Wave Life Sciences, Inc. (WVE) Earnings Call Transcript & Summary

Hello, and welcome to Wave Life Sciences Third Quarter 2026 Earnings Call. [Operator Instructions] 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.

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, Monika Vnuk, who joined Wave last month. The press release issued this morning is available on the Investors 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 the 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 WVE-007 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 extra-hepatic siRNA, RNA editing and our emerging bifunctional modalities. I'll 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. INHBE target is strongly supported by human genetics. Individuals who have a protective loss of function variant and 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. And 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 Active 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. 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 risk 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 preclinically and clinically with differentiated data from other approaches in the field. Preclinically, our INHBE 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 INHBE 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 I 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 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 3 distinct treatment settings: monotherapy, combination therapy and a post-incretin 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. 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 1 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 derisk development pathways in NASH 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. 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. Our preclinical data provide compelling support for 007'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 discontinued 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-incretin 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 setting. 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 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 health care 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 onetime 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 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. 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 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 a proprietary chemistry across our hepatic and extra-hepatic 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 phenodesign 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'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 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 received 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. 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 IIa combination trial. This portion of INLIGHT has a randomized controlled 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 the fourth quarter 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 the fourth quarter. 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. We continue to make excellent progress advancing WVE-006 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 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. 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 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 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. This leads to misfolded in 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 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. In our ongoing RestorAATion-2 clinical trial, 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 the fourth quarter, which will help inform an optimal dosing regimen. With the compelling profile of 006 we've observed to date and following our FDA meeting, we're planning for a single 2-year registrational trial with a one-year interim analysis for potential accelerated approval based on AATD biomarkers. We believe the single trial design without the need for a separate confirmatory study offers an efficient path for full approval, bringing 006 to patients in need as quickly as possible. In addition, we're encouraged that the agency supported the use of our LCMS assay to measure M-AAT and Z-AAT proteins. We also continue to make strong progress advancing our second RNA editing candidate, WVE-006 for homozygous PNPLA3 I148M liver disease. Similar to 006 and 007, our approach for 008 is strongly rooted in human genetics. There are an estimated 9 million homozygous PNPLA3 I148M carriers with liver disease across the U.S. and Europe who are at a ninefold higher risk of dying from liver disease as compared with noncarriers. The PNPLA3 variant is a well-established driver of NASH and liver diseases more generally, if 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. 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 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. We will evaluate target engagement with circulating biomarkers and assess early signs of efficacy using noninvasive 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 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 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. Our net loss was $61.9 million for the third quarter of 2026 as compared to a net loss of $53.9 million in the prior year quarter. We ended the third quarter with $431 million in cash, cash equivalents and marketable securities, which we expect to be sufficient to fund operations into the third quarter of 2028. 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 3 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 WVE-007, we're 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-incretin 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?

[Operator Instructions] We'll take our first question from Rick Bienkowski with Ladenburg.

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? And also, I know you 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?

Yes, I'll start the question, and then I'll let Chris join in. But I think it's important as you laid out 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 2-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 LCMS assays that we can use to quantify.

Sure. So I would say we had a really excellent meeting with the FDA. The Pulmonary Division in CEDAR 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 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 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 we're highly supportive of us moving forward for patients.

Our next question comes from Joon Lee with UBS.

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? And just a quick follow-up, a question for Dr. Monika Vnuk she's on. What is your first order business update? And what is your midterm and long-term goals at Wave?

It's great to have you back. And I'll take the first part and then I think Monika will join. Obviously, she's sitting back to me for the second part, and we're excited to have her. But first, I mean, I think it's nice to see the recognition on chirality. As you point out, it's not just an award for a prize, but it's the recognition of just how important chirality and stereochemistry is the 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 that's AGo2, whether we see it with ADAR, whether we saw it with [ RNA ], 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, 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. So we've been able to build the platform capability to drive that to manufacturing where our costs are not different to unlock that potential. And I think having that clarity of understanding of medicines lets us understand in preclinical studies why something is 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 has dove in with both feet or I guess, yes, that's jumping. But yes, go for it.

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 the 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.

Our next question comes from Amer Ahmad with William Blair.

This is [ Rema ]on for Alethia. We have 2. First one on 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/III 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 at for time lines?

Yes. I mean, first, thank you for recognizing. I think Chris' statement on the baseline adiposity. I mean I think it's good. I would say some of these things are -- they're planning and you should be expecting them because Phase II/III 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 Phase II/III study would yield patients with higher baseline adiposity, meaning more fat to lose. I think it's very consistent with the analysis and modeling we're doing that point us to a path to potential 5% weight loss after on therapy, which is the regulatory bar, meaning this mechanism should drive more fat, which is, I think, 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 in the Phase I moving into our IIa data. So we're excited about that. And as for 006, I'll let Chris 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 with enrollment, but I'll let Chris answer that.

Yes, sure. Thanks, Paul. So we are engaged with a number of foundations and societies in Alpha-1, and they have these large registries. And so working together with them and 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 like a convenient, easy to administer therapy that's reversible in the sense that like 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.

[Operator Instructions] We'll take our next question from Samantha Semenkow with Citi.

Hi. This is [ Jean ] for Sam at Citi. And congratulations on the progress. 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? And based on what data you have right now, do you believe you have already demonstrated a proof-of-concept against that bar?

I'm assuming that the reflection is for AATD for the one year, just to make sure I would say it's multiple aspects important to confirm.

Right.

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 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. And so I think I'll let Chris add to that, but that's the premise of how we think about that interim assessment.

Yes. 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're able to achieve all those 3 things, which we've been able to show already in our data for RestorAATion-2, we'll be in a very strong position.

Our next question comes from Ananda Ghosh with H.C. Wainwright UK.

Paul, recently, Endocrine Society published a review urging to move beyond weight loss. 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 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 the FDA on similar ideas?

Yes. As we said, this is an engagement that we expect this quarter and not just for once, but on an ongoing basis. And not just weight, very much to your point, when we met with the obesity patient advocacy organizations, they're having their own conversations with the agency around a similar approach. And 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 focus on fat and importantly, visceral fat, which is dangerous. And so the best measurement of that, as you point out, I mean, we have already in our Phase I healthy volunteer comorbidity patient population have seen substantial fat reduction, visceral fat reduction, weight circumference changes. So differences that we've seen with the profile of 007 that are distinctly different than other even INHBE siRNAs that have generated data. So I think we're compelled by that data that the medicine is 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 Syed with Mizuho.

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 trial starts to converge more like into the Wave trial single trial instead of separate confirmatory trial design?

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 CBER and CDER 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 why that you see differences coming out from these companies relative to this is, and I'll 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're seeing in coming out on other sides, which is people start with this idea to kind of getting to 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. And so I think the team's approach was to really approach it differently, which was not to forgo, again, feeding 2 birds one hand, not to forgo 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.

Yes. I mean 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'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 2 years for the full approval and a year for accelerated approval.

Our next question comes from Joe Schwartz with Leerink Partners.

So following WVE-006 monthly data in the fourth quarter, once dose is blocked, when do you expect to enroll the first patient in the registrational trial? And then is a 3-month look at data in the Phase IIa for WVE-007 still planned? And if so, when could that occur? Thank you.

And I'll take the last question in terms of cadence and timing on the IIa INLIGHT. And we said, well, we have the potential to deliver the IIa data 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 3-month time point, which we know will be a body composition time point. I think we've seen that in the past that at 3 months with 007, that initial fat loss comes with muscle or lean mass increase. And so it's 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. And so we're going to do our analysis of whether we cut it at the 3 months or the 6 months and 6 months being a time where we can assess weight loss. More to come on that this quarter in terms of timing and updates. Chris, do you want to take the first question?

Sure. So our RestorAATion-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.

Our next question comes from Ben Burnett with Wells Fargo.