Q1 2021 WAVE Life Sciences Ltd Earnings Call

Good morning, and welcome to the wave life Sciences first quarter 2021 financial results conference call. At this time, all participants are in a listen only mode.

Operator: Good morning, and welcome to the Wave Sciences first quarter 2021 Financial Results Conference Call. At this time, all participants are in a listen-only mode.

Operator: As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rauch, head of investor relations at Wave Life Sciences. Please go ahead.

As a reminder, this call is being recorded and webcast.

Now turn the call over to Kate Rausch head of Investor Relations at Wave Life Sciences. Please go ahead.

Thank you operator, good morning, and thank you for joining us today to discuss our recent business progress and review <unk> first quarter 2021 operating results.

Kate Rausch: Thank you, operator. Good morning, and thank you for joining us today to discuss our recent business progress and review this week's first quarter 2021 operating results. On the call with me today is Dr. Paul Bolna, we've President and Chief Executive Officer, Dr. Mike Panzara, Chief Medical Officer, Head of Therapeutics Discovery and Development, and Kyle Moran, Chief Financial Officer. This morning, we issued a news release detailing our first quarter financial results and provided a business update.

On the call with me today is Dr. Pablo <unk>, President and Chief Executive Officer, Dr. Mike Pinza, Chief Medical Officer head of Therapeutics Discovery and development and Paul Moran Chief Financial Officer.

This morning, we issued a news release detailing our first quarter financial results and provided a business update this news release and a slide presentation to accompany this webcast are available in the investors section of our website Www Dot wave life Sciences dotcom.

Kate Rausch: This news release and a slide presentation to accompany this webcast are available in the investor section of our website, www.wavlif Sciences.com. Before we begin, I would like to remind you that the discussions during this conference call will include forward-looking statements.

Before we begin I would like to remind you that discussions during this conference call will be include forward looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in forward looking statements.

Kate Rausch: These statements are subject to a number of risks and uncertainties that could cause our actual results to be different.

Kate Rausch: actual results to differ materially from those described in the forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10K for the year ended December 31, 2020. We undertake no obligation to update or revise any forward-looking statements for any reason.

That could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on form 10-K for the year ended December 31st timeframe, we undertake no obligation to update or revise any forward looking statement for any reason I'd now like to turn the call over to Paul Paul.

Paul B. Bolno: Thank you, Kate. Good morning to everyone on the call, and thank you for joining us. During the call today, I will provide some opening remarks, after which Mike will give an update on our clinical trials, and Kyle will briefly review our financials. It has been an incredibly productive start to the year for Waves as we advance three next-generation stereopure oliginucleotides into clinical development. We have formally initiated clinical trials for WVE-004, our C9 Orch 72 candidate, an ALS, and FD.

Thanks, Keith good morning to everyone on the call and thank you for joining us during.

During the call today I will provide some opening remarks, after which Mike will give an update on our clinical trials I will briefly review our finance.

It's been an incredibly productive start to the year for wave as we advanced three generation aerial pure oligonucleotides into clinical development.

We have formally initiated clinical trials for <unk> zero zero or are seen iron ore, it's gonna be two candidates in a O N E.

And W. V E 003, or SNP three candidates in Huntington's disease. We've also received important regulatory approvals towards initiating our third PMO chemistry program targeting exon 53 in DMD WB and 531.

Paul B. Bolno: And WVE003, our SNP3 candidates in Huntington. We've also received important regulatory approvals towards initiating our third PN chemistry program, targeting Exxon 53 in DMB, WVE-N-531. These clinical trials are designed to enable rapid proof of concept using biomarker-driven adaptive designs and are the first investigative candidates designed with our novel PM backbone chemistry modification. Next year, we expect that data from these clinical trials will enable decision-making about next steps for these programs, as well as provide insight into PN chemistry across different modalities, tissue types, and targets.

These clinical trials are designed to enable rapid proof of concept using biomarker driven adaptive design and are the first investor day of candidates designed with our novel Pn backbone chemistry modification.

Next year, we expect the data from these clinical trials will enable decision, making about next steps for these programs as well as provide insight into pn chemistry across different modalities tissue types and targets.

Paul B. Bolno: We've also made substantial progress with our endogenous ADAR editing capability, which we believe is the most advanced in its class. We've generated a breadth of RNA editing data demonstrating activity across in vivo and in vivo features systems, including in vivo editing in the central nervous system. Much of this data is being presented in an oral presentation tomorrow, May 14, at the ASGCT annual meeting.

We've also made substantial progress with our endogenous eight are editing capability, which we believe is the most advanced in its class we.

We've generated a breath of RNA editing data demonstrating activity across in vivo and in vivo each other systems, including in vivo editing in the central nervous system.

Much of this data is being presented in an oral presentation tomorrow may 14th at the a S. GCG annual meeting.

Our first day to our editing program for Alpha one Antitrypsin disease has generated promising initial results and we are on track to share in vivo data this quarter.

Paul B. Bolno: Our first data editing program for Alpha One antitriotin disease has generated promising initial results, and we are on track to share in vivo data this quarter. Our prison platform is unique and differentiated from others developing RNA therapeutics. At our foundation, we set out to embrace, rather than ignore, the reality and importance of geochemistry that exists in each and every oligonuclea type.

Our prism platform is unique and differentiated from others developing RNA therapeutics.

Our foundation, we set out to embrace rather than ignore the reality and importance of stereochemistry that exists in each and every oligonucleotide.

Paul B. Bolno: In choosing to control for the three-dimensional orientations of backflow linkages and advanced single-isomer therapeutics, we can apply the principles of rational drug design to our pipeline candidate, which is impossible with mixture-based oliginucleate. This resolution enables us to define distinct profiles for our stereocure molecules, and we now have several years of clinical data to further inform our platform. Earlier this year, we announced the discontinuation of our remaining first generation programs following the results of the Precision H.D. trial.

And choosing to control for the three dimensional orientations of backbone linkages and had been single isomer therapeutics, we can apply the principles of rational drug design to our pipeline candidates, which is impossible with mixture base oligonucleotides.

Resolution enabled defined distinct profiles for our stereo per molecule and we now have several years of clinical data to further inform our platform.

Earlier this year, we announced the discontinuation of our remaining first generation programs. Following the results of the precision HD trials.

Paul B. Bolno: While we only saw modest and inconsistent reductions in Mewton Huntington, it is important to note there were no clinically meaningful trends in disease progression or laboratory values, such as elevations in CSF white blood cells, proteins, and neurofilment, flight chain, or NFL. There were, however, suggestions of illegal activity underscoring the precision in April by our. In our next generation programs, we have prioritized the use of EnVivo models during preclinical development to ensure we advance clinical candidates that will reach the desired side of action and engage targets.

While we only saw modest and inconsistent reductions of Huntington. It is important to note there were no clinically meaningful trends and disease progression or laboratory values, such as elevations in CSF white blood cell proteins generic government light chain for NFL.

However, suggestions of a willful activity underscoring the precision enabled by our platform.

And our next generation program, we have prioritized the use of in vivo models drove preclinical development to ensure we advanced clinical candidates that will reach the desired live action and engage target.

Paul B. Bolno: In addition to the wealth of data collected over the past several years, we're also leveraging an influx of new talent in oligonucleotide therapeutics to further advance our understanding of design principles, pharmacology, and toxicology. For example, the application of PN Backbone Chemistry Modifications in the context of controlling stereochemistry was a major advancement that emerged from our platform.

In addition to the wealth of data collected over the past several years. We're also leveraging an influx of new talent in the oligonucleotide therapeutics to further advance our understanding of design principles pharmacology and toxicology.

The application of Pn backbone chemistry modifications in the context of controlling stereochemistry with a major advancement that emerge from our platform and based on what we've seen pre clinically. This innovation has the potential to significantly improve the profile of therapeutic oligonucleotides independent of sequence tissue type of core modality.

Paul B. Bolno: And based on what we have seen preclinically, this innovation has the potential to significantly improve the profiles of therapeutic oliginucleotides, independent of sequence, tissue type, or modality. Additionally, our ADR editing capability further expands our toolkit beyond silencing and splicing, enabling us to select the best modality to address the root cause of genetic diseases. We anticipate sharing more on PN Chemistry and AdD editing at a research date later this year. Our current pipeline is comprised of programs designed with the next generation of Prism, including P&K.

Separately, our ADR editing capability further expands our tool kit beyond silencing and spicy, enabling us to select the best modality to address the root cause of genetic diseases, we anticipate sharing more on pn chemistry and eight are editing at a research day later this year.

Our current pipeline is comprised of programs designed with next generation of president, including piano chemistry.

Paul B. Bolno: I am extremely proud of how quickly we have advanced this innovation to the clinic, and we are rapidly approaching the first of many opportunities for clinical proof of concept for PN chemistry. I'd now like to turn the call over to Mike Panzera for an update on our neurology program. Thanks, Paul.

I'm extremely proud of how quickly we have advanced this innovation to the clinic and we are rapidly approaching the first of many opportunities for clinical proof of concept of Pn chemistry.

I'd now like to turn the call over to Mike <unk> for an update on our neurology programs Mike.

Thanks, Paul.

Michael Linden: The foundational work that has been done throughout the evolution of Prism has provided us with a diverse and robust neurology focus portfolio that is currently moving through stages of pre-clinical discovery and clinical development, as illustrated here. As Paul just mentioned, all of our current discovery stage and preclinical programs utilize PN Chemistry, including multiple discovery programs in collaboration with our partner, Takeda. These programs are yielding exciting results, including target engagement and distribution and the essential nervous system of non-human primates, which further validate our approach.

The foundational work that has been done throughout the evolution of prison has provided us with a diverse and robust neurology focused portfolio that is currently moving through stages preclinical discovery and clinical development as illustrated here.

As Paul just mentioned all of our current discovery stage and preclinical program to utilize PM chemistry, including the multiple discovery programs in collaboration with our partner Takeda.

These programs are yielding exciting results, including target engagement and distribution in the central nervous system of non human primates, which further validate our approach.

Our therapeutics discovery portfolio continues to build upon this progress to maximize the potential of oligonucleotide therapeutics for the treatment of neurological disorders with high unmet need.

Michael Linden: Our therapeutic discovery portfolio continues to build upon this progress to maximize the potential of all of the nucleotide therapeutics for the treatment of neurological disorders with high-end met. Now I'd like to discuss the programs currently in clinical development with three next generation Kennedys. Our development organization is focused on site activation and initiating dosing simultaneously in three clinical trials across four disease areas. C9RF72 associated myotrophic lateral sclerosis, or ALS, and frontodumbral dementia, or FD with WVE 004, our candidate targeting C9 or F72 hexonucleotide repeat expansion, Huntington's disease with WVE003, R-Snip 3 targeting candidate, and Duchenne muscular dystrophy with WVE N531, RX on 53, skipping candidates.

Now I'd like to discuss the programs currently in clinical development with three next generation candidates.

Our development organization is focused on site activation and initiating dosing simultaneous simply in three clinical trials across board disease area.

C&I North 72 associated Myotrophin lateral sclerosis, our AOS and Frontotemporal dementia or F. D D with <unk> zero zero for our candidate targeting <unk>, nine or 72, hex and nucleotide repeat expansions.

Huntington's disease with WV easier zero, three or snip III targeting candidates.

And Duchenne muscular dystrophy with W. B E N 531, our exon 53 skipping candidate.

Each of these clinical candidates incorporates P M chemistry, and the availability of relevant preclinical models has enabled a greater understanding of PK PD relationships to guide development.

Michael Linden: Each of these clinical candidates incorporates PM chemistry, and the availability of relevant pre-clinical models has enabled a greater understanding of PKPD relationships to guide development. Further, the learnings from our first generation programs are being incorporated to mitigate risk, and more efficiently execute our plans.

Further the learnings from our first generation programs are being incorporated mitigate risks and more efficiently execute our plans.

Starting with gene INR 72 are.

Michael Linden: Starting with C9R 72, our clinical candidate, WVE 004, is designed to target a Hetsonucleotide repeat expansion in the C9RF 72 transcript, which is one of the most common genetic causes of ALS and FTD. These expansions drive the common pathophysiology underlying these two diverse and devastating phenotypes. And 004 is the first C9 R72 candidate being advanced simultaneously in a single basket-like study for both C9 ALS and C9 FDD. G9R72 mutations lead to multiple drivers of toxic, the hexanucleotide repeat-containing RNA transcripts deposited in tissues and are toxic on their own.

Our clinical candidate WP easier as Air force designed to target a hedge the nucleotide repeat expansion in the C&I <unk> 72 transfer, which is one of the most common genetic causes of ALS and F. T D.

These expenses expansions drive the common pathophysiology underlying was true diverse and devastating phenotypes and zero zero core is the first thing on our 72 candidates being as Dan simultaneously in a single basket life study for both C&I and E. L F and C&I in F T D.

G&A are 72 mutations lead to multiple drivers of toxicity.

The heck the nucleotide repeat containing RNA transcripts to profit in tissues and are toxic on their own but they are also translated into long life peptide with Pete proteins or DPR proteins that trigger cellular toxicity through a variety of downstream mechanisms.

Michael Linden: But they are also translated into long-dipeptide repeat proteins or DPR proteins that trigger cellular toxicity through a variety of downstream mechanisms. Theer Zero4 selectively targets the pre-MRNA ovarian transcripts that contain the hexanucleotide expansion with the goal of suppressing both the RNA and DPR associated toxicities while allowing C9L protein expression. In the first quarter, our foundational work to identify and validate the targeting site used to achieve the selective knockdown was published in Nature Communication.

Near Zero force selectively targets.

<unk> operating and transcripts that contain the heck the nucleotide expansion with the goal of suppressing both the RNA and DPR associated toxicity, while allowing <unk> protein expression.

In the first quarter, our foundational work to identify and validate that targeting site used to achieve this selective knockdown was published in nature Communications.

On the right of the Slide 11, you can see the preclinical data that demonstrates <unk> ability to rapidly and durably reduce over 90% of the DPR apology.

Michael Linden: On the right side of slide 11, you can see the pre-clinical data that demonstrates 004's ability to rapidly and durably reduce over 90% of the DPR PolyGP in the spinal cord and reduce at least 80% of PolyGP in the Corte. This effect lasted at least six months only after two ICB injections of 004, administered seven days apart at the start of the study. T9 or 72 protein was unchanged over the same period.

The spinal cord and reduced at least 80% of probably GP in the cortex.

This effect lasted at least six months only after two ICB injections of zero zero or administered seven days apart started the study.

G nine or 72 protein was unchanged over the same period.

Michael Linden: The effect of 004 and PolyGP in the CSF is a key endpoint in our clinical study, so we were looking forward to assessing the impact of treatment in humans given these promising preclinical results. These results, along with data from non-human primates, have also allowed us to start a dose in our clinical trial predicted to be pharmacologically active. This week at the European Network to Cure ALS virtual meeting, or NPELS, we introduced Focus C9, an adaptive trial that is designed to enable faster optimization of dose and frequency of 004 based upon review of unblinded data throughout the study.

The effect of zero zero for oncology in the CSF as the key endpoints in our clinical studies. So we're looking forward to assessing the impact of treatment and humans given these promising preclinical results.

These results along with data from non human primates have also allowed us to start at a dose in our clinical trial predicted to be pharmacologically active.

Yeah.

This week at the European network secure AOS virtual meeting or Npls we.

<unk> focused C&I and adaptive trial that is designed to enable faster optimization of dosing frequency of 004 based upon our review of unblinded data throughout the study.

Focus denying that the phase one b to a global multicenter randomized double blind placebo controlled trial in which we're planning to enroll approximately 50 patients with documented Jeannine <unk> 72 expansions and confirmed a L. S T D or mixed phenotypes.

Michael Linden: Focus, V9 is a Phase 1B2A global, multi-center, randomized, double-blind placebo-controlled trial in which we are planning to enroll approximately 50 patients with documented C9472 expansions and confirmed ALS, FTD, or mixed phenotype. Focus C9 includes single and multiple ascending dose portions of 004 administered intrathletically at points throughout the study based upon predefined data-driven milestones and an independent committee where we review unblinded data to determine the next single dose level to be escalated to and the optimal frequency in the next multi-dose cohort, meaning whether the dosing interval should be monthly or less frequent.

Focused jeannine includes single and multiple ascending dose portion of the zeros, you'll report administered interest equal.

At points throughout the study based upon pre defined data driven milestones and independent Committee will review unblinded data to determine next single dose level to be escalated to and the optimal frequency and the next multi dose cohort, meaning whether the dosing interval should be monthly or less frequent.

Michael Linden: Samples are collected for biomarker analysis and multiple time points within both the single and multi-ascending dose portions to enable the assessments required to make these recommendations. Regulatory and ethics approvals have been received in clinical site activation is underway, so we anticipate dosing sometimes. I'll now turn over to WVE003, our allele selective candidate for the Huntington system, which is designed to selectively lower mutant huntington while preserving wild pet hunting. The presentations, posters, and feedback from experts at the recent virtual CHDI-HE Therapeutics Conference only serve to bolster our confidence that we are pursuing the right approach to hunting. Let's review what we know.

Samples are collected per biomarker analysis at multiple time points within both the single and multi ascending dose portions to enable the assessments required to make these recommendations.

Regulatory and ethics approvals have been received and clinical site activation is underway. So we anticipate dosing sometime soon.

I'll now turn over to W. V E 003, or allele selective candidate for Huntington's disease.

Which is designed to selectively lower mutant Huntington, while preserving wild type.

The presentations posters and feedback from experts at the recent virtual <unk> Therapeutics conference only serve to bolster our confidence that we are pursuing the right approach to huntington's.

Let's review, what we know.

Michael Linden: Patients with Huntington disease have an expanded CAG repeat in their Huntington gene that leads to production of mutant Huntington protein. This is a monogenic, autosomal dominant genetic disease that is fully penetrant and affects the entire brain. Preserving wild type hunting is as important as lowering youth.

Patients with Huntington's disease have expanded CABG repeat and their Huntington gene that leads to production of the mutant Huntington protein.

This is a monogenic autosomal dominant genetic disease that is fully kind of trends and affects the entire brand.

Preserving wild type Huntington is as important as lower tonnage.

Michael Linden: Evan supports that Huntington's disease is driven by both the gain of function of the mutant Huntington protein and the loss of function of wildfire, which is essential for homeostasis of the central nervous system. Wild type protein is critical for the protection of neurons that are under stress and plays a key role in trafficking synaptic proteins and vesicles, including the production and transport of brain-derived neurotrophic factor of EDNF in the cortex. It is also critical for the formation and function of celia, which control the flow of CSF and help maintain CNS homeostasis. In healthy individuals, these important functions of wild-type hunting can balance out the collective stresses based on the central nervous system.

And then support that Huntington's disease is driven by both the gain of function of mutant Huntington protein and the loss of function of wild type protein.

Which is essential for homeostasis of the central nervous system.

Wild type protein is critical for the protection of neurons that are under stress from plays a key role in trafficking synaptic proteins and vegetables, including the production and transport of brain derived neurotrophic factor or median off from the cortex.

Wild type protein is also critical for the formation and function, Australia, which control the flow of CSF and help maintain CNS homeostasis.

In healthy individuals these important functions of wild type Huntington balance out the collective stresses on the central nervous system.

Michael Linden: However, in the case of HG, there is the added burden of the mutant protein itself. Those living with HD have been subjected to decades of toxic stress that come with mutant hunting protein years prior to symptom onset. Looking at levels of wild type and healthy individuals or models that lack the effect of the mutant protein does not adequately represent the role the healthy protein plays in the context of Huntington's disease.

However, in the case of H D. There is the added burden of the mutant protein itself.

Those living with H D have been subjected to decades of toxic stress that come with mutant Huntington protein years prior to symptom onset.

Looking at levels of wild type and helping individual are modeled that blocks. The effect of mutant protein does not adequately represented the wall. The healthy protein plays in the context of Huntington's disease.

This smaller protective reservoir of wild type Huntington eventually loses the battle to the expected stress placed on the CNS along with the toxic effects of mutant Huntington, resulting in disease progression.

Michael Linden: This smaller protective reservoir of wild-type Huntington eventually loses the battle to the expected stresses placed on the DNS along with the toxic effects of mutant Huntington, resulting in disease progression. If one thinks about this as a push and pull of positive and negative factors in this balance of wild type protein along with mutant protein, as with non-selective approaches, could shift the balance towards disease progression, erasing any benefit, or even potentially accelerating decline.

If one thinks about this as a push Paul are positive and negative factors in this balance of wild type and mutant Huntington in the CNS. It stands to reason that depletion of wild type protein along with mutant protein as with non selective approaches, but shifts the balance towards disease progression of racing any benefit or even potentially.

Accelerating decline.

Michael Linden: This has been our hypothesis since we began our HG program, and the data that are emerging support our position and make us resolute in our differentiated approach to treating this disease. Zero-03 has been improved over our prior SNIP targeting candidates by applying P&B backbone chemistry modifications in the context of control over stereo chemistry.

This has been our hypothesis since we began our HD program and the data that are emerging support our position to make us resolute and our differentiated approach to treating this disease.

003 has been improved over our prior snip targeted candidates by applying <unk> backbone chemistry modifications in the context of control over stereochemistry.

Further the presence of the SNP and a relevant animal model has allowed us to do in vivo preclinical work to determine a dose predicted to be pharmacologically active right from the start of Portland.

Michael Linden: Further, the presence of this SNIP and a relevant animal model has allowed us to do pre-clinical work to determine a dose predicted to be pharmacologically active right from the start. Slide 16 illustrates some of these in vitro and in vivo data demonstrating that zero zero three is highly selective for Mutant Huntington and able to achieve potent and durable knockdown of Mutant Huntington in vivo in the back HD mouse model We investigated this model knowing that there were several limitations, including the fact that it contains multiple copies of the MHTG gene, some of which do not have the SNP-free variant. Nonetheless, as shown in the bottom of the slide, we observe potent and durable knockdown of Mutant Huntington and the striatum out to 12 weeks. Similar effect was observed in the quality.

Slide 16 illustrates some of these in vitro and in vivo data demonstrating that <unk> is highly selective from Huntington enabled to achieve potent and durable knockdown of mutant Huntington in vivo in the back HD mouse model.

We investigated this model knowing that there were several limitations, including the fact that it contains multiple copies of the <unk> gene some of which do not have the SNP free bearing.

Nonetheless shown on the bottom of the slide we observed potent and durable knockdown of mutant Huntington in the striatum. After 12 weeks of similar effect observed in the contents.

Non human primates, do non cash necessary and as such we're not able to evaluate the pharmacokinetics dynamic effects in this model.

Michael Linden: Non-human primates do not have SNP 3, and as such, we are not able to evaluate the pharmacosidetic dynamic effects in this model. Therefore, we use the concentration data from the back H-G mouse compared with tissue concentrations in the CSS of CSF and CNS of non-human primates, and then used PKPB modeling to estimate tissue concentrations required to achieve stradal and cortical knockdown in humans with zero zero three. These analyses are guiding the starting dose and dosing regimen plan for our clinical trial.

Therefore, we used the concentration data from the back HD mouse compared with tissue concentrations in the CSS CSS.

A non human primate.

And then used PK PD modeling to estimate tissue concentrations required to achieve straddle and cortical knockdown in humans with <unk> III.

These analyses are guiding the starting dose and dosing regimen plan for our clinical trial.

While target engagement studies in CNS of non human primates were not possible per zero-zero III they weren't possible for our most advanced therapeutic candidate in our CNS discovery collaboration with Takeda <unk> 005.

Michael Linden: While Target engagement studies in the CNS of non-human primates were not possible for 003, they were possible for our most advanced therapeutic candidate in our CNS discovery collaboration with Takeda, WVE005. Like 003, this candidate uses PN chemistry. But unlike 003, the human transcript targeted by 005 is homologous to the monkey sequence, allowing us to assess target engagement throughout the CNF. In this study, for an undisclosed target, non-human primates received a single 12 milligram intracial injection of 005.

003. This candidate uses piano chemistry, but unlike the earlier three of the human transcript targeted by 005 years from Alagoas, the monkey see quest, allowing us to assess target engagement throughout the CNS.

In this study for an undisclosed target non human primates received a single 12 milligram enter depot injection Zero-zero bought one months after administration.

Michael Linden: One month after administration, we observed that the candidate was widely distributed throughout the CNS and led to substantial knockdown of the target, including in the strident. This experiment once again highlights the potential of this next-generation chemistry.

We observed that the candidate was widely distributed throughout the CNS and led to substantial knockdown of target including in Australia.

This experiment once again highlights the potential of this next generation chemistry.

Okay.

Michael Linden: In the first quarter, we received regulatory and ethics approvals to initiate select HT, a phase 1B2A global multi-center randomized double-blind placebo-controlled trial of 003 in early manifest HD. We are targeting enrollment of approximately 36 patients carrying SNP 3 in association with the expanded CHE repeat. Patients from the precision HD studies will be able to transition to select HD after a wash-up period, assuming they meet other inclusion and exclusion criteria. Unfortunately, based on the recently discussed safety and efficacy data, patients who received active treatment with Toma Nursing and the Generation HD study will not be permitted to enroll in select HD.

In the first quarter, we received regulatory and ethics approval to initiate the select Ht a phase one b to a global multicenter randomized double blind placebo controlled trial of 003 in early manifest HD.

We are targeting enrollment of approximately 36 patients carrying SNP three in association with expanded CABG repeat.

Patients from the precision HD studies, we'll be able to transition to select HD. After a washout period, assuming they meet other inclusion and exclusion criteria.

Unfortunately based on the recently disclosed safety and efficacy data patients to receive active treatment with from a nurse in the generation HD study, we will not be permitted to enroll on select HD, although those who received placebo in generation HD are eligible to be screened for study entry.

Michael Linden: Although those who've received placebo in Generation HD are eligible to be screened for study entry, like Focus C9, Select HD has an adaptive design to enable optimization of dosing frequency and more rapid determination of target engagement. An independent committee will evaluate unblinded data on an ongoing basis to guide dose escalation, and dosing interval in each cohort.

Like focus Jeannine select HD has an adaptive design to enable optimization of dosing frequency and more rapid determination of target engagement.

An independent committee will evaluate unblinded data in an ongoing basis to guide dose escalation.

And dosing interval in each cohort.

Michael Linden: Key objectives, in addition to safety and tolerability, include plasma PK, CSF exposure of 003, and changes in key biomarkers, including Mutant Huntington, Wild Type Huntington, and neurofilament light chain over the course of the trial. Clinical site activation is underway, and we expect to dose our first patient soon. WVE N531 is our systemically administered candidate for patients with Duchenne muscular dystrophy or DMD that are This is also our first stereopure slicing candidate designed, applied, and PN chemistry.

Key objectives. In addition to safety and Tolerability include plasma PK CSF exposure of 003 and changes in key biomarkers, including mutant Huntington Wild type Huntington and neuro filament light chain over the course of the study.

Clinical site activation is underway and we expect to dose our first patient share.

<unk> three one is our systemic Lee administered candidate for patients with Duchenne muscular dystrophy or DMD that are amenable to exon 53 skipping.

This is also our first area of course stereo pure pricing splicing candidate designed applying pm chemistry.

As we have shared previously when applying this format to an exon 23 targeting surrogate treatment of aggressive double knockout or detail mouse model lap it lacking both your troponin dystrophin.

Michael Linden: As we have shared previously, when applying this format to an Exxon 23 targeting surrogate, treatment of an aggressive double knockout or DKO mouse model, lacking both utrophin and destrofen, resulted in rescue of mice treated with 75 milligrams every other week as compared with PBS or first generation chemistry dose at 150 milligram per kilogram week. Once again, application of the PN background modifications had a profound effect. In March 2021, we initiated clinical development of N531 with the submission of a clinical trial application.

<unk> and rescue of mice treated with 75 milligrams every other week as compared with PBS.

Our first generation chemistry, dosed at 150 milligram per kilogram weekly.

Once again application of the PMO backbone modifications had a profound effect.

In March 2021, we initiated clinical development of <unk> three one with the submission of a clinical trial application.

Michael Linden: Since then, we've received regulatory approval for an open label clinical trial that is powered to evaluate whether N531 dose every other week increases stroke and production in stroke and production in up to 15 boys with DMD. The trial will also assess drug concentration and muscle and initial safety. Dosing is expected to initiate this year. I'll now pass the call back over to Paul to discuss our ADR editing capability and upcoming milestones there.

Since then we've received regulatory approval for an open label clinical trial that is powered to evaluate whether <unk> hundred one dose every other week increases just growth in production and up to 15 boys with DMD.

The trial will also assess drug concentration in muscle muscle and initial safety dosing is expected to initiate this year.

I'll now pass the call back over to Paul to discuss our eight are editing capability and.

Upcoming upcoming milestones there Paul.

Paul B. Bolno: Thanks, Mike. We continue to generate compelling RNA editing results with our 8R editing capability, which we believe has many advantages over others and positions us at the forefront of this space. As a reminder, our approach to RNA editing employs short, fully chemically modified oligalitide to recruit endogenous RNA editing enzymes called ADAR. Our ADR editing compounds are optimized using our proprietary stereochemistry and TN chemistry, which enables us to avoid delivery vehicles, such as AAB vectors or nanoparticles, and allows us to leverage to establish manufacturing processes.

We continued to generate compelling RNA editing results with our ADR editing capability, which we believe has many advantages over others.

And positions us at the forefront of this space as a reminder, our approach to RNA editing employee short fully chemically modified oligonucleotide to recruit endogenous RNA editing enzymes called hadar.

Our HR editing compounds are optimized using our proprietary stereochemistry MTN chemistry, which enables us to avoid delivery vehicles, such as AAV vectors or nanoparticle and allows us to leverage to establish manufacturing processes.

Paul B. Bolno: To date, we have demonstrated editing activity across in vivo and in vitro systems, including durable RNA editing of up to 50% in non-human primates with Galnec conjugated oliginiquid. Our ADR editing oligonucleotides are also highly specific. Our practical approach to RNA-headiting opens the door to a number of therapeutic applications, such as restoring or modifying protein function and upregulation of protein expression.

To date, we've demonstrated editing activity across in vivo and in vitro systems, including durable RNA editing of up to 50% in non human primates with <unk> conjugated oligonucleotides.

Our ADR editing oligonucleotides are also highly specific.

Our practical approach to RNA editing opens the door to a number of therapeutic applications, such as restoring or modifying protein function and up regulation of protein expression.

Paul B. Bolno: These applications greatly expand the landscape of disease variants that we can potentially address, and we are advancing discovery work for multiple ADR editing targets, as well as evaluating new potential targets. For example, our first ADR editing program uses a GALNEC conjugated oliginuclite to correct the single RNA-based mutation in the MRNA coded by the Serpent A1-ZOO, which triggers Alpha-1 anti-tripsin ADR editing is a simple and efficient approach to treating the disease by simultaneously reducing aggregation of the mutated, misfolded alpha-1 protein and increasing circulating levels of wild-type alpha-1 antitripsin protein, thus addressing both the liver and lung manifestations of AATD, all while avoiding the risk of permanent off-target changes to DNA.

These applications greatly expand the landscape of these variance that we can potentially address and we are advancing discovery work for multiple HR editing targets as well as evaluating new potential targets.

Our first aid our editing program uses a <unk> conjugated oligonucleotides to correct. The single RNA based mutation mrna coded by the serpent, <unk>, which triggers alpha one antitrypsin deficiency or <unk>.

Hadar editing is a simple and efficient approach to treating this disease by simultaneously reducing aggregation of the mutated misfolded Alpha one protein and increasing circulating levels of wild type Alpha one antitrypsin protein that's addressing both the liver and lung manifestations of T D.

All while avoiding the risk of permanent off target changes to DNA.

Last year, we successfully demonstrated upwards of 60% editing of the <unk> transcripts to wildfire in hepatocytes in vitro, which led to a three fold increase in functional wildfire AAC protein.

Paul B. Bolno: Last year, we successfully demonstrated upwards of 60% editing of the Serpinae1 ZOE transcript to wild type and hepatocytes in vitro, which led to a threefold increase in functional wild type AAT protein. Encouraged by these results, we move forward to successfully develop a proprietary transgenic mouse model containing both humanized Serpinae 1 and humanized radar that enables pharmacokinetic and pharmacodynamic assessment of human sequences We are on track to share in vivo data from this model in the first half of 2021.

Encouraged by these results we move forward to successfully develop a proprietary transgenic mouse model containing both <unk>, one and human data that enables pharmacokinetic and pharmacodynamic assessment of human sequences in vivo.

We are on track to share in vivo data from this model in the first half of 2021, and we expect to present additional data at a scientific Congress later this year.

Paul B. Bolno: We expect to present additional data at a scientific Congress later this year. These in vivo results are expected to enable lead candidate optimization, as well as informed potential preclinical development studies and time. In summary, 2021 is a year of execution for Wave at a busy time as our next generation pipeline advances. As you heard today, we are advancing three unique clinical programs that will each provide insights into our novel PN chemistry and potentially rapid proof of concepts and clinical validation of our platform with biomarker data.

In vivo results are expected to enable lead candidate optimization as well as inform potential preclinical development studies and timeline.

In summary, 2021 is a year of execution for wave and a busy time as our next generation pipeline advances in the clinic as you heard today, we are advancing three unique clinical programs that will each provide insight into our novel chemistry, and potentially rapid proof of concept and clinical validation of our platform with biomarker.

Data.

Paul B. Bolno: We're making excellent progress with our ADR editing capability, and in addition to the expected in vivo data update for AATD that I just mentioned, I look forward to speaking further about our RNA editing platform at a research day later this year, which we expect to share more details about on our next quarterly call. I will now turn the call over to Kyle Moran, our chief financial officer, to report our financial results before turning the call over to questions. Kyle said, Thanks, Paul. We ended the first quarter with $148.5 million in cash and cash equivalents and marketable securities.

We're making excellent progress with our ADR editing capability and in addition to the expected in vivo data update from <unk> that I just mentioned I look forward to speaking further about our RNA editing platform and a research day later this year, which we expect to share more details about on our next quarterly call.

I'll now turn the call over to Paul Moran, Our Chief Financial Officer to report our financial results before turning the call over to questions.

Thanks, Paul we ended the first quarter with $148 $5 billion in cash and cash equivalents and marketable securities. This balance does not include an additional $30 million in committed research support that we received in early April under our collaboration with Takeda.

Kyle B. Moran: This balance does not include an additional $30 million in committed research support that we received in early April under our collaboration with Decatur. Our total operating expenses for the first quarter of 2021 were $43.4 million, as compared to $54.2 million last year. R&D expenses were $33.4 million, as compared to $41.2 million in the same period 2020. This decrease was primarily related to a decrease in external expenses related to our discontinued Subudurson program, as well as decreases in compensation related and other external expenses, partially offset by increases related to our clinical and preclinical activities for our HP programs and C9 or 72 programs for ALS and FDD. G&A expenses were $10.1 million for the first quarter of 2021, as compared to $13 million last year, with a decrease driven by lower compensation-related and other external expenses.

Our total operating expenses from the first quarter of 2021 were $43 4 million.

As compared to $54 $2 million last year.

R&D expenses were $33 4 million as.

As compared to $41 2 million in the same period of 2020.

This decrease was primarily related to a decrease in external expenses related to our discontinued <unk> program as well as decreases in compensation related and other external expenses.

Really offset by increases related to our clinical and preclinical activities for our <unk> HD programs have seen INR 72 program for ALS and F. T D.

G&A expenses were $10 1 million for the first quarter of 2021 as compared to $13 million last year.

With the decrease driven by lower compensation related and other external expenses.

Finally, we continue to expect that our existing cash and cash equivalents together with our expected and committed cash from our existing collaboration will enable us to fund our operating and capital expenditure.

Kyle B. Moran: Finally, we continue to expect that our existing cash and cash equivalents, together with our expected and committed cash from our existing collaboration, will enable us to fund our operating and capital expenditure requirements into the second quarter of 2023. As a reminder, this does not include potential milestone payments or other uncommitted payments under Articator Collaboration. Thanks, Kyle. With that, we'll open up the call for questions. Operator. Thank you. To ask a question, you will need to press Star 1 on your telephone, and to withdraw your question, just press the pound key. Please stand by and comply with the TNA roster.

Furniture requirements into the second quarter of 2023.

As a reminder, this does not include potential milestone payments or other uncommitted payments under our Takeda collaboration.

Thanks, Kyle with that we'll open up the call for questions operator.

I think you ask a question you will need to press star one on your telephone until literally a question just press the pound key please.

Please send probably compile the Q&A roster.

Our first question comes from the line.

Operator: Our first question on the Council of Salaam Sadi from Zahed from Zuhu. He may begin. Hi, good morning.

Southern said from Mizuho you may begin.

Hi, Good morning. This is Michael on for Celine. Thanks, So much for taking our questions.

Operator: This is Mike Wyndonan for Selim. Thanks so much for taking our questions. A few, if possible.

A few if possible first on the scene on trial design, just wondering about the protocol.

Operator: First, on the C9 trial design, just wondering about the protocol and how adaptive these trials would be. Are they being written to be able to enroll many, hundreds of patients would potentially be converted to registration? I'll follow up after that. Thank you. I'll pass the call over to Mike.

Adapted these trials will be are they being written to be able to enroll many hundreds.

Hundreds of patients could potentially be converted to registrational.

I'll follow up after that.

Thank you I'll pass the call over to Mike.

Michael Linden: Yeah, hi. The way the study is designed is that you can see it. It allows the study to be expanded as necessary to collect additional information. I mean, we made it flexible to enable us to really, once we're, get recommendations from the independent committee on next steps to be able to adapt the study as necessary. So I think we'll have to wait to see what the data shows, but it's our intention to make it adaptable and flexible to enable us to direct it the way we need to to understand the clinical meaningfulness of both ALS and FPD.

Yeah, Hi.

So you know the.

The way. The study is designed as you as you can see it allows the study to be expanded as necessary to collect additional information I mean, we made it flexible.

About.

To enable us to really once we once word get recommendations from the independent committee on next steps to be able to adapt the study is necessary. So I think we'll have to wait to see what the data show, but it is our intention to make it adaptable and flexible to enable us to direct at the way we need to.

To understand the clinical meaningfulness in both AOS and <unk>.

So I can't expand on number of patients based on the committees assessment dance.

Michael Linden: So it can expand the number of patients based on the committee's assessment. And that's the specific question; yes. Great, thank you.

Specific question, yes.

Great. Thank you and one on <unk> on the upcoming data.

Michael Linden: And one on AATD: on the upcoming data, what will you be looking for specifically to move forward with this into the clinic or not? How would you prioritize this if it did move forward versus the other pipeline programs? So the prioritization for AATD and the reason we worked on generating the model was really driven based on identifying, one, the production of the protein. So again, not working on, you know, what percent editing is.

What would you be looking for specifically to move forward into the clinic or not.

How would you prioritize this if it did move forward versus the other pipeline programs.

So the prioritization for ATV and then the reason we worked on generating the model was really driven based on identifying one the production of the protein. So again not working on what percentage of editing.

Michael Linden: That's interesting, but what drives the progress of a medicine is, does it generate the protein? So one will be protein production. Other features that will be evaluating, obviously, our protein, not just protein production, but protein function. So we'll be able to look at a number of those assessments. And that's going to guide our decision.

Interesting, but what's driving the progress on a medicine is does it generate the proteins. So one will be protein production.

Other features that we'll be evaluating obviously our protein without this protein production of a protein function. So we'll be able to look at a number of those assessments and that's going to guide our decision on translation.

Okay, great. Thank you and last one.

Michael Linden: Okay, great, thank you. And last one, on Alzheimer's disease mentioned today. After the nanomab data, how are you thinking about treatment, specifically from the ASO side? Maybe what should we think about in terms of potential targets? So just for clarification, I want to make sure on the frontal temporal dementia. I just want to make sure we're not thinking about Alzheimer's.

Alzheimer's disease I mentioned today after the day that in my data how are you thinking about treatment specifically from the ASO side, maybe what should we think about in terms of potential targets.

So just for clarification that I want to make sure on that.

You might be think about frontal temporal dementia, just want to make sure we're not thinking about numbers. So we have FTE.

Michael Linden: So we have FTD, so frontal temporal dementia, otherwise it's frontal temporal degeneration, is the one area of dementia that we mentioned today. So I want to be careful that, you know, we didn't discuss Alzheimer's as a target therapeutic. But I'm happy to discuss antisense treatment and therapeutics for the treatment of CNS and neurologic diseases more broadly, if that's the question. But I just want to make sure we understand your question, correct. Yes, that would be a good book.

FTE, so frontal temporal dementia other mines.

It'll temporal degeneration.

Is the one area of dementia that we mentioned today, so I'm gonna be careful that we can discuss all numbers diseases as a target therapeutic but happy to discuss antisense treatment and therapeutics for the treatment of CNS and neurologic diseases more broadly if thats the question, but I want to make sure we get your question correct.

Yes that would be helpful. Thanks.

Yes my question on income.

Michael Linden: I mean, what I was going to say is that, as you see with the focus C9 study, the emphasis on FTD, getting patients in, and actually the cortical effects that we saw in the preclinical models make us very excited about being able to access the CNS to be able to have an effect on FD. It's, you know, we're going to be using clinically some of the clinical outcome measures that you'd want to measure cognitive change in our FTT study to be able to get at that question.

Oh go ahead.

I was going to say I finish answering it.

To say is that yes, I mean work, whereas you see with the focusing <unk> studied the emphasis on FTE getting patients and actually the critical.

<unk> that we saw in the preclinical models make us very excited about being able to access the CNS to be able to have an effect on FTE D zone.

We're going to be using clinically.

Some of the clinical outcome measures that you would want to measure cognitive change in RFP day study to be able to get at that question. I mean, I think if we step back and think about neurologic diseases more broadly I mean, I think one of the dataset that's compelling that Mike share. In addition to a number of the in vivo mouse studies that we see really great interest equal distribution across the <unk>.

Michael Linden: I mean, I think if we step back and think about neurologic diseases more broadly, I mean, I think one of the data sets that's compelling that Mike shared, in addition to a number of the in vivo mouth studies, is that we see really great intrathecal distribution across the brain. So I think as we think about delivering drugs to the regions of the brain that are necessary for a whole variety of neurologic diseases, we see intracical administration.

So I think as we think about distributing to the regions of the brain that are necessary for a whole variety of neurologic diseases, we see interest equal administration delivery, that's not different than some of our colleagues in the space discussed around distribution. So we do believe antisense oligonucleotides can distribute what we see with the Pn is this broad distribution. So this addition.

Michael Linden: That's not different than some of our colleagues in the space discuss around distributions, so we do believe antisense oligonucleotides can distribute. What we see with the PN is this broad distribution, so this addition is highly controlled.

Hi, early control so the data we're generating the value of stereochemistry said beginning in addressing the reality of it is all the assessments are targeting gives you were seeing or what the actual compounds because we're not dealing with a mixture of $523204 233 different molecules that can distribute differently. So by having a single drug we know that the knockdown.

Paul B. Bolno: So the data we're generating, the value of stereochemistry is that beginning and addressing the reality of it is all the assessments of targeting agents we're seeing are with the actual compound because we're not dealing with a mixture of 523,000, 204,23 different molecules that could distribute differently. So by having single drugs, we know that the knockdown that we're seeing is based on the design of that single oligid duplicate test. And I think what we've also seen is the benefit of durability.

What we're seeing is based on the design of that single Oligonucleotides and I think what we've also seen is the benefit of durability. So as Mike said in the adaptive design piece, we're going to be testing and exploring them in the clinic and so as we think about chronic administration of medicines at a whole host of different diseases, and importantly is dosing frequency so being able to.

Paul B. Bolno: So, as Mike said in the adaptive design piece, we're going to be testing and exploring them in the clinic. And so as we think about the chronic administration of medicine in a whole host of different diseases, the important thing is dosing frequency. So being able not to sacrifice potency for dosing frequency is something that we're excited to continue to explore in the clinic. So as we think about the future of anti-economic, sense oligonucleotides for the treatment of neurological diseases.

Not the sacrifice potency for dosing frequency is something that we're excited to continue to explore in the clinic. So as we think about the future of antisense oligonucleotide for the treatment of neurologic diseases. We think the future is promising and a data driven way.

Paul B. Bolno: You know, we think the future is promising in a data-driven way, and we'll be assessing that further across three clinical studies currently. So, you know, I hope that answers your question. We're always happy to explore that more. But I think, you know, the future looks bright for treating genetic diseases with oliginiquidase. Thanks, that's super helpful.

Be assessing that further across three clinical studies currently so I hope that answer your question, we're always happy to explore that more but I think.

The future looks bright for treating genetic diseases with all of them.

Thanks, That's super helpful. I guess, what I was referencing was just the mention of Alzheimers and the press release.

Operator: I guess what I was referencing was just the mention of Alzheimer's in the press release, along with other CNS indications. Okay. Hi.

Along with other CNS indications.

Okay.

Okay.

Hi.

Operator: Okay. Our next question. Oh, sorry.

Okay.

Our next question sorry, now now from Washington.

Operator: Sorry, now I'm looking at that. I think we are talking, now I know where you're going, which is the holistic list of targets that we've been exploring in the Decatur Cloud, large indications, where we said, for example, that's why we're thinking about indications. We said, for example, what represents large neurologic indications, so Parkinson's, Alzheimer's, and other large indications. So thank you.

I think we're talking Paul I know now I know, where you're going which is the holistic list of targets that are that we've been exploring and indicated quite large indications, where we said for example, if I were thinking about indicate.

For example, wet represented large neurologic indications, so Parkinson's Alzheimer's and other large indications. So thank you I apologize for our we're focused on the pipeline that we're exploring as opposed to what the potential so apologies for that.

Operator: I apologize for our, we were focused on the pipeline that we're exploring as opposed to what the potential is. So apologies for our, um, misunderstanding of your question. And our next question on the line with June Lee from Chus.

Yes.

Misunderstanding of your question.

Okay.

And our next question comes from the line of Joon Lee from choice you may begin.

Operator: You may begin. Hey, thanks for taking our questions. For all of your CNS programs, in addition to the new and improved backbone chemistry, have you considered a different route of delivery? Another company has recently disclosed proceeding with an intra-sterebral ventricular route using alloyaport, I believe, for Huntington's Disease. It does give you more direct access compared to Intracical, and I'm not aware of any IP that prevents you from doing that. So I would appreciate it.

Hey, thanks for taking our questions.

For all of your CNS programs. In addition to the new and improved backbone chemistry have you considered a different route of delivery.

The other company as recently disclosed proceeding with entrust suitable ventricular.

Route.

A lawyer Port I believe for Huntington's disease.

Giving you a more direct access compared to the people and I'm not aware of any IP that prevents you from doing that so I would appreciate if you could provide some perspective, there and I have a follow up question.

Michael Linden: If you could provide some perspective there and have a follow-up. Yeah, I mean, there's always opportunities to think about different approaches. When we think about permanent catheter placements and other, you know, drilling holes into the skulls for delivery, I think our first question always is about what problem, and this is true for anything, what problem are we trying to solve for? So I think as we currently think about the data that we've generated to date, interthecal access to the central nervous system is available.

I mean, there's always opportunities to think about different approaches when we think about permanent catheter placements and other <unk>.

Drilling holes and Scholes for delivery I think our first question always is about what problem and this is true for anything what problem are we trying to solve for so I think as we currently think about the data that we've generated to date interest equal access to the central nervous system is available we still in that now and interest equaled non human Primate studies, we've looked at it.

Michael Linden: We've shown that now in intracial non-human primate studies. We've looked at ICB injections in mice, and we see correlation in terms of distraceal. distribution in TNS tissue. So for the data to look at, and if we, again, also see durability, which we're assessing in the clinic, the less frequent administration also calls into question whether it's not without risk to leave permanent doiling catheters in the TNS. They can get clogged.

<unk> injections in mice, and we see correlation in terms of distribution in CNS tissue. So for the day to look at and if we again also see durability, which were assessing in the clinic the less frequent administration and also causing the question, it's not without risk delete permanent as oil and catheters in the CNS.

Can get clogged and they need to be changed and so again it really comes down to what is that in every medicine is different so we can't speak for other companies and what challenges they are addressing using the delivery mechanism, where we assess with ours is are we what are we solving for and so when we think about interest equal distributions, we've demonstrated across multiple tissues utilizing the pn.

Michael Linden: They need to be changed. And so, again, it really comes down to what is the best medicine, and every medicine is different. So we can't speak for other companies and what challenges they're addressing using the delivery mechanism. Well, we assess with ours. Is, what are we solving for? And so if we think about intracial distributions, which we've demonstrated across multiple tissues, utilizing the PN enhancement on our medicines themselves, we don't right now see that, you know, as we look at durability and, you know, different indications, we could want to solve other problems in the future.

And <unk> of our medicines themselves.

We don't right now see that as we look at durability in different indications, we could want to solve other problems of the future.

Michael Linden: Could come up, but right now, that doesn't seem to address the solution that we have with the current administration. Mike, I don't know if there's any. No, I'm just going to, I would just say the same thing. It's like, you have to.

Could could come off but right now that doesn't seem to address the solution that we have with the current Australia, but I don't know if there's anything I mean, I'm just going to I would just say the same thing. It's like you have to and generally you want to go for the simplest form of administration you can that gives you.

Michael Linden: In general, you want to go for the simplest form of administration you can that gives you the access you're looking for. So, you know, given the progress we've made with accessing all parts of the brain and these diseases through indirect administration, that would be the simplest approach, especially, as Paul indicates, when you're talking about the durability of effect after single doses, that leads us to. to the approach that we don't need to do ICV with a catheter and we can do what's necessary, doing something that, you know, any neurologist can do.

The access you are looking for so given the progress we've made with accessing all parts of the brain and these diseases through entered equal administration that with.

That would be the simplest approach, especially as Paul indicated when you're talking about.

The durability of effect after a single a single doses.

That leads us to the to the approach that we don't need to do ICB with a catheter and we can do what's necessary doing something that.

Any neurologist can do I think the other thing I mean, we have now and we have the benefit with an extensive amount of time now been able to explore multiple animal models across multiple species again, ITV and mice interest equal in non human primates. We also have clinical data to look at distribute.

Michael Linden: I think the other thing, I mean, we have now, I mean, we have the benefit of an extensive amount of time now being able to explore multiple animal models across multiple species. Again, ICV in mice, intrathecal, and non-human primates.

Michael Linden: We also have clinical data to look at distribution. As we shared in our experience in understanding different concentration levels with different back home chemistry. So I think as we look at the totality of data that we've generated and the totality of data generated that our colleagues and other companies have generated, I think we see meaningful, meaningful changes with the implementation of the PM backbone that's translating into animal PKPD that we're exploring currently in the clinic through adaptive designs that are going to give us answers in the, Okay.

As we shared in our experience, it's understanding different concentration levels with different back from industry. So I think as we look at the totality of data that we've generated and the totality of generated that our colleagues in other companies have generated I think we see a meaningful meaningful changes with the implementation of the <unk> backbone and that's translating into animal PK PD that.

We are exploring currently in the clinic do adaptive designs, they're gonna give us answers in the clinic.

Got it.

Michael Linden: And I'm looking forward to your AIDR presentation tomorrow at ASGCT. Can you talk about some differences between the approach you're taking with, you know, galenic conjugated RNA versus circular guide RNA? That's being used by another company, I think.

And looking forward to your eight or presentation tomorrow at ACC team now can you talk about the differences between the approach you're taking with.

GAAP net conjugated that Arnie.

Versus circular guide RNA.

That's been because east by another company I guess, we'll find out tomorrow, but just wanted to.

Operator: We'll find out tomorrow, but just wanted to.., get an input that you can share on what we should be focusing on tomorrow and some perspectives on the pros and cons of the Thank you. Yeah, I mean, I can't speak necessarily for the pros and cons of others. We're all learning about the other approaches to treating this. I can speak about, you know, our approach, which importantly, Galnick is not, let's say, just

Get an input that you can share on what we should be focusing on tomorrow.

Some perspectives on the pros and cons of different approaches. Thank you, yeah, I mean, I can't speak necessarily to the pros and cons of others. We're all learning about the other approaches to treating I can speak about our approach, which importantly, <unk> is not let's say an approach gollnick as a targeting wave for the tissue targeting of interest so.

Operator: GALNIC is a targeting moiety for the tissue target of interest. So one of the advantages when we built the ADR platform from the beginning, and we've demonstrated this with some of our CNS data as well, is that where short oligonucleotides go and distribute, we can generate an editing, keep a bit of the beginning there.

One of the advantages when we built our platform from the beginning and we've demonstrated this with some of our CNS data as well is that we're short oligonucleotides go and distribute we can generate and editing capability. There. So we've done book did that in vivo in Sps CNS. So looking at non-GAAP net conjugated distribution.

Paul B. Bolno: So we've done and looked at that in vivo and in our CNS, but looking at non-GALNIC conjugated distribution and correction. What we're looking at for AATD, obviously, as a hepatic target and a hepatocyte, is galenic then becomes an advantage because we can just target the cell type of interest. So I think what's really important from a platform perspective is the platform can exist without Galnec, but we are using Galnec as well, where we think about the liver specifically. So I think, you know, in both the platform context, we think we've got a really interesting approach in that we don't need to use various delivery vehicles.

And correction, where we're looking at for a T. D. Obviously is a hepatic targeted hepatocytes is galvanic then becomes an advantage because we can just target cell type of interest. So I think what's really important from a platform perspective is the platform.

Can can exist without gal Mac, but.

But we are using gallagher as well, where we think about the liver specifically so I think on both the platform context, we think we've got a really interesting approach and that we don't need to use various delivery vehicles. We can take all of our learnings around stereo control opinion containing oligonucleotides and continue to demonstrate and learn from data that we've generated.

Paul B. Bolno: We can take all of our learnings around stereo control, PN containing all of the nucleotides, and continue to demonstrate and learn from data that we've generated across multiple species and even past clinical studies experience learning about serial analogues, and apply that to this ADR platform and take the advantage of, you know, GALNAC conjugation for specific hepatocyte targeting. And, you know, I think tomorrow as we start to learn more about what's happening across the field, we'll be able to parse that out more. But we're excited to have a presentation tomorrow and really be there, again, at the forefront of ADR RNA editing to be able to share these data. Great, thank you.

Across multiple species.

And even past clinical site experience learning about studio controls oligos and apply that to the HR platform and take the advantage of <unk>.

Conjugation or specific patents they are targeting and I think tomorrow as we start to learn more about what's happening across the field will be able to parse that out more but we're excited to have a presentation tomorrow really be there again at the forefront of eight our RNA editing could be able to share those data.

Great. Thank you.

Operator: Our next question on the Conflint of Mani Furohar from SGB Lyrick, you may begin. I guess thanks for taking the question. I'll ask one quick question on enrollment. When we look at rolling over placebo patients from Generation HD and select, how many of those patients are still eligible? I worry a little bit that obviously Huntington is a relentlessly progressive disease, so some proportion of those patients may now be meaningfully more severe than they were when they were first screened for generation.

Yeah.

Our next question will come from the line of.

Manny for higher from there.

You'd be Larry you may begin.

Hey, guys. Thanks for taking the question.

Ask one quick one on enrollments when we look at.

Moot rolling over placebo patients from generation HD in the select.

How many of those patients are still eligible I worry a little bit but obviously.

Obviously, huntington's is a relentlessly progressive disease. So some proportion of those patients may now be meaningfully more severe than they were.

When they were first screen for generation.

Operator: And secondarily, based on whatever portion of those patients, likely in your view to roll over, how much of a head start does that give you on enrollment intelligence and other mechanisms that you can pursue, sort of changes in the trial process to sort of accelerate the completion of enrollment there, given there were a couple of delays and hiccups along the way for generations. I'll pass this question all to Mike. Yeah, no, hi, thanks.

Secondarily.

Based on whatever portion of those patients are likely in your view to rollover.

How much of a head start with like give you on enrollment and select and other.

Other mechanisms that you can pursue other changes in trial process.

Sort of accelerate the completion of enrollment there.

There were a couple of delays and hiccups along the way for generation previously.

I'll pass the other question to Mike, Yes, hi, Thanks.

So regarding the.

Michael Linden: So regarding the movement from Generation H.G., you know, right now, the way it stands is patients haven't been disclosed to patients whether they've been receiving placebo or active treatment. So we're hopeful that that will happen, and then patients can make the choice about whether they want to make that transition. And we're not exactly sure when that will be, but we're hoping that that happens relatively soon, as we have disclosed to all the patients now what they've been receiving.

The movement from generation HD.

You know right now the way it stands as patients who don't have it hasnt been disposed of patients whether they had been receiving placebo or active treat so we're hopeful that that will happen and then patients can make the choice about whether they want to do that transition.

We're not exactly sure when that will be but we're hoping that that happens relatively soon as we have disclosed to all the patients now what they what they had been receiving.

Michael Linden: Second of all, there is that possibility that patients will have progressed out of our inclusion criteria, which is why they are going to have to be rescreened for both inclusion and exclusion, including whether they have SNF3. So that'll be an important inclusion and exclusion criteria. But as we think about the overall population, we'd expect about 40% of them to basically have the appropriate SNP. Regarding the other operational things to help move things along, we've learned a lot from the generation, from the precision H.D1 and precision H2 studies. We've learned a lot about how to operationalize interthecal administration more efficiently.

Second of all there is that possibility that patients will have progressed out of our inclusion criteria, which is why they are going to have to be re screened for both inclusion and exclusion, including whether they have three so that'll be an important inclusion exclusion criteria, but as we think about the overall population we'd expect about four.

The percentage of them are essentially to have.

The appropriate snip.

Regarding the.

The other operational things to help move things along and we've learned a lot from the generation from the precision HD, one and precision AG. Two studies, we've learned a lot about how to operationalize interest equal administration more efficiently we have a lot of site overlap between.

Michael Linden: We have a lot of site overlap between Generation HG and Precision HG, which has allowed us to patients are in positions to get experienced in the screening process. We have new laboratories to do SNP identification. You know, there's a variety of things that have really helped accelerate, made us feel comfortable that we'll be able to accelerate the recruitment for select, HD, including the addition of regions that we know have higher representations of SNP 3.

Generation, HG and precision HD, which has allowed us to patients our positions to get experienced in the screening process, we have new laboratories to do SNP identification.

You know theres a variety of things that have really helped accelerate.

<unk> make us feel comfortable that we'll be able to accelerate.

The the recruitment force select.

H D, including the addition of.

Regions that we know have higher representation of snips through so there's a variety of things. We're doing that have that we were comfortable will help and in addition, with the adaptive design.

Michael Linden: So there's a variety of things we're doing that we're comfortable will help. In addition, with the adaptive design, you know, there's going to be changes along the way. The committee is going to be looking at unblinded data to guide next steps and make recommendations. So that in and of itself is a huge change versus data generation. precision 801 and All right, thanks.

Now theres going to be a whole along the way the committee is going to be looking at.

Unblinded data to guide next steps and make recommendations so that in and of itself is a huge change versus data generation and precision HD one chip.

Alright. Thanks.

Our next question will come off.

Operator: Our next question will be in the mind of Paul Matase from Stiefel. It may begin. Thanks for taking the question. This is Alex on behalf of Paul.

We will be one line of Paul Matteis from Stifel maybe.

Hey, Thanks for taking the questions Alex on for Paul a couple of questions on <unk> III.

Operator: A couple questions on SNF3. You know, I appreciate the OO5 targeting engagement data in non-human primates, but I was wondering if you could, you know, maybe quantify a little bit some of the biological distribution that you mentioned you're seeing in non-human primates with OO3 that you're using for the PKPD modeling, knowing that's not really a disease model, but anything you can say there would be really helpful.

I appreciate the five target engagement data in non human primates, but I was wondering if you could maybe quantify a little bit some of that.

Bio distribution that you mentioned youre seeing in non human primates without three that you're using for the PK PD modeling, knowing that's not really a disease model, but anything you can say there would be really helpful. And then secondarily I'm curious.

Michael Linden: And then secondarily, I'm curious if OO3 targets the Exxon 1 fragment of MHTT, and generally your thoughts on, you know, the Exxon 1 fragment is a potential driver of pathology and HVS. Do you want to start around? Yeah, so I mean, regarding the non-human primate data, I think that the what I can say about the distribution in the non-human primate, even though it's not targeting engagement data for the SNP3 compound, we are very clearly able to achieve concentrations throughout the brain, including in deep gray structures and the striatum.

L three targets.

Target to the X on one fragment of M. A C T and generally your thoughts on the exon one segment as a potential driver of patent allergy in HD.

I think you're going to start and yeah. So I mean regarding the nonhuman primate data I think that.

The.

What I can say about the distribution and the non human primate, even though its not.

Target engagement data.

For the SNP three compounds.

We are very clearly able to achieve concentrations throughout the brain.

<unk> and deep gray structures in stride.

Michael Linden: That would be predicted to engage the target based on what we have from the back HD. So, and a very large window to be able to, um, increase the dose to, again, engage the target. So I think that we are quite comfortable, based on the preclinical data we have, that we are able to, um, get into the regions that matter and engage the target. So, um, and again, we're starting at a dose that we believe is pharmacologically active right from the beginning. And then the committee will tell us how close we are to that and then be able to adjust as necessary. So that's regarding that.

That would be predicted to engage target based on what we have from the back HD, So and I very a large window to be able to.

And dose escalate.

Again engage.

Targets. So I think that we are quite comfortable based on the preclinical data we have that we are able to get.

You get into the regions that matter and engage targets, so and again, we're starting at a dose that we believe is pharmacologically active right from the beginning and then the committee will tell us how close we are to that and then be able to adjust as necessary. So that's regarding them that now in terms of the.

Michael Linden: Now, in terms of the, in terms of Exxon 1 and what we think there, I mean, as we said previously, that, you know, a lot of the Xxon 1 data, I mean, this is from post-mortem, this is from, it seems to be most relevant in those with extremely long expansions. Nonetheless, when we're bringing down mutant protein, we would expect to also have an impact on XM1.

In terms of exon one.

And what we think there I mean as we've said previously.

That you know a lot of the exon one data I mean this is from postmortem. This is from.

It seems to be most relevant and those would have been.

Extremely long expansion. Nonetheless, you know when we're bringing down mutant protein, we would expect to be able to also have an impact on an exon one so yeah just to add to that I mean, the antisense oligonucleotides can reach in tronic Anecdotic transcript. So we should therefore index on one but as Mike I think.

Michael Linden: Yeah, just to add to that, I mean, antithens, olive, and nucleotides can reach intronic and exotic transcripts, so we should therefore hit XM1. But, as Mike said, I think the most important piece, I think the data is still, you know, independently of whether or not we hit it, I think that the data is still questionable and beyond a really, really long repeat. So I think as we go back and think about our targeting for SNP 3, I think we can leverage a ton of experience with SIP 1 and 2 and what we've seen in general with the enhancement and Philippian chemistry.

Most important because I think the data.

Independently of whether or not we hit it I think the data is still questionable and beyond really really long repeat so I think as we go back and think about our targeting for three I think we can leverage a ton of experience with six wanted to and what we've seen in general with the enhancement of gain demonstrates a distribution.

Operator: I think we can see and believe that mutant protein suppression is important. Yes, we're distributing and knocking down the mutant protein, but I think what we've learned a lot about in the first, you know, clinical trial of pan silencing is, you know, and Mike alluded to post-DHDI, a substantial focus on doubling down on our efforts that wild type sparing is as important a driver of disease pathology as mutant protein production is.

Okay.

I think we can see.

And believe that mutant proteins depression is important yes, we're distributing at knocking down the mutant protein, but I think what we've learned a lot about in the first clinical trial and silencing is.

Then Mike alluded to both the HDI is a substantial focus.

Doubling down on our efforts that wild type sparing is as important a driver and disease pathology as protein.

Production and so the approach that we set out two years ago with tablet for the treatment of disease, which is wildly disparate views reduction. We believe is the way to address the pathology Ann will be happy to generating clinical data and be able to assess that again.

Operator: And so the approach that we set out to a year ago established the treatment of disease, which is wildlife sparing mutant reduction, you know, we believe is the way to address the pathology. And we'll be having to generate clinical data and be able to assess that, again, with step three using, Great, thanks so much. Our next question is Confluent of Yung, from Jeffries. You may begin.

Three using the new Penn chemistry.

Great. Thanks, so much.

And our next question will come from the life of.

Young from Jefferies you may begin.

Operator: Thank you. I have a few questions. First, on the ATD program. So, as Polity mentioned, it's not just editing efficiency.

Thank you I have a few questions. The first out on a television program. So our point of view you mentioned is not just yeah.

Efficiency, you you've already shown 50 preceding non human primates.

Operator: You've already shown 50% in non-human primates, but producing wild type aAT protein and then function. So the question to you is that do you know what level of normal water type AAT protein is needed in order to see some clinical benefits? What kind of minimum level is that? So that's question one, and the second question is on 004. So are you already doing side activations? So when should we expect data, clinical data from this trial? And lastly, the 30 million, additional 30 million that you received from Takeda in April, how will that be amortized? In the income statement, would it be similar to what you've done in the past? Thank you.

But producing why Gabby IAP proteins. So and then function. So question too is that do you know one lever. Other Noam are all from what is kind of any day protein even need eating or to see some clinical benefit. So that's the kind of a minimum level. So thats your question.

Gen. One and second question is on Yeah those channel.

Sure. So are you already doing site activations.

So when you should we expect data.

Clinical data from this trial and lastly, the 30 million additional fundamentally under you received from Takeda in April how did it be amortized.

The income statement or would that be similar to what you've done in the past. Thank you.

Operator: All right, well, the good news is question, you're getting a lot of voices around the table, so it's great. I'll take the AAT question or pass the mic for the second one. Highalk and insert your treatment.

Alright.

The good news is the question that Youre getting a lot of voices around the table says great I'll take the easy question for Mike for the second one okay.

And that's true for treatment.

Paul B. Bolno: Your important question is how do we look at this in vivo data that's upcoming and what are we looking at in terms of advancing the AETP program? I think when we think about Alpha-1 antitripsin, and I think you're spot on, we're looking at protein levels. The Serpent A1 model is different because they're all there than humans, let's say, in that you can generate protein.

Your important question is how do we look at this in vivo data that's coming in.

Are we looking at that in terms of advancing.

TD program I think when we think about alpha one antitrypsin and I think youre spot on we're looking at protein levels, but certainly one model with different they're all other than.

In humans, but saying that you can generate protein and I think we'll be looking at levels of protein generated in that model to be able to model that towards kind of where one would expect to be at the human level. I think the day, one sees kind of a threshold level around 11 micro molar protein to be clinically relevant that's kind of the basis for the number of <unk>.

Paul B. Bolno: And I think we'll be looking at levels of protein generated in that model to be able to model that towards kind of where one would expect to be at the human level. I think to date once these kind of a threshold level around 11 micromolar protein to be clinically relevant. That's kind of the basis for the number of protein infusion products. And we know that protein infusion products tend to tail off at the end because the protein degrades, and patients have to be reduced on a weekly basis.

Rotea infusion product and we know that the protein infusion product tend to tail off at the end because the protein degraders and they have patients that would be we would dose on a weekly basis. So these patients have these gaps in treatment I think if we can have sustained correction, where maybe you don't have to drop as we do that kind of the minimum threshold criteria, where not only are we treat.

Paul B. Bolno: So these patients have these gaps in treatment. I think if we can have sustained correction where you don't have those drops, we would see that kind of minimum threshold criteria where not only are we treating the hepatic issue, but really at that level, know that you're at levels that can treat the pulmonary complications. I think that would be exciting.

The hepatic issue, but really at that level that you are at levels that can treat pulmonary complications I think that would be exciting, but I think the key for us and as we generate that data and share that more broadly exactly to that point. That's the data that we'll be assessing from those models in terms of translation I think the important piece, there that will be assessing as well as non.

Paul B. Bolno: But I think the key for us, and, you know, as we generate that data and share that more broadly, exactly to that point, that's the data that we will be assessing from those models in terms of translation. And I think the important piece there that we'll be assessing as well is not just the protein production, but as we demonstrated before from the in vitro correction of the AAT. The AAT protein is that, you know, we could generate it, and it was functional.

Just the protein production, but as we demonstrated before from the in vitro correction.

<unk> protein is that we could generate it and it was functional and wanted to see that replicated now in the animal models. So I think we're taking a deliberate approach to make sure we generate the preclinical data that's going to position us for thinking about how this program transitions and I think that's why we've been excited the day one around the <unk> program, but I think more.

Paul B. Bolno: We want to see that replicated now in the animal model. So I think we're taking a deliberate approach to make sure we generate the preclinical data that's going to position us to think about how this program transitions. And I think that's why we've been excited to date about the AETD program, but I think more broadly about wave's ability to bring ADR editing into the patient across a whole variety of indications, importantly, CNS indications as well, where we don't. What we've got to be able to target neurons.

Broadly what it really represents in waves ability to bring eight are editing into the into patients across a whole variety of indications importantly, CNS indications as well, where we don't need to be able to target neurons. So I think there's a whole variety of approaches that we can take but obviously this is the first in vivo demonstration that we'll be able to look at it on a correct.

Paul B. Bolno: So I think there's a whole variety of approaches that we can take, but obviously this is the first in vivo demonstration that we'll be able to look at on a corrected protein and be able to study that more broadly. I'll pass on any questions, just because of the difference. Are there any questions there?

<unk> proteins and be able to study that more broadly.

Any questions.

I'll just say are there any questions.

Operator: And if not, I'll hand it over to Mike to address your question. So then, Mike, do you want to take the next time? Sure.

Non I'll hand over to Mike to address your question.

So there might be able to take the next sure I mean also I mean.

Michael Linden: I mean, also, regarding next year, I mean, you know, three biomarker studies underway that are going to allow us to have, with these adaptive designs that are going to allow us to have a continuous flow of data. And that's very exciting. And I mean, specifically regarding zero-zero-one, as I indicated, we're going to be dosing soon, and we'll have a good sense of how the studies are progressing throughout the year.

Regarding next year I mean, we you know our three biomarker studies underway that are going to allow us to have with these adapters designs that are going to allow us to have a continuous.

<unk> data, that's very exciting and I mean, specifically regarding <unk> as I indicated we're gonna be dosing soon and we'll have a good sense of how the studies are moving throughout the year, but while we share from the studies is going to be informed by how the studies proceed the types of data that comes in the <unk>.

Michael Linden: But what we share from the studies is going to be informed by how the studies proceed, the types of data that come in, meaning the meaningful, whether there's a meaningful number of patients at any given point in time, and whether the feedback we receive from the independent committees. And that feedback is going to be coming in throughout the course of this year and next, and from there, we'll guide when we disclose data and what that data will be.

Meaning the meaningful whether there is a meaningful number of patients at any given point in time and whether the feedback we received from the <unk> independent committees and those that feedback is going to be coming in throughout the course of this year and next and from there We'll guide.

What what when we disclosed data in what that data will be and we anticipate data. However, during this time that will enable us to make decisions and then provide greater insights into the chemistry. So that that's sort of how it's proceeding now it's obviously going to be driven by how quickly we can get those patients in and and we're optimistic now given.

Michael Linden: And we anticipate data, however, during this time that will enable us to make decisions and then provide greater insights into the chemistry. So that's sort of how it's proceeding now. It's obviously going to be driven by how quickly we can get those patients in, and we're optimistic now, given site activations and the fact we're going to be dosing soon. But it is an important notion, you know, when we think about just the adaptive design principle of running studies, which is different than running the kind of mile marker-driven studies where you've got to aggregate the data, then analyze it, and aggregate and then flip the carve at the end.

Site activation in the back we're gonna be dosing soon.

But it isn't an important notion when we think about just the adaptive design principle of running studies, which is different than running kind of biomarker driven studies, where you've got to aggregate the data and analyze it in aggregate in the book.

The car, but I think as Mike said it is evaluated an ongoing wave by an independent committee, that's going to inform things in with those studies running now and data being generated for this year.

Michael Linden: I think, as Mike said, data is being evaluated in an ongoing way by an independent committee that's going to inform things. And with those studies running now and data being generated this year and next, I think there's a variety of times where, you know, those committees could fight, should share data. So it's a little less specific. And as Mike said, we have to provide more updates to guidance alone. Paii, we want to take the 30-minute flight.

I think there's a variety of times where.

The committees can fight Mr. Chair made it so it's a little less specific and as Mike said, we'll be able to provide more updates to guidance along the way.

I'm going to take them there is a true.

Michael Linden: Yeah, June, thanks for your question. And your assumption is correct. We would account for that in the same way that we've accounted for the upfront cash payments and other committed cash payments we've gotten to date, you know, with gap revenue and characterization.

Yeah. Thanks for your question.

And your assumption is correct, we would account for that in the same way that we've accounted for the upfront cash payments and other committed cash payments, we've gotten to date.

With GAAP revenue amortization.

Thank you.

Operator: Thank you. Thank you. And once again, that's all one for questions. Our next question will come from Luca Issy from RBC. You may begin.

Thank you.

And once again Thats star one for questions. Our next question from flying from Luca <unk> from.

RBC you may begin.

Oh, great. Thanks for taking our question. This is Lee saw answer Luca here a.

Operator: Oh, great, thanks for taking the question. This is Lisa from Feluka here.

Operator: A couple questions for us. So, first of all, we have obviously seen the phase three data from Rocheonis, and it seems to me that their ASO may have had a detrimental impact on patients versus placebo, as placebo directionally outperforms the high dose, and we have seen a dose-dependent increase there in ventricular volume in the brain. Did you have the same read on this data? And if so, do you think that it's possible that a wild-type sparing approach may not have caused a detrimental impact here?

A couple of questions for us.

So first one.

You know we have obviously seen the phase III data from Shanghai on Us and it seems to me that our various on NAV have detrimental impact to patients.

Versus placebo as supposed to go Directionally outperformed the high dose.

And we have seen a dose dependent increase in ventricular volume.

Did you have the same read on this data and if so do you think that it's possible that a wild type sparing approach.

Paul detrimental impact here.

Operator: And the second question, you know, you've obviously discontinued SNIP 1 and SNIP 2 with the oil chemistry. Just wondering, what is the plan going forward? Are you planning to explore the PN chemistry for SNP 1 and SNP 2, or only for Smith 3? Thank you.

And second question.

You know, you've obviously discontinued a sniff bonding connected with it with the old chemistry.

Just wondering what is the plan going forward are you planning to explore the pan chemistry person, that's fun and Smith to our only first Nancy Thank you.

Operator: Thank you. You know, to take the first of your version, and I think, like everybody else, we have to view it as we're only seeing what everybody else is seeing from the outset. So it's, it's hard to comment on what they saw. I think objectively you pointed out what they saw, which was a dose-dependent change in clinical measurements. And importantly, those clinical measurements were cortical andstrial. So I think it's, you know, there's a jump to distribution. I think it was a broader question than just street distribution.

Thank you.

To take the burden of your grocery then I think like everybody else, we have to view it as youre only seeing what everybody else is seeing from the outset.

It's hard to comment on.

What they thought I think objectively you pointed out what they saw which was a dose dependent been change in clinical measurements and importantly, the clinical measurements from a critical element strike at all so I think it is.

It jumped to distribution I think it was.

One other question then just stable distributions. So I think as we think about that data in the context of the biology as Mike laid out on this call I think very very well.

Paul B. Bolno: So I think as we think about that data in the context of the biology, as Mike laid out on this call, you know, I think very, very well we do think that there are two approaches to one characterization of the drug. One is obviously to your point on my hypothesis, have wild type sparing, and that if one thinks about the disease is both one of a toxic gain of function and a toxical loss of function, taking that below the 50%, I know there's a lot of discussion after Roche's data, people just saying, well, studies have been done in 50% reductions in normal animals and shown it to be safe.

We do think that there is two approaches.

One characterization drug one is obviously to your point on the opposite.

Wild type spirit and that if one thinks about the diseases. Both one of a toxic gain of function in talks with loss of function.

Taking that below the 50% I know theres a lot of discussion after Roche data people, just saying well studies have been done at 50% reductions in normal animals and showed its Dave I think one has to remember that the situation that those animals. We're under we're one of 50% reduction of a normal phenotype. When we're dealing with in Huntington's patients as we kind of havent been explaining from.

Paul B. Bolno: I think one has to remember that the situation that those animals were under was one of 50% reduction of a normal phenotype. What we're dealing with in Huntington's patients, as we kind of have been explaining for a while now, is that those reductions that are being studied in the clinic are reductions that are happening in the setting of already a 50% reduction and under the setting of stress of patients who are progressing in their disease. So one has to think about the totality of removing the neuroprotective feature of wild-type proteins and a whole host of other functions, the scylo function, which involves CSX flow. Those are really important characteristics,

While now is that the fact that those reductions that are being studied in the clinic are reductions that are happening.

Are you setting of already a 50% reduction and under the setting of stress the patients were progressing in disease. So one has to think about the totality of removing the neuroprotective feature of wild type protein and a whole host of other folks just to put a serial function.

Which involves CNS CFS flow those are really important characteristics. So yes, I think that's something that needs to be explored and I think that's why we're excited about seeing that.

Paul B. Bolno: So, yes, I think that's something that needs to be explored, and I think that's why we're excited about seeing that. I think we were also, you know, happy in the analysis that patients in the studies that we were looking at didn't progress. Now, you know, that's for where it is.

We were also happy and the analysis that patients on the study that we were looking at didn't progress now.

Pick up from where it is I think as other characterization, we didnt see increases or elevations in white counted protein to the NFL. So I think if we think about the totality of both the alagoas approaches as well as the wild type sparing I think thats driven why we believe a stereo controls approach of wild type sparing is.

Paul B. Bolno: I think as with other characterizations, you know, we didn't see increases or elevations in white counts of protein in NFL. So I think if we think about the totality of both the oligo approaches as well as wild type sparing, I think that's why we believe a stereo control approach of wild type sparing is important. It's why we're excited about bringing PN into the clinic with Smit 3. And to your question, yes, we can apply it and have generated, you know, early data around being ready with SNP 1 and 2.

Important.

It's why we're excited about bringing <unk> into the clinic with three and to your question. Yes, we can apply and have generated early data around being ready with Nick pointed to I think the measured approach, we're going to say it wouldn't be it demonstrates I think the measured approach right now as Mike alluded to with the trial design is let's get the data with Pn chemistry with nib three and.

Paul B. Bolno: I think the measured approach we're going to take, with PN chemistry. I think the measured approach right now is, as Mike alluded to with the trial design, is let's get the data with PN chemistry with SNP 3 and use that as a driver before spending more resources on SNP 1 and 2. But yes, we are prepared to go back to looking at the totality of HD within an allele-specific approach. I don't like if there's... No, I mean, just, I mean, my...

We use that as a driver before spending more resources supporting too, but yes. We are prepared to go back to looking at the totality of HD within allele specific approach.

I mean just.

I mean listen we've been concerned from the beginning that in non selective approach could have detrimental effects. We have said that in burps and that's why we're doing what we're doing.

Michael Linden: Listen, we've been concerned from the beginning that a non-selective approach could have detrimental effects. We have said that for since, and that's why we're doing what we're doing. There are a lot of reasons that could be assessed for what happened with that phase three study, but certainly, effects on wild type have to be part of the consideration, which is why, you know, we're making our wild type assay available. This is an important data set we need to understand, but we're concerned enough that we are, unfortunately, saying initially we would allow patients who have been treated with Toma Nurse in Select HD.

There are a lot of reasons that could be assessed for what happened with that phase III study, but certainly effects on wild type path would be part of the consideration, which is why we're making are wild type assay available. That's an important data set we need to understand but we're concerned enough.

That we are unfortunately, we said initially we would allow patients who had been treated with Tom and Ericsson into select HD. We've had it now not do that out of out of whatever is happening there because we're concerned enough.

Michael Linden: We've had to now not do that out of whatever is happening there because we're concerned enough not to, unfortunately, have to exclude those patients. So it's a concern, it's an observation, it needs to be studied. We have the tools now to study it, and we're hoping that the community will ask these questions because we believe it's important.

Not to want to unfortunately have to exclude those patients. So it's a concern it's an observation it needs to be studied we have the tools now to study it and we're hoping that the community asked these questions because we believe it's important.

Operator: Great, thanks for taking our questions. Absolutely.

Great. Thanks for taking our question absolutely.

Absolutely.

Operator: Thank you. Nice to know there are further questions in the queue. I'd like to turn the call back over to Dr. Paul Bono for any calls or much.

Thank you and I see no further questions in the queue I'd like to.

I'll turn the call back over to Dr. Paul Wagner for any closing remarks.

Paul B. Bolno: Thank you everyone for joining the call this morning to review our first quarter 2021 corporate updates. And thank you to our Wave employees for our hard work and commitment to patients. We look forward to speaking to you all again soon. Have a nice day. Thank you. This concludes today's conference call. Thank you for participating. You may not disconnect.

Thanks, everyone for joining the call. This morning to review, our first quarter 2021, corporate update and thank you to our wave employees for their hard work and commitment to patients. We look forward to speaking to you. All again soon have a nice day. Thank you.

Yeah.

This concludes today's conference call. Thank you for participating you may now disconnect.

Operator: and the

Okay.

Yes.

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