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spk05: Good morning and welcome to the Waves Life Sciences first quarter 2023 earnings call. At this time, all participants are in a listen-only mode. As a reminder, this call is being recorded and webcast. I'll turn the call over to Kate Roush, Vice President, Investor Relations and Corporate Affairs. Please go ahead.
spk04: Thank you, Operator. Good morning, and thank you for joining us today to discuss our recent business progress and review WAVE's first quarter 2023 financial results. Joining me today are Dr. Paul Bolno, 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 SEC filings, including our annual report on Form 10-K for the year ended December 31st, 2022, and our quarterly report on Form 10-Q for the quarter ended March 31st, 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.
spk08: Thanks, Kate. Good morning, and thank you all for joining us on today's call. Today, I'll share highlights on our progress during the first 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 also on the line today and will be available for Q&A. The first quarter marked a fundamental strategic change in how we at Wave are leveraging our leadership in oligonucleotide chemistry, including the formal beginning of our transformational collaboration with GSK, publicly announced in mid-December of last year. Let's take a moment to reflect on our evolution. More than 10 years ago, we started as a company focused on optimizing antisense oligonucleotide chemistry. We then leveraged relatively well-understood biological mechanisms of RNSH, directed silencing, and exon skipping. Gratifyingly, at this point in our evolution, we believe we are finally seeing the fruits of these chemistry efforts in our recent preclinical and clinical work. We see them in our positive BMD clinical data announced last December, to which I will return, and we are seeing them in our recent preclinical data with strong and durable RNAi-mediated silencing in liver and beyond. Over recent years, advances in chemistry combined with emerging genetic and genomic insights have enabled us to think more aggressively about engaging novel target biology, such as ADAR enzymes for editing, where we can use our validated chemistry to unlock high-value, first-in-class therapeutic franchises. Marrying novel biology with validated, best-in-class chemistry opens opportunities to make first-in-class medicine that can grow into class leaders. More, the sorts of targets we're interested in with biological validation rooted in human genetics when combined with validated pharmacology have improved the probability of success and development. Our demonstration at WAVE of best-in-class RNA editing, best-in-class exon skipping, and now also potentially best-in-class RNAi silencing allows us to be driven in a way we describe as multimodal in RNA medicine. This means we have a broad toolkit in RNA-directed pharmacology across multiple modalities, and we believe we can select the optimal tool for the job across the most attractive molecular targets and associated disease states. It is rare for a company to have both a validated pharmacologic platform and access to genetically validated targets, and a decade of work has uniquely positioned us to capitalize on this opportunity. Wave is leveraging our multimodal platform to pioneer first-in-class RNA medicine with a strategic focus on protein restoration and repair targets such as Alpha-1 Antitrypsin Deficiency, or AETD, that will provide life-changing medicines for patients and build major value for shareholders. Our unique capabilities enable us to quickly move beyond AETD to build value through pipeline expansion and de-risking. We intend to hold an investor event in the third quarter of this year, to highlight how we are translating our capabilities in protein restoration and repair into compelling new programs. Since we last gathered six weeks ago, we have made substantial progress in several aspects of our business, three of which I'd like to highlight today. First, our GSK collaboration with significant milestones that could be achieved in 2023 and beyond. dead-fast execution on driving WVE-006 to the clinic in alpha-1 antitrypsin deficiency, and rapidly generating data on the next set of RNA editing programs. And third, continued progress advancing WVE-N531 for DMD, a wholly-owned commercial opportunity for WAVE, into a study that would support potential accelerated approval. First, our transformational collaboration with GSK is off to a strong start. As a reminder, this partnership not only validates our leadership in RNA editing with our first-in-class 8R editing modality, it also acknowledges our best-in-class multimodal RNA medicine discovery and development platform. Through the collaboration, GSK provides WAVE with proprietary genetic insights to expand our pipeline both with partnered and wholly-owned WAVE programs. It has been an exciting and productive start to the collaboration, with both the WAVE and GSK teams working together to begin advancing the first set of targets. It's important to remind everyone that GSK has made significant investments in genetic discovery, as well as has a long history and clear current leadership in respiratory medicine development and commercialization. Both of these capabilities sets makes GSK the ideal partner for WAVE's pioneering AATD program. Importantly, The GSK deal bolstered our balance sheet with $170 million in upfront cash and equity to accelerate our existing pipeline and provide meaningful near-term milestone payment opportunities, including clinical development milestones related to WVE-006. These potential milestone payments, while confidential in their quantity and trigger events, have the potential to add substantially to our already strong balance sheet in the near term, including meaningful milestones anticipated in 2023, and beyond. Next, we continue to make steady progress advancing WVE-006 toward our first in-human trials. As a reminder, OO6 is our first-in-class galnet-conjugated RNA editing candidate for AATD. Since our last update, we have successfully completed the in-life portion of GLP toxicology studies as planned for OO6, and we are rapidly advancing towards CTA submissions this year. Among the fields, we continue to generate excitement for our novel treatment approach to AATD, which is a first-in-class therapy designed for restoration of both healthy hepatic and pulmonary function with a reversible and reducible therapeutic. There is major unmet need in AATD with current therapies largely confined to treating either pulmonary or in the future hepatic manifestations of the disease. Despite the limitations of current therapy, AADD 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. OO6 is on track to be the first RNA editing therapeutic taken into human clinical trials where we intend to utilize validated biomarkers to deliver proof of concept for OO6 and the field of RNA editing. Similar to the exponential growth of RNAi medicine following the de-risking of GalNec siRNA silencing in the liver, we believe early clinical data with OO6 would increase the probability of success of WAVE's future RNA editing program in the liver and beyond. We believe this would enable us to build substantial shareholder value in a way that is comparable to the early pioneers of RNA medicine. As we continue to expand our wholly-owned pipeline, we are focused on investing in first-in-class RNA editing therapeutics designed to repair and restore protein, such as with our AATD program. Our discovery team is intensely working on the next wave of RNA medicines to sustain our pipeline. We plan to hold an investor event in the third quarter of this year, during which we will demonstrate how we are continuing to extend our leadership in RNA editing and we also expect to share preclinical data on new programs. In DMV, we are laser focused on initiating our potentially registrational phase two study of WVEN531, our exon 53 skipping candidate, following our positive data in December. Our proof of concept data continues to be met with excitement by neuromuscular clinicians and the DMV community. As a reminder, These results included the impressive 53% exon skipping observed after just three consecutive biweekly doses, high muscle tissue concentration, and a favorable safety profile. With longer dosing, we expect these high levels of skip transcripts to result in downstream accumulation of substantial, fully functional dystrophin protein, as has been the case with other exon skipping strategies observed across the industry to date. A key distinction of exon skipping approaches such as N531 from gene therapy is the intent to generate functional Becker-like dystrophin protein, not mini or micro truncated dystrophin. Functional dystrophin protein has been established by the FDA as a surrogate endpoint for accelerated approval in DMD, something that is still in question for micro dystrophin. More, our hope for the DMD community is that options for patients continue to expand, and we believe that convenient, safe production of endogenous functional dystrophin can be a highly valuable and attractive option for patients as an alternative to or in combination with gene therapy approaches should they become available. Our team is quickly moving to initiate dosing in Part B of our study, a Phase II open-label study with doses of 10 milligrams per kilogram administered every other week. and plans to assess dystrophin proteins after 24 and 48 weeks of treatment. We will continue to share updates as we progress with Part B of the study, and we expect to share data in 2024. If the data are supportive, we intend to use them to file for accelerated approval. Importantly, our vision extends beyond Exxon 53, and we are planning a broad multi-exxon strategy which we would accelerate following positive distress and data for N5G1 to build a wholly owned DMD franchise. Turning to WV004 and 003, our CNS silencing programs are advancing in adaptive clinical trials. And as a reminder, these programs are part of an active collaboration with CICADA. WV004, our candidate for C9 ORF72-associated ALS and FTD, is being evaluated in the FOCUS C9 clinical trial. We remain on track to deliver a substantial data set consisting of several single and multi-dose cohorts in the first half of this year. This will enable discussions with our partner and inform next steps for this program. WVE003 is the first-in-class allele selective candidate for Huntington's disease, which is being evaluated in patients with a SNP3 polymorphism in the SelectHG clinical trial. Last year, we adapted the SelectHD study to expand the single-dose cohorts based on initial positive clinical mutant and wild-type Huntington biomarker data. Recently, the vendor of our mutant Huntington assay announced that they were subject to a cybersecurity attack, and we remain in close contact with them as they work to address this issue. Our patient samples were not impacted, and we will ensure that our vendor's relevant computer systems are fully operational and validated before processing. With this shift in timing, we now expect to deliver additional single-dose biomarker and safety data, along with some multi-dose data, in the second half of 2023. Like with 004, these clinical data will also enable us to discuss next steps for the program with our partners. As a multimodal RNA medicines company, we are able to leverage our collaborations to explore our best-in-class potential in RNAi silencing. RNAi is one of multiple modalities being advanced in our strategic collaboration with GSK. Just a few weeks ago, we announced the first publication of our siRNA design in nucleic acid research, and we have since received highly positive feedback from our peers, recognizing the transformational impact these findings have for the field of RNAi. The published data demonstrated unprecedented AGO2 loading following administration of a single subcutaneous dose leading to improved potency and durability in vivo as compared to a comparator from a commercial company with a clinically proven track record in RNAi. We believe these data are critical and highly enabling as the translatability of RNAi-based approaches from preclinical observation to clinical proof of concept have been well established. there remain many high-value RNAi targets in attractive accessible tissues, and more novel targets continue to flow from leading work in human genetics, including work by our collaborator, GSK. In sum, we are building a leading multimodal RNA medicines company with significant opportunity to expand our foundational work in the field of RNA editing. We are working with urgency to bring a novel RNA editing medicine to people living with AATD and important new treatment options for boys with DMD. We will deliver two important data sets this year to inform our CNS silencing programs for the ALS, FTD, and HD communities, and we're also excited to share more on our work with GSK and our emerging RNA editing portfolio beyond the ATDs later this year. It is a uniquely busy time at WAVE, and we believe we are well-positioned to capitalize on now years of hard work to enable rapid pipeline development. With that, we'll now turn the call over to Kyle Moran, our CFO, for our financial update.
spk09: Thanks, Paul. Turning to the financials, our net loss for the first quarter of 2023 was $27.4 million. That's compared to $37.8 million for the prior year quarter. The decrease in net loss was primarily due to revenue earned under our collaboration with GSK which became effective January 2023. Revenue earned under the GSK and Takeda collaborations in the first quarter of 2023 was $12.9 million. In the prior year quarter, revenue of $1.8 million was primarily earned under the Takeda collaboration. Research and development expenses were $31 million for the first quarter of 2023, as compared to $27.5 million in the prior year quarter. The increase in R&D expenses was primarily due to increased external expenses related to our clinical program, as well as compensation-related expenses driven by growth to support our program. G&A expenses slightly declined for the first quarter to $12.2 million, as compared to $12.4 million in the prior year quarter, primarily due to a decrease in compensation-related expenses. We ended the first quarter with $207.6 million in cash and cash equivalents, as compared to $88.5 million as of December 31st, 2022. The increase is primarily attributable to upfront cash and equity investment of $170 million from way of strategic collaboration with GSK. We expect that our cash and cash equivalents will be sufficient to fund operations into 2025. As a reminder, we do not include future milestones or opt-in payments under our GSK or Takeda collaboration in our cash runway. As Paul stated earlier, WAVE has the potential to receive meaningful near-term milestone payments in 2023 and beyond, including clinical development milestones related to WDE006, our RNA editing candidate for the treatment of AATD. I'll now turn the call back over to Paul.
spk08: Thanks, Kyle. This is an exciting time for WAVE. We are sharply focused on execution as we approach several meaningful clinical milestones in 2023 and 2024. We are leading the field in RNA editing, and with WVE-006, we are on the cusp of bringing the first candidate from this innovative new class of therapeutics to the clinic. We continue to leverage our multimodal platform and our collaboration with GSK to build our pipeline. Importantly, we are well capitalized to deliver on these near-term milestones, and I look forward to sharing continued progress with you over the course of the year. With that, I will now turn the call over to the operator for Q&A. Operator.
spk05: Thank you. At this time, we will conduct the question and answer session. As a reminder, to ask a question, you will need to press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. Please stand by while we compile the Q&A roster. One moment, please. Our first question comes from the line of Celine Saeed of Mizuho. Your line is now open.
spk00: Hi, good morning. This is Mike London on for Salim. Thanks so much for taking our questions. Just a couple from us, if possible. I'm wondering, so for DMD, wave N531, since phase two, we're now saying is potentially registrational, I'm wondering if there's any more additional details you can give us what it might look like. And specifically, if you think you might need more than 10 patients for registration or confidence around the number of patients there. And then separately for wave 004, now that we've seen a recent approval in ALS based on NFL, how does that change at all, if at all, thinking on a potential registrational path going forward? Thanks.
spk08: Thank you, Mike, for your question. And, Anne-Marie, I'll hand it to you in a minute. But just to follow up on the potentially registrational design, when we moved into Part B, as we provided the update earlier this year, we designed that study to be powered for greater dystrophin than the existing commercial program. And so in those calculations, that included the number of patients that we're including in the study. If we go back to some of the other therapies that were approved in the exon skipping space, they were approved on studies with eight, four patients. So we believe that the study is significantly powered enough to give us dystrophin. as a clinical surrogate endpoint for filing for accelerated approval. And subsequently, we continue to do the work necessary to have the confirmatory, or we call it phase three study, up and enrolling at the time we would file for that. So this study in both its design powering was set up to deliver on that potential registration pathway. Anne-Marie, is there anything you want to add to that question? And then I'll take the second.
spk06: I think I would just add that there's clearly a registrational path using accelerated approval using dystrophin, and so we would expect to access that pathway with positive study.
spk08: For the second question, relative to the impact on the recent ADCOM and the Toperson approval looking at NFL as a biomarker for our O4 program and study, I think absolutely. I mean, when we have those data now with single and multi-dose data, you know, the study has a long enough follow-up period of time with repeat doses for us to make similar assessments and access similar pathways. But we've got to wait until the data is cut and analyzed before we make that decision. Thanks. Thank you. Emerick, sorry. Emerick, anything to add to that?
spk06: I think I would just add that obviously, to first-in experiences provides a really interesting biomarker in NFL. And we know that NFL is important. We'll be assessing it in its totality with things like white blood cells in CSF and protein in CSF, as well as the safety and the pharmacodynamic effects.
spk08: I think just to add on to that one last piece is that I think one of the confluence was in the case of Toperson was biomarker data confluence with the NFL signal. And I think, you know, as we look into this study as well, definitely biomarkers and NFL in the confluence. I mean, with ALS, you know, this is a unique situation with ALS. So I think, you know, we're in a position to make those same evaluations.
spk03: Thank you. Please hold for our next question. One moment, please.
spk05: Our next question comes from the line of Jun Li of Truist Securities. Your line is now open.
spk11: Hi. Thanks for taking our questions. Given that neurofilament light chain is now an approvable surrogate biomarker for ALS, are there any studies you can point to that shows correlation between polyGP reductions and improvements in either functional or reductions in your filament might change as a follow-up.
spk08: Yeah, I mean, what's interesting to your question, and I think after, as we were saying earlier, after the outcome, the evaluation potential for O4 to have a potential path to accelerate approval is interesting. But in a lot of the same ways, SOD1 wasn't correlated to the NFL reduction. The study dictated that target engagement led to a change in outcomes that related to nfl being decreased so there aren't any correlations between polygp and nfl as we're running this study first study that's going to come forward you know we'll have data to look at polygp related to nfl for this particular molecule so i think that's why you know these data would be significant in the context of thinking forward about a potential accelerated approval and why we make the correlation, if we see it, between those two potential biomarkers. Emery, is there anything you want to add to that?
spk06: No, nothing to add, that's all.
spk11: Okay, great. And, you know, on the RNA editing front, our understanding is that one of your peer company, or maybe companies, is delivering their guide RNA for 8R-mediated RNA editing using LNP or ATD. Can you remind us your delivery strategy and any thoughts on packaging it with LNP? And I have one last follow-up.
spk08: Yeah, I mean, I think the beauty from when we introduced our RNA editing platform a couple years ago, and we're doing the work on chemical optimization as we talked about the evolution wave is, the ability not to have to use LMPs. I mean, the challenge in developing chemistries that are compatible with LMPs is a very short, unstable oligo. When we think about the data that's been shown by our peers, it shows protein levels in the course of hours. I think the key for us has been durability, potency, and accessibility, absent the need for delivery vehicles, Starting with the opportunity we have, which is without the need for vehicles means we can think about editing in multiple tissues where LMPs can't go. So that opens up the possibility of thinking about CNS, renal, other tissues. I think what's been exciting about us in starting our RNA editing platform and AATD with GalNec has been taking advantage of the precedent of GalNec in subcutaneous load doses, accessibility to hepatocytes, durability, and stable constructs. And then being able to leverage, much like the RNAi silencing world and our peers there, created the uniformity of if you see data in this, then the probability of success of program two, three, four, five, six, beyond, get better and better. And I think the advantage we have and why we're excited to provide that update later this year is taking advantage of GalNIC and what was done in silencing and applying it to the field of editing gives us highly potent, highly durable, subcutaneously administered therapies that we're excited about, not just for AATD, but continuing to open up that space for other substantial indications. I mean, we shared this data in NHPs in our Nature Biotech paper. But I think, you know, the field of LMT feels a little beyond that, where you have oligos that don't require them. And, you know, we've really, from the beginning, made that a fundamental component of building out the editing franchise.
spk11: Great. And one last question, you know, AAV discovery for CNS targeted delivery is a very active area of development with some recent progress. Do you have any thoughts on packaging your deliverables, especially RNAI, which can be vectorized in something like AAV, CNS targeted AAV, and, you know, would you be open to collaborating with someone with that capability?
spk08: I mean, I think we watch the space. I think it's something that, you know, obviously we, talked to a number of different companies. I think what's been interesting in thinking about CNS has really been the path to infrequent administration. So I think if one is relegated to monthly or less frequent administration, I think that changes the discussion. I think what we've seen is the ability for quarterly, twice a year dosing. I think as we look at some of our CNS RNAi silencing data, so the next generation of what we shared on our last earnings call, about being able to use RNAi and CNS without having to use conjugates. We see potent durable silencing using mechanisms that in other tissues have prolonged durability, such that I'm less concerned that we have to vectorize something and put added complexities and risk on a reversible medicine that has really infrequent dosing. I think it's been exciting to look at the work that we have getting beyond antisense silencing and CNS. We'll see that data already. We showed last year potential for quarterly or twice-a-year dosing. I think we're excited by the progress we've made in RNAi and CNS and other technologies, too. So I think it's something we'll always continue to evaluate, but we really need to see where the advantage is coming over some of the therapies that are already in our RNA medicines toolbox.
spk11: Great. Thanks, Paul. Thank you. Thank you.
spk05: Thank you. Please hold for our next question. As a reminder, to ask a question, you will need to press star 11 on your telephone and wait for your name to be announced. One moment, please. Our next question comes from the line of Paul Matias of Stifel. Your line is now open.
spk10: Hi, this is Julian. I'm for Paul. Thanks so much for taking our question. In the prepared remarks, you spoke at length about your collaboration with GSK and how you're working together to advance a set of targets. In terms of INDs that are coming down the pipeline, I guess, how do you anticipate the distribution to play out in terms of what may be wholly owned versus partnered with GSK? And any initial perspectives on how that may differ across specific TAs or disease targets would be great to hear. Thanks so much.
spk08: Thank you for the question. And you're right. I mean, we're excited about the collaboration because it's not distributed across therapeutic areas. I think what's important in the collaboration is really opening up access to the extensive work GSK has been doing in genetic insights on targets uniformly and broadly, both with their collaborations with the UK Biobank, 23andMe, and other genetic data sets that they've spent a lot of resources in investing in. So the exciting thing to us is really to think about GSK's partnership with WAVE in three approaches. One is, and to be very clear, we will continue to deliver wholly owned programs out of our portfolio, and we'll share more on the R&D editing space, that are unaffiliated with GSK. So these will be programs that we've done our own genetic work on advancing in the protein repair and restoration space. Second will be programs that GSK has identified that we're advancing with them, and that will span across the fields of RNA editing and siRNA silencing and beyond. And we will have some interesting work, as we said at the beginning of this call, those targets are underway and initiated that we're working on with them. And then the third piece, to your point, is our opportunity set. And we are evaluating those targets now. So as part of that initiation, that process has already begun of looking at targets from that genetic database that we ourselves are interested in and continuing to evaluate and analyze. So I think the key is it's a new collaboration coming fresh off the first quarter where it's initiated. I think both teams are energized in terms of the work that's coming off of it. So there was a lot of foundational work in the lead up to this that enabled us both to start this collaboration and be progressing it with targets very near term. And we'll provide more updates on that. I think a nice place for that next update will be at our investor day that we alluded to in the third quarter, where we'll be able to share more, not just about the work that we're doing, preclinical work that we're doing on targets, but really begin to start guiding to a future sustainable pipeline. And that's what I think we're excited about, a sustainable pipeline of new genetic medicine.
spk10: Excellent. Thanks so much.
spk05: Thank you. Please hold for our next question. One moment, please. Our next question comes from the line of Manny Beruhar of SCB Securities. Your line is now open.
spk07: Hey, guys. Thanks for taking the call. I guess a little more of a structural question around the GSK partnership. Obviously, based in the terms of that, a lot of opportunities to bring in substantial amounts of free cash flow around opt-in dates, et cetera, for new programs and targets. Can you give us a sense of mechanically in that partnership? So how far along does an asset need to be for you to engage? Is that defined in terms of how mature the preclinical data has to be before an opt-in decision gets made? Just give us a little bit of clarity into that so we can think about when we can start really rigging the register on that cash flow.
spk08: Yeah, no, and thank you for the question, Bobby. I mean, I think there's really two ways to think about cash flow in 2023 and beyond. And the first is before we get into the programs themselves, is just on the progress that we're making with OO6. So the advancement of WV-OO6, our Alpha-1 Antitrypsin RNA editing program, has substantial milestones associated with its progress. And so that's one sleeve with which we can look at substantial cash inflows going forward. I think the second which you bring up is looking at this concept of milestones related to programs. And I think what's important is The notion of the programmatic milestones, I mean, one, they're in some ways independent of data that's getting generated, more program initiation. So you can think of it as the start and identification of programs, and as those programs move forward, they then have their own milestone sleeves to them as those programs advance through the clinic and commercial. So I think we can start and say we're off to a really good start around the work on the targets. and we can provide updates as these programs become initiated. So we have, you know, the initiation of program payments, candidate payments when they translate, and then beyond as they become clinical programs. So, you know, I can't, you know, I can't provide updates on the exact timing at this stage with each of those programs now, but I think it is important to note that they don't have certain data inflections that are requirements for those program initiation fees.
spk03: All right. That's helpful. Thanks, guys.
spk05: Thank you. Please hold for our next question.
spk03: One moment, please.
spk05: Our last question comes from the line of Luca Issy of RBC. Your line is now open.
spk01: Oh, excellent. Thanks for taking your questions. This is Lisa. I'm for Luca. First, maybe just one on DMD. I'm just wondering about the regulatory path for the potentially registration of Phase II study. Will the accelerated approval path still be open to you if Vyonda 53 ends up gaining full approval based on their Phase III study, which is ongoing? If any color there would be helpful.
spk08: Yeah, I'll turn the call over to Anne-Marie. I mean, I think this is why we think about moving with urgency with our current plan and making sure that we're running a confirmatory study in parallel as we begin next year to assure that we have progress in either direction. I think the important thing is the full approval base in the clinical study would then validate dystrophin as a clinical surrogate endpoint. So there's an advantage to having that. I think we also want to make sure that we establish functional outcomes and clinical data on our molecule independently of the accelerated approval pathway. But, Emery, is there anything you want to add to that?
spk06: Yes, I think what I'd add is that it's important to note that the accelerated approval pathway is open to conditions that are serious, of course, and where you have a surrogate endpoint, but also meet an unmet medical need. I think everybody would agree that there is still unmet need, and even if the arm just becomes fully approved, there is still significant unmet need in DMD, and certainly that's the case we would be making.
spk01: All right. That's helpful. And then maybe just a follow-up. For a confirmatory trial, would you also use six-minute walk tests as the primary endpoint?
spk08: Emery, do you want to take that one?
spk06: Sure, I think it's too early for us to talk about what that endpoint would be, but I think what you're alluding to is the need to demonstrate that we're having impact on functional outcomes, which are, of course, the whole aim of producing dystrophin and helping preserve function for boys with DMD. So the endpoint that we will select will reflect that and will be agreed in with regulators.
spk08: I think just to add to that, and I think it's important as we reflect on our preclinical data for N531, second from our clinical data, because I think there's an interesting correlate there. But in our preclinical data, both in double knockout mouse and our non-human primate studies, we saw substantially more exon skipping in heart and diaphragm than skeletal muscles. So that 53% exon skipping we were seeing in skeletal muscle is most likely underrepresenting the amount of skipping we're seeing heart and diaphragm, which is substantially differentiated from the other exon skipping therapies that are either in the market or in development. And so as we think about the potential, and as Anne-Marie said, a lot of what we're reflecting on forward, both on the current study that we'll be initiating in, subsequent studies, we'll be opening up to more endpoints to think about beyond just the measurements of walk and skeletal muscle, but really being able to build in a differentiation in terms of those other endpoints that are really effective for quality of life as well as ultimately can lead to mortality. Just one more thing to add. There was an interesting reflection on the prior question, too, relating to GSK, and You know, while the question was very much focused on program initiation milestones, I just wanted to reflect back and just remind people, because I think there sometimes is forgotten that all of the research phases that are happening kind of prior to this program initiation are paid for by 100% by GSK. So there are cash inflows related to pre-specified research expenses that are 100% covered by GSK that will be coming into cash flow to support our discovery research efforts at WAVE. And then supplementing on top of that 100% research are the program initiations, which have full payments through the eight programs that they can initiate. So I do want to make sure that we distinguish that prior to receiving those initiation payments and differentiate it from the upfront payment that came in. There is additional cash inflow that will come in through research payments to waive. Sorry, important additional points for this.
spk01: Thanks. That's helpful. And maybe just one last one on the A1AT study. Just wondering, will you include liver biopsies as part of the trial design in the A1AT patients in order to assess editing efficiency as well as maybe potential impact on Z protein globules and fibrosis in the liver as well?
spk08: Emery, do you want to answer the beginning part of the question? Sure.
spk06: So our initial studies will be looking at restoration of MAAT. As you know, in our mechanism, we are actually correcting with editing to reproduce an empty phenotype for patients. And so production of MAAT is confirmation that we have successfully edited. So that's everything, Paul.
spk08: I think to your question on liver biopsies, the full protocol is being analyzed. But to Anne-Marie's point, I think what we've seen preclinically and clinically that the most important assessment of are we editing is the generation of the protein. So we should be able to see that based on our modeling as part of that. clinical trial design. And obviously, that becomes critically important, that biomarker, not just for assessment of alpha-1 antitrypsin for the AATD program itself, but really unlocking our GalNec conjugated ADAR editing platform and our editing platform more broadly.
spk01: Thanks. That's very helpful. Thanks for taking our questions.
spk02: Thank you.
spk05: Thank you. At this time, I would like to turn it back to Paul Bolno, President and CEO, for closing remarks.
spk08: Thank you, everyone, for joining the call this morning. We made significant progress advancing our pipeline and sustaining our leadership position in RNA editing in the first quarter. And we are 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. Thank you.
spk05: Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.
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