of the restored human M-AAT
protein. Results were analyzed at a single timepoint (day 7) and
demonstrated:
- Up to 40 percent editing of Z allele mRNA was observed in the
liver of Wave’s transgenic human ADAR mice, correlating with levels
nearing correction to an MZ phenotype.
- Editing was highly specific with no bystander edits.
- A three-fold increase in circulating human AAT compared with
placebo was observed, similar to the fold difference seen between
ZZ and MZ patients.
- 75 percent of circulating AAT protein was confirmed as M-AAT.
This also suggests a reduction of Z-AAT in the liver and
serum.
- Confirmation of functionality of the M-AAT protein using a
neutrophil elastase inhibition assay.
Wave’s preclinical studies for its AATD program are ongoing and
additional data on durability and dose response are expected in the
second half of 2021. Wave also continues to evaluate ADAR editing
compounds for other disease targets, leveraging its proprietary
mouse model which expresses human ADAR and is crossed with
disease-specific mouse models.
These proof-of-concept preclinical data were also presented at
the Jefferies Virtual Healthcare Conference on June 2, 2021 and the
presentation can be viewed by visiting the investor relations page
of the Wave Life Sciences corporate website at
http://ir.wavelifesciences.com.
About ADAR EditingWave’s novel RNA editing
platform capability uses endogenous ADAR (adenosine deaminases
acting on RNA) enzymes via free uptake of A-to-I (G) RNA editing
oligonucleotides. ADAR editing may provide an attractive
alternative to DNA editing, as the effects of RNA editing are both
reversible and titratable, and avoid potential long-term risks
associated with permanent off-target genome edits. Wave’s ADAR
editing modality also offers potential advantages over other RNA
editing approaches, including the use of short oligonucleotides
that are freely taken up by cells and do not require viral or
nanoparticle delivery. Wave’s design also reduces the risk of
immunogenicity from exogenous proteins and off-target effects.
About PRISM™PRISM is Wave Life Sciences’
proprietary discovery and drug development platform that enables
genetically defined diseases to be targeted with stereopure
oligonucleotides across multiple therapeutic modalities, including
silencing, splicing and editing. PRISM combines the company’s
unique ability to construct stereopure oligonucleotides with a deep
understanding of how the interplay among oligonucleotide sequence,
chemistry and backbone stereochemistry impacts key pharmacological
properties. By exploring these interactions through iterative
analysis of in vitro and in vivo outcomes and machine
learning-driven predictive modeling, the company continues to
define design principles that are deployed across programs to
rapidly develop and manufacture clinical candidates that meet
pre-defined product profiles.
About Wave Life SciencesWave Life Sciences
(Nasdaq: WVE) is a clinical-stage genetic medicines company
committed to delivering life-changing treatments for people
battling devastating diseases. Wave aspires to develop
best-in-class medicines across multiple therapeutic modalities
using PRISM, the company’s proprietary discovery and drug
development platform that enables the precise design, optimization
and production of stereopure oligonucleotides. Driven by a resolute
sense of urgency, the Wave team is targeting a broad range of
genetically defined diseases so that patients and families may
realize a brighter future. To find out more, please visit
www.wavelifesciences.com and follow Wave on Twitter
@WaveLifeSci.
Forward-Looking StatementsThis press release
contains forward-looking statements within the meaning of the
Private Securities Litigation Reform Act of 1995, as amended,
including, without limitation, the potential significance of Wave’s
first proof-of-concept in vivo data for RNA editing with respect to
AATD and the genetic medicines field; the anticipated plans, type
of data and timing from Wave’s ongoing preclinical studies for its
AATD program; Wave’s evaluation of additional ADAR-amenable disease
targets. The words “may,” “will,” “could,” “would,” “should,”
“expect,” “plan,” “anticipate,” “intend,” “believe,” “estimate,”
“predict,” “project,” “potential,” “continue,” “target” and similar
expressions are intended to identify forward-looking statements,
although not all forward-looking statements contain these
identifying words. Any forward-looking statements in this press
release are based on management's current expectations and beliefs
and are subject to a number of risks, uncertainties and important
factors that may cause actual events or results to differ
materially from those expressed or implied by any forward-looking
statements contained in this press release, including, without
limitation, the risks and uncertainties described in the section
entitled “Risk Factors” in Wave’s most recent Annual Report on Form
10-K filed with the Securities and Exchange Commission (SEC), as
amended, and in other filings Wave makes with the SEC from time to
time. Wave undertakes no obligation to update the information
contained in this press release to reflect subsequently occurring
events or circumstances.
Investor Contact:Kate
Rausch617-949-4827krausch@wavelifesci.com
Media Contact:Alicia
Suter617-949-4817asuter@wavelifesci.com
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