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Item 1. Business

2026-02-26 compared with 2025-03-04 · 502 added, 569 removed, 1641 unchanged (39% of the section changed)

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Our 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.

Our toolkit of RNA-targeting modalities includes RNA editing, splicing, silencing using RNA interference (“siRNA") and antisense silencing, providing us with unique capabilities for designing and sustainably delivering candidates that optimally address disease biology.

Our 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 our versatile RNA medicines platform.

Our toolkit of RNA-targeting modalities, including RNAi (SpiNA) and RNA editing (AIMers), provides us with unmatched capabilities for designing and sustainably delivering candidates that optimally address disease biology.

Our pipeline is focused on our obesity (WVE-007), alpha-1 antitrypsin deficiency (“AATD”) (WVE-006) and PNPLA3 I148M liver disease (WVE-008) programs, and also includes clinical programs for Duchenne muscular dystrophy (“DMD”) and Huntington’s disease (“HD”), as well as several preclinical programs utilizing our versatile RNA medicines platform.

We were founded on the recognition that there was a significant, untapped opportunity to use chemistry innovation to tune the pharmacological properties of oligonucleotides.

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We believe that we have 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.

We are actively advancing programs using four distinct modalities, including novel A-to-I RNA editing oligonucleotides (“AIMers”).

These modalities include:

• RNA editing, which uses AIMers that are designed to target single bases on an RNA transcript and recruit endogenous ADAR enzymes that naturally possess the ability to change an adenine (A) to an inosine (I), which cells read as guanine (G).

This approach enables both the correction of G-to-A point mutations and the modulation of RNA to either upregulate protein expression, modify protein-protein interactions, or alter RNA folding and processing.

AIMers are short in length, fully chemically modified, and use our novel chemistry, which make them distinct from other ADAR-mediated editing approaches.

• Antisense (silencing) , which uses our oligonucleotide designed to bind to a specific sequence in a target RNA strand that encodes a disease-associated protein or pathogenic RNA.

The resulting double-stranded molecule (“duplex”) is then recognized by a cellular enzyme called RNase H, which cleaves, or cuts, the target RNA in the duplex, thereby preventing the disease-associated protein from being made.

• RNA interference (RNAi ) (silencing) , which uses our double-stranded RNAs called siRNAs to engage the RNAi machinery known as the RNA-induced silencing complex (“RISC”) and to silence a target RNA that is either pathogenic itself or encodes a disease-associated protein, thereby preventing the accumulation of the pathogenic species (RNA or protein).

• Splicing / exon skipping , which is the processing of a nascent pre-mRNA transcript into mRNA by removing introns and joining exons together.

Exon skipping uses our oligonucleotide designed to bind to a particular sequence within a target pre-mRNA and direct the cellular machinery to alter the final composition of exons in mature mRNA by deleting, or splicing out, certain specific regions of that RNA.

We are actively advancing programs across modalities, including RNA interference (“RNAi”) (silencing), RNA editing, which uses novel A-to-I RNA editing oligonucleotides (“AIMers”), antisense silencing, and splicing.

We have also advanced novel bifunctional modalities designed to silence multiple targets or silence one target while simultaneously editing or upregulating another unique target.

We intentionally focus on targeting the transcriptome using oligonucleotides rather than other nucleic acid modalities such as gene therapy and DNA editing.

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• Leverage well-established industry manufacturing processes and regulatory, access, and reimbursement pathways.

We have 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:

WVE-007 is a GalNAc-conjugated siRNA targeting inhibin βE (“INHBE”);

• Alpha-1 antitrypsin deficiency ("AATD"):

WVE-006 is a GalNAc-conjugated SERPINA1 AIMer;

• Liver disease:

GalNAc-conjugated AIMer targeting PNPLA3 I148M for correction;

• 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;

• 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.

We are currently prioritizing lead programs that use GalNAc delivery for hepatic and metabolic diseases, each of which have potential to translate powerful human genetic insights into potentially transformational RNA medicines:

• WVE-007 is a GalNAc-conjugated siRNA (SpiNA design) targeting inhibin βE (“INHBE”) for obesity;

• WVE-006 is a GalNAc-conjugated RNA editing oligonucleotide (AIMer) for AATD;

• WVE-008 is a GalNAc-conjugated RNA editing oligonucleotide (AIMer) for PNPLA3 I148M liver disease.

Our clinical-stage portfolio also includes WVE-N531, an exon 53 splicing oligonucleotide for DMD, and WVE-003, an allele-selective oligonucleotide designed to lower mutant huntingtin (“mHTT”) protein and preserve healthy, wild-type huntingtin (“wtHTT”) protein.

We are also advancing several emerging siRNA and RNA editing programs targeting both hepatic and extra-hepatic tissues.

Our Current Programs

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Obesity is increasingly being recognized as a growing global epidemic.

In the United States, an estimated 42% of the adult population is living with obesity, and there are an estimated 175 million adults with obesity in the United States and Europe.

In the United States, an estimated 42% of the adult population is living with obesity, and there are an estimated 175 million people in the United States and Europe and over one billion people globally, living with obesity.

Adults with obesity have higher risk for many serious health conditions, including heart disease, type 2 diabetes, and some forms of cancer;

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Current Treatments

There are two GLP-1 receptor agonists approved in the United States and the European Union (“EU”) for the treatment of obesity:

There are two GLP-1 receptor agonists (“GLP-1s”) approved in the United States and the European Union (“EU”) for the treatment of obesity:

Saxenda (liraglutide, Novo Nordisk) and Wegovy (semaglutide, Novo Nordisk).

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Other FDA-approved therapies for obesity include Xenical (H2-Pharma, approved in the United States in 1999), Qsymia (Vivus, approved in the United States in 2012), and Contrave (Currax Pharmaceuticals, approved in the United States in 2014).

Although GLP-1 receptor agonists induce weight loss, there remains a substantial unmet need in obesity, as GLP-1 receptors lead to weight loss at the expense of muscle mass.

Although GLP-1s induce weight loss, there remains a substantial unmet need in obesity, as GLP-1s lead to weight loss at the expense of muscle mass.

For instance, in a Phase 3 study of semaglutide, 34% of total weight loss was from loss of lean mass (King 2021), and in a Phase 3 study of tirzepatide, treatment led to an approximately 34% loss in fat mass and an approximately 11% loss in lean mass (Jastreboff 2022).

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Our 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 our 2023 Research and Development Day, we 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 our next generation GalNAc-siRNA format.

In preclinical diet-induced obesity (“DIO”) mouse models, our 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.

WVE-007 is a GalNAc-siRNA, that utilizes Wave’s proprietary design (“SpiNA”).

WVE-007 is designed to silence INHBE mRNA to induce fat loss by stimulating lipolysis (fat breakdown) while preserving muscle mass to promote and maintain a healthy metabolic profile.

In preclinical diet-induced obesity (“DIO”) mouse models, a single dose of our INHBE GalNAc-siRNA has demonstrated highly potent and durable INHBE silencing (and >70% Activin E reductions), supporting once or twice a year subcutaneous dosing in humans.

Weight loss was driven by visceral fat loss, and muscle mass was preserved in the mice, which is consistent with the profile of human INHBE LoF carriers.

In DIO mice studies, a single dose of our INHBE GalNAc-siRNA led to a weight loss effect that was similar to daily subcutaneous injections of semaglutide for 28 days.

We also observed a decrease in high fat diet-induced expansion of visceral adipose mass.

This reduction of visceral fat mass was associated with significant shrinkage of adipocyte enlargement induced by a high fat diet compared with phosphate-buffered saline (“PBS”) treatment.

Collectively, these results support the promotion of healthy adipose tissue with this mechanism of action, while muscle mass was preserved.

(left, middle, right) Linear Mixed Effects ANOVA with post hoc comparisons of marginal treatment effects vs.

PBS per timepoint (left) or per tissue (middle, right) * p < 0.05

In a head-to-head study in DIO mice, we have observed a weight loss effect from a single dose of our INHBE GalNAc-siRNA similar to semaglutide.

In addition, treatment with our 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 our INHBE GalNAc-siRNA doubled the weight loss observed with semaglutide alone, and this effect was sustained throughout the duration of the study.

In a head-to-head study in DIO mice, treatment with our INHBE GalNAc-siRNA prior to cessation of semaglutide treatment curtailed expected rebound weight gain.

When administered as an add-on to semaglutide, a single dose of our INHBE GalNAc-siRNA doubled the weight loss observed with semaglutide alone, and this effect was sustained throughout the duration of the preclinical study.

10 nmol/kg in mouse is equivalent to therapeutic dose of GLP-1s in human.

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Day 56 marginal effects per treatment * p < 0.05

In February 2025, we announced that we 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 we expect to deliver clinical data from INLIGHT in the second half of 2025.

In preclinical studies, we have also observed that infiltration of macrophages into visceral adipose was significantly decreased by a single dose of INHBE GalNAc-siRNA compared with PBS controls.

INHBE GalNAc-siRNA also significantly reduced proinflammatory M1 macrophage (CD11c positive) while sustaining levels of anti-inflammatory M2 macrophages in visceral fat, indicating an overall shift away from a pro-inflammatory state.

Further, RNA sequencing data from subcutaneous adipose tissue indicates that INHBE GalNAc-siRNA leads to the upregulation of genes promoting insulin sensitivity, fatty acid utilization and beiging of white adipose, while downregulating adipose inflammation and fibrosis pathways.

RNA sequencing data from visceral adipose tissue demonstrate that our INHBE GalNAc-siRNA increased glucose and fatty acid utilization, and reduced inflammation and fibrosis in adipose tissue.

INLIGHT is our first-in-human clinical trial of WVE-007 in individuals living with obesity.

The Phase 1 single ascending dose (“SAD”) portion of INLIGHT includes otherwise healthy adults living with overweight or obesity to assess safety, tolerability, pharmacokinetics (“PK”), Activin E, body weight, biomarkers and body composition as measured by DEXA.

Key inclusion criteria for the SAD portion of INLIGHT include hemoglobin A1c (“HbA1c”) of less than 5.9 and BMI between 28 and 35 kg/m 2 .

The SAD portion of INLIGHT does not include any diet or exercise modifications.

In December 2025, we announced positive interim data from the ongoing Phase 1, SAD portion of INLIGHT, including three-month follow-up from the single subcutaneous 240 mg dose cohort in 32 individuals with an approximate mean baseline BMI of 32 kg/m 2 , a population with less visceral and subcutaneous fat than typical obesity studies.

Key highlights include:

- A single 240 mg dose of WVE-007 demonstrated improved body composition with fat loss similar to GLP-1 at three months, with muscle preservation.

- From baseline, a single dose of WVE-007 improved body composition and led to a 9.4% reduction in visceral fat (p=0.02), a 4.5% reduction in total body fat (3.5 lbs;

p=0.07), and a 3.2% increase in lean mass (4.0 lbs;

p=0.01) as measured by DEXA scan at Day 85.

No statistically significant changes from baseline in these parameters were observed in the placebo group (0.2% reduction in visceral fat, 0.5% reduction in total body fat, 2.3% increase in lean mass).

- When adjusting for placebo, a single dose of WVE-007 led to a 9.2% reduction in visceral fat, a 4.0% reduction in total fat mass, a 0.9% increase in lean mass, and a 0.9% decrease in total mass from baseline as measured by DEXA.

- Consistent and durable serum Activin E reductions were observed across participants and support WVE-007’s potential for once or twice-yearly dosing.

- Maximum reductions in serum Activin E of 78% were observed 43 days post a single 240 mg dose.

Mean reductions of greater than 75% were maintained at least up to Day 85, the end of the data cut.

WVE-007 was generally safe and well tolerated across all dose levels (75 mg, 240 mg, 400 mg, and 600 mg).

There were no discontinuations, and no severe or serious treatment emergent adverse events (“TEAEs”).

All TEAEs were mild or moderate, and all treatment-related adverse events were mild.

There were no clinically meaningful changes in laboratory measurements, including lipid profiles and liver function tests.

The INLIGHT clinical trial is currently ongoing with 240 mg (n=32), 400 mg (n=32), and 600 mg (n=32) cohorts fully dosed.

INLIGHT is ongoing at multiple trial sites including in the US, following clearance of an Investigational New Drug (“IND”) application.

In the first quarter of 2026, we expect to deliver six-month follow-up data from Cohort 2 (240 mg) and three-month follow-up data from Cohort 3 (400 mg).

Planning is underway to initiate the Phase 2a multidose (“MAD”) portion of the ongoing INLIGHT clinical trial in individuals living with higher BMI and comorbidities in the first half of 2026.

We also expect to initiate new clinical trials evaluating WVE-007 as an incretin add-on and as post-incretin maintenance in 2026.

Alpha-1 antitrypsin deficiency (“AATD”)

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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;

Weekly intravenous augmentation therapy is the only treatment option for AATD in those with lung pathology;

there are currently no approved therapies to address the liver pathology.

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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 does not require lipid nanoparticle (“LNP”) delivery, which may be associated with systemic and liver toxicities, and comes without the risk of irreversible, collateral bystander edits and indels, which are associated with DNA base editing.

WVE-006 is first-in-class in AATD and is the most advanced program currently in clinical development using an oligonucleotide to harness an endogenous enzyme for RNA editing.

Our RestorAATion clinical program investigating WVE-006 as a treatment for AATD is comprised of 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.

We have 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, we 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, we 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.

We expect to share multi-dose data from RestoraAATion-2 in 2025.

GSK has an exclusive global license for WVE-006, with clinical development and commercial responsibilities transitioning to GSK after we complete the RestorAATion trial.

Under the terms of the collaboration, we are eligible to receive up to $525 million in development, launch, and commercial milestone payments, as well as double-digit tiered royalties up to the high teens, as a percentage of net sales for WVE-006.

In December 2023, we announced that we achieved the first WVE-006 milestone in our collaboration with GSK, resulting in a $20 million payment.

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).

Preclinical data show that treatment with WVE-006 resulted in serum AAT protein levels of up to 30 µM (7-fold increase) 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.

Our AATD AIMers are highly specific to SERPINA1 RNA in vitro and in vivo based on transcriptome-wide analyses.

Our RestorAATion clinical program investigating WVE-006 as a treatment for AATD is comprised of two parts:

RestorAATion-1, a study of healthy volunteers, and RestorAATion-2, a Phase 1b/2a open label study designed to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of WVE-006 in patients with AATD.

The trial includes both single ascending dose and multiple ascending dose portions.

In September 2025, we announced positive data from the 200 mg single and multidose (n=8), and 400 mg single dose (n=8) cohorts of the ongoing RestorAATion-2 study.

Key highlights included:

- Following a single 200 mg dose of WVE-006, a total AAT level of 20.6 µM, including a M-AAT level of 10.3 µM, was observed in one individual during an acute phase response due to a kidney stone.

These data demonstrate that treatment with WVE-006 enables endogenous regulation and dynamic increased secretion of AAT protein during an acute phase response as indicated by a concurrent C-reactive protein elevation.

- In the 200 mg multidose cohort, we observed 11.9 µM of total AAT and M-AAT of 7.2 µM, which was significantly increased from levels achieved during the single dose portion of the cohort.

M-AAT levels reached 64.4% of total AAT, and mutant Z-AAT protein declined from baseline by 60.3%.

- In the 400 mg single dose cohort, we observed total AAT of 12.8 µM and M-AAT of 5.3 µM.

- WVE-006 was generally safe and well tolerated with a favorable safety profile.

All adverse events were mild to moderate in intensity, and there were no SAEs.

Circulating M-AAT, Z-AAT, and total (M + Z) AAT protein in the serum were measured by highly selective and sensitive LC-MS/MS assays (LLOQ:

0.096 µM (M), 0.029 µM (Z)) and reported as mean participant SAD and MAD maximums

from 200 mg MAD cohort;

from 200 mg SAD cohort

The RestorAATion-2 clinical trial is fully enrolled through the 600 mg cohort, and dosing is ongoing.

We expect to deliver data from the 400 mg multidose cohort in the first quarter of 2026.

We also expect to deliver single and multidose data from the 600 mg cohort in 2026.

In February 2026, we announced we were accelerating regulatory engagement for WVE-006, and we expect to receive regulatory feedback on a potential accelerated approval pathway mid-2026.

PNPLA3 I148M liver disease

Background and Market Opportunity

PNPLA3 I148M is a genetic driver of liver disease, including metabolic dysfunction-associated fatty liver disease (“MAFLD”), metabolic dysfunction-associated steatohepatitis (“MASH”) and Alcoholic Steatohepatitis (“ASH”).

There are an estimated nine million homozygous PNPLA3 I148M individuals with liver disease in the United States and Europe.

Homozygous carriers have a near five-fold higher risk of liver-related death compared to heterozygous carriers.

Additionally, homozygous PNPLA3 I148M carriers with MASH may experience more severe disease with faster progression to advanced fibrosis and end-stage liver disease.

The PNPLA3 protein plays a critical role in hepatic lipid metabolism by balancing triglyceride storage and secretion, and supporting lipid remodeling, lipid mobilization, and retinol metabolism.

The PNPLA3 I148M variant leads to a gain-of-function and contributes to liver disease by aggravating steatosis, inflammation, fibrosis, and ballooning.

Therapeutic approaches aimed at silencing PNPLA3 may address liver fat accumulation, but they provide limited benefit in restoring retinol metabolism;

fibrosis, ballooning, and inflammation are expected to persist.

In contrast, an RNA editing approach to restore, rather than silence, PNPLA3 function in homozygous PNPLA3 I148M carriers should address liver disease by restoring lipid metabolism and reversing steatosis, fibrosis, ballooning, and inflammation.

Current Treatments

Currently, there are no therapeutic options specifically addressing the root cause of PNPLA3 I148M-driven liver disease.

There are two therapies currently approved for MASH - Rezdiffra (resmetirom) from Madrigal Pharmaceuticals (US and EU) and Wegovy (semaglutide) from Novo Nordisk (US) – but neither directly addresses the pathology driven by PNPLA3 I148M.

Our PNPLA3 I148M Liver Disease Program

To effectively address the manifestations of PNPLA3 I148M liver disease, we use our novel RNA editing approach and have advanced WVE-008, a GalNAc-conjugated AIMer, as our clinical candidate.

In preclinical studies, we have demonstrated that our PNPLA3 GalNAc-AIMer restores functional PNPLA3 protein and decreases lipid accumulation.

We expect to file a clinical trial application for WVE-008 in 2026.

Duchenne muscular dystrophy (“DMD”)

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In most countries, corticosteroids are the standard drug therapy, which slows the progression of muscle weakness and delays loss of ambulation by two to three years.

In 2017, Emflaza (deflazacort) became the first corticosteroid approved by the FDA as a treatment for patients with DMD.

Santhera Pharmaceuticals’ Agamree (vamorolone), an alternative steroid, was approved in the United States and EU in 2023.

In 2024, FDA granted approval to Italfarmaco/ITF Therapeutics’ Duvyzat (givinostat), a histone deacetylase inhibitor.

Approved steroids for DMD include Emflaza (deflazacort) and Santhera Pharmaceuticals’ Agamree (vamorolone), an alternative steroid.

Four exon skipping therapies have been approved in the United States, all under the accelerated approval pathway.

They include three products from Sarepta Therapeutics:

Exondys 51 (eteplirsen) for exon 51 skipping, approved in 2016;

Vyondys 53 (golodirsen) for exon 53 skipping, approved in 2019;

and Amondys 45 (casimersen) for exon 45 skipping, approved in 2021.

NS Pharma’s Viltepso (viltolarsen) was approved for exon 53 skipping in 2020.

They include NS Pharma’s Viltepso (viltolarsen) for exon 53 skipping and three products from Sarepta Therapeutics:

Exondys 51 (eteplirsen) for exon 51 skipping;

Vyondys 53 (golodirsen) for exon 53 skipping;

and Amondys 45 (casimersen) for exon 45 skipping.

All of these products require weekly IV infusion, and to date, none of these products has demonstrated clinical benefit in a confirmatory trial.

Sarepta Therapeutics’ Elevidys, a microdystrophin gene therapy, is available in the United States and select ex-EU markets.

The labeled indication in the United States is currently for ambulatory and non‑ambulatory DMD patients aged at least four years who have a confirmed mutation in the DMD gene.

The indication that includes ambulatory DMD patients was granted under a traditional approval, and the indication that includes non‑ambulatory DMD patients was approved under accelerated approval based on expression of Elevidys microdystrophin.

Continued approval for non‑ambulatory DMD patients may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

In 2014, PTC Therapeutics’ Translarna (ataluren) was the first disease-modifying treatment to receive conditional approval by the EMA for patients with DMD who have a nonsense mutation (12% of DMD cases) in the dystrophin gene.

However, in 2023, the Committee for Medicinal Products for Human Use (“CHMP”) of the EMA issued a negative opinion on the renewal of the conditional marketing authorization, and in 2024, CHMP re-confirmed this negative opinion.

Once adopted by the European Commission, this ruling will result in the withdrawal of Translarna from the EU market.

Sarepta Therapeutics’ Elevidys, a microdystrophin gene therapy, is available in the United States and select ex-EU markets for ambulatory DMD patients aged at least four years who have a confirmed mutation in the DMD gene.

In 2024, the FDA granted approval to Italfarmaco/ITF Therapeutics’ Duvyzat (givinostat), a histone deacetylase inhibitor.

Our DMD Program

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In the third quarter of 2024, the FDA granted Rare Pediatric Disease Designation and Orphan Drug Designation to WVE-N531.

In December 2022, we 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, we 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, we 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, we 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.

We 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.

*Excluded from prespecified mean analysis of ambulatory patients;

Muscle content adjustment was done using the formula:

MHC-normalized dystrophin/(total myofiber area/total area of biopsy section);

Graph shows all patients (including non-ambulatory) with appropriate biopsy sample;

dystrophin measured by Western Blot (AB15277)

Dystrophin expression was quantified from two isoforms consistent with those observed in Becker muscular dystrophy patients who display milder disease.

In addition, we 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, we expect to deliver the 48-week FORWARD-53 data and feedback from regulators on a pathway to accelerated approval.

Pending positive results from this trial, we are 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.

FORWARD-53, the Phase 1b/2a proof-of-concept, open label trial of WVE-N531 included “Part A,” in which 3 boys received 3 doses of WVE-N531 at 10 mg/kg every two weeks and “Part B,” in which 11 boys initially received 10 mg/kg every two weeks for 48 weeks.

In “Part B”, biopsy data was gathered from eight boys after 24 and 48 weeks, as well as safety and functional outcome assessments for all participants.

Key results from the study included:

- WVE-N531 uptake in myogenic stem cells, which are integral to muscle regeneration, and in myofibers;

- Mean WVE-N531 skeletal muscle concentrations of ~41,000 ng/g and a 61-day tissue half-life support monthly dosing;

- Statistically significant and clinically meaningful improvement of 3.8 seconds in Time-to-Rise vs.

natural history with largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks;

additional functional benefits observed in other outcome measures including North Star Ambulatory Assessment (“NSAA”);

- First-ever demonstration of substantial improvements in muscle health with exon skipping – statistically significant reduction in fibrosis driven by decreases in inflammation and necrosis, coupled with transition from regenerative to mature muscle;

decreases in creatine kinase and circulating inflammatory biomarkers;

- Dystrophin expression stabilized between 24 and 48 weeks and averaged 7.8% with 88% of boys above 5% average dystrophin;

- WVE-N531 was generally safe and well-tolerated with no SAEs observed.

All participants in FORWARD-53 elected to advance to the extension portion of the clinical trial, which is currently ongoing with boys receiving monthly doses of WVE-N531.

To augment monthly data and ensure a monthly regimen at a potential launch, we

expanded FORWARD-53 to include additional boys on a monthly dosing regimen.

We plan to file a New Drug Application in 2026 to support accelerated approval of WVE-N531 with monthly dosing.

Huntington’s disease (“HD”)

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HD is caused by a mutation (an expanded cytosine-adenine-guanine (“CAG”) triplet repeat) in the Huntingtin (“ HTT”) gene, which results in production of mHTT protein and decreases the amount of wtHTT protein that is expressed.

Patients with HD still express some wtHTT protein, which is important for neuronal function, and which may be neuroprotective in an adult brain.

Patients with HD still express some wtHTT protein, which is important for neuronal function, and which may be neuroprotective in an adult brain and specifically protective against HD.

Studies suggest a multifaceted mechanism by which gain of mHTT protein and a concurrent loss of wtHTT protein may drive the pathophysiology of HD.

Accordingly, therapeutic approaches for HD that aim to lower mHTT but that also suppress wtHTT may have detrimental long-term consequences.

Wild-type HTT is important both for normal neuronal function in the adult CNS and for protection against HD.

It can protect against stress-induced neurodegeneration in multiple model systems:

in cultured neurons, wtHTT is protective against stress-induced apoptosis;

in mice, postnatal deletion of wtHTT leads to progressive neurological phenotypes, neurodegeneration, and premature death, whereas overexpression of wtHTT conveys neural protection during stress, including ischemia and other types of CNS injury, as well as NMDA-induced excitotoxicity.

In the YAC128 mouse model of HD, overexpression of wtHTT ameliorates striatal neuropathology, whereas loss of the wild-type mouse Htt worsens motor performance, survival, and striatal neuronal size.

In patients with HD, a variant in a regulatory element impacts expression of the associated HTT gene.

An A variant decreases expression relative to a G variant at this position.

Accordingly, when the A variant associates with mHTT, expression of mHTT is reduced and disease onset is delayed (on average, 10 years).

By contrast, when the A variant associates with wtHTT, expression of wtHTT is reduced and disease onset is earlier (on average, four years), indicating that increased expression of wtHTT can be protective against HD in patients.

Together, these studies provide evidence that wtHTT is both neural protective during stress and is specifically protective against HD;

thus, we believe an allele-selective therapeutic, one that can diminish the production of mHTT while sparing wtHTT, may be ideal.

In patients with HD, a variant in a regulatory element impacts expression of the associated HTT gene.

Accordingly, the variant that decreases expression of mHTT associates with delayed onset of disease (on average by 10 years compared with the variant that increases mHTT expression).

By contrast, the same variant that decreases expression of wtHTT associates with earlier onset (on average four years compared with increased wtHTT expression), indicating that increased expression of wtHTT can be protective against HD in patients.

Together, these studies provide evidence that wtHTT is both neural protective during stress and is specifically protective against HD;

thus, we believe an allele-selective therapeutic, one that can diminish the production of mHTT while sparing wtHTT, may be ideal.

We believe an allele-selective therapeutic, one that can diminish the production of mHTT while sparing wtHTT, may be ideal.

Symptoms of HD typically appear between the ages of 30 and 50 and worsen over the next 10 to 20 years.

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Our allele-selective approach may enable us to address both the symptomatic and pre-symptomatic populations.

Medium spiny neurons in a deep brain region called the striatum, which is composed of caudate and putamen, are particularly sensitive to death in HD.

Medium spiny neurons in a deep brain region called the striatum, which includes caudate and putamen, are particularly sensitive to death in HD.

Caudate volume, as measured by magnetic resonance imaging (“MRI”), is an imaging biomarker that consistently shows atrophy at the earliest stages of disease, and it is one of the biomarkers that serves as a landmark for disease progression (Tabrizi et al., 2022 Lancet Neurol).

Our evaluation of longitudinal natural history data from TRACK-HD and PREDICT-HD demonstrate that an absolute reduction of 1% in the rate of caudate atrophy is associated with a delay of onset of disability for individuals with HD of at least 7.5 years.

TRACK-HD (n=366) and PREDICT-HD (n=1,078) are longitudinal HD natural history studies that include MRI brain imaging, clinical outcome assessments.

Paulson et al., Neurosci.2014, Tabrizi et al., Lancet Neurol 2009, Tabrizi et al., Lancet Neurol 2012, Tabrizi et al., Lancet Neurol.

Current Treatments

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Our HD Program

In HD, we are currently 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).

Approximately 40% of the HD population carries SNP3 according to published literature (Carroll et al., Molecular Therapy, 2011), and up to 80% of HD may be addressed in the future with other SNP-targeted candidates.

WVE-003 incorporates our proprietary PN chemistry.

WVE-003 is our stereopure allele-selective oligonucleotide that incorporates our proprietary PN chemistry and is 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).

Targeting mRNA through SNP3 allows us 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.

In the third quarter of 2023, we achieved a milestone in our collaboration with Takeda Pharmaceutical Company Limited (“Takeda”), which pertained to the positive results from a non-clinical study of WVE-003 in non-human primates and resulted in a payment of $7.0 million to us.

This study showed significant tissue exposure levels of WVE-003 in the deep brain regions, including striatum and bolstered our existing datasets that confirm the ability of our oligonucleotides to distribute to the areas of the CNS important for HD.

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.

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 were 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, we announced positive clinical data from the Phase 1b/2a SELECT-HD study of WVE-003.

In June 2024, we announced positive clinical data from the SELECT-HD study.

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.

* p<0.05, **p<0.01, ***p<0.001, ****p<0.0001

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.

Baseline MRI single-dose day 1-3 MRI;

final MRI multi-dose day 169;

Volumes derived through Jacobian integration after normalization in MNI space.

Results are from mixed model repeated measures (MMRM) analysis;

CSF mHTT concentration:

single-dose baseline, multi-dose day 141

In the multi-dose cohort, WVE-003 was generally safe and well-tolerated, with mild-to-moderate adverse events (“AEs”) and no SAEs.

Caudate atrophy, as measured by MRI, is a well-characterized measure 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 we assessed to be not related to WVE-003.

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In November 2024, we received supportive initial feedback from the FDA, who recognize the severity of HD and are receptive to and engaged with us regarding a potential pathway to accelerated approval.

The FDA is open to our plan to evaluate biomarkers, including caudate atrophy, as an endpoint to assess HD progression with the potential to predict clinical outcome.

The FDA is open to our plan to evaluate biomarkers, including caudate atrophy, as an endpoint to assess HD progression with the potential to predict clinical outcomes.

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.

We expect to submit an Investigational New Drug (“IND”) application for WVE-003 in the second half of 2025.

We have prepared an IND application for a potentially registrational Phase 2/3 study of WVE-003 and would plan to submit it in conjunction with a prospective strategic partner.

Discovery Pipeline

We are advancing new targets across multiple disease areas to expand our pipeline of wholly owned programs.

Our compelling preclinical data indicates our oligonucleotides can distribute to various tissues and cells without complex delivery vehicles, enabling us to address a wide variety of diseases, including pulmonary and renal diseases.

Within RNA editing, we have demonstrated preclinically that we can edit to correct monogenic diseases by restoring or correcting protein function for the treatment of AATD.

Building on our work in AATD, we have demonstrated our 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 our proprietary “edit-verse,” which is powered by genetic datasets and deep learning models, we have identified several RNA editing targets in indications that leverage easily accessible biomarkers, offer efficient paths to proof-of-concept in humans, and represent meaningful commercial opportunities.

Our 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 our collaboration with GSK, we are also leveraging GSK’s novel genetic insights to expand our wholly owned pipeline.

In addition, we and GSK are actively working on multiple target validation programs as GSK-partnered programs, for which all of our 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 us of $12.0 million from GSK.

These programs utilize our next generation GalNAc-siRNA format and are in hepatology.

We plan to share new preclinical data from our wholly owned hepatic and extra-hepatic RNA editing programs in 2025.

In 2026, we expect to initiate clinical development of additional RNA editing programs, including PNPLA3, LDLR, and APOB.

We are 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.

We have a robust and diverse pipeline of first- or best-in-class RNA medicines using our RNA editing, splicing, silencing using siRNA, and antisense silencing modalities.

Our 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.

Our compelling preclinical data demonstrate that our oligonucleotides can distribute to various tissues and cells without complex delivery vehicles, enabling us to address a wide variety of diseases.

Within RNA editing, we have demonstrated clinically that we can address monogenic diseases by correcting the disease-causing mutation, as evidenced by restoration of healthy protein function for the treatment of AATD.

Beyond correction, we have preclinical data demonstrating our ability to increase the stability of the mRNA transcript to upregulate protein levels.

Within RNAi, we have shared preclinical data which show that our SpiNA designs enable RNAi-mediated silencing by further improving Ago2 loading and pharmacokinetics, leading to increased potency and durability compared to industry benchmarks.

With our SpiNA designs, our preclinical data demonstrate we can silence targets in extra-hepatic tissues including adipose, skeletal muscle, heart, CNS, and kidney.

We are utilizing a combination of human genetics and AI for target discovery and oligonucleotide design, and we have initiated a number of preclinical RNA editing and RNAi programs supported by evidence from human genetics, that leverage easily accessible biomarkers, offer efficient paths to proof-of-concept in humans, and represent meaningful commercial opportunities.

We have applied learnings from across our platform and chemistry optimization to investigate new bifunctional modalities which combine RNAi and RNA editing or dual RNAi silencing into a single oligonucleotide construct.

These constructs are designed to silence multiple targets or silence one target while simultaneously editing or upregulating another distinct target.

We demonstrated the ability of a single bifunctional oligonucleotide to engage in silencing and editing in vivo in mice using a GalNAc-conjugated oligonucleotide that is designed to edit UGP2 and silence TTR.

In a separate preclinical study, we also demonstrated that we were able to upregulate low-density lipoprotein receptor and silence PCSK9 using a single construct in primary human hepatocytes.

Through our collaboration with GSK, we are actively working on multiple target validation programs as GSK-partnered programs, for which all of our costs and expenses are prepaid by GSK.

GSK has selected four programs, across multiple modalities and hepatic and extra-hepatic tissues, to advance to development candidates following achievement of target validation, which have resulted in additional payments to us under the collaboration.

We are building a leading RNA medicines company by utilizing our PRISM platform to translate powerful human genetic insights into potentially transformational therapeutics.

Our therapeutic pipeline is focused on our clinical-stage obesity program (WVE-007) and our RNA editing (AIMer) portfolio (WVE-006 for AATD and WVE-008 for PNPLA3 I148M liver disease), all of which leverage GalNAc delivery.

In addition to driving clinical and preclinical programs, we are continuously investing in PRISM to fully unlock the potential of our unique and expanding platform capabilities.

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• Extend our leadership in RNA medicines .

We intend to establish a dominant position in the field of oligonucleotides, advancing basic research and pharmacology using stereochemistry and other novel modifications across multiple therapeutic modalities and target classes.

Our work has already led to the development of AIMers for RNA editing, as well as the introduction of PN backbone chemistry modifications for potential therapeutic use and novel base modifications such as N3U.

We are establishing dominant position in the field of oligonucleotides, advancing basic research and pharmacology using stereochemistry and other novel modifications across multiple therapeutic modalities and target classes.

Through PRISM, our efforts continue to reveal structure-activity relationships among base modifications and sequence, chemistry and backbone stereochemistry that may allow us to further tune the activity of our oligonucleotides in a previously unexplored, modality-specific manner.

• Rapidly advance and sustainably grow our differentiated portfolio of RNA medicines.

We are committed to transforming the care of devastating diseases where patients have limited treatment options.

Our current and future portfolio is focused on novel therapeutic approaches that optimally address disease biology, that offer biomarkers for target engagement, and that inform on clinical effects early in development.

We are currently advancing multiple clinical programs:

WVE-007 (obesity), WVE-006 (AATD), WVE-N531 (DMD), and WVE-003 (HD), which were all designed with novel PN backbone chemistry modifications and developed from our PRISM platform.

We continue to conduct discovery-stage research on novel therapeutic approaches, and have the opportunity, through our GSK collaboration, to advance programs leveraging GSK’s novel genetic insights.

We expect these activities will add multiple first-in-class therapeutics to our pipeline over the next several years.

• Expand our pipeline of high-value programs.

In 2024, we made meaningful progress in advancing preclinical programs utilizing our versatile PRISM platform.

With multiple modalities at our disposal, we are positioned to unlock new biology and develop first-in-class therapeutics.

To build on our demonstration of first-ever RNA editing in humans with WVE-006 (AATD), we announced three wholly owned GalNAc-AIMer programs that offer first-in-class approaches to address unmet needs in cardiometabolic diseases.

These new programs include PNPLA3, which uses mRNA correction for those at high risk for a genetically defined liver disease, and LDLR and APOB, which utilize first-in-class mRNA upregulation and mRNA correction, respectively, to achieve target LDL-c levels in people with heterozygous familial hypercholesterolemia.

We are committed to transforming the care of individuals living with the burden of disease, including those with both rare and common diseases.

Our current and future portfolio is focused on novel therapeutic approaches that optimally address disease biology, offer biomarkers for target engagement, inform on clinical effects early in development, and represent attractive commercial opportunities.

With a focus on our clinically-validated RNAi (SpiNA) and RNA editing (AIMer) capabilities, we are positioned to unlock new biology and develop first-in-class therapeutics, including for extra-hepatic disease targets.

• Leverage manufacturing leadership in oligonucleotides.

We have built a hybrid internal / external manufacturing model that gives us the capability to produce stereopure oligonucleotides at scales from one micromole to potential commercial scale.

We have built a hybrid internal / external manufacturing model that enables us to produce stereopure oligonucleotides at scales from one micromole to potential commercial scale.

Through our internal manufacturing, based in our Lexington, Massachusetts facility, we have the capacity to support multiple discovery, preclinical, and early clinical-stage programs, and we have the expertise to conduct manufacturing runs for oligonucleotides spanning multiple modalities.

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Our stereopure oligonucleotides are distinct from the chiral backbone-modified or “mixture-based” oligonucleotides currently on the market or in development by others, which we believe are not optimized for stability, catalytic activity, efficacy or toxicity.

We believe that PRISM has the potential to set a new industry standard for the molecular characterization of complex oligonucleotide mixtures.

We believe that PRISM has the potential to set a new industry standard for the molecular characterization of therapeutic oligonucleotides.

Our rational process for designing stereopure oligonucleotides allows us to selectively optimize chemical modifications to a specific therapeutic modality in order to generate best-in-class oligonucleotides.

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By exploring these interactions through iterative analysis of in vitro and in vivo outcomes and machine learning-driven predictive modeling, we continue to define design principles that we deploy across programs to rapidly develop and manufacture clinical candidates that meet pre-defined product profiles.

PRISM has also enabled us to further innovate our chemistry, including the application of novel PN backbone chemistry modifications to our pipeline programs.

PRISM has also enabled us to further innovate our chemistry, including the application of new chemistry modifications, to our pipeline programs.

• Broad applicability .

PRISM is applicable to oligonucleotides acting via multiple therapeutic modalities, including RNA editing, splicing, and silencing (including siRNA and antisense).

PRISM is applicable to oligonucleotides acting via multiple therapeutic modalities, including RNAi, RNA editing, splicing, antisense and bifunctional modalities.

It is also compatible with a broad range of chemical modifications and targeting moieties.

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We can take advantage of simplified delivery strategies, such as free-uptake or GalNAc conjugation, to reach the site of action in the right tissue.

This approach avoids the need, and certain limitations, for complex delivery vehicles such as lipid nanoparticles (“LNPs”) or adeno-associated viruses (“AAV”).

This approach avoids the need, and certain limitations, for complex delivery vehicles such as LNPs or adeno-associated viruses (“AAV”).

• Proprietary production of stereopure oligonucleotides and scalable manufacturing .

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These and other preclinical studies have demonstrated that stereochemistry impacts pharmacology, and that by controlling stereochemistry, we can tune multiple aspects of pharmacology, including stability, catalytic activity, and efficacy.

We have subsequently published multiple additional manuscripts that provide evidence that stereopure oligonucleotides can be developed to have superior pharmacology to stereorandom oligonucleotides.

We have subsequently published multiple additional manuscripts that provide robust evidence that stereopure oligonucleotides can be developed to have superior pharmacology to stereorandom oligonucleotides.

PN Backbone Chemistry Modifications

Our 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, we introduced PN chemistry to our repertoire of backbone modifications;

this backbone modification replaces a non-bridging oxygen atom in a phosphodiester linkage with a nitrogen-containing moiety, as shown below.

this backbone modification replaces a non-bridging oxygen atom in a phosphodiester linkage with a nitrogen-containing moiety.

We have incorporated these PN modifications – specifically phosphoryl guanidine – into oligonucleotide compounds.

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In preclinical experiments, we have demonstrated that judicious use of PN backbone chemistry modifications in stereopure oligonucleotides have generally increased potency, tissue exposure and durability of effect across our RNA editing, siRNA, splicing, and antisense modalities.

We have also investigated the impact of PN chemistry and performed experiments under gymnotic or free uptake conditions.

In the graph labeled one below, the data demonstrate the contrast between AIMer uptake in cells, depending on whether it incorporates PN chemistry, shown in light blue, or not, shown in dark blue.

We have also investigated the impact of PN chemistry on cellular uptake and trafficking using gymnotic or free uptake conditions.

In the graph labeled one below, the data demonstrate the cellular uptake improvement for AIMers containing PN chemistry, shown in light blue, compared to those without PN chemistry, shown in dark blue.

To the right, in the graph labeled two, the data demonstrate the proportion of AIMer released from endosomes inside the cell.

The addition of PN chemistry drove a greater than 2-fold increase in cellular uptake and an over 4-fold increase in endosomal release compared with PS chemistry.

The addition of PN chemistry drove a greater than 2-fold increase in cellular uptake and an over 4-fold increase in endosomal release compared with AIMers lacking PN chemistry.

Below, we also demonstrated the benefits of PN chemistry on cellular residency, with a higher percentage of PN-containing molecules persisting within the cell, a 5-fold benefit on nuclear uptake, and ultimately, evidence this modification leads to a dramatic 30-fold improvement in target engagement in a cell free lysate system.

RNA editing – AIMer designs

With PRISM, we have generated stereopure AIMers, optimized for chemistry and stereochemistry, which promote RNA editing with endogenous ADAR enzymes in cellular models.

We have demonstrated that the addition of PN chemistry substantially improves both potency and editing efficiency.

Our foundational RNA editing paper published in Nature Biotechnology (Monian P, et.

doi.org/10.1038/s41587-022-01225-1) was the first scientific publication to report successful RNA base editing in NHPs using only single-stranded, GalNAc-conjugated oligonucleotides.

In this manuscript, we demonstrated efficient RNA editing in vitro with our AIMers across a variety of cell lines, including non-human primate (“NHP”) and human primary hepatocytes.

We observed potent, dose-dependent RNA editing with three chemically distinct stereopure AIMers (ACTB 1, ACTB 2, ACTB 3) via GalNAc-mediated uptake.

We next evaluated these same GalNAc-conjugated ACTB-editing AIMers in vivo in NHPs.

For this study, we dosed NHPs subcutaneously once a day for five days.

We took liver biopsy samples at baseline at two days and 45 days after the last dose to evaluate editing.

We detected up to 50% editing two days after the last dose as compared to a baseline of 0% editing.

These editing results were durable:

we continued to see significant editing 45 days after the last dose.

The PK data confirmed that a significant amount of AIMer was still detectable in the liver at that time.

To assess off-target editing for the whole transcriptome, a mutation-calling software was used to call edit sites.

From this analysis, we observed nominal off-target editing across the transcriptome.

Sites where potential off-target editing occurred mapped predominantly to non-coding regions of the transcriptome and had either low read coverage in the analysis or occurred at low percentages of less than 10%, indicating that these are relatively rare events.

Base Modifications

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In our 2024 Nucleic Acids Research paper (Lu et al., 2024 Nuc Acid Res;

doi.org/10.1093/nar/gkae681 N), we described the development of new AIMer designs with base modifications and sequence, sugar and backbone modifications that improve RNA editing efficiency over our previous design.

AIMers incorporating a novel pattern of backbone and 2′ sugar modifications support enhanced editing efficiency across multiple sequences.

doi.org/10.1093/nar/gkae681 N), we described the development of new AIMer designs (AIMer-D) with base modifications and sequence, sugar and backbone modifications that improve RNA editing efficiency over our previous design (AIMer-S).

AIMers incorporating the AIMer-D pattern of backbone and 2′ sugar modifications supported enhanced editing efficiency across multiple sequences.

Further efficiency gains were achieved through incorporation of N3U in place of cytidine (C) in the orphan position.

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We continuously explore how new modifications and new combinations of modifications from our expansive repertoire can redefine what’s possible with oligonucleotide therapeutics

PRISM Supports Multiple Therapeutic Modalities

Using PRISM, we have designed and optimized diverse sets of stereopure oligonucleotides, which allows us to characterize and compare the impact of various chemical modifications on key properties that impact a specific modality.

In the next section, we describe different therapeutic modalities for which we have used PRISM to optimize stereopure oligonucleotides and develop built-for-purpose candidates to optimally address disease biology.

We have applied our PRISM platform to the generation of short, single-stranded, highly specific A-to-I (G) RNA editing oligonucleotides – called “AIMers”.

Because our AIMers are relatively short and stable (fully chemically modified), we can leverage clinically proven GalNAc-mediated delivery to hepatocytes with subcutaneous dosing.

We are developing fully chemically modified AIMers with and without GalNAc conjugation.

In preclinical studies, we have 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, we have 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, we show 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 our foundational RNA editing paper published in Nature Biotechnology (Monian P, et.

doi.org/10.1038/s41587-022-01225-1), we demonstrated efficient RNA editing in vitro with our AIMers across a variety of cell lines, including non-human primate (“NHP”) and human primary hepatocytes, as shown in the figures below.

We observed potent, dose-dependent RNA editing with three chemically distinct stereopure AIMers (ACTB 1, ACTB 2, ACTB 3) via GalNAc-mediated uptake.

We next evaluated these same ACTB-editing AIMers in vivo in NHPs, and the results are shown in the figures below.

For this study, we dosed NHPs subcutaneously once a day for five days.

We took liver biopsy samples at baseline at two days and 45 days after the last dose to evaluate editing.

We detected up to 50% editing two days after the last dose as compared to a baseline of 0% editing, as shown in the figure below in the middle.

These editing results were durable:

we continued to see significant editing 45 days after the last dose.

The PK data, shown in the figure below on the left, confirmed that a significant amount of AIMer was still detectable in the liver at that time.

To assess off-target editing for the whole transcriptome, a mutation-calling software was used to call edit sites.

From this analysis, we observed nominal off-target editing across the transcriptome.

We have demonstrated potent (up to 65%) and durable (out to at least four months) editing of UGP2 mRNA in vivo in multiple regions of the CNS following a single unconjugated AIMer dose in a mouse model with human ADAR, as shown in the figure below.

We have also demonstrated that RNA editing observed in mice translates when moving to non-human primates.

As shown in the figure below on the left, we observed editing of UGP2 mRNA in vivo in multiple regions of CNS following a single unconjugated AIMer dose in a mouse model with human ADAR.

As shown in the figure below on the right, we observed editing of ACTB mRNA in multiple regions of CNS following a single, intrathecal unconjugated AIMer dose in non-human primates.

We have also observed productive editing beyond liver and CNS with unconjugated AIMers in multiple tissue types including the retina in mice (below top right), kidney, liver, lung and heart of NHPs (below bottom left), and human PBMCs in vitro (below bottom right).

We 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.

The application of PRISM to RNA editing opens the door to therapeutic applications extending beyond precise correction of genetic mutations, including upregulation of expression, modification of protein function, or alteration of protein stability.

To date, we have achieved in vivo proof-of-concept modulating protein-protein interactions and upregulating protein expression.

To exemplify our ability to modulate protein-protein interactions using ADAR, we evaluated the well characterized KEAP1/NRF2 system.

Through direct protein-protein interactions, KEAP1 negatively regulates the activity of NRF2 as an inducer of antioxidant gene expression.

As a proof-of-concept experiment, we investigated if we could mimic the cellular stress response by using ADAR to edit individual amino acids at the protein-protein interaction interface between NRF2 and KEAP1 in vivo in mice.

If these edits work as designed, we would expect to see downstream upregulation of the NRF2-dependent gene expression program even in the absence of cellular stressors.

As shown below, treatment with AIMers resulted in increased expression of known downstream NRF2-dependent genes involved in the antioxidant response.

Control treatment did not increase expression of any of the NRF2-dependent genes, indicating that AIMer treatment did not lead to NRF2-dependent gene expression changes through non-specific mechanisms such as increased cellular stress.

To exemplify our ability to upregulate protein expression levels using ADAR, we evaluated AIMers designed to modify regulatory elements in RNA that mediate protein-RNA or RNA-RNA interactions.

Specific structural or sequence motifs that mediate these intermolecular interactions impact RNA processing and stability.

In the figures below, we demonstrate in vivo proof-of-concept for this application of AIMers using an undisclosed target.

Moving from left to right, we first demonstrate over 75% RNA editing of the target, which leads to >2-fold upregulation of that mRNA, and, ultimately, an increase in protein expression (as shown on the far right).

Silencing – RNAi and RNase H-mediated degradation

Using PRISM, we can produce stereopure PN-modified oligonucleotides that promote potent and specific RNA transcript silencing activity in preclinical experiments.

We have applied our 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.

RNAi - SpiNA design

We have applied our stereopure PS and PN modifications to the siRNA modality using double-stranded siRNAs.

In April 2023, we announced the publication of preclinical data for our 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.

The data, shown below, illustrate a GalNAc-siRNA, with controlled stereochemistry and PN backbone chemistry, that led to remarkably durable transcript silencing in mice three months after a single dose, compared with mice treated with a siRNA based on state-of-the-art designs, where expression levels had recovered to control levels (left).

The data below (middle and right) also highlight that siRNAs developed with PRISM show improved activity profiles because they support more Ago2 loading than controls.

Left, Middle, and right:

Mice expressing human HSD17B13 transgene treated with siRNA (3 mg/kg) or PBS, liver mRNA, guide strand concentration, Ago2 loading quantified.

Two-way ANOVA with post-hoc test * P<0.05, ****P<0.0001.

Liu et al., 2023 Nuc Acids Res doi:

We continue to improve upon our GalNAc-siRNA with our SpiNA designs, which enable improved RNAi-mediated silencing by further increasing Ago2 loading, leading to improved potency and durability compared to our earlier siRNA designs (NAR) and industry benchmark (Ref, NAR:

Liu et al., 2023 Nucleic Acids Research doi:

10.1093/nar/gkad268).

We continue to improve upon our GalNAc-siRNA designs, and our next generation siRNA format has best-in-class potential.

As shown in the figure below, our next generation GalNAc-siRNA (shown in dark blue) further improves on the potency and duration of silencing in mice over our first generation GalNAc-siRNA format (shown in light blue) and the benchmark, which is based on a clinically proven format.

Translation from preclinical experiments to the clinic is well understood for RNAi, and we expect our next generation siRNA format may support six month or annual subcutaneous dosing.

2018, 26(3), 708.

B6 mice administered PBS or 0.5 mg/kg of siRNA (subcutaneous).

Mixed Two-way ANOVA followed by post hoc test comparing siRNA vs.

Next gen siRNA per day derived from linear mixed effects model * P < 0.0001

Additionally, in an in vivo non-GalNAc siRNA study, we demonstrated that we 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.

PBS (dotted line) or 100 μg of App siRNA administered ICV (n=5-6).

PCR assays for RNA PD, relative fold changes of App to Hprt mRNA normalized to % of PBS;

derived from Three-way ANOVA (treatment, tissue, time point) followed by Bonferroni-adjusted post hoc test comparing condition to PBS (data not shown), Next gen siRNA significantly lower than PBS at week 16 for all tissues at P < 0.0001 level;

Immunohistochemical analysis of FFPE Mouse Brain tissue labeling App protein (Color Brown) with CS#19389 followed by a ready to use Polymer-HRP 2nd Detection antibody.

Nuclei were counterstained with Hematoxylin (Color Blue).

Single 100 ug ICV injection

We further demonstrated how our PN chemistry allows us to access new tissues through eight-week mouse experiments using siRNAs to silence gene expression.

On the far left, we highlight the well-described impact of using GalNAc to access hepatocytes in the liver.

This graph also highlights the limits of a conjugate, as it is cell and tissue specific, so it does not enable silencing in other tissues of interest, like white adipose, muscle or cardiac tissue.

To the right, we demonstrate our ability to alternate designs with PN variants to enable access to new and various combinations of tissues, including liver, adipose and muscle, in the absence of any targeting ligand.

Depending on the target and indication, we can deploy the design that best fits the biology.

Using PRISM, we can change the physicochemical properties of our oligos to deliver to numerous extrahepatic tissues and achieve potent and durable silencing with a single dose.

With PRISM, we have optimized stereopure oligonucleotides that promote efficient splicing in vitro , ex vivo , and in vivo to restore protein production.

In our splicing programs, as with our other modalities, the base modifications and sequence, chemistry and backbone stereochemistry of oligonucleotides impact their activity.

In our Nucleic Acids Research paper (Kandasamy et al., 2022;

10.1093/nar/gkac018), we highlight the impact of PN chemistry on exon skipping.

In one application from the paper, we plotted the in vitro skipping efficiency of compounds containing PS / PO backbone chemistry modifications, depicted in the graph below by the teal dots, which are rank-ordered from left-to-right based on their exon-skipping potency in human myoblasts.

The more potent molecules are shifted upwards as they are restoring expression.

The navy dots represent the impact of a few stereopure PN modifications in compounds with otherwise identical sequences and 2’-ribose chemical modifications.

There is an overall shift upwards in activity among the PS / PO / PN compounds, representing a substantial potency gain in most cases.

Moving in vivo , we demonstrated successful exon skipping in double knockout mice (“dKO”), which lack both utrophin and dystrophin and therefore develop a severe muscular dystrophy phenotype comparable to that observed in patients with DMD.

In these mice, exon skipping correlated with dystrophin protein expression, and PN-modified oligonucleotides led to more exon skipping and dystrophin production in all muscles examined after six weeks of treatment (shown below, left).

Exon skipping and dystrophin expression improvements correlated with improved serum biomarker profiles in the same mice (shown below, right).

These results demonstrate the impact of the judicious placement of PN linkages – with no delivery vehicle or conjugate – which can significantly improve the pharmacological profiles for stereopure compounds.

Data adapted from Figure 8, Kandasamy et al., 2022;

10.1093/nar/gkac018 (Stats:

One-way ANOVA:

*P<0.05, **P<0.01, ***P<0.001, ****P<0.0001)

RNase H-mediated degradation (antisense) :

In our Nucleic Acids Research paper (Kandasamy et al., 2022;

10.1093/nar/gkac018), we illustrated the impact of PN backbone chemistry modifications for an RNase-H mediated silencing modality.

In addition to the data reported in the paper, we have 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, we 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 ~80% of them yielding at least 75% knockdown.

These results, shown below, suggest we are able to target sequence space that would otherwise be inaccessible.

Moving in vivo , we have demonstrated potent silencing activity of multiple targets in the CNS of non-human primates with stereopure, PN-modified oligonucleotides.

In one study, non-human primates received a single 12 mg dose of PN-modified MAPT silencing oligonucleotide by intrathecal injection.

This single dose led to substantial and widespread mRNA reduction in the CNS one month after administration, as well as potent mRNA silencing (as shown on the left).

In a separate study (shown on the right), NHPs were treated with four monthly intrathecal doses of a stereopure PN-modified MAPT silencing oligonucleotide across three dose levels.

This repeat dosing led to 80-90% knockdown though out the CNS.

As shown in the figure below, we have seen improvements in Ttr mRNA silencing in mice with our GalNAc-conjugated siRNAs following a single dose at 2 mg/kg.

All siRNAs have the same sequence and 2’-modifications as the literature reference construct with state-of-the-art siRNA chemistry

Compared to reference and our previous published siRNA constructs, SpiNA designs have also substantially improved the potency and duration of silencing, and we have observed up to 95% Ttr mRNA knockdown in mice at least up to 8 weeks after a single dose as shown in the figure below on the left.

We have demonstrated that the shifts in potency and duration of activity of SpiNA is driven by increases in both Ago2 loading and PK, with SpiNA driving up to ten-fold improvement in Ago2 versus a reference compound, as shown below on the right.

Single subcutaneous dose of 0.5 mg/kg in C57BL/6 mice;

single subcutaneous dose of 2 mg/kg in C57BL/6 mice;

single subcutaneous dose of 0.5 mg/kg in C57BL/6 mice

Our Collaborations

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("Wave USA") and Wave Life Sciences UK Limited ("Wave UK"), two of our 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, we and GSK have agreed to collaborate on the research, development, and commercialization of oligonucleotide therapeutics, including a global exclusive license to WVE-006.

Pursuant to the GSK Collaboration Agreement, we and GSK have agreed to collaborate on the research, development, and commercialization of oligonucleotide therapeutics.

The discovery collaboration has an initial four-year research term and combines our proprietary discovery and drug development platform, PRISM TM , with GSK’s novel genetic insights and its global development and commercial capabilities.

In addition, the GSK Collaboration Agreement originally contained a global exclusive license to GSK for WVE-006, our first-in-class A-to-I(G) RNA editing candidate for alpha-1 antitrypsin deficiency, and in February 2026, we announced that we had regained full rights to WVE-006 from GSK.

Under the terms of the GSK Collaboration Agreement, we received an upfront payment of $170.0 million, which included a cash payment of $120.0 million and a $50.0 million equity investment.

In addition, assuming WVE-006 and GSK’s eight collaboration programs achieve initiation, development, launch, and commercialization milestones, we would be eligible to receive up to $3.3 billion in cash milestone payments, which are described in the following paragraphs.

GSK received an exclusive global license to WVE-006, our first-in-class A-to-I(G) RNA editing candidate for alpha-1 antitrypsin deficiency, with development and commercialization responsibilities transferring to GSK after we complete the first-in-patient study.

We will be responsible for preclinical, regulatory, manufacturing, and clinical activities for WVE-006 through the initial Phase 1/2 study (RestorAATion), at our sole cost.

Thereafter, GSK will be responsible for advancing WVE-006 through pivotal studies, registration, and global commercialization at GSK’s sole cost.

For the WVE-006 program, we would be eligible to receive up to $225.0 million in development and launch milestone payments and up to $300.0 million in commercialization milestone payments, as well as double-digit tiered royalties up to the high teens as a percentage of net sales.

The collaboration has three components:

(1) a discovery collaboration which enables us to advance up to three programs leveraging targets informed by GSK’s novel genetic insights;

(2) a discovery collaboration which enables GSK to advance up to eight programs leveraging PRISM and our oligonucleotide expertise and discovery capabilities;

and (3) an exclusive global license for GSK to WVE-006, our AATD program, that uses our proprietary AIMer technology.

Wave will maintain development responsibilities for WVE-006 through completion of RestorAATion-2, at which point development and commercial responsibilities will transition to GSK.

The collaboration will enable us to continue building a pipeline of transformational oligonucleotide-based therapeutics and unlock new areas of disease biology, as well as realize the full value of WVE-006 as a potential best-in-class treatment for AATD that has potential to simultaneously address both liver and lung manifestations of the disease.

In addition, assuming GSK’s eight collaboration programs achieve initiation, development, launch, and commercialization milestones, we would be eligible to receive up to $2.8 billion in cash milestone payments, which are described in the following paragraphs.

The collaboration currently includes (1) a discovery collaboration which enables us to advance up to three programs leveraging targets informed by GSK’s novel genetic insights;

and (2) a discovery collaboration which enables GSK to advance up to eight programs leveraging PRISM and our oligonucleotide expertise and discovery capabilities.

The collaboration will enable us to continue building a pipeline of transformational oligonucleotide-based therapeutics and unlock new areas of disease biology.

The GSK Collaboration Agreement includes options to extend the research term for up to three additional years, which would increase the number of programs available to both parties.

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The GSK Collaboration Agreement contains customary termination provisions, including certain termination rights for convenience, breach, and others, including on a target/program basis or of the GSK Collaboration Agreement in its entirety.

we agreed to sell to GGL 10,683,761 of our ordinary shares at a purchase price of $4.68 per share, for an aggregate purchase price of approximately $50.0 million (the “GSK Equity Investment”).

With respect to the $50.0 million equity investment referred to above, simultaneously with our entry into the GSK Collaboration Agreement, we entered into a share purchase agreement with Glaxo Group Limited (“GGL”), an affiliate of GSK, pursuant to which we agreed to sell to GGL 10,683,761 of our ordinary shares at a purchase price of $4.68 per share, for an aggregate purchase price of approximately $50.0 million (the “GSK Equity Investment”).

The GSK Equity Investment closed on January 26, 2023.

The shares purchased by GGL in the GSK Equity Investment are subject to lock-up and standstill restrictions and carry certain registration rights, customary for transactions of this kind.

The shares purchased by GGL in the GSK Equity Investment carry certain registration rights, customary for transactions of this kind.

In November 2019, we 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 our investigational allele-selective therapeutic programs targeting HD.

This collaboration uses 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, our current HD program being investigated in the ongoing SELECT-HD clinical trial as well as those SNPs targeted by our previous investigational therapeutic programs.

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, our HD program.

These tests are designed to aid clinicians in selecting HD patients by identifying the SNPs that are in phase with the CAG-expanded allele.

Manufacturing

To provide internal cGMP manufacturing capabilities and increase control and visibility of our drug product supply chain, we entered into a lease in September 2016 for a multi-use facility of approximately 90,000 square feet in Lexington, Massachusetts and initiated the build out of manufacturing space and related capabilities.

To provide internal cGMP manufacturing capabilities of drug substance and increase control and visibility of our drug product supply chain, we entered into a lease in September 2016 for a multi-use facility of approximately 90,000 square feet in Lexington, Massachusetts and initiated the build out of manufacturing space and related capabilities.

Through our internal manufacturing, we have the capacity to support multiple discovery-, preclinical-, and early clinical-stage programs and have the established expertise to efficiently conduct manufacturing runs for oligonucleotides across a spectrum of modalities.

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There are two GLP-1 receptor agonists approved in the United States for the treatment of obesity:

Saxenda (liraglutide, Novo Nordisk) and Wegovy (semaglutide, Novo Nordisk).

Saxenda (liraglutide, Novo Nordisk) and Wegovy / Wegovy pill (semaglutide, Novo Nordisk).

Zepbound (tirzepatide, Eli Lilly), approved by the FDA in November 2023, is a GLP-1/GIP receptor agonist.

Beyond these approved therapies, there are investigational oral GLP-1 receptor agonists and other GLP-1 receptor agonist combinations (e.g., GLP-1/GIP/glucagon receptor agonists, GLP-1/glucagon receptor agonists, GLP-1/amylin receptor agonists, GLP-1/GLP-2 receptor agonists, etc.) in various stages of clinical development.

Beyond these approved therapies, there are other investigational oral GLP-1 receptor agonists, other GLP-1 receptor agonist combinations (e.g., GLP-1/GIP/glucagon receptor agonists, GLP-1/glucagon receptor agonists, GLP-1/amylin receptor agonists, GLP-1/GLP-2 receptor agonists, etc.), and other mechanisms (e.g., amylin) in various stages of clinical development.

Other FDA-approved therapies for obesity include Xenical (H2-Pharma), Qsymia (Vivus), and Contrave (Currax Pharmaceuticals).

Arrowhead has a program targeting INHBE in Phase 1/2 development, and Alnylam has a preclinical INHBE program.

Arrowhead, Rona Therapeutics, Vial, BaseCure Therapeutics, SanegeneBio, and Hengrui have siRNA programs targeting INHBE in Phase 1 or Phase 1/2 development, and Alnylam and Innovent, among others, have preclinical INHBE programs.

iBio has a preclinical antibody program targeting Activin E.

In addition, multiple other companies are pursuing approaches for obesity that are complementary to GLP-1 receptor agonists and aim to reduce fat mass while preserving or increasing lean mass.

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The prescribing information for each states that the effect of augmentation therapy with any alpha1-proteinase inhibitor on pulmonary exacerbations and on the progression of emphysema in Alpha1-PI deficiency has not been demonstrated in randomized, controlled clinical trials.

Beyond WVE-006, we are aware of one other clinical stage RNA editing program in development for AATD lung and/or liver disease from Korro Bio (Phase 1/2).

Beam Therapeutics has a Phase 1/2 study ongoing with a DNA base editing approach.

To our knowledge, there are no RNA editing programs currently in clinical development for AATD other than WVE-006, but Korro Bio and AIRNA have programs in preclinical development.

Beam Therapeutics has a Phase 1/2 study and YolTech Therapeutics has a Phase 1 investigator-initiated trial ongoing with a DNA base editing approach, and three companies are developing prime editing approaches, including Tessera Therapeutics, which is initiating a Phase 1/2 study, and CRISPR Therapeutics and Prime Medicine which have programs in preclinical development.

There are also a number of companies with investigational drugs in clinical development for AATD lung disease:

Kamada (Phase 3), Krystal Biotech (Phase 1), Mereo BioPharma (Phase 2 completed), and Sanofi (Phase 2), among others.

Arrowhead Pharmaceuticals and Takeda have an investigational drug in Phase 3 clinical development for AATD liver disease, and Biomarin is initiating a Phase 1 study for this indication.

Krystal Biotech (Phase 1), Mereo BioPharma (Phase 2 completed), and Sanofi (Phase 2), among others.

Arrowhead Pharmaceuticals and Takeda have an investigational drug in Phase 3 clinical development for AATD liver disease.

Duchenne Muscular Dystrophy (“DMD”)

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Sarepta Therapeutics’ Elevidys, a microdystrophin gene therapy, is available in the United States and some ex-EU markets.

Its current indication in the US is for ambulatory and non‑ambulatory DMD patients aged at least four years who have a confirmed mutation in the DMD gene.

Its current indication in the US is for ambulatory patients with DMD aged at least four years who have a confirmed mutation in the DMD gene.

This includes patients who have a DMD mutation amenable to exon 53 skipping.

Continued approval for non‑ambulatory DMD patients may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Other therapies available for DMD include Santhera Pharmaceuticals’ Agamree (vamorolone), an alternative steroid which was approved in the US and EU in 2023 and Italfarmaco/ITF Therapeutics’ Duvyzat (givinostat), a histone deacetylase inhibitor which was approved in the United States in 2024.

Other therapies available for DMD include Catalyst Pharmaceuticals’ Agamree (vamorolone), an alternative steroid which was approved in the US and EU in 2023, PTC Therapeutics’ Emflaza (steroid, now generic), and Italfarmaco/ITF Therapeutics’ Duvyzat (givinostat), a histone deacetylase inhibitor which was approved in the United States in 2024.

Several other companies have investigational drugs in clinical development targeting DMD more broadly, including patients amenable to exon 53 skipping.

These include Capricor Therapeutics (Preregistration with FDA), Dystrogen Therapeutics (Phase 1), Edgewise Therapeutics (Phase 2), Regenxbio (Phase 1/2), and Solid Biosciences (Phase 1/2), among others.

These include Capricor Therapeutics (Preregistration with FDA), Dystrogen Therapeutics (Phase 1), Edgewise Therapeutics (Phase 2), Regenxbio (Phase 3), Satellos Bioscience (Phase 1), and Solid Biosciences (Phase 3), among others.

Based on available information, we do not believe there are other companies with investigational programs specifically for exon 53 skipping in clinical development.

Several companies also have ongoing preclinical programs for DMD that may directly or indirectly target patients amenable to exon 53 skipping.

These companies include Code Bio, Dyne Therapeutics, PepGen, Precision BioSciences, Ultragenyx Pharmaceutical, and Vertex Pharmaceuticals, among others.

These companies include Dyne Therapeutics, Precision BioSciences, and Vertex Pharmaceuticals, among others.

Huntington’s Disease (“HD”)

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Austedo (Teva), tetrabenazine (generic), and, in 2023, Ingrezza (Neurocrine Biosciences) have been approved for the treatment of chorea associated with HD.

We believe, based on publicly available information, that Alnylam (Phase 1), Annexon Biosciences (Phase 2 completed), Ionis Pharmaceuticals and Roche (Phase 2), Mitochon Pharmaceuticals (Phase 1/2), Prilenia Therapeutics (Preregistration with EMA), PTC Therapeutics (Phase 2), Skyhawk Therapeutics (Phase 1), uniQure (Phase 1/2), and Vico Therapeutics (Phase 1/2), among others, have investigational drugs aimed at slowing the progression of HD in clinical development.

We believe, based on publicly available information, that Alnylam (Phase 1), Annexon Biosciences (Phase 2 completed), Ionis Pharmaceuticals and Roche (allele-selective in Phase 1 and pan-silencing in Phase 2), Prilenia Therapeutics (Phase 3), PTC Therapeutics / Novartis (Phase 2), Roche (Phase 1/2), Skyhawk Therapeutics (Phase 2/3), uniQure (Phase 1/2), and Vico Therapeutics (Phase 1/2), among others, have investigational drugs aimed at slowing the progression of HD in clinical development.

To our knowledge, we have the most advanced clinical stage program targeting allele-selective mHTT lowering.

Several companies have ongoing discovery or preclinical programs for HD, including Atalanta Therapeutics, Ophidion, Roche, Sangamo Therapeutics and Takeda, Spark Therapeutics, and Voyager Therapeutics and Novartis, among others.

Several companies have ongoing discovery or preclinical programs for HD, including Atalanta Therapeutics, Ophidion, Sangamo Therapeutics and Takeda, Sarepta Therapeutics, and Voyager Therapeutics and Novartis, among others.

Molecules to treat symptoms associated with HD are also in development.

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• satisfactory completion of an FDA pre-approval inspection of one or more clinical trial site(s) or the sponsor’s site and/or contract research organization responsible for conduct of key clinical trials in accordance with GCP;

• submission to the FDA of a New Drug Application (“NDA”), which must be accepted for filing by the FDA;

• submission to the FDA of an NDA, which must be accepted for filing by the FDA;

• completion of an FDA advisory committee review, if applicable;

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These are commonly referred to as pivotal studies.

When Phase 2 evaluations demonstrate that a dose range of the product appears to be effective and has an acceptable safety profile, trials are undertaken in larger patient populations

to further evaluate dosage, to obtain substantial, statistical evidence of clinical efficacy and safety, generally at multiple, geographically-dispersed clinical trial sites, to establish the overall risk-benefit relationship of the product and to provide adequate information for approval of the product.

When Phase 2 evaluations demonstrate that a dose range of the product appears to be effective and has an acceptable safety profile, trials are undertaken in larger patient populations to further evaluate dosage, to obtain substantial, statistical evidence of clinical efficacy and safety, generally at multiple, geographically-dispersed clinical trial sites, to establish the overall risk-benefit relationship of the product and to provide adequate information for approval of the product.

In some cases, the FDA may condition approval of an NDA for a product candidate on the sponsor’s agreement to conduct additional clinical trials to further assess the product’s safety and effectiveness after NDA approval.

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The FDA may grant a waiver for some or all of the requirements for a diversity action plan.

It is unknown at this time how the diversity action plan may affect Phase 3 trial planning and timing, but if FDA objects to a sponsor’s diversity action plan and requires the sponsor to amend the plan or take other actions, it may delay trial initiation.

If FDA objects to a sponsor’s diversity action plan and requires the sponsor to amend the plan or take other actions, it may delay trial initiation.

Assuming successful completion of the required clinical testing, the results of the preclinical studies and clinical trials, along with information relating to the product’s pharmacology, chemistry, manufacturing, and controls, and proposed labeling, are submitted to the FDA as part of an NDA requesting approval to market the product for one or more indications.

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The FDA is not bound by the recommendation of an advisory committee, but it considers such recommendations when making final decisions on approval.

The FDA likely will re-analyze the clinical trial data, which could result

in extensive discussions between the FDA and the applicant during the NDA review process.

The FDA likely will re-analyze the clinical trial data, which could result in extensive discussions between the FDA and the applicant during the NDA review process.

The FDA also may require submission of a risk evaluation and mitigation strategy (“REMS”) if it determines that a REMS is necessary to ensure that the benefits of the drug outweigh its risks and to assure the safe use of the drug or biological product.

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The approval process is lengthy and often difficult, and the FDA may refuse to approve an NDA if the applicable regulatory criteria are not satisfied or may require additional clinical or other data and information.

On the basis of the FDA’s evaluation of the NDA and accompanying information, including the results of the inspection of the manufacturing facilities, it may issue an approval letter or a Complete Response Letter (“CRL”).

On the basis of the FDA’s evaluation of the NDA and accompanying information, including the results of the inspection of the manufacturing facilities, it may issue an approval letter or a Complete

Response Letter (“CRL”).

An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.

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The CRL may require additional clinical or other data, additional pivotal Phase 3 clinical trial(s) and/or other significant and time-consuming requirements related to clinical trials, nonclinical studies or manufacturing.

In September 2025, the FDA began publishing CRLs soon after issuing them to the respective sponsors, breaking with long standing agency tradition of publishing CRLs with approval documentation after the product is approved.

Although the CRLs are made public, the FDA redacts trade secrets and confidential commercial information prior to release.

If a CRL is issued, the applicant may choose to either resubmit the NDA addressing all of the deficiencies identified in the letter or withdraw the application.

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The FDA must take certain actions with respect to breakthrough therapies, such as holding timely meetings with and providing advice to the product sponsor, which are intended to expedite the development and review of an application for approval of a breakthrough therapy.

Finally, the FDA may designate a product for priority review if it is a drug or biologic that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness over existing therapy.

The FDA may designate a product for priority review if it is a drug or biologic that treats a serious condition and, if approved, would provide a significant improvement in safety or effectiveness over existing therapy.

The FDA determines at the time that the marketing application is submitted, on a case-by-case basis, whether the proposed drug represents a significant improvement in treatment, prevention or diagnosis of disease when compared with other available therapies.

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A priority review designation is intended to direct overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months for an NME NDA from the date of filing.

Even if a product qualifies for one or more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Furthermore, fast track designation, breakthrough therapy designation and priority review do not change the standards for approval and may not ultimately expedite the development or approval process.

In 2025, the FDA created a new pilot voucher program called the Commissioner’s National Priority Voucher (“CNPV”) with the goal of radically expediting the drug and biological product review and approval process.

The agency may award a CNPV to a company or a specific product candidate that demonstrates alignment with certain national health priorities.

The FDA aims to take action on a marketing application for which a CNPV is used within one to two months after the filing date.

Even if a product qualifies for one or

more of these programs, the FDA may later decide that the product no longer meets the conditions for qualification or decide that the time period for FDA review or approval will not be shortened.

Furthermore, none of these programs change the standards for approval and may not ultimately expedite the development or approval process.

Accelerated Approval Pathway

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An intermediate clinical endpoint is a measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on IMM.

There have been a limited number of Accelerated Approvals based on intermediate clinical endpoints.

The FDA has limited experience with accelerated approvals based on intermediate clinical endpoints, but has indicated that such endpoints generally may support accelerated approval when the therapeutic effect measured by the endpoint is not itself a clinical benefit and basis for traditional approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate long-term clinical benefit of a drug.

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Furthermore, the Drug Supply Chain Security Act (“DSCSA”) was enacted with the aim of building an electronic system to identify and trace certain prescription drugs distributed in the United States.

The DSCSA mandates phased-in and resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors, and dispensers over a ten‑year period that culminated in November 2023.

After an additional one-year stabilization period to give entities subject to the DSCSA additional time to finalize interoperable tracking systems and to ensure supply chain continuity, the applicable requirements under the DSCSA became fully enforceable as of November 27, 2024.

The DSCSA mandates resource-intensive obligations for pharmaceutical manufacturers, wholesale distributors, and dispensers.

From time to time, new legislation and regulations may be implemented that could significantly change the statutory provisions governing the approval, manufacturing and marketing of products regulated by the FDA.

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In the EU, orphan drug designation by the European Commission (the “EC”) provides regulatory and financial incentives for companies to develop and market therapies that meet the following requirements:

(1) the product is intended for the diagnosis,

prevention or treatment of life-threatening or chronically debilitating conditions;

(1) the product is intended for the diagnosis, prevention or treatment of life-threatening or chronically debilitating conditions;

(2) either (a) such condition affects no more than five in 10,000 persons in the European Union when the application is made, or (b) the product, without the benefits derived from orphan status, would not generate sufficient return in the European Union to justify investment;

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In 1984, with passage of the Hatch-Waxman Amendments to the FDCA, Congress authorized the FDA to approve generic drugs that are the same as drugs previously approved by the FDA under the NDA provisions of the statute and also enacted Section 505(b)(2) of the FDCA.

To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application (“ANDA”) to the agency.

To obtain approval of a generic drug, an applicant must submit an abbreviated new drug application (“ANDA”) to the

In support of such applications, a generic manufacturer may rely on the preclinical and clinical testing conducted for a drug product previously approved under an NDA, known as the reference listed drug (“RLD”).

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If a sponsor or the FDA believes that a diagnostic test is essential for the safe and effective use of a corresponding therapeutic product, a sponsor will typically work with a collaborator to develop an appropriate in vitro diagnostic product (“IVD”) for such use.

IVDs are regulated by the FDA as medical devices, and since 2014 the agency has issued final and draft guidance documents that are intended to assist companies developing in vitro companion diagnostic devices and companies developing therapeutic products that depend on the use of a specific in vitro companion diagnostic for the safe and effective use of the therapeutic product.

devices and companies developing therapeutic products that depend on the use of a specific in vitro companion diagnostic for the safe and effective use of the therapeutic product.

The three types of marketing pathways for medical devices, including IVDs, are clearance of a premarket notification under Section 510(k) of the FDCA (“510(k)”), approval of a premarket approval application (“PMA”) or authorization of a De Novo classification request (“ De Novo ”).

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In addition, a diagnostic test that was approved through the PMA process, or one that was cleared through the 510(k) process or classified through the De Novo process, and placed on the market will be subject to many of the same regulatory requirements that apply to approved drugs.

unapproved or uncleared in vitro companion diagnostic device are so pronounced as to outweigh the risks from the lack of an approved or cleared in vitro companion diagnostic device.

However, the FDA may decide that it is appropriate to approve such a therapeutic product without an approved or cleared in vitro companion diagnostic device when the drug or therapeutic biologic is intended to treat a serious or life-threatening condition for which no satisfactory alternative treatment exists and the FDA determines that the benefits from the use of a product with an unapproved or uncleared in vitro companion diagnostic device are so pronounced as to outweigh the risks from the lack of an approved or cleared in vitro companion diagnostic device.

The FDA encourages sponsors considering developing a therapeutic product that requires a companion diagnostic to request a meeting with both relevant device and therapeutic product review divisions to ensure that the product development plan will produce sufficient data to establish the safety and effectiveness of both the therapeutic product and the companion diagnostic.

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This harmonized submission process became mandatory for new CTA submissions to be filed beginning on February 1, 2023.

However, the extent to which ongoing and new clinical trials will be governed by the Clinical Trials Regulation varies.

Clinical trials for which an application was submitted prior to January 31, 2022 under the Clinical Trials Directive, or between January 31, 2022 and January 31, 2023 and for which the sponsor has opted for the application of the Clinical Trials Directive, remained governed by the Directive until January 31, 2025.

After January 31, 2025, all clinical trials, including those that are ongoing, are now subject to the provisions of the Clinical Trials Regulation.

As of January 31, 2025, all clinical trials, including those initiated prior to such date, are subject to the provisions of the Clinical Trials Regulation.

Under the new centralized process, if the EU member state leading the CTA review approves or rejects the application, the decision will apply to all involved member states.

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(i) are derived from biotechnology processes, such as genetic engineering, (ii) contain a new active substance indicated for the treatment of certain diseases, such as HIV/AIDS, cancer, diabetes, neurodegenerative diseases, autoimmune and other immune dysfunctions and viral diseases, (iii) are officially designated “orphan drugs” (drugs used for rare human diseases) and (iv) are advanced-therapy medicines, such as gene-therapy, somatic cell-therapy or tissue-engineered medicines.

The centralized procedure may at the request of the applicant also be used for human drugs which do not fall within the above mentioned categories if (a) the human drug contains a new active substance which was not previously authorized in the European Community;

The centralized procedure may at the request of the applicant also be used for human drugs which do not fall within the above mentioned categories if (a) the human drug contains a

new active substance which was not previously authorized in the European Community;

or (b) the applicant shows that the medicinal product constitutes a significant therapeutic, scientific or technical innovation or that the granting of authorization in the centralized procedure is in the interests of patients at the European Community level.

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In this circumstance, EMA ensures that the evaluation for the opinion of the CHMP is completed within 150 days (excluding clock stops) and the opinion issued thereafter.

The mutual recognition procedure (“MRP”) for the approval of human drugs is an alternative approach to facilitate individual national marketing authorizations within the European Union.

There are also two other possible routes to authorize medicinal products in several EU countries, which are available for investigational medicinal products for which the centralized procedure is not obligatory:

the decentralized procedure and the mutual recognition procedure (“MRP”).

Using the decentralized procedure, an applicant may apply for simultaneous authorization in more than one EU country of a medicinal product that has not yet been authorized in any EU country and that does not fall within the mandatory scope of the centralized procedure.

The MRP for the approval of human drugs is an alternative approach to facilitate individual national marketing authorizations within the European Union.

Basically, the MRP may be applied for all human drugs for which the centralized procedure is not obligatory.

The MRP is applicable to the majority of conventional medicinal products and is based on the

principle of recognition of an already existing national marketing authorization by one or more member states.

The MRP is applicable to the majority of conventional medicinal products and is based on the principle of recognition of an already existing national marketing authorization by one or more member states.

In the MRP, a marketing authorization for a drug already exists in one or more member states of the European Union and subsequently marketing authorization applications are made in other European Union member states by referring to the initial marketing authorization.

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As in the centralized procedure, this process entails consulting various European Commission Directorates General and the Standing Committee on Human Medicinal Products or Veterinary Medicinal Products, as appropriate.

In April 2023, the European Commission issued a proposal to revise and replace the existing general pharmaceutical legislation.

As of December 2025, the three European Union institutions, the European Commission, the European Parliament and the Council of the European Union are in the process of negotiating the final content of the new Directive and Regulation.

Once negotiations are complete, the European Parliament and the Council of the EU will vote on whether to approve the Directive and Regulation.

If adopted and implemented as currently proposed, these revisions will significantly change several aspects of drug development and approval in the European Union.

European Union Regulation of IVD Products

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The manufacturers of such devices remaining on the market must comply with specific requirements in the IVDR, but ultimately, such products, as with all new IVDs, will have to undergo the IVDR’s conformity assessment procedures.

In addition, IVDs in the highest risk class will have to be tested by a Designated Reference Laboratory.

addition, IVDs in the highest risk class will have to be tested by a Designated Reference Laboratory.

The IVDR imposes additional requirements relating to post-market surveillance and submission of post-market performance follow-up reports.

The EC has designated thirteen Notified Bodies to perform conformity assessments under the IVDR.

The EC has designated more than a dozen Notified Bodies to perform conformity assessments under the IVDR.

MedTech Europe has issued guidance relating to the IVDR in several areas, e.g., clinical benefit, technical documentation, state of art, accessories, and EUDAMED.

In April 2023, the European Commission issued a proposal that will revise and replace the existing general pharmaceutical legislation.

If adopted and implemented as currently proposed, these revisions will significantly change several aspects of drug development and approval in the European Union.

Most recently, on December 6, 2025, the European Commission released a proposal to amend the IVDR with the goal of simplifying the applicable rules, reducing the administrative burden on manufacturers, and enhancing the predictability and cost-effectiveness of the certification procedure while maintaining a high level of public health protections for EU patients and consumers.

However, it is currently unknown whether such amendments to the IVDR will be enacted, or even if they become effective, whether they will have a significant impact on manufacturers distributing IVDs in the European Union.

Regulation of Pharmaceutical Products in the United Kingdom

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Sales of our products, when and if approved for marketing in the United States, will depend, in part, on the extent to which our products will be covered by third-party payors, such as federal, state, and foreign government healthcare programs, commercial insurance and managed healthcare organizations.

The process for determining whether a payor will provide coverage for a product

may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved.

The process for determining whether a payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is approved.

Third-party payors may limit coverage to specific products on an approved list, or formulary, which might not include all of the approved products for a particular indication.

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We cannot be sure whether additional legislative changes will be enacted, or whether any of the FDA’s regulations, guidance or interpretations will be changed, or what the impact of such changes on the agency and its scientific review staff, if any, may be.

For example, the next FDA user fee reauthorization package is expected to enter stakeholder negotiations beginning in mid-2025, with any agreement sent to Congress in early 2027 for purposes of initiating the legislative process.

Reauthorization of the prescription drug user fee program would need to be finalized by Congress by the end of September 2027 in order to avoid a disruption in FDA’s review goals for NDAs and other activities supported by user fees assessed against industry.

For example, negotiations on the next FDA user fee reauthorization package began in mid-2025, and the resulting agreement is expected to be sent to Congress in early 2027 for purposes of initiating the legislative process.

Reauthorization of the prescription drug user fee program must be finalized by Congress by the end of September 2027 in order to avoid a disruption in

FDA’s review goals for NDAs and other activities supported by user fees assessed against industry.

If we are slow or unable to adapt to changes in existing requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we may lose any marketing approval that we otherwise may have obtained and we may not achieve or sustain profitability, which would adversely affect our business, prospects, financial condition and results of operations.

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116-94) and includes a piece of bipartisan legislation called the Creating and Restoring Equal Access to Equivalent Samples Act of 2019 (“CREATES Act”).

The CREATES Act aims to address the concern articulated by both the FDA and others in the industry that some brand manufacturers have improperly restricted the distribution of their products, including by invoking the existence of a REMS for certain products, to deny generic product developers access to samples of brand products.

The CREATES Act was enacted to address the concern articulated by both the FDA and others in the industry that some brand manufacturers had improperly restricted the distribution of their products, including by invoking the existence of a REMS for certain products, to deny generic product developers access to samples of brand products.

Because generic product developers need samples of an RLD to conduct certain comparative testing required by the FDA, some have attributed the inability to timely obtain samples as a cause of delay in the entry of generic products.

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This calculation is made on a product-by-product basis and the amount of the rebate owed to the federal government is directly dependent on the volume of a drug product that is paid for by Medicare Parts B or D.

Additionally, starting in payment year 2026, CMS will negotiate drug prices annually for a select number of single source Part D drugs without generic or biosimilar competition.

Additionally, CMS will negotiate drug prices annually for a select number of single source Part D drugs without generic or biosimilar competition.

CMS will also negotiate drug prices for a select number of Part B drugs starting for payment year 2028.

If a drug product is selected by CMS for negotiation, it is expected that the revenue generated from such drug will decrease.

CMS has begun to implement these new authorities and entered into the first set of agreements with drug and biological product manufacturers for negotiated prices of 10 products, which will become applicable for payment year 2026.

CMS has begun to implement these new authorities, announcing the first round of negotiated prices for the first 10 drug products in August 2024, which will become applicable for payment year 2026.

The second round of negotiated prices for 15 drug products was announced in November 2025.

However, the IRA’s impact on the pharmaceutical industry in the United States remains uncertain, in part because multiple large pharmaceutical companies and other stakeholders (e.g., the U.S.

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Those lawsuits are currently ongoing.

On May 12, 2025, an executive order was issued by the Trump Administration to implement a most favored nation ("MFN") drug pricing policy that would tie U.S.

drug prices to the prices paid for drugs in other countries.

The Trump Administration has continued to exert pressure on drug manufacturers to implement MFN pricing, including by suggesting that the administration may impose significant tariffs on pharmaceuticals if such manufacturers do not reach agreements to implement MFN pricing.

Individual states in the United States have also increasingly passed legislation and implemented regulations designed to control pharmaceutical product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

F or example, in recent years, several states have formed prescription drug affordability boards (“PDABs”).

For example, in recent years, several states have formed prescription drug affordability boards (“PDABs”).

Much like the IRA’s drug price negotiation program, these PDABs have attempted to implement upper payment limits (“UPLs”) on drugs sold in their respective states in both public and commercial health plans.

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We and our 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,

laboratory controls, records and reports, and returned or salvaged products.

The manufacturing facilities for our products must meet cGMP requirements to the satisfaction of the FDA pursuant to a pre-approval inspection before we can use them to manufacture commercial products.

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Human Capital

As of December 31, 2024, we employed 288 employees, of which 287 were full-time employees.

As of December 31, 2025, we employed 317 employees, all of whom were full-time employees.

A significant number of our management and employees have had prior experience with pharmaceutical, biotechnology or medical product companies.

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Management considers relations with our employees to be good.

Social Factors and Supporting Our Workforce :

Our approach to how we recruit, develop, retain and manage our talent is driven by our values statement:

Our approach to attracting, engaging, and aligning our talent is driven by our values statement;

making an impact through innovation, inclusion, and inspiration.

Our values are at the core of who we are as an organization, and what drive us to reimagine possible for science, for medicine, and for human health.

Critical to achieving our strategic imperatives is our ability to build and retain an exceptional team in which each member plays a unique and important role.

We were recently recognized by the Boston Business Journal and won the distinction of being one of the 2024 “Best Places to Work”, which underscores our employees’ recognition of our collective focus, resilience, and commitment to our mission.

We also value diversity, equity, inclusion, and social responsibility, with the goal of fostering a strong sense of belonging and contributing, while being empowered to make a real difference.

This commitment is company-wide.

Our Nominating and Corporate Governance Committee of our Board of Directors (“Board”) oversees our strategies and policies related to our people and diversity, equity and inclusion (“DEI”) initiatives, in addition to those for our environmental, social and governance (“ESG”) initiatives.

We recognize that maintaining an engaged and high-performing workforce who share a connection with the communities we serve is critical to our success.

Camaraderie and cohesion are key to our collective corporate identity and are integral facets of our human capital strategy.

Whether it is coming together throughout the year to connect at our town halls or participating in local walks for the patient communities for whom we work, we take a team and human connections-based approach to our work.

We are inspired by the communities we serve, the opportunities to engage and learn from individuals and their families, and the possibilities of what we can achieve together.

We understand that in order to drive innovation, we must continuously improve our people strategies and find ways to foster engagement and growth within our organization.

To this end, below are some of our initiatives:

Employee Engagement :

Having an engaged and dedicated workforce is essential for us to achieve our goals.

It is also more apparent than ever that we set our employees up for success and continue to cultivate their engagement with Wave.

We conduct surveys as a means of engaging with employees and gaining their insights.

We use the data and input as a tool for improving our human resources management going forward.

Engagement is also directly correlated to the interactions our employees have with each other and their teams.

We also have a cross functional team dedicated to organizing activities, such as themed social gatherings, charity and volunteer opportunities, and health and wellness events, which enrich our culture and bring employees together.

We also work to ensure that we are deeply aligned with our corporate goals as a company, that functional goals are clear and transparent, and that employees understand how their work contributes to the company’s success.

Professional Development Programs and Opportunities :

Employees are our most valuable resource, and we focus on providing them with opportunities so that they can continue to grow and excel in their functions and our company.

Professional development of our

employees drives engagement and allows us to leverage opportunities to grow and promote key talent from within our organization.

We encourage individual development planning and leadership and management development programs for our employees, including our Building Coaching Leaders program that is a learning series designed to build strong coaching capabilities and strengthen a manager’s engagement with their teams, and our Management Essentials Program that is focused on building the leadership skillset of first-time managers and rising leaders.

Through development planning, we strive for employees at all levels to focus on strengthening the skills required in their current role and potentially their next role.

We conduct annual performance reviews for all employees, but, as importantly, we are focused on building a culture of continuous coaching, feedback and open communication between managers and their direct reports throughout the entire year.

We provide managers and employees with training on how to conduct effective forward-looking performance conversations and to set effective goals that are specific, measurable, attainable, relevant and timebound (SMART).

We also provide company-wide leadership and development opportunities through the Wave Learning Series, which was developed to build awareness of all functional areas, special areas of interest or importance, timely subject matters and to expand knowledge of industry trends and other matters of interest and relevance within the biopharmaceutical industry.

The Wave Learning Series is conducted through company-wide presentations by employees at various levels, providing opportunities for development and cross-functional exposure for our employees.

We also offer all full-time employees the option to participate in our Education Assistance Program, where we reimburse employees for tuition and eligible expenses.

These values are core to who we are as an organization and what drives us to reimagine possible for science, for medicine, and for human health.

Our Workforce Strategy:

Critical to fulfilling our mission is our ability to build and retain an exceptionally skilled, highly innovative team that shares a purposeful connection with the communities we serve and in which each member plays a unique and important role.

We understand that to do this, we must remain an employer of choice for top talent and continuously find novel ways to maintain a

culture that emphasizes respect, inclusion, collaboration, and continuous development.

We regularly conduct surveys as a means of gaining employee insights, and we use the data to inform workforce engagement initiatives aligned with our strategy and culture.

Additionally, we invest in regular leadership and management development programming designed to strengthen coaching and communication capabilities and, by extension, each manager’s ability to build, engage, and develop high-performing teams at every level of the organization.

To support our ability to recruit top talent in a competitive hiring environment, we offer a differentiated total rewards package that includes base salary, cash bonuses aligned to company and individual achievement, compelling benefits, and equity compensation for all employees.

We believe that providing employees with an ownership interest in Wave reinforces a shared commitment to our long-term success and value creation.

We were previously recognized by the Boston Business Journal and won the distinction of being one of the 2024 “Best Places to Work”, which underscores our employees’ recognition of our collective focus, resilience, and commitment to our mission of unlocking the broad potential of RNA medicines to transform human health.

This commitment is company-wide, and our Board of Directors remains actively involved in overseeing human capital strategy, providing input on key decisions related to succession planning, compensation, and the continued development of our workforce.

Environmental Health and Safety :

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Our training programs provide training to our employees that is commensurate with their level of risk exposure and are designed to ensure that employees have the knowledge and equipment available to mitigate risk.

Our cross-functional Safety Committee meets monthly to discuss any concerns and ways to improve our EH&S programs.

Employees are also required to report any incidents, no matter how small, and are encouraged to voice any health or safety concerns to management or a member of our EH&S team.

Health and Well-Being :

We believe that the overall well-being of our employees and ensuring that their basic health and wellness needs are met is fundamental for us to achieve success as a company.

We understand that a key part of our ongoing efforts to prioritize wellness initiatives includes providing our employees with access to mental health, behavioral health, and/or substance abuse services through our medical plans.

We provide an Employee Assistance Program as a cost-free benefit, which is available to help employees and their household members to confidentially manage everyday life, arising work challenges, stress, and other personal issues, by providing consultation, referrals, and resources, along with ongoing webinars on various work-life, mental health, and wellness topics for employees.

We prioritize providing mental health resources for our employees, while creating forums for dialogue.

In addition, we understand that workplace flexibility is an important component to our employees’ well-being.

Prioritizing employee safety while achieving our goals has provided us with a greater appreciation for workplace flexibility, which keeps our employees engaged and motivated, while also creating a sense of trust throughout our organization.

Diversity, Equity and Inclusion (“DEI”) :

Our commitment to maintaining a top-performing company means investing in and creating ongoing opportunities for employee development in a diverse and inclusive workplace.

We believe that a diverse and inclusive workforce positively impacts our performance, fosters innovation and inspires us to achieve greater results.

We provide equal employment opportunities without regard to race, color, religion, gender, sexual orientation, national origin, age, disability, veteran status or genetics, among other personal characteristics.

Our DEI Steering Group leads various initiatives to help us maintain a diverse, equitable, culturally competent and supportive environment for all of our employees and other stakeholders.

In addition to this, our intentional focus on DEI helps ensure that we continue to cultivate the next generation of experienced, diverse leaders and managers necessary to execute on our mission and plans for ambitious growth.

As of December 31, 2024, women made up approximately 52% of our global workforce and constitute approximately 52% of senior management (defined as vice president level and above).

As of December 31, 2024, racially diverse employees (those self-identifying as Black or African American, Hispanic or Latino, Asian, or being of two or more races) make up approximately 37% of our global workforce and approximately 23% of senior management (defined as vice president level and above) (10% of our employees did not provide us with this information).

Some of our DEI initiatives include DEI-focused training, educational and awareness building events, social hours celebrating various cultural themes, and our summer internship program with Project Onramp, which is an organization working to bridge the opportunity gap for Massachusetts-based college students in under-served and minority communities.

We recently established a partnership with Bioversity, a nonprofit launched by MassBio to create and implement industry-aligned workforce training initiatives.

Additionally, we encourage the formation of Employee Resource Groups and currently have three – Women+ of Wave, Black Employee Network , and

LGBTQIA+ – with more likely to be formed.

We also have a supplier diversity program that identifies and classifies our suppliers, encouraging the use of a more diversified supply base.

We believe that having a diverse group of suppliers will allow us to effectively meet the needs of our organization while expanding our pool of suppliers to create more competitive business opportunities, and ultimately creating positive social impact by generating economic opportunities for those in our community who may be disadvantaged.

Patient Advocacy and Community Engagement :

Our community engagement activities are focused on seeking to better understand the lived experience of people i mpacted by rare and prevalent diseases and identifying opportunities to support these communities .

We believe that listening to, learning from, and partnering with individuals impacted by the diseases we hope to address , including families and caregivers, connects us more deeply to our mission, and enhances our ability to discover and develop meaningful therapies.

Advocacy and Community Engagement:

Our community engagement activities are focused on seeking to better understand the lived experience of people impacted by rare and prevalent diseases and identifying opportunities to support these communities.

We believe that listening to, learning from, and partnering with individuals impacted by the diseases we are aiming to address, including families and caregivers, connects us more deeply to our mission and enhances our ability to discover and develop meaningful therapies.

Through collaboration with patient communities and advocacy organizations, including participation in community- focused conferences and events, we aim to incorporate community voices and perspectives into every aspect of our work.

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Employee volunteering is another important component of our community engagement initiatives.

We partner with advocacy and service organizations to provide opportunities for employees to contribute directly to our local communities, including through our Wave Service Day and holiday giving drives.

By participating in a broad range of volunteer activities, our employees donate time and resources to support individuals and families in our community and beyond.

We also recognize that external factors and current events, including systems and policies, impact our employees, as well as the communities with which we are connected.

Rewards and Recognition :

We have a multi-tiered awards program, including peer-to-peer recognition, which our employees use to recognize and reward one another for their contributions and achievements, taking into consideration the combination of employees who best exemplify our values and the achievement of results.

We believe that providing a rewards program not only increases engagement and performance, but meaningfully recognizes those employees who go above and beyond to positively impact our company and culture.

In addition, we offer a team rewards and recognition program to provide another opportunity to recognize and reward collaborative teamwork.

Compensation, Equity and Benefits (Total Rewards) :

Compensation programs are one of the most powerful tools available to companies to attract, retain and motivate employees, as well as align their interests with those of shareholders.

We have developed a broad-based compensation program that is designed to attract, retain and motivate our employees, while driving sustainable long-term value creation.

We seek to deliver performance-driven, market competitive reward opportunities commensurate with company and individual performance.

All of our employees receive competitive base salaries, cash bonus eligibility, new hire equity grants and annual long-term incentive grants eligibility, in addition to our comprehensive benefits package.

We believe that providing employees with an ownership interest in Wave through grants of equity awards further strengthens the level of employee engagement.

In addition, our Employee Share Purchase Plan, as amended (“ESPP”), provides our U.S.

employees with an opportunity to purchase our ordinary shares at a 15% discount to the market price.

Offering a highly competitive, industry-leading benefits package is another integral piece of our total rewards package and differentiated employee value proposition.

Notably, we provide our employees with access to choice and offer employees a very progressive health insurance package, with no premiums.

We also offer a 401(k) plan with matching contributions for all eligible employees.

We provide innovative solutions that are key to attracting, engaging and motivating employees, including (i) our excellent benefits and compensation programs and strategies;

(ii) our employee well-being approach and strategy;

(iii) our health plan;

and (iv) internal communications and education around our total rewards strategy.

We will continue to evolve and strengthen our strategies relating to talent, while furthering our investment in our employees, culture, community partnerships and outreach, and other human capital measures .

As an innovative organization focused on ongoing improvement, we will continue to evolve and strengthen our strategies relating to talent while furthering our investment in our employees, culture, community partnerships and outreach, and other measures to engage and align our talent with our purpose .

Corporate Information

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We make available free of charge through our website our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments to those reports filed or furnished pursuant to Sections 13(a) and 15(d) of the Exchange Act.

We make these reports available through the “For Investors & Media – SEC Filings” section of our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the SEC.

We make these reports available through the “Investors – SEC Filings” section of our website as soon as reasonably practicable after we electronically file such reports with, or furnish such reports to, the SEC.

We also make available, free of charge on our website, the reports filed with the SEC by our executive officers, directors and 10% shareholders pursuant to Section 16 under the Exchange Act as soon as reasonably practicable after copies of those filings are filed with the SEC.

You can review our electronically filed reports and other information that we file with the SEC on the SEC’s website at http://www.sec.gov.

In addition, we regularly use our website to post information regarding our business and governance, and we encourage investors to use our website, particularly the information in the section entitled “For Investors & Media,” as a source of information about us.

Ris k Factors

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Our 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.

Our toolkit of RNA-targeting modalities, including RNAi silencing (SpiNA) and RNA editing (AIMers), provides us with unmatched capabilities for designing and sustainably delivering candidates that optimally address disease biology.

Our pipeline is focused on our obesity, alpha-1 antitrypsin deficiency (“AATD”) and PNPLA3 I148M liver disease programs, and also includes clinical programs for Duchenne muscular dystrophy (“DMD”) and Huntington’s disease (“HD”), as well as several preclinical programs utilizing our versatile RNA medicines platform.

We have not generated, and do not expect to generate, any product revenue for the foreseeable future, and we expect to continue to incur significant operating losses for the foreseeable future due to the cost of research and development, manufacturing, preclinical studies and clinical trials and the regulatory review process for product candidates.

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• our ability to obtain marketing approval for our product candidates;

• the impacts of any local or global health issues, the conflict involving Russia and Ukraine, the conflict in the Middle East, global economic uncertainty, volatility in inflation, volatility in interest rates or market disruptions on our business;

• the impacts of any local or global health epidemics, geopolitical conflicts, global economic uncertainty, tariffs, rising inflation, rising interest rates or market disruptions on our business;

• the achievement of milestones and other development targets that trigger payments under our agreements with our key collaboration partners, or any other strategic collaborations into which we may enter;

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Our ability to effectively run our business could be adversely affected by general conditions in the global economy and in the financial services industry.

Various macroeconomic factors could adversely affect our business, including fears concerning the banking sector, volatility in inflation, and interest rates and overall changes in economic conditions and uncertainties.

Various macroeconomic factors could adversely affect our business, including fears concerning the banking sector, rising inflation, and interest rates and overall changes in economic conditions and uncertainties.

A severe or prolonged economic downturn could result in a variety of risks, including our ability to raise additional funding on a timely basis or on

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Our operating history as a clinical-stage biotechnology company may make it difficult for shareholders to evaluate the success of our business to date and to assess our future viability.

We are a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines (also known as oligonucleotides), or those targeting RNA, to transform human health.

Our 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.

Our toolkit of RNA-targeting modalities includes RNA editing, splicing, silencing using siRNA and antisense silencing, providing us with unique capabilities for designing and sustainably delivering candidates that optimally address disease biology.

Our diversified pipeline includes clinical programs in obesity, AATD, DMD, and HD, as well as several preclinical programs utilizing our versatile RNA medicines platform.

We are a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health.

Our pipeline is focused on our obesity, AATD and PNPLA3 I148M liver disease programs, and also includes clinical programs for DMD and HD, as well as several preclinical programs utilizing our versatile RNA medicines platform.

We have not yet demonstrated our ability to successfully complete pivotal clinical trials, obtain marketing approvals, or conduct sales and marketing activities necessary for successful product commercialization.

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Any predictions about our future success or viability may not be as accurate as they could be if we had a longer operating history or a history of successfully developing and commercializing pharmaceutical products.

We, or third parties upon whom we depend, may face risks related to local and global health epidemics, which may delay our ability to complete our ongoing clinical trials, initiate additional clinical trials, delay regulatory activities and have other adverse effects on our business and operations.

As a clinical-stage company with multiple programs and multiple clinical trials currently underway, any local or global health issues could impact the execution of our clinical trials.

For example, beginning in March 2020, multiple countries throughout the world and their economies, including the United States, were subject to intermittent shutdowns and were adversely affected by the COVID-19 global pandemic.

We had clinical trial sites located in countries that had been affected by COVID-19 and variants thereof.

Clinical site initiation and patient enrollment was delayed due to prioritization of hospital resources in favor of COVID-19 patients and difficulties in recruiting clinical site investigators and clinical site staff.

Some patients were not able to travel or gain access to clinical trial sites due to local restrictions.

Similarly, our ability to recruit and retain patients and principal investigators and site staff was negatively impacted, which delayed the timelines of our clinical trial operations.

We rely upon third parties for many aspects of our business, including the raw materials used to make our product candidates and the conduct of our clinical trials and preclinical studies.

While we have built up inventory to assist us through this uncertain operating environment, our suppliers may be disrupted now or in the future due to a local or global health epidemic, which could affect our ability to procure items that are essential for our research and development activities and could cause increases to our costs, inflation, and significant disruptions to our business.

While we have adapted our processes to lessen the impact of a potential local or global health epidemic may have on our business, any potential delays or long-term impacts on our business, our clinical trials, healthcare systems or the global economy could be highly uncertain.

These effects could materially adversely affect our business, financial condition, results of operations, and prospects.

Risks Related to the Discovery, Manufacturing, Development and Commercialization of Our Product Candidates

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Moreover, the FDA or other foreign homologues may respond to these submissions by defining requirements we may not have anticipated.

Addressing such requirements could lead to significant delays in the development of our product candidates.

Addressing such requirements could lead to significant delays in the development of our

product candidates.

In addition, because there may be approved treatments for some of the diseases for which we may seek approval, in order to receive regulatory approval, we may need to demonstrate through clinical trials that the product candidates we develop to treat these diseases, if any, are not only safe and effective, but safer or more effective than existing products.

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If we are unable to commercialize our product candidates or experience significant delays in doing so, our business may be materially harmed.

We have a robust and diverse pipeline of first- or best-in-class RNA medicines using our RNA editing, splicing, silencing using siRNA and antisense silencing modalities.

Our diversified pipeline includes clinical programs in AATD, DMD, HD, and obesity, as well as several preclinical programs utilizing our broad RNA therapeutics toolkit.

We have a robust and diverse pipeline of first- or best-in-class RNA medicines.

However, we currently have no products on the market.

We have invested a significant portion of our efforts and financial resources in the identification and preclinical and clinical development of our oligonucleotides , the development of our RNA medicines platform, PRISM, including our RNA editing capability, and our novel chemistry modifications, and the continued growth of our manufacturing capabilities.

We have invested a significant portion of our efforts and financial resources in the identification and preclinical and clinical development of our oligonucleotides, the development of our RNA medicines platform, PRISM, including our toolkit of RNA-targeting modalities, and our novel chemistry modifications, and the continued growth of our manufacturing capabilities.

Our ability to generate product revenue, which we do not expect will occur for many years, if ever, will depend heavily on the successful development, regulatory approvals, and eventual commercialization of our product candidates.

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We also may make changes to our manufacturing process at various points during development, and even after commercialization, for various reasons, such as optimizing costs, achieving scale, decreasing processing time, increasing manufacturing success rate, or other reasons.

Such changes carry the risk that they will not achieve their intended objectives, and any of these changes could cause our product candidates to perform differently and affect the results of current or future clinical trials, or the performance of the product, once commercialized.

the performance of the product, once commercialized.

In some circumstances, changes in the manufacturing process may require us to perform ex vivo comparability studies, and/or conduct animal studies, and to collect additional data from patients prior to undertaking more advanced clinical trials.

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If preclinical and/or clinical data are not ultimately comparable to those seen in the earlier trials, we may be required to make further changes to our process and/or undertake additional clinical testing, either of which could significantly delay the clinical development or commercialization of the associated product candidate.

We are a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines (also known as oligonucleotides), or those targeting RNA, to transform human health.

Our diversified pipeline includes clinical programs in obesity, AATD, DMD, and HD, as well as several preclinical programs utilizing our versatile RNA medicines platform.

We are a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines (also known as oligonucleotides) to transform human health.

Although we continue to build on our experience in manufacturing oligonucleotides, we have limited experience as a company manufacturing product candidates for commercial supply.

We may never be successful in manufacturing product candidates in sufficient quantities or with sufficient quality for commercial use.

Our manufacturing capabilities

could be affected by cost-overruns, unexpected delays, equipment failures, labor shortages, operator error, natural disasters, unavailability of qualified personnel, difficulties with logistics and shipping, problems regarding yields or stability of product, contamination or other quality control issues, power failures, and numerous other factors that could prevent us from realizing the intended benefits of our manufacturing strategy and have a material adverse effect on our business.

Our manufacturing capabilities could be affected by cost-overruns, unexpected delays, equipment failures, labor shortages, operator error, natural disasters, unavailability of qualified personnel, difficulties with logistics and shipping, problems regarding yields or stability of product, contamination or other quality control issues, power failures, and numerous other factors that could prevent us from realizing the intended benefits of our manufacturing strategy and have a material adverse effect on our business.

Furthermore, compliance with cGMP requirements and other quality issues may arise during our internal efforts to scale-up manufacturing, and with our current or any future CMOs.

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We, the FDA or comparable foreign regulatory authorities or an IRB, or similar foreign review board or ethics committee, may suspend clinical trials of a product candidate at any time for various reasons, including if we or they believe the healthy volunteer subjects or patients participating in such trials are being exposed to unacceptable health risks.

Among other reasons, unacceptable side effects or other more serious adverse events of a product candidate in healthy volunteer subjects or patients in a clinical trial could result in the FDA or comparable foreign regulatory authorities suspending or terminating the trial and refusing to approve a particular product candidate for any or all indications of use.

Among other reasons, unacceptable side effects or other more serious adverse events of a product candidate in healthy volunteer subjects or patients in a clinical trial could

result in the FDA or comparable foreign regulatory authorities suspending or terminating the trial and refusing to approve a particular product candidate for any or all indications of use.

Clinical trials also require the review, oversight and approval of IRBs or ethics committees, which review the clinical protocols and informed consent form for investigations that will be conducted at their institutions in order to protect the rights and welfare of human subjects.

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If we, or any third parties that we engage to assist us are unable to successfully identify patients with the appropriate SNP that we are targeting, the percentage of patients with the SNP we are targeting is lower than expected, or we experience delays in testing, we may not realize the full commercial potential of any product candidates we develop.

Congress also recently amended the FDCA to require sponsors of a Phase 3 clinical trial, or other “pivotal study” of a new drug to support marketing authorization, to design and submit a diversity action plan for such clinical trial.

Congress also amended the FDCA to require sponsors of a Phase 3 clinical trial, or other “pivotal study” of a new drug to support marketing authorization, to design and submit a diversity action plan for such clinical trial.

The action plan must describe appropriate diversity goals for enrollment, as well as a rationale for the goals and a description of how the sponsor will meet them.

Although none of our product candidates has reached Phase 3 of clinical development, we must submit a diversity action plan to the FDA by the time we submit a Phase 3 trial, or pivotal study, protocol to the agency for review, unless we are able to obtain a waiver for some or all of the requirements for a diversity action plan.

It is unknown at this time how the diversity action plan may affect the planning and timing of any future Phase 3 trial for our product candidates.

However, initiation of such trials may be delayed if the FDA objects to our proposed diversity action plans for any future Phase 3 trial for our product candidates, and we may experience difficulties recruiting a diverse population of patients in attempting to fulfill the requirements of any approved diversity action plan.

Initiation of such trials may be delayed if the FDA objects to our proposed diversity action plans for any future Phase 3 trial for our product candidates, and we may experience difficulties recruiting a diverse population of patients in attempting to fulfill the requirements of any approved diversity action plan.

If we are unable to successfully develop or obtain regulatory approval for companion diagnostic tests for our product candidates, or experience significant delays in doing so, our clinical trials may be delayed and our business could be materially harmed.

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The success of certain of our product candidates will depend on several factors, including the successful development of, and ability to obtain regulatory approval for, companion diagnostic tests that will be used to screen and identify the right patients for our product candidates.

Our goal is to develop and commercialize disease-modifying medicines for genetically defined diseases with a high degree of unmet medical need, and to become a fully integrated RNA

medicines company.

Our goal is to develop and commercialize disease-modifying medicines for genetically defined diseases with a high degree of unmet medical need, and to become a fully integrated RNA medicines company.

The target patient populations for several of our product candidates are relatively small, and it will be difficult to successfully identify the appropriate patients for whom our product candidates are being designed without performant, fit-for-purpose, accessible, relatively inexpensive, and easy-to-use companion diagnostic tests.

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We are not guaranteed to maintain or receive orphan designation for our current or future product candidates, and if our product candidates that were granted orphan designation were to lose their status as an orphan drug or the orphan marketing exclusivity provided to it in the United States, our business and results of operations could be materially adversely affected.

While orphan status for any of our products, if granted or maintained, would provide market exclusivity in the United States for the time periods specified above, we would not be able to exclude other companies from manufacturing and/or selling products using the same active ingredient for the same indication beyond the exclusivity period applicable to our product on the sole basis of orphan drug status.

While orphan status for any of our products, if granted or maintained, would provide market exclusivity in the United States for the time periods specified

above, we would not be able to exclude other companies from manufacturing and/or selling products using the same active ingredient for the same indication beyond the exclusivity period applicable to our product on the sole basis of orphan drug status.

In addition, orphan exclusivity does not block the approval of a different drug or biologic for the same rare disease or condition, nor does it block the approval of the same drug or biologic for different conditions.

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Although effective compliance programs can mitigate the risk of investigation and prosecution for violations of these laws, these risks cannot be entirely eliminated.

Any action against us for an alleged or suspected violation could cause us to incur significant legal expenses, could divert our management’s attention from

the operation of our business, and could harm our reputation, even if our defense is successful.

Any action against us for an alleged or suspected violation could cause us to incur significant legal expenses, could divert our management’s attention from the operation of our business, and could harm our reputation, even if our defense is successful.

In addition, achieving and sustaining compliance with applicable laws and regulations may be costly to us in terms of money, time and resources.

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The FDA or a comparable foreign regulatory authority may also impose requirements for costly post-marketing nonclinical studies or clinical trials (often called “Phase 4 trials”) and post-marketing surveillance to monitor the safety or efficacy of the product.

If we or a regulatory authority discover previously unknown problems with a product, such as adverse events of unanticipated severity or frequency, production issues with the facility where the product is manufactured or processed, such as product contamination or significant non-compliance with applicable cGMP requirements, a regulator may impose restrictions on that product, the manufacturing facility or us.

If we or a regulatory authority discover previously unknown problems with a product, such as adverse events of unanticipated severity or frequency,

production issues with the facility where the product is manufactured or processed, such as product contamination or significant non-compliance with applicable cGMP requirements, a regulator may impose restrictions on that product, the manufacturing facility or us.

If we or our collaborators or third-party service providers, including our CMOs, fail to comply fully with applicable regulations, then we may be required to initiate a recall or withdrawal of our products.

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however, many of our programs are currently in the earlier stages of development and we will not be able to assess the impact of price regulations for a number of years.

As a result, we might obtain regulatory approval for a product in a particular country, but then be

subject to price regulations that could delay our commercial launch of the product and negatively impact any potential revenues we may be able to generate from the sale of the product in that country and potentially in other countries due to reference pricing or other measures to reduce drug prices.

As a result, we might obtain regulatory approval for a product in a particular country, but then be subject to price regulations that could delay our commercial launch of the product and negatively impact any potential revenues we may be able to generate from the sale of the product in that country and potentially in other countries due to reference pricing or other measures to reduce drug prices.

Our ability to commercialize any products successfully will also depend in part on the extent to which coverage and adequate reimbursement/payment for these products and related treatments will be available from government health administration authorities, private health insurers and other organizations.

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At this time, we are unable to determine their cost effectiveness or the likely level or method of reimbursement for our product candidates.

Increasingly, third-party payors, such as government and private insurance plans, are requiring that drug companies provide them with predetermined discounts from list prices, and are seeking to reduce the prices charged or the amounts paid for pharmaceutical products.

prices charged or the amounts paid for pharmaceutical products.

If the price we are able to charge for any products we develop, or the payments provided for such products, is inadequate in light of our development and other costs, our return on investment could be adversely affected.

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The Inflation Reduction Act of 2022 (“IRA”) was signed into law in August 2022 (see above “Government Regulation—Healthcare Reform”).

In addition, Executive Order 14087, issued October 2022, called for CMS to prepare and submit a report to the White House on potential payment and delivery modes that would complement to IRA, lower drug costs, and promote access to innovative drugs.

In February 2023, CMS published its report which described three potential models focusing on affordability, accessibility and feasibility of implementation for further testing by the CMS Innovation Center.

The CMS Innovation Center continues to test the proposed models and has started to roll out plans for access model testing of certain product types (e.g., cell and gene therapies) by states and manufacturers.

Additional state and federal healthcare reform measures are expected to be adopted in the future, any of

which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for certain biopharmaceutical products or additional pricing pressures.

Additional state and federal healthcare reform measures are expected to be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for certain biopharmaceutical products or additional pricing pressures.

In some foreign countries, particularly the member states of the European Union, the pricing of prescription pharmaceuticals is subject to governmental control.

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Congress most recently reauthorized the user fee programs in September 2022 without any substantive policy changes.

The next FDA user fee reauthorization package is expected to enter stakeholder negotiations beginning in mid-2025, with any agreement sent to Congress in early 2027 for purposes of initiating the legislative process.

The next FDA user fee reauthorization package entered the stakeholder negotiation phase in mid-2025, and the resulting agreement is expected to be sent to Congress in early 2027 for purposes of initiating the legislative process.

Reauthorization of the prescription drug user fee program must be finalized by Congress by the end of September 2027 in order to avoid a disruption in FDA’s review goals for NDAs and other activities supported by user fees assessed against industry.

Among policy makers and payors in the United States and elsewhere, there is significant interest in promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access.

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Such scrutiny has resulted in several recent congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to product pricing, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for products.

For example, CMS promulgated a regulation permitting Medicare Advantage plans to use step therapy for Part B drugs

beginning January 1, 2020.

For example, CMS promulgated a regulation permitting Medicare Advantage plans to use step therapy for Part B drugs beginning January 1, 2020.

In addition, the 2021 Consolidated Appropriations Act incorporated extensive healthcare provisions and amendments to existing laws, including a requirement that all manufacturers of drug products covered under Medicare Part B report the product’s average sales price to CMS beginning on January 1, 2022, subject to enforcement via civil money penalties.

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We cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or administrative or executive action, either in the United States or abroad.

We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services.

We expect that additional state and federal healthcare reform measures will be

adopted in the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services.

Risks associated with our operations outside of the United States and developments in international trade by the U.S.

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Changes impacting our ability to conduct business outside of the United States, or changes to the regulatory regime applicable to our operations in countries outside of the United States (such as with respect to the approval of our product candidates), may materially and adversely impact our business, prospects, operating results, and financial condition.

We or third parties upon whom we depend may be adversely affected by natural disasters and/or health epidemics, and our business, financial condition and results of operations could be adversely affected.

Natural disasters could severely disrupt our operations and have a material adverse effect on our business operations.

We or third parties upon whom we depend may be adversely affected by natural disasters and/or local and global health epidemics, and our business, financial condition and results of operations could be adversely affected.

Natural disasters or local and global health epidemics could severely disrupt our operations and have a material adverse effect on our business operations.

If a natural disaster, health epidemic, or other event beyond our control occurred that prevented us from using all or a significant portion of our office, manufacturing and/or lab spaces, that damaged critical infrastructure, such as the manufacturing facilities of our third-party contract manufacturers, or that otherwise disrupted operations, it may be difficult for us to continue our business for a substantial period of time.

Any outbreak of contagious diseases, or other adverse public health developments, could have a material and adverse effect on our business operations.

For example, during the COVID-19 global pandemic, clinical site initiation and patient enrollment in our clinical trials were delayed due to prioritization of hospital resources in favor of COVID-19 patients and difficulties in recruiting clinical site investigators and clinical site staff.

Any local or global health issues could impact our business, our preclinical studies and clinical trials, healthcare systems or the global economy.

In addition, certain of our research and development efforts are conducted globally.

A health epidemic or other outbreak could materially and adversely affect our business, financial condition and results of operations.

The disaster recovery and business continuity plans we have in place may prove inadequate in the event of a serious disaster or similar event.

We may incur substantial expenses as a result of the limited nature of our disaster recovery and business continuity plans, which could have a material adverse effect on our business.

As a clinical-stage company with multiple programs and multiple clinical trials currently underway, any natural disasters and/or local or global health issues could impact the execution of our preclinical studies and clinical trials, and could have a material and adverse effect on our business operations.

While we have adapted our processes to lessen the potential impact that a natural disaster and/or health epidemic may have on our business, any potential delays or long-term impacts on our business, our clinical trials, healthcare systems or the global economy could be highly uncertain and the disaster recovery and business continuity plans we have in place may prove inadequate.

For example, w e rely upon third parties for many aspects of our business, including the raw materials used to make our product candidates and the conduct of our clinical trials and preclinical studies.

While we have built up inventory to assist us through uncertain operating environments, our suppliers may be disrupted now or in the future due to a natural disaster and/or health epidemic, which could affect our ability to procure items that are essential for our research and development activities and could cause increases to our costs, inflation, and significant disruptions to our business.

These effects, among others, could materially adversely affect our business, financial condition, results of operations, and prospects.

There is a substantial risk of product liability claims in our business.

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Risks Related to Our Dependence on Third Parties

We depend on collaborations with third parties for the development and commercialization of certain of our product candidates.

We depend on third-party collaborators for the development and commercialization of certain of our product candidates.

We may depend on collaborations with third parties for the development and commercialization of certain of our product candidates.

We may depend on third-party collaborators for the development and commercialization of certain of our product candidates.

Our potential future collaborators include large and mid-size pharmaceutical companies, regional and national pharmaceutical companies and biotechnology companies.

In January 2023, we commenced a collaboration with GSK to research, develop, and commercialize oligonucleotide therapeutics, including WVE-006, our first-in-class A-to-I(G) RNA editing candidate for AATD.

For example, in January 2023, we commenced a collaboration with GSK to research, develop, and commercialize oligonucleotide therapeutics.

Collaborations are complex and time-consuming to negotiate and document.

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Our future revenues may depend heavily on the success of the efforts of these third parties.

For example, under our collaboration with GSK, GSK is responsible for later clinical development and commercialization of our program in AATD.

We may not be successful in our collaborations due to various factors, including our ability to successfully demonstrate proof of mechanism in humans, our ability to demonstrate the safety and efficacy of our specific product candidates, our ability to manufacture or have third parties manufacture our product candidates, the strength of our intellectual property and/or concerns about potential challenges to or limitations of our intellectual property.

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Because we rely on third parties and do not have the ability to conduct preclinical studies or clinical trials independently, we have less control over the timing, quality and other aspects of preclinical studies and clinical trials than we would if we conducted them on our own, including our inability to control whether sufficient resources are applied to our programs.

If any of our CROs are acquired or consolidated, these concerns are likely to be exacerbated and our preclinical studies or clinical trials may be further impacted due to potential integration, streamlining, staffing and logistical changes.

If any of our CROs are acquired or consolidated, these concerns are likely to be

exacerbated and our preclinical studies or clinical trials may be further impacted due to potential integration, streamlining, staffing and logistical changes.

These investigators, CROs and consultants are not our employees and we have limited control over the amount of time and resources that they dedicate to our programs.

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In addition, raw materials, reagents, and components used in the manufacturing process, particularly those for which we have no other source or supplier, may not be available, may not be suitable or acceptable for use due to material or component defects, or may introduce variability into the supply of our product candidates.

Furthermore, with

the increase of companies developing oligonucleotides, there may be increased competition for the supply of the raw materials that are necessary to make our oligonucleotides, which could severely impact the manufacturing of our product candidates.

Furthermore, with the increase of companies developing oligonucleotides, there may be increased competition for the supply of the raw materials that are necessary to make our oligonucleotides, which could severely impact the manufacturing of our product candidates.

We may be unable to identify manufacturers on acceptable terms or at all because the number of potential manufacturers is limited and they must be acceptable to the FDA or approved by foreign regulatory authorities.

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To the extent that we have existing, or enter into future, manufacturing arrangements with third parties, we will depend on these third parties to perform their obligations in a timely manner consistent with contractual and regulatory requirements, including those related to quality control and assurance.

In complying with the manufacturing regulations of the FDA and other comparable foreign regulatory authorities, we and our third-party manufacturers must spend significant time, money, and effort in the areas of design and development, testing, production, record-keeping and quality control to assure that the products meet applicable specifications and other regulatory requirements.

In complying with the manufacturing regulations of the FDA and other comparable foreign regulatory authorities, we and

our third-party manufacturers must spend significant time, money, and effort in the areas of design and development, testing, production, record-keeping and quality control to assure that the products meet applicable specifications and other regulatory requirements.

Although our agreements with third-party manufacturers require them to perform according to certain cGMP requirements such as those relating to quality control, quality assurance and qualified personnel, we cannot otherwise control the conduct of our third-party manufacturers to implement and maintain these standards.

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We currently have no sales, marketing or distribution capabilities.

In addition, while our collaboration with GSK will provide us with know-how and experience related to commercialization, we have limited experience of our own.

If any of our product candidates is approved, we will need to develop internal sales, marketing and distribution capabilities to commercialize such products, which would be expensive and time-consuming, or rely on or enter into additional collaborations with third parties to perform these services.

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The loss of the service of any of the members of our senior management or other key employees could delay our research and development programs and materially harm our business, financial condition, results of operations and prospects.

In addition, we expect that we will continue to have an increased need to recruit and hire qualified personnel as we advance our programs and expand operations.

In addition, we expect that we will continue

to have an increased need to recruit and hire qualified personnel as we advance our programs and expand operations.

Failure to successfully recruit and retain personnel could impact our anticipated development plans and timelines.

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Although we have assembled a team of employees with experience developing medicines and obtaining regulatory approval to market those medicines, we have limited experience as a company in drug development.

We are a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines (also known as oligonucleotides), or those targeting RNA, to transform human health.

Our diversified pipeline includes clinical programs in

obesity, AATD, DMD, and HD, as well as several preclinical programs utilizing our versatile RNA medicines platform.

We are a clinical-stage biotechnology company focused on unlocking the broad potential of RNA medicines to transform human health.

As we advance product candidates through preclinical studies and clinical trials, we will need to expand our development, regulatory and manufacturing capabilities or contract with other organizations to provide these capabilities for us.

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If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the imposition of significant fines or other sanctions.

Security breaches, cybersecurity threats, loss of data and other disruptions could compromise sensitive information related to our business, prevent us from accessing critical information or expose us to liability, which could adversely affect our business and our reputation.

Security breaches, cybersecurity threats, misuse of AI tools, loss of data and other disruptions could compromise sensitive information related to our business, prevent us from accessing critical information or expose us to liability, which could adversely affect our business and our reputation.

In the ordinary course of our business, we, our CROs and other third parties, including our managed service providers (“MSPs”), on which we rely collect and store sensitive data, including legally protected patient health information, personally identifiable information about our employees, intellectual property, vendor information, and proprietary business information.

We, along with our MSPs, manage and maintain our applications and data utilizing cloud-based and on-site systems.

These applications and data encompass a wide variety of business-critical information, including research and development information and business and financial information.

These applications and data

encompass a wide variety of business-critical information, including research and development information and business and financial information.

The secure processing, storage, maintenance and transmission of this critical information by us, or our CROs and other third-party partners, is vital to our operations and business strategy.

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Although we are proactive in our approach and take measures to protect sensitive information from unauthorized access or disclosure, our information technology and infrastructure, or that of our CROs or other third party partners, may be vulnerable to attacks by hackers, viruses, breaches, interruptions due to employee error, malfeasance or other disruptions, lapses in compliance with privacy and security mandates, or damage from natural disasters, terrorism, war and telecommunication and electrical failures.

For example, as previously disclosed in May 2023 and August 2023, we became aware that our mHTT assay vendor experienced a cybersecurity incident in April 2023.

None of our data or patient samples were impacted by the incident and we remain in close contact with the vendor as they address this issue.

The financial impact of this incident was not material, and there were no changes to the previously released financial results or financial statements.

We continue to monitor, investigate and address potential incidents as they arise.

In addition, cyberattacks, malicious internet-based activity and fraud are prevalent and continue to increase in frequency.

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Any such access, disclosure or other loss of information could result in legal claims or proceedings, liability under laws that protect the privacy of personal information (including but not limited to GDPR, HIPAA and HITECH), government enforcement actions and regulatory penalties.

Unauthorized access, loss or dissemination could also adversely

affect our business, damage our reputation, and disrupt our operations, including our ability to conduct research and development activities, process and prepare company financial information, and manage various general and administrative aspects of our business.

Unauthorized access, loss or dissemination could also adversely affect our business, damage our reputation, and disrupt our operations, including our ability to conduct research and development activities, process and prepare company financial information, and manage various general and administrative aspects of our business.

For example, the loss of intellectual property or clinical trial data from completed or ongoing or planned clinical trials, in addition to privacy concerns, could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data.

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To the extent that any disruption or security breach were to result in a loss of or damage to our data or applications, or inappropriate disclosure of personal, confidential or proprietary information, we could incur liability and the further development of our product candidates could be delayed.

Numerous federal, state and international laws address privacy, data protection and the collection, storing, sharing, use, disclosure and protection of personally identifiable information and other user data, including in the context of the development and deployment of artificial intelligence technologies.

Artificial Intelligence (“AI”) is increasingly being used within many different industries.

While we have developed policies governing the use of AI to encourage appropriate use of AI by our employees, contractors, and other third-parties, any failure to adhere to such policies that we may establish could violate confidentiality obligations or applicable laws and regulations, jeopardize our intellectual property rights, or result in the misuse of personally identifiable information or the injection of malware into our systems, any of which could have a material adverse effect on our business.

In the United States, many states have already implemented state laws addressing privacy or are set to enact data protection legislation.

In addition, several states have enacted privacy laws to specifically regulate consumer health data that is not subject to HIPAA.

As the patchwork of U.S.

privacy laws expands, state enforcement of data privacy and cybersecurity breaches has increased, along with the cost.

In addition to state enforcement of privacy laws, the Federal Trade Commission has increased enforcement of cybersecurity and data privacy, and related fines in 2024.

As the patchwork of state and federal U.S.

privacy laws expands, enforcement of data privacy and cybersecurity breaches has increased, along with the cost (for example, the Federal Trade Commission increased enforcement of cybersecurity and data privacy, and related fines in 2025).

Outside the United States, personally identifiable information and other user data is increasingly subject to legislation and regulations in numerous jurisdictions around the world, the intent of which is to protect the privacy of information that is collected, processed and transmitted in or from the governing jurisdiction.

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Additionally, post-Brexit the United Kingdom has also adopted its own version of the GDPR.

While we have taken steps to comply with all applicable privacy laws and regulations, including the GDPR, by taking measures including but not limited to enhancing our security procedures, updating our website, revising our clinical trial informed consents, adopting the standard contractual clauses for cross-border transfers of personal data, increasing our cyber insurance, and entering into data processing agreements with relevant CROs and third party partners, we cannot completely assure you that our efforts to remain in compliance will be fully successful.

While we have taken steps to comply with all applicable privacy laws and regulations, including the GDPR, by taking measures including but not limited to enhancing our security procedures, updating our website, revising our clinical trial informed consents, adopting the standard contractual clauses for cross-border transfers of personal data, increasing our cyber insurance, developing policies governing the use of AI, and entering into data processing agreements with relevant CROs and third party partners, we cannot

completely assure you that our efforts to remain in compliance will be fully successful.

The GDPR and other changes in laws or regulations associated with the enhanced protection of personal data may increase our costs of compliance and result in greater legal risks.

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We are subject to income and other taxes in the United States and foreign jurisdictions.

Changes in laws and policy relating to taxes or trade, including increases in tax rates or modifications, technical corrections or clarifications to tax laws, such as the Tax Cuts and Jobs Act of 2017, which eliminates the option to deduct research and development expenditures currently and requires corporations to capitalize and amortize them over a period of years, may have an adverse effect on our business, financial condition and results of operations.

This Annual Report on Form 10-K does not discuss any such tax legislation or changes to tax laws and legislation, or the

manner in which it might affect us or purchasers of our securities.

Changes in laws and policy relating to taxes or trade, including increases in tax rates or modifications, technical corrections or clarifications to tax laws, such as the One Big Beautiful Bill Act of 2025 (“OBBBA”), which contained several pieces of tax legislation, some of which made permanent, and some of which reversed, certain of the significant U.S.

tax law changes originally enacted in 2017 (under the legislation informally titled the Tax Cuts and Jobs Act).

For example, the OBBBA reinstated immediate expensing of certain research and experimental research expenses incurred in tax years beginning after December 31, 2024 if incurred in the United States, though the requirement to amortize non-U.S.

research and experimental expenses over 15 years remains unchanged.

Any future changes may have an adverse effect on our business, financial condition and results of operations.

This Annual Report on Form 10-K does not discuss any such tax legislation or changes to tax laws and legislation, or the manner in which it might affect us or purchasers of our securities.

We urge our investors to consult with their legal and tax advisors with respect to such legislation and the potential tax consequences of investing in our securities.

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In addition, government funding of the SEC and other government agencies on which our operations may rely, including those that fund research and development activities, is subject to the political process, which is inherently fluid and unpredictable.

Disruptions at the FDA and other agencies may also extend the time necessary for new drugs to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.

For example, over the last several years, the U.S.

government has shut down several times and certain regulatory agencies, such as the FDA and the SEC, have had to furlough critical FDA, SEC and other government employees and stop critical activities.

Future legislative and regulatory proposals may impact the ability of regulatory agencies to operate as they have historically operated.

We cannot be sure whether additional legislative changes or executive orders will be enacted, or whether any of the regulations, guidances or interpretations of any such agencies will be changed, or what the impact of such changes, if any, may be.

In addition, disruptions at the FDA and other agencies may also extend the time necessary for new drugs to be reviewed and/or approved by necessary government agencies, which would adversely affect our business.

For example, political disputes in Congress may result in a shutdown of the U.S.

government, and in such cases certain regulatory agencies, such as the FDA and the SEC, would have to furlough employees and stop critical activities during that period.

Moreover, government shutdowns or slowdowns can increase the time needed for an agency to complete its review or make final approvals or other administrative decisions.

If a prolonged government shutdown or slowdown occurs, it could significantly impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business.

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In such an event, competitors might be able to enter the market earlier than would otherwise have been the case.

The standards applied by the USPTO and foreign patent offices in granting patents are not uniform, can vary substantially from country to country, and are not always applied predictably, requiring country-specific patent expertise in each jurisdiction in which patent protection is sought.

jurisdiction in which patent protection is sought.

For example, there is no uniform worldwide policy regarding patentable subject matter or the scope of claims allowable in biotechnology and pharmaceutical patents.

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Once granted, patents may remain open to opposition, interference, re-examination, post-grant review, inter partes review, nullification or derivation action in court or before patent offices or similar proceedings for a given period after allowance or grant, during which time third parties can raise objections against such initial grant.

In the course of such proceedings, which may continue

for a protracted period of time, the patent owner may be compelled to limit the scope of the allowed or granted claims attacked or may lose the allowed or granted claims altogether.

In the course of such proceedings, which may continue for a protracted period of time, the patent owner may be compelled to limit the scope of the allowed or granted claims attacked or may lose the allowed or granted claims altogether.

In addition, there can be no assurance that:

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To the extent that we use, and ultimately rely on, in-licensed technologies in our platform and our programs, our success will depend in part on the ability of our licensors to obtain, maintain and enforce patent protection for those in-licensed technologies.

Our licensors may not successfully prosecute the patent applications licensed to us.

Our licensors may not successfully prosecute the patent

applications licensed to us.

Even if patents issue or are granted, our licensors may fail to maintain these patents, may determine not to pursue litigation against other companies that are infringing these patents, or may pursue litigation less aggressively than we would.

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The timing and outcome of these and other proceedings is uncertain and may adversely affect our business, particularly if we are not successful in defending the patentability and scope of our pending and issued patent claims or if third parties are successful in obtaining claims that cover any of our product candidates or our platform.

In addition, third parties may attempt to

invalidate our intellectual property rights.

In addition, third parties may attempt to invalidate our intellectual property rights.

Even if our rights are not directly challenged, invalidated or circumvented, disputes could lead to the weakening of our intellectual property rights.

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Many countries have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties, allowing competitors to manufacture and sell their own versions of our product, thereby reducing our sales.

In addition, many countries do not permit enforcement of patents, or limit the enforceability of patents against government agencies or government contractors.

addition, many countries do not permit enforcement of patents, or limit the enforceability of patents against government agencies or government contractors.

In these countries, the patent owner may have limited remedies, which could materially diminish the value of such a patent.

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We are generally obligated under our license or collaboration agreements to indemnify and hold harmless our licensors or collaborators for damages arising from intellectual property infringement by us.

If we or our licensors, collaborators or any future strategic partners are found to infringe a third-party patent or other intellectual property

rights, we could be required to pay damages, potentially including treble damages, if we are found to have willfully infringed.

If we or our licensors, collaborators or any future strategic partners are found to infringe a third-party patent or other intellectual property rights, we could be required to pay damages, potentially including treble damages, if we are found to have willfully infringed.

In addition, we or our licensors, collaborators or any future strategic partners may choose to seek, or be required to seek, a license from a third party, which may not be available on acceptable terms, if at all.

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It is possible that at the time that we commercialize our products these third-party patent portfolios may include issued patent claims that cover our products or critical features of their production or use.

Our competitive position may suffer if patents issued to third parties or other third-party intellectual property rights cover, or may be alleged to cover, our products or elements thereof, or methods of manufacture or use relevant to our development plans.

Our competitive position may suffer if patents issued to third parties or other third-party intellectual property rights cover, or may be alleged to cover, our products

or elements thereof, or methods of manufacture or use relevant to our development plans.

In such cases, we may not be in a position to develop or commercialize product candidates unless we successfully pursue litigation to nullify or invalidate the third party intellectual property right concerned or enter into a license agreement with the intellectual property right holder, if available on commercially reasonable terms.

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There is uncertainty as to whether judgments of courts in the United States based upon the civil liability provisions of the federal securities laws of the United States would be recognized or enforceable in Singapore.

In addition, holders of book-entry interests in our shares will be required to be registered shareholders as reflected in our shareholder register in order to have standing to bring a shareholder action and, if successful, to enforce a foreign judgment against us, our directors or our executive officers in the Singapore courts.

In addition, holders of book-entry interests in our shares will be required to be registered shareholders as reflected in our shareholder register in order to have standing to bring a shareholder action in the United States and, if successful, to enforce a foreign judgment against us, our directors or our executive officers in the Singapore courts.

The administrative process of becoming a registered holder could result in delays prejudicial to any legal proceedings or enforcement action.

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Our corporate affairs are governed by our constitution and by the laws governing corporations incorporated in Singapore.

The rights of our shareholders and the responsibilities of the members of our Board under Singapore law are different from those applicable to a corporation incorporated in the United States.

The rights of our shareholders and the responsibilities of the members of our Board of Directors (“Board”) under Singapore law are different from those applicable to a corporation incorporated in the United States.

Principal shareholders of Singapore companies do not owe fiduciary duties to minority shareholders, as compared, for example, to controlling shareholders in corporations incorporated in Delaware.

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Investors in our shares who are not specifically registered as shareholders in our shareholder register (for example, where such shareholders hold shares indirectly through the Depository Trust Company) are required to become registered as shareholders in our shareholder register in order to institute or enforce any legal proceedings or claims against us, our directors or our executive officers relating to shareholder rights.

Holders of book-entry interests in our shares may become registered shareholders by exchanging their book-entry interests in our shares for certificated shares and being registered in our shareholder register.

Holders of book-entry interests in our shares may become registered shareholders by exchanging their book-entry interests in our shares for certificated shares and being registered in our

shareholder register.

Such process could result in administrative delays which may be prejudicial to any legal proceeding or enforcement action.

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These same provisions could discourage potential investors from acquiring a stake or making a significant investment in our company and may substantially impede the ability of our shareholders to benefit from a change of effective control and, as a result, may adversely affect the market price of our ordinary shares and the ability to realize any benefits from a potential change of control.

On May 5, 2025, the Securities Industry Council ("SIC") published a consultation paper seeking feedback on proposed amendments to the Singapore Takeover Code (the consultation exercise, the "Consultation").

The Consultation had closed on June 5, 2025.

As at the date of this Annual Report on Form 10-K, the SIC has not published the conclusions of the Consultation, nor provided any indication as to when the conclusions of the Consultation would be available.

Accordingly, please note that there may be further amendments to the provisions of the Singapore Takeover Code after the date of this Annual Report on Form 10-K.

Investors and/or shareholders should consult their own legal advisers and obtain specific legal advice in respect of their rights under the Singapore Takeover Code.

For a limited period of time, our directors have general authority to allot and issue new ordinary shares on terms and conditions and for such purposes as may be determined by our Board in its sole discretion.

Under Singapore law, we may only allot and issue new shares with the prior approval of our shareholders in a general meeting.

At our most recent annual general meeting of shareholders, our shareholders provided our directors with a general authority, subject to the

provisions of the Singapore Companies Act and our constitution, to allot and issue any number of new ordinary shares and/or make or grant offers, agreements, options or other instruments (including the grant of awards or options pursuant to our equity-based incentive plans and agreements in effect from time to time) that might or would require ordinary shares to be allotted and issued (collectively, the “Instruments”);

At our most recent annual general meeting of shareholders, our shareholders provided our directors with a general authority, subject to the provisions of the Singapore Companies Act and our constitution, to allot and issue any number of new ordinary shares and/or make or grant offers, agreements, options or other instruments (including the grant of awards or options pursuant to our equity-based incentive plans and agreements in effect from time to time) that might or would require ordinary shares to be allotted and issued (collectively, the “Instruments”);

and unless revoked or varied by us in a general meeting, such authority will continue in force until the earlier of (i) the conclusion of our next annual general meeting of shareholders, or (ii) the expiration of the period within which our next annual general meeting of shareholders is required by law to be held.

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Our financial results reflect the effect of certain tax credits and the operation of certain tax regimes within the United Kingdom.

Legislation in the United Kingdom will limit the amount we may be able to claim as a payable tax credit in the future which could impact our financial condition, results of operations and cash flows.

As a company that carries out extensive research and development activities, we benefit from the U.K.

research and development tax credit regime for small and medium-sized companies, whereby our subsidiary in the United Kingdom is able to surrender the trading losses that arise from its research and development activities for a payable tax credit of generally up to 18.6% of such expenditures.

Expenditures of staff supplied by unconnected third parties incurred are eligible for a cash rebate of generally up to 12.1%.

Due to a change in the U.K.

legislation affecting the U.K.

research and development tax credit regime for small- and medium-sized companies, our ability to receive a payable tax credit for the surrender of our trading losses from research and development activities may be limited to the amount equal to three times our “pay as you earn” and U.K.

national insurance tax liabilities, absent our qualification under an exception from such limitation.

Further, we may not be able to continue to claim a U.K.

tax credit for research and development tax credits under the small and medium-sized companies regime in the future if our revenue or turnover exceeds €100 million for two consecutive years.

In such an event, we will no longer qualify as a small or medium-sized enterpri se .

Recently enacted U.K.

legislation merges the small and medium-sized companies regime and the research and development expenditure credit regime generally for large companies.

This legislation applies a 20% rate to qualifying research and development expenditures.

The legislation also includes changes to other rules and types of qualifying expenditure, such as the treatment of subcontracted and overseas costs.

We are currently evaluating the impact of the legislation on our future tax credit claims.

Recent changes to the U.K.

research and development tax credit regime will reduce the amount of tax credits we can claim and impose new limitations, which could impact our financial condition, results of operations and cash flows.

As a company carrying out extensive research and development activities, we have historically benefited from the U.K.

research and development tax credit regime.

For accounting periods that began prior to April 1, 2024, our subsidiary in the United Kingdom qualified under the Small and Medium-sized Enterprise (“SME”) R&D tax credit regime, which allowed us to surrender our U.K.

subsidiary’s trading losses from qualifying research and development activities for a payable tax credit of generally up to 18.6% of such expenditures.

Expenditures of staff supplied by unconnected third parties incurred were eligible for a payable tax credit of generally up to 12.1%.

Our payable tax credit amounts were historically capped at an amount that was equal to three times our “pay as you earn” (or PAYE) and U.K.

national insurance tax liabilities.

Effective for accounting periods beginning on or after April 1, 2024, the U.K.

Finance Act 2024 combined the previous SME regime and the large-company R&D credit regime (known as the “RDEC” regime) into one unified R&D tax credit regime.

Under this merged R&D credit regime, all companies (regardless of size) may claim a tax credit equal to 20% of qualifying research and development expenditures, with a net benefit of up to 16.2% after tax.

In addition to changing the credit rates, the U.K.

legislation tightened the rules on eligible R&D expenditures, which may further limit the amount of credit we can claim.

For accounting periods beginning on or after April 1, 2024, R&D credit claims are subject to new restrictions on costs related to overseas subcontracted R&D work and externally provided R&D workers.

To be eligible for the tax credit, any subcontracted R&D activities generally must be performed in the United Kingdom.

R&D activities or workers outside the United Kingdom are largely excluded from creditable expenditures, unless they fall within an exception.

These new rules mean that certain R&D costs we incur overseas may no longer qualify for U.K.

tax credits going forward.

Risks Related to Our Ordinary Shares

The public market for our ordinary shares may not be liquid enough for our shareholders to sell their ordinary shares quickly or at market price, or at all.

Our ordinary shares are currently listed for trading on the Nasdaq Global Market.

There is no assurance that the trading market for our shares will be or remain active.

Our shareholders may not be able to sell their ordinary shares quickly or at the market price, or at all.

Our executive officers, our directors and their respective affiliates, and our other significant shareholders beneficially own a significant portion of our outstanding ordinary shares, and therefore, liquidity in our ordinary shares is limited.

Due to the limited liquidity in our ordinary shares, relatively small orders can have a disproportionate impact on the trading price of our shares.

Further, the limited liquidity in our ordinary shares may also impair our ability to raise capital by conducting offerings of our ordinary shares and may impair our ability to enter into strategic partnerships or acquire companies or products by using our ordinary shares as consideration.

The market price of our ordinary shares is likely to be highly volatile, and our shareholders may lose some or all of their investment.

The market price of our ordinary shares is likely to continue to be highly volatile, including in response to factors that are beyond our control.

The stock market in general experiences extreme price and volume fluctuations.

In particular, the market prices of securities of pharmaceutical and biotechnology companies are extremely volatile, and experience fluctuations that are often unrelated or disproportionate to the operating performance of these companies.

These broad and sector-specific market fluctuations can result in extreme fluctuations in the price of our ordinary shares, regardless of our operating performance, and can cause our shareholders to lose some or all of their investment in us.

We have issued pre-funded warrants in certain of our financings, which may cause additional dilution to our shareholders.

In several of our financings beginning in June 2022, we issued and sold ordinary shares and, in some instances, in lieu of additional ordinary shares, pre-funded warrants (the “Pre-Funded Warrants”) to purchase ordinary shares at an exercise price of $0.0001 per share.

The Pre-Funded Warrants contain a so-called “blocker” provision which provides that they are only exercisable upon receipt of shareholder approval or if such exercise would not cause the aggregate number of ordinary shares or the combined voting power of total securities, in each case, beneficially owned by the holder (together with its affiliates) to exceed, depending on the terms of the applicable Pre-Funded Warrants and in certain cases at the election of the holder, either 4.99%, 9.99% or 19.99% of the number of ordinary shares or total securities, respectively, outstanding immediately after giving effect to the exercise.

To the extent the Pre-Funded Warrants are exercised, additional ordinary shares will be issued and such issuance would dilute existing shareholders and increase the number of shares eligible for resale in the public market.

Our principal shareholders and management own a significant percentage of our ordinary shares and will be able to exert significant control over matters subject to shareholder approval.

Based on information publicly available to us as of December 31, 2025, our executive officers, our directors and their respective affiliates, and our other significant shareholders beneficially own a significant portion of our outstanding ordinary shares.

As a result, these shareholders, if acting together, will continue to have significant influence over the outcome of corporate actions requiring shareholder approval, including the election of directors, any merger, consolidation or sale of all or substantially all of our assets and any other significant corporate transaction.

The interests of these shareholders may not be the same as or may even conflict with the interests of our other shareholders.

For example, these shareholders could delay or prevent a change of control of our company, even if such a change of control would benefit our other shareholders, which could deprive shareholders of an opportunity to receive a premium for their ordinary shares as part of a sale of our company or our assets and might affect the prevailing market price of our ordinary shares.

The significant concentration of share ownership may adversely affect the trading price of our ordinary shares due to investors’ perception that conflicts of interest may exist or arise.

We incur significant costs due to operating as a public company, and our management is required to devote substantial time to compliance initiatives.

As a public company, we incur significant legal, accounting and other expenses.

We are subject to the reporting and other requirements of the Exchange Act, the Sarbanes-Oxley Act of 2002 (the “Sarbanes-Oxley Act”), and the Dodd-Frank Wall Street Reform and Protection Act, as well as rules subsequently adopted by the SEC and the Nasdaq Stock Market.

These rules and regulations require, among other things, that we file annual, quarterly and current reports with respect to our business and financial condition and establish and maintain effective disclosure and financial controls and corporate governance practices.

We expect that compliance with these rules and regulations will continue to result in substantial legal and financial compliance costs and will make some activities more time-consuming and costly.

Our management and other personnel devote a substantial amount of time to these compliance requirements.

If we fail to maintain proper and effective internal controls, our ability to produce accurate and timely financial statements could be impaired, which could harm our operating results, our ability to operate our business and investors’ views of us.

We are required to comply with Section 404 of the Sarbanes-Oxley Act.

Section 404 of the Sarbanes-Oxley Act requires public companies to maintain effective internal control over financial reporting.

In particular, we must perform system and process evaluation and testing of our internal control over financial reporting to allow management to report on the effectiveness of our internal control over financial reporting.

Ensuring that we have adequate internal financial and accounting controls and procedures in place so that we can produce accurate financial statements on a timely basis is a costly and time-consuming effort that is evaluated frequently.

If we fail to maintain the effectiveness of our internal controls or fail to comply in a timely manner with the requirements of the Sarbanes-Oxley Act, or if we identify deficiencies in our internal control over financial reporting that are deemed to be material weaknesses, this could have a material adverse effect on our business.

We could lose investor confidence in the accuracy and completeness of our financial reports, which could have an adverse effect on the price of our ordinary shares and we could be subject to sanctions or investigations by Nasdaq, the SEC or other regulatory authorities, which would require additional financial and management resources.

In addition, if our efforts to comply with new or changed laws, regulations, and standards differ from the activities intended by regulatory or governing bodies due to ambiguities related to practice, regulatory authorities may initiate legal proceedings against us and our business may be harmed.

Our ability to successfully implement our business plan and comply with Section 404 of the Sarbanes-Oxley Act requires us to be able to prepare timely and accurate financial statements.

We expect that we will need to continue to improve existing, and implement new operational and financial systems, procedures and controls to manage our business effectively.

Any delay in the implementation of, or disruption in the transition to, new or enhanced systems, procedures or controls, may cause our operations to suffer and we may be unable to conclude that our internal control over financial reporting is effective and to obtain an unqualified report on internal controls from our independent registered public accounting firm as required under Section 404 of the Sarbanes-Oxley Act.

This, in turn, could have an adverse impact on trading prices for our ordinary shares, and could adversely affect our ability to access the capital markets.

Although we determined that our internal controls over financing reporting were effective as of December 31, 2025, we may in the future identify internal control deficiencies that could rise to the level of a material weakness or uncover other errors in financial reporting.

During the course of our evaluation of these material weaknesses, we may identify areas requiring improvement and may be required to design additional enhanced processes and controls to address issues identified through this review.

There can be no assurance that such remediation efforts will be successful, that our internal control over financial reporting will be effective as a result of these efforts or that any such future deficiencies identified may not be material weaknesses that would be required to be reported in future periods.

In addition, we cannot assure you that our independent registered public accounting firm will be able to attest that such internal controls are effective.

The estimates and judgments we make, or the assumptions on which we rely, in preparing our consolidated financial statements could prove inaccurate.

Our consolidated financial statements have been prepared in accordance with accounting principles generally accepted in the United States (“U.S.

The preparation of these consolidated financial statements requires us to make estimates and judgments that affect the reported amounts of our assets, liabilities, revenues and expenses, the amounts of charges accrued by us and related disclosure of contingent assets and liabilities.

We base our estimates on historical experience and on various other assumptions that we believe to be reasonable under the circumstances.

We cannot assure, however, that our estimates, or the assumptions underlying them, will not change over time or otherwise prove inaccurate.

For example, our estimates as they relate to anticipated timelines and milestones for our clinical trials or preclinical development may prove to be inaccurate.

If this is the case, we may be required to restate our consolidated financial statements, which could, in turn, subject us to securities class action litigation.

Defending against such potential litigation relating to a restatement of our consolidated financial statements or otherwise would be expensive and would require significant attention and resources of our management.

Moreover, our insurance to cover our obligations with respect to the ultimate resolution of any such litigation may be inadequate.

As a result of these factors, any such potential litigation could have a material adverse effect on our financial results, harm our business, and cause our share price to decline.

We do not anticipate paying any cash dividends on our ordinary shares in the foreseeable future.

We have never declared or paid cash dividends on our ordinary shares.

We currently intend to retain all of our future earnings, if any, to finance the growth and development of our business, and we do not anticipate paying any cash dividends on our ordinary shares in the foreseeable future.

In addition, the terms of any future debt agreements may preclude us from paying dividends.

As a result, capital appreciation, if any, of our ordinary shares will be our shareholders’ sole source of gain for the foreseeable future.

We may incur significant costs from class action litigation due to share volatility.

Our share price may fluctuate for many reasons, including as a result of public announcements regarding the progress of our development efforts or the development efforts of our collaborators and/or competitors, the addition or departure of our key personnel, variations in our quarterly operating results and changes in market valuations of pharmaceutical and biotechnology companies.

Holders of stock that has experienced significant price and trading volatility have occasionally brought securities class action litigation

against the companies that issued the stock.

If any of our shareholders were to bring a lawsuit of this type against us, even if the lawsuit is without merit, we could incur substantial costs defending the lawsuit.

The lawsuit could also divert the time and attention of our management, which could harm our business.

Sales of additional ordinary shares could cause the price of our ordinary shares to decline.

Sales of substantial amounts of our ordinary shares in the public market, or the availability of such shares for sale, by us or others, including the issuance of ordinary shares upon exercise of outstanding options or Pre-Funded Warrants or vesting of outstanding restricted share units, or the perception that such sales could occur, could adversely affect the price of our ordinary shares.

Certain of our shareholders have required us, or have the right to require us, to register the sales of their shares under the Securities Act under agreements between us and such shareholders.

For example, in August 2019, we filed a registration statement on Form S-3, which was declared effective on August 14, 2019, to register the resale from time to time by certain of our executive officers, directors and their affiliates of up to approximately 7.1 million ordinary shares.

If securities or industry analysts do not publish research or publish inaccurate or unfavorable research about our business, our share price and trading volume could decline.

The trading market for our ordinary shares may depend in part on the research and reports that securities or industry analysts publish about us or our business.

If too few securities or industry analysts cover our company, the trading price for our ordinary shares would likely be negatively impacted.

If one or more of the analysts who cover us downgrade our ordinary shares or publish inaccurate or unfavorable research about our business, our share price would likely decline.

If one or more of these analysts cease coverage of our company or fail to publish reports on us regularly, demand for our ordinary shares could decrease, which might cause our share price and trading volume to decline.

Unresolve d Staff Comments

Cybersecurity

We recognize the importance of maintaining the trust and confidence of the patients we serve, our business partners, employees and our shareholders and are committed to protecting the confidentiality, integrity and reliance of our business operations and systems.

Effective data protection practices, including responsible stewardship of our intellectual property and the secure processing, storage, maintenance and transmission of critical information by us and other third parties with whom we do business is vital to our operations.

Our cybersecurity practices, policies, and standards are based on recognized frameworks established by the National Institute of Standards and Technology (“NIST”) (NIST SP 800-53), the Center for Internet Security (“CIS”), along with adopting best practices from Control Objectives for Information and Related Technologies (“COBIT”) and other applicable industry standards.

In general, we seek to address cybersecurity risks through a comprehensive, cross-functional approach that is focused on preserving the confidentiality, security and availability of the information that we collect and store by identifying, preventing and mitigating cybersecurity threats and effectively responding to cybersecurity incidents if they occur.

Cybersecurity Risk Management and Strategy

We may face risks related to cybersecurity, such as unauthorized access, cybersecurity attacks and other security incidents, which could adversely affect our business and operations.

To identify and assess material risks from cybersecurity threats, we maintain a robust cybersecurity program to ensure our systems are effective and prepared for information security risks and have integrated these processes into our overall risk management systems and processes .

We also identify our cybersecurity threat risks by comparing our processes to standards set by NIST, CIS, and COBIT, as well as by engaging experts to attempt to infiltrate our information systems.

We consider risks from cybersecurity threats alongside other company risks as part of our overall risk assessment process.

We employ a range of tools, services and capabilities, including regular network and endpoint monitoring, audits, vulnerability assessments, penetration testing, threat modeling, disaster recovery and business continuity planning activities, red team testing, mandatory training for our employees, and tabletop exercises to inform our risk identification and assessment.

Our processes also address cybersecurity threat risks associated with our use of third-party service providers, including our vendors, CROs, suppliers and/or manufacturers who may have access to patient and employee data or our systems.

We perform diligence on third parties that have access to our systems, data or facilities that house such systems or data, and continually monitor cybersecurity threat risks identified through such diligence.

Additionally, we generally require those third parties that could introduce significant cybersecurity risk to us to agree by contract to manage their cybersecurity risks in specified ways, and to agree to be subject to cybersecurity audits, which we conduct continuously through third-party risk management tools.

Our incident response plan coordinates the activities we take to prepare for, detect, respond to and recover from cybersecurity incidents, which include processes to triage, assess severity for, escalate, contain, investigate and remediate the incident, as well as to comply with potentially applicable legal obligations and mitigate damage to our business and reputation.

As part of the above processes, we regularly engage with consultants and other third parties, including a bi-annual review of our cybersecurity program by an independent Qualified Security Assessor.

In the last three fiscal years, we have no t experienced any material cybersecurity incidents and the expenses we have incurred from cybersecurity incidents were immaterial.

We describe whether and how risks from identified cybersecurity threats, including as a result of any previous cybersecurity incidents, have materially affected or are reasonably likely to materially affect us, including our business strategy, results of operations, or financial condition, under the heading “ Security breaches, cybersecurity threats, loss of data and other disruptions could compromise sensitive information related to our business, prevent us from accessing critical information or expose us to liability, which could adversely affect our business and our reputation ,” in Item 1A.

Risk Factors, which disclosures are incorporated by reference herein.

Cybersecurity Governance

Our Board is actively involved in oversight of our risk management activities, and cybersecurity represents an important element of our overall approach to risk management.

Our Board delegates to the Audit Committee oversight of certain aspects of our risk management process, including risks related to information technology, data privacy and cybersecurity.

At least quarterly, our Audit Committee receives an update from management of our cybersecurity threat risk management and strategy processes, including recent cybersecurity incidents and related responses, cybersecurity testing, activities of third parties, and other similar matters.

Our cybersecurity risk management and strategy processes are led by our Data Security Officer, Data Privacy Officer, Chief Financial Officer and General Counsel.

Such individuals have collectively over 50 years of prior work experience in various roles involving managing information security, developing cybersecurity strategy , implementing effective information and cybersecurity programs, as well as several relevant degrees and certifications.

Our Audit Committee is encouraged to regularly engage in conversations with management on cybersecurity-related news and events and discuss any updates to our cybersecurity risk management and strategy programs.

Management is informed about and monitors the prevention, mitigation, detection, and remediation of cybersecurity incidents through their management of, and participation in, the cybersecurity risk management and strategy processes described above, including the operation of our incident response plan.

We have processes in place to ensure that our Audit Committee shall receive prompt and timely information regarding any cybersecurity incident that meets establishing reporting thresholds, as well as ongoing updates regarding any such incident until it has been addressed.

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business