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WAVE LIFE SCIENCES
2023 ANNUAL REPORT
2023
Annual Report
6/7/24 8:39 AM
Dear Wave Life Sciences Shareholders,
I am pleased to share our 2023 Annual Report, which highlights progress made last year toward
becoming the leading RNA medicines company.
2023 was a year of execution and tremendous progress for Wave as we advanced and expanded our
differentiated pipeline of novel RNA medicines, further enhanced the broad capabilities of our
PRISMTM discovery and development platform, and made significant progress in the first full year of our
collaboration with GSK. These achievements underscore the far-reaching potential of our multimodal
platform to reimagine what   s possible for human health and pioneer medicines that truly change
people   s lives.
We are leading in RNA editing with our ongoing RestorAATion clinical program for WVE-006 in alpha-1
antitrypsin deficiency (AATD), the industry   s first RNA editing candidate to enter a human clinical trial.
The initiation of this clinical program last year also resulted in the achievement of a $20 million milestone
under our collaboration with GSK. Beyond WVE-006, we unveiled a pipeline of wholly owned RNA
editing programs that we are advancing across a range of potentially high-impact GalNAc hepatic and
extra-hepatic targets, as well as our proprietary    edit-verse,    which we are using to identify new targets
that we believe will leverage easily accessible biomarkers, offer efficient path to proof-of-concept in
humans, address diseases of high unmet need, and represent meaningful commercial opportunities.
In 2023, we made significant progress translating clinical genetics into medicines and unlocking novel
targets for prevalent diseases. We introduced our wholly owned GalNAC-siRNA INHBE program for
the treatment of obesity at our annual Fall R&D Day. Preclinical data from this program support a
potential best-in-class profile and the ability to overcome limitations of GLP-1 agonists. Beyond our
INHBE program, we further demonstrated the broad potential of our siRNA capabilities with the
publication of positive preclinical data in Nucleic Acids Research demonstrating unprecedented Ago2
loading following a single dose that led to improved potency and durability in vivo relative to
comparator siRNA formats with both hepatic and extra-hepatic delivery.
We also made significant progress advancing our clinical trials for Duchenne muscular dystrophy (DMD)
and Huntington   s disease (HD). In DMD, we initiated dosing in our potentially registrational
FORWARD-53 clinical trial of WVE-N531, and we continued to advance our SELECT-HD trial of WVE003 in HD. During the year, we shared additional data from both programs, including clinical data
indicating that WVE-N531 was present in myogenic stem cells and positive results from a nonclinical
study of WVE-003 in non-human primates, which resulted in the achievement of a milestone under our
collaboration with Takeda. We continued to advance SELECT-HD and FORWARD-53 throughout the
year and expect to share data from both trials in the second and third quarters of 2024, respectively.
   Powered by multiple RNA modalities, a decade of chemistry
innovation, and deep genetic insights, we are opening up
new areas of disease biology and designing optimal ways of
treating rare and common diseases. Our achievements in
2023 have put us in the unique position to deliver expected
data updates from multiple clinical programs throughout
2024, each of which is targeted to addresses areas of high
unmet need and unlock future pipeline opportunities.   
PAUL B. BOLNO, MD, MBA
President & CEO, Wave Life Sciences
As we look to the remainder of 2024, we are focused on the following priorities:
    Delivering proof-of-mechanism data from the RestorAATion-2 clinical trial of WVE-006
in patients with AATD and unlocking additional opportunities for Wave   s leading RNA
editing capability
Our progress in dose-escalating healthy volunteers in RestorAATion-1 has enabled the rapid
identification of a starting dose level in RestorAATion-2 that, based on preclinical data, is
expected to engage target in patients. RestorAATion-2 is a Phase 1b/2a open-label study that is
designed to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of
WVE-006 in patients with AATD who have the homozygous Pi*ZZ mutation. The trial is designed
to provide an efficient path to proof-of-mechanism as measured by restoration of wild-type
alpha-1 antitrypsin (M-AAT) protein in serum.
There remains a major unmet need in AATD because other investigational treatment approaches
are often confined to either lung or liver manifestations, rely on exogenously delivered enzymes,
or utilize complex delivery systems such as lipid nanoparticles. WVE-006 is a potential best-inclass therapy for AATD that is designed to correct the disease-causing Z mRNA mutation and
address AATD lung disease, liver disease, or both. WVE-006 utilizes a GalNAc conjugate, which
is a highly specific and elegant delivery tool that is used by multiple approved silencing
therapeutics on the market. GalNAc enables the ease and convenience of subcutaneous dosing,
and our proprietary chemistry has enabled WVE-006 to effectively recruit endogenous ADAR
enzymes and achieve potent and durable editing in preclinical studies.
We believe demonstrating proof-of-mechanism in RestorAATion-2 would not only meaningfully
de-risk WVE-006 in AATD, but would also serve as proof-of-concept for our wholly owned
pipeline of RNA editing therapeutics focused on protein restoration and repair targets.
    Advancing lead INHBE clinical candidate for obesity toward anticipated clinical trial
initiation in the first quarter of 2025 and progressing GSK discovery programs under
strategic collaboration
We are sharply focused on advancing our INHBE clinical candidate for obesity toward the clinic.
Our wholly owned INHBE clinical candidate is a GalNAc-siRNA that utilizes our next-generation
siRNA format and is designed to silence the INHBE gene, with a goal of inducing lipolysis (fat
burning) while preserving muscle mass to restore and maintain a healthy metabolic profile. Using
GalNAc-siRNA silencing, we aim to recapitulate the protective phenotype of INHBE loss-offunction heterozygous carriers, who have a favorable cardiometabolic profile, including reduced
abdominal obesity and reduced odds of type 2 diabetes and coronary artery disease.
Although GLP-1 agonists remain the standard of care for weight loss, these therapies come with
several limitations, including loss of muscle mass, poor tolerability, and high discontinuation
rates. Because the INHBE mechanism of action is distinct from that of the GLP-1 agonists, we see
an opportunity to use INHBE siRNA as a front-line or potentially maintenance therapy following
induction of weight loss with GLP-1 agonists. Our INHBE program aims to be a next-generation
obesity therapeutic, and we have seen preclinical evidence supporting a potential best-in-class
profile. In preclinical studies, we have demonstrated weight loss similar to semaglutide, fat loss
with no loss of muscle mass, curtailed rebound weight gain upon cessation of semaglutide, and
the potential for dosing one to two times per year. We plan to file a clinical trial application (CTA)
for our INHBE candidate as early as end-of-year and expect to initiate our first clinical trial in the
first quarter of 2025.
INHBE is the first wholly owned program to emerge from our collaboration with GSK. In addition
to this program, we are leveraging GSK   s genetically validated targets to advance up to two
additional wholly owned Wave programs.
    Delivering multidose data for our novel, allele-selective HD program in the second quarter
of 2024 and potentially registrational data from our FORWARD-53 trial in DMD in the third
quarter of 2024
In HD, we are advancing WVE-003 in our SELECT-HD study. WVE-003 is our first-in-class,
allele-selective candidate for HD designed to reduce toxic mutant huntingtin protein and
preserve healthy, wild-type huntingtin protein. The multidose portion of the SELECT-HD clinical
trial is evaluating patients with HD receiving 30-mg doses of WVE-003 administered every 8
weeks. We remain on track to report data from the 30-mg multidose cohort with extended
follow-up, along with all single-dose data, in the second quarter of 2024.
We also continue to advance our FORWARD-53 clinical trial. In our    Part A    clinical trial,
WVE-N531 demonstrated an industry-leading mean 53% exon skipping, driven by muscle tissue
concentrations of 42 micrograms per gram, and demonstrated evidence of myogenic stem cell
uptake. We look forward to building on this compelling dataset as we plan to deliver potentially
registrational 24-week dystrophin expression data in the third quarter. If positive, these data
would support our plans to file for accelerated approval in the United States and would accelerate
our clinical development plans to build a multi-exon DMD franchise beyond exon 53.
As we reflect on our achievements so far this year and our numerous milestones expected throughout
the remainder of 2024, we are reminded of the patients, families, and caregivers who drive the work
we do each day. They remain our strongest source of inspiration, and we extend our deepest gratitude
to them.
It is an exciting time for our company, and we are focused on executing and delivering on our ambitious
goal to unlock the broad potential of RNA medicines to transform human health. On behalf of
everyone at Wave, we thank you for your continued support and are grateful to be sharing this journey
with you.
Sincerely,
PAUL B. BOLNO, MD, MBA
President and Chief Executive Officer
 • shareholder letter icon 6/21/2024 Letter Continued (Full PDF)
 • stockholder letter icon More "Drugs & Pharmaceuticals" Category Stockholder Letters
 • Benford's Law Stocks icon WVE Benford's Law Stock Score = 65


WVE Shareholder/Stockholder Letter Transcript:

WAVE LIFE SCIENCES
2023 ANNUAL REPORT
2023
Annual Report
6/7/24 8:39 AM

Dear Wave Life Sciences Shareholders,
I am pleased to share our 2023 Annual Report, which highlights progress made last year toward
becoming the leading RNA medicines company.
2023 was a year of execution and tremendous progress for Wave as we advanced and expanded our
differentiated pipeline of novel RNA medicines, further enhanced the broad capabilities of our
PRISMTM discovery and development platform, and made significant progress in the first full year of our
collaboration with GSK. These achievements underscore the far-reaching potential of our multimodal
platform to reimagine what   s possible for human health and pioneer medicines that truly change
people   s lives.
We are leading in RNA editing with our ongoing RestorAATion clinical program for WVE-006 in alpha-1
antitrypsin deficiency (AATD), the industry   s first RNA editing candidate to enter a human clinical trial.
The initiation of this clinical program last year also resulted in the achievement of a $20 million milestone
under our collaboration with GSK. Beyond WVE-006, we unveiled a pipeline of wholly owned RNA
editing programs that we are advancing across a range of potentially high-impact GalNAc hepatic and
extra-hepatic targets, as well as our proprietary    edit-verse,    which we are using to identify new targets
that we believe will leverage easily accessible biomarkers, offer efficient path to proof-of-concept in
humans, address diseases of high unmet need, and represent meaningful commercial opportunities.
In 2023, we made significant progress translating clinical genetics into medicines and unlocking novel
targets for prevalent diseases. We introduced our wholly owned GalNAC-siRNA INHBE program for
the treatment of obesity at our annual Fall R&D Day. Preclinical data from this program support a
potential best-in-class profile and the ability to overcome limitations of GLP-1 agonists. Beyond our
INHBE program, we further demonstrated the broad potential of our siRNA capabilities with the
publication of positive preclinical data in Nucleic Acids Research demonstrating unprecedented Ago2
loading following a single dose that led to improved potency and durability in vivo relative to
comparator siRNA formats with both hepatic and extra-hepatic delivery.
We also made significant progress advancing our clinical trials for Duchenne muscular dystrophy (DMD)
and Huntington   s disease (HD). In DMD, we initiated dosing in our potentially registrational
FORWARD-53 clinical trial of WVE-N531, and we continued to advance our SELECT-HD trial of WVE003 in HD. During the year, we shared additional data from both programs, including clinical data
indicating that WVE-N531 was present in myogenic stem cells and positive results from a nonclinical
study of WVE-003 in non-human primates, which resulted in the achievement of a milestone under our
collaboration with Takeda. We continued to advance SELECT-HD and FORWARD-53 throughout the
year and expect to share data from both trials in the second and third quarters of 2024, respectively.
   Powered by multiple RNA modalities, a decade of chemistry
innovation, and deep genetic insights, we are opening up
new areas of disease biology and designing optimal ways of
treating rare and common diseases. Our achievements in
2023 have put us in the unique position to deliver expected
data updates from multiple clinical programs throughout
2024, each of which is targeted to addresses areas of high
unmet need and unlock future pipeline opportunities.   
PAUL B. BOLNO, MD, MBA
President & CEO, Wave Life Sciences

As we look to the remainder of 2024, we are focused on the following priorities:
    Delivering proof-of-mechanism data from the RestorAATion-2 clinical trial of WVE-006
in patients with AATD and unlocking additional opportunities for Wave   s leading RNA
editing capability
Our progress in dose-escalating healthy volunteers in RestorAATion-1 has enabled the rapid
identification of a starting dose level in RestorAATion-2 that, based on preclinical data, is
expected to engage target in patients. RestorAATion-2 is a Phase 1b/2a open-label study that is
designed to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of
WVE-006 in patients with AATD who have the homozygous Pi*ZZ mutation. The trial is designed
to provide an efficient path to proof-of-mechanism as measured by restoration of wild-type
alpha-1 antitrypsin (M-AAT) protein in serum.
There remains a major unmet need in AATD because other investigational treatment approaches
are often confined to either lung or liver manifestations, rely on exogenously delivered enzymes,
or utilize complex delivery systems such as lipid nanoparticles. WVE-006 is a potential best-inclass therapy for AATD that is designed to correct the disease-causing Z mRNA mutation and
address AATD lung disease, liver disease, or both. WVE-006 utilizes a GalNAc conjugate, which
is a highly specific and elegant delivery tool that is used by multiple approved silencing
therapeutics on the market. GalNAc enables the ease and convenience of subcutaneous dosing,
and our proprietary chemistry has enabled WVE-006 to effectively recruit endogenous ADAR
enzymes and achieve potent and durable editing in preclinical studies.
We believe demonstrating proof-of-mechanism in RestorAATion-2 would not only meaningfully
de-risk WVE-006 in AATD, but would also serve as proof-of-concept for our wholly owned
pipeline of RNA editing therapeutics focused on protein restoration and repair targets.
    Advancing lead INHBE clinical candidate for obesity toward anticipated clinical trial
initiation in the first quarter of 2025 and progressing GSK discovery programs under
strategic collaboration
We are sharply focused on advancing our INHBE clinical candidate for obesity toward the clinic.
Our wholly owned INHBE clinical candidate is a GalNAc-siRNA that utilizes our next-generation
siRNA format and is designed to silence the INHBE gene, with a goal of inducing lipolysis (fat
burning) while preserving muscle mass to restore and maintain a healthy metabolic profile. Using
GalNAc-siRNA silencing, we aim to recapitulate the protective phenotype of INHBE loss-offunction heterozygous carriers, who have a favorable cardiometabolic profile, including reduced
abdominal obesity and reduced odds of type 2 diabetes and coronary artery disease.
Although GLP-1 agonists remain the standard of care for weight loss, these therapies come with
several limitations, including loss of muscle mass, poor tolerability, and high discontinuation
rates. Because the INHBE mechanism of action is distinct from that of the GLP-1 agonists, we see
an opportunity to use INHBE siRNA as a front-line or potentially maintenance therapy following
induction of weight loss with GLP-1 agonists. Our INHBE program aims to be a next-generation
obesity therapeutic, and we have seen preclinical evidence supporting a potential best-in-class
profile. In preclinical studies, we have demonstrated weight loss similar to semaglutide, fat loss
with no loss of muscle mass, curtailed rebound weight gain upon cessation of semaglutide, and
the potential for dosing one to two times per year. We plan to file a clinical trial application (CTA)
for our INHBE candidate as early as end-of-year and expect to initiate our first clinical trial in the
first quarter of 2025.
INHBE is the first wholly owned program to emerge from our collaboration with GSK. In addition
to this program, we are leveraging GSK   s genetically validated targets to advance up to two
additional wholly owned Wave programs.

    Delivering multidose data for our novel, allele-selective HD program in the second quarter
of 2024 and potentially registrational data from our FORWARD-53 trial in DMD in the third
quarter of 2024
In HD, we are advancing WVE-003 in our SELECT-HD study. WVE-003 is our first-in-class,
allele-selective candidate for HD designed to reduce toxic mutant huntingtin protein and
preserve healthy, wild-type huntingtin protein. The multidose portion of the SELECT-HD clinical
trial is evaluating patients with HD receiving 30-mg doses of WVE-003 administered every 8
weeks. We remain on track to report data from the 30-mg multidose cohort with extended
follow-up, along with all single-dose data, in the second quarter of 2024.
We also continue to advance our FORWARD-53 clinical trial. In our    Part A    clinical trial,
WVE-N531 demonstrated an industry-leading mean 53% exon skipping, driven by muscle tissue
concentrations of 42 micrograms per gram, and demonstrated evidence of myogenic stem cell
uptake. We look forward to building on this compelling dataset as we plan to deliver potentially
registrational 24-week dystrophin expression data in the third quarter. If positive, these data
would support our plans to file for accelerated approval in the United States and would accelerate
our clinical development plans to build a multi-exon DMD franchise beyond exon 53.
As we reflect on our achievements so far this year and our numerous milestones expected throughout
the remainder of 2024, we are reminded of the patients, families, and caregivers who drive the work
we do each day. They remain our strongest source of inspiration, and we extend our deepest gratitude
to them.
It is an exciting time for our company, and we are focused on executing and delivering on our ambitious
goal to unlock the broad potential of RNA medicines to transform human health. On behalf of
everyone at Wave, we thank you for your continued support and are grateful to be sharing this journey
with you.
Sincerely,
PAUL B. BOLNO, MD, MBA
President and Chief Executive Officer



shareholder letter icon 6/21/2024 Letter Continued (Full PDF)
 

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