Q3 2020 WAVE Life Sciences Ltd Earnings Call

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Listen only mode. Later, we will conduct a question and answer session and instructions will follow at that time, if anyone should require assistance. During the conference. Please press Star then zero on your Touchtone telephone as a reminder, this conference call is being recorded I would.

Operator: Listen Only Mode. Later, we will conduct a question and answer session, and instructions will follow at that time. If anyone should require assistance during the conference, please press star, then zero on your touchtone telephone. As a reminder, this conference call is being recorded. I would now like to turn the conference over to Graham Morell, Investor Relations, at WAVE. Please do so.

I'd now like to turn the conference over to grab Morrell and Investor Relations that wave. Please go ahead.

Thank you operator, good morning, and thank you for joining us today to discuss our recent business progress and review weaves third quarter 2020 financial results. This morning, we issued a news release detailing these results which is available in the investors section of our website Www Dot Weve life Sciences.

Graham Morell: Thank you, operator. Good morning and thank you for joining us today to discuss our recent business progress and review WAVE's third quarter 2020 financial results. This morning we issued a news release detailing these results, which is available in the investor section of our website www.wavelifesciences.com. The slide presentation that accompanies this webcast will also be available on our website following this presentation. Before we begin, I would like to remind you that the discussions during this conference call will include forward-looking statements. We believe that these statements are subject to a number of risks and uncertainties that can cause our actual results to differ materially from those described in these full reports. The factors that could cause actual results to differ are discussed in the press release, including our annual report on Form 10. The year ended December 31, 2011.

The slide presentation that accompanies this webcast will also be available on our website. Following this call.

Before we begin I would like to remind you that discussions during this conference call will 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 these forward looking statements. The factors that could cause actual results to differ 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 30, Onest 2019 that our quarterly report on form 10-Q for the quarter ended September Thirtyth 2020, we undertake no obligation to update or revise any forward looking statements for any reason.

Paul B. Bolno: Quarterly Report on Form 10-Q for the quarter- We undertake no obligation to update or revise any forward- I'd now like to turn the call over to Dr. Paul Bolno, President and CEO of WAVE Life. Thank you, Graham. Good morning to everyone on the call, and thank you for joining us. I hope you and your families are staying healthy and safe during these challenging times. We are excited to share the latest on our progress, new programs, and future plans. I'll start us off this morning by providing an overview of recent achievements, a summary of the data that will be included in the readout for our PRECISION-HD clinical trials in the first quarter of 2021, and a quick overview of our recently announced PN Chemistry advancement. And then I'll talk about our first ADAR editing program. Our Chief Medical Officer and Head of Therapeutics Discovery and Development, Dr. Mike Panzara, will then discuss our three upcoming clinical trial submissions, including our newly announced clinical trial in Duchenne Muscular Dystrophy. Finally, Dave Gallero, our Interim Chief Financial Officer, will discuss WAVE's third quarter financial results.

I'd now like to turn the call over to Dr., Paul Vogel, President and CEO of wave life Sciences Paul.

Thank you Graham good morning to everyone on the call and thank you for joining us today.

I Hope you and your families are staying healthy and safe during these challenging times.

We are excited to share the latest on our progress new program and future plans ill.

Ill start us off this morning by providing an overview of recent achievement. The summary of the data that will be included in the readout for our precision HD clinical trials in the first quarter of 2021, a quick overview of our recently announced Pn chemistry advancement.

And then I'll talk about our first eight are editing program.

Our chief Medical Officer, and head of therapeutic discovery and development Dr., Mike Panthera will then discuss our three upcoming clinical trial submission, including our newly announced clinical trial in Duchenne muscular dystrophy.

Finally deeper arrow, our interim Chief financial Officer will discuss wave third quarter financial results.

Chandra Vargeese: Dr. Chandra Vargeese, our Chief Technology Officer, and Dr. Ken Rhodes, our Senior Vice President of Therapeutic Discovery, will also be available during the Q&A portion. This past quarter, we continued to make significant progress with our clinical and preclinical pipeline, as well as advances in expanding the potential of our innovative PRISM platform. Despite the challenges of COVID-19 around the world, our research and clinical teams made tremendous strides. As we look ahead to 2021, I believe we are ushering in a new and exciting phase for WAVE.

After Counterparties, our Chief Technology Officer, and Dr., Ken Road, our senior Vice President of therapeutic discovery will also be available during the Q and a portion of this call.

This past quarter, we continued to make significant progress with our clinical and preclinical pipeline as well as advances and expanding the potential of our innovative prison platform.

Despite the challenges of COVID-19 around the world Our research and clinical team has made tremendous strides as we look ahead to 2021 I believe we are ushering in a new and exciting phase for wave.

To start we now anticipate having five clinical trials in 2021.

Paul B. Bolno: To start, we now anticipate having five clinical trials in 2021. This concludes our two ongoing Phase 1b, 2a Precision HD studies in Huntington, for which we continue to expect data in the first quarter of 2021, as well as our new First in Human Studies of WVE-003 and WVE-004. As a reminder, WVE-003 is our third allele-selective Huntington's Disease candidate, and WVE004 is our candidate for Amyotrophic Lateral Sclerosis and Frontal Temporal Dementia in patients with a hexanucleotide expansion in the C9HORF72 gene. The fifth clinical trial, which we are announcing today, will be for WVE-N531, our Notably, the preclinical work needed to submit the CTA was completed last year, and we expect to complete this trial with no change to our cash guidance.

This includes our two ongoing phase one b to a precision HD studies in Huntington disease for which we continue to expect data in the first quarter of 2021.

As well as our new first in human studies of W., Ve 003, and W. Ve 004.

As a reminder, w. Ve 003 is our third wheel selective huntingtons disease candidate and W. Ve 004 is our candidate for a mile trophic lateral sclerosis, and frontotemporal dementia in patients with a hex and nucleotide expansion in the Cnine or 72 gene.

The fifth clinical trial, which we are announcing today will be for WB and 531, our candidate for patients with dish and muscular dystrophy amenable to exon 53 skipping.

Notably the preclinical work needed to submit the DTA was completed last year and we expect to complete this trial with no change to our cash guidance.

Mike will share more about how we reached the decision to initiate this clinical trial, which is intended to assess dystrophin and initial safety as well as help us understand the impact of Pn chemistry on placing in muscle.

Of note WV and 531, W., Ve 003, and WB zero zero for all incorporate RPN backbone chemistry advancement I'll talk more about this later.

Paul B. Bolno: Mike will share more about how we reached the decision to initiate this clinical trial, which is intended to assess dystrophins and initial safety, as well as help us understand the impact of PN chemistry on splicing and muscle tissue. Of note, WVE-N531, WVE-003, and WVE-004 all incorporate our PN Backbone Chemistry Advancement. I'll talk more about this later.

Thanks to the rapid advancements in our eight our platform NPM chemistry. We are also announcing today that our first aid our editing program will be an alpha one antitrypsin deficiency or a TD.

The disease is ideally suited for an R&D editing approach and we believe that our novel Aydar editing modality has the potential to address both the lung and liver manifestations of the disease.

The program will also lead the way for future wave eight are editing programs.

We believe our approach has the potential to become best in class aren't editing system with applicability in many disease areas, including neurology.

We're also continuing to grow our neurology pipeline through our CNS collaboration with Takeda.

Paul B. Bolno: Thanks to the rapid advancements in our ADAR platform and NPN Chemistry, we are also announcing today that our first ADAR editing program will be for Alpha-1 Antitrypsin, or AATD. This disease is ideally suited for an RNA editing approach, and we believe that our novel ADAR editing modality has the potential to address both the lung and liver manifestations of the disease. The program will also lead the way for future WAVE ADAR editing programs.

Where we work collaboratively on up to six preclinical CNS targets are pn backbone chemistry is helping us optimize profiles for these candidates, resulting in compelling nonhuman primate data that we will share today.

On August 25th we held an investor analyst webcast, where we announced the advancements to our prism platform, including our novel Pn backbone chemistry. This backbone modification has been shown to improve the pharmacologic properties of our oligonucleotides across all three of our modalities silencing, placing and R&D editing.

Finally, we are well positioned financially to progress our all of our planned and existing programs. We are reiterating that our current cash runway. It takes us into the second quarter of 2023.

Paul B. Bolno: We believe our approach has the potential to become a best-in-class RNA editing system with applicability in many disease areas, including neurology. We are also continuing to grow our neurology pipeline through our CNS collaboration with Cicada, where we work collaboratively on up to six preclinical CNF targets. Our PN Backbone Chemistry is helping us optimize profiles for these candidates, resulting in compelling non-human primate data that we will share today.

Dosing in both the 32 milligram cohort in the precision HD phase one b to a clinical trials continues.

And we are on track to share data from all cohorts as well as an issue initial data from the ongoing open label extension study in the first quarter of 2021.

Specifically in the oil way, we will share data for patients who have received multiple doses of eight or 60 milligrams at the time of the data cut right.

Results from the trials are expected to include safety and Tolerability as well as biomarker data, including mutant Huntington knockdown total Huntington knockdown and the effect on neuro filament light chain.

We also continue to focus on the scientific challenge of measuring wild type Huntington protein and have made good progress. We believe that is critical to understand the impact of potential treatment on wild type Huntington and look forward to keeping you updated as we strive to complete this work in time for our data readout.

Paul B. Bolno: On August 25th, we held an Investor Analyst Webcast where we announced advancements to our PRISM platform, including our novel PN Backbone Chemistry. This backbone modification has been shown to improve the pharmacologic properties of our oligonucleotides across all three of our modalities, silencing, splicing, and RNAi. Finally, we are well positioned financially to progress all of our planned and existing programs.

As I mentioned, we announced in August that we expanded our repertoire of backbone linkages with PMO chemistry.

This advancement has quickly become an important component of our prison platform as it provides another tool we can use to optimize the pharmacologic properties of our candidate.

Pn chemistry involves replacing a non bridging oxygen at him with a nitrogen containing moiety piece.

Pn modifications are neutral, allowing them to break up the charge of the backbone while retaining specificity.

To the complementary based pairings, our preclinical experiments utilizing pn chemistry have demonstrated a general increase in potency exposure and durability when compared to identical sequences without the PMD modification.

Paul B. Bolno: We are reiterating that our current cash runway takes us into the second quarter of 2023. Dosing in both the 32 mg cohorts in the PRECISION-HD Phase 1b, 2a clinical trials. And we are on track to share data from all cohorts, as well as initial data from the ongoing Open Label Extension Study in the first quarter of 2021. Specifically, in the OLA, we will share data for patients who have received multiple doses of 8 or 16 mg at the time of diagnosis.

We are seeing the significant impact of Pn chemistry on the amount of knockdown and durability across CNS tissues. As we have previously shown in mice. The pn containing molecule. In this study showed meaningful persistent transcript knockdown of 80%, 90% throughout the central nervous.

Importantly, we continue to see the effects of Pn chemistry translate in our therapeutic program on.

On this slide you can see recent in vivo data for the most advanced therapeutic candidate in our CNS discovery collaboration with Takeda.

In this study for an undisclosed target non human primates received a single Intrathecal injection 12 milligram dose.

Paul B. Bolno: Results from these trials are expected to include safety and tolerability, as well as biomarker data, including mutant Huntington knockdown, total Huntington knockdown, and the effect on neurofilm that might change. We also continue to focus on the scientific challenge of measuring wild-type Huntington protein and have made good progress. We believe that it is critical to understand the impact of potential treatments on wild-type Huntington and look forward to keeping you updated as we strive to complete this work in time for our data release. As I mentioned, we announced in August that we expanded our repertoire of backbone linkages with PNC. This advancement has quickly become an important component of our PRISM platform, as it provides another tool we can use to optimize the pharmacologic properties of our care. PN Chemistry involves replacing a non-bridging oxygen atom with a nitrogen-containing moisture.

One month after administration, we observe that the candidate was widely distributed across the cnf, including the spinal cord cerebral cortex and have the campus.

The single dose led to approximately 90% knockdown of the target across CNS tissues.

We view this new NHP data has a considerable advancement for our platform and the field in general.

Further these results have enormous implications for wave as we look to deepen our pipeline and add new wholly owned neurology programs in the future.

Our latest pipeline chart highlights the considerable impact Pn chemistry is having on our portfolio.

As all of our current discovery and preclinical stage programs utilizes backbone modification.

We are excited to start investigating the role of Pn chemistry in the clinic through the planned clinical trials WV easier. There are three WV easier there are four and WB and 531.

The advances Weve made with Cairo control Pn chemistry modification and our prison platform have helped us to unlock our novel eight are editing platform capability.

Our approach to R&D editing employees short fully chemically modified oligonucleotide, usually 30 nucleotides are left to recruit endogenous R&D editing enzymes called aydar.

Eight our enzymes can be used to change in eight to Eni, which the sales read as GE and our net.

Paul B. Bolno: PN Modifications are neutral, allowing them to break up the charge of the backbone while retaining specificity to the complementary base. Our preclinical experiments utilizing PN chemistry have demonstrated a general increase in potency, exposure, and durability when compared to identical sequences without the PN. We are seeing the significant impact of PN chemistry on the amount of knockdown and durability across the... As we have previously shown in mice, the PN-containing molecule in this study showed meaningful persistent transcript knockdowns of 80-90% throughout the central nervous system. Importantly, we continue to see the effects of PN chemistry translate in our therapeutic program. On this slide, you can see recent in vivo data for the most advanced therapeutic candidate in our CNS Discovery Collaboration with Decatur. In this study for an undisclosed target, non-human primates received a single intrathecal injection of 12 mg. One month after administration, we observed that the candidate was widely distributed across the CNS, including the spinal cord, cerebral cortex, and hippocampus. The single dose led to approximately 90% knockdown of the target across the entire population.

Nearly half of known human pathogenic SNET RG DNA mutations.

The capacity to leverage aydar to correct. These mutations opens the door to a number of therapeutic applications, including restoring or modifying protein function and upregulating protein expression, which greatly expands the landscape of disease variance that we can potentially address.

Our technology has many advantages in the editing space and is at the forefront of R&D editing our decision to pursue M&A instead of DNA editing was deliberate as R&D editing avoid irreversible off target genomic candidates.

And because we use endogenous eight our enzyme we avoid the risk that introducing exactness proteins may trigger immunogenicity it off target effects.

In addition, our oligonucleotides are optimized using an expanding repertoire of chemical and stereo chemical modifications available through prism, including Pn chemistry.

Importantly, we employ.

Simplify delivery strategy that does not require avi vectors for nanoparticle, which would allow us to leverage established oligonucleotides managed manufacturing processes.

We saw many of these attributes represented in our proof of concept in vivo study in non human primates, which you may recall from our research webcast. The study showed up to 50% editing of Beta Act and transcript two days both last dose will sustain editing at 45 days. We've also shown that our aydar editing oligonucleotides are highly specific.

In this mornings press release, we announced our first aid our editing program, which will target therapy, not one for the treatment of Alpha one antitrypsin deficiency.

Alpha one antitrypsin deficiency or Eightd is a rare inherited genetic disorder that is commonly caused by a single GE to eight point mutation in M&A quoted by Vizio of the subpoena one gene.

Paul B. Bolno: We view this new NHP data as a considerable advancement for our platform and the field in general. Further, these results have enormous implications for WAVE as we look to deepen our pipeline and add new, wholly-owned neurology programs. Our latest pipeline chart highlights the considerable impact PN Chemistry is having on our portfolio, with all of our current discovery and preclinical stage programs utilized as backbone models. We are excited to start investigating the role of PN chemistry in the clinic through the planned clinical trials at WVE-003, WVE-004, and WVE-N531. The advances we've made with chiral control, pn-chemistry modifications, and our PRISM platform have helped us to unlock our novel ADAR editing platform capability. Our approach to RNA editing employs short, fully chemically modified heliconucleotides, usually 30 nucleotides or less, to recruit endogenous RNA editing enzymes called ADEs. ADAR enzymes can be used to change an A to an I, which cells read as G in RNA.

This mutation leads to miss folding and aggregation of Alpha one antitrypsin protein or 80, and how to sites and a lack of functional protein in the loans, where it would protect lung tissue from neutrophil elastase.

Patients with Eightd typically exhibit progressive lung damage liver damage or both leading to frequent hospitalization and potentially terminal lung disease, where liver disease.

While the few approved therapies modestly increased circulating levels of 80 in those with lung pathology. There are currently no approved therapies to address the liver pathology in.

It is estimated there are approximately 250000 patients worldwide with the most severe form of Eightd.

These patients are homozygous for the G. to eight point mutation on the deal.

Well the HCV landscape is growing quickly we continue to see opportunities to develop a best in class treatment approach, which would have three key attributes first we would want to restore wild type 80 protein and we believe and editing approach provides the opportunity to substantially improve upon the modest levels of.

That are delivered through augmentation therapy.

We would want to simultaneously address the aggregation of 80 in the liver by addressing both we potentially remove the need for augmentation therapy and give patients the option for a single therapeutic regardless of lung or liver phenotype. We.

Paul B. Bolno: Nearly half of known human pathogenic SNPs are G to A mutations. The capacity to leverage ADAR to correct these mutations opens the door to a number of therapeutic applications, including restoring or modifying protein function and upregulating protein expression, which greatly expands the landscape of disease variants that we can potentially address. Our technology has many advantages in the editing space and is at the forefront of RNA editing. Our decision to pursue RNA instead of DNA editing was deliberate, as RNA editing avoids irreversible off-target genomic... And because we use endogenous ADAR enzymes, we avoid the risk that introducing exogenous proteins may trigger immunogenicity and off-target. In addition, our oligonucleotides are optimized using an expanding repertoire of chemical and stereochemical modifications which are available through PRISM, including PN Chemical.

I would also want to develop a treatment that retains eightys physiologic regulation.

Based on publicly available information and our understanding of the disease and the editing approach appears to be the only one that can address all these attributes.

We believe our M&A editing is preferable to DNA editing to avoid the potential for irreversible off target edits to the genome.

Leveraging the work we already did with Galnac conjugate version and Hps, we turned our attention to correlating the corrected transcripts to wild type protein.

Here, we show that we've accomplished this in primary mouse hepatic disease sell model, we saw upwards of 60% correction of busy transcript back to wild type transcript, which prevented protein this holding and allowed for better secretion from that pad site, resulting in a threefold increase in protein concentration.

The question. We then asked ourselves is do we have the right in vivo modeling systems in place to develop best in class aren't editing candidates with our eight our platform.

One important learning for us with the limitations of the humanized subpoena one mouse model. This model contains mouse radar, which behaves differently from human data.

Paul B. Bolno: Importantly, we employ a simplified delivery strategy that does not require AAV vectors or nanoparticles, which would allow us to leverage established oligonucleotide manufacturing processes. We saw many of these attributes represented in our proof-of-concept in vivo study in non-human primates, which you may recall from our research webpage. This study showed up to 50% editing of the beta-actin transcript two days post the last dose with sustained editing at 45 days. We've also shown that our ADAR editing oligonucleotides are highly... In this morning's press release, we announced our first ADAR editing program, which will target SERPINA-1 for the treatment of Alpha-1 antitrypsin deficiency. Alpha-1 Antitrypsin Deficiency (or AATD) is a rare inherited genetic disorder that is commonly caused by a single G-to-A point mutation in mRNA coded by the Z allele of Serpina-1G. This mutation leads to misfolding and aggregation of the alpha-1 antitrypsin protein, or AAT, in hepatocytes and a lack of functional protein in the lungs, where it would protect lung tissue from neutrophil elastin. Patients with AATD typically exhibit progressive lung damage, liver damage, or both, leading to frequent hospitalizations and potentially terminal lung disease or liver disease.

Our scientists therefore Susan.

Due to develop a profit proprietary model, which contain both humanized serpico, one and humanized aydar, what's really exciting about this model is that we can now crossed a humanized eight our mouth with any specific disease bounce model, thus, providing a modeling system that can be used across our eight are editing programs.

We're looking forward to optimizing this model further and generating data from our Eightd program next year and applying the model system in neurology and other areas.

At this time I'd like to pass the call to our Chief Medical Officer, and head of Therapeutics Discovery and development Dr., Mike pens, Aaron to discuss our three upcoming clinical trial initiation.

Thanks, Paul.

This quarter has been highlighted by tremendous progress we not only anticipate sharing data in the first quarter from precision HD wanting precision HG jeweler Miro east as Paul already mentioned, but.

Well, we are also preparing to file two cts before the end of the year one for W.B. easier zero three our third wheel selective candidate and Huntingtons disease, and one for W.B.E. near zero for our variance selective simonton candidate in a less in FTD.

In addition in the first quarter of next year, we are planning to submit a ceta for WV and 531, our candidate for DMD patients with mutations amenable to exon 53 skipping.

More on that later in my presentation.

I'll start with a few words on Huntingtons disease, our work and the work of others. In this area over the past few years has emboldened us and our belief that a legal selectivity is critically important as a foundational concept in the treatment of HD and.

And that preserving as much wild type Huntington as possible, while lowering mutant Huntington is essential for not only proper function of the central nervous system, but systemically.

In essence this is balanced between these two proteins in a push pull scenario a tug of war of sorts between their opposing effects that overtime leads to the invariable progression of disease, a process involving intense biological stress, where the beneficial effects of wild type protein maybe.

Paul B. Bolno: While the few approved therapies modestly increase circulating levels of AAT in those with lung pathology, there are apparently no approved therapies to address the liver. It is estimated there are approximately 250,000 patients worldwide with the most severe form of AATD. These patients are homozygous with a G to A point mutation on the Z allele. While the AATD landscape is growing quickly, we continue to see opportunities to develop a best-in-class treatment approach, which would have three key attributes. First, we would want to restore wild-type AAT proteins, and we believe an editing approach provides the opportunity to substantially improve upon the modest levels of AAT that are delivered through augmentation therapy. We would want to simultaneously address the aggregation of AAT in the liver.

Even more important.

Wild type Huntington carries out essential functions in both developing an adult brain. It protects neurons against various types of stress present themselves with help with high metabolic activity.

Including exciting toxic oxidative and protein Miss folding stress.

While Ted Pennington also plays a key role in traffic in synaptic protein and synaptic testicles.

This trafficking function has been shown to affect synaptic plasticity, which is important for learning and memory as well as for supplying the essential growth factor bdnf two straight on their arms to ensure their survival.

Paul B. Bolno: By addressing both, we potentially remove the need for augmentation therapy and give patients the option of a single therapeutic, regardless of lung or liver. We would also want to develop a treatment that retains AAT's physiologic regulation, based on publicly available information and our understanding of the disease, and any editing approach appears to be the only one that can address all these attributes. And we believe RNA editing is preferable to DNA editing to avoid the potential for irreversible off-target editing. Leveraging the work we already did with GalNet Conjugation and NHPs, we turned our attention to correlating the corrected transcript to wildcats. Here we show that we've accomplished this in primary mouse hepatocyte Z-cell models.

Additionally, wild type Huntington is critical for the formation and function of Celia, which control the flow of CSF and help maintain homeostasis in the CNS.

Our approach to HD is guided by the recognition that in addition to a gain of function of the mutant I mean can poking patient.

Patients with this disease have lost one copy of wild type Remington, leaving them with a smaller protective reservoir than on affected individuals.

We believe this scenario necessitates trying to preserve as much wild type humming come as possible to give these individuals the best opportunity for beneficial outcomes.

W.V. easier zero three is our third a Leo selective HD candidate and the first to incorporate PMO chemistry it.

It is designed to selectively target an undisclosed Smith that we're turning around at three.

On the mutant HKG Amani transcript, while leaving wild type transcript and thus protein relatively intact.

Paul B. Bolno: We saw upwards of 60% correction of the Z-transcript back to wild-type transcript, which prevented protein misfolding and allowed for better secretion from the hepatocyte, resulting in a three-fold increase in protein content. The question we then ask ourselves is, do we have the right in vivo modeling systems in place to develop best-in-class RNA editing candidates with our ADAR platform? One important learning for us were the limitations of the humanized SERPINA-1 mouse model. This model contains mouse radar, which behaves differently from human radar.

And it's also the first of our HD compounds evaluated in an in vivo models system to better understand PK PD relationships to guide initiation of human dosing.

This slide illustrates some of the in vitro and in vivo data supporting near zero three its movement into the clinic.

On the left we clearly see the in vitro selectivity of our candidate over a wide range of concentrations versus similar concentrations of a Pam silencing reference compound.

While we see a similar reduction and mutant Huntington transcripts from both compounds zeros. Your three leaves the wild type Huntington on a relatively intact.

Michael Linden: Our scientists, therefore, developed a proprietary model that contains both humanized Serpino-1 and humanized ADAR. What's really exciting about this model is that we can now cross a humanized ADAR mouse with any specific disease mouse model, thus providing a modeling system that can be used across our ADAR editing program. We're looking forward to optimizing this model further and generating data from our AETD program next year and applying the model system in neurology and other areas. At this time, I'd like to pass the call to our Chief Medical Officer and Head of Therapeutics Discovery and Development, Dr. Mike Panzera, to discuss our three upcoming clinical trial initiatives. Thanks, Paul.

As I mentioned, we also examine the effect of our candidate in vivo model the backing HD transgenic mouse we.

We did this knowing that there were several limitations to the model, namely that it does not contain wild type HCT gene and it contains multiple copies of the mutant Huntington gene some of which do not have the snow three variant therefore, setting a higher bar for Snthree selected mutant Huntington knockdown.

Nonetheless, as shown on the right, we observed potent and durable knockdown of mutant Huntington Mr. Trade him back HD transgenic mice outreach to 12 weeks with a similar effect in the core test, although not shown in this slide.

These demonstrations of selectivity.

Leasing and durability leave us enthusiastic about the prospects for years there are three as we prepare to enter clinic.

Further with the entry of this candidate into clinic, we are positioned to provide ideal selective therapeutic options for up to 80% of people with HD.

Michael Linden: This quarter has been highlighted by tremendous progress. We not only anticipate sharing data in the first quarter from Precision HD1 and Precision HD2 and their OLEs, as Paul already mentioned, but we are also preparing to file two CTAs before the end of the year. One for WVE003, our third allele-selective candidate in Huntington's disease, and one for WVE004, our variant-selective silencing candidate in ALS and FTD. In addition, in the first quarter of next year, we are planning to submit a CTA for WVE-N531, our candidate for DMD patients with mutations amenable to exon 53 skipping. More on that later in my presentation.

Now moving onto W. Ve zero zero for our candidate targeting Cnine or 72 mutations for the treatment of Monitronics lateral sclerosis, and Frontotemporal dementia.

There is year four is designed to address the GCC hexis nucleotide repeat expansions and as seen on our 72 gene that lead to reduced expression of healthy protein.

Accumulation of repeat containing transcripts and the abnormal expression at the neurotoxic that peptides proteins or DPR.

Cnine North 72, Hexham nuclear type repeat expansions are the most common drive genetic driver of LSW in FTD, both familial on sporadic forms both diseases are devastating and represent areas of high unmet need.

The preclinical data from our 004 program illustrate why we are excited about the potential of this variance selective compound.

Michael Linden: I'll start with a few words on Huntington's disease. Our work and the work of others in this area over the past few years have emboldened us in our belief that allele selectivity is critically important as a foundational concept in the treatment of HD, and that preserving as much wild-type Huntington as possible while lowering mutant Huntington is essential for not only proper function of the central nervous system but also systemically. In essence, it is this balance between these two proteins in a push-pull scenario, a tug-of-war of sorts between their opposing effects, that over time leads to the invariable progression of disease, a process involving intense biological stress, where the beneficial effects of wild-type Huntington protein may be even more important. Wild-type Huntington carries out essential functions in both developing and adult brains. It protects neurons against various types of stress prevalent in cells with high metabolic activity, including excitotoxic, oxidative, and protein misfolding stress. Wild-type Huntington's also plays a key role in trafficking synaptic proteins and synaptic desiccants.

In addition to in vitro data from I. PSC lines that we've shared previously the in vivo data from the Cnine back transgenic mice, which express the human CNR 72, continuing Hexham nucleotide repeat expansion clearly tell the story after only two CB doses and.

Days zero in seven 004 show potent and durable knockdown of over 90% of the poly glycine propylene or poly GP DPR protein in the spinal cord and at least 80% in the quarter.

This impressive effect persisted for at least six months.

Particularly exciting results as we consider dosing intervals and the clinical setting.

Given that 004 was designed to be very selective we were further encouraged by these results from the Fame study demonstrating preservation of health, we see nine or 72 protein at the same six month time point confirming selectivity of the compound we look forward to evaluating this candidates combination of variance select.

Targeting potency and sustained activity in the clinic next year.

One important aspect of our clinical program is the inclusion of patients diagnosed with LSW FTD or both and our proof of concept clinical study.

The primary objective will be to assess safety and tolerability of single and multiple doses of 004, but as in our preclinical in vivo studies, we will measure the poly GP biomarker in humans CSS to assess target engagement.

Michael Linden: This trafficking function has been shown to affect synaptic plasticity, which is important for learning and memory, as well as for supplying the essential growth factor BDNF to striatal neurons to ensure their survival. Additionally, wild-type Huntington is critical for the formation and function of cilia, which control the flow of CFF and help maintain homeostasis in the CNF. Our approach to HD is guided by the recognition that, in addition to a gain of function of the mutant Huntington protein, patients with this disease have lost one copy of wild-type punnington, leaving them with a smaller protective reservoir than unaffected individuals. We believe this scenario necessitates trying to preserve as much wild-type Huntington as possible to give these individuals the best opportunity for beneficial outcomes. WVE003 is our third allele-selective HD candidate and the first to incorporate PN chemistry.

We also intend to look at neuro filament light chain as well as other biomarkers.

As noted previously we plan to file with DTA this quarter and expect to provide an update on the trial design early next year.

Finally, I will discuss our announcement that we plan to advance W. Ve and 531 to the clinic next year.

And 531 targets exon 53, and boys with DMD, who have mutations amenable to exon 53 skipping.

Like near Zero, three and zero zero for this candidate was designed with PM chemistry.

Stepping back you may recall that we were fully prepared to file a CPA for this candidate at the end of last year.

At that time, our preclinical data package, which included in vitro data demonstrating a dose dependent increase in dystrophin production of up to 71% in DMD patient derived Meyer blasts supported rapidly advancing the candidate.

Michael Linden: It is designed to selectively target an undisclosed SNP that we're terming SNP3 on the mutant HTT mRNA transcript while leaving the wild-type transcript and thus protein relatively intact. It is also the first of our HD compounds evaluated in an in vivo model system to better understand PK-PD relationships to guide initiation of human dosing. This slide illustrates some of the in vitro and in vivo data supporting 003's movement into the clinic. On the left, we clearly see the in vitro selectivity of our candidate over a wide range of concentrations versus similar concentrations of a pan silencing reference. While we see a similar reduction in mutant Huntington transcripts from both compounds, 003 leaves the wild-type Huntington RNA relatively intact. Furthermore, we also examine the effect of our candidate in an in vivo model, the BackHG transgenic mouse.

However, as you also know we had suspended development of and 531 and other DMD programs. Following the discontinuation of our Supercenters and program.

Since then our assessment of muscle biopsies from the program indicated that the drug did not engage target most likely due to poor intra cellular access in dystrophic model and muscle.

Based on the preclinical data for our PM containing compounds, including M. Three one there is a possibility that we may overcome this challenge and a clinical study is the best way to rapidly assess the impact of chemistry on tissue distribution and splicing in dystrophic muscle.

One key piece to support a preclinical data is from an ongoing study in a mouse model for DMD with a devastating phenotype.

This study was done in a double knockout or Dk old mouse model, which has a mutation and excellent 23, leading to a lack of dystrophin as welcome mutation leading to a lack of neutrolin.

Michael Linden: We did this knowing that there were several limitations to the model, namely that it does not contain the wild-type HCT gene, and it contains multiple copies of the mutant Huntington gene, some of which do not have the SNP3 variant, therefore setting a higher bar for SNP3-selective mutant Huntington to occur. Nonetheless, as shown on the right, we observed potent and durable knockdown of mutant Huntington in the striatum of BackHG transgenic mice out to 12 weeks, with a similar effect in the cortex, although not shown in this slide.

We compared the effects of a PS PEO containing molecule dose at a 150 milligrams per kilogram weekly to a PM containing compound dosed at 75 milligram per kilogram every other week as well as a control.

Other than the placement of the three P.M. backbone linkages. These molecules have the same sequencing chemistry.

Despite administering 50% less drug.

50% less frequently the mice, receiving the PM containing molecule showing unlike green of all reach at least 36 weeks of age. They are thriving in the study remains ongoing indicating the PMO chemistry is having a compelling effect.

Michael Linden: These demonstrations of selectivity, potency, and durability leave us enthusiastic about the prospects for 003 as we prepare to enter clinical trials. Further, with the entry of this candidate into clinical trials, we are positioned to provide allele-selective therapeutic options for up to 80% of people with HD. Now moving on to WVE-004, our candidate targeting C9-ORF72 mutations for the treatment of myotrophic lateral sclerosis and frontotemporal dementia. WVE-004 is designed to address the GGGGCC hexanucleotide repeat expansions in the C9RF72 gene that lead to reduced expression of healthy protein, accumulation of repeat-containing transcripts, and the abnormal expression of neurotoxic dipeptide C9Nrf72 hexonucleotide repeat expansions are the most common genetic driver of ALS and STD, in both familial and sporadic forms.

Based upon a greater understanding of the subrogation study outcome.

Preclinical evidence supporting improved muscle distribution, and skipping efficiency with PM chemistry, and extensive obligation to the DND community DMD community. We are now ready to initiate a clinical trial we.

We are planning an open label trial with up to 15 boys with DMD, who will eventually recede and 531 every other week.

The trial will be powered to detect a change in dystrophin production.

Measure drug concentration in muscle and to assess initial safety we plan to conduct the trial in Europe. If successful there is a potential to apply PM chemistry to other exxon's as well as the opportunity to advance other compounds for neuro muscular disease.

We look forward to submitting the ceta in the first quarter of next year, continuing our mission to help patients in desperate need of new therapies.

I'll now turn the call over to Dave Guy or girl, the interim CFO to bring you through our financial results Dave.

Michael Linden: Both diseases are devastating and represent areas of high unmet need. The preclinical data from our 004 program illustrate why we are excited about the potential of this variant-selective compound. In addition to in vitro data from iPSC lines that we've shared previously, the in vivo data from the C9-backed transgenic mice, which expressed the human C9RF72-containing hexanucleotide repeat expansion, clearly tell the story. After only two ICV doses on days 0 and 7, 004 showed potent and durable knockdown of over 90% of the polyglycine proline or poly-GP-DPR protein in the spinal cord and at least 80% in the cortex.

Thanks, Mike.

Weve ended the third quarter of 2020 with approximately $216.4 million in cash and cash equivalents compared to $147.2 million as of December 30, Onest 2019.

During the third quarter of 2020, we substantially extended our cash runway by raising $93.7 million in net proceeds from our September 2020, public offering and $48 million in net proceeds from our at the market equity program and receiving $16.8 million in refundable tax credits.

Now I would like to review our interest in our income statement for the quarter.

For the third quarter of 2020 wave recorded a net loss of $33.1 million compared to $50.7 million for the same period in 2019.

Michael Linden: This impressive effect persisted for at least six months, particularly exciting results as we consider dosing intervals in the clinical setting. Given that 004 was designed to be variant-selective, we were further encouraged by these results from the same study demonstrating preservation of healthy C9ORF72 protein at the same six-month time point, confirming selectivity of the complex. We look forward to evaluating this candidate's combination of variant-selective targeting, potency, and sustained activity in the clinic next year. An important aspect of our clinical program is the inclusion of patients diagnosed with ALS, FTD, or both in our proof-of-concept clinical studies. The primary objective will be to assess safety and tolerability of single and multiple doses of 004. Additionally, as in our preclinical and vivo studies, we will measure the poly-GP biomarker in human CSF to assess target engagement. We also intend to look at neurofilament by chain as well as other biomes.

Research and development expenses were $28.3 million in the third quarter of 2020 compared to $44.6 million for the same period in the prior year.

The decrease in research and development expenses in the third quarter was primarily due to decreased external expenses related to Super Dursun due to our December 2019 decision to discontinue the program.

As well as decreased headcount and other external expenses driven by our February 2020 cost reduction plan.

Partially offset by increased external expenses related to our clinical and preclinical activities related to our HD programs NRC nine or 72 program LS in FTD.

General and administrative expenses were $9.6 million in the third quarter of 2020 compared to $12.5 million in the same period in 2019.

The decrease in general and administrative expenses in the third quarter of 2020, but is primarily due to the February 2020 cost reduction plan, which included a workforce reduction.

Michael Linden: As noted previously, we plan to file a CTA this quarter and expect to provide an update on the trial design early next year. Finally, I will discuss our announcement that we plan to advance WVEN 531 to the clinic next year. N531 targets exon 53 and boys with DMD who have mutations amenable to exon 53 skipping.

We expect that our existing cash and cash equivalents together with expected and committed cash from our existing collaborations.

Will enable us to fund, our operating and capital expenditure requirements into the second quarter of 2023.

As a reminder, we do not include potential milestones and other uncommitted payments related to our Takeda collaboration in our cash runway.

Michael Linden: Like 003 and 004, this candidate was designed with PM chemistry. Stepping back, you may recall that we were fully prepared to file a CTA for this candidate at the end of last year. At that time, our preclinical data package, which included in vitro data demonstrating a dose-dependent increase in dystrophin production of up to 71% in DMD patient-derived myoblasts, supported rapidly advancing the candidate. However, as you also know, we had suspended development of N531 and other DMD programs following the discontinuation of our Suva-Dursen program. Since then, our assessment of muscle biopsies from the program indicated that the drug did not engage targets, most likely due to poor intracellular access in dystrophic muscles. However, based on the preclinical data for our PN-containing compounds, including N531, there is a possibility that we may overcome this challenge.

I will now turn the call back over to Paul for closing remarks, Paul.

Thanks, Dave I Hope you all are sharing in our excitement for what we expect to be a catalyst rich year ahead, driven mostly by the five clinical trials that we expect will be ongoing in 2021.

To recap this quarter, we expect to submit the Cts for WV easier zero three end WV easier zero four in the first quarter of 2021, we plan to submit a third ceta for W. Ve and 531.

Also in the first quarter, we expect to report data from all cohorts of the precision HD studies as well as initial early data.

Finally, we plan to share updates on our Eightd program, including data into humanized model and I expect we'll have other eight are editing updates to share as we continue to build this novel platform capability.

We are well capitalized to advance our pipeline of potentially transformational programs and realize the value of our platform and with that we'll open up the call for questions.

Operator.

Ladies and gentlemen, if you have a question at this time. Please press the star and then the number one key on your Touchtone telephone. If your question has been answered or you wish to remove your sales barbecue. Please press the pound key.

Your first question is from the line of Joon Lee What's Trust Truest Securities.

Hi, guys. Thanks for the questions and the updates I have couple of questions for you in our program for the Antitrypsin program number one and what percent editing would you need to have a therapeutic effect and could you explain in what way your approach is better or different than the mapped out approach being taken by on that.

Michael Linden: And a clinical study is the best way to rapidly assess the impact of its chemistry on tissue distribution and splicing in dystrophic muscles. One key piece of supportive clinical data is from an ongoing study in a mouse model for DMD with a devastating phenotype. This study was done in a double knockout or DKO mouse model, which has a mutation in exon 23 leading to a lack of dystrophin, as well as a mutation leading to a lack of eutrophin.

Let me end by sirna and for the DMD program.

Can you remind us again, how European chemistry is able to overcome the tissue access limitations.

Michael Linden: We compared the effects of a PSPO-containing molecule dosed at 150 mg per kg weekly to a PN-containing compound dosed at 75 mg per kg every other week, as well as to a control. Other than the placement of the three PM backbone linkages, these molecules have the same sequence in chemistry, despite administering 50% less drugs. 50% less frequently, the mice receiving the PN-containing molecules, shown in light green, have all reached at least 36 weeks of age. They are thriving, and the study remains ongoing, indicating that PN chemistry is having a compelling effect. Based upon a greater understanding of the Suva-Durson study outcome, preclinical evidence supporting improved muscle distribution and skipping efficiency with PN chemistry, and a sense of obligation to the DMD community We are planning an open-label trial with up to 15 boys with DMD who will eventually receive N531 every other week. The trial will be powered to detect a change in dystrophin production, measure drug concentration in muscle, and to assess initial safety. We plan to conduct the trial in Europe.

Of your prior chemistry backbone chemistry. Thank you.

Thank you Jim I will divide this into two parts and I'll I'll bring tenderness second.

As it relates to aydar.

We're excited about the differentiation as we laid out for bringing in editing approach or a correction approach forward over silencing and while there has been a lot of excitement around silencing and we don't discount that on knocking down or that the mutated protein within the liver I think when we think and approached the alpha one antitrypsin.

Deficiency, we really approach it from the area of corrections. So that is how do we fix this point mutations such that we can restore the physiologic balance of the protein, enabling it to treat both the pulmonary as well as the hepatic complications of liver and loan. So this is a key driver for us to drive down the correction arm as well.

Talk about the heterozygosity these patients we do know that.

Patient is heterozygous, so 50% corrections of risk restoration.

It doesn't manifest the disease, so we think about where that where that where the correction needs to be with the physiologic protein between that up to 50%, but you don't by no means into 100% correction in terms of restoring normal physiology.

Wondered you is there anything you want to add to the eight our question.

No I think you pretty much covered.

Hey, Paul Yes.

And just to finish up the eight our question assuming both the napkin approach and works at they expect slowly and then your approach works slowly as you expect by editing.

Dave Gallero: If successful, there is the potential to apply PN chemistry to other exons as well as the opportunity to advance other compounds for neuromuscular development. We look forward to submitting the CTA in the first quarter of next year, continuing our mission to help patients in desperate need of new therapies. I'll now turn the call over to Dave Guerrero, the Interim CFO, to bring you through our financial results. Thanks, Mike. WAVE entered the third quarter of 2020 with approximately $216.4 million in cash and cash equivalents, compared to $147.2 million as of December 31, 2019.

I would too many envisioned.

Envision diesel coated manifesting clinically differently, how would it be correct.

Yes, so I mean as we know now that is the initial therapies that are out in terms of the protein replacement the tree pulmonary complications. So theres is augmentation therapy that there and so there is a desire to kind of think about the interchangeability of protein.

Protein replacement, our protein augmentation therapy.

As well as now liver correction with silencing I think we stand to be able to work in both therefore really correcting and restoring the normal protein to the wild type protein to restore physiologic balance flooding the body use the proteins as they need for both the loan and deliver.

They would really.

Potentially wouldn't require the necessity of silencing or protein their replacement therapy.

Yep.

At the EPS.

Yes, and as it relates to DMD and I'll, let Mike continue continued it and answer the question of the subsequently I mean as we shared on research day. There is a lot of it and excitement as we think about the in vivo data that were generating a cross sell uptake of Pn chemistry, and we'll talk about this in the context of muscle obviously for DMD, but as we just shared today once.

Dave Gallero: During the third quarter of 2020, we substantially extended our cash runway by raising $93.7 million in net proceeds from our September 2020 public offering and $48 million in net proceeds from our at-the-market equity program and receiving $16.8 million in refundable tax credits. Now, I would like to review our income statements for the quarter. For the third quarter of 2020, WAVE reported a net loss of $33.1 million compared to $50.7 million for the same period in 2019.

See that transitioning across neurons and other aspect Mike do you want to answer the question of the sure sure Paul Yes.

So as as Paul just said I mean, we're seeing something very different in terms of tissue access distribution and importantly durability when the.

The PNG backbones are added to.

Identical PS PEO molecules, so DMD, where we are why were thinking this.

Could have addressed these issues first of all the in vivo model it.

Targets exon 23, but.

Dave Gallero: Research and development expenses were $28.3 million in the third quarter of 2020, compared to $44.6 million for the same period in the prior year. The decrease in research and development expenses in the third quarter was primarily due to decreased external expenses related to Suva Durson due to our December 2019 decision to discontinue the program, as well as decreased headcount and other external expenses driven by our February 2020 cost reduction plan. Partially offset by increased external expenses related to our clinical and preclinical activities related to our HD programs and our C9-ORF72 program for ALS and FTD. General and administrative expenses were $9.6 million in the third quarter of 2020, compared to $12.5 million in the same period in 2019.

You see a clear difference in terms of tissue in terms of clinical effects in terms of what we're seeing in that model of a PS PEO versus the PM. So clearly we are seeing a difference there that is that is encouraging.

The Pn does team as Paul alluded to earlier.

I'd to introduce a negative I introduced neutral charges to the backbone, which changes the overall.

Potentially affect.

On how that molecule accesses tissues and as I said the durability here is clearly different so may be having it in the tissues longer at higher concentrations with better access.

Could address this this this this change we saw this lack of access that we shall supercenters and so the overall picture here is that there are a lot of characteristics of the molecule and preclinical data that we are seeing that give us hope, but you can only take that so far and with an x. I'm targeting over them.

So targeting a different Exxon and animal and you just need to take it into a human study to really answer that question and we can do that im very efficiently.

As described.

Yes, thanks on that I mean, I think do one or the other as Mike alluded to with the DKL Mouse study and the comparison that together. The piece that was also important was that substantial reduction in dose. So really not just seeing that improvement, but seeing that improvement at 50% less than that FPO drugs. So 75 milligrams per kilogram.

Dave Gallero: The decrease in general and administrative expenses in the third quarter of 2020 was primarily due to the February 2020 cost reduction plan, which included a workforce reduction. We expect that our existing cash and cash equivalents, together with 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, we do not include potential milestones and other uncommitted payments related to our Takeda collaboration in our cash runway. I will now turn the call back over to Paul for closing remarks. Thanks, Dave. I hope you all are sharing in our excitement for what we expect to be a catalyst-rich year ahead, driven mostly by the five clinical trials that we expect will be ongoing in 2020.

And every other week, so not even weekly so I think we see that as important I think we also see good distribution in that model, which is heavily sensitive across cardiac and pulmonary phenotype with distribution to heart and diaphragm. So we're pretty excited about the characteristics. There one other point just to bring backup to alpha one antitrypsin deficiency as you were asking a question.

It is about protein augmentation and it should be noted that therapy that weekly infusions. So in terms of just correcting not just in terms of the hepatic, but also being able to restore the normal protein to the lung being able to move patients off of weekly Ivy administration to real correction of the physiologic protein is something we're pretty excited about bringing forward.

Great. Thank you and looking towards the data update thank you.

Your next question is from the line of money from higher with SVB Leerink.

Dave Gallero: To recap, this quarter, we expect to submit the CTAs for WVE-003 and WVE-004. In the first quarter of 2021, we plan to submit a third CTA for WVE N531. Also in the first quarter, we expect to report data from all cohorts of the PrecisionHD studies, as well as initial OLE data. Finally, we plan to share updates on our AATD program, including data from the humanized model, and I expect we'll have other ADAR editing updates to share as we continue to build this novel platform capability. We are well capitalized to advance our pipeline of potentially transformational programs and realize the value of our platform. And with that, we'll open up the call to questions. Operator. Ladies and gentlemen, if you have a question at this time, please press the star and then the number 1 key on your touchtone telephone. If your question has been answered or you wish to remove yourself from the queue, please press the pound key.

Hi, Good morning. This is Rick on the line for money Congrats on all the progress.

My first question is also on and 531. So I was hoping you can elaborate a little bit more on what you're seeing in the preclinical studies the pn chemistry.

I guess besides tissue access would you would you expect to see any improvements in either tolerability or therapeutic window compared to Super Gerson.

I mean, I'll, let Mike and see I mean, I think is as we alluded one with the distribution, we're seeing it's substantially less dose so half the amount of drug at expanding the time interval out longer we're seeing that those changes in a mouse that had the phenotype and I think thats really important to know because oftentimes we talked.

People talk about Mdx data, where there isn't a phenotype in its purely around the service I think what's exciting about this model for US is that model does have a phenotype, that's being corrected with Exxon 23, skipping compound as Mike said with the PMO chemistry. So we're excited about that in terms of exposure distribution and being able to evaluate that in them.

Model, Mike do you have anything you want to add to that yes, and I would say, we also expect a therapeutic window to be quite different I mean, we're seeing that lower doses given less frequently.

Our leading two effects.

That suggests that there is clearly a difference in that therapy.

Therapeutic window.

As well supported by all of the other preclinical stuff.

Operator: Your first question is from the line of Joon Lee with Truist Security. Hi guys. Thanks for the questions and the updates. I have a couple of questions. For your ADAR program, for the antitrypsin program, number one, what percent of editing would you need to have a therapeutic effect? And could you explain in what way your approach is better or different than the knockdown approach being taken by Onalim and Dyserna? And for the DMV program, can you remind us again how your PN chemistry is able to overcome the tissue access limitations of your prior chemistry, backbone chemistry? Thank you. Thank you, June. And We'll divide this into two parts. And, you know, I'll bring Chandra in a second.

Studies between the molecule. So we would anticipate there being a defense, but obviously until you test that hypothesis in humans.

Don't know, which is why we've decided that the best way to proceed here is to proceed with a study that can be focused.

Focusing on target engagement engagement.

And a small number of patients, but definitive to give us enough information to make that determination whether that use this difference.

Okay got it thanks for that and I have a follow up about a 100 since program similar.

Can you maybe discuss some of the learnings from previous precision HIV. One HIV two that you are bringing with you into the dose escalation of where you are with street.

Do you think you'll be able to.

To start the escalation at a more clinically relevant dose than earlier studies or maybe could you escalate more rapidly than potentially its 282 in the newer study.

Paul B. Bolno: You know, as it relates to ADAR, we're excited about the differentiation as we laid out for bringing an editing approach or a correction approach forward over silencing. And while there's been a lot of excitement around silencing, and we don't discount that on knocking down the mutated protein within the liver. I think when we think about and approach the alpha-1 antitrypsin deficiency... We really approach it from the area of corrections. So that is, how do we fix this point mutation such that we can restore the physiologic balance of the protein, enabling it to treat both the pulmonary as well as the hepatic complications, so the liver and the heart. So this is a key driver for us to drive down the correct.

Mike you want to take that question.

Sure absolutely so.

I think we've learned a lot obviously from precision HD, one and two we've learned.

That.

How to run these studies have engaged community how to find patients I think the important thing here is as I mentioned earlier as we're in a situation where we have.

Where we have in vivo data to help give us a bit more guidance on where we are.

Need to be so we would anticipate.

Therefore, starting at dosing levels that would be more in that window, where we would expect to engage target and a dose escalation scenario driven by.

Paul B. Bolno: As we talk about the heterozygosity of these patients, we do know that a patient is heterozygous, so a 50% correction, so restoration, you know, doesn't manifest a disease. So we think about where the correction needs to be with a physiologic protein between that and 50%, but you don't, by no means, need a 100% correction in terms of restoring normal. Chandra, is there anything you want to add to the ADAR? No, I think you pretty much covered it. Hey, hey, Paul, just to finish the 8R question, assuming both the knockdown approach works as they expect, slowly, and then your approach works slowly, as you expect, by editing, you know, how would you imagine these two approaches manifesting clinically differently? How would it be clinically?

Those in vivo data as well as the data that we're going to be generate an ongoing fashion from the clinical study itself and I think what's very important is this once and once again.

Every molecule that comes out of the prison platform has a different pharmacology.

Has a different different characteristics in vivo and in vitro and that's what's going to guide how we approach.

The next study so when when we when you see the study you'll see there are elements we've adapted.

From our existing studies and you'll also see some pretty meaningful differences that we have.

That have been driven by the pharmacology of the 003 molecule.

I think the other thing just to add to that in terms of identifying patients is within a two year to your point Rick with the ability now to have ongoing studies, where we're screening for sniff the apparatus around the phasing.

Paul B. Bolno: Yeah, so, as we know now, there are the initial therapies that are out in terms of protein replacement to treat pulmonary complications. So there's this augmentation therapy that's out there. And so there's a desire to kind of think about the interchangeability of protein replacement or protein augmentation therapies, as well as now liver correction with Simon. I think we stand to be able to work in both, therefore really correcting and restoring the normal protein, so the wild-type protein, to restore physiologic balance, letting the body use the proteins that it needs for both the lung and the liver, potentially wouldn't require the necessity of silencing or protein replacement therapy.

Where we're able to do that a lot more efficiently now with a practice around the point is that too and also by screening those patients having a good understanding of that three and where those the three patients ourselves as we look at this totality of the three program beyond just.

The three characteristics of the medicine itself the broader infrastructure for clinical trial operations is in place to do this EPS.

Absolutely.

All right great. Thanks for taking the questions.

Thank you Gil.

Your next question is from the line of Selim Sayiid with Mizuho.

Great. Good morning, everybody and thanks for the color guys. Just three from me if I can.

Paul on the precedent trials.

Third quarter call.

You talked about site locked down in Australia, driven half of your size are currently there.

I Wonder if you could just give us an update on what you're seeing with COVID-19 in Australia are you still seeing the Sitelock downs there.

Or are you seeing new patients coming back on into those trials are the ones that you identified and are you close to finishing enrollment.

Paul B. Bolno: And as it relates to DMD, and I'll let Mike continue to answer the question, but subsequently, I mean, as we shared on Research Day, there's a lot of excitement as we think about the in vivo data that we're generating across cell uptake of PNK. We'll talk about this in the context of muscle, obviously, for DMT, but as we just shared today, one can see that transitioning across neurons Mike, do you want to answer the question on DMT? Sure, sure, Paul.

Number two on the going higher than 32 milligrams now that we're getting close to the end of the fourth quarter here.

What does your framework here.

To potentially higher than 32 milligrams, given you don't need all the data from that cohort.

And will you disclose this to the street if you decide to go higher and how will you do that and.

And then just lastly on Fivethirty one DMD.

If you can just give us some color as to whether you plan on keeping 100% of the economics there are partnering up.

Michael Linden: Yeah. So, as Paul just said, I mean, we're seeing something very different in terms of tissue access, distribution, and importantly, durability when the PNs, the backbones, are added to identical PSPO molecules. So DMT, where we are, why we're thinking this, could address these issues. First of all, the in vivo model, it targets exon 23, but you see a clear difference in terms of tissue, in terms of clinical effects, in terms of what we're seeing in that model of a PSPO versus a PN. So clearly, we're seeing a difference there that is encouraging. The PN does seem, as Paul alluded to earlier, introduce neutral charges to the backbone, which changes the overall potentially effect on how that molecule accesses tissues. And as I said, the durability here is clearly different.

Graham out thanks, so much.

Thank you and I'll, let Mike take the first two questions related to HD and then I'll I'll answer your last question on on on DMD, Mike You went up to the questions on each day.

Sure So I.

First of all focusing on there would be environment with Cove. It as we said at the last call. There were locked down so that was clearly having.

Differences, along the way and impacting our ability to recruit and that is a moving target, but I can say that as sites have closed down others have opened up as as Lockdowns and.

Hi to open up again, so weve been actually.

Very fortunate that last time it was at one of the biggest factors was Melbourne. It just shut down opens up and certainly cities and different places are opening and closing I mean, this is an evolving landscape, where but where what's what's been great is that we have really good communication we invest.

Michael Linden: So maybe having it in the tissues longer at higher concentrations with better access could address this change we saw, this lack of access that we saw with Suvidursin. So the overall picture here is that there are a lot of characteristics of the molecule and the preclinical data that we are seeing that give us hope. But you can only take that so far with an exon targeting gene or with an IASO targeting a different exon in an animal.

The Gators so we can anticipate when these things are happening and then redirect if necessary, but right now with the way we're headed none of that has impacted our ability to have the data readout in the first quarter, which is what we are reaffirming.

We're going to have.

Today in terms of the.

Framework to go higher.

You know with being one quarter away from the definitive multi dose read out at this point, we thought it made just makes the most sense to wait to see that dataset.

Paul B. Bolno: And you just need to take it into a human study to really answer that question. And we can do that very efficiently, as described. Yeah, just to follow up on that. I mean, Joon, one of the other things, as Michael alluded to, with the DKO mouse study and the comparison, I think the other piece that was also important was that substantial reduction in dose. So really, you know, not just seeing that improvement but seeing that improvement at 50% less than that PSPO drug, so 75 milligrams per kilogram and every other week, so not even weekly. So I think we should see that as important. I think we also see, you know, good distribution in that model, which is heavily sensitive across cardiac and pulmonary, with distribution to the heart and diaphragm.

In terms of degree of knockdown in terms of the overall profile of the product before making that decision I mean, we can as we've said previously we have the therapeutic window, we have the.

The ability to to to go higher from a preclinical perspective of being so close to the definitive read out. We just thought it was best to wait for that at this time, so thats, where we are with that.

And then I'll pass it back to Paul the question about the partnering.

And just I mean, and as a means to wrap up on HD I mean, we're excited about getting to this data readout I mean as you know we provided updates if there are any changes that impacted the updates to the readout timing and we remain on track for the first quarter 2021 data readout as far as DMD and the percent of economic I think this is something that we thought very carefully about.

Paul B. Bolno: So we're pretty excited about the characteristics there. One other point just to bring back to alpha-1 antitrypsin deficiency is that you were asking questions about protein augmentation. And it should be noted that that therapy is a weekly IV infusion. So in terms of just correcting, not just in terms of the hepatic, but also being able to restore the normal protein to the lung, being able to move patients off of weekly IV administration to real correction of the physiologic protein is something we're pretty excited about. Great

Around where and how to partner I say often partner because you required the the financial means to deliver on the data or you need to leverage them sort of operating capability or capacity to deliver that and I think what the team's done and where we are is we can deliver this study that Mike laid out today.

Within within our runway and therefore, I think it's important for us to continue to generate that data for both the platform and this particular program specifically and for right now retain 100% of the economics as we push forward, but as anything it's something that we'll continue to evaluate as we move that program forward.

Super helpful. Thanks, So much guys.

Paul B. Bolno: Thank you. I'm looking forward to the data updates. Thank you, guys. Your next question is from the line of Mani Foroohar with SVB Larynx. Hi, good morning. This is Rick on the line for Mani.

Your next question is from the line of Paul Matteis with stifle.

Hey, Thanks for taking the question. This is Alexandre Paul just a couple on your HDD program.

First I was just curious you did.

Michael Linden: Congratulations on all the progress. My first question is also about N531, so I was hoping you could elaborate a little bit more on what you're seeing in preclinical studies with the PN chemistry. And I guess, besides tissue access, would you expect to see any improvements in either tolerability or therapeutic window compared to subadderson?

Elaborate on how what proportion of the disease that you guys have that GE to eight mutation the land and then along with that curious if you could talk a little bit more about I am the rationale for the eight our strategy and its ability to allow for that physiologic regulation of 18. Thanks. So much.

Yeah, No great question, it's something we focused and.

About 5% to 15% I know, that's a reasonable range.

Patients who are amenable so our number on the 250000 patients are the anticipated estimated patient population worldwide to 250000 patients worldwide that are amenable to the direction of this mutation.

Michael Linden: I mean, I think, as we alluded to, one, with the distribution, we're seeing it's substantially less dose, so half the amount of drug. Expanding the time interval out longer, we're seeing those changes in a mouse that has a phenotype. And I think that's really important to know, because oftentimes, we talk about MDX data where there isn't a phenotype, and it's purely around disturbance. So I think what's exciting about this model for us is this model does have a phenotype that's being corrected with this exon 23 skipping compound, as Mike said, with the... So we're excited about that in terms of exposure distribution and being able to evaluate that in the model. Mike, do you have anything you want to add to that?

I think we stayed focused on this concept of correction around bringing kind of that the concept around physiologic regulation meeting restoring and so by correcting the transcript therefore, not knocking it out but allowing for the production of a wild type protein that thing can be used as a physiologically required so oftentimes it's known.

Since it began engaging elastase, along which can result from injury in the lung to activating and acquiring this protein by having that protein around enables it to be responsive as it would be under normal circumstances. So I think the exciting aspect to bring this program is really bringing a different way of thinking about the treatment of the disease, which is one around correction, but not take.

The way things have mutant protein and or requiring weekly ivy protein augmentation therapy, but rather restoring physiologic balance through the correction of the transcript, which is really the hallmark of our an additive. So we're excited about this space and brought more broadly we're excited about what it means as we think about different diseases in aydar as a platform. So we do look.

Michael Linden: Yeah, and I would say we also expect a therapeutic window to be quite different. I mean, we're seeing that lower doses given less frequently are leading to effects that suggest that there's clearly a difference in that therapeutic window, as well as being supported by all the other preclinical studies between the molecules. So we would anticipate there being a difference, but obviously until you test that hypothesis in humans, you don't know, which is why we've decided that the best way to proceed here is to proceed with a study that can be focused, focusing on target engagement in a small number of patients, but definitive to give us enough information to make that determination whether there is a difference. All right, got it. Thanks for that!

That obviously.

He is a initial therapeutic approach, but I think when we step back and say what are we learning about aydar, we're investing and building. This proprietary model that will now let us be able to cross it with multiple diseases and look at the human eight our enzyme in the context of disease, we build a model for therapeutic program I think we think much more broadly.

About.

About the treatment that could be possible with Apple and interesting deficiency.

Thanks, so much.

Your next question is from the line of Bill gain with Jefferies.

Thank you I have more.

Hello, Tim a question to sell on.

Michael Linden: And I have a follow-up question about Huntington's program. Could you maybe discuss some of the learnings from Precision HD1 and HD2 that you're bringing with you into the dose escalation of WAVE-003? Do you think you'll be able to, you know, start at an escalation at a more clinically relevant dose than the earlier studies? Or maybe you could escalate more rapidly than Precision HD1 and HD2 in the newer study? Mike, do you want to take that question?

HDD program as we expected data in the first quarter of next year.

Hypothetically, if we you see similar.

H.T.K. reduction at 32 milligram has.

What you saw at 16.

When do you make a go no go decision at that point or still pursue a higher.

I think thats exactly to Mike's point, what we want to stay focused on in terms of analyzing the data so being data driven there's a variety of biomarkers to look at ascertain at that point do we believe going higher will be there are we at that dose because as we as we think about that that that thats a point I think if we see.

Michael Linden: Yeah, sure, absolutely. So, you know, I think we've learned a lot, obviously, from PrecisionHD 1 and 2. We've learned how to run these studies, how to engage the community, how to find patients. I think the important thing here is, as I mentioned earlier, we're in a situation where we have in vivo data to help give us a bit more guidance on where we need to be. So, we would anticipate, therefore, starting at dosing levels that would be more in that window of where we would expect to engage the target, and a dose escalation scenario driven by those in vivo data, as well as the data that we're going to be generating in an ongoing fashion from the clinical study itself. I think what's very important is this, once again, every molecule that comes out of the PRISM platform has a different pharmacology, has different characteristics in vivo and in vitro, and that's what's going to guide how we approach the next study.

Applied telling there's there's a variety of other biomarkers to assessed as part of that clinical data and we will have to do that in the first quarter. Once we have that data.

Mike any any additional thoughts no nothing nothing else that Paul I mean, we have a lot of things we are going to be looking at salads and not the least of which is.

What is meaningful in this in this setting a very specific.

Knock down as opposed to Pan and selective switches is different they have to be looked at differently and that will all be part of the conversation.

But I think in in terms of having tools for the LTL selective therapy as one advantage of why we're not gating business threesome WV 003 on that readout. So were excited about driving that program forward independently because we do believe in essence. This affiliate selective approach the data that we're seeing in the literature continues to grow.

And wild type sparing and.

And so we'll have other programs to to be able to assess that but we'll have to look at the totality of the data in the first quarter yes.

Yeah. That's helpful. My till then last question is on DMD program I assume 53 candidates.

So in in vitro model, yes.

You saw it does it depend on to increase in dystrophin production up to 70% of the normal and I understand that how we improve it to ability and tissue penetration.

How much can you extrapolate from.

Michael Linden: So, when you see the study, you'll see there are elements we've adapted from our existing studies, and you'll also see some pretty meaningful differences that have been driven by the pharmacology of the 003 molecule. I think the other thing just to add to that in terms of identifying patients is, to your point, Rick, with the ability now to have ongoing studies where we're screening for SNPs, the apparatus around SNP phasing, we're able to do that a lot more efficiently now with the practice around SNP1 and SNP2, and also by screening those patients, and having a good understanding of SNP3 and where those SNP3 So as we look at the totality of the SNP3 program beyond just, you know, the Broad Infrastructure for Clinical Trial Operations is in place to do this. All right, great.

The same vitro study data to wide you could realistically expect impairments.

I think we're going to reserve speculation from the in vitro studies I think we see substantial dystrophin production with the with the candidate Thats going to be tested in the clinic that gives us a lot of confidence on dystrophin production in the preclinical data supporting exposure I think coupling that with the detailed data which is.

You have a phenotype that you can correct and restore I think that gives us confidence that indeed, we are getting into dystrophic muscle and having an impact granted with the 23 molecule, but in vivo data at lower doses less frequently which give us.

Give us confidence I think this study that Mike laid out that we're going to be pursuing is measured for that exact reason I think we are where we.

Disciplined after our suitors and experience that we do need to see what happens in the DMD boys.

And we've had a lot of conversations with the community having seen the data who are extraordinarily supportive of our profit this approach and the data that weve generated but we need to generate that data and we're excited to be able to do that Mike I don't know thank you Andy I would add to that yes, no. The only thing I would add that high I think as you captured nicely.

Michael Linden: Thanks for taking our questions. Thank you. Thank you. Your next question is from the line of Salim Syed with Mizzou Host. Great. Good morning, everybody. Thanks for the call, guys. Just three from me, if I can.

This entire that entire DMD space is.

His unfortunately lots of disappointment about what what what can translate pre clinically to clinically we have a lot of evidence that suggests that we have something here that could be different but really the best way is to get it into human beings take a look.

Paul B. Bolno: Paul, on the precision trials, and on the second quarter call, we talked about site lockdowns in Australia, given half of your sites are currently there. I was wondering if you could just give us an update on what you're seeing with COVID-19 in Australia. Are you still seeing site lockdowns there?

Judiciously as we execute the study in a way that allows us to assess that profile and make determinations of next steps that we felt that was the most responsible way to proceed.

Paul B. Bolno: Or are you seeing new patients coming back into those trials, the ones that you identified? And are you close to finishing enrollment? Number two, on going higher than 32 mg. Now that we're getting close to the end of the fourth quarter here, what is your framework here to go potentially higher than 32 mg given you don't need all the data from that cohort, and will you disclose this to the street if you decide to go higher, and how will you do that? And then, lastly, on 531 DMD. If you can just give us some colors as to whether you plan on keeping 100% of the economics there or partnering that program out. Thanks so much.

Okay. Thank you very much attention.

Your next question is from the line of Darren Werber with Cowen.

Hi, guys just Brendan on for your own thanks, very much for taking on the question just a couple of quick ones from Us I guess.

First an HD I just wanted to check in on the Wild type Huntington ethane fee was this Dan I know in the past there has been talk of maybe some.

Update to the asset itself just to make sure you're really able to see differences and kind of illegal sparing affecting just kind of I just wanted to check in on that and then for DMD.

Paul B. Bolno: No, thank you. And I'll let Mike take the first two questions related to HD, and then I'll answer your last question about DMV. Mike, do you want to answer the questions in HD? Oh, sure. So I'm, first of all, focusing on the environment with COVID. As we said at the last call, there were lockdowns that were clearly having differences along the way and impacting our ability to recruit. That is a moving target. But I can say that, you know, as sites have closed down, others have opened up. As lockdowns end, sites open up again. So we've been actually very fortunate that, you know, last time it was, one of the big factors was Melbourne. It just shut down. Melbourne's up.

As as we're kind of looking across the space, obviously between the exon skippers. Unlike gene therapy. For example, we're seeing kind of different.

Besides different mechanism just different results here, so just kind of trying to get your thoughts on where Youre bar is for this phase one are you really hoping to see.

Level of protein restoration, or maybe improve on and I'd say that we've seen with gene therapy or are you really aiming for the bar close.

Closer to where we stand with exon skipping asked us. Thanks.

Excellent I mean, I've a short answer on the on the first question as we continue to do the work as we alluded to earlier on the wild type assay and we anticipate and we're working hard to deliver that with our data in the first quarter. We do we agree that in an important way of driving have driving that assessment as it relates to.

Michael Linden: And certainly, cities in different places are opening and closing. I mean, this is an evolving landscape where, but where, what's, what's been great is that we've had really good communication with the investigators so we can anticipate when these things are happening and then redirect if necessary. But right now, with the way we're headed, none of that has impacted our ability to have the data readout in the first quarter, which is what we're reaffirming we're going to have today. In terms of the framework to go higher, you know, with being one quarter away from the definitive multi-dose readout, at this point, we thought it may just make the most sense to wait to see that data set. In terms of degree of knockdown, in terms of the overall profile of the product before making that decision.

To the bar I think what we're excited about now is restoring dystrophin and having an impact. This study is initially anticipated is not a clinical outcome study for that right now looking at this in the context of.

That would be something that would follow up as you pointed out the NFC and other metrics that's something that we could continue to follow I think the first question. We want to ask is this trophic muscle exposure dystrophin production and safety those are the key drivers to give us.

Sense moving forward and we're excited about the prospects based on the preclinical work, but we also want to be really measured on where we are I think if we see what we're seeing in the DKL mouse, which is your view these mice that should actually not be living.

We're restoring a survival phenotype in them and Thats not just about skeletal muscle and I think one nuance that we are excited about with the prospects of the addition to Pn chemistry now is exposure to heart diaphragm. So these might have the full phenotypes and are dying from cardiac and respiratory complications so the ability to access both those other tissues.

Michael Linden: I mean, as we've said previously, we have the therapeutic window, we have the ability to go higher from a preclinical perspective, but being so close to the definitive readout, we just thought it was best to wait for that at this point. So that's where we are with that. And then I'll pass it back to Paul for the question about, um, the park.

Beyond skeletal muscle is really what excites us about this program and at the dosing intervals and doses that were using so I think there's a lot to be excited about to go forward, but again. This first study is about that measured approach to assessing that middle part Mike is there anything you want to add to either of those points no nothing to add to that thanks bye.

Great. Thanks, guys.

We'll take our next question is from the line of Luca Issi with RBC capital.

Terrific. Thanks for taking my questions and congratulation on all the progress here I have two quick one for me on one it was my understanding that all five studies that are ongoing in 2021 will be actually ex US one is that correct. Two if so are you planning to open a 90 day you exploration program.

Michael Linden: And just, I mean, to wrap up on HD, I mean, we're excited getting to this data readout. I mean, as you know, we provided updates if there were any changes that impacted the updates to the readout timing, and we remain on track for the first quarter. As far as DMD and the percent of economics, I think this is something that we thought very carefully about around where and how to partner. I say you often partner because you require the financial means to deliver on the data, or you need to leverage some sort of operating capability or capacity to deliver that.

And how should we think about timeline there too I think our youngest showed their initial data for sod one ill EPS was actually more impressive for fast Progressors. How do you expect the same pristine nine and if so are you planning to enrich your trials for such patients. Thank you.

Thank you for your questions Mike do you want to take the question sure. Yes. So regarding your first question about where we are conducting the study design.

Paul B. Bolno: And I think what the team did and where we are is we can deliver this study that Mike laid out today within our runway, and therefore, I think it's important for us to continue to generate that data for both the platform and this particular program specifically, and, for right now, retain 100% of the economics as we push forward. But as anything, it's something that we'll continue to evaluate as we move that program forward. Super helpful. Thanks so much, guys. Your next question is from the line of Paul Mattheis with Stifle. Hey, thanks for taking the question. This is Alex on for Paul, just a couple on your ATD program.

It is our intention for I mean as you as you know position actually one precision HD too we have some.

Sites in us and we have some sites outside the U.S.

So on multi dose is outside the us as we've always talked about so.

Regarding our other programs, we anticipate that these are going to be global studies I.

I mean, we anticipate conducting these studies.

In the us.

Except for in 531, as we've already said will be just a small proof of concept study X.

Ex U.S, so I would so.

That is our intention we're very optimistic that we'll be able to do that regarding.

Paul B. Bolno: First, I was just curious if you could elaborate on what proportion of the ZZ homozygous have that G to A mutation, and then, along with that, curious if you could talk a little bit more about the rationale for the ADAR strategy and its ability to allow for that physiologic regulation of AAT. Thanks so much. Yeah, no, great question. It's something we focused on and, you know, about five to 15%. I know that's a reasonable range for our patients who are amenable. So our number of 250,000 patients is the anticipated estimated patient population worldwide.

The second question.

Which was again.

I was I was just wondering about sod one I think are you on its shell are yet to start.

Yes go ahead Im sorry, yes, no. Thank you now sorry, yes, so we'll give more details of the of the study design early.

Early next year, but what I can say is that I mean, one thing about nine or 72 disease in a less patients. It is a fairly rapidly progressive they.

They progress it a little more rapid rate than other.

Groups today less patients so.

That's going to be something that's going on that will just be a factor of the population itself. The way we're approaching our cnine. Our 72 program is really focusing on.

Paul B. Bolno: So 250,000 patients worldwide that are amenable to this. I think we've stayed focused on this concept of correction around bringing the concept of physiologic regulation, meaning restoring, and so by correcting the transcript, therefore not knocking it out, but allowing for the production of a wild-type protein that then can be used as it is physiologically required. So oftentimes, it's known that since it's engaging elastase in the lung, which can result from injury in the lung to activating and acquiring this protein, by having that protein around enables it to be responsive as it would be under normal circumstances.

See nine disease. If you well these are patients that could at Alice ticketed FTD. They can have the overlap condition, which is actually.

Certainly not was not unusual and that we are really looking to target the disease itself at its origins in both population focusing on a biomarker readout.

That will allow US then to make those decisions on how we progressed clinically so thats how were approaching it again, we're pushing it as a single rapidly progressive devinder focused on target engagement.

At the biomarker level.

Great.

Terrific. Thanks, guys. Thank.

Thank you.

I am showing no further questions at this time I would now like to turn the conference back to Dr. Paul Bono.

Paul B. Bolno: So I think the exciting aspect of this program is really bringing a different way of thinking about the treatment of the disease, which is one around correction, but not taking away a mutant protein or requiring weekly IV protein augmentation therapy, but rather restoring physiologic balance through the correction, really the hallmark of RNA editing. So we're excited about this space. And more broadly, we're excited about what it means as we think about different diseases in ADAR as a platform. So we do look at this, you know, obviously, AATD is an initial therapeutic approach. But I think when we step back and say, what are we learning about ADAR, we're investing in building this proprietary model that will now let us be able to cross it with multiple diseases and look at Adar Enzyme on the Continent, build models for therapeutic programs, I think we think, you know, much more broadly about the treatment that could be possible with um... Thanks so much.

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

Ladies and gentlemen. This concludes today's conference. Thank you for your participation and have a wonderful day you may all disconnect.

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Paul B. Bolno: Your next question is from the line of Eun Yang with Jeffrey. Thank you. I have more speculative questions.

Paul B. Bolno: So on the HD program, as we expect the data in the first quarter next year, hypothetically, if you see similar mutant HTT reduction at 32 mg as what you saw at 16, would you make a go, no-go decision at that point or still pursue a higher dose? I think that's exactly, to Mike's point, what we want to stay focused on in terms of analyzing the data. So, being data-driven, there are a variety of biomarkers to look at and ascertain at that point, you know, do we believe going higher will be there? You know, are we at that dose? Because, you know, as we think about that, you know, that's a point. I think, you know, if we see a plateauing, there are a variety of other biomarkers to assess as part of that clinical data outcome, and we'll have to do that in the first quarter once we have that data. Mike, any... No, nothing else to add, Paul. I mean, we have a lot of things we're going to be looking at, not the least of which is what's meaningful in this setting of very specific knockdown as opposed to hand-selective, which is different. They have to be looked at differently, and that'll all be part of the conversation.

Paul B. Bolno: But I think in terms of having tools for the allele selective therapy, it's one advantage of why we're not gating the SNP3, the WV003 on that readout. So we're excited about driving that program forward independently because we do believe in this and, you know, this allele selective approach, the data that we're seeing in the literature continues to grow in wild type sparing. And so you know, we'll have other programs to be able to assess that. But we'll have to look at the totality of, Yeah, that's informative. And the last question is on the DMD program, Exon 53 Candid. So in a virtual model, you saw a dose-dependent increase in dystrophin production up to 70% of normal. And I understand that with improved durability and tissue penetration. Can you extrapolate from this in vitro study data to what you could realistically expect in humans?

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Paul B. Bolno: I think we're going to have to reserve speculation from the in vitro studies. I think we see substantial dystrophin production with the candidate that's going to be tested in the clinic. That gives us a lot of confidence about dystrophin production. I think coupling that with the DKO data, which is, you know, here you have a phenotype that you can correct and restore, I think that gives us confidence that, indeed, we are getting into dystrophic muscle and having an impact with the 23 molecule. But in vivo data, at lower doses, less frequently, which gives us...

Paul B. Bolno: I think the study that Mike laid out that we're going to be pursuing is measured for that exact reason. I think we're, you know, being disciplined after our subadderson experience that we do need to see what happens in the DMD voice. And you know, we've had a lot of conversations with the community, having seen the data, who are extraordinarily supportive of this approach and the data that we've generated. But we need to generate that data, and we're excited to be able to do that. Mike, I don't know if you have anything you want to add to that.

Michael Linden: Yeah, no, the only thing I would add, I think, as you captured nicely, this entire DMD space is unfortunately full of lots of disappointment about what can translate pre-clinically to clinically. We have a lot of evidence that suggests that we have something here that could be different, but really, the best way is to get it into human beings, take a judiciously look at, you know, we conduct this study in a way that allows us to assess that profile and make determinations about next steps. We felt that it was the most responsible way to go.

Michael Linden: Okay, thank you very much. Thank you. Your next question is from Yaren Werber with Cowan. And then for DMD, you know, as we're kind of looking across the space, obviously between the exon skippers and like gene therapy, for example, we're seeing kind of different, besides different mechanisms, just different results here. So just kind of trying to get your thoughts on where your bar is for this phase one. Are you really hoping to see a level of protein restoration or maybe improvement on NSA that we've seen with gene therapy? Or are you really aiming for the bar closer to where we've seen with exon skipping ASOs?

Paul B. Bolno: Thanks. Excellent I mean, a short answer to the first question is, you know, we continue to do the work, as we alluded to earlier, on the wild-type assay, and we anticipate and we're working hard to deliver that with our data in the first quarter. We agree that it's an important way of driving that assessment. As it relates to the BAR, I think what we're excited about now is restoring dystrophin and having an impact. This study, as it's initially anticipated, is not a clinical outcome study. We're not, you know, we're not right now looking at this in the context of, That would be something that would follow up, you know, as you just pointed out, the NSA and other metrics; that's something that we could continue to follow. I think the first question we want to ask is dystrophic muscle exposure, dystrophin production, and safety. You know, those are the key drivers to give us direction.

Paul B. Bolno: We're excited about the prospects based on the preclinical work, but we also want to be really measured on where we are. I think if we see what we're seeing in the DKO mouse, which are these mice that should actually not be living, we're restoring a survival phenotype in them, and that's not just about skeletal muscle.

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Paul B. Bolno: And I think one nuance that we are excited about with the prospect of the addition of PN chemistry now is exposure to heart and diaphragm. So these mice have the full phenotypes and are dying from cardiac and respiratory complications. So, the ability to access both those other tissues beyond skeletal muscle is really what excites us about this program, and at the dosing intervals and doses that we're using.

Paul B. Bolno: So, I think there's a lot to be excited about going forward, but again, this first study is about that measured approach to assessing that. And I'll pause. Mike, is there anything you want to add to either of those points? No, nothing to add to that.

Paul B. Bolno: Great. Thanks, guys. Your next question is from the line of Luca Issi with RBC Capital.

Paul B. Bolno: Oh, terrific. Thank you for taking my questions and congratulations on all the progress here. Two quick ones for me.

Michael Linden: One, it is my understanding that all five studies that are ongoing in 2021 will be ex-U.S. One, is that correct? Two, if so, are you planning to open an IND in the U.S. for any of the programs? And how should we think about timelines there? Two, I think IONIS showed that their initial data for SOD1 ALS was actually more impressive for fast progressors. Do you expect the same for C9?

Michael Linden: And if so, are you planning to enrich your trials for such patients? Thank you. Thank you for your questions. Mike, do you want to take the question?

Michael Linden: Sure, yeah. So regarding the first question about where we're conducting the studies, it is our intention for, I mean, as you know, Precision HD1, Precision HD2. We have some sites in the US, and we have some sites outside the US.

Michael Linden: So multi-dose is outside the US, as we've always talked about. So regarding our other programs, we anticipate that these are going to be global studies. And we anticipate conducting these studies in the US, except for N531, which as we've already said, will be just a small proof of concept study outside the US.

Michael Linden: So that is our intention. We're very optimistic that we'll be able to do that. Regarding the second question, which was, again, I was just wondering about SOD1, I think Ionesh mentioned it.

Michael Linden: Oh, yeah. Yeah. Go ahead. I'm sorry. Yeah, no, thank you. No, sorry about that.

Michael Linden: Yeah, so we'll give more details of the study design early next year, but what I can say is that, I mean, one thing about C9-ORF72 disease in ALS patients is that it is fairly rapidly progressive. They progress at a little more rapid rate than other groups of ALS patients. So that's going to be something that will just be a factor of the population itself.

Michael Linden: The way we're approaching our C9-ORF72 program is really focusing on... C9 disease, if you will. These are patients, they could have ALS, they could have FDD, they can have the overlap condition, which is actually fairly common, and we are really looking to target the disease itself at its origins in both populations, focusing on a biomarker readout that will allow us then to make those decisions about how we progress clinical So that's how we're approaching it. Again, we're approaching it as a single, rapidly progressive syndrome focused on target engagement at the biomarker. Terrific. Thank you, guys. Thank you. I am showing no further questions at this time. I would now like to turn the conference back to Dr. Paul Bolno.

Paul B. Bolno: Thanks, everyone, for joining the call this morning to review our third quarter update. And thanks to our employees for their hard work and commitment to patients. We look forward to speaking with you all again soon. Have a nice day. Thank you. Ladies and gentlemen, this concludes today's conference. Thank you for your participation and have a wonderful day. You may all disconnect. ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? www.wavelife.com.au, ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ?? ??

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