Good morning, and welcome to the Wave Life Sciences First Quarter 2021 Financial Results Conference Call. At this time, all participants are in listen only mode. As a reminder, this call is being recorded and webcast. I will now turn the call over to Kate Rausch, Head of Investor Relations at Wave Life Sciences, p lease go ahead. Thank you, operator. Good morning, thank you for joining us today to discuss our recent business progress and review Wave's first quarter 2021 operating results. On the call with me today is Dr. Paul Bolno, Wave's President and Chief Executive Officer, Dr. Mike Panzara, Chief Medical Officer, Head of Therapeutics Discovery and Development, and Kyle Moran, Chief Financial Officer. This morning, we issued a news release detailing our first quarter financial results and provided a business update. This news release and a slide presentation to accompany this webcast are available in the investors section of our website, www.wavelifesciences.com. 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 are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31st, 2020. We undertake no obligation to update or revise any forward-looking statements for any reason. I'd now like to turn the call over to Paul, Paul? Thanks, Kate. Good morning to everyone on the call, and thank you for joining us. During the call today, I will provide some opening remarks, after which Mike will give an update on our clinical trials and Kyle will briefly review our financials. It has been an incredibly productive start to the year for Wave as we advance three next-generation stereopure oligonucleotides into clinical development. We have formally initiated clinical trials for WVE-004, our C9orf72 candidate in ALS and FTD, and WVE-003, our SNP3 candidate in Huntington's disease. We've also received important regulatory approvals towards initiating our third PN chemistry program targeting exon 53 in DMD, WVE-N531. These clinical trials are designed to enable rapid proof of concept using biomarker driven adaptive designs and are the first investigative candidates designed with our novel PN backbone chemistry modification. Next year, we expect that data from these clinical trials will enable decision-making about next steps for these programs, as well as provide insight into PN chemistry across different modalities, tissue types, and targets. We've also made substantial progress with our endogenous ADAR editing capability, which we believe is the most advanced in its class. We have generated a breadth of RNA editing data demonstrating activity across in vivo and in vitro systems, including in vivo editing in the central nervous system. Much of this data is being presented in an oral presentation tomorrow, May 14th at the ASGCT annual meeting. Our first ADAR editing program for alpha-1 antitrypsin disease has generated promising initial results, and we are on track to share in vivo data this quarter. Our PRISM platform is unique and differentiated from others developing RNA therapeutics. At our foundation, we set out to embrace rather than ignore the reality and importance of stereochemistry that exists in each and every oligonucleotide. In choosing to control for the three-dimensional orientations of backbone linkages and advance single isomer therapeutics, we can apply the principles of rational drug design to our pipeline candidates, which is impossible with mixture-based oligonucleotides. This resolution enables us to define distinct profiles for our stereopure molecules, and we now have several years of clinical data to further inform our platform. Earlier this year, we announced the discontinuation of our remaining first-generation programs following the results of the PRECISION-HD trials. While we only saw modest and inconsistent reductions of mutant huntingtin, it is important to note there were no clinically meaningful trends in disease progression or laboratory values such as elevations in CSF, white blood cells, proteins, and neurofilament light chain or NfL. There were, however, suggestions of allele selectivity underscoring the precision enabled by our platform. In our next generation programs, we have prioritized the use of in vivo models during preclinical development to ensure we advance clinical candidates that will reach the desired site of action and engage targets. In addition to the wealth of data collected over the past several years, we are also leveraging an influx of new talent in oligonucleotide therapeutics to further advance our understanding of design principles, pharmacology, and toxicology. The application of PN backbone chemistry modifications in the context of controlling stereochemistry was a major advancement that emerged from our platform, and based on what we have seen preclinically, this innovation has the potential to significantly improve the profiles of therapeutic oligonucleotides independent of sequence, tissue type, or modality. Separately, our ADAR editing capability further expands our toolkit beyond silencing and splicing, enabling us to select the best modality to address the root cause of genetic diseases. We anticipate sharing more on PN chemistry and ADAR editing at a research day later this year. Our current pipeline is comprised of programs designed with next generation of PRISM, including PN chemistry. I'm extremely proud of how quickly we have advanced this innovation to the clinic, and we are rapidly approaching the first of many opportunities for clinical proof of concept of PN chemistry. I'd now like to turn the call over to Mike Panzara for an update on our neurology programs, Mike? Thanks, Paul. The foundational work that has been done throughout the evolution of PRISM has provided us with a diverse and robust neurology-focused portfolio that is currently moving through stages of preclinical discovery and clinical development as illustrated here. As Paul just mentioned, all of our current discovery stage and preclinical programs utilize PN chemistry, including the multiple discovery programs in collaboration with our partner, Takeda. These programs are yielding exciting results, including target engagement and distribution in the central nervous system of non-human primates, which further validate our approach. Our therapeutics discovery portfolio continues to build upon this progress to maximize the potential of oligonucleotide therapeutics for the treatment of neurological disorders with high unmet need. Now I'd like to discuss the programs currently in clinical development with three next-generation candidates. Our development organization is focused on site activation and initiating dosing simultaneously in three clinical trials across four disease area. C9orf72-associated amyotrophic lateral sclerosis, or ALS, and frontotemporal dementia, or FTD, with WVE-004 at repeat expansions, Huntington's disease with [guess] Duchenne muscular dystrophy with WVE-N531, our exon 53 skipping candidate. Each of these clinical candidates incorporates PN chemistry, and the availability of relevant preclinical models has enabled a greater understanding of PK/PD relationships to guide development. Further, the learnings from our first-generation programs are being incorporated to mitigate risk and more efficiently execute our plans. Starting with C9orf72, our clinical candidate, WVE-004, is designed to target a hexanucleotide repeat expansion in the C9orf72 transcript, which is one of the most common genetic causes of ALS and FTD. These expansions drive the common pathophysiology underlying these two diverse and devastating phenotypes. WVE-004 is the first C9orf72 candidate being advanced simultaneously in a single basket-like study for both C9 ALS and C9 FTD. C9orf72 mutations lead to multiple drivers of toxicity. The hexanucleotide repeat-containing RNA transcripts deposit in tissues and are toxic on their own. They are also translated into long dipeptide repeat proteins, or DPR proteins, that trigger cellular toxicity through a variety of downstream mechanisms. WVE-004 selectively targets the pre-mRNA or RNA transcripts that contain the hexanucleotide expansion, with the goal of suppressing both the RNA and DPR-associated toxicities while allowing C9orf72 protein expression. In the first quarter, our foundational work to identify and validate the targeting site used to achieve this selective knockdown was published in "Nature Communications." On the right of slide 11, you can see the preclinical data that demonstrates WVE-004's ability to rapidly and durably reduce over 90% of the DPR poly(GP) in the spinal cord and reduce at least 80% of poly(GP) in the cortex. This effect lasted at least six months only after two ICV injections of WVE-004 administered seven days apart at the start of the study. C9orf72 protein was unchanged over the same period. The effect of WVE-004 on poly(GP) in the CSF is a key endpoint in our clinical study. We are looking forward to assessing the impact of treatment in humans, given these promising preclinical results. These results, along with data from non-human primates, have also allowed us to start at a dose in our clinical trial predicted to be pharmacologically active. This week at the European Network to Cure ALS virtual meeting, or ENCALS, we introduced FOCUS-C9, an adaptive trial that is designed to enable faster optimization of dose and frequency of WVE-004 based upon review of unblinded data throughout the study. FOCUS-C9 is a phase I-B/II-A global, multicenter, randomized, double-blind, placebo-controlled trial in which we are planning to enroll approximately 50 patients with documented C9orf72 expansions and confirmed ALS, FTD, or mixed phenotypes. FOCUS-C9 includes single and multiple ascending dose portions of WVE-004 administered intrathecally. At points throughout the study, based upon predefined data-driven milestones, an independent committee will review unblinded data to determine next single dose level to be escalated to, and the optimal frequency in the next multi-dose cohort, meaning whether the dosing interval should be monthly or less frequent. Samples are collected for biomarker analysis at multiple time points within both the single and multi-ascending dose portions to enable the assessments required to make these recommendations. Regulatory and ethics approvals have been received, and clinical site activation is underway, so we anticipate dosing sometime soon. I'll now turn over to WVE-003, our allele-selective candidate for Huntington's disease, which is designed to selectively lower mutant huntingtin while preserving wild-type huntingtin. The presentations, posters, and feedback from experts at the recent virtual CHDI HE Therapeutics Conference only serve to bolster our confidence that we are pursuing the right approach to Huntington's. Let's review what we know. Patients with Huntington's disease have an expanded CAG repeat in their huntingtin gene that leads to production of mutant huntingtin protein. This is a monogenic, autosomal dominant genetic disease that is fully penetrant and affects the entire brain. Preserving wild-type huntingtin is as important as lowering mutant huntingtin. Evidence supports that Huntington's disease is driven by both the gain of function of mutant huntingtin protein and the loss of function of wild type protein, which is essential for homeostasis of the central nervous system. Wild type protein is critical for the protection of neurons that are under stress and plays a key role in trafficking synaptic proteins and vesicles, including the production and transport of brain-derived neurotrophic factor, or BDNF, in the cortex. Wild type protein is also critical for the formation and function of cilia, which control the flow of CSF and help maintain CNS homeostasis. In healthy individuals, these important functions of wild type huntingtin balance out the collective stresses placed on the central nervous system. However, in the case of HD, there is the added burden of the mutant protein itself. Those living with HD have been subjected to decades of toxic stress that come with mutant huntingtin protein years prior to symptom onset. Looking at levels of wild type in healthy individual or models that lack the effect of mutant protein does not adequately represent the role the healthy protein plays in the context of Huntington's disease. This smaller protective reservoir of wild type huntingtin eventually loses the battle to the expected stresses placed on the CNS, along with the toxic effects of mutant huntingtin, resulting in disease progression. If one thinks about this as a push-pull of positive and negative factors in this balance of wild type and mutant huntingtin in the CNS, it stands to reason that depletion of wild type protein along with mutant protein, as with non-selective approaches, could shift the balance towards disease progression, erasing any benefit or even potentially accelerating decline. This has been our hypothesis since we began our HD program. The data that are emerging support our position and make us resolute in our differentiated approach to treating this disease. WVE-003 has been improved over our prior SNP-targeting candidates by applying PN backbone chemistry modifications in the context of control over stereochemistry. The presence of this SNP in a relevant animal model has allowed us to do in vivo preclinical work to determine a dose predicted to be pharmacologically active right from the start of first cohort. Slide 16 illustrates some of these in vitro and in vivo data, demonstrating that WVE-003 is highly selective for mutant huntingtin and able to achieve potent and durable knockdown of mutant huntingtin in vivo in the BACHD mouse model. We investigated this model knowing that there were several limitations, including the fact that it contains multiple copies of the mHTT gene, some of which do not have the SNP3 variant. Nonetheless, as shown in the bottom of the slide, we observed potent and durable knockdown of mutant huntingtin in the striatum out to 12 weeks, a similar effect observed in the cortex. Non-human primates do not have SNP3, as such, we are not able to evaluate the pharmacodynamic effects in this model. We used the concentration data from the BACHD mouse compared with tissue concentrations in the CSF and CNS of non-human primates, and then used PK/PD modeling to estimate tissue concentrations required to achieve striatal and cortical knockdown in humans with 003. These analyses are guiding the starting dose and dosing regimen planned for our clinical trial. While target engagement studies in the CNS of non-human primates were not possible for WVE-003, they were possible for our most advanced therapeutic candidate in our CNS discovery collaboration with Takeda, WVE-005. Like WVE-003, this candidate uses PN chemistry. Unlike WVE-003, the human transcript targeted by WVE-005 is homologous to the monkey sequence, allowing us to assess target engagement throughout the CNS. In this study, for an undisclosed target, non-human primates received a single 12 mg intrathecal injection of WVE-005. One month after administration, we observed that the candidate was widely distributed throughout the CNS and led to substantial knockdown of target, including in the striatum. This experiment once again highlights the potential of this next generation chemistry. In the first quarter, we received regulatory and ethics approvals to initiate SELECT-HD, a phase I-B/II-A global multi-center randomized double-blind placebo-controlled trial of WVE-003 in early manifest HD. We are targeting enrollment of approximately 36 patients carrying SNP 3 in association with the expanded CAG repeat. Patients from the PRECISION-HD studies will be able to transition to SELECT-HD after a washout period, assuming they meet other inclusion and exclusion criteria. Unfortunately, based on the recently disclosed safety and efficacy data, patients who received active treatment with tominersen in the GENERATION-HD study will not be permitted to enroll in SELECT-HD. Although those who've received placebo in GENERATION-HD are eligible to be screened for study entry. Like FOCUS-C9, SELECT-HD has an adaptive design to enable optimization of dose and frequency and more rapid determination of target engagement. An independent committee will evaluate unblinded data in an ongoing basis to guide dose escalation and dosing interval in each cohort. Key objectives, in addition to safety and tolerability, include plasma PK, CSF exposure of WVE-003, and changes in key biomarkers, including mutant huntingtin, wild type huntingtin, and neurofilament light chain over the course of the study. Clinical site activation is underway, and we expect to dose our first patient soon. WVE-N531 is our systemically administered candidate for patients with Duchenne muscular dystrophy or DMD that are amenable to exon 53 skipping. This is also our first stereopure splicing candidate designed applying PN chemistry. As we have shared previously, when applying this format to an exon 23 targeting surrogate, treatment of an aggressive double knockout or DKO mouse model lacking both utrophin and dystrophin, result in rescue of mice treated with 75 mg every other week as compared with PBS or first-generation chemistry dosed at 150 mg/kg weekly. Once again, application of the PN backbone modifications had a profound effect. In March 2021, we initiated clinical development of WVE-N531 with the submission of a clinical trial application. Since then, we've received regulatory approval for an open label clinical trial that is powered to evaluate whether WVE-N531 dosed every other week increases dystrophin production in up to 15 boys with DMD. The trial will also assess drug concentration in muscle and initial safety. Dosing is expected to initiate this year. I'll now pass the call back over to Paul to discuss our ADAR editing capability and upcoming milestones there. Paul? Thanks, Mike. We continue to generate compelling RNA editing results with our ADAR editing capability, which we believe has many advantages over others and positions us at the forefront of this space. As a reminder, our approach to RNA editing employs short, fully chemically modified oligonucleotides to recruit endogenous RNA editing enzymes called ADAR. Our ADAR editing compounds are optimized using our proprietary stereochemistry and PN chemistry, which enables us to avoid delivery vehicles such as AAV vectors or nanoparticles, and allows us to leverage established manufacturing processes. To date, we have demonstrated editing activity across in vivo and in vitro systems, including durable RNA editing of up to 50% in non-human primates with GalNAc conjugated oligonucleotides. Our ADAR editing oligonucleotides are also highly specific. Our practical approach to RNA editing opens the door to a number of therapeutic applications, such as restoring or modifying protein function and upregulation of protein expression. These applications greatly expand the landscape of disease variants that we can potentially address, and we are advancing discovery work for multiple ADAR editing targets, as well as evaluating new potential targets. Our first ADAR editing program uses a GalNAc conjugated oligonucleotide to correct the single RNA base mutation in the mRNA coded by the SERPINA1 Z allele, which triggers alpha-1 antitrypsin deficiency, or AATD. ADAR editing is a simple and efficient approach to treating this disease by simultaneously reducing aggregation of the mutated misfolded alpha-1 protein and increasing circulating levels of wild type alpha-1 antitrypsin protein, thus addressing both the liver and lung manifestations of AATD. All while avoiding the risk of permanent off-target changes to DNA. Last year, we successfully demonstrated upwards of 60% editing of the SERPINA1 Z allele transcript to wild type in hepatocytes in vitro, which led to a threefold increase in functional wild type AAT protein. Encouraged by these results, we moved forward to successfully develop a proprietary transgenic mouse model containing both humanized SERPINA1 and humanized ADAR that enables pharmacokinetic and pharmacodynamic assessment of human sequences in vivo. We are on track to share in vivo data from this model in the first half of 2021. We expect to present additional data at a scientific congress later this year. These in vivo results are expected to enable lead candidate optimization as well as inform potential preclinical development studies and timelines. In summary, 2021 is a year of execution for Wave and a busy time as our next generation pipeline advances in the clinic. As you heard today, we are advancing three unique clinical programs that will each provide insight into our novel PN chemistry and potentially rapid proof of concepts and clinical validation of our platform with biomarker data. We're making excellent progress with our ADAR editing capability, and in addition to the expected in vivo data update for AATD that I just mentioned, I look forward to speaking further about our RNA editing platform at a research day later this year, which we expect to share more details about on our next quarterly call. I will now turn the call over to Kyle Moran, our Chief Financial Officer, to report our financial results before turning the call over to questions, Kyle? Thanks, Paul. We ended the first quarter with $148.5 million in cash and cash equivalents in marketable securities. This balance does not include an additional $30 million in committed research support that we received in early April under our collaboration with Takeda. Our total operating expenses for the first quarter 2021 were $43.4 million as compared to $54.2 million last year. R&D expenses were $33.4 million as compared to $41.2 million in the same period 2020. This decrease was primarily related to a decrease in external expenses related to our discontinued suvodirsen program, as well as decreases in compensation-related and other external expenses, partially offset by increases related to our clinical and preclinical activities for our HD programs and C9orf72 program for ALS and FTD. G&A expenses were $10.1 million for the first quarter of 2021 as compared to $13 million last year. With the decrease driven by lower compensation-related and other external expenses. Finally, we continue to expect that our existing cash and cash equivalents, together with our expected and committed cash from our existing collaboration, will enable us to fund our operating and capital expenditure requirements into the second quarter of 2023. As a reminder, this does not include potential milestone payments or other uncommitted payments under our Takeda collaboration. Thanks, Kyle. With that, we'll open up the call for questions, o perator? Thank you, to ask a question you will need to press star one on your telephone and to withdraw your question, just press the pound key. Please stand by with compiler Q&A roster. Our first question comes from Salim Syed from Mizuho, y ou may begin. Hi, g ood morning. This is Michael Linden on for Salim, t hanks so much for taking our questions. A few, if possible. First, on the C9 trial design, just wondering about the protocol and how adaptive these trials would be. Are they being written to be able to enroll many of the hundreds of patients and potentially be converted to registrational? I'll follow up after that. Thank you, I'll pass the call over to Mike for another question. Yeah, h i, t he way the study is designed is, you can see it allows the study to be expanded as necessary to collect additional information. We made it flexible to enable us to really, once we get recommendations from the independent committee on next steps, to be able to adapt the study as necessary. I think we'll have to wait to see what the data show, but it's our intention to make it adaptable and flexible to enable us to direct it the way we need to understand the clinical meaningfulness in both ALS and FTD. It can expand on the number of patients based on the committee's assessment then, i f that's the specific question, yes. Great, t hank you. One on AATD, on the upcoming data. What will you be looking for specifically, to move forward into the clinic or not? How would you prioritize this if it did move forward versus the other pipeline programs? The prioritization for AATD and the reason we worked on generating the model was really driven based on identifying one, the production of the protein. Again, not working on what a percent editing is. That's interesting, but what drives the progress on a medicine is does it generate the protein. One will be protein production. Other features that we'll be evaluating, obviously, are not just protein production, but protein function. We'll be able to look at a number of those assessments, and that's going to guide our decision on translation. Okay, great, t hank you. Last one, on Alzheimer's disease, mentioned today. After the donanemab data, how are you thinking about treatment, specifically from the ASO side? Maybe what should we think about in terms of potential targets? Just for clarification, I want to make sure you might be thinking about frontotemporal dementia. I just want to make sure we're not thinking about Alzheimer's. We have FTD, so frontotemporal dementia, otherwise known, I think, it's frontotemporal degeneration, is the one area of dementia that we mentioned today. I want to be careful of that. We didn't discuss Alzheimer's disease as a target therapeutic. Happy to discuss antisense treatment and therapeutics for the treatment of CNS and neurologic diseases more broadly, if that's the question, but I just want to make sure we get your question correct. Yes,, t hat would be helpful, t hanks. Next question, o h, sorry, go ahead. I was going to say- Finish answering his question. ... all I was going to say is that. As you see with the FOCUS-C9 study, the emphasis on FTD, getting patients in, and actually the cortical effects that we saw in the preclinical models make us very excited about being able to access the CNS to be able to have an effect on FTD. We're going to be using some of the clinical outcome measures that you'd want to measure cognitive change in our FTD study to be able to get at that question. I think if we take a step back and think about neurologic diseases more broadly, I think one of the datasets that's compelling that Mike shared, in addition to a number of the in vivo mouse studies, is we see really great intrathecal distribution across the brain. I think as we think about distributing to the regions of the brain that are necessary for a whole variety of neurologic diseases, we see intrathecal administration delivering medicines. That's not different than some of our colleagues in the space discuss around distribution. We do believe antisense oligonucleotides can distribute. What we see with the PN is this broad distribution. This addition of it's highly controlled. The data we're generating, the value of stereochemistry, we said beginning and addressing the reality of it is all the assessments of target engagement we're seeing are with the actual compound, because we're not dealing with a mixture of 523,000, 204,233 different molecules that could distribute differently. By having single drugs, we know that the knockdown that we're seeing is based on the design of that single oligonucleotide. I think what we've also seen is the benefit of durability. As Mike said in the adaptive design piece, we're going to be testing and exploring that in the clinic. As we think about chronic administration of medicines on a whole host of different diseases, importantly is dosing frequency. Being able not to sacrifice potency for dosing frequency is something that we're excited to continue to explore in the clinic. As we think about the future of antisense oligonucleotides for the treatment of neurologic diseases, we think the future's promising in a data-driven way. We'll be assessing that further across three clinical studies currently. I hope that answers your question. We're always happy to explore that more, but I think the future looks bright for treating genetic diseases with oligonucleotides. Thanks, t hat's super helpful. I guess what I was referencing was just the mention of Alzheimer's in the press release, along with other CNS indications. Oh, okay, I Yeah, o kay. Our next question. Sorry, s orry, I know where you're going, which is the holistic list of targets that we've been exploring in the large indications where we said, for example, that's why we're thinking about indicating. We said, for example, what represents large neurologic indications, so Parkinson's disease, Alzheimer's disease, and other large indications, t hank you. I apologize, we were focused on the pipeline that we're exploring as opposed to what the potential is, so apologies for our misunderstanding of your question. Our next question comes from the line of Joon Lee from Truist, y ou may begin. Hey, thanks for taking our questions. For all of your CNS programs, in addition to the new and improved backbone chemistry, have you considered a different route of delivery? Another company has recently disclosed proceeding with intracerebroventricular route using Ommaya port, I believe, for Huntington's disease. It does give you more direct access compared to intrathecal, and I'm not aware of any IP that prevents you from doing that. I would appreciate if you could provide some perspective there. I have a follow-up question. Yeah, there's always opportunities to think about different approaches. When we think about permanent catheter placements and other drilling holes in skulls for delivery, I think our first question always is about, and this is true for anything, what problem are we trying to solve for? I think as we currently think about the data that we've generated to date, intrathecal access to the central nervous system is available. We've shown that now in intrathecal non-human primate studies. We've looked at ICV injections in mice, and we see correlation in terms of distribution in CNS tissue. For to date, and if we, again, also see durability, which we're assessing in the clinic, the less frequent administration also calls into question that it's not without risk to leave permanent drilling catheters in the CNS. They can get clogged. They need to be changed. Again, every medicine's different. We can't speak for other companies and what challenges they're addressing using the delivery mechanism. What we assess with ours is, what are we solving for? As we think about intrathecal distributions, we've demonstrated across multiple tissues utilizing the PN enhancements on our medicines themselves. We don't right now see that. As we look at durability and different indications, we could want to solve other problems in the future that could come up. Right now, that doesn't seem to address the solution that we have with the current administration. Mike, I don't know if there's anything you want to- No, I would just say the same thing. In general, you want to go for the simplest form of administration you can that gives you the access you're looking for. Given the progress we've made with accessing all parts of the brain and these diseases through intrathecal administration, that would be the simplest approach, especially as Paul indicates, when you're talking about the durability of effect after single doses. That leads us to the approach that we don't need to do ICV with a catheter, and we can do what's necessary, doing something that any neurologist can do. I think the other thing, we have the benefit with an extensive amount of time now, been able to explore multiple animal models across multiple species. Again, ICV in mice, intrathecal in non-human primates. We also have clinical data to look at distribution. As we shared in our experience in Huntington's, understanding different concentration levels with different backbone chemistry. I think as we look at the totality of data that we've generated and the totality of generated that our colleagues and other companies have generated, I think we see meaningful changes with the implementation of the PN backbone that's translating into animal PK/PD that we're exploring currently in the clinic through adaptive designs that are going to give us answers in the clinic. Got it, l ooking forward to your AR presentation tomorrow at ASGCT. Can you tell me about some differences between the approach you're taking with GalNAc conjugated guide RNA versus circular guide RNA that's being used by another company? I guess we'll find out tomorrow, but just wanted to get any input that you can share on what we should be focusing on tomorrow and some perspectives on the pros and cons of different approaches? Thank you. I can't speak necessarily to the pros and cons of others. We're all learning about the other approaches to treating. I can speak about our approach, which importantly, GalNAc is not, let's say, an approach. GalNAc is a targeting moiety for the tissue target of interest. One of the advantages when we built the ADAR platform from the beginning, and we've demonstrated this with some of our CNS data as well, is that where short oligonucleotides go and distribute, we can generate an editing capability there. We've done and looked at that in vivo in our CNS. Looking at non-GalNAc conjugated distribution and correction. What we're looking at for AATD obviously as a hepatic target in a hepatocyte, is GalNAc then becomes an advantage because we can just target the cell type of interest. I think what's really important from a platform perspective is the platform can exist without GalNAc, but we are using GalNAc as well, where we think about the liver specifically. I think, on both the platform context, we think we've got a really interesting approach in that we don't need to use various delivery vehicles. We can take all of our learnings around stereo-controlled PN-containing oligonucleotides and continue to demonstrate and learn from data that we've generated across multiple species, and even have clinical site experience learning about stereo-controlled oligos and apply that to this ADAR platform and take the advantage of GalNAc conjugation for specific antibody targeting. I think tomorrow as we start to learn more about what's happening across the field, we'll be able to parse that out more. We're excited to have a presentation tomorrow, really be there again at the forefront of ADAR RNA editing to be able to share those data. Great, t hank you. Yeah. Our next question will come from the line of Mani Foroohar from SVB Leerink, y ou may begin. Hey, guys, t hanks for taking the question. I'll ask one quick one on enrollment. When we look at rolling over placebo patients from GENERATION HD2 into SELECT, how many of those patients are still eligible? I worry a little bit that obviously Huntington's is a relentlessly progressive disease. Some proportion of those patients may now be meaningfully more severe than they were when they were first screened for Generation. Secondarily, based on whatever portion of those patients are likely, in your view, to roll over, how much of a head start does that give you on enrollment in SELECT? Are there other mechanisms that you can pursue, sort of changes in trial process, to sort of accelerate the completion of enrollment there, given there were a couple of delays and hiccups along the way for GENERATION previously? I'll pass the question to Mike. Yeah, n o, hi, t hanks. Regarding the movement from GENERATION HD. Right now the way it stands is it hasn't been disclosed to patients whether they've been receiving placebo or active treatment. We're hopeful that will happen, and then patients can make a choice about whether they want to do that transition. We're not exactly sure when that will be, but we're hoping that that happens relatively soon, as we have disclosed to all the patients now what they've been receiving. Second of all, there is that possibility that patients will have progressed out of our inclusion criteria, which is why they are going to have to be rescreened for both inclusion and exclusion, including whether they have SNP3. That'll be an important inclusion/exclusion criteria. As we think about the overall population, we'd expect about 40% of them are essentially to have the appropriate SNP. Regarding the other operational things to help move things along, we've learned a lot from the PRECISION- HD1 and PRECISION-HD2 studies. We've learned a lot about how to operationalize intrathecal administration more efficiently. We have a lot of site overlap between GENERATION HD and PRECISION-HD, which has allowed our physicians to get experienced in the screening process. We have new laboratories to do SNP identification. There's a variety of things that have really helped accelerate, make us feel comfortable that we'll be able to accelerate the recruitment for SELECT-HD, including the addition of regions that we know have higher representations of SNP3. There's a variety of things we're doing that we're comfortable will help. In addition, with the adaptive design, there's going to be all along the way, the committee is going to be looking at unblinded data to guide next steps and make recommendations. That in and of itself is a huge change versus data generation in PRECISION-HD1 and PRECISION-HD2. All right, t hanks. Our next question call will be from the line of Paul Matteis from Stifel, y ou may begin. Hey, t hanks for taking the question. This is Alex on for Paul, a couple questions on SNP3. Appreciate the WVE-005 target engagement data in non-human primates, but I was wondering if you could maybe quantify a little bit some of the biodistribution that you mentioned you're seeing in non-human primates with WVE-003 that you're using for the PK/PD modeling, knowing that's not really a disease model, but anything you can say there would be really helpful. Secondarily, I'm curious if WVE-003 targets the exon 1 fragment of mHTT and generally your thoughts on the exon 1 fragment as a potential driver of pathology in HD, t hanks. Mike, you want to start and then turn it over to me? Yeah, I mean, regarding the non-human primate data, I think that what I can say about the distribution in the non-human primate, even though it's not target engagement data for the SNP3 compound, we are very clearly able to achieve concentrations throughout the brain, including in deep gray structures and striatum, that would be predicted to engage target based on what we have from the BACHD. And a very large window to be able to dose escalate to again, engage target. I think that we are quite comfortable based on the preclinical data we have, that we are able to get into the regions that matter and engage targets. Again, we're starting at a dose that we believe is pharmacologically active right from the beginning, and then the committee will tell us how close we are to that and then be able to adjust as necessary. That's regarding that. In terms of exon 1 and what we think there, as we've said previously, that a lot of the exon 1 data, this is from postmortem. It seems to be most relevant in those with extremely long expansion. Nonetheless, when we're bringing down mutant protein, we would expect to be able to also have an impact on exon 1. Yeah, j ust to add to that, antisense oligonucleotides can reach intronic and exonic transcripts, we should therefore hit exon 1. I think the most important piece, independently of whether or not we hit it, I think the data is still questionable and beyond really long repeat. I think as we go back and think about our targeting for SNP3, I think we can leverage a ton of experience with SNP1 and SNP2 and what we've seen in general with the enhancement of PN chemistry in terms of distribution, durability, dosing. I think we can see and believe that mutant protein suppression is important, yes, we're distributing and knocking down the mutant protein. I think what we've learned a lot about in the first clinical trial of [guess] is, and Mike alluded to post-CHDI, is a substantial focus in doubling down on our efforts that wild type sparing is as important a driver of disease pathology as mutant protein production is. The approach that we set out to years ago establish for the treatment of disease, which is wild type sparing, mutant reduction, we believe is the way to address the pathology, and we'll be generating clinical data and be able to assess that again with SNP3 using the new PN chemistry. Great, t hanks so much. The next question will come from the line of Eun Yang from Jefferies, y ou may begin. Thank you, I have a few questions. First, on AATD program, Paul already mentioned it's not just editing efficiency. You've already shown 50% in non-human primates, but producing wild type AAT protein and then function. Question two is that do you know what level of a number of wild type AAT protein is needed in order to see some clinical benefits? What's the kind of a minimum level? That's question one. Second question is on WVE-004. Are you already doing site activations? When should we expect clinical data from this trial? Lastly, the additional $30 million that you received from Takeda in April, how would that be amortized in income statement? Would it be similar to what you've done in the past? Thank you. All right, w ell, the good news is this question, you'll get a lot of voices around the table, so it's great. I'll take the AAT question; I'll pass to Mike for the second one. Kyle can answer the Takeda quesion. Your important question is how do we look at this in vivo data that's upcoming, and how are we looking at that in terms of advancing AATD program? I think when we think about alpha-1 antitrypsin, I think you're spot on. We're looking at protein levels. The SERPINA1 model is different because they're all in humans, let's say, in that you can generate protein. I think we'll be looking at levels of protein generated in that model to be able to model that towards where one would expect to be at the human level. I think to date, one sees kind of a threshold level around 11 micromolar of protein to be clinically relevant. That's kind of the basis for a number of the protein infusion products. We know that the protein infusion products tend to tail off at the end because the protein degrades, and then they have patients that have to be redosed on a weekly basis. These patients have these gaps in treatment. I think if we can have sustained correction where you don't have those drops, we would see that as this minimum threshold criteria where not only are we treating the hepatic issue, but really at that level know that you're at levels that can treat the pulmonary complications, I think that would be exciting. I think the key for us and, as we generate that data and share that more broadly, exactly to that point, that's the data that we'll be assessing from those models in terms of translation. I think the important piece there that we'll be assessing as well is not just the protein production, but as we demonstrated before from the in vitro correction of the AAT protein, is that we could generate it and it was functional. We want to see that replicated now in the animal model. I think we're taking the deliberate approach to make sure we generate the preclinical data that's going to position us for thinking about how this program transitions, and I think that's why we've been excited to date, one, around the AATD program. I think more broadly, what it really represents in Wave's ability to bring ADAR editing into patients across a whole variety of indications. Importantly, CNS indications as well, where we don't need GalNAc to be able to target neurons. I think there's a whole variety of approaches that we can take. Obviously, this is the first in vivo demonstration that we'll be able to look at on a corrected protein and be able to study that more broadly. I'll pass any questions, just because of the demo, I'll just say, are there any questions there? If not, I'll hand it over to Mike to address your question. Mike, do you want to take the next one? Regarding next year, we have three biomarker studies underway with these adaptive designs that are going to allow us to have a continuous flow of data. That's very exciting, and specifically regarding WVE-001, as I indicated, we're going to be dosing soon, and we'll have a good sense of how the studies are moving throughout the year. What we share from the studies is going to be informed by how the studies proceed, the types of data that comes in, whether there's a meaningful number of patients at any given point in time, and whether the feedback we receive from the independent committees. That feedback is going to be coming in throughout the course of this year and next, and from there, we'll guide when we disclose data and what that data will be. We anticipate data, however, during this time that will enable us to make decisions and then provide greater insights into the chemistry. That's sort of how it's proceeding now. It's obviously going to be driven by how quickly we can get those patients in, and we're optimistic now given site activations and the fact we're going to be dosing soon. It is an important notion, when we think about just the adaptive design principle of running studies, which is different than running kind of mile marker driven studies where you've got to aggregate the data and then analyze it and aggregate it and then flip the card at the end. I think as Mike said, data is evaluated in an ongoing way by an independent committee that's going to inform things. With those studies running now and data being generated this year and next, I think there's a variety of times where those committees could flag that we should share data. It's a little less specific, and as Mike said, we'll be able to provide more updates to guidance along the way. Kyle, you want to take the two minutes then? Yeah, Eun, thanks for your question. Your assumption is correct, w e would account for that in the same way that we've accounted for the upfront cash payments and other committed cash payments we've gotten to date with GAAP revenue and amortization. Thank you. Thank you. Once again, that's dial one for questions. Our next question will come from line of Luca Issi from RBC, y ou may begin. Thanks for taking the question, t his is Lisa for Luca here. A couple questions for us. First one, we have obviously seen the phase III data from Roche Ionis, and it seems to me that [guess] may have had a detrimental impact to patients, versus placebo, as placebo directionally outperformed the high dose. We have seen a dose-dependent increase there in ventricular volume in the brain. Did you have the same read on this data? If so, do you think that it's possible that a wild type sparing approach may not have caused a detrimental impact here? The second question, you've obviously discontinued SNP1 and SNP2 with the old chemistry. Just wondering, what is the plan going forward? Are you planning to explore the PN chemistry for SNP1 and SNP2 or only for SNP3? Thank you. Thank you, t o take the view of Roche, I think like everybody else, we have to view it as we're only seeing what everybody else is seeing from the outset. It's hard to comment on what they saw. I think objectively, you pointed out what they saw, which was a dose-dependent change in clinical measurements. Importantly, those clinical measurements were cortical and striatal. I think there's a jump to distribution. I think it was a broader question than just striatal distribution. I think as we think about that data in the context of the biology, as Mike laid out on this call I think very well, we do think that there's two approaches of one characterization of drug. One is obviously to your point on my hypothesis of wild type sparing, and that if one thinks about the disease as both one of a toxic gain of function and a toxic loss of function, taking that below the 50%, I know there's a lot of discussion after Roche's data of people just saying, "Well, studies have been done in 50% reductions in normal animals and shown it's safe." I think one has to remember that the situation that those animals were under were, one, a 50% reduction of a normal phenotype. What we're dealing with in Huntington's patients, as we kind of have been explaining for a while now, is that those reductions that are being studied in the clinic are reductions that are happening in the setting of already a 50% reduction and under the setting of stress of patients who are progressing in disease. One has to think about the totality of removing the neuroprotective feature of wild type protein, a whole host of other functions, including cilia function, which involves CSF flow. Those are really important characteristics. Yes, I think that's something that needs to be explored, and I think that's why we're excited about seeing that. I think we were also happy in the analysis that patients on the studies that we were looking at didn't progress. Now, take that for where it is. I think as other characterization, we didn't see increases or elevations in white counts of protein and NfL. I think if we think about the totality of both the oligo approaches as well as the wild type sparing, I think that's driven why we believe a stereo controlled approach of wild type sparing is important. It's why we're excited about bringing PN into the clinic with SNP3. To your question, yes, we can apply and have generated early data around being ready with SNP1 and SNP2. I think the measured approach right now is, as Mike alluded to with the trial design, let's get the data with PN chemistry with SNP3 and use that as a driver before spending more resource on SNP1 and SNP2. Yes, we are prepared to go back to looking at the totality of HD within an allele-specific approach, I don't know, Mike, if there's- No, listen, we've been concerned from the beginning that a non-selective approach could have detrimental effects. We have said that's why we're doing what we're doing. There are a lot of reasons that could be assessed for what happened with that phase III study, certainly effects on wild type have to be part of the consideration, which is why we're making our wild type assay available. It's an important data set we need to understand. We're concerned enough that unfortunately, we said initially we would allow patients who have been treated with tominersen in SELECT-HD. We've had to now not do that out of whatever is happening there, because we're concerned enough to unfortunately have to exclude those patients. It's a concern. It's an observation. It needs to be studied. We have the tools now to study it, and we're hoping that the community asks these questions because we believe it's important. Great, t hanks for taking our questions. Absolutely. Thank you, I see no further questions in the queue. I'd like to turn the call back over to Dr. Paul Bolno for any closing remarks. Thanks, everyone, for joining the call this morning to review our first quarter 2021 corporate updates. Thank you to our Wave employees for their hard work and commitment to patients. We look forward to speaking to you all again soon. Have a nice day, t hank you. This concludes today's conference call. Thank you for participating, y ou may now disconnect.