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spk05: Good morning, and welcome to the Wave Life Sciences second quarter 2023 financial results conference call. At this time, all participants are in the listen-only mode. As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Rausch, Vice President of Investor Relations in Corporate Affairs. Please go ahead.
spk14: Thank you, Haley. Good morning, and thank you for joining us today to discuss our recent business progress and review Wave's second quarter 2023 financial results. Joining me today are Dr. Paul Bono, President and Chief Executive Officer, Anne-Marie Lee-Kwai Chung, Chief Development Officer, Kyle Moran, Chief Financial Officer, and Dr. Chandra Varghese, Chief Technology Officer. The press release issued this morning is available on the investor 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 several 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 SFC filings, including our annual report on Form 10-K for the year ended December 31, 2022, and our quarterly report on Form 10-Q for the quarter ended June 30, 2023. 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.
spk09: Thanks, Gabe. Good morning, and thank you all for joining us on today's call. Today, I'll share highlights on our progress during the second quarter and then turn the call to Kyle to review our financials. Then we'll open up the call for questions. Anne-Marie and Chandra are on the line today and will be available for Q&A. In the second quarter, we continue to execute on our vision of pioneering transformational RNA medicines using our multimodal platform. We remain on track to submit CTAs for our AATB program the first RNA editing medicine to enter human clinical trials. We're accelerating work on a number of compelling targets in our collaboration with GSK, and we continue to advance our clinical programs in DMV and HD. Today, I'll begin with AATD and RNA editing, then review our progress with GSK and building a sustainable pipeline. And finally, we'll end with an update on our clinical trials. As I speak with you today, we are preparing for the imminent submission of our first clinical trial applications, or CTAs, for WVE-006, the first RNA editing clinical candidate for the treatment of AATD. This milestone is important on multiple fronts. First, WVE-006 signifies an entirely new modality moving into the clinic. We are incredibly excited about this milestone, which is an important advancement for the nucleic acid field and for all patients who stand to benefit from RNA editing therapeutics. With AAPD, our ability to utilize validated biomarkers in the clinic is expected to enable rapid delivery of proof of concept data for OO6. This early clinical data set would increase the probability of success with ways future RNA editing programs in the liver and beyond. Second, our path from target to the clinic with OO6 reflects the translational speed of our platform. Upon first human dosing, we will demonstrate that we have expediently advanced this clinical candidate with a novel modality from the bench to patients at a remarkably fast pace. As we build our pipeline, we expect to drive further efficiencies with each new RNA editing clinical candidate. Importantly, OO6 is not only first of its kind, but it's also best in class in AATB as supported by our robust preclinical data package. We are able to achieve remarkable potency and durability of editing with convenient subcutaneous dosing because of our unique fully chemically modified oligonucleotides. OO6 is also compatible with GalNac conjugation, a highly specific and elegant delivery tool that is well validated through multiple approved silencing therapeutics on the market. For AATD, it is a significant advantage to have a stable and optimized candidate that can leverage GalNac and thereby avoid lipid nanoparticles, which require intravenous dosing. Among the AATD field, we continue to generate excitement for our RNA editing approach, which is a first-in-class therapy designed for restoration of both healthy hepatic and pulmonary function with a reversible, redosable therapeutic agent. Our team has heard the enthusiasm firsthand from the community at the Alpha-1 National Conference in Dallas, Texas in June. There is major unmet need in AATV with current therapies largely confined to treating either pulmonary or in the future, hepatic manifestations of the disease. Despite the limitations of current therapy, AATD already represents a substantial pharmaceutical market, with augmentation therapy alone currently accounting for about $1.3 billion in annual pharmaceutical revenue worldwide, and this market is expected to grow. Our collaboration with GSK puts us in a strong position to execute on bringing our novel therapeutic option to this market. GSK has a long history and clear leadership in respiratory medicine, development and commercialization, And under the terms of our deal, WAVE is eligible to receive substantial development, launch and sales milestone payments, including meaningful near-term clinical milestones, as well as significant loyalties. As with AETD, our internal discovery work on the next wave of RNA medicine is substantially focused on first-in-class RNA editing therapeutics designed to repair and restore proteins. With ADAR editing, we have a versatile modality that allows us to impact target biology in novel ways. As we look at the universe of genetic mutations driving disease, the majority of these mutations lead to a loss of protein function, meaning they can't be addressed with silencing tools such as siRNA or antisense. WAVE is best positioned to capitalize on these loss-of-function disease targets using our protein restoration and repair tools, including our leading RNA editing modality and validated pharmacological platforms. We are not constrained by therapeutic area and have previously shown robust editing in extrahepatic tissues, including CNS, kidney, and lungs. Beyond rare monogenic disorders, there's also a growing opportunity for RNA medicines for prevalent diseases. With genetic insights being unlocked from large genome-wide association studies, new druggable targets are rapidly becoming available. These targets have existing biological validation rooted in human genetics. GSK is at the forefront of investing in genetic discovery. Through our strategic collaboration, we are benefiting from their proprietary genetic insights, which augment our own internal data sets and are informing and accelerating our next wave of programs, including partnered and wholly owned programs. We are rapidly building momentum within our collaboration, and the WAVE and GSK teams are already actively working on multiple targets. Importantly, GSK pays 100% of the costs and expenses related to target validation for these partner programs. As a reminder, the GSK deal includes meaningful near-term milestone payment opportunities beyond the clinical development milestones related to WV006, which has the potential to add substantially to our balance sheet in 2023 and beyond. We are planning to hold a virtual R&D day on September 28, 2023, during which we will demonstrate how we are continuing to extend our leadership in RNA editing. We will also discuss how we are uniquely translating genetic insights into internal, fully-owned programs for both rare and more prevalent diseases. During the event, we will share new preclinical data for both hepatic and extrahepatic disease indications, highlighting the potential depth and breadth of our next wave of pipeline programs. Moving on to DMV, We are on track to initiate Part B, a potentially registrational Phase II study of WVN531, our exon 53 skipping candidate. This open-label study will evaluate doses of 10 mg per kg of N531 administered every other week, and we plan to assess dystrophin protein after 24 and 48 weeks of treatment. Since our last update, our clinical development team has filed the clinical trial protocol with regulatory authorities and identified additional trial studies. We expect to share clinical data inclusive of dystrophin proteins in 2024. If these data are supported, we intend to use them to file for accelerated approval in the U.S. As a reminder, our excitement for N531 is grounded in the proof-of-concept data from Part A of the study, which showed 53% exon skipping after just three biweekly doses, high muscle tissue concentration, and a favorable safety profile. We presented these results to the DMD community at the PPMD conference in June, where they were met with excitement and optimism. With the extended dosing period in the forthcoming trial, we expect these high levels of skip transcript to result in downstream accumulation of substantial fully functional dystrophin protein. We know the DMD community is waiting for additional and better therapeutic options. With N531, we aim to provide a treatment option that delivers convenient safe production of endogenous functional dystrophin and ultimately meaningful clinical benefit for all patients amenable to exon 53 skipping. We're also planning a broad strategy to expand the number of exons we can address, which we would accelerate rapidly following positive dystrophin data for N531 to build the wholly owned DMD franchise. Turning to WVE003, our first in class allele selective candidate for Huntington's disease or HD. HD patients have no disease-modifying therapies available to them today, and we believe OO3 is the most promising HD compound in development. OO3 takes advantage of broad delivery to the CNS, thereby reaching the variety of brain regions implicated in HD. We've now confirmed the ability of all of the nucleotides to distribute in the CNS in multiple NHP studies with our partner, including relevant concentrations in the cortex and striatum. Therefore, we are confident that OO3 is getting to the right part of the brain. It is also the most advanced approach designed to selectively knock down the toxic mutant Huntington protein while sparing the healthy wild-type HTT protein. Wild-type HTT is essential and plays several critical roles in the CNS, including regulation of the synaptic and protein transport, promoting neuronal survival, and formation and function of cilia, which are essential to regulate CSF flow and reabsorption. Dysfunction in any of these pathways could be expected to adversely impact response and could potentially cause declines. With only single doses of WV-003, we have already demonstrated positive initial mutant Huntington reductions of approximately 35% as compared to placebo in the CSS, with wild-type HTT levels appearing consistent with allele selectivity. The SelectHD trial has continued to progress. And in the second quarter of 2023, we initiated the multi-ascending dose phase of the trial, dosing at 30 milligrams every eight weeks. Given our robust and durable knockdown data observed in the multi-dose cohorts of the FOCUS-C9 clinical trial of WBE004, we believe the multi-dose data for 003 will be most important to informing our next phase of development. In the second half of 2023, We intend to share additional single-dose biomarker and safety data, along with any available multi-dose data. With that, I'll now turn the call over to Kyle Moran, our CFO, for our financial update. Thanks, Paul.
spk08: Turning to the financials, our net loss in the second quarter of 2023 was $21.1 million, as compared to $41.3 million in the prior year quarter. The decrease in net loss was primarily driven by revenue recognized under our collaboration with GSK. under the GSK and Takeda collaborations in the second quarter of 2023 was $22.1 million. In the prior year quarter, revenue of $0.4 million was recognized under the Takeda collaboration. Research and development expenses were $33.3 million from the second quarter of 2023, as compared to $29.7 million in the prior year quarter. This increase in R&D expenses was primarily due to increased external expenses related to our clinical program. GSK expenses slightly declined in the second quarter. Sorry, G&A expenses slightly declined in the second quarter to $12.3 million as compared to $12.8 million in the prior year quarter, primarily due to decrease in share-based compensation. We ended the second quarter with $173 million in cash and cash equivalents as compared to $88.5 million as of December 31, 2022. The increase is primarily attributable to the upfront cash and equity investment of $170 million received in the first quarter from our strategic collaboration with GSK. We expect that our cash and cash equivalents will be sufficient to fund operations since 2025. As a reminder, we do not include future milestones or opt-in payments under our GSK or CACDA collaborations in our cash runway. As Paul stated earlier, we have the potential to receive meaningful near-term milestone payments in 2023 and beyond, including clinical development milestones related to WVE-006, our RNA editing candidate, and treatment of AATV. I'll now turn the call back over to Paul. Thanks, Kyle.
spk09: We are well positioned to execute on multiple upcoming milestones across our pipeline in 2023 and beyond. I look forward to seeing many of you at upcoming investor conferences and to speaking with you at our R&DA day event in September. And with that, I'll turn it over to the operator for Q&A. Operator.
spk05: Thank you. We will now conduct the question and answer session. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Steven Seedhouse from Raymond James. Go ahead with your question.
spk00: Steven Seedhouse Good morning. Thanks so much for taking the question for the broad update. Paul, you mentioned rapid delivery of proof of concept data from the AATD study. I was hoping you could just expand on that. Comment on sort of the initial doses you'll be in the clinic with. When gene editing went into the clinic in vivo, you know, there were pretty profound editing rates already, even at the lowest doses. Just curious if that's the type of thing you're expecting to sort of manifest here at the early doses and study. And what other, other than editing, what other sort of proof of concept features do you think you can generate pretty quickly?
spk09: Wonderful. I'll take the question, Steve, and thanks for it, and then hand the call to Anne-Marie. But I think when we talk about rapid proof of concept, our goal is, as stated, to as quickly as possible get to a measurement of protein, both through, as we stated before, the study rapid healthy human volunteer section and then treatment section. But the goal here is you bring up measuring editing efficiency. I think what's unique and really special about the alpha-1 antitrypsin indication is that we can measure the most important contribution of editing, which is protein formation. And so the biomarker we'll be able to measure in that study is the alpha-1 antitrypsin protein, and we'll also be able to characterize how much of it is fixed corrected protein. So I think it gives us a really unique way of confirming preclinical studies in the clinic, both in the magnitude of production, but also the quality of production. Emery, I don't know if you have other comments you want to make to the clinical trial design team.
spk04: No, well, I would perhaps add that we're in the final stages before submitting, almost ready to submit the CTAs, and we'll comment further on the design once we're locked and loaded there.
spk00: Okay, thanks. And just when you think about assessing off-target RNA editing, can you just describe, is this much different than you would do for an siRNA, for instance? Is it any more onerous? What's your understanding of the sort of regulatory landscape for establishing an off-target margin for RNA editing therapeutics?
spk09: Yeah, I mean, I think what's exciting about know rna editing as we think about a standardized oligonucleotide approach and looking at our experience in si rna and antisense is the ability to assess normal you know what are the what are the potential targets in the same way we would do that for others as you know and as we've shared previously we've done the characterization to look for bystander edits and others on the transcriptome and saw highly specific editing and therefore we didn't see bystander edits so in preparation for this submission, we obviously did a lot of that work to preempt that in terms of demonstrating as a new modality that we don't see by standard as it's highly specific and behaves the same way as other oligonucleotides. And so I think we're excited about the prospect of thinking about this like others, as opposed to, as you alluded to, kind of the more onerous work that needs to be done on DNA editing. I mean, I think to the other point is, I think it really reflects the ability and the importance of reversible editing, the idea that we're working on the transcript and not inducing permanent genetic mutations on DNA. So I think as we approach this, particularly as we think about prevalent diseases, we think it's an important contribution that we get to make to the space of really thinking about how do you go after not just devastating rare diseases, but actually apply these technologies to broad chronic diseases, which is important, obviously, to ourselves and to our partners at GSK.
spk00: Yeah, just lastly for me, I appreciate that. This is maybe thinking a little bit ahead, but as you think about initial patient selection for AATD, how broad is that demographic going to be? Like, will you be looking for patients with lung and liver involvement right away to sort of, you know, show the power of this approach and specific genotypes that, you know, would be early targets? Any comments there would be appreciated. Thanks so much.
spk09: Yeah, I mean, I I'll hand it over to Anne-Marie in a second on the clinical side, but I think it is important as we think about the application initially where we're pursuing it, which is you think about the homozygous ZZ patients, it's both liver and lung. And so as we think less about where the manifestation is, the actual driver of that disease is in the underlying genetics. And therefore, it's about correcting those ZZ patients to MZ patients. and therefore following the protein relative to that. So it's much more about selecting for the genotype and demonstrating, evaluating the protein and the constitution of that protein in this initial period. Later, we can then say, look, we can describe that to the lung and think about where Protein infusions have been developed in thinking about achieving threshold levels of alpha-1 antitrypsin protein and looking at liver demyographics. But I think initially, the proof of concept really is focused on demonstrating that translational potential of both for AATD with this particular medicine, but even the RNA editing field more broadly and what the impact is we think through other hepatic targets and beyond. Emery, I don't know if there's anything else you want to add to that in terms of clinical trial demyographics.
spk04: No, I mean, I think you hit it. We're focusing on ZZ patients, phenotype patients for now, and there'll be more details about the study once we're in full agreement with regulators.
spk09: I think the other piece is, you know, if we think about the ZZ population, the ZZ population by itself is about 100,000 patients there in the U.S. So as we think about that, there is a consequential patient population to study. So, you know, we're not concerned that we'll be able to find the patients for the study.
spk00: Thanks so much.
spk03: Thank you. Our next question comes from a line of Paul Matias from Cecil. Go ahead, Paul. Hi, this is Julian on for Paul.
spk07: Thanks so much for taking our question. On AETD, I know you said for O6, you're not constrained by therapeutic area. I'm just curious, you know, regardless, is there anywhere else in particular that you find compelling Beyond AETD for where you may be interested in establishing proof of concept moving forward. And then any other color also you could just provide in the GSK collaboration. I know you mentioned that you're currently working with them on numerous targets, but any other color you could provide on how that's coming along and how you plan on allocating your resources for joint programs versus your own moving forward would be super helpful. Thank you.
spk09: No, thank you, Julian. I'll take it from the beginning. And, you know, I think you set up a really important context at the very beginning, which is, you know, I think you said AATD is not concerned by therapeutic error. I mean, AATD, you're right, liver, lung, but we're treating the liver to ultimately create the protein that protects the lung. So I think it's important in the context of AATD optimizes in a POC of galnet conjugation and what it can do across functions. What we've done, and I think these are important data sets that we've previously shown, and again, as we said earlier, that we plan to do the update on September 28th at our R&D day is, we have shown data extrahepatic, meaning absent galnet, the chemical modifications that we have distribute to a number of tissues, CNS, lung, kidney, and others. So I think as we think about those therapeutic areas and what each of the potential within those tissues unlock, I think what we're seeing is an expansion of indications. On a previous call, and we'll obviously share more on R&D day, I think we're also excited as we talk about not just, as we said, rare and prevalent, but really thinking about mechanisms. So in AATD, here we're talking about the ability of a correction that actually changes a protein from a mutated form to a wild type or healthy form. There are applications in a number of tissues and therapeutic areas where we can apply that in developing meaningful therapeutics. What's been exciting and what we've shared previously some in vivo data on and we'll continue to share more on that is the ability to do upregulation. So to think about areas where you're underexpressing a protein and then rather than trying to augment that by trying to deliver an mRNA therapeutic or other technology, which could be constrained even by mechanism of delivery, the ability to actually stabilize a transcript increases expression and therefore increase the protein that's produced lets us think about other applications beyond just the base correction, fixing a protein. And as we think about that area, we think that universe is really broad. It gives us a lot of opportunities to think about multiple therapeutic areas for us. So we are excited about sharing more data on programs in those areas and data that supports the growth of the RNA editing field and what it can do beyond alpha-1 antitrypsin.
spk03: Excellent, thanks so much.
spk09: Oh, sorry, last question. I just, with the GSK component. So, you know, as much as I'd love to be able to speak for a partner, I think we, you know, as we share today, I think it's safe to say there is an extraordinary amount of momentum. It was evident anybody who attended BIO, we were on, we were the participants with GSK as they were sharing kind of where they see the translational potential of their genetics investment. and have really been highlighted by them as the opportunity that we provide with a multimodal platform. I think editing is one. Importantly, as GSK looks across their universe, it's not just constrained to loss of function and editing. There are a lot of really prominent programs in silencing, and we are partnering with them across silencing using siRNA and some of that data we shared last year. as well as on the editing approach. And so really being able to think about diseases holistically, where we're not constrained to either an upregulation, gain-of-function disease, or loss-of-function, but can really pick the best tool for the right job. So I think there's a lot of momentum on the collaboration across programs, and we're excited to continue to provide updates where we can.
spk07: Excellent. I appreciate the caller.
spk10: Thank you.
spk05: Thank you. Our next call comes online of Ian Yang from Jefferies. Go ahead.
spk11: Thank you. I have a couple of questions on RNA editing. So obviously you have the most advanced program in RNA editing, but others are doing as well. So could you comment on your technology, how you are better positioned to for RNA editing compared to others, although there is not a lot of data out there from others. So that's question number one. And second question is on AATD program. And obviously, you are going to be talking more about this at the R&D day. But as you are very close to filing a CTA, when do you think we will be able to see the data? And in terms of serum AAT protein levels, you have shown remarkable increases in rodents. But how should we think about in humans and how many fold over increase would be your objective? Thank you.
spk09: Great. We'll unpack that a lot. I think if we start with the front and then I'll move to your final question, which is really the translation of why are we leading in editing? How does that translate to AAPD? And ultimately, what do we expect to see in the translation in humans? I think you said a lot at the beginning when you said, why are we ahead of others? And I think you really brought up the important piece, which is there's not a lot of data out there from others. And I think what I'd like to say is this doesn't come from an immediacy of saying, well, we're interested in RNA editing. It comes from over a decade of investment in building an oligonucleotide chemistry engine. And what we were poised to do when we entered in the editing space was really bring together this convergence of best-in-class nucleic acid chemistry, the how, how do you create guide strands that better interact with enzymes? How do we design that to more specifically and enhance the opportunity set that we have with ADAR? And ultimately, how does that translate both in our non-human primate studies in the liver, you know, using GalNec, in the liver not using GalNec, and in other tissues beyond the liver? And I think if we get to the root of really how we approach things, It is a chemistry-driven exercise. And I think in doing so, we've been able to get to short oligonucleotides that aren't long, that don't require a delivery vehicle. So we're not constrained to lipid nanoparticles that I do think ultimately complicates delivery and accessibility. That's important because I think a lot of times for those not familiar with LMPs, the chemistry that one would use to be compatible with an LMP versus what we can do to not be in one means that we can focus on really enhancing not just potency, but stability and durability. So as we think about optimizing pharmacology, as we transition programs and think of this not as a science experiment on editing, but ultimately translating it to a human therapeutic means we are thinking about what's going to be a best in class therapeutic in frequent subcutaneous administration. being something that's potent and durable in terms of patients and safe, you know, as we think about being able to avoid off-target editing, bystander editing, and reversibility. So as we put that whole profile together, we built this program systematically from the beginning off of our chemistry engine in a data-driven way through our publications, presentations, and have built that up through models. Now, what's important in translation, we said, okay, well, how do we know that this is going to translate? You know, what's giving us confidence there? I think the day-to-day, and I appreciate your recognition that that data is consequential that we've seen approach production. By starting in Galnick, what we're able to see is there is good precedence for that translation of thinking about human hepatocytes into rodent studies into humans, given that we've got a delivery agent in Galnick. And so we're going to learn a lot about the translational pharmacology both on the disease and the new modality via that translation. And that's going to teach us, obviously, a lot about preclinical modeling as we think about subsequent programs as they go forward. The benefit of all of that is we can look to other modalities and their translation to be able to start predicting where we think doses need to be as we get into the clinic. And that's important because, as you said, we think about levels oftentimes as a protein in vivo studies, The fold increase off of baseline is the best way to start thinking about translational potential. And as we think about being able to increase this fold from baseline, we saw seven fold from baseline. If we went back and looked at human studies, you're in the range of, I think it's like two and a half to, you know, three fold to five fold improvement that ultimately translate from these easy patients to MZ. So, you know, it's not just a measurement of the protein that's being produced in the rodent model, but ultimately in the translation of how much the fold of editing is translating to fold protein production. That's giving us our confidence as we move in the clinic. So like anything else, we do need to run that first study. I think we picked the right program with the right delivery tool to demonstrate first-in-class editing. But really excited as we go into September to talk about a multitude of opportunities beyond the ATD, beyond just protein correction, beyond the liver, that we're very excited to share with everyone. And it'll be a great opportunity to talk about the future of RNA editing.
spk11: Great. Can I have a follow-up question? So you have about $225 million in development milestones from GSK on this AATD program. So starting Phase 1-2 this year, how much of a milestone would you be expecting from that? Thank you.
spk09: Great question on terms of, you know, as we alluded to before, that we've got a number of development milestones beyond commercial milestones. from GSK that come in over time. What we can't do, obviously, is break out those payments at various points. Obviously, as we receive them, there are opportunities where those are disposed, obviously, in our financial statements. But, you know, key is delivering this program into the clinic and beyond, which contributes milestone payments, importantly, beyond AETD. And I think that was another important feature is There are a whole host of programs that are moving collectively with GSK beyond AATD. And it's important to note, not only do we have those programs where GSK pays 100% of the R&D expenses as we're advancing them, but those also have milestones, both preclinical and clinical and commercial milestones. So as we think about the magnitude across the collaboration, there are multiple potential inflows coming from executions. And I think it's important, as you said, that those are not counted in our runway statement. So those would be accretive to our current cash flow.
spk11: Thank you.
spk05: Thank you. Our next call comes from a line of Asim Rana of Truist Securities. Go ahead.
spk02: Good morning. This is Asim for June. Thanks for taking the questions. My first question is, you know, given that you've improved upon RNA c-mediated degradation, splice-blocking ASOs, RNAi, RNA editing, all with your AMR platform, I'm just wondering if you have any plans to design guide RNAs with enhanced properties like stability and low off-target cutting, basically to improve upon the hybrid DNA-RNA guides similar to those being used by Caribou. And as a follow-up question, just wondering, you know, maybe could you comment on the potential to use patients who've already received microdischarge and gene therapy from a competitor for your N531 program. And I'm specifically referring to throughout this program. Thank you.
spk09: Thank you. I mean, I think if we take the first question, as you pointed out, and, you know, I think it parallels Yoon's question earlier, which is, you know, we have made a substantial investment in building what we would view as best-in-class guide stress. We think about all of these opportunities. and you elegantly laid them out, all of them involve kind of this mechanism with RNA protein interaction, right? It's all about, you know, a guide RNA interacting with a protein and exerting a biological endogenous effect, whether that's cutting by a RNA stage or ego two, whether that's exercising and utilizing the splicing machinery to generate a protein correction or generate protein or RNA editing using ADAR. I think the opportunity sets that sit in front of us are, you know, a multitude. I think we're going to be focused on portfolio construction and translation right now with this toolbox into meaningful medicine. However, as you've known, in our history, we've always had through various collaborations and internal research exercises, collaborations that have pushed us into new areas. So whether that's editing beyond data, I whether or not that editing, including, as you said, highly specific editing around other mechanisms, whether it is DNA, well, that's not our core capability. there are always opportunities that we have in being approached to by others and saying, what are the opportunities that our proprietary chemistry can bring to other modalities? So we're not closed-minded to say, this is all we do. We recognize that you can't always predict what's coming behind. But I think the key is, and I think it's very important to say, that we are focused on building out a therapeutic portfolio in the areas that we've outlined, particularly using our RNA ethnic capability. And that's where we're going to put our internal resources. Collaborations are great resources that we have in research payments that we can use into exploiting and exploring these other capabilities that our chemistry can present with. Your last question, and I would want a little bit of clarity because I think there are two different components to it, which is where do we see N531 splicing and really exon skipping as we move it forward relative to the newly approved gene therapy or whether or not it's potentially combined, you know, whether you can work in combination. So, you know, I think it's important as we think about demonstrating best-in-class editing, you know, being able to deliver a highly specific, stable, durable skipping agent that doesn't require conjugates to get into cells to generate substantial amounts of exon skipping. I think we've got a very clear path in the exons that we hope to skip given our franchise. And I think seeing that translate and building that franchise is important. We know that gene therapy currently is only approved for one year of age for four to five-year-olds. So it's within that range. And only in the U.S. under an accelerated approval. So we're watching. We're paying attention to where that data is. There's, I know, data forthcoming at the end of this year really on the translation of that microdiscipline. So I think like everybody else, While we all saw that recent accelerated approval, I think there's a lot to continue to follow on the benefits of microdystrophin and whether or not it's functional. So I think there, we're not gonna take our eye off the ball and be distracted on not delivering functional dystrophin protein that we believe has, based on our preclinical data, based on following the Becker point, being able to ultimately see that that protein, when you can create functional protein, demonstrates a benefit. Importantly as well, as we think about the benefit of our skipping capability, comes down to that question around our chemistry, which is different than others. I think sometimes, Within the enigma of talking about these companies, we think about all exon skipping being kind of fairly similar where it can go on a distribution basis. And there have been a number of companies trying to drive better distributions in skeletal muscles. What's important is that our constructs preclinically, both in our double knockout model as well as non-eurocrimate, actually have higher levels of exon skipping in the heart and the diaphragm. So as we think about ultimately being able to change the outcome for these boys' lives, It's not only by repairing and fixing muscle and improving emulation. What's most important to us is making sure we protect the heart and protect respiratory function. So as we think about the totality of what we can bring forward potentially for exon skipping, you know, we're excited about what we can do with N531 and beyond, and we'll continue to watch the field evolve in terms of microdistributions.
spk02: Paul, thank you very much.
spk10: Thank you.
spk05: Thank you. Our next call comes from the line of Delane Zaid from Mizuho. Go ahead.
spk01: Great. Thanks for the questions, guys. Paul, just a few quick ones from us, just more clarification than anything here. So with the CTAs now being imminent, I'm sure you have some idea when we're getting data, and I think folks have tried to ask it on the call, but I'll try to ask it maybe differently. Is the baseline thinking here that we'll be able to get data in 2024 and also just curious when you'll be able to is a phase one trial design being shared this year or are we getting that also in 24 on DMD the functional endpoints that you've mentioned do those have any bearing on whether this phase two is registrational or is it just going to be solely dependent on dystrophin levels and then on 003 The wording in the press release, it seems like it changed a little bit versus the first quarter. So I'm just curious. I think this time you guys added the word available multi-dose data versus last press release. The word available wasn't in the press release. This press release was additional single dose and any available multi-dose. Last press release was additional single and multi-dose. So curious what exactly has changed there in the multi-dose side. Thank you.
spk09: Excellent. All right. So, if we start, and thanks for the question, Celine. So, if we think about, we'll just go right down in order, AATD, TMJ, HD. So, as it relates to the AATD timelines, as we said, the CTA submissions are imminent. Once we begin the trial, we can give a further update in terms of the expectations for data. I think it's always important just to see that trial kick off. I think it's obviously safe to assume that data won't be in 2023 for that study. But looking forward, I think when and what data we'll have as we move into 2024 is something that we can provide updates on once that trial initiates. As it relates to DMD, you brought up the question on differentiation of filing based on dystrophin and what functional data we have. I think first and foremost, and as we've seen from others, dystrophin will be a very important trigger for us in potential filing. So getting that data is critical to us. What we have is the benefit, and I'll let Anne-Marie comment on as we think about function, is the availability as we follow these boys, not just from where the biopsies are, but really continue that study, as we said, for 24 weeks and 48 weeks. We have an opportunity to measure a number of different functional endpoints, and those don't only include the ambulatory. They include ability to look at respiratory function and others. So, Anne-Marie, I'll pause and let you answer any additional questions on potential filing or on DMD. And then I'll come back to HD.
spk04: Thanks, Paul. So, as you know, there is a well-trodden regulatory pathway for filing with dystrophin data, so we would expect that to be adequate. But, of course, as Paul said, we're running the study through 48 weeks, so we'll, of course, be providing any of the functional data available for that filing. Back to you, Paul.
spk09: Great. And so on HD, on the call, we mentioned available data. I mean, the key is there's no change. Actually, we're excited that the multidose is, you know, I think that's the update is that the multidose is underway in HD. So I think our update is being able to have available multidose data while we have single-dose data would be the update. I think it's very safe to say with that initiated that we would not expect full multidose data in 2023. That's hence the available data.
spk01: got it thanks guys just um quickly the phase one trial my question was on the phase one trial design are we getting that this year for 006 or is that something you also plan to share in 24. oh no you i mean we'll share the trial design once the studies initiate so we that won't be it that'll be 2023 so i i think that think about imminent filing and
spk09: I think we'll be able to share the clinical trial plan, which, to your question, will provide a lot more clarity as to timing of data as that study initiates. Perfect. Thanks so much, guys. You got it. Thank you.
spk05: Thank you. The next call comes from a line of Joe Schwartz from Leonique Partners. Go ahead.
spk13: Hi, Jenny. I'm for Joe. Thanks for taking our question. I was just wondering if you guys have commented on the stoichiometry of the AMLRs for RNA editing and how that compares to your other LIGOs for exon skipping or cyanogen, et cetera. I guess what I'm really trying to get at is do you expect dosing to be in a similar range or higher, lower? And how does that influence how you guys are thinking about therapeutic index and any likelihood of potential dose-limiting toxicity?
spk09: Yeah, I'll take the beginning and then I can turn some of that over to, we'll see how, you know, I think, I think as you mentioned, as we think about the stoichiometry, or we just think about the pharmacology, I think is the better way of translational pharmacology of AMER editing, is it is a catalytic pathway. So we are able to harness a catalytic mechanism within the enzyme. So to your point, both on being able to give smaller amounts of drugs that then be able to stay. And that's where stability becomes such an important component of the drug staying stable, not being degraded, staying in the cell and able to exert its effect. So it is catalytic, as are a number of the mechanisms that we're utilizing. I think the other advantage as we think about AETD is by leveraging GalNec, we're getting, you know, we look at this a lot like other, you know, potential siRNAs and approaches where you're using GalNec conjugated oligonucleotides to hepatocytes with a catalytic machinery. So I think we're seeing it act very similar to other catalytic oligonucleotides in development. So this wouldn't be kind of... would be like a stoichiometric dose where you have to give more and more drug to try to exert an effect. So I think the catalytic efficiency of these enzymes is a huge advantage as we think about ambers. And we think about them a lot like we do RNAi. I don't know, Chandra, if there's other behavioral enzymatic features that you think about with ambers versus others.
spk12: No, this is a foundational technology benefit, right? Looking at how you can use this catalytic machinery to work to enable fast turnover kinetics. So that's really the basis. And to Paul's point, you know, all these looking at catalytic machinery, that's talking about it.
spk09: And I think it's important, too, as we think about extrahepatic, that we're not having to give large volumes to drugs, particularly as we think, too, about being able to dose and other routes as we think about other tissues. So, I mean, I do think that, you know, ultimately, as we think about the AMER platform, we should be thinking a lot like other silencing capabilities like mRNA.
spk10: Great.
spk13: Thank you. That's really helpful.
spk10: Thank you.
spk05: All right. I'm showing no further questions at this time. I would now like to turn the conference back to Dr. Paul Bona for a closing remark.
spk09: Thank you everyone for joining the call this morning. We've made significant progress advancing our pipeline and driving forward our leadership position in RNA medicine in the second quarter. I am grateful to every Wave employee for their dedication and focus on our mission and on the patients and families we serve. Have a great day.
spk05: This concludes today's conference call. Thank you for participating. You may now disconnect.
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