Good morning, welcome to the Wave Life Sciences Q2 2021 earnings call. My name's Brandon, and I'll be your operator for today. At this time, all participants are in a listen- only- mode. Later, we will conduct a question-and-answer session during which you may dial star one if you have a question. Please note this conference is being recorded. I will now turn the call over to Kate Rausch, Head of Investor Relations at Wave Life Sciences. Kate, you may begin. Thank you, operator. Good morning and thank you for joining us today to discuss our recent business progress and review Wave's Q2 2021 operating results. On the call with me today are Paul Bolno, Wave's President and Chief Executive Officer, Michael Panzara, Chief Medical Officer, Head of Therapeutics Discovery and Development, Paloma Giangrande, Vice President of Platform and Discovery Sciences and Biology, and Kyle Moran, Chief Financial Officer. This morning we issued a news release detailing our Q2 financial results and providing 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, and our quarterly report on Form 10-Q for the quarter ended June 30th, 2021. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul. Paul? Thanks, Kate. Good morning, everyone on the call, and thank you for joining us. During the call today, I will provide opening remarks, after which Mike will give an update on our three ongoing clinical programs. We'll then turn the call over to Paloma Giangrande to provide an update on our discovery stage alpha-1 antitrypsin program, which provides ongoing proof of concept for our ADAR editing capability. Paloma joined Wave from Moderna at the start of this year as VP, Platform Discovery Sciences and Biology. Finally, Kyle will briefly review our financials. Since the start of the Q2, we achieved several important milestones. Most significantly, we started dosing in our FOCUS-C9 clinical trial of WVE-004, our C9orf72 candidate in amyotrophic lateral sclerosis and frontotemporal dementia. This marked the first human dosing with an oligonucleotide containing our next generation PN chemistry, which is a critical and very exciting milestone for the company. Right behind C9, we're advancing two additional clinical trials, the SELECT-HD trial of WVE-003, our SNP3 candidate in HD, and a clinical trial of WVE-N531, our exon 53 candidate in DMD. Each of these innovative adaptive clinical trials is designed to quickly establish a dose level and frequency, and ultimately clinical effects to enable decision-making on next steps for these programs. Data generated over the next 18 months will also provide insight into the clinical effects of PN chemistry, both with intrathecal and systemic administration, as well as provide the opportunity to confirm the promising in vivo preclinical results. RNA editing is the most recent therapeutic approach to emerge from our PRISM platform, which also utilizes oligonucleotides with our novel PN backbone modifications. For this new modality, we design the oligonucleotides to engage the endogenous ADAR to achieve RNA editing. During the Q2, we shared proof of concept data that demonstrates restoration of functional alpha-1 antitrypsin protein with in vivo ADAR editing, an important achievement for both the platform and for this exciting program. Paloma will review these data later on in the call. These recent accomplishments are direct results of our investment in our PRISM platform and our swift execution advancing PN chemistry from concept to discovery into therapeutic molecules. Since the founding of Wave, we have been innovating of an oligonucleotide chemistry to optimize our therapeutic candidates using the resolution of StereoPure design. Our novel PN chemistry is the first significant new modification that we've advanced, which has demonstrated a step change in pharmacology across many in vitro and in vivo studies. These studies show that the addition of even just a few properly placed PN backbone chemistry modifications to oligonucleotides consistently enhances potency, distribution, and durability of effect. These improvements appear to be independent of sequence, tissue type, or modality, enabling us to expand the use of these chemistry modifications to build our next generation oligonucleotide pipeline. Less than a year after first unveiling this new chemistry, we have ongoing clinical studies for three PN-modified candidates that are now dosing in the first of these clinical trials with others soon to follow in the coming weeks. Given the complexities of many nucleic acid therapeutics today, it's important to note this novel chemistry is scalable. We are manufacturing the supply for all three clinical trials and multiple preclinical therapeutic programs within our GMP manufacturing facility. We have a robust portfolio of oligonucleotides led by our clinical programs WVE-004 in ALS and FTD, WVE-003 in HD, and WVE-N531 in DMD. These ongoing clinical trials all include biomarker assessments and clinical data which will enable potential paths to registration and unlock value for our additional pipeline programs, including those in collaboration with Takeda and our wholly owned targets. Our chemistry experience with optimizing silencing and exon-skipping compounds enables us to rapidly apply our PRISM platform to develop RNA editing oligonucleotides and accelerate this capability such that we are now among the leaders advancing ADAR editing towards the clinic. Our StereoPure editing oligonucleotides are fully chemically modified and incorporate PN backbone modifications. They're also single-stranded and short in length. Altogether, these features enable simplified delivery, avoiding the need for AAV or nanoparticles such as LNPs. As you can see on the lower left of slide eight, once our oligonucleotides reach the target RNA, they engage endogenous ADAR, a ubiquitously expressed enzyme across tissue types, to correct or modify single RNA bases. By staying focused at the RNA level, we avoid potentially permanent off-target DNA base edits. The target landscape for this modality is vast, enabling therapeutic applications such as restoration of protein function, modification of protein function, and upregulation of protein expression. We intend to show the versatility of editing we can achieve at an upcoming research day on September 28th. I'd now like to turn the call over to Mike Panzara for an update on our clinical trials. Mike? Thanks, Paul. Good morning, everyone. Today, we'll provide an update on the progress made over the last few months with our clinical programs. For CNS diseases, we are advancing two programs in the clinic, WVE-004, our candidate targeting C9orf72 hexanucleotide repeat expansions in ALS and FTD, and WVE-003, our SNP3 targeting candidate in HD. These are the first two PN-modified clinical candidates designed to silence targets in the CNS. For both programs, we have demonstrated prolonged knockdown of the desired target in vivo in the CNS of transgenic disease models. Such in vivo assessments are now routine across our pipeline programs, including our multiple wholly owned neurology discovery programs and those in collaboration with our partner, Takeda, where sequence homology in non-human primates allows us to explore pharmacology in a more relevant species using the intended intrathecal route of delivery. We have shown as part of these programs the ability to potently knock down target transcript and demonstrate widespread distribution throughout the CNS. One consistent observation has been the durability of target engagement with PN-modified oligonucleotides, leading to the expectation that dosing intervals in humans will be less frequent than the monthly dosing in our previous trials. This is most clearly illustrated by our C9orf72 Program. Our clinical candidate, WVE-004, is designed to target a hexanucleotide repeat expansion in 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 disease phenotypes, and WVE-004 is being advanced simultaneously in a single basket-like trial for both C9 ALS and C9 FTD. This makes sense biologically, but the response from the community has been overwhelmingly positive, particularly amongst those with FTD or a mixed ALS/FTD phenotype, as these patients have to date been excluded from C9-associated ALS studies. C9orf72 protein is important for normal regulation of neuronal function and the immune system. These functions are well understood, which is why therapeutic approaches to target hexanucleotide repeat-containing transcripts should preserve the pre-mRNA V2 transcripts that are responsible for generating C9orf72 protein. 004 therefore selectively targets the pre-mRNA variant transcripts that lead to loss of normal C9orf72 function and production of pathological mRNA products and toxic dipeptide repeats or DPR proteins. poly-GP is an important one of these DPR proteins in that it is transcribed from both the sense and antisense transcripts, making it a very sensitive biomarker of target engagement for toxic mRNA transcripts as well as other toxic proteins. Poly-GP was chosen as the biomarker for both our preclinical and clinical studies, allowing us to make certain assumptions regarding dosing and translation of preclinical observations to humans, thus guiding starting dose in our trial. In addition, we plan to assess the effect of 004 on CSF measurements of neurofilament light chain or NfL, as it remains an important biomarker for providing insights into potential neuroprotective effects of treatment. This slide illustrates the results from the BAC transgenic mouse model. As you can see, two I.C.V doses of 004 administered seven days apart result in 80%- 90% reduction in Poly-GP in the spinal cord and cortex for at least six months, with sustained meaningful CNS tissue concentrations of 004 throughout the duration of the study. Further, C9orf72 protein was unchanged over the course of the study, including at the six-month time point, confirming 004 selectivity. FOCUS-C9 is expected to enroll approximately 50 patients with a documented C9orf72 expansion and confirmed ALS, FTD, or mixed phenotypes, and includes both single and multiple ascending portions. At predefined data-driven milestones, an independent committee will review unblinded data to determine each single-dose level and the optimal dosing frequency of each multi-dose cohort, which, based upon the preclinical data to date, is expected to be less frequent than monthly. Successful poly-GP knockdown, along with a favorable safety and tolerability profile, would enable registrational studies for ALS and FTD with clinical endpoints. We expect to generate clinical data from the study through 2022 to enable decision-making for this program. Our approach to Huntington's disease remains like that of C9orf72 targeting, lower toxic protein while preserving beneficial protein. 003 is designed to silence transcripts that will lead to toxic mutant huntingtin protein, while sparing transcripts that allow synthesis of healthy huntingtin protein, thus addressing both drivers of HD progression. Our ability to measure the effects of 003 is enabled by assays that allow direct measurement of target engagement in the CSF, mutant huntingtin knockdown, wild type preservation, and possible neuroprotection through the measurement of NfL. What's unique to our approach is how we accomplish selectivity, namely by targeting a known SNP called SNP3 that is associated with the CAG expansion on the mutant allele of many patients with Huntington's disease. Again, the purpose of this and other allele-selective approaches is to maintain the beneficial effects of wild types, which should maximize the beneficial effects of mutant huntingtin reduction. If one thinks about this as a push and pull of positive and negative factors in the CNS, it stands to reason that non-selective depletion of both wild type and mutant protein could shift the balance towards disease progression, erasing any benefit or even potentially accelerating decline, especially in the setting of stress. This has been our hypothesis since we began our HD program, and emerging data support our position, making us resolute in this differentiated treatment approach. Slide 16 illustrates data demonstrating the highly selective, potent, and durable effects of 003 on mutant huntingtin in in vitro and in vivo disease models. The BAC HD mouse model used is somewhat limited in that it contains multiple copies of the mutant huntingtin gene, some of which do not have the SNP3 variant. Nonetheless, as shown on the bottom of the slide, we observed potent and durable knockdown in mutant huntingtin in the striatum out to 12 weeks, with a similar effect observed in cortex. SELECT-HD is planned to enroll approximately 36 patients with HD and confirmed SNP3. With FOCUS-C9, the preclinical data to date allow us to make certain assumptions regarding dose selection and frequency, with an independent committee reviewing unblinded data to determine dose levels and the optimal frequency for future multi-dose cohorts. As of today, clinical trial sites have been activated, recruitment is underway, and we expect to initiate dosing in the coming weeks. While target engagement studies in the CNS of non-human primates were not possible for 003 and 004, homology of target sequence between transgenic mice and non-human primates in some of our newer discovery programs enables us to evaluate drug distribution and target engagement in a large animal species using the intended route of clinical administration. What's been clear from these programs is that the application of stereochemistry in the PN chemistry backbone modifications enhance distribution throughout the CNS, leading to widespread and sustained knockdown. This is illustrated on slide 19 from a study for an undisclosed target with our most advanced Takeda collaboration candidate, WVE-005, which contains PN modifications and was administered as a single 12 mg intrathecal dose to non-human primates. One month after administration, we observed broad distribution and substantial knockdown of target throughout the CNS, including the striatum. It is this consistent, widespread CNS distribution of PN-modified oligonucleotides across species, the possibility of infrequent IT administration, and the availability of disease biomarkers for proof-of-concept studies that are the key feature of our differentiated CNS portfolio moving through preclinical and clinical development. Moving on to WVE-N531. This is our first PN-modified clinical candidate to be administered systemically. As also our first splicing candidate, it will provide insight into the ability of PN- modifications to enhance access to dystrophic muscle and restore functional dystrophin expression. We are optimistic about this program given the compelling preclinical data comparing systemically administered PN-modified exon-skipping oligonucleotides with oligonucleotides containing only PS and PO modifications. These data are shown on slide 21 from experiments using an aggressive double knockout or DKO DMD mouse model lacking both utrophin and dystrophin. Following treatment with a PN-modified exon 23 targeting surrogate, we saw a dramatic treatment effect, rescuing all mice treated with the surrogate, which was very different from the mice treated with PBS or first-generation PS/PO-modified ASOs dosed equivalently. In fact, the mice survived even when treated with a lower, less frequent dose of the PN-containing surrogate, once again highlighting the improved pharmacology of the PN-containing compound. Just as a reminder, the relevance of these observations is the potential impact for Duchenne muscular dystrophy. DMD is an area of significant unmet need, with current exon-skipping treatments demonstrating only minimal dystrophin expression without yet establishing clinical benefit. WVE-N531 has similar chemistry to the exon 23 surrogate used in the DKO model, and when applied to DMD patient-derived human myoblasts amenable to exon 53 skipping, resulted in dose-dependent increases in dystrophin restoration, up to 71% of normal at the highest concentrations tested. These in vitro and in vivo observations, along with other preclinical data illustrating widespread distribution of N-531 in the normal muscle of NHPs, prompted us to proceed with a human proof of concept study. As of today, our clinical trial sites are activated and recruiting eligible patients in our first-in-human clinical trial for N-531 in boys amenable to exon 53 skipping. This open label study is powered to determine whether N-531 treatment intravenously leads to dystrophin production and whether the drug can readily access muscle cells, thus addressing the limitations that led to suvodirsen's lack of effect. We will also be assessing safety and tolerability of IV infusions, initially at a frequency of every other week, mimicking the dosing frequency in the DKO animal model. We plan to dose the first patient in the coming weeks and plan to apply PN chemistry backbone modifications to other exon-skipping candidates if the study is successful. Now I will turn things over to Paloma, who will provide an update on our ADAR editing capabilities. Paloma? Thank you, Mike, and good morning to everyone on the call. I'm excited to join you today to talk about ADAR editing and our progress in translating this capability into a therapeutic program for alpha-1 antitrypsin deficiency. On a personal note, Wave's approach to RNA editing was a significant draw for me when I was offered the opportunity to join the company. Since then, I have only become more enthusiastic about the science and potential of ADAR editing as a new way to treat genetic diseases. AATD is an inherited genetic disorder that is most commonly caused by a point mutation in the Z allele of the SERPINA1 gene. This mutation leads to misfolding and aggregation of alpha-1 antitrypsin protein, or ZAAT, in hepatocytes, and a lack of functional AAT in the lungs, which results in progressive lung damage, liver damage, or both. With ADAR editing, we aim to correct the RNA to restore circulating functional wild type alpha-1 antitrypsin protein, or MAAT, to protect the lungs and reduce ZAAT protein aggregation in liver, all while retaining the innate physiological regulation of MAAT. With our GalNAc conjugated StereoPure oligonucleotides, we may be able to replace chronic weekly IV AAT augmentation therapy with a subcutaneously administered therapy that addresses all goals of treatment. Approximately 200,000 people in the US and EU are homozygous for the ZZ mutation, which is the highest risk of lung and liver disease. Last fall, we successfully demonstrated upwards of 6% 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 initial 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. This human ADAR mouse enables us to optimize oligonucleotides to human ADAR, which is expected to improve translation into the clinic. Following three subcutaneous doses of two unique ADAR editing oligonucleotides, we achieved up to 40% editing at day seven. We are encouraged by these initial results, as we are approaching the level of correction that represents a heterozygous MZ patient with very low risk of disease. Notably, we also did not observe any bystander editing. We looked at how this level of editing impacted the circulating human AAT protein. We saw a threefold increase in circulating AAT as compared to PBS control at this initial time point. This magnitude of increase is promising, as it is representative of, one, the fold increase that may achieve phenotypes with lower risk of disease, and two, total circulating AAT concentrations approaching 570 micrograms/mL, or 11 micromolar in these mice. This also establishes a floor from which to further optimize potency as we advance towards a clinical candidate. Using mass spectrometry, we investigated the isoforms of this circulating AAT protein and confirmed that the majority was restored wild type MAAT. Consistent with the RNA editing results, there were no other isoforms identified that may have signaled bystander edits. It was very exciting to see such levels of wild type protein being generated post-editing at this time point. When we look at longer duration data, we would expect to potentially see ZAAT increase initially as MAAT reduces aggregation in the liver and ZAAT protein is cleared. At steady state, with approximately 50% RNA correction, we expect to see a greater percentage of MAAT consistent with what is observed in MZ patients. As you can see on the right side of the slide, we also observed that there was a significant increase in neutrophil elastase inhibition post-editing, confirming the functionality of this restored wild type of MAAT protein. In summary, we're excited to see these initial results, up to 40% editing in vivo translating to meaningful increases in circulating AAT that are driven by restored functional wild type protein, which again, are from an initial time point. We also evaluated these compounds in a wild type AATD mouse model and achieved comparable RNA editing and fold change in AAT protein restoration. Our ongoing studies are assessing duration of activity, dose response, and PK/PD to provide insight into how MAAT secretion levels will trend over time. We'll also be looking at the reduction in ZAAT protein aggregates and changes in liver pathology. At the same time, we are advancing optimized compounds with increased potency in new in vivo studies. We expect to share an update on these data sets at Research Day and other settings in the H2 of the year. I will now hand the call over to Kyle. Kyle? Thanks, Paloma. We ended the Q2 with $143.8 million in cash equivalents, and marketable securities. This includes 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 Q2 2021 were $42.6 million as compared to $41.7 million last year. R&D expenses were relatively consistent year-over-year at $31.6 million as compared to $31.5 million in the same period, 2020. Within R&D, there were increased external expenses related to our C9orf72 program and other discovery and development programs, including PRISM and our reimbursed research and preclinical expenses related to our Takeda collaboration. These increases were almost entirely offset by decreased external expenses related to our discontinued clinical programs. G&A expenses were $11 million for the Q2 of 2021 as compared to $10.2 million last year, with the increase driven by external expenses as well as compensation-related expenses. Finally, we continue to 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 Q2 of 2023. As a reminder, this does not include potential additional milestone payments and other uncommitted payments under our Takeda collaboration. With that, I'll turn the call back over to Paul. Thanks, Kyle. With dosing underway in our WVE-004 clinical trial and 003 N531 soon behind, we are entering a potentially transformational period of data generation for Wave. We believe clinical data will unlock value in multiple ways. These three clinical trials will provide insight into the clinical effects of PN chemistry by way of biomarker results and implications for dosing intervals, as well as safety and tolerability. For WVE-004 and WVE-003, two intrathecally delivered compounds designed to engage targets in the CNS, success with these trials would de-risk our existing pipeline of CNS programs, including multiple programs in collaboration with Takeda and our undisclosed wholly owned targets. With WVE-N531, we'll gain insight into clinical effects on an entirely different modality, exon skipping, and the ability of PN chemistry to improve cellular uptake and distribution, potentially unlocking our ability to apply this chemistry to other exons in DMD. Positive results from any of these studies would enable paths to registration across multiple therapeutic indications. Our advances in chemistry set us apart from others in the field and are enabling us to lead the way in developing ADAR editing therapeutics. Starting with GalNAc conjugated oligonucleotides to the liver, we are generating exciting preclinical data, and we are building on these results with new editing targets. This is an exciting time for the Wave team as we generate a continuous flow of data from multiple programs through 2022 to enable decision-making. We look forward to updating you on our progress. Additionally, we hope you will tune in to our upcoming Analyst and Investor Research Day on September 28th, which will highlight our ADAR editing capability, feature new data from our AATD program, and provide updates on how we are advancing ADAR editing beyond the liver. More details on the research day will be shared in the coming weeks. With that, we'll open up the call for questions. Operator? Thank you. Thank you. We will now begin the question-and-answer session. If you have a question, please press star one on your phone keypad. If you'd like to be removed from the queue, please press the pound sign or the hash key. If you're on a speakerphone, please pick up your handset first before dialing. Once again, if you have a question, please press star one on your phone keypad. On the line from Truist, we have Joon Lee. Please go ahead. Hi. This is Mary Budazi for Joon Lee. Thanks for taking our question. Our question is related to FOCUS-C9 study. It would be great if you could provide some color on your expected efficiency of these treatments, specifically considering unchanged level of C9orf72 and the possibility of haploinsufficiency for this disease pathology. Thank you. We're happy to take your question. I'll refer to Mike to go through how we're approaching, again, the disease targeting and clinical study. Right. I think that we recently did have a publication on our targeting strategy that shows that the approach we're taking is to take in consideration the importance reducing the mutant variants while preserving the healthy variants to avoid that haploinsufficiency. I think that we have considered that in our approach, and it has driven our targeting strategy. We anticipate that with the current compound 004, that it is that balance of bringing down the toxins while preserving, again, the normal C9orf protein. Great. If I may, I have a follow-up question. Your WVE-004 is variant selective. Is this molecule also allele-specific or not? It's a little different than the case of HD, all right, where the way the gene, as was shown in the presentation, the way transcription occurs is you get these multiple transcripts that are produced. The goal here is not to silence the entire allele. The goal is to actually go after the variants that contain the expansion, because not all the variants have the expansion. You're getting the selectivity of targeting a mutant, but you're also allowing normal transcription. In essence, we call it variant selective because the objective in C9 is a bit different than the objective in HD. The paper that we published on this actually goes through it all in very good detail. Thank you. From Mizuho, we have Salim Syed. Please go ahead. Great. Good morning, and thanks for the questions, guys, and congrats on the progress. Paul or Mike, I just wanted to ask a couple of questions, one on ADAR, one on C9orf. On ADAR, as the field develops here, I was wondering if there are any things that you guys can point to as you compare your ADAR program to Korro or Shape, or things that you're looking for there in terms of differentiation as the field develops. Just on the C9 program. The language here says clinical data through 2022, and I'm just wondering here what the triggers are for data release publicly, and if we could potentially get anything in 2021. Thank you. Great. I'll start with ADAR and then pass over to Mike, who will talk about C9. I think your question on ADAR is great, and it's something that we stayed focused on at the very beginning in building that capability in-house and building it and leveraging it off of our unique chemistry capability. I believe we shared this at an early R&D Day last time, so it's just nice to continue to see the progress, which is building on short, chemically modified oligonucleotides that gain access to cells, that leverage the best of the chemistry adaptations we've made. Using PN and seeing the advantage both on the potency to ADAR, so using the endogenous enzyme and getting potency to it. That's critical to getting accessibility, so the ability of these short oligonucleotides to get into the cell and to the compartment to engage endogenous ADAR. Lastly, to sustain that activity as we think about durability. I think that's the work that we've been set out to do over time. I think it's great to see more people entering the field of endogenous ADAR editing as a space. What we've consistently done, and as Paloma alluded to on the call today, is continuing to optimize. Establishing the floor, the editing where we have today, which approaches now what we think is therapeutically relevant, functional alpha-1 antitrypsin protein production, and continuing to build on that on the pharmacology that'll go into our clinical candidate, meaning potency and sustaining and growing that. Durability, reducing the frequency of subcutaneous administration. Ultimately continuing to measure the functionality of that protein over time for patients. I think others have taken different approaches in terms of their oligonucleotide designs and the toolbox that they're using to build their chemistries. I think what's accelerated the work here at Wave is being able to take advantage of our chemistry capability and manufacturability, because we also know that one of the key drivers of this is not just to make preclinical molecules that we can test in rodent models and Non-Human Primates, but ultimately to take the scalability of the chemistry forward as we think about making this a potentially commercializable therapeutic. We'll pause on that one, Salim, to make sure to answer the ADAR question, then we'll talk about the C9 question. Yeah, I think that was helpful. Thanks, Paul. Sure. Great. I assume on C9, the process here is the adaptive design of the study. You can imagine an ongoing flow where you have recruitment, dosing, follow-up, safety, independent committee evaluation, and then recommendations as to dose and frequency. It's going to be this continuous process that is illustrated in the study design. There is positive or negative feedback that could come out of those committee assessments that would prompt a disclosure. This could be material changes to study design, changes in durations of treatment, other aspects that suggest patients are benefiting, including disclosing moving on to a next phase of development, like a registrational study, some sort of regulatory feedback. There's a variety of things that would prompt those disclosures throughout that time frame. Again, the concept is its ongoing, the data are being generated, and it's the material nature of things that would make us disclose. It's not just unique to C9, Salim. I think we've purposefully, and I think over time, thought about the multitude of clinical programs moving that could generate that. That is why we brought, to Mike's point, I think we've been innovative on our clinical designs as much as we have on our molecules to bring this forward in terms of generating data and then interpreting that data quickly to make decisions on programs. I think we've got ample opportunity as we move forward now through 2022. Is there a specific time point that you're looking at? For cohort one, for example, are you going to wait for a certain amount of time to pass before you would even consider releasing data for that first cohort or the first two cohorts? How are you planning to disclose the data, given there are those four cohorts in the single ascending? I think it's displayed. Studies enroll, as you saw, and that's on the trial designs. There are ample opportunities where assessments are being made on target engagement across studies. That's built into the design of the studies across cohorts. I think what we're not guiding to is that each one of those dots is a sampling, that that's a regularly scheduled update on the clinical studies. I think Mike did a great job of pointing out that there are material changes that would occur in the study that would cause us to say, "We need to disclose an update on the study." There are opportunities where, for example, again, forward-looking, we see potency, we see knockdown, and the safety committee in reviewing that data says, "You're engaging targets substantially. You don't have to move to the next cohort, just expand the existing cohort. Where there are design changes to the study that can be informed by data, that would be a deviation from what we've set out publicly as this is the clinical trial design. I think we're going to let the data drive those updates, and I think it's exciting to now be in a position where we're not running as historically in a lot of the CNS studies and given our past experience, kind of landmark events where enroll five cohorts that all look the same at fixed periods of time, evaluate the data at the end, and then flip the card at the end of that and see where we are. What this provides, and I know this is the challenging part of it, is these periodic assessments that can provide that. What that enables us to do is substantially contract the time that it would take for us to get to an important decision, as Mike said, that could lead to changing that study to a registrational study. We'll provide updates as this year progresses and others as to the progress we're making on those studies. Understand. Thank you very much. From Stifel, we have Paul Matteis. Please go ahead. Hey, thanks for taking our question. This is Alex on for Paul. Another question on C9. I was wondering, from natural history, do we have an understanding of how poly-GP lengths relate to disease severity? Is there sort of a threshold knockdown that you're looking for, or how are you thinking about that? I have another quick follow-up. Thanks. Sure. This is Mike. Regarding the level of poly-GP, the data that is out there now suggests that the actual severity of disease may not be directly linked to the level of poly-GP in the CSF. You can have people who are sort of those disease carriers that have poly-GP detectable at a pretty high level, and you can have people who are symptomatic and the level's relatively low. As an indicator of progression, those data are evolving. We have to see what happens with interventional studies and whether changes translate into clinical changes. In the end, the goal is to get as much knockdown as possible because of that. We want to be able to lower that level to the minimal level in the CSF detectable, because remember, it is just an indicator of multiple polypeptide proteins that are there. There are other DPRs that we are also trying to affect through the treatment, of which poly-GP is just one indicator. Also, CSF concentrations are just an indicator of CSF. The tissue levels may be different. Again, it's a marker. The goal is to get it down. It would confirm target engagement, and it would drive us forward into a clinical efficacy study. That's its purpose. Great. That makes sense. On AAT and the ADAR program, sounds like it's sort of just optimization at this point, but can you walk us through kind of the steps that you see for an IND filing? Yeah, I think a lot of the steps forward are not different. I can take away kind of the normal IND-enabling safety studies that you would do, your CTA-enabling safety studies. I think what's important there in terms of the approach, and I think as Salim mentioned, there's a whole bunch of different approaches. I think as we bring forward an RNA therapeutic approach that's impacting transcript, we wouldn't anticipate that the studies we would be doing there for a GalNAc oligonucleotide would be different than other oligonucleotides. This is different than the biologics approach using viral vectors or impacting DNA. Put that piece aside, that's the standard high preclinical toxicology package. Prior to that, to your point on optimization, I think, the first step in this program was what we delivered in the H1 of this year, which is demonstrate target engagement in a relevant model that tells us that we've achieved levels that were at that threshold, or as we mentioned on the call, to that floor. Where optimization's occurring now, as Paloma alluded to on the call, is about continuing to see the enhancement of editing efficiency and potency, so pushing us higher into that range and balancing that with durability. Again, reducing the frequency of administration. I think we're on track for doing that and building a compelling program in that space, and that's why we're excited to give a much more comprehensive update on the progress we've made since that data release, as it will line up with our path to advancing a clinical candidate. More to come at the research day on ADAR. That's what we talk about with optimization. We think we're there now. It's about fine-tuning the durability potency to achieve maximum level without letting great being the enemy of good. I think we're achieving substantial levels where we are today. It's just the finalization of what will go into the candidate package. Great. Thanks so much. Our last question from RBC, we have Luca. Luca, please go ahead. Oh, hi. Great. Thanks for taking the question. This is Lisa in for Luca here. Two from us. I wanted to ask first off; we know that Ionis and Biogen are expecting to report data for SOD1 ALS in the fall. I know you're not going after SOD1, but just wondering, how are you thinking about that data and any implications for your programs? I also have a follow-up question on A1AT. Is achieving 11 micromolar A1AT in the serum the bar for success here, or do you think patients could get back to potentially normal levels? The reason I ask this is because we know that 11 micromolar is the bar for MZ patients, but we also know, at least from KOLs that we've talked to, that MZ patients aren't always asymptomatic as originally believed, and they can still have some liver and lung issues. Thank you. No, it's a great question. I'll take your second one first. We'll transition. While we're talking about the 11 micromolar, I think there's a reason why we don't stay focused on that. We talk about continued optimization and dosing regimens. I think key for us was the identification of could we get functional AAT restoration and achieve certain threshold levels, exactly to your point. I think that was key for us, saying that we've opened the door to establishing that floor and continue to bring forward what the possible advantages are. I think the key is going to be following this over time as well. It's not just about pushing a reactive protein and sustaining it. It's really what the underlying thesis, as Paloma explained, is about restoring a functional protein that's there when the body needs it. It can be expressed at the requisite levels that the body needs and do the work that it needs to do over periods of time. To your point, we've had discussions in sharing the data with where we are and where we're going with Key Opinion Leaders. I think there's a lot of enthusiasm for this approach. One, on not being a DNA modifier, and importantly, we're seeing an equivalent approach and excitement about this restoration of the functional side. Again, the elastase assay, meaning that we're making this protein, the protein is functional, and it's there and transcribed when it's needed. I think those are the pieces and building blocks going into the program, and we're excited to, again, show this as the floor and really push the availability of being able to do more. As we transition to SOD1, and I'll let Mike pick up on the other side, but I do think it's important, and we've looked at this historically in comparison to a number of features. I think it is exciting that we're bringing new designs, new chemistries forward that have differences in terms of distribution, durability, exposure. It's always challenging what to compare and read through from somebody else's programs in chemistry on our own. I think we're letting our data support now with extensive preclinical in vivo data that we have for our programs, letting those data drive those programs forward. I'll let Mike speak specifically to SOD1 and how we think about the space. Yeah. I think that obviously it'll depend upon what the data look like. A result demonstrating that in target engagement reduction that leads to a clinically meaningful outcome is obviously certainly great for patients, but it also, once again, validates the approach of doing intrathecal administration with the engagement of target in neurological disease translating into clinical benefit. When you think about our approach to C9, where now with the PN pharmacology, we have all the advantages that we've been talking about of this next-generation approach and potential for durable effect, potential for high potency for a different target, but still in this disease, and actually in two diseases when you pull in FTD, it makes us quite optimistic about that we're on the right track, and now this is about engaging target and then measuring that effect in the clinic. Looking at it as the potential it brings to intrathecal administration for our C9 program leading to clinical effect, it actually makes us pretty optimistic where we are. Yeah. I think in the end, and just to put a summary on that, I think what we've seen in devastating neurologic diseases is the desire for medicines to work. I think we are hopeful that there are approaches to ALS and SOD1 that do bring hope for patients in the sense that while it is a smaller variant than C9 and there's not an overlap, I think it continues to open up discussions around regulatory pathways and others for patients to have hope. I think we wish the best for everyone in the space. Great. Thank you. Very helpful. Thank you. We'll now turn it back to Paul Bolno for closing remarks. Thanks, everyone, for joining the call this morning to review our Q2 2021 corporate updates. Thank you to our Wave employees for their hard work and commitment to patients. We look forward to speaking to you again at our research day in the fall. Have a great day. Thank you. Ladies and gentlemen, this concludes today's conference. Thank you for joining. You may now disconnect.