Wave Life Sciences Ltd. (WVE) Q3 FY2025 Earnings Call Transcript & Summary

Hello, and welcome to Wave Life Sciences Third Quarter 2025 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 2025 earnings update. Joining me today with prepared remarks is Dr. Paul Bolno, President and Chief Executive Officer; and Kyle Moran, Chief Financial Officer. Dr. Chris Wright, Chief Medical Officer; Dr. Erik Ingelsson, Chief Scientific Officer; and Dr. Chandra Vargeese, Chief Technology Officer, will be available for questions following the prepared remarks. The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause our 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. I would like to first thank those of you who are able to join us for our 2025 Research Day on October 29, where we shared the first ever demonstration of activin E reductions in a clinical trial. Notably, with a single dose of WVE-007, our INHBE GalNAc siRNA, we were excited to show highly significant and durable human activin E reductions that exceeded levels needed in preclinical models to drive meaningful weight loss and prevent rebound weight gain following cessation of the GLP-1. In addition, we provided an in-depth overview of our recent progress in RNAi and RNA editing and how we are building on the successful clinical translation of our WVE-007 and WVE-006 programs to advance our pipeline, including our new RNA editing clinical candidate, WVE-008 for the treatment of the up to 9 million homozygous individuals living with PNPLA3 I148M liver disease in the U.S. and Europe. We also unveiled how we're harnessing the power of both siRNA and RNA editing to advance an innovative new bifunctional single oligonucleotide construct that is designed to silence one target while simultaneously editing or upregulating another distinct target. All of these clinical and preclinical advancements are made possible by our unique and proprietary chemistry and platform innovations. Just last week, we had the privilege of sharing data on WVE-007 at Obesity Week, where we received significant attention from the patient community, key opinion leaders and companies with deep understanding of and strategic interest in the obesity space. There was a clear recognition for the need for non-incretin treatment approaches and overwhelmingly positive engagement on 007's potential to induce fat loss, preserve lean mass and improve cardiometabolic health, all without the negative GLP-1 class effects and with the convenience of once to twice a year dosing. There is particular excitement in 007's potential as a maintenance therapy, which would allow patients to transition off chronic incretin therapies while at the same time preventing rebound weight gain, preserving lean mass and sustaining cardiometabolic health. Reflecting on the rapid progress we've made advancing 007 in our INLIGHT clinical trial, we have now enrolled over 70 participants and are well-positioned to deliver data on over 100 participants from the clinical trial sites in Europe and the U.S. in the first half of 2026. We began testing WVE-007 in INLIGHT at our lowest subtherapeutic dose cohort of 75 milligrams in 8 participants. Then for the subsequent cohorts, 240 milligrams, 400 milligrams and 600 milligrams, which are in the potential therapeutic range, we have expanded to 32 participants. WVE-007 was generally safe and well tolerated, and our independent data monitoring committee has approved further escalation to a next higher dose in Cohort 5. At Research Day, we shared highly significant dose-dependent and durable activin E reductions 1 month post single dose of 007 in the first 3 cohorts of INLIGHT, including a 56% reduction for the 75-milligram cohort, 75% reduction for the 240-milligram cohort and an 85% reduction for the 400-milligram cohort compared to baseline. In addition, we had the opportunity to evaluate our lowest dose cohort out to 6 months. And throughout the 6-month follow-up period, we continue to see sustained reduction, supporting 007's potential for once or twice yearly dosing. The durability and potency we've observed thus far is particularly encouraging as we expect consistent and robust activin E reduction over time is necessary to achieve meaningful weight loss. As we shared at Research Day, Wave's unique Pena design and proprietary chemistry enabled the achievement of the potent and durable suppression needed for the INHBE target. In our DIO mouse model, we demonstrated that weight loss in the same range as semaglutide occurred when activin E was durably reduced by greater than 70% from baseline. The knockdown we've observed in the 240 and 400-milligram cohorts already exceed these levels. In our preclinical studies, we have shown extensive data supporting 007's unique mechanism of action to drive weight loss in monotherapy as well as maintenance in combination settings. Specifically, we shared data that support 007's ability to double weight loss when added to semaglutide and prevent rebound weight gain following cessation of GLP-1 in DIO mice. Furthermore, we've shown that INHBE reduction led to adipocyte shrinkage, fewer pro-inflammatory macrophages, less fibrosis and improved insulin sensitivity in adipose tissues, highlighting mechanisms that could explain the risk reduction for type 2 diabetes and coronary artery disease observed in human genetic data. With robust and durable target engagement in the clinic and comprehensive preclinical data that support both the mechanism of action and impact of our proprietary chemistry, we're incredibly excited to build on this positive momentum. We plan to deliver multiple near-term updates that assess blood-based biomarkers of metabolic health, body composition and weight loss across multiple cohorts. Beginning this quarter, we'll have the first opportunity to assess the early impact of INHBE reduction at 3 months in the 240-milligram cohort. And importantly, in the first quarter of 2026, we'll be able to assess 6-month follow-up data from the 240-milligram cohort as well as 3-month follow-up data from the 400-milligram cohort. In RNA editing, we continue to lead the field with WVE-006, our GalNAc RNA editing oligonucleotide for AATD. WVE-006 has the potential to be the first treatment for AATD that addresses the root cause of the disease with a convenient subcutaneously dosed therapeutic. WVE-006 does not require IV-administered LNPs or complex delivery vehicles like other investigational treatments in development. This profile supports treating individuals living with AATD, including those living with lung or liver manifestations of the disease or both. Since the approval of weekly IV augmentation therapies to help manage lung disease, the field has focused on keeping serum AAT levels above a minimum threshold of 11 micromolar, in part because ZZ individuals do not produce any M-AAT and have limited ability to increase serum AAT levels during an acute phase response or exacerbation. However, with RNA editing, our goal is to restore the MZ phenotype by achieving 3 criteria: keeping basal protein levels at or above 11 micromolar, driving 50% or greater circulating M-AAT with corresponding decreases in Z-AAT protein and most importantly, restoring the physiological response of serum AAT protein to acute inflammatory events. In September, we delivered data from our RestorAATion-2 trial demonstrating that we have already achieved these goals with 006. We observed AAT levels of up to almost 13 micromolar. We showed 64% of AAT was wild-type M-AAT with a corresponding 60% decrease in mutant Z-AAT protein. And these effects were highly consistent and durable across individuals, supporting infrequent dosing of monthly or less. Most notably, we are able to restore a ZZ participants ability to respond to an acute inflammatory event with total AAT levels of greater than 20 micromolar, just 2 weeks after a single dose of 006. Encouragingly, the magnitude and 4-week duration of this response were also proportional to the levels you'd anticipate in an MZ patient based on natural history. Following our September data, we've had multiple interactions with key opinion leaders in the field who expressed their excitement about these data. In particular, the ability of WVE-006 to restore physiologic AAT production represents a major paradigm shift from weekly IV augmentation therapies. As we look ahead to the remainder of our RestorAATion-2 trial, we are highly encouraged by our initial results progressing rapidly and excited to advance a potentially transformational new medicine to individuals living with AATD. Dosing is ongoing in the 400-milligram multi-dose cohort, and we remain on track to deliver data in the first quarter of 2026. We've also initiated the single-dose portion of our third and final 600-milligram cohort, and we look forward to delivering single and multi-dose data from the 600-milligram cohort in 2026. Building on our success with 006, we are advancing WVE-008, a GalNAc-conjugated RNA editing program for PNPLA3 I148M liver disease as our next RNA editing clinical candidate. Like 006 and 007, PNPLA3 is a compelling target with strong human genetic evidence and a clear translational path to early clinical proof of concept. There are an estimated 9 million homozygous I148M carriers with liver disease across the U.S. and Europe who are at a ninefold higher risk of dying from their liver disease compared to noncarriers. The PNPLA3 I148M variant is a well-established driver of steatosis, inflammation, ballooning and fibrosis, and yet there are no approved medicines that directly address this biology. Emerging preclinical and clinical data indicate that simply knocking down PNPLA3 is not the right solution as loss of PNPLA3 function can worsen the very features we're trying to treat. By contrast, with 008, we aim to correct I148M using our leading RNA editing capability, which is expected to restore PNPLA3 activity and lipid mobilization, reverse steatosis as well as improve inflammation, ballooning and fibrosis. We've shared preclinical data that corroborate this approach. We've demonstrated that O08 restores functional PNPLA3 and decreases lipid accumulation. And importantly, we showed that we were able to achieve robust editing with no bystander edits or off-target signals and achieve high deliver tissue exposure, which supports infrequent dosing. Clinical planning is underway for our first-in-human study, where we will leverage previously genotype populations to efficiently identify homozygous I148M carriers, and we are on track for a CTA submission in 2026. Turning to DMD and HD clinical programs. Earlier this year, we shared data from FORWARD-53 in DMD, which supported WVE-N531 as a potentially best-in-class and important new therapeutic option for individuals with exon 53 amenable DMD. We observed a statistically significant and clinically meaningful improvement of 3.8 seconds in time to rise versus natural history, which is the largest effect observed relative to any approved dystrophin restoration therapy at 48 weeks. We also observed the first ever demonstration of substantial improvements in muscle health with exon skipping, including a statistically significant reduction in fibrosis and decreases in creatinine kinase and circulating inflammatory biomarkers. Moreover, we saw additional clinical evidence of myogenic stem cell or satellite cell uptake in N531 earlier in our trial, which supports the improvements in muscle health and muscle fiber maturation we observed at 48 weeks. WVE-N531 is also differentiated by supporting preclinical evidence, demonstrating even greater access to heart and diaphragms as compared to skeletal muscle. We remain on track to submit an IND in 2026 for accelerated approval of N531 with a monthly dosing regimen. In HD, we are continuing to prepare for a global potentially registrational Phase II/III study of WVE-003 in adults with STP3 and HD using caudate volume as a primary endpoint, and we are actively engaged in discussions with prospective strategic partners. Developed using our platform's specificity of stereochemical control and best-in-class chemistry, we designed 003 to be the first allele-selective approach in HD. By reducing mutant Huntington at the mRNA and protein level, 003 addresses the underlying drivers of neurodegeneration. And by sparing wild-type Huntington protein, which is critical to central nervous system health, 003 is uniquely positioned to address the full spectrum of HD from early asymptomatic stage through the onset of symptoms and beyond. In SELECT-HD, we demonstrated potent and durable mutant Huntington reductions of up to an industry-leading 46% and preservation of wild-type Huntington with just 3 doses. Importantly, we observed a statistically significant correlation between allele-selective mutant Huntington reductions and slowing of caudate atrophy, marking the first time this correlation has been observed in HD. As a reminder, our own internal analysis of natural history data sets, including Track and Predict-HD, showed that an absolute reduction of just 1% in the rate of caudate atrophy is associated with a delay of onset of disability by more than 7.5 years. This is a staggering number with meaningful implications for health and economic outcomes and provides further evidence supporting the rate of caudate atrophy as a primary endpoint for an efficient clinical trial. These analyses, along with the complete clinical results from our SELECT-HD trial were both part of our engagement with FDA that led to supportive feedback. We remain on track to submit an IND application for this Phase II/III study in the second half of this year. With that, I'd like to turn the call over to Kyle to provide an update on our financials. Kyle?

Thanks, Paul. Our revenue for the third quarter of 2025 was $7.6 million compared to negative $7.7 million in the prior year quarter. The year-over-year increase was attributable to the timing of revenue recognized under our collaboration agreement with GSK. Research and development expenses were $45.9 million in the third quarter of 2025 as compared to $41.2 million in the same period of 2024. This increase was primarily driven by our rapidly advancing INHBE program and RNA editing programs as well as compensation-related expenses, including share-based compensation. Our G&A expenses were $18.1 million for the third quarter of 2025 as compared to $15 million in the prior year quarter. The increase was primarily related to share-based compensation and other external expenses. As a result, our net loss was $53.9 million for the third quarter of 2025 as compared to a net loss of $61.8 million in the prior year quarter. We ended the third quarter of 2025 with $196.2 million in cash and cash equivalents compared to $302.1 million as of December 31, 2024. Subsequent to quarter-end, an additional $72.1 million in ATM proceeds and committed GSK milestones extended our expected cash runway into Q2 2027. By contrast, it is important to note that potential future milestones and other payments to us under our GSK collaboration are not included in our cash runway. I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. We are incredibly encouraged by the progress we've made across our pipeline. In the past 2 months alone, we've rapidly advanced INLIGHT and delivered robust and durable activin E reductions, and we have achieved the key treatment goals for 006 in RestorAATion-2. Looking ahead, we have a tremendous opportunity to build on our strong momentum as we continue to reimagine what's possible for patients. We look forward to keeping you updated on our progress. And with that, I'll turn it over to the operator for Q&A. Operator?

[Operator Instructions] We will take our first question from Joon Lee with Truist Securities.

And it's really great to see a nice dose response of activin E knockdown and weight loss in the DIO model. Have you looked into what happens to all the fat that's mobilized post activin E knockdown? Specifically, have you checked the liver fat deposits or looked at lipid panels for any LDL or triglycerides in these mice? And I have a quick follow-up on Huntington's.

Yes. Thank you, Joon. And yes, one, it was wonderful to see dose responses, as you pointed out, in the DIO mouse, -- it's even better when we got to see dose responses in humans, which is obviously incredibly encouraging. To the point that you're making on fat, I mean, I think we can comment on -- positively on multiple approaches. One, to your point, preclinically, we haven't observed any changes in increased lipids and deposits in the liver. That's both in the DIO studies we've done, but also in our preclinical toxicology studies. So, nothing to suggest that, that stat is finding its way to other tissues. I also point back to the clinical genetics, which show these patients actually have a decreased risk of NASH and liver disease. And then most importantly, as we look at the clinical study progressing, as we said on the last update that we're up to 600 milligrams with an FDA review so that we could start in the U.S. at 600. And they got to review all the safety data that preceded that. And so, at that point, again, encouraging, not just from a preclinical and mouse perspective, but also from a human perspective. And while we get this question, I mean, I think what we have to think about is lipolysis breaks up these free fatty acids and they're used as energy, energy and muscle, energy and heart. And so, these are positive findings that have been seen in other heart failure activities. So, nothing that we would -- that would suggest any concerns from our standpoint.

And on Huntington's, have you had a pre-IND meeting with the FDA? And any changes to their comments on the use of MRI as a reasonable surrogate for Huntington's? And any thoughts regarding recent backtracking by the FDA according to some of the companies that you -- in your peer group?

Yes. No, and we appreciate the question. I know there's a lot of discussions about HD recently. And yes, I mean, I think we have -- and we've shared this, have alignment with the FDA on the use of MRI as an imaging endpoint in connection with all of the other clinical data we're measuring. But it's important to note that we're running this as a placebo-controlled study as we're using that imaging endpoint as a primary endpoint. I think there is a lot of consternation over the agency's perceived changes of opinion. And to date, we haven't observed that or found that. I think it is important when we think about caudate. And I reflect on this relative to some of the discussions that are ongoing relating to utility of natural history studies in clinical trials. And I think it's important to note that when we use Track and Predict-HD as the natural history studies for comparison and supporting use of MRI imaging data, those 2 studies include MRI as a prominent feature. And I do think -- the recognition is we just reminded people on the call today, and we've shared a number of times that a 1% change in caudate atrophy can translate to a 7.5-year delay in clinical disability really does set the stage that small meaningful changes in caudate can change clinical outcome measurements. And I think what's important there, if we think about other studies that have been done that haven't looked at propensity matching of caudate volume to patient sizes in natural history, some natural history roll don't include MRI imaging. Actually, if you have a larger caudate at the beginning of that study, that could actually be attributable to a delay in clinical disability on CHDURS and other clinical outcome measurements. So, I think it is important that while there's a lot of discussion about the agency, we feel very confident in both what's driving our decision on the utility of MRI imaging caudate, but also making sure we run a well-powered, well-designed clinical trial to determine that.

Paul, just a quick follow-up. How variable is the caudate volume within the same Huntington's stage, like Stage 2 and Stage 3 and et cetera. Within the same stage, are there variabilities in the caudate volume? And how much?

There can be -- I think what we've seen is very steady changes in caudate. And actually, with the shift in the staging criteria now, actually caudate is becoming a core component of that staging criteria. And so actually, you can assess stages and what patients have -- what change in caudate at each particular stage. And I think that's why it's helpful as we think about other studies that are done and trying to benchmark their size of caudate volume relative to that. We could assess that in looking at those data sets externally. And I think if you had to bias a study towards larger caudate, let's say, so that they would be accessible, that could be attributable to actually delaying and slowing clinical progression, not related to potential medicines. I mean I think what's critical about the data we've generated to date is we've seen the most substantial reductions in mutant Huntington. I think looking at target engagement, coupled with changes in anatomical findings is important. We actually -- people remember, but at the HSG meeting back in October, even the oral small molecules showed a lower reduction in mutant Huntington. I mean, I think we looked at the data presented by Novartis on PTC, I mean they had less than 20% target engagement and actually had ventricular enlargement and brain volume reduction. So, I think looking at target engagement relative to outcomes is going to be critical. And I think we remain -- have high conviction on an allele-specific approach to mutant huntingtin lowering. And I think post all of this have been actively engaged with our potential partners in terms of accelerating the study.

We'll take our next question from Cheng Li with Oppenheimer.

Congrats on the progress. I have a question on the obesity we poster. It just seems like some gene expression changes actually happen pretty early, but some maybe happen later. So, I'm just wondering, by the time you report initial data in the fourth quarter, what kind of changes in those biomarkers related to metabolism, inflammation and fibrosis you would like to see and maybe which biomarkers are more important? And I have a quick follow-up.

Yes. I'll let Erik add his thoughts to this. But there is an induction over time. I think what we do see is the rapid engagement of both the target and suppression of protein happens fairly rapidly and is sustained. And as you point out, that change over time drives lipolysis as we saw in the DIO models. And then along that way, are going to be able to track various biomarkers of metabolic health that correspond with that. I don't know, Erik, if you want to add to that.

No, I think that's a good summary. There is a trajectory. I think maybe worth just pointing out that on the obesity week poster, those are from liver biopsies. And obviously, these are healthy individuals living with obesity and -- so there will not be any liver biopsies. But we -- as we have reported, we are able to look at some circulating biomarkers, but we haven't shared exactly what we're going to look at.

And just wondering, based on your like preclinical study, when do you think the weight loss can plateau with 007?

Yes. I think one of the encouraging findings is even out of that study where -- and everybody has that image in their head of the INHBE fat loss, which is weight loss, but all driven off of fat, similar to semaglutide's total body weight reduction. It doesn't appear at that point that we necessarily start to plateau versus the GLP-1 as it relates to fat loss. So, I think that's going to be -- while we talk about the early changes in kinetics, I think the opportunity is really to establish that floor. I mean I think people often talk about basically greater than a year on the GLP-1s plateauing. But I think what's nice is we haven't seen that point yet. So, I think we'll have an opportunity to continue to see what that curve looks like for INHBE over time, and the study is designed to assess that.

We'll take our next question from Salim Syed from Mizuho Securities.

Congrats on the progress, Paul and team. Just a couple from us. One on alpha-1 antitrypsin. Paul, just curious to get your thoughts around some of the DNA editor ATD programs that we've seen some recent preclinical data on some discussion there, obviously, being able to reduce 20 micromolar plus M-AAT, and just how does that framework you thinking all do you need to be in that sort of range for outside the acute phase response? And then the second question is just on DMD. I noticed in the press release, there's no more reference to the additional exon skipping program, CTAs for 2026. I'm wondering if that was removed, it's no longer the plan.

Yes. To start with the first one. I mean, I think as we've learned in trying to benchmark preclinical to clinical data, recognizing a lot of that's driven in the sort of A1 mouse model, that's high copy number. I think the absolute translation if we were to compare those data, let's say, DNA editing to DNA editing at beam, I think we've seen the corresponding changes that there's so much opportunity to edit transcript. But for that, that I don't necessarily think there's going to be substantially more editing than necessarily what we're seeing across potential other editors on the DNA editing side. I think what the opportunity is, is whether or not that changes the off-target potential, and we've seen that across a number of DNA editing constructs, both in AATD and not in AAT that off-target rates are consequential and can be detrimental. I think we see bystander edits that create apparent proteins, and that's challenging. And so, I think people are trying to work and address that. And with hepatic turnover, the potential to see that change. So, I think all of that is to say, I think we need to see how those others translate, not from what data they're posting preclinically to differentiate and distinguish, let's say, them from being on the DNA editing side, but really how they ultimately translate into human clinical data. I mean I think at the end of the day; the most important feature is really can you get to MZ phenotype levels. And as we've seen, it's not about getting higher. I think the real misnomer in this space is applying the recombinant protein strategy, which is pour more protein into the body because it gets utilized as soon as there's an acute event. I think we have to all remember that alpha-1 antitrypsin is a chronic disease of acute exacerbations. And I think if we think about it in that context, it always comes down to what is the requirement to have enough protein so that you have this event, you don't deplete everything. I mean, theoretically, you could argue that maybe 11 micromolar was a questionable threshold for replacement because by the time you have an acute event, there's no protein left to actually protect your lung. And we've had a KOL recently remind us that his biggest fear is a patient who between infusions has an acute event, can't get infused and is now left exposed to the insult in the lung. We have to reframe that whole narrative as we think about the paradigm shift for RNA editing, which is about rising to meet the need of what's required during those periods of acute inflammation. And as we've shown, we can achieve over 20 micromolar of protein during the acute exacerbation. So, I don't think this is a competition of like us because we're in RNA editing being limited to how we respond. We respond extraordinarily well. We respond with infrequent sub-Q administration. We have no by edits. We have no off target editing, no indels. And so, I think long-term, for treating a chronic disease, I think RNA editing and particularly our approach to RNA editing with our AMR designs, I think really meet the therapeutic need of patients with these diseases. To your second question, I think on other exons, I don't think there's a fundamental change. We're ready to progress. I think what we want to see is the continued progress that we're making on exon 53 and where we're allocating capital to make sure that we progress on 53 and then continue to move other programs forward behind that. So, it's less about a formal change and more saying that as we reflect on guidance, I think the key is advancing exon 53, drive that forward and be prudent on the acceleration of other exons. I think as we look forward to '26, and we're going to share a lot more on this during the year, we are highly encouraged about the progress we're making in obesity space and with reflection that we're seeing from a number of parties, the work that we're doing on potential maintenance where we can wash patients off of GLP-1s and support them on a once to twice a year sub-Q therapy that actually prevents rebound weight gain, drives metabolic health and really becomes, I think, the standard for maintenance has us thinking about 2026 in a really positive way about studies that will continue to drive and support that. And we just have to think about the totality of where we're allocating capital, hence, why collaborations are important to us. So yes.

We'll take our next question from Steve Seedhouse with Cantor.

Congrats on all the recent progress. I wanted to ask in the AATD study, obviously, that is ongoing, and you have that one really profound example of the acute phase response. Are you able to maybe gather more examples of that by protocolizing AAT assessment if people get sick this winter or if they get their flu shots. Just curious if there's anything you can do in the study to supplement that finding.

It's an interesting question, Steve. It's one of the things that we obviously can identify. So, I think corresponding as we saw there, CRP levels with changes in AAT levels give us a way to be able to not miss those opportunities for assessment. We're not changing the protocol design on a prospective basis. But to your point, as we come into the winter season, the opportunities that we have to be able to capture those events. are there. I think what's highly encouraging is at a basal level, we recognize that we believe we are at an MZ phenotype editing capability. So, these patients, to your point, should be responding as such, and we'll be able to identify them.

And then just in INLIGHT, I was curious if you could clarify or just guide us what proportion of that study enrolled in the U.S. versus ex-U.S.? And even if it's sort of relevant, would you expect any difference in the patient demographics or something that would affect the results?

Yes, I'll let Chris join in. So obviously, the study started ex-U.S., and we provided the update during the last update that we now had the FDA IND acceptance to begin and begin at the highest dose, so at 600. So proportionately, obviously, in the early setting, it's proportionately ex U.S. with the opportunity to come here. I wouldn't expect any changes. Chris?

No, that's right. So as Paul said, we're just starting up in the U.S. now. So, we're going to be recruiting patients there going forward. And we haven't really changed our inclusion criteria based on region. So, we'd expect that all the subjects here would meet those criteria just like the ones in the ex-U.S.

I think it's important so that as we are able to, in the future, start analyzing data, I mean, there's the ability to look at the dose cohorts, but also to substantially power the ability to look at activity reduction related to body composition changes and other, which would allow us to work across cohorts as well as we get to the later data points. So, to Chris' point, it is important that we have cohesiveness amongst these patients so that we can do better analysis across the study.

Our next question comes from Madison El-saadi with B. Riley Securities.

A couple from us. On the single AATD patient that experienced the acute phase response, curious if there's any additional insights or observations from that patient that you could comment on? And then secondly, I actually wanted to ask about your bifunctional single nucleotide construct. Curious if you've optimized this construct to avoid any type of intermolecular interference and if you're seeing any off-target end, basically where you're at in the optimization phase.

Yes. I mean I think to the first one, there's no new insights other than, obviously, patient recovered, and we saw like very good corresponding relationship between that CRP exacerbation and down. I think it's important to this point, that is the disease. The disease of these infrequent, but they happen. There are these acute exacerbations. And so that response rate is what you expect to see in an MZ patient who is protected. But I think they responded exactly as you would anticipate an MZ patient response to occur. I'll look to Chandra just to confirm, but I mean, we did the work. We've shared some of those recent updates. And I think that was the piece that had me most excited about the fact that these bifunctional approaches to SI and editing could provide really compelling ways to treat diseases. I mean, as we shared the opportunity to think about things like the combinations and actually watching, PCSK9 reductions coupled with LDLR upregulation is a fascinating approach long-term to effectively treat cardiovascular disease and lipodystrophies. And so I think the opportunity is seeing each of those behave, and I think that was Chandra's compelling data on knockdown wasn't blocked by editing and editing wasn't blocked by knockdown shows that there wasn't steric hindrance across, and I don't -- we haven't seen any -- because AIMers are specific to the enzyme that they're working on in Dels or bystander edits, but I'll let Chandra. We haven't seen anything to that effect.

Yes. So, this is -- the platform provides us an opportunity to be highly specific for both enzymes. So that's the design principles, taking into consideration how our SpiNA react with our Ago2 highly specific and see specific knockdown and adding to that the AIMer that is also highly specific recruiting ADAR. And we found -- using our platform, we found a way to combine these 2 properties to give us exactly what we observed with single entity, but with one construct.

So, the best way to think about it is the uniqueness and specificity of each endogenous enzyme is able to observe its own unique endogenous function. So, the enzymes are highly specific for their approach.

Our next question comes from Bill Mohan from Clear Street.

I was hoping you could comment on the recent data from Sarepta's exon skippers that failed to confirm benefit in the confirmatory studies. Obviously, this highlights the unmet need in the space. But at the same time, do you expect any difficulties in maybe a changing FDA attitude towards dystrophin expression as a proper accelerated approval endpoint?

Yes. I think it's critical as we shared data very early on, on looking at consistent dystrophin expression across patients. If you remember, one of the key highlights, both 6-month and the 48-week data that we shared was not just an amplitude of how much protein. I think there's been a lot of discussions about mean protein levels. I think the narrative that was important for us to make sure people start pushing is how well distributed was that across patients? Because if patients don't have adequate amounts of protein level, then it shouldn't be unexpected if they don't continue to show benefit because they don't have adequate levels of protection. So, the highly consistent distribution we were seeing was important. I think what was most important to us was the fact that we actually did see that translate to statistically significant clinical meaningful improvements in time to rise. We saw those corresponding changes in muscle fibrosis. And I think that is really what was important and driving for us, and we're going to have the opportunity by the time we file in '26 to continue to follow those patients who are on the open-label extension study and additional patients being treated monthly to continue to see those clinical improvements. So, I think while we haven't seen any correspond from the FDA changing on dystrophin, I think we do recognize the importance of seeing clinical meaningful responses and being an important part of our decision.

And it might be a little early for this question. I know there's a lot of clinical derisking left in your INHBE program. But do you have a view on the pricing dynamic in the obesity market where there seems to be this sort of a sustained pricing pressure that we probably wouldn't expect to go away for a while.

No. And I think that's the unique opportunity that we have with INHBE and particularly the modality we're using to drive activin E reduction. So, we continue to see strong durability looking again beyond 6 months. So, we're through that at the lowest subtherapeutic dose. So again, highly supportive of once to twice a year sub-Q dosing. And if we think about the global greater than 1 billion people living with obesity, many of whom don't have access to GLP-1s. If we think about the markets more broadly, the ability to expand where we don't have to -- manufacturing, let's say, is not as big a challenge as with the protein therapies. The ability to really drive accessibility, we think, is a unique feature. And I think if we imagine a world where patients are even currently being able to transition to a once-a-year maintenance therapy where they still get the benefits in cardiovascular outcomes as we've seen with human clinical genetics and sustained weight loss. I think there's a really unique opportunity to think about the true global landscape for obesity. And I think actually a GalNAc siRNA approach with our chemistry that drives durability is highly disruptive as we think about the evolving obesity landscape, which is really dominated by similar increase. I mean a shift from once a week to once a month still doesn't really radically change the environment and the landscape. And so, what does is the ability to do this with a once or twice a year drug. I think the other piece that's becoming more and more apparent to us coming out of the week is who's being treated. And as we think about the evolution of patients who -- and think about this with Medicare and other things picking up reimbursement, patients who really can't have sustained loss of lean muscle mass, loss of bone, loss of muscle as they continue to age and have to treat these diseases, the opportunity really to bring a medicine that drives fat loss, healthy outcomes, but retains lean muscle mass, I think, is both therapeutically relevant, but also as we think about the cost of transition.

Our next question comes from Roger Song at Jefferies.

Great to see you at the Obesity Week as well. So also, a couple of questions related to obesity inhibitor program. Just interested in learning a little bit more about the kinetics of the weight loss. I know you have the DIO model. And then -- so any reason you have to guide 6 months versus earlier or longer for the substantial weight loss similar to semaglutide? And maybe any insight from the human genetics can give us a little bit more color around that? And then also related to the dose response, yes, in the DIO, you see the dose response for the weight loss. Just curious about your human dose. How should we think about you step up from 240 to 400 and 600, what's the range of the corresponding dose to preclinical? And then if that possible, you can dose even higher than 600, is that necessary?

Yes. Thank you. And I'll have Erik chime in on the other side because I think he'll have some valuable thoughts about kinetics, too. But I think most importantly, we do look to the modeling of our models. The DIO models translated well for GLP-1. So, it's been great to see that corresponding positive control as we look to not just weight loss. And I think it's important to think about it as fat loss, so healthy weight loss. So, if we think about those kinetics, we achieved in the DIO mouse model up to similar levels of total body weight reduction of GLP-1s, but it's all fat. And so, there is a rate of kinetics on that curve that does appear to take more time. So that's something in that early time point as we think about these first 3 months into the 6 months, we're going to learn about the kinetics of INHBE reduction together. We know we potently lower it, and we're going to get to see what transpires during that window of time and whether or not the mouse model is reflective of that curve or is it similar both. I think what we feel more confident about is you get to 6 months and longer, the ability to see that continue to transition. And I think the opportunity there is then whether or not that plateauing is what's seen because it does look like you can continue to drive fat loss beyond that point of where you have GLP-1 weight loss. So, I think the ability to kind of follow this over time, much like we all did with the GLP-1s is going to be critical as we understand what that journey looks like. The human clinical genetics gives us kind of a benchmark of what happens with a protective loss of function from birth. So, what happens when you have that. In a lot of ways, it both supports what we've seen in the DIO mouse model in the human study, but it's also really supportive of what we see with these revised maintenance therapies where you kind of have this weight loss and create a set point and then drive that forward. So, I think it's highly encouraging as we look at those genetics, both on initiation of weight loss, but also as we think about the potential future for maintenance therapy, which is incredibly exciting. So, I think that in totality, and Erik, I'd love your opinion on that. As it relates to dose, Roger, I think the ability that we do see this dose responsiveness in the animal models, I think we're going to get an opportunity to evolve that as we said on both -- Chris said on the past call at Research Day and as we reiterated on this call, we are approved to go higher than 600, whether or not we need to is a different story. But I think the ability to continue to drive a dose responsiveness of not just the totality of fat loss, but whether or not the kinetics happen faster in a dose responsive way is something we'll be able to study in humans over the course of the study. But with that, Erik, I don't know if you want to add on a couple of points.

Yes. I think you summarized it very nicely, but just, I guess, to double-click on a few things. So, from the human genetics, then obviously, we know that if you have a germline loss of function variant from birth, then you have a substantially better cardiometabolic profile and lower type 2 diabetes risk and cardiovascular risk. So that's 50%, right? And then we know from our in vivo models that if you can achieve more than 70% activin E reduction, we see that translate in the mouse models to weight loss and a better -- all driven from fat and especially as Paul pointed out, this double effect from semaglutide, the prevention of weight regain, cessation of GLP-1s, all of those effects. And we do observe that kinetics looks a bit slower than semaglutide. So that's why we're anchoring on the 6-month time point. But again, this is a novel mechanism we're learning together on the kinetics of this. But we're -- just to remind everyone, we're already in that range now in the 240 and the 400 mg cohort. We're in that range where we would expect this to translate to better cardiometabolic health and weight loss from fat loss.

Our next question comes from Joseph Schwartz with Leerink Partners.

This is Jenny on for Joe. For obesity, assuming you have positive early data, how do you envision the next steps in development beyond the INLIGHT study? What could these studies look like? And will you be able to do these on your own? Or would you consider strategic partnerships for this program? And would the GSK collaboration affect your ability to pursue anything if there are opportunities?

Thank you. I'll start with that last one because I think it's an important one to get out of the way. There is no inhibition for us to do anything related to INHBE with GSK. So INHBE is a wholly owned Wave program, and we have full control over that, not just clinically but commercially. So, it is a Wave asset. So, move past that one. As we think about the opportunities ahead, I think one of the things coming out of obesity, we enhanced our meetings with a number of KOLs who are incredibly excited about the profile, both not just the driver of fat loss without lean muscle mass loss and that profile as a monotherapy, particularly for a substantial number of patients with it. We're learning more and more, there is concern about anhedonia over time, hair loss, lean muscle mass, loss meaning muscle and bone and the ability to drive healthy weight loss with an infrequent injection and accessibility, I think, was highly encouraging. So, I think that, coupled with a huge amount of excitement for what maintenance could look like and a number of interested parties saying, how could we think about these things in conjunction, give us a number of opportunities as we think forward around what the right strategy is for running these studies. Irrespective of partnering, we're committed to driving these studies forward. We think that there is a huge need for this in these therapies as we've seen with really the innovation coming in this space from more less frequent administration of incretins and other forms of incretins as opposed to really treating the underlying healthy fat loss and preservation of lean mass. So, with that, I think we're working on planning for running studies in obese patient populations and maintenance that we could drive and we'll give more updates as we think about these studies in 2026 that don't necessarily have us waiting to the completion of INLIGHT. I think INLIGHT is a study that we can envision ongoing as providing ample safety coverage. We're seeing that now with durability. But we don't have to look at these things in cession that INLIGHT needs to complete before we accelerate studies in obese patients and potentially, as we said, in maintenance. So, we're actively underway in that. We see that as a huge need, and we're working very quickly with a number of KOLs in the field to accelerate the studies.

Our next question comes from Yun Zhong with Wedbush Securities.

So first question on DMD program. I wanted to check if you have had any interactions with the FDA on your 48-week data and any additional clarity that you are able to provide in terms of how much monthly dosing data you will need to or you will be able to include in the package, please? And I have a follow-up question, please.

Yes. I mean, as we provided, we've had updates with the agency that we've discussed our plans as we think about filing. One, and as you point out, key was generating data, not just OLE data on a monthly basis, but ensuring that we have de novo patients that are treated on a monthly regimen with which we can study. We have, as we said on prior calls, enough patients, we believe, based on the existing approvals on both new patients as well as the existing patients to support that filing. And we'll continue to stay engaged with the agency as we advance those discussions towards that filing to avoid surprises.

Then on the Huntington's disease program, it's very encouraging to see or hear the FDA is open to accelerated approval pathway. But you commented on the capital allocation. So, I just wanted to ask, would you be able -- would you be open to moving the program independently even without a partner? Or would you prefer to have a partner before taking the next step?

No, thank you. And I think we've been consistent on this point. So, within HD, I think why we have conviction and why we have aligned with the agency is we're running a well-powered placebo-controlled study, and that's -- the design is advancing. I think what we're also having in conversations with potential strategic partners for the discussion is assuring that we're aligned on what that trial needs to look like to make sure it does meet the criteria, not just for the accelerated approval, but potentially in design the full approval of that study continues to progress. So, we don't have to go back. And so, as we get that alignment, that study, we would prefer to progress alongside another collaborator.

Our next question comes from Samantha Semenkow with Citi.

This is Ben on for Sam. Going back to obesity, you shared in the R&D slides, the placebo-adjusted benchmark based on semaglutide was approximately minus 2.5%. Are you expecting you'll see that in the upcoming data this quarter for the 240-milligram 3-month data? Or is it possible we'll need more time to reach that benchmark, just given what you kind of had described earlier about the kinetics?

Yes. And I think that's what we were -- I mean, if we go back to that slide on Research Day, it was really important that we're anchoring on is the 6-month data to that point. So that curve continues, remember about 4.4% out at the 5-month time point with fat loss for semaglutide. And I think that was key for us is we have the benchmark of fat loss following the GLP-1s over time. And I think what we're -- as we said before, what we're going to learn together is what happens on those rates of fat loss at the early time points. We now have benchmarks, as you said, of what we're benchmarking with GLP-1s. But I think it's really important as it relates to kind of a set point and what is a target range of fat loss to really get 6 months further than in the initial 6 months simply because, as we said, anchoring on preclinical data, there does appear to be a rate of kinetics that looks apparently different. And I think it's important for us to assess that in humans. So, it's why we're not guiding to a specific target number of fat loss in this first 3-month data set, but rather looking at continued engagement and reductions of activity, durability of activity, which is going to be critical and other biomarkers of metabolic health as well as body composition. So, we're going to have a number of features. We're measuring body weight, so it will be important to not miss but it really is important to look at that kinetics over time.

And if I may ask a follow-up question. What is other consideration for initiating the Cohort 5 given the IV MZ approved escalation?

Yes. I mean the only thing now is given how -- I mean, we are at 85% reduction at the 400-milligram cohort and now have a 600-milligram cohort. So, some of that is how much more utility we're going to get from going higher, and we'll have some of that biomarker data to assess. From a safety perspective, we can continue to go up substantially higher. But at the end of the day, it's still about understanding not again, leaving activin E in the efficacy on the table, what's going to drive durability, but also realizing what's going to be, frankly, necessary. And again, that's why we're highly encouraged and already planning what are the next subsequent Phase II studies start to look like as it relates to studying this in obese patients as well as men. So, we have the coverage beyond what we think we need currently, and it's why we are confident about the subsequent studies.

Our next question comes from Luca Issi with RBC Capital Markets.

This is Cassie on for Luca. Congrats on all the progress. And we have another one on INHBE, and this is circling back on the ex-U.S. versus U.S. You have a single site now in Moldova listed on clinicaltrial.gov. But you did mention that you have activated other sites, including the U.S. at 600-milligram. So, can we assume that the second quarter 2026 update in the 600-milligram cohort is when we will start seeing data from the U.S. patients? Or is that update still going to be data from the Moldova patients?

Yes. No, look, we appreciate the question. One, it's on -- just to make sure because at one point you mentioned, just to make sure that it's not confusing this is obesity, this is 007. And it's beyond Moldova. We have sites in U.K., Moldova, Europe, and the update was moving beyond Europe to starting in the U.S. So, there's a number of sites that will be generating patients. As we provided on the call, the real shift is from Europe to the U.S. And as we said, the U.S. is coming online at the 600-milligram cohort. That's what we shared at Research Day because one, the agency didn't have us restart at a lower dose. We could start at the subsequent cohort, which is 600. So, I think it's obvious from that, that we would expect that you wouldn't have U.S. patients not at 600. So, the U.S. contribution would come at 600.

Our last question comes from [indiscernible.

Just looking at your preclinical DIO mouse data you showed at Obesity Week, do you think the reduction in macrophages is simply due to reduction in adipocyte size? Or do you think there are other anti-inflammatory mechanisms involved?

Yes, I'll let Erik add, but it's not just reduction in that its shift to macrophage phenotype from an anti-inflammatory phenotype to anti-inflammatory. But Erik, I don't know if you want to add anything.

Yes. I mean exactly. So, it's a shift from less pro-inflammatory to more larger proportion anti-inflammatory, as Paul said. We also do see with the RNA-Seq data that we also see supportive evidence of that as well. There is less inflammatory -- inflammation in both the subcutaneous and visual fat. So, I think something is going on. It is probably partly driven by adipocyte size, but there could be additional mechanisms that are all related to the lipolysis.

And just a quick follow-up on DMD. Do you have any sense of the FDA's opinion on muscle content adjusted dystrophin versus unadjusted?

I think all of the conversations to date across a number of programs have been really exciting. I do think as we look at the new programs that have come in, looking at actually the production of dystrophin in muscle is important, realizing the high propensity for fat and making sure to look at that. So, there's been nothing from our standpoint that seems to change the agency's opinion on that.

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

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