Hello and welcome to Wave Life Sciences' third quarter 2026 earnings call. We ask that you please hold all questions until the completion of the formal remarks, at which time you'll be given instructions for the question and answer session. Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Invest and Investor Relations.

Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our third quarter 2026 earnings update. Joining me today with prepared remarks are Paul Bolno, President and Chief Executive Officer, Chris Wright, Chief Medical Officer, and Kyle Moran, Chief Financial Officer. Also on the call are Chandra Vargeese, Chief Technology Officer, Erik Ingelsson, Chief Scientific Officer, as well as our new Chief Business Officer, Monica Vinuk, who joined WAVE last month. The press release issued this morning is available on the investor section of our website, www.wavelifesciences.com. Before we begin, I'd 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. 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.

Thanks, Kate, and good morning to everyone joining us on today's call. At WAVE, we are harnessing the convergence of deep genetic insights with our proprietary chemistry to rapidly advance a pipeline of transformational RNA medicines. Our broadly enabled oligonucleotide platform has leading capabilities in both siRNA and RNA editing that are now translating across both our wholly owned pipeline and in our collaboration with GSK. In siRNA, our best-in-class SPINA design is demonstrating the potency and durability that we believe are needed to unlock important genetically validated targets. We've seen this translate clinically with WVE007, and during the third quarter, GSK selected an siRNA development candidate to transition to its pipeline. Next week, at Research Day, we'll take a deeper look at these capabilities and how we are continuing to push the boundaries of our proprietary chemistry across hepatic and extrahepatic siRNA, RNA editing, and our emerging bifunctional modalities. I'll begin today by discussing WVE-007, our inhibitory siRNA for obesity, before moving to WVE-006, our RNA editing therapeutic for AATD, and other recent updates. The Inhibit E target is strongly supported by human genetics. Individuals who have a protective loss of function variant and one copy of the Inhibit E gene have a healthier cardiometabolic profile, including less abdominal fat, less liver disease, lower triglycerides, and lower risk of type 2 diabetes and cardiovascular disease. With 007, the goal is to replicate this healthy metabolic profile by silencing inhibini and lowering serum activini, thereby taking the brakes off lipolysis or fat metabolism. 007 offers a distinct therapeutic approach from incretins by driving fat loss without muscle loss. This makes it a differentiated alternative to GLP-1s or other incretins, a potentially powerful combination with incretins. And importantly, when we think about the challenges of sustaining chronic long-term incretin therapy, O7 offers new potential to prevent weight regain with just a once or twice a year dose. There are several reasons we chose to target inhibiny mRNA directly and turn off activiny production rather than the receptor of activiny, ALK7. Turning off protein production in hepatocytes, the upstream source with a GalNec siRNA, is the most efficient and durable way to impact this pathway. Suppressing active NE is a more selective approach with a lower risk of unintended consequences as compared to disabling a receptor that transduces signals via multiple ligands across different tissues. We believe this selectivity is especially important for long-term safety and clinical translation. O7's unique ability to durably suppress inhibin E is enabled by our proprietary chemistry and Spina siRNA design, which distinguishes us from others in the field and has been shown to enhance interactions with AGO2, stabilize the loaded risk complex, and improve liver exposure. Across Inhibin E and other targets, our proprietary chemistry has repeatedly delivered greater potency and more durable effects than industry-leading siRNA designs, setting us apart from others attempting similar silencing approaches. With 007, we have now seen the compelling Inhibin E biology translate both preclinically and clinically with differentiated data from other approaches in the field. Preclinically, Our inhibini silencing drove substantial visceral and subcutaneous fat loss with muscle preservation and GLP-1-like weight loss in the DIO mouse model. Our preclinical data also demonstrate inhibini silencing increases adipocyte lipolysis, shrinks adipocytes, reduces pro-inflammatory macrophages and fibrosis, and improves insulin sensitivity, all key indicators of better cardiometabolic health, which further validate the human genetics. And in the clinic, we're seeing this profile translate in our Phase 1 single-dose study with clinically meaningful reductions in visceral and total fat and prevention of lean mass. We have also observed a favorable tolerability profile and durable, dose-dependent active NE suppression, supporting once- or twice-yearly dosing, further highlighting the advantages of our Spina SRA design. Our upcoming 600 milligram data from the phase one portion of ENLIGHT is expected this quarter and will help further characterize potency, duration, as well as safety and tolerability. We continue to make significant progress advancing O7 across three distinct treatment settings, monotherapy, combination therapy, and as post-incretins maintenance therapy to prevent weight recurrence. With our ongoing Phase IIa monotherapy trial, we are now evaluating 007 in our target patient population, individuals with higher BMI and comorbidities, in other words, a typical population observed in Phase II and III obesity trials. Thank you so much for joining us. Collectively, these factors support the potential of this Phase IIa study to cross the one-year regulatory threshold of 5% weight loss. This monotherapy trial will also include multiple assessments of cardiometabolic biomarkers, including liver fat, which have the ability to de-risk development pathways in MASH and other cardiometabolic diseases. The second part of our strategy is to evaluate 007 as a combination therapy with incretins. Thank you for joining us. We believe that 007's orthogonal mechanism, ability to drive reductions in fat while preserving muscle, and favorable safety profile are well suited to a combination approach. Despite the commercial success of Incretins, there remains a clear opportunity for orthogonal approaches. Incretins reduce body weight through both fat loss and muscle loss, and they carry high discontinuation rates due to GI side effects, limiting the potential for long-term health benefits. Muscle loss associated with current standard of care therapies is substantial, representing upwards of 40% of the total weight loss. The consequence of muscle loss is particularly notable as skeletal muscle plays an important role in both metabolism and weight maintenance. We believe 007 could enable GLP-1 down titration and help patients achieve fat loss with a more favorable tolerability profile and less muscle loss. In addition to mitigating muscle loss and improving tolerability, O7 also garners the potential to help patients achieve further fat loss on top of incretins, as up to 40% of patients don't reach treatment goals. Our preclinical data provide compelling support for O7's ability to help these patients, as we've observed approximately twofold greater weight loss as an add-on to incretins versus incretins alone. Lastly, and perhaps one of the most exciting and unique opportunities, we plan to evaluate 007 in the maintenance setting to enable an off-ramp for GLP-1s. We often hear from patients about the fear of weight regain post-cessation of incretins. Up to 70% of patients discontinue GLP-1 therapy within the first year of treatment, and for many, it's due to the challenges that 007 may address, including treatment burden and tolerability issues. Notably, following discontinuation of GLP-1 treatment, upwards of 70% of lost weight is regained and driven by increase in total fat, not muscle regain. In this maintenance setting, 007 would have the potential to enable individuals and payers to realize the sustained health benefits of fat loss and improve metabolic health for the long term. We remain on track to initiate a trial investigating 007 as post-increased maintenance in the fourth quarter. Collectively, we believe 007 Development Program can redefine the treatment landscape in obesity and are working expeditiously to examine its potential across treatment settings. We look forward to engaging with key opinion leaders and the community to present and discuss 007's differentiated approach at Obesity Week. In RNA editing, we're advancing WVE-006, our GALNAC RNA editing candidate for AATD towards a potentially registrational study. Our clinical data support O6's potential to offer a new standard of care for individuals living with AATD by treating both lung and liver manifestations of the disease and restoring dynamic AATD response with convenient infrequent subcutaneous dosing and would offer a potentially differentiated value proposition for both healthcare providers and payers. As a reminder, current IV augmentation standard of care does not have any impact on liver manifestations of the disease. And importantly, those augmented protein levels are depleted during acute inflammatory events, leaving the lung unprotected and potentially prone to damage. Investigational DNA editing, a different therapeutic approach, carries with it both safety concerns and, just as notably, payer challenges for a one-time very costly therapy with uncertain durability. This leaves RNA editing well-suited as a first-line therapy. As Chris will speak to in further detail momentarily, following our recent meeting with FDA, planning is now underway for a single registrational trial of O6 for ATD, offering an efficient path to full as well as potentially accelerated approval without the need for a separate confirmatory trial. Building on our RNA editing success, we also continue to advance our second RNA editing candidate, WVE008 for PNPLA3 liver disease, towards the clinic this year. OO8 aims to address an area of high unmet need with 9 million individuals living with PNPLA3 I148N liver disease. At our research day next week, we look forward to having Dr. Arun Sanyal, a leading hepatologist, join us to share additional perspectives on PMPLA-3, I-148, and liver disease, and the opportunity for an RNA editing correction approach. We will also provide further updates on how we are continuing to push the boundaries of innovation with the proprietary chemistry across our hepatic and extrahepatic RNAi, RNA editing, and bifunctional modalities. Beyond our internal pipeline, our PRISM platform and proprietary chemistry continue to demonstrate their value, as evidenced by GSK's recent development candidate selection. The transition of this development candidate to GSK provides further validation of our best-in-class SPINA-designed siRNA. We have also welcomed Monica Vanook to WAVE as Chief Business Officer. Monica brings extensive corporate development experience and joins WAVE from Sanofi. Monica will leverage her background to further capitalize on and expand the potential of our platform and support WAVE's next phase of growth. Now, I'd like to turn the call over to Chris, who will discuss our clinical development plans for WVE-007, 006, and 008. Chris.

Thank you, Paul. We continue to make strong progress on our WVE-007 clinical development plan. Let's start with our Phase IIa monotherapy trial. This is a global placebo-controlled trial enrolling individuals living with obesity with BMI of 35 to 50 and comorbidities. There is a total of four cohorts with up to 40 participants each across two doses, 240 and 400 milligrams, and two study populations with and without type 2 diabetes. Participants receive two doses of 007, one on day one and one on day 85, and are followed for up to 12 months. To date, with dosing underway, we're observing that participants have baseline levels of adiposity that are substantially higher than the Phase I portion, in line with Phase II and III obesity trials. Given 007's mechanism of action, we believe this population is well-suited to demonstrate 007's potential to deliver meaningful improvements in body composition and healthy weight loss. This trial also specifically includes measurements of liver fat content by MRI-PDFF to inform 007's potential in NASH. Our preclinical data and a growing body of clinical evidence support the potential for substantial reductions in liver fat. In parallel with this progress, we remain actively involved with the patient community, key opinion leaders, and foundations. Together, we're working to engage with regulators on the importance of improving body composition, including reducing excess fat and preserving muscle, consistent with recent guidance. Turning to combination therapy. In the third quarter, we initiated our Phase 2A combination trial. This portion of InLight has a randomized control design that will evaluate 240 and 400 milligram doses of WVEO7 in combination with weekly trisepatide versus trisepatide alone in individuals living with obesity with a range of BMIs from 35 to 50 and type 2 diabetes. For our third treatment opportunity, we remain on track to initiate a clinical trial of OO7 in the fourth quarter as a maintenance therapy to preserve weight loss following discontinuation of treatment. In addition, we look forward to sharing 600 milligram data from the phase one single ascending dose portion of NLITE in the fourth quarter. This will help us further characterize potency, duration, as well as safety and tolerability. Turning to WVE-006 for AATD. WVEO-06 is our investigational RNA editing therapy with the potential to address both lung and liver manifestations of AETD. We continue to make excellent progress advancing WVEO-06 for patients in need and following a productive meeting with the FDA are now planning our registration trial. Our discussions with the agency, key opinion leaders, and the Alpha-1 community underscore the high unmet need and limitations of current standard of care. As a reminder, the only currently approved treatment for AETD is weekly IV plasma-derived augmentation therapy, which carries several limitations. With a fixed scheduled dose, there is no restoration of the dynamic response, leaving individuals with Alpha-1 at risk if AET protein levels fall too low during an infectious or inflammatory event. IV therapy is time-consuming and often requires inpatient visits and does nothing to lower the ZAAT to address the risk of liver disease. While DNA best editing approaches target both lung and liver disease in AETD, they introduce permanent DNA modifications, carry bystander editing risk, and rely on LNP delivery, which is associated with liver enzyme elevations. The risk of irreversible off-target effects is particularly notable as genomic DNA editing in cancer-associated genes has been reported in preclinical studies. In addition, treatment with DNA editing therapies may render patients ineligible for future base editing, RNA editing, or other new therapies. SiRNA approaches reducing ZAAT are also in development for AATD liver disease. However, this approach does not restore MAAT, and even worse, it leaves the lung unprotected due to the chronic AAT knockdown. AATD is a uniquely compelling disease for RNA editing. It is a monogenic disorder caused by a single, well-characterized genetic variant in the Serpina1 gene. This leads to misfolded ZAAT protein and an absence of healthy circulating MAAT protein, which normally protects the lung during inflammatory or infectious events. Without dynamic production of functional AAT protein, individuals with Alpha-1 are at risk for lung damage, ultimately developing emphysema and bronchiectasis, characterized by chronic cough, recurrent infections, and shortness of breath. In parallel, misfolded Z accumulates in hepatocytes and causes progressive liver injury and increased risk of liver disease. With OO6, which targets the underlying causes of AETD, we've generated a growing body of data supporting its potential as a new standard of care for individuals living with Alpha-1 by restoring an MZ-like phenotype, which has a low risk of lung and liver disease. and our ongoing Restoration II clinical trial, 006, delivered substantially reduced levels of ZAAT, protective basal levels of total AAT with a percent of wild type MAAT well into the MZ range, as well as a restored dynamic physiologic response to inflammatory events. Enrollment and dosing are complete in the 200, 400 and 600 milligram cohorts of Restoration II. We remain on track to share data from the 600 milligram monthly dosing cohort in the fourth quarter, which will help inform an optimal dose and regimen. With the compelling profile of 06 we've observed to date and following our FDA meeting, we're planning for a single two-year registrational trial with a one-year interim analysis for potential accelerated approval based on AETD biomarkers. We believe this single trial design without the need for a separate confirmatory study offers an efficient path for full approval, bringing OO6 to patients in need as quickly as possible. In addition, we're encouraged that the agency supported the use of our LC-MS assay to measure MAAT and GAAT proteins. We also continue to make strong progress advancing our second RNA editing candidate, WVEO6 for homozygous PNPLA3 I148M liver disease. Similar to 06 and 07, our approach for 08 is strongly rooted in human genetics. There are an estimated 9 million homozygous PNPLA3 I148M carriers with liver disease across the US and Europe who are at a nine-fold higher risk of dying from liver disease as compared with non-carriers. The PNPLA-3 variant is a well-established driver of MASH and liver diseases more generally, yet there are no approved medicines that directly address this underlying disease mechanism. Currently, the only treatment options are non-precision medicines aimed at reducing liver steatosis and early fibrosis, which have limited efficacy for these I-148M carriers. Silencing PNPLA3 can only partially address this disease biology and is likely to leave residual pathology as it knocks down all PNPLA3 protein without restoring healthy wild-type protein, which has several important physiologic functions in the liver. As a result, silencing may partially address steatosis, but inflammation and fibrosis may remain unaddressed or worse. Recent clinical trials of PNPLA3 silencing support this notion. A dose-dependent increases in liver enzymes were observed. By contrast, with WV008, we aim to correct the I-148M variant using our leading RNA editing platform with the goal of restoring normal PNPLA3 function. This is expected to enhance lipid mobilization from the liver, reverse steatosis, reduce inflammation and fibrosis, and ultimately improve overall liver health. In our upcoming first in human study of OO8, we plan to leverage previously genotyped populations to efficiently identify homozygous I148M carriers and accelerate enrollment. We will evaluate target engagement with circulating biomarkers and assess early signs of efficacy using non-invasive liver imaging. We remain on track for a CTA submission in 2026. With that, I'll turn the call over to Kyle to provide an update on our financials. Kyle?

Thanks, Chris. Our revenue for the third quarter of 2026 was $13.2 million, compared to $7.6 million in the prior year quarter, and this relates to our ongoing collaboration agreement with GSK. Research and development expenses were $53.8 million in the third quarter of 2026, as compared to $45.9 million in the same period of 2025. The increase primarily reflects continued investment in our advancing clinical programs, including the phase two portion of InLight and progress across our RNA editing pipeline. Our GNA expenses were $25.4 million in the third quarter of 2026, as compared to 18.1 million in the prior year quarter. The increase primarily reflects costs associated with supporting our advancing pipeline and preparing for the next stages of development. Thank you for joining us. We are also due to receive an incremental $12 million milestone payment from GSK in the fourth quarter of this year following their candidate selection. As a reminder, GSK has three additional programs advancing towards development candidate. Any potential future milestone and other payments to us under our collaboration are not included in our cash runway. I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. Our strong execution and progress throughout the year leave us well positioned to unlock value across our pipeline. With WV-007, we're actively advancing our phase 2A monotherapy and combination trials towards key data in our target patient population and remain on track to initiate our post-increte and maintenance trial later this year. We're advancing 006 towards a potentially registrational trial and building on our success in RNA editing with 008, which remains on track for CTA this year. We look forward to connecting with many of you next week for our annual research day. Before turning to questions, I want to thank our team for the progress we've made and for their continued commitment to reimagining what's possible for patients. I'll now turn the call to the operator for questions. Operator.

Thank you. We will now move into our Q&A session. For those of you who are joining us via Zoom, if you would like to ask a question at this time, please raise your hands by clicking the raise hand at the bottom of your Zoom window. Once called upon, please unmute your audio to ask your question. We'll take our first question from Rick Bienkowski with Leidenberg. Please unmute your line and ask your question.

Hey, good morning and thanks for taking the question. Now that you have clarity from the FDA on the accelerated approval pathway for wave 006, do you have any insight on how large of a trial you might need to run for the pivotal study and also I know you've shared in the press release that you've aligned on the accelerated approval based on biomarkers, but I was curious if the full approval would also be based on these biomarkers, or has the FDA asked for evidence of improved functional outcome for the full approval?

Yeah, I'll start the question and then I'll let Chris join in. But I think it's important as you laid out to this kind of the first into your second, the second part of that first question that went into what's required for the full approval. I think that was stepping back. I think what was impressive for the team, I was excited that the team came back with a really innovative design that was efficient for patients, efficient from a capital standpoint, and could get us to a potential full approval in a two-year time point with the interim analysis being available for the accelerated approval. So the predicated design is for that single study without the need for a separate confirmatory study. As it relates to the individual biomarkers that we're going to use, I think we've been pretty clear that we're not going to competitively disadvantage ourselves as others are still going through processes of laying out what's required for those analysis for both full approval and for accelerated approval. But I think as Chris alluded to, it's nice to see that we've got validated LC-MS assays that we can use to quantify post.

Sure, so I would say we had a really excellent meeting with the FDA. The pulmonary division in CDER doesn't always have an opportunity to review genetic medicines, and so they were particularly, I think, excited about our approach and really saw that we were hitting our target as intended in terms of hitting the underlying cause of the disease with increasing M, decreasing Z. And then also, they actually picked up quite quickly on the acute phase response as being one of the more relevant things in terms of treating the disease so that you know you are increasing the level into the event to protect the tissue when it needs it the most. And they also appreciated that from the protein replacement perspective, you're kind of highest when you start and that kind of goes down over time. And so if you get an event as that's going down, you may end up being unprotected. And so they were, I think, quite understanding of that and getting it quickly and were highly supportive of us moving forward for patients.

Our next question comes from June Lee with UBS. Please unmute your line and ask your question.

Great, thanks for taking our questions, and great to be following you guys again. This year's Nobel Prize in Chemistry, Manon, how validating is that to your stereochemistry platform, and how do you think it helps you differentiate from your competitors, and are you able to provide some examples? And just a quick follow-up, questions for Dr. Monica Banouk, if she's on. What is your first order of business at Wave, and what is your midterm and long-term goals at Wave?

Thank you. Thanks, June. It's great to have you back. And I'll take the first part of them. I think Monica will join. Obviously, she's sitting next to me for the second part. I mean, we're excited to have her. But to your first piece, I mean, I think it's nice to see the recognition on chirality, as you point out. It's not just the award for a prize, but it's the recognition of just how important chirality and stereochemistry is to fundamental biology. We've often talked about it in the context of other therapeutic examples like thalidomide and others, and that specificity matters and stereochemistry matters. But if we think about what happens on every enzymatic structure we work with, whether it's a AGO2, whether we see it with ADAR, whether we saw it with RNase H and antisense, whether we see it with the innate immune system recognizing various patterns, biology recognizes single structures. And I think the most important piece in drug development is being able to optimize from a mixture. And I think if we look back over a decade now, Thank you so much for joining us. And I think having that clarity of understanding of medicines lets us understand in preclinical studies why something's working or not. And frankly, in clinical studies, lets us understand what needs to continue to be optimized as we watch the evolution. So I think it's fundamental and it's nice to see it widely recognized. I'll turn to Monica to answer. She's dove in with both feet, or I guess, yeah, that's jumping, but yeah, go for it.

Great. Thank you, Paul and June. Thank you so much for the question. I'm very excited to be joining WAVE and this highly accomplished team. I have been following WAVE for over a decade, and it has been on my Radar for Partnering as it matured to emerge as the leading siRNA and RNA editing company. When I reflect on the portfolio that we have, I see a lot of opportunity to create value through partnering both on a clinical side as well as our preclinical portfolio and of course the platform. In the immediate term, what I'm doing is jumping straight in into the ongoing partnering discussions. and working on the mid and longer term plans.

A lot of work to be done, but it's great to have you back here.

Our next question comes from Reem Al Ahmed with William Blair. Please unmute your line and ask your question.

Hi, this is Reem. I'm on for Olivia. Thanks for taking our questions. We have two. First one on 007 for inhibini. Good to see that phase 2a baseline adiposity is coming in much higher than phase 1 and in line with phase 2-3 obesity studies. Given that and what you've seen on body composition so far, do you still feel confident you can get to the 5% weight loss at 12 months? And second, on AATD, how do you think about enrollment relative to competitors? How does your population differ from what other programs are enrolling like Arrowhead and Takeda? And if there are any comparable studies, we should look out for timelines.

Yeah, I mean, first, thank you for recognizing, you know, I think Chris's statement on the baseline adiposity. I mean, I think it's good. It was expected. I always say that some of these things are, they're planned and you should be expecting them because phase two, three studies in obesity as we've laid out have that, but To your point, it's nice to see when that's recognized. And I think to that point, that's exactly just like we said, going into a 2-3 study would yield patients with higher baseline adiposity, meaning more fat to lose. I think it's very consistent with the analyses and modeling we're doing that point us to a path to potential 5% weight loss after your own therapy, which is the regulatory bar, meaning this mechanism should drive more fat, which is and take us back to preclinical data, translating to clinical data, the DIO obese mice models lost substantial weight. It takes a little bit longer for that to happen because the weight loss in the DIO mouse in the SEMA arm is coming off of predominantly muscle initially, which is why the curve moves more quickly. But we do see substantial fat loss in the DIO mouse model. So again, all aligned with our preclinical clinical data and the phase one moving into our 2A data. So we're excited about that. And as for 06, I'd like Chris to speak to the study specifically, but I think it's important, as you point out, The SIRNAs, because you pointed out the arrowhead Takeda, that's a liver-driven study. So we're not specifically looking at a... We're going to take lung and liver patients holistically. Augmentation isn't approved outside the United States. So as we think about a global study, we don't see any challenges within knowing that. But I'll let Chris add to that.

Yeah, sure. Thanks, Paul. So we are engaged with a number of foundations and societies in Alpha One. And they have these large registries. And so, you know, working together with them, we're going to leverage those registries, which have actually several thousand patients in them for our trial. So I think that will really help us to accelerate enrollment. The other thing that I think is notable is we've had a number of discussions with KOLs and actually with patients. And what we're hearing is that people are excited about a convenient, easy to administer therapy that's reversible in the sense that if you need to stop it for some reason, you can, or if The environment changes. There's other options. You can use those. So I think what we're hearing is that people are excited to have this be the first thing that they start with and to help us to move it forward and get it to the market. And then the last thing just to highlight what Paul said is that just like our other studies, we don't really have any liabilities from the hepatic perspective. And in fact, We've already enrolled a number of individuals with liver fibrosis, so we'll continue to study individuals that have lung disease and liver disease throughout our program and we're interested in showing benefits in both of those.

Thank you. As a reminder, we are allowing analysts to ask one question today. If you do have a second question, please re-raise your hand to join the queue and we'll try to get back around to you. We'll take our next question from Samantha Semenko with Citi. Please unmute your line and ask your question.

Hi, this is Jing for SAM at CITI, and congratulations on your progress. And thanks for taking our question. My first question is about, can you help frame the bar you will need to meet at the one year internal analysis to support your accelerated approval? And based on what data you have right now, do you believe you have already demonstrated the proof of concept against that bar? Thank you.

Thank you. I'm assuming that the reflection was for AETD for the one year, just to make sure. I always say it's Multiple assets important to confirm. Yes, I mean, as we said at the beginning, we're not going to get into the specifics of this from a competitive standpoint. But what we can say is in the conversations that we went into saying that the premise around RNA editing, editing in general, is to restore an MZ-like phenotype and following discussions with the agency. The one-year interim analysis would be predicated on delivering an MZ-like result. So I think I'll let Chris add to that, but that's the premise of how we think about that interim assessment.

Yeah, so as Paul mentioned, really, we're looking to restore the MZ-like phenotype where individuals would have increased M of 50% or greater or in the range of an MZ patient, decreased Z, and then recapitulating the acute phase response so that M increases at the time that there's infections or lung inflammation at the time that the tissue most needs protection. So I think if we are able to achieve all those three things which we've been able to show already in our data for Restoration 2, we'll be in a very strong position.

Our next question comes from Anand Agosh with HC Wayne Wright & Co. Please unmute your line and ask your question.

Hey, thanks guys and congrats on the quarter. Paul, recently Endocrine Society published a review urging to move beyond weight loss. You know, given this, you know, we get a lot of inbounds on regulatory clarity on monotherapy in terms of weight loss. So looking at other measures such as DEXA and, you know, the waist circumference were actually considered to be some of the important endpoints other than weight loss. And there was this push for regulatory agencies to kind of accept it. So from a sponsor point of view, have you engaged with FDA on similar ideas?

Yeah, as we've said, this is engagement that we expect this quarter, and not just for once, but on an ongoing basis. And not just WAVE. Very much to your point, when we've met with the obesity patient advocacy organizations, they're having their own conversations with the agency around a similar approach. And I think Thank you for joining us. and others have seen substantial fat reduction, visceral fat reduction, waist circumference changes. So differences that we've seen with the profile of O7 that are distinctly different than other even inhibity siRNAs that have generated data. So I think we're compelled by that data that the medicine's working like it should. And we're moving forward at a time where I think we're seeing the holistic narrative from clinicians. And as you point out, regulators shift towards what does healthy weight loss look like and really that being driven off of body composition. So we're very much aligned with that. The profile demonstrates that. Our preclinical data shows that. But I think it is important because we know there's a number of folks who listen on the call and hear all of that and the importance of body composition improvement being driven and say, but is there still a regulatory pathway for that? And if we go back to the regulatory draft guidance, This one-year time point with greater than 5% change in body weight does emphasize the body composition improvement. So we're very much set up to how do we deliver on a regulatory threshold and get to build on the labeling with what's going to be meaningful for patients in the long term, which is this improvement in body composition, all of which are captured across the clinical trials that we're running. So these are all measurements that we're already capturing as part of those clinical trials.

Our next question comes from Salim Saeed with Mizuho. Please unmute your line and ask your question.

Great. Thanks for the question, guys. And welcome to Monica. Paul, Chris, maybe just one on 006. Could you just clarify for us, when you guys were in discussion with the FDA on getting this single trial design for both accelerated and full approval. Obviously that contrasts to BEAM where I think there's still an ongoing dialogue to get a confirmatory trial design Is your view here that the FDA has drawn a line now between RNA and DNA medicines, or was this kind of wave suggesting to them, hey, look, we think this makes sense, and we may see at some point later where the beam trials start to converge more into the wave trial, single trial, instead of separate confirmatory trial design? Thank you.

Thanks for the question. I'm going to hand it to Chris, but I think at the general level to that last point you're making, I do think that there's an attempt now for better harmonization, and we're seeing that in a number of reports coming out of the FDA, starting with the Rare Disease Hub and then thinking about how the Rare Disease Hub helps orchestrate between Zebra and Cedar to get better alignment across endpoints. And so I think we'll continue, I very much believe, based on what we're hearing too, that there will be even more of that to come, which I think is just great for the industry at large and rare disease at large. Stepping back from that to the very specific point of, you know, why that you see differences coming out from these companies relative to this is, and I'll hand this to Chris, is Thank you so much for joining us. And so I think the team's approach was to really approach it differently, which was not to forego, again, feeding two birds one hand, not to forego the conversation on what a pathway to accelerated approval could look like. But most importantly, lock down what a path to full approval could look like and work backwards. And so I'll hand it over to Chris to kind of the thought process and the engagement.

I think Paul covered it quite well. It really was our strategy and the thinking of the team that really brought us forward with the single trial design, which would enable us to get to a full approval as quickly as possible, but also have an accelerated approval on the table. I think it's a great approach. We had discussions with the FDA on that trial design, and we're moving forward with a single trial with the duration mentioned, two years for the full approval. and a year for accelerated approval. Thank you.

Our next question comes from Joe Schwartz with Learing Partners. Please unmute your line and ask your question.

Hi, thanks for taking my questions. So following WVEO6 monthly data in the fourth quarter, once dose is locked, when do you expect to enroll the first patient in the registrational trial? And then is a three-month look at data in the phase 2A for WVEO7 still planned? And if so, when could that occur? Thank you.

No, thank you. And I'll take the last question in terms of cadence and timing on the 2A. We said, well, we have the potential to deliver the 2A data. It could start coming as early as this year. I think we'll provide an update later this quarter as we do our analysis of whether we would cut the data and look at the three-month time point, which we know will be a body composition time point. I think we've seen that in the past, that at three months with... That initial fat loss comes with muscle and lean mass increase. And so it's really important to the question that came out earlier, important from a body composition standpoint, but not the time point for weight loss. And so we're going to do our analysis of whether we cut it at the three month or the six month, the six month being a time where we can assess weight loss. More to come on that this quarter in terms of timing and updates. Chris, you want to take the first question?

Sure. So our Restoration 2 study is still ongoing, and we look forward to getting the 600 milligram data, multiple dose data. And once we have the 600 milligram multiple dose data, then we'll be able to have a better sense of what dose and what dose interval we'll be taking forward into the pivotal trial, and we'll provide updates at that time. Thank you.

Our next question comes from Ben Burnett with Wells Fargo. Please unmute your line and ask a question.

Hi, thank you. Just one on OO6 and AATD, just the registrational study that's being planned. Can you talk about what endpoints might support full approval? And I guess are some of these endpoints easier to power for than others?

I mean, I think, you know, in principle, It's a competitive space and we're not disclosing the endpoints that we're moving forward with. But just generically speaking, there are certainly some that are a lot better than others. So I think what we've heard and what we've seen and what our own analyses have shown and actually that of others is like FEV1 is not really a feasible endpoint for ATD in a reasonable time frame with a reasonable amount of patients. So that's one thing to say. There's a number of and other measures you could look at. You can look at exacerbations. You can look at a number of respiratory symptom questionnaires. Also up and coming that's quite interesting is CD densitometry. And so that's something that's been used for approvals in Europe. The FDA isn't quite there yet, but I think that's something that's quite interesting and is advancing and would be able to allow a A shorter, well-powered trial with not as many individuals going forward for a registration study. So those are the things we're thinking about currently.

Our next question comes from Yeon Jung with Wedfish. Please unmute your line and ask your question.

Hi, good morning. Thank you very much for taking the questions. And on 007, monotherapy, I understand that you are confident to meet the bar of 5% for approval. But in reality, for market adoption, do you have a sense of the magnitude of weight reduction that you will have to achieve for obese population to be willing to try this therapy option? Well, understanding that the benefit of muscle preservation and also for combination therapy for the bar for approval, do you think incremental weight loss alone versus GLP will be sufficient or do you have to show additional clinical benefit when compared with GLP? Thank you very much.

Thank you for the question. As we think about crossing the bar and as that grows, that's a weight loss bar on pounds. If you think about the requirement of pounds of fat to lose relative to the pounds of muscle, it's not equilibrated. You ultimately have to lose more fat in order to lose the equivalent pounds of what's being lost in muscle weight. As we think about Thank you so much for joining us. Thank you very much. It was equivalent weight loss from inhibity to GLP-1. I think if we think about what does that mean, it doesn't mean that that was truly equivalent. In order for that DIO mouse to reach that same point meant it actually had to lose more fat than the equivalent GLP-1 to achieve that same profile. And so as we think about this over the course of a year, I think that profile could continue to enrich what happens when you substantially lose fat. What Happens When You Preserve Muscle, and ultimately what that means from both patients and physicians and payers as we think about this medical progressing. As to what's going to be required on the combination side, I think there's a variety of settings, which is why we're looking at that, meaning if we achieve the regulatory bar, then you don't need a separate approval for the combination. This is like other medicines where those examples will be giving physicians the tools to see how inhibitor In this case, terzapatide, but you could think about that as incretins coexist. And so people would get the experience data set and how to use that. If you think about asking the regulatory question in the context of combination is the first approval, then there's obviously the additive effect. And that's been demonstrated, discussed around an approval. Our next question comes from Whitney Ijen with Canaccord Genuity. Please unmute your line and ask your question.

Hey guys, thanks for taking the question. Excuse me, just another one on 007. And I know you've talked about in the past kind of expectations for the 600 meg MAD data. Excuse me, but can you just refresh our memory? How should we be thinking about that? What should we expect to learn? And I guess the related question is, is there a scenario where you move the 600 meg dose forward into the maintenance study? I know you've chosen the lower two doses for the combo study, but just kind of trying to get a sense of if there could be different doses in different settings. Thanks.

No, thank you. And I think it's important. It's a SAD study still. So it's still the phase one SAD 600 that's coming. So just to put it in context, the MADS part of the 2A study with the Malditos. But no, the upcoming data, if we think about it, it gives us another opportunity to that point. I mean, we We know that the lowest dose activity was suppressed out at seven and a half months. So the ability to continue to see what the profile looks like at both higher doses from a PKPD perspective, obviously, we'd be looking at body composition. We do reflect on the fact that there's no reason to believe that the baseline body compositions for that and many more. The maintenance setting is probably the setting where there exists the best data set, right? If we think about the human genetics is a 50% loss of function that is pretty much like a maintenance study over life in terms of preventing fat regain. So it makes sense. You take the break off lipolysis at that 50% threshold and you don't gain that adiposity that you see elsewhere. Thank you very much. A monotherapy weight loss. And so thinking about that over time, both on an induction and maintenance becomes interesting. And like I said, it's nice to have the pathway. It's nice to have a potent on target, durable approach to being able to look at that and we can assess it. I don't know, Chris, your thoughts on that.

No, I think we just, 600 milligrams is to get more information about, you know, the dose, the duration, you know, the dose interval. What do we need to get to once yearly or twice yearly dosing with an optimal suppression and to learn about safety at higher doses? I mean, it's part of the dose escalation, single ascending dose study. But as you can see from the data that we've already presented, we have substantial knockdown with the lower doses, 240 and 400, with a single dose. So we think that the regimen that we have for our phase 2A study will also have substantial and durable knockdown at these lower doses.

Yeah, I mean, it's nice to see dose-dependent knockdown having the durability. And then to your point, we're able to look at that across longer time points to ultimately optimize for the regimen.

Our next question comes from Danielle Brill with Tru Securities. Please unmute your line and ask your question.

Hi, good morning. Thank you so much for the question. Just a quick one on 006. Given that you've already demonstrated the MZ-like phenotype that the FDA is looking for, just curious what incremental benefit you're hoping to see with this 600-milligram dose. And since you said that this data is going to inform dosing interval as well, What would give you confidence to take a less frequent than monthly regimen forward when that interval hasn't been directly tested in the clinic? Thank you.

So if I'm stepping back, I've got part of it, but if I'm stepping back and saying to your point of what the 600-406 could look like, given what we've already seen, I think to the point that Chris mentioned and that you mentioned, what we'll learn from 600 will inform just dose and frequency. And I think if we think about the prior doses, We had, you know, there's the 200 biweekly and the 400 monthly. So those were looking at exposure over that. Having 600 monthly will help us complete the modeling curve so that we can look at total exposure, duration, so drug product on board and be able to optimize that regimen, as Chris mentioned, for the subsequent study.

Our next question comes from Steve Seedhouse with Cancer Fitzgerald. Please unmute your line and ask a question.

Great, thanks so much. I was hoping you could talk a little bit more about the dialogue you had with the FDA on the assay itself for AATD in Phase 3, just like how flexible were they? Do you think assays are going to need to be standardized across companies and across the industry going forward, or were they sort of flexible on what you could use?

Yeah, so we had quite a bit of dialogue around the assay. They had a lot of questions, which the team did a great job at kind of answering to their satisfaction. And so on the basis of them really digging deeply into our assay, they were comfortable with us utilizing that as we move forward as part of our registration study. So, you know, I think that they saw the value of what I think if you if you have an assay that you've well characterized and done the appropriate work on, they're open for you to be able to use that all the way through your development program.

and I think it's just, I mean, to add on to the work that Chris and the team have done, you know, the ability to know that we can use the same assay from these early studies through, again, provides consistency for ourselves, clinicians and others to be able to look and cross-compare data and I think Thank you very much. Those levels of M and Z in those patients, you don't need to redefine or try to characterize a non-native protein. So I think to Chris's point, we've got an assay that we can now use to make those assessments through the study and frankly beyond.

Our next question comes from Catherine Novak with Jones Trading. Please unmute your line and ask a question.

Hi, good morning. Thanks for taking the question. Just curious if you can give any additional expectations on what kind of dose response you would expect from 400 to 600 mix monthly based on prior modeling data and exposure, and whether this is an opportunity that you can use to explore whether the MZ ratio can further improve with multi-dose regimen. Thanks.

Thank you so much for joining us. So I think, you know, the ability to see that, whether or not you can see an impact on Z faster. I mean, I think those will be opportunities. But I always step back and kind of reflect that two weeks after the lowest single dose at 200, we could get over 20 micromolar protein. And so the notion that even at that lower dose, we were seeing and a pretty robust response across was very clear. I think the other thing to add to that is when we do look at the natural history cohort of MZ patients, We're right there on the percent of M there. So again, in terms of what one needs to achieve, and this gets back to some of the conversations that we were having in the profile of going into what needs to be achieved to deliver on an MZ-like phenotype, we're delivering right at the percent of M that's seen in the natural history cohorts of MZ. So again, some of the other balance may be a function of what happens with protein over time, but we're already delivering on the profile with the existing data sets that we've had at the MZ ratio that you'd expect to see in an MZ cohort.

Our next question comes from Madison Alsady with B Reilly Securities. Please unmute your line and ask your question.

Hi, congrats on the progress and thanks for taking our question. Regarding your 006 readout and 4Q, what would push you to a bi-weekly regimen versus a higher monthly dose for the pivotal? And then with the 006 trial design that you discussed, Do you think this could be sufficient for submission and potential approval in the EU? I mean, it seems like you could reach the EU market fairly soon after the US, or am I being a bit too optimistic there? Thanks. Sure.

I mean, Chris and I are like, you know, in terms of the 4Q data update, I mean, again, I think, you know, to the prior question, I think we're going to get to look at that modeling data and see. I think it's highly likely to stay, you know, monthly just because based on the 200 and 400 alone, I think we could model that. So, you know, whether or not the 600 adds anything else to that, you know, in terms of and many more. Thank you.

You might be aware that in the EU they have accepted CT densitometry as a primary endpoint for a pivotal study in the past. So I think that opens up a great rapid path forward there.

Our next question comes from Luke. Sorry.

No, no.

Our next question comes from Luca Issy with RBC Capital Markets. Please unmute your line to ask the question.

Oh, great. Thanks so much. Can you guys hear me okay?

Perfectly, yes.

Great, great. Yeah, maybe, Paul, maybe like bigger picture questions here on GSK. Can you just maybe talk high level about how your relationship with them has evolved over time? Again, obviously, you signed a deal back in 2022. Then they subsequently decided to return the rights for 2006, which maybe was not what you were anticipating. But now they're obviously decided to opt in for these novel aquatic acids. Yes, when you look at it from the outside, it may appear that their interest in WAVE has been kind of somewhat waxing and waning, if you will, over time, maybe as a function of their leadership changes and whatnot. But again, I'd love to hear your thoughts on how your dialogue with them has evolved over time, and most importantly, where you think this relationship is going from here. Thanks so much.

Yeah, no, thank you. I mean, I think as you point out, I mean, the decision around leadership change and we kind of step back and the decision of what assets are moving forward and, you know, frankly, what we're able to bring back into the portfolio really is a function of this kind of rare and, you know, we're not allowed to disclose liver or hepatic indications, but what I'd say is it's very much aligned, I think, with that similar profile. So I think, you know, that see them move Thank you for joining us. It was always kind of at its core an ability to access platform capability and be able to unlock targets. And so it's been nice for both sides. And I say that because it's been mutually beneficial in terms of the things that we've learned as well around looking at various cell types that we can get exposure to and how do we open up targets in that space and how do we validate that with modalities. And so Yeah, I mean, I think on both sides, you know, I'd like to think that each of us are getting out of it what we went into it saying this was going to be aligned with a portfolio construction and, you know, with us, you know, and now having full ownership of OO6. And frankly, if you remember OO7 with Inhibit E that we selected out of the genetic target database early on in the collaboration, I think the collaboration has been mutually beneficial.

Our next question comes from Alex Renahan with Bank of America Securities. Please unmute your line and ask your question.

Hey, guys. Thanks for taking our question. Good to see the Phase 2a has higher adequacy. One thing we've heard from KOLs in the space is that Thank you so much for joining us. Your outlook on the lean mass preservation in these higher BMI patients. Obviously, having a higher BMI means that the delta on the weight overall could be greater. And then just one quick one, if I may, on ATD. Any additional FDA meetings planned ahead of launching the pivotal? And I guess when could those happen? Thank you.

No, thank you. Let me get back to the... He had a positive question and body composition improvements. I mean, I think, you know, it's spot on by preserving lean mass. You actually could accelerate fat loss. So the notion that you accelerate fat loss, you preserve muscle, muscle itself as an endocrine organ helps continue to drive that metabolic response. Thank you for joining us. Thank you for having me. and many more. Thank you. goes net favorably with the direction of travel that this program is taking and hopefully the conversations that continue to emerge within what is healthy weight loss. As it relates to O6, we don't comment on individual regulatory interactions, but it's safe to assume that we'll be well prepared when we go into that trial to deliver.

Our last question comes from Chacha Yang with Jefferies. Please unmute your line and ask your question.

Hey team, this is Chacha on for Roger. Thanks for taking our question. I wanted to drill down on some of the expectations for 06 for your post-Inkerton maintenance trial. Can you speak to the magnitude of weight regain prevention that you'd consider clinically meaningful in the maintenance setting? Thanks.

Yeah, thank you. And just to be clear, because I know it's 07, just for others dialing in just to make sure. So for inhibity 07, We'll share more details when that study initiates on the design and how we think about the characterization. But what I thought was, if we go back to the DIO data where we demonstrated the ability to drive that prevention of weight regain, I think it's important as we do look at that is to quantify it as the Thank you so much for joining us. Thank you very much. That's what we saw in the DIO. The hedonic eating comes back. You take that signaling off. And when the weight regains, it comes back predominantly as fat, which is a less healthy state than when you started your therapy. And so the ability to curtail that fat regain, but to potentially regain some muscle, we see as advantageous. And we'll give the specifics when the study initiates.

Thank you. There are no further questions at this time. I will now turn the call back over to Paul Bolno for closing remarks.

Thank you for joining our call this morning and we appreciate your continued support. Have a great day.

This concludes the call for today. Thank you for joining. You may now disconnect.