Operator: Hello, and welcome to Wave Life Sciences' Q3 2026 earnings call. We ask that you please hold all questions until the completion of the formal remarks, at which time you will 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 Affairs and Investor Relations.
Kate Rausch: Thank you, operator, and good morning to everyone on the call. Earlier this morning, we issued a press release outlining our Q3 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, Monika Vnuk, 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 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.
Kate Rausch: 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 statements for any reason. I would now like to turn the call over to Paul.
Paul Bolno: 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 have seen this translate clinically with WVE-007, and during the Q3, GSK selected an siRNA development candidate to transition into its pipeline. Next week at Research Day, we will 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 bi-functional modalities.
Paul Bolno: I will begin today by discussing WVE-007, our INHBE siRNA for obesity, before moving to WVE-006, our RNA editing therapeutic for AATD and other recent updates. The INHBE target is strongly supported by human genetics. Individuals who have a protective loss-of-function variant in one copy of the INHBE 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 INHBE and lowering serum Activin E, 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.
Paul Bolno: Importantly, when we think about the challenges of sustaining chronic long-term incretin therapy, 007 offers new potential to prevent weight regain with just a once or twice a year dose. There are several reasons we chose to target INHBE mRNA directly and turn off Activin E production rather than the receptor of Activin E, ALK7. Turning off protein production in hepatocytes, the upstream source with a GalNAc siRNA, is the most efficient and durable way to impact this pathway. Suppressing Activin E 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.
Paul Bolno: 007's unique ability to durably suppress INHBE 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 RISC complex, and improve liver exposure. Across INHBE 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 INHBE biology translate both pre-clinically and clinically, with differentiated data from other approaches in the field. Pre-clinically, our INHBE silencing drove substantial visceral and subcutaneous fat loss with muscle preservation and GLP-1-like weight loss in the DIO mouse model.
Paul Bolno: Our pre-clinical data also demonstrate INHBE silencing incretins adipocyte lipolysis, shrinks adipocytes, reduces pro-inflammatory macrophages and fibrosis, and improves insulin sensitivity, all key indicators of better cardiometabolic health, which further validates the human genetics. In the clinic, we are seeing this profile translate in our phase I single dose study with clinically meaningful reductions in visceral and total fats and prevention of lean mass. We have also observed a favorable tolerability profile and durable dose-dependent Activin E suppression supporting once or twice yearly dosing, further highlighting the advantages of our SpiNA siRNA design. Our upcoming 600-milligram data from the phase I portion of INLIGHT is expected this quarter and will help further characterize potency, duration as well as safety and tolerability. We continue to make significant progress advancing 007 across three distinct treatment settings, monotherapy, combination therapy, and as post-incretins maintenance therapy to prevent weight recurrence.
Paul Bolno: 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. These patients are expected to have greater excess fat at baseline and will receive multiple doses of 007. With more excess fat to lose, we expect both visceral and total fat loss with 007 to be substantially more pronounced in our phase IIa higher BMI participants. Clinical experience also highlights the importance of baseline adiposity. Leaner individuals without comorbidities typically show more modest fat reductions versus individuals with higher baseline adiposity. Collectively, these factors support the potential of this phase IIa study to cross the one-year regulatory threshold of 5% weight loss.
Paul Bolno: 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, which has the potential to deepen weight loss and enhance metabolic benefits. During the quarter, we made strong progress on this initiative with the initiation of our phase IIa combination trial, which is evaluating 007 in combination with weekly doses of tirzepatide in individuals with BMIs between 35 and 50 and type 2 diabetes. 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.
Paul Bolno: 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, 007 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.
Paul Bolno: Our preclinical data provide compelling support for 007's ability to help these patients, as we've observed approximately two-fold 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.
Paul Bolno: In this maintenance setting, WVE-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 WVE-007 as post incretin maintenance in Q4. Collectively, we believe WVE-007's 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 KOLs and the community to present and discuss WVE-007's differentiated approach at ObesityWeek. In RNA editing, we are advancing WVE-006, our GalNAc RNA editing candidate for AATD, towards a potentially registrational study.
Paul Bolno: Our clinical data support WVE-006'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 AAT 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. 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.
Paul Bolno: 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 WVE-006 for AATD, 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, WVE-008 for PNPLA3 liver disease towards the clinic this year. WVE-008 aims to address an area of high unmet need with 9 million individuals living with PNPLA3 I148M 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 PNPLA3 I148M liver disease and the opportunity for an RNA editing correction approach.
Paul Bolno: We will also provide further updates on how we are continuing to push the boundaries of innovation with a 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 Monika Vnuk to Wave as Chief Business Officer. Monika brings extensive corporate development experience and joins Wave from Sanofi. Monika 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 would like to turn the call over to Chris, who will discuss our clinical development plans for WVE-007, WVE-006, and WVE-008. Chris?
Chris Wright: 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 4 cohorts with up to 40 participants each across 2 doses, 240 and 400 milligrams, and 2 study populations with and without type 2 diabetes. Participants receive 2 doses of 007, one on day 1 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.
Chris Wright: 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 MASH. 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, KOLs, 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 Q3, we initiated our phase IIa combination trial.
Chris Wright: This portion of INLIGHT has a randomized control design that will evaluate 240 and 400 milligram doses of WVE-007 in combination with weekly tirzepatide versus tirzepatide 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 007 in Q4 as a maintenance therapy to preserve weight loss following discontinuation of incretin treatment. In addition, we look forward to sharing 600 milligram data from the phase I single-ascending dose portion of INLIGHT in Q4. This will help us further characterize potency, duration, as well as safety and tolerability. Turning to WVE-006 for AATD. WVE-006 is our investigational RNA editing therapy with the potential to address both lung and liver manifestations of AATD.
Chris Wright: We continue to make excellent progress advancing WVE-006 for patients in need. Following a productive meeting with the FDA, we are now planning our registration trial. Our discussions with the agency, KOLs, 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 AATD 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 AAT 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 Z-AAT to address the risk of liver disease.
Chris Wright: While DNA base editing approaches target both lung and liver disease in AATD, 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 and 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 Z-AAT are also in development for AATD liver disease. However, this approach does not restore M-AAT, 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.
Chris Wright: This leads to misfolded Z-AAT protein and an absence of healthy circulating M-AAT 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 WVE-006, which targets the underlying causes of AATD, 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.
Chris Wright: In our ongoing RestorAATion-2 clinical trial, WVE-006 delivered substantially reduced levels of Z-AAT, protective basal levels of total AAT with a percent of wild type M-AAT 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 RestorAATion-2. We remain on track to share data from the 600 milligram monthly dosing cohort in Q4, which will help inform an optimal dosing regimen. With the compelling profile of WVE-006 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 AATD biomarkers. We believe this single trial design, without the need for a separate confirmatory study, offers an efficient path for full approval, bringing WVE-006 to patients in need as quickly as possible.
Chris Wright: In addition, we're encouraged that the agency supported the use of our LC-MS assay to measure M-AAT and Z-AAT proteins. We also continue to make strong progress advancing our second RNA editing candidate, WVE-008, for homozygous PNPLA3 I148M liver disease. Similar to WVE-006 and WVE-007, our approach for WVE-008 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 ninefold higher risk of dying from liver disease as compared with non-carriers. The PNPLA3 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 I148M carriers.
Chris Wright: In addition, we're encouraged that the agency supported the use of our LC-MS assay to measure M-AAT and Z-AAT proteins. We also continue to make strong progress advancing our second RNA editing candidate, WVE-008, for homozygous PNPLA3 I148M liver disease. Similar to WVE-006 and WVE-007, our approach for WVE-008 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 ninefold higher risk of dying from liver disease as compared with non-carriers. The PNPLA3 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 I148M carriers.
Chris Wright: 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 supported this notion. A dose-dependent incretins in liver enzymes were observed. By contrast, with WVE-008, we aim to correct the I148M 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 008, we plan to leverage previously genotyped populations to efficiently identify homozygous I148M carriers and accelerate enrollment.
Chris Wright: 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 will turn the call over to Kyle to provide an update on our financials. Kyle?
Kyle Moran: Thanks, Chris. Our revenue for Q3 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 Q3 2026, as compared to $45.9 million in the same period in 2025. The increase primarily reflects continued investment in our advancing clinical programs, including the phase II portion of INLIGHT and progress across our RNA editing pipeline. Our G&A expenses were $25.4 million in Q3 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. Our net loss was $61.9 million for Q3 2026 as compared to a net loss of $53.9 million in the prior year quarter.
Kyle Moran: We ended Q3 with $431 million in cash equivalents, and marketable securities, which we expect to be sufficient to fund operations into Q3 2028. We are also due to receive an incremental $12 million milestone payment from GSK in Q4 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 will now turn the call back over to Paul for closing remarks.
Paul Bolno: Thank you, Kyle. Our strong execution and progress throughout the year leave us well positioned to unlock value across our pipeline. With WVE-007, we are actively advancing our phase IIa monotherapy and combination trials towards key data in our target patient population and remain on track to initiate our post-treatment maintenance trial later this year. We are advancing WVE-006 towards a potentially registrational trial and building on our success in RNA editing with WVE-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 have made and for their continued commitment to reimagining what is possible for patients. I will now turn the call to the operator for questions. Operator?
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 hand by clicking the raise hand at the bottom of your Zoom window. Once called upon, please unmute your audio to ask your question. We will take our first question from Rick Bienkowski with Ladenburg. Please unmute your line and ask your question.
Rick Bienkowski: Hey, good morning, and thanks for taking the question. Now that you have clarity from the FDA on the accelerated approval pathway for WVE-006, do you have any insight on how large of a trial you might need to run for the pivotal study? Also, I know you have shared in the press release that you have 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?
Paul Bolno: Yeah, I will start the question, and then I will let Chris join in. I think it is important, as you laid out, so this is kind of the first into your second, the second part of that first question that went into what is 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.
Paul Bolno: As it relates to the individual biomarkers that we are going to use, I think we have been pretty clear that we are not going to competitively disadvantage ourselves as others are still going through processes of laying out what is required for those analysis for both full approval and for accelerated approval. But I think as Chris alluded to, it is nice to see that we have got validated LC-MS assays that we can use to quantify those biomarkers.
Chris Wright: Sure. I would say we had a really excellent meeting with the FDA. The Pulmonary Division in CDER does not always have an opportunity to review genetic medicines, 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. 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 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 are kind of highest when you start, and that kind of goes down over time.
Chris Wright: If you get an event as that is going down, you may end up being unprotected. So they were, I think, quite understanding of that and getting it quickly and were highly supportive of us moving forward for patients.
Operator: Our next question comes from Joon Lee with UBS. Please unmute your line and ask your question.
Joon Lee: Great. Thanks for taking our questions, and great to be following you guys again. This year's Nobel Prize in chemistry, 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? Just a quick follow-up question for Dr. Monika Vnuk, 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.
Paul Bolno: Thanks, Joon. It's great to have you back. I'll take the first part, and then I think Monika will join. Obviously, she's sitting next to me for the second part, and we're excited to have her. To your first piece, 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.
Paul Bolno: But if we think about what happens on every enzymatic structure we work with, whether that it's an AGO2, whether we see it with ADAR, whether we saw it with RNase H in antisense, whether we see it with the innate immune system recognizing various patterns, biology recognizes single structures. I think the most important piece in drug development is being able to optimize from a mixture. I think if we look back over a decade now, we're able to do this in a highly consistent, programmable way. Meaning if you think about, again, INHBE, it was 18 months from mouse data to human data, so it's efficient. It doesn't cost any additional features, so this isn't separation. We've been able to build the platform capability to drive that to manufacturing, where our costs are not different to unlock that potential.
Paul Bolno: 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 Monika to answer. She's dove in with both feet, or I guess, yeah, that's jumping. Go for it.
Monika Vnuk: Great. Thank you, Paul. Jun, thank you so much for the question. I am 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 am doing is jumping straight into the ongoing partnering discussions and working on the mid and longer term plans.
Paul Bolno: A lot of work to be done, but it is great to have you back.
Operator: Our next question comes from Reem Al-Ahmed with William Blair. Please unmute your line and ask your question.
Reem Al-Ahmed: Hi, this is Reem. I am on for Olivia. Thanks for taking our questions. We have two. First one on WVE-007 for INHBE. Good to see that phase IIa baseline adiposity is coming in much higher than phase I, and in line with phase II, 3 obesity studies. Given that and what you have seen on body composition so far, do you still feel confident you can get to the 5% weight loss at 12 months? 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? If there are any comparable studies we should look out for timelines.
Paul Bolno: Yeah. First, thank you for recognizing, I think Chris's statement on the baseline adiposity. I think it is good. I always say that some of these things, if they are planned, then you should be expecting them because phase II, III studies in obesity, as we have laid out, have that. To your point, it is nice to see when that is recognized. I think to that point, that is exactly, just like we said going into a phase II, III study would yield patients with higher baseline adiposity, meaning more fat to lose. I think it is very consistent with the analyses and modeling we are doing that points us to a path to potential 5% weight loss after a year on therapy, which is the regulatory bar, meaning this mechanism should drive more fat, which takes us back to preclinical data translating to clinical data. The DIO obese mice models lost substantial weight.
Paul Bolno: 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. We do see substantial fat loss in the DIO mouse model. Again, all aligned with our preclinical, clinical data in the phase I moving into our 2a data. We are excited about that. As for WVE-006, I will let Chris speak to the study specifically, but I think it is important, as you point out, the siRNAs, as you pointed out, the Arrowhead Takeda. That is a liver-driven study. We are going to take lung and liver patients holistically. Augmentation is not approved outside the United States, so as we think about a global study, we do not see any challenges with enrolling that. I will let Chris add to that.
Chris Wright: Yeah, sure. Thanks, Paul. We are engaged with a number of foundations and societies in Alpha-1, and they have these large registries. Working together with them, we are going to leverage those registries, which have actually several thousand patients in them for our trial. I think that will really help us to accelerate enrollment. The other thing that I think is notable is we have had a number of discussions with KOLs and actually with patients. What we are hearing is that people are excited about a convenient, easy-to-administer therapy that is reversible in the sense that if you need to stop it for some reason, you can, or if the environment changes, there are other options, you can use those.
Chris Wright: I think what we are 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. The last thing, just to highlight what Paul said, is that just like our other studies, we do not really have any liabilities from the hepatic perspective. In fact, we have already enrolled a number of individuals with liver fibrosis. We will continue to study individuals that have lung disease and liver disease throughout our program, and we are interested in showing benefits in both of those.
Operator: Thank you. As a reminder, we are allowing analysts to ask one question today. If you do have a second question, please raise your hands to join the queue and we will try to get back around to you. We will take our next question from Samantha Semenkow with Citi. Please unmute your line and ask your question.
Samantha Semenkow: Hi. This is Jane for Sam at Citi, and congratulations on the progress. 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 interim analysis to support your accelerated approval? Based on what data you have right now, do you believe you have already demonstrated the proof of concept against that bar? Thank you.
Paul Bolno: Yeah, thank you. I am assuming that the reflection was for AATD for the one year, just to make sure. I always say it is multiple aspects.
Samantha Semenkow: Right
Paul Bolno: It is important to confirm. Yes. As we said at the beginning, we are not going to get into the specifics of this from a competitive standpoint. What we can say is in the conversations that we went into saying that the premise around RNA editing in general, is to restore an MZ-like phenotype. Following discussions with the agency, the one-year interim analysis would be predicated on delivering an MZ-like result. I think I will let Chris add to that, but that is the premise of how we think about that interim assessment.
Chris Wright: Yeah. As Paul mentioned, really, we are 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 incretins at the time that there is infections or a lung inflammation, at the time that the tissue most needs protection. I think if we can able to achieve all those three things, which we have been able to show already in our data for RestorAATion-2, we will be in a very strong position.
Operator: Our next question comes from Ananda Ghosh with H.C. Wainwright & Co. Please unmute your line and ask your question.
Ananda Ghosh: Hey, thanks guys, and congrats on the quarter. Paul, recently Endocrine Society published a review urging to move beyond weight loss. Given that we get lot of inbounds on regulatory clarity on monotherapy in terms of weight loss. Looking at other measures such as DEXA and 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. From a sponsor point of view, have you engaged with the FDA on similar ideas?
Paul Bolno: Yeah. As we said, this is engagement that we expect this quarter, and not just for once, but on an ongoing basis. Not just Wave, very much to your point, when we have met with the obesity patient advocacy organizations, they are having their own conversations with the agency around a similar approach. I think getting this beyond weight loss to what is healthy weight loss, meaning, there is a reduction of moving beyond just scale weight on pounds where a good majority of that is coming off of muscle, to really focused on fat and importantly visceral fat, which is dangerous. The best measurements of that, as you point out, we have already in our phase I healthy volunteer without comorbidity patient population, have seen substantial fat reduction, visceral fat reduction, waist circumference changes.
Paul Bolno: Differences that we've seen with the profile of WVE-007 that are distinctly different than other even INHBE siRNAs that have generated data. I think we're compelled by that data that the medicine's working like it should. 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. Really that being driven off of body composition. We're very much in line with that. The profile demonstrates that. Our preclinical data shows that.
Paul Bolno: 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?" If we go back to the regulatory draft guidance, this 1-year time point with greater than 5% change in body weight does emphasize the body composition improvement. 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. These are all measurements that we're already capturing as part of those clinical trials.
Operator: Our next question comes from Salim Syed with Mizuho. Please unmute your line and ask your question.
Salim Syed: Great. Thanks for the question, guys, and welcome to Monika. Paul, Chris, maybe just one on WVE-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 trial starts to converge more into the Wave trial single trial instead of separate confirmatory trial design. Thank you.
Paul Bolno: No, thanks for the question. I am going to hand it to Chris, but I think at the general level to that last point you are making, I do think that there is an attempt now for better harmonization, and we are 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 CBER and CDER to get better alignment across endpoints. I think we will continue. I very much believe based on what we are 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.
Paul Bolno: Stepping back from that to the very specific point of why you see differences coming out from these companies relative to this, and I will hand this to Chris, is I really want to give the team a lot of credit for thinking differently in rare disease. I think too often the standard, which is kind of what you are seeing in coming out on other sides, which is people start with this idea to get into an accelerated approval, and then you end up having to run by the time you file these longer studies without alignment. That ends up continuing to add to cost patients time. I think the team's approach was to really approach it differently, which was not to forego, which again, feeding two birds one hand, not to forego the conversation on what a pathway to accelerated approval could look like.
Paul Bolno: Most importantly, lock down what a path to full approval could look like and work backwards. I will hand it over to Chris to the thought process and the engagement.
Chris Wright: Yeah, 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. So, I think it is a great approach. We had discussions with the FDA on that trial design, and we are moving forward with a single trial with the duration mentioned, 2 years for the full approval and a year for accelerated approval.
Salim Syed: Thank you.
Operator: Our next question comes from Josh Schwartz with Leerink Partners. Please unmute your line and ask your question.
Josh Schwartz: Hi. Thanks for taking my questions. Following WVE-006 monthly data in Q4, once dose is blocked, when do you expect to enroll the first patient in the registrational trial?
Josh Schwartz: Is a 3-month look at data in the phase IIa for WVE-007 still planned? If so, when could that occur? Thank you.
Paul Bolno: No, thank you. I will take the last question in terms of cadence and timing on the phase IIa INLIGHT. We said, we have the potential to deliver the phase IIa data. We could start coming as early as this year. I think we will provide an update later this quarter as we do our analysis of whether we would cut the data and look at the 3-month time point, which we know will be a body composition time point. I think we have seen that in the past, that at 3 months with WVE-007, that initial fat loss comes with muscle lean mass increase. It is really an important, and to the question that came out earlier, important from a body composition standpoint, but not the time point for weight loss.
Paul Bolno: We are going to do our analysis of whether we cut it at the 3-month or the 6-month, the 6-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?
Chris Wright: Sure. Our RestorAATion-2 study is still ongoing. We look forward to getting the 600 milligram data, multiple dose data. Once we have the 600 milligram multiple dose data, then we will be able to have a better sense of what dose and what dose interval we will be taking forward into the pivotal trial. We will provide updates at that time.
Paul Bolno: Thank you.
Operator: Our next question comes from Ben Burnett with Wells Fargo. Please unmute your line and ask a question.
Ben Burnett: Hi, thank you. Just one on WVE-006 and AATD, just the registrational study that's being planned. Can you talk about what endpoints might support full approval? I guess are some of these endpoints easier to power for than others?
Chris Wright: I think, in principle, this is a competitive space and we're not disclosing the endpoints that we're moving forward with. But generically speaking, there are certainly some that are a lot better than others, right? I think what we've heard and what we've seen and what our own analysis have shown, and actually that of others, is FEV1 is not really a feasible endpoint for AATD in a reasonable timeframe with a reasonable amount of patients. So that's one thing to say. There's a number of 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 CT densitometry, and so that's something that's been used for approvals in Europe.
Chris Wright: 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 shorter, a well-powered trial with not as many individuals going forward for a registration study. So those are the things we're thinking about currently.
Operator: Our next question comes from Yun Zhong with Wedbush. Please unmute your line and ask your question.
Yun Zhong: Hi. Good morning. Thank you very much for taking the questions. On WVE-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 populations to be willing to try this therapy? Well, understanding that the benefit of muscle preservation. 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.
Paul Bolno: No, and thank you for the question. I think 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 pounds of muscle, it's not equilibrated, right? 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 what's going to be meaningful for patients, and particularly to the prior question, which I think was spot on, that there really is a shift to what's driving health benefits. I know some people are saying, well, these medicines have both health benefits as well as potential aesthetic benefits. The benefits to losing fat and preserving muscle, I think achieve both of those aims.
Paul Bolno: They help on the health outcomes perspective and aesthetically by preserving muscle and losing fat. So I think ultimately the profile is going to be that. If we go back to the DIO mouse data where it took time, that mouse data, just to put this into perspective, it was equivalent weight loss from INHBE 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.
Paul Bolno: 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 medicine progressing. As to what is going to be required on the combination side, I think there is a variety of settings, which is why we are looking at that. Meaning if we achieve the regulatory bar, then you do not need a separate approval for the combination. This is like other medicines where those examples will be giving physicians the tools to see how Activin E and, in this case, tirzepatide, but you could think about that as incretins, coexist. People would get the experience data set and how to use that.
Paul Bolno: If you think about and asking the regulatory question in the context of combination is the first approval, then there is obviously the additive effect, and that has been demonstrated or discussed around an approvability pathway of the impact of incretin alone, plus the additive benefit of putting another medicine on top. But I think the key ultimately is the power of what happens when you can reduce fat and preserve lean mass.
Operator: Our next question comes from Whitney Ijem with Canaccord Genuity. Please unmute your line and ask your question.
Whitney Ijem: Hey, guys. Thanks for taking the question. Excuse me. Just another one on WVE-007, and I know you have talked about in the past expectations for the 600 mg MAD data. Excuse me, but can you just refresh our memory? How should we be thinking about that? What should we expect to learn? I guess the related question is there a scenario where you move the 600 mg dose forward into the maintenance study? I know you have chosen the lower two doses for the combo study, but just trying to get a sense of if there could be different doses in different settings. Thanks.
Paul Bolno: No, thank you. I think it's important it's a SAD study still. So it's still the phase I SAD 600 that's coming for WVE-007, just to put it in context. The MAD is part of the phase IIa study with the multi-dose. No, the upcoming data, if we think about it gives us another opportunity to that point. We know that the lowest dose activity was suppressed out at 7 and a half months. So the ability to continue to see what the profile looks like at both higher doses from a PK/PD perspective. Obviously, we'll 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 group would be different than the other dose ranges. But we're going to learn about safety and PK/PD.
Paul Bolno: In terms of your question around different, an interesting one, on different doses for different settings. What's different potentially about maintenance versus the combination and monotherapy, I reflect more the other direction, which is that the maintenance setting is probably the setting where there exists the best data set. Right? If we think about the human genetics, there's 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 brake off lipolysis at that 50% threshold, and you don't gain that adiposity that you see elsewhere, similar to what we saw in the animals, versus induction where you're losing that more fat.
Paul Bolno: So what we may find over time is actually that the need and balance in doses that's required for maintenance may not be as high as what's required, let's say, for a monotherapy weight loss. 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 if Chris has any, your thoughts on that.
Chris Wright: No, I think we just, 600 milligrams is to get more information about the dose, the duration, the dose interval. What do we need to get to once yearly or twice yearly dosing with the optimal suppression and to learn about safety at higher doses. 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 IIa study will also have substantial and durable knockdown at these lower doses.
Paul Bolno: Yeah. Nice to see dose-dependent knockdown having the durability, and then to your point, we are able to look at that across longer time points to ultimately optimize for the regimen.
Operator: Our next question comes from Danielle Brill with Truist Securities. Please unmute your line and ask your question.
Danielle Brill: Hi. Good morning. Thank you so much for the question. Just a quick one on WVE-006. Paul, given that you have already demonstrated the MZ-like phenotype that the FDA is looking for, just curious what incremental benefit you are hoping to see with the 600 milligram dose. 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 has not been directly tested in the clinic? Thank you.
Paul Bolno: If I am stepping back, you got part of it, but if I am stepping back and saying to your point of what the 600 for WVE-006 could look like, given what we have already seen, I think to the point that Chris mentioned and that you mentioned, what we will learn from 600 will inform dose and frequency. I think if we think about the prior doses we had, there was the 200 biweekly and the 400 monthly. 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, durations of drug product on board, and be able to optimize that regimen, as Chris mentioned, for the subsequent study.
Operator: Our next question comes from Steve Seedhouse with Cantor Fitzgerald. Please unmute your line and ask a question.
Steve Seedhouse: 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 III. Just like how flexible were they? Do you think the assay is going to need to be standardized across companies and across the industry going forward, or were they flexible on what you could use?
Chris Wright: 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 and to their satisfaction. 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. I think that they saw the value of what. I think if you have an assay that you have well-characterized and done the appropriate work on, they are open for you to be able to use that all the way through your development program.
Madison El-Saadi: I think it just, to add on to the work that Chris and the team have done, 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. I think when you think about how you can validate that against samples, when you are looking and assessing Z and we have human M, so we have no bystander edits, so we are not trying to assess non-native proteins. The ability to take existing data sets of MZ patients, MM patients, ZZ patients, and characterize those levels of M and Z in those patients, you do not need to redefine or try to characterize a non-native protein.
Paul Bolno: So I think to Chris Wright's point, I think we've got an assay that we can now use to make those assessments through the study, and frankly, beyond.
Operator: Our next question comes from Catherine Novack with JonesTrading. Please unmute your line and ask your question.
Catherine Novack: 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 mgs 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.
Paul Bolno: No, thank you. One, we're going to look at it. The wonderful thing about GalNAc is we know it's distributed. So there's a question really on a function of time to continue to produce. We saw that in early studies and translate that with time, how do sites recover and start producing more protein more efficiently. So I think the ability to see that, whether or not you can see an impact on Z faster, I think those will be opportunities. But I always step back and kind of reflect that 2 weeks after the lowest single dose of 200, we could get over 20 micromolar of protein. And so the notion that even at that lower dose, we were seeing a pretty robust response across was very clear.
Paul Bolno: I think the other thing just to add to that is when we do look at the natural history cohort of MZ patients, we are right there on the percent of M there. 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 are delivering right at the percent of M that is seen in the natural history cohorts of MZ. Again, some of the other balance may be a function of what happens with protein over time, but we are already delivering on the profile with the existing data set that we have had at the MZ ratio that you would expect to see in an MZ cohort.
Operator: Our next question comes from Madison El-Saadi with B. Riley Securities. Please unmute your line and ask your question.
Madison El-Saadi: Hi, Bradson from Bradson. Thanks for taking our question. Regarding your 006 readout in Q4, what would push you to a biweekly regimen versus a higher monthly dose for the pivotal? Would the 006 trial design that you discussed, do you think this could be sufficient for submission and potential approval in the EU? It seems like you could reach the EU market fairly soon after the US, or if I am being a bit too optimistic there. Thanks.
Paul Bolno: Sure. Chris and I are looking at each other. Chris, go on. I think, in terms of the Q4 data update, again, to the prior question, I think we are going to get to look at that modeling data and see. I think it is highly likely to stay monthly, just because based on the 200 and 400 alone, I think we could model that. Whether or not the 600 adds anything else to that in terms of what the dosing frequency could be, even less if we look at the totality of exposure. I think we are going to be able to make a number of those assessments. But I will let Chris speak to the registrational strategy.
Chris Wright: Great. So that is a great point about the EU, and we definitely have that in our overall registration plans. 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.
Operator: Our next question comes from Luke Izzy. Sorry.
Paul Bolno: No.
Operator: Our next question comes from Luke Izzy with RBC Capital Markets. Please unmute your line to ask your question.
Luca Issi: Oh, great. Thanks so much. Can you guys hear me okay?
Paul Bolno: Perfect.
Chris Wright: Yes.
Luca Issi: Great. Yeah, maybe, Paul, maybe a bigger picture question 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 WVE-006, which maybe was not what you were anticipating. But now they have obviously decided to opt in for this novel hepatic asset. So I guess 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 it is a function of their leadership changes and whatnot. But again, 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.
Paul Bolno: Yeah, no. Thank you. I think as you point out, the decision around leadership change, and we kind of step back and the decision of what assets are moving forward and frankly what we are able to bring back into the portfolio really is a function of this kind of rare and we are not allowed to disclose liver or hepatic indications, but what I would say is it is very much aligned, I think, with that similar profile. So I think, to see them move forward with the assets that they are is exciting for us. The team is heavily engaged. There is a lot of work that we have done and they presented actually at a Research Day a little while ago on the work that we have done on unlocking cell types and targets with various modalities.
Paul Bolno: And so it was always kind of at its core, an ability to access platform capability and be able to unlock targets. And so it has been nice for both sides. And I say that because it has been mutually beneficial in terms of the things that we have 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?
Paul Bolno: And so, yeah, I think on both sides, I would like to think that each of us are getting out of it what we went into it saying, "This is going to be aligned with a portfolio construction." And, with us, and now having full ownership of WVE-006, and frankly, if you remember WVE-007 with INHBE that we selected out of the genetic target database early on in the collaboration, I think the collaboration has been mutually beneficial.
Operator: Our next question comes from Alec Stranahan with Bank of America Securities. Please unmute your line and ask your question.
Alec Stranahan: Hey, guys. Thanks for taking our question. Good to see the phase IIa has higher adiposity. One thing we have heard from KOLs in the space is that, yes, like you said, Paul, more weight to lose, but these patients also often have more muscle to carry that weight, so maybe more muscle to lose as well. Just curious to hear your thoughts around 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. Then just one quick one, if I may, on AATD. Any additional FDA meetings planned ahead of launching the pivotal, and I guess when could those happen? Thank you.
Paul Bolno: Well, thank you. To get back to the adiposity question and body composition improvements, I think that it is spot on. By preserving lean mass, you actually could accelerate fat loss. The notion that you accelerate fat loss, you preserve muscle. Muscle itself as an endocrine organ helps continue to drive that metabolic rate that then ultimately could lead to further fat loss. There is not a huge need to lose muscle. I think preserving that and actually sustaining that in the setting of fat reduction is crucial. I do think, as you are pointing out, what we are continuing to hear on is that this BMI is kind of almost an antiquated way of doing these assessments. On one hand, you could be a bodybuilder with elevated BMI, or you could be overweight.
Paul Bolno: I think the notion of really getting into body composition as a function of subq fat, visceral fat, and lean mass is important. I know we have said this before, but I do think it is wonderful to start seeing the fact that scales that people can have in their homes are now almost inexpensive to be able to measure and characterize that. The only tool people kind of were able to use before was a scale where they could look at pounds, they could measure height, and they could try to calculate what is happening in terms of BMI and say, "Okay, I need to lose weight." I think the discipline that we are able to see now, where people are able to really quantify the characterization of what weight is being lost, the quality of that weight loss, as a function of health is important.
Paul Bolno: And is very much tied to what we hear from the patients that we are speaking to and their advocates, as well as the clinicians we are speaking to. So, I think it all 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 WVE-006, we do not comment on individual regulatory interactions, but it is safe to assume that we will be well prepared when we go into that trial to deliver.
Alec Stranahan: Sure.
Operator: Our last question comes from Cha Cha Yang with Jefferies. Please unmute your line and ask your question.
Operator: Thanks for taking our question. I wanted to drill down on some of the expectations for WVE-007 for your post-incretin maintenance trial. Can you speak to the magnitude of weight regain prevention that you would consider clinically meaningful in the maintenance setting? Thanks.
Paul Bolno: Yeah. Thank you. And just to be clear, because I know it is WVE-007, just for others dialing in, just to make sure. So for INHBE WVE-007, the maintenance study and the prevention of weight gain. We will 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 is important as we do look at that, is that to quantify it, as we actually saw essentially what we saw when you use this mechanism, which is you get a slight bump, which comes from lean mass incretins, and then the fat stays solid, hence why it stays flat.
Paul Bolno: What you would expect to see when we provide that update is a requisite update on not just prevention of weight gain as a total pounds number, but also both as a function of how weight is being regained, right? Because the prevention will be of fat coming back, which is the principal driver. If you think about what happens when people come off their incretins, it is 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. The ability to curtail that fat regain, but to potentially regain some muscle we see as advantageous, and we will give the specifics when the study initiates.
Operator: Thank you. There are no further questions at this time. I will now turn the call back over to Paul Bolno for closing remarks.
Paul Bolno: Thank you for joining our call this morning, and we appreciate your continued support. Have a great day.
Operator: This concludes the call for today. Thank you for joining. You may now disconnect.
