Wave Life Sciences Ltd. operates as a clinical-stage biotechnology company focused on unlocking the broad potential of ribonucleic acid (RNA) medicines (also known as oligonucleotides), or those targeting RNA, to transform human health.
The company’s RNA medicines platform, PRISM, combines multiple modalities, chemistry innovation and deep insights into human genetics to deliver scientific breakthroughs that treat both rare and common disorders. The company’s toolkit of RNA-targeting modalities...
Wave Life Sciences Ltd. operates as a clinical-stage biotechnology company focused on unlocking the broad potential of ribonucleic acid (RNA) medicines (also known as oligonucleotides), or those targeting RNA, to transform human health.
The company’s RNA medicines platform, PRISM, combines multiple modalities, chemistry innovation and deep insights into human genetics to deliver scientific breakthroughs that treat both rare and common disorders. The company’s toolkit of RNA-targeting modalities includes RNA editing, splicing, silencing using RNA interference (‘siRNA’) and antisense silencing, providing it with unique capabilities for designing and sustainably delivering candidates that optimally address disease biology. The company’s diversified pipeline includes clinical programs in obesity, alpha-1 antitrypsin deficiency (AATD), Duchenne muscular dystrophy (DMD), and Huntington’s disease (HD), as well as several preclinical programs utilizing its versatile RNA medicines platform.
The company's novel chemistry also allows it to avoid using complex delivery vehicles, such as lipid nanoparticles and viruses, and instead use clinically proven conjugates (e.g. N-acetylgalactosamine or (GalNAc)) or free uptake for delivery to a variety of cell and tissue types. The company maintains strong and broad intellectual property, including for its novel chemistry modifications.
The company's best-in-class chemistry capabilities have also unlocked new areas of biology, such as harnessing adenosine deaminases acting on RNA (ADAR) enzymes for messenger RNA (mRNA) correction and upregulation, selectively silencing a mutant allele, and more. By opening up new areas of biology, the company has also opened up new opportunities to slow, stop or reverse disease and have expanded the possibilities offered through its platform.
The inspiration for the company’s multimodal platform is based on the recognition that the biological machinery (i.e., enzymes) needed to address human disease already exists within its cells and can be harnessed for therapeutic purposes with the right tools. The company has built the most versatile toolkit of RNA-targeting modalities in the industry, with multiple means of repairing, restoring, or reducing proteins and designing best-fit solutions based on the unique biology of a given disease target. The company is actively advancing programs using four distinct modalities, including novel A-to-I RNA editing oligonucleotides (‘AIMers’).
The company intentionally focuses on targeting the transcriptome using oligonucleotides rather than other nucleic acid modalities, such as gene therapy and DNA editing. This focus enables the company to:
Leverage diversity of expression across cell types by modulating the many regulatory pathways that impact gene expression, including transcription, endogenous RNAi pathways, splicing, and translation;
Address diseases that have historically been difficult to treat with small molecules or biologics;
Access a variety of tissue types or cell types throughout the body and modulate the frequency of dosing for broad distribution in tissues over time;
Avoid the risk of permanent off-target genetic changes and other challenges associated with DNA editing or gene therapy approaches; and
Leverage well-established industry manufacturing processes and regulatory, access, and reimbursement pathways.
The company has a robust and diverse pipeline of potential first-or best-in-class programs addressing both rare and common diseases:
GalNAc-conjugated oligonucleotides for hepatic and metabolic diseases including:
Obesity: WVE-007 is a GalNAc-conjugated siRNA targeting inhibin ßE (INHBE);
Alpha-1 antitrypsin deficiency (AATD): WVE-006 is a GalNAc-conjugated SERPINA1 AIMer;
Liver disease: GalNAc-conjugated AIMer targeting PNPLA3 I148M for correction; and
Heterozygous Familial Hypercholesterolemia (HeFH): GalNAc-conjugated AIMer targeting low-density lipoprotein receptor (LDLR) for upregulation and GalNAc-conjugated AIMer targeting apolipoprotein B (APOB) for correction.
Unconjugated oligonucleotides for muscle, CNS and other disease areas, including:
Duchenne muscular dystrophy (DMD): WVE-N531 is an exon 53 splicing oligonucleotide; and
Huntington’s disease (HD): WVE-003 is an allele-selective oligonucleotide designed to lower mutant huntingtin (mHTT) protein and preserve healthy, wild-type huntingtin (wtHTT) protein.
Obesity Program
WVE-007 is a GalNAc-siRNA that is designed to silence the INHBE gene to induce lipolysis (fat-burning) while preserving muscle mass to restore and maintain a healthy metabolic profile. Heterozygous INHBE loss-of-function (‘LoF’) human carriers exhibit a healthy metabolic profile, including reduced waist-to-hip ratio and reduced odds of developing type 2 diabetes or coronary artery disease, and reduction of INHBE by 50% or more is expected to restore a healthy metabolic profile. In connection with the company’s 2023 Research and Development Day, the company shared in vivo proof-of-concept data in diet-induced obesity (‘DIO’) mice demonstrating INHBE silencing well beyond the anticipated 50% therapeutic threshold, which led to substantially lower body weight and reduction of visceral fat as compared to controls. These are the first data to demonstrate INHBE silencing in vivo in an animal model is consistent with the phenotypes of heterozygous loss-of-function carriers.
WVE-007 utilizes the company’s next generation GalNAc-siRNA format. In preclinical diet-induced obesity (‘DIO’) mouse models, the company’s INHBE GalNAc-siRNA has demonstrated highly potent INHBE silencing (ED50 < 1 mg/kg), durable silencing following one, low-single digit dose supporting every-six-month or annual subcutaneous dosing in humans, weight loss with no loss of muscle mass and reduction in fat mass, with preferential effect to the visceral fat, consistent with the profile of INHBE LoF in human genetics.
In a head-to-head study in DIO mice, the company has observed a weight loss effect from a single dose of the company’s INHBE GalNAc-siRNA similar to semaglutide. In addition, treatment with the company’s INHBE GalNAc-siRNA prior to cessation of semaglutide treatment curtailed expected rebound weight gain. Additionally, in a separate ongoing study in DIO mice, when administered as an add-on to semaglutide, a single dose of the company’s INHBE GalNAc-siRNA doubled the weight loss observed with semaglutide alone, and this effect was sustained throughout the duration of the study.
In February 2025, the company announced that it had initiated INLIGHT, the first-in-human Phase 1 clinical trial of WVE-007 in obesity. INLIGHT is enrolling adults living with overweight or obesity to assess safety, tolerability, pharmacokinetics, (PK) biomarkers for target engagement, body weight and composition, and metabolic health. Dosing in INLIGHT is underway, and the company expects to deliver clinical data from INLIGHT in the second half of 2025.
Alpha-1 antitrypsin deficiency (AATD)
The company is leveraging its RNA editing platform capability to develop a first-in-class treatment for AATD. AATD is a rare, inherited genetic disorder that is commonly caused by a G-to-A point mutation in the SERPINA1 gene; this mutant allele is termed the Z allele. This mutation leads to misfolding and aggregation of Z-AAT protein in hepatocytes and a lack of functional Alpha-1 antitrypsin (‘AAT’) in the lungs. People with AATD typically exhibit progressive lung damage, liver damage or both, leading to frequent hospitalizations and potentially terminal lung disease and/or liver disease. Weekly intravenous augmentation therapy is the only treatment option for AATD in those with the lung pathology; there are no approved therapies to address the liver pathology. Approximately 200,000 people in the United States and Europe are homozygous for the Z allele, which is the most common form of severe disease.
The company’s AATD program uses its novel GalNAc-conjugated AIMers (RNA editing oligonucleotides) and endogenous ADAR enzymes to correct a single base in the mutant SERPINA1 mRNA. By correcting the single RNA base mutation that causes a majority of AATD cases with the Pi*ZZ genotype (approximately 200,000 in the United States and Europe), RNA editing may provide an ideal approach for increasing circulating levels of wild-type AAT protein and reducing mutant protein aggregation in the liver, thus simultaneously addressing both the lung and liver manifestations of the disease.
WVE-006 is first-in-class in AATD and is the most advanced program in clinical development using an oligonucleotide to harness an endogenous enzyme for RNA editing. The company’s RestorAATion clinical program investigating WVE-006 as a treatment for AATD comprises two parts: RestorAATion-1, a study of healthy volunteers; and RestorAATion-2, a study in patients with AATD who have the homozygous Pi*ZZ mutation. The company has completed multi-dosing in healthy volunteers in the top cohort of RestorAATion-1 at a dose level greater than those planned for any cohort in RestorAATion-2. RestorAATion-2 is a Phase 1b/2a open label study designed to evaluate the safety, tolerability, pharmacodynamics (PD) and PK of WVE-006 in individuals with AATD who have the homozygous Pi*ZZ mutation. The trial includes both single ascending dose (SAD) and multiple ascending dose (MAD) portions.
In October 2024, the company announced positive proof-of-mechanism data from the ongoing Phase 1b/2a RestorAATion-2 study: Following a single subcutaneous dose of 200 mg of WVE-006 in the study’s first two patients, circulating wild-type M-AAT protein in plasma reached a mean of 6.9 micromolar at day 15, representing more than 60% of total AAT. Increases in neutrophil elastase inhibition from baseline were consistent with production of functional M-AAT. Mean total AAT protein increased from below the level of quantification at baseline to 10.8 micromolar at day 15, meeting the level that has historically been the basis for regulatory approval for AAT augmentation therapies. Increases in total AAT from baseline and M-AAT protein were observed as early as day 3 and through day 57. WVE-006 was well-tolerated with a favorable safety profile. All adverse events in RestorAATion-2, as well as in the RestorAATion-1 trial of healthy volunteers, were mild to moderate, with no serious adverse events (‘SAEs’) reported. These data were the first-ever clinical demonstration of RNA editing in humans.
In the first quarter of 2025, the company initiated multi-dosing in the first cohort of RestorAATion-2, where patients are receiving 200 mg subcutaneous doses every two weeks, and initiated the second single dose cohort of RestorAATion-2 at 400 mg. The company expects to share multi-dose data from RestoraAATion-2 in 2025.
Preclinical data show that treatment with WVE-006 resulted in serum AAT protein levels of up to 30 micromolar in an established AATD mouse model (NSG-PiZ). WVE-006 also led to restoration of approximately 50% wild-type M-AAT protein in serum and a 3-fold increase in neutrophil elastase inhibition activity, indicating that the restored M-AAT protein was functional. Wave's AATD AIMers are highly specific to SERPINA1 RNA in vitro and in vivo based on transcriptome-wide analyses.
Duchenne Muscular Dystrophy (DMD) Program
In DMD, the company is advancing WVE-N531, which is designed to skip exon 53 within the dystrophin gene - a therapeutic approach that would address approximately 8-10% of DMD cases. WVE-N531 is designed to cause the cellular splicing machinery to skip over exon 53 during pre-mRNA processing, which restores the dystrophin mRNA reading frame and enables production of a truncated, but functional, dystrophin protein. Exon skipping produces dystrophin from the endogenous dystrophin gene (not micro or mini dystrophin expressed from a foreign vector), under the control of native gene-regulatory elements, resulting in normal expression. WVE-N531 is the company's first splicing candidate incorporating PN backbone (PN) chemistry to be assessed in the clinic. In the third quarter of 2024, the FDA granted Rare Pediatric Disease Designation and Orphan Drug Designation to WVE-N531.
In December 2022 the company announced a positive update from Part A of the Phase 1b/2a proof-of-concept, open label trial of WVE-N531 in three boys with DMD amenable to exon 53 skipping. High muscle concentrations of WVE-N531 and exon skipping were observed six weeks after initiating multi-dosing at 10 mg/kg every other week, achieving proof-of-concept in the trial. WVE-N531 also appeared safe and well-tolerated.
In September 2023, the company shared an analysis of muscle biopsy data from the Part A proof-of-concept trial indicating that WVE-N531 was present in myogenic stem cells, which are integral to muscle regeneration. This is the first demonstration of uptake in myogenic stem cells in a clinical study and supports the potential differentiation of WVE-N531 from other therapeutics, including gene therapies.
In December 2023, the company-initiated dosing of WVE-N531 in FORWARD-53, the Phase 2 portion of the open-label trial (Part B). The study is designed to administer 10 mg/kg infusions of WVE-N531 every two weeks (Q2W), and muscle biopsies are taken after 24 and 48 weeks of dosing. The primary endpoint will be dystrophin protein levels, and the trial will also evaluate PK, digital and functional endpoints, and safety and tolerability.
In September 2024, the company announced positive interim data from the ongoing Phase 2 FORWARD-53 study. Eleven boys amenable to exon 53 skipping (age 5-11; 10 ambulatory and 1 non-ambulatory) are enrolled. The interim analysis was conducted after 24 weeks of 10 mg/kg dosing Q2W. WVE-N531 appeared safe and well tolerated. The company observed mean muscle content-adjusted dystrophin expression of 9.0% and unadjusted dystrophin of 5.5%, with high consistency across participants, in a prespecified analysis of ambulatory participants.
Dystrophin expression was quantified from two isoforms consistent with those observed in Becker muscular dystrophy patients who display milder disease. In addition, the company observed meaningful improvements in serum biomarkers for muscle health, with localization of WVE-N531 in myogenic stem cells and in myofibers. Mean skeletal muscle concentrations of ~41,000 ng/g and a 61-day tissue half-life support monthly dosing going forward.
The FORWARD-53 trial is ongoing and all patients have elected to continue treatment in the planned extension portion of the study with monthly doses of WVE-N531. In the first quarter of 2025, the company expects to deliver the 48-week FORWARD-53 data and feedback from regulators on a pathway to accelerated approval. Pending positive results from this trial, the company is planning to advance a broader DMD pipeline with PN-modified splicing oligonucleotides designed to skip other exons, with the goal of providing new treatment options for a larger population of boys with DMD.
Huntington’s Disease (HD) Program
In HD, the company is advancing WVE-003, a stereopure allele-selective oligonucleotide designed to selectively target rs362273, a variant of the single nucleotide polymorphism (SNP), ’mHTT SNP3’, associated with the disease-causing mHTT mRNA transcript within the HTT gene (Iwamoto et al., MTNA).
WVE-003 incorporates the company's novel PN chemistry. Targeting mRNA with SNP3 allows the company to lower expression of transcript from the mutant allele, while leaving the healthy transcript relatively intact, thereby preserving wild-type (healthy) huntingtin (wtHTT) protein, which is important for neuronal function. Only an allele-selective approach to mHTT lowering has the potential to both protect the reservoir of wtHTT protein and decrease the mHTT to wtHTT ratio in neurons, potentially releasing wtHTT from the inhibitory actions of mHTT. In preclinical studies, WVE-003 showed dose-dependent and selective reduction of mHTT mRNA in vitro, as well as potent and durable knockdown of mHTT mRNA and protein in vivo in mouse models.
SELECT-HD was a global, multicenter, randomized, double-blind, placebo-controlled Phase 1b/2a clinical trial to assess the safety and tolerability of WVE-003 in people with a confirmed diagnosis of HD who are in the early stages of the disease and carry SNP3 in association with their CAG expansion. Additional objectives included assessing PK and exploratory PD and clinical endpoints.
In June 2024, the company announced positive clinical data from the Phase 1b/2a SELECT-HD study of WVE-003. Results from the multi-dose portion of the trial, which evaluated three doses of 30 mg WVE-003 administered every eight weeks, showed clear translation of target engagement to clinic with statistically significant, potent, durable and allele-selective reductions in cerebrospinal fluid (CSF) mHTT of up to a mean 46% with preservation of wtHTT protein.
The multi-dose cohort also revealed a statistically significant correlation between mHTT reduction and slowing of caudate atrophy, indicating a potential benefit of allele-selective mHTT reductions. Caudate atrophy, as measured by MRI, is a well-characterized measures of disease progression in HD.
In the multi-dose cohort, WVE-003 was generally safe and well-tolerated, with mild-to-moderate adverse events (AEs) and no SAEs. In November 2024, five months after a patient completed their final safety visit, an SAE was reported that the company assessed to be not related to WVE-003.
Following the company’s positive clinical results, the company initiated engagement with the FDA. In November 2024, the company received supportive initial feedback from the FDA, who recognize the severity of HD and are receptive to and engaged with the company regarding a potential pathway to accelerated approval. The FDA is open to the company’s plan to evaluate biomarkers, including caudate atrophy, as an endpoint to assess HD progression with the potential to predict clinical outcome. Also in November 2024, the FDA granted Orphan Drug Designation to WVE-003.
Preparation is ongoing for a global, potentially registrational Phase 2/3 study of WVE-003 with caudate atrophy as a primary endpoint. The company expects to submit an Investigational New Drug (IND) application for WVE-003 in the second half of 2025.
Discovery Pipeline
The company is advancing new targets across multiple disease areas to expand its pipeline of wholly owned programs. The company's compelling preclinical data indicates its oligonucleotides can distribute to various tissues and cells without complex delivery vehicles, enabling it to address a wide variety of diseases, including pulmonary and renal diseases. Within RNA editing, the company has demonstrated preclinically that it can edit to correct monogenic diseases by restoring or correcting protein function for the treatment of AATD. Building on its work in AATD, the company has demonstrated its ability to address more prevalent diseases by editing RNA to upregulate or increase the stability of the mRNA transcript, thereby increasing endogenous protein production. Utilizing its proprietary 'edit-verse,' which is powered by genetic datasets and deep learning models, the company has identified several RNA editing targets that leverage easily accessible biomarkers, offer efficient paths to proof-of-concept in humans, and represent meaningful commercial opportunities.
The company’s wholly owned discovery-stage pipeline includes hepatic and extra hepatic targets, including three RNA editing programs in liver that leverage GalNAc conjugates and have efficient clinical paths to proof-of-concept.
PNPLA3, which uses mRNA correction to restore the heterozygous phenotype for those at high risk for genetically defined liver disease. Homozygous PNPLA3-I148M patients are at high risk for a variety of liver diseases and there are more than nine million impacted individuals in the United States and Europe.
LDLR and APOB, which utilize first-in-class mRNA upregulation and mRNA correction approaches, respectively, to achieve target low-density lipoprotein cholesterol (LDL-c) levels in people with heterozygous familial hypercholesterolemia. Combined, LDLR and APOB AIMers could address approximately one million HeFH patients in the United States and Europe. LDLR upregulation also offers significant expansion opportunities in patients with statin intolerance or prior cardiovascular events which represent approximately 30 million patients in the United States and Europe.
Through the company’s collaboration with GSK, the company is also leveraging GSK’s novel genetic insights to expand the company’s wholly owned pipeline. In addition, the company and GSK are actively working on multiple target validation programs as GSK-partnered programs, for which all of the company’s costs and expenses are prepaid by GSK. In April 2024, GSK selected its first two programs to advance to development candidates following achievement of target validation, triggering an aggregate initiation payment to the company of $12.0 million from GSK. These programs utilize the company’s next generation GalNAc-siRNA format and are in hepatology.
The company plans to share new preclinical data from its wholly owned hepatic and extra-hepatic RNA editing programs in 2025. In 2026, the company expects to initiate clinical development of additional RNA editing programs, including PNPLA3, LDLR, and APOB.
Strategy
The company is building a leading RNA medicines company by leveraging PRISM to design, develop and commercialize optimized disease-modifying medicines for indications with a high degree of unmet medical need. The company has a robust and diverse pipeline of first- or best-in-class RNA medicines using the company’s RNA editing, splicing, silencing using siRNA, and antisense silencing modalities. The company’s lead programs aim to address both rare and common diseases, including obesity, AATD, DMD, and HD, as well as preclinical programs for liver diseases and HeFH. In addition to driving clinical and preclinical programs, the company is continuously investing in PRISM to fully unlock the potential of the company’s unique and expanding platform capabilities.
The key components of the company's strategy are to extend its leadership in RNA medicines; rapidly advance and sustainably grow the company's differentiated portfolio of RNA medicines; expand the company's pipeline of high-value programs; and leverage manufacturing leadership in oligonucleotides.
PRISM: The company's Proprietary Discovery and Drug Development Platform
The company's PRISM platform demonstrates the powerful convergence of best-in-class chemistry with human genetics. The platform was built on the recognition that a significant opportunity exists to tune the pharmacological properties of oligonucleotides by leveraging three key features of these molecules: base modifications and sequence, chemistry, as well as stereochemistry. The company's unique ability to control stereochemistry provides the resolution necessary to optimize pharmacological profiles and develop and manufacture stereopure oligonucleotides. Stereopure oligonucleotides comprises molecules with atoms precisely and purposefully arranged in three-dimensional orientations at each linkage. The company's rational process for designing stereopure oligonucleotides allows it to selectively optimize chemical modifications to a specific therapeutic modality in order to generate best-in-class oligonucleotides.
Proprietary Chemistry
Backbone Stereochemistry
In its foundational Nature Biotechnology paper (Iwamoto N, et al. Nature Biotechnol. 2017;35(9):845-851), the company described its studies using its proprietary chemistry to design and synthesize stereopure oligonucleotides and oligonucleotide mixtures based on mipomersen. Mipomersen, an oligonucleotide containing 20 nucleotides and 19 PS modifications, is synthesized by traditional oligonucleotide chemistry; thus, it is a mixture of over 500,000 different stereoisomers (219 = 524,288). The company rationally designed and synthesized individual stereoisomers of mipomersen, each having position-specific and distinct stereochemistry, and conducted studies comparing these defined stereoisomers with the mipomersen stereomixture. These and other preclinical studies have demonstrated that stereochemistry impacts pharmacology, and that by controlling stereochemistry, the company can tune multiple aspects of pharmacology, including stability, catalytic activity, and efficacy.
The company has subsequently published multiple additional manuscripts that provide evidence that stereopure oligonucleotides can be developed to have superior pharmacology to stereorandom oligonucleotides.
PN Backbone Chemistry Modifications
The company's initial investigations into the impact of backbone chemistry and stereochemistry on oligonucleotide pharmacology focused on the widely used phosphodiester (PO) and phosphorothioate (PS) backbones because they are amenable to all oligonucleotide modalities. In 2020, the company introduced PN chemistry to its repertoire of backbone modifications; this backbone modification replaces a non-bridging oxygen atom in a phosphodiester linkage with a nitrogen-containing moiety.
The company has incorporated these PN modifications – specifically phosphoryl guanidine – into oligonucleotide compounds. As with PS modifications, PN modifications are chiral, and the company has the capacity to control PN backbone stereochemistry. Unlike PS modifications, PN modifications are neutral, meaning that the negative charge of the oligonucleotide is reduced with every PN modification added to the backbone. In preclinical experiments, the company has demonstrated that judicious use of PN backbone chemistry modifications in stereopure oligonucleotides has generally increased potency, tissue exposure, and durability of effect across the company's RNA editing, siRNA, splicing, and antisense modalities.
PRISM Supports Multiple Therapeutic Modalities
Using PRISM, the company has designed and optimized diverse sets of stereopure oligonucleotides, which allows the company to characterize and compare the impact of various chemical modifications on key properties that impact a specific modality.
In the next section, the company describes different therapeutic modalities for which it has used PRISM to optimize stereopure oligonucleotides and develop built-for-purpose candidates to optimally address disease biology.
RNA editing
The company has applied its PRISM platform to the generation of short, single-stranded, highly specific A-to-I (G) RNA editing oligonucleotides – called AIMers. Because the company's AIMers are relatively short and stable (fully chemically modified), it can leverage clinically proven GalNAc-mediated delivery to hepatocytes with subcutaneous dosing. The company is developing fully chemically modified AIMers with and without GalNAc conjugation. In preclinical studies, the company has evaluated thousands of AIMers, assessing a variety of sugar and base modifications, backbone chemistry and stereochemistry, and other parameters such as AIMer length to produce insight into the relationship between an AIMer’s structure and its ability to elicit RNA editing activity.
With PRISM, the company has generated stereopure AIMers, optimized for chemistry and stereochemistry, which promote RNA editing with endogenous ADAR enzymes in cellular models. As shown in the figure below, the company presents the activity of beta-actin-editing stereopure AIMers, with and without PN linkages, compared to a matched stereorandom AIMer (shown in black) in primary human hepatocytes. These AIMers are GalNAc conjugated to increase uptake in hepatocytes. The addition of PN chemistry substantially improves both potency and editing efficiency.
In its foundational RNA editing paper published in Nature Biotechnology (Monian P, et al., 2022; doi.org/10.1038/s41587-022-01225-1), the company demonstrated efficient RNA editing in vitro with its AIMers across a variety of cell lines, including non-human primate (NHP) and human primary hepatocytes. The company observed potent, dose-dependent RNA editing with three chemically distinct stereopure AIMers (ACTB 1, ACTB 2, ACTB 3) via GalNAc-mediated uptake.
The company also observed potent, durable, and specific editing across multiple additional tissues following systemic administration of a single dose of an unconjugated UGP2 AIMer in mice. These additional tissues in mice include heart, kidney, lung, pancreas and spleen, as well as liver cells beyond hepatocytes.
Silencing – RNAi and RNase H-mediated degradation
Using PRISM, the company can produce stereopure PN-modified oligonucleotides that promote potent and specific RNA transcript silencing activity in preclinical experiments.
RNAi: The company has applied its stereopure PS and PN modifications to the siRNA modality using double-stranded siRNAs and demonstrated potent and durable silencing in vivo in transgenic mice, leveraging GalNAc to enhance delivery to liver hepatocytes.
In April 2023, the company announced the publication of preclinical data for its novel siRNA formats in the journal of Nucleic Acids Research. The preclinical data demonstrated unprecedented Argonaute2 (Ago2) loading following administration of single subcutaneous GalNAc-siRNA doses, leading to improved potency and durability in vivo in mice versus comparator siRNA formats.
Additionally, in an in vivo non-GalNAc siRNA study, the company demonstrated that it can achieve potent and sustained silencing with a single dose, with greater than 75% reduction in amyloid-beta precursor protein (APP) transcripts across all the brain regions through the end of the 16 week study.
Splicing
With PRISM, the company has optimized stereopure oligonucleotides that promote efficient splicing in vitro, ex vivo, and in vivo to restore protein production. In its splicing programs, as with the company’s other modalities, the base modifications and sequence, chemistry and backbone stereochemistry of oligonucleotides impact their activity.
RNase H-mediated degradation (antisense): In its Nucleic Acids Research paper (Kandasamy et al., 2022; doi: 10.1093/nar/gkac018), the company illustrated the impact of PN backbone chemistry modifications for an RNase H-mediated silencing modality. In addition to the data reported in the paper, the company has performed screens for identifying RNase H-targeting sequences in iCell neurons in vitro using free uptake. This screen was initially performed with stereopure molecules with PS and PO backbone chemistry modifications, and the oligonucleotides are rank-ordered from left to right according to their potency. Next, the company performed a head-to-head comparison with molecules that contained the same sequence and the same 2’-ribose chemistry, but with the addition of PN chemistry at select locations in the backbone. The introduction of a few PN linkages significantly increases the potency of the vast majority of the stereopure PS/PO molecules, with approximately 80% of them yielding at least 75% knockdown.
Collaborations
The company's business strategy is to develop and commercialize a broad pipeline of RNA medicines. As part of this strategy, the company has entered into, and may enter into, new partnership and collaboration agreements as a means of advancing its own therapeutic programs and maximizing their potential for patients, investing in third-party technologies to further strengthen PRISM, and leveraging external partnerships to extend the reach of PRISM into therapeutic areas where the company's platform demonstrates a competitive advantage.
GSK
On December 13, 2022, Wave Life Sciences USA, Inc. (Wave USA) and Wave Life Sciences UK Limited (Wave UK), two of the company's direct, wholly owned subsidiaries, entered into a Collaboration and License Agreement (the GSK Collaboration Agreement) with GSK, which became effective on January 27, 2023. Pursuant to the GSK Collaboration Agreement, the company and GSK have agreed to collaborate on the research, development, and commercialization of oligonucleotide therapeutics, including a global exclusive license to WVE-006. The discovery collaboration has an initial four-year research term and combines the company's proprietary discovery and drug development platform, PRISM, with GSK’s novel genetic insights and its global development and commercial capabilities.
Asuragen
In November 2019, the company entered into an agreement with Asuragen (which was acquired by Bio-Techne Corporation in April 2021), a molecular diagnostics company, for the development and potential commercialization of companion diagnostics for its investigational allele-selective therapeutic programs targeting HD. This collaboration utilizes Asuragen’s market-leading repetitive sequence diagnostic expertise to provide scalable SNP phasing to support development programs and future commercialization at a global level. Asuragen has leveraged its AmplideX PCR technology to develop companion diagnostic tests designed to size and phase HTT CAG repeats with the SNPs targeted by WVE-003, the company's HD program being investigated in the ongoing SELECT-HD clinical trial, as well as those SNPs targeted by its previous investigational therapeutic programs. These tests are designed to aid clinicians in selecting HD patients by identifying the SNPs that are in phase with the CAG-expanded allele.
Intellectual Property
The company's portfolio includes multiple issued patents, including in major market jurisdictions, such as the United States, Europe, and Japan.
Synthetic Methodologies
The company’s patent portfolio includes multiple families that protect synthetic methodologies and/or reagents for generating stereopure oligonucleotide compositions.
Certain such families have 20-year expiration dates that range from 2029 to at least 2043. Some of these families have issued patents in several jurisdictions, including in major market jurisdictions such as the United States, Europe, and/or Japan, have pending applications in multiple jurisdictions, including in these major market jurisdictions, or are in the international stage.
The company also co-owns with the University of Tokyo filings that are directed to certain methods and/or reagents for synthesizing oligonucleotides; their 20-year expiration dates fall in 2031.
Stereopure Oligonucleotide Compositions
The company also co-owns with Shin Nippon Biomedical Laboratories, Ltd. various patent families, some of which include one or more issued patents, including in major market jurisdictions; these filings have 20-year terms extending to 2033-2035.
Government Regulation
In the United States, pharmaceutical products are subject to extensive regulation by the FDA. The Federal Food, Drug and Cosmetic Act (FDCA), and other federal and state statutes and regulations, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling, promotion and marketing, distribution, post-approval monitoring and reporting, sampling, and import and export of pharmaceutical products.
The company and its third-party manufacturers must comply with applicable cGMP requirements.
The cGMP requirements include requirements relating to, among other things, organization of personnel, buildings and facilities, equipment, control of components and drug product containers and closures, production and process controls, packaging and labeling controls, holding and distribution.
The manufacturing facilities for the company's products must meet cGMP requirements to the satisfaction of the FDA pursuant to a pre-approval inspection before it can use them to manufacture commercial products. The company and its third-party manufacturers are also subject to periodic announced or for-cause unannounced inspections of facilities by the FDA and other authorities, including procedures and operations used in the testing and manufacture of the company's commercial products, if any, to assess the company's compliance with applicable regulations.
Research and Development
The company’s research and development expenses were $159.7 million for the year ended December 31, 2024.
History
Wave Life Sciences Ltd. was founded in 2012. The company was incorporated in 2012.
