Q3 2025 Wave Life Sciences Ltd Earnings Call

Speaker #1: Hello, and welcome to Wave Life Sciences' third quarter 2025 earnings call. We ask that you please hold all questions until the completion of the formal remarks, at which time you'll be given instructions for the question and answer session.

Speaker #1: 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.

Speaker #2: 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.

Speaker #2: 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. Shandra Varghese, Chief Technology Officer, will be available for questions following the prepared remarks.

Speaker #2: The press release issued this morning is available on the Investor section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements.

Speaker #2: 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.

Speaker #2: 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.

Speaker #2: I'd now like to turn the call over to Paul.

Speaker #3: Thanks, Kate, and good morning to everyone joining us on today's call. I would like to first thank those of you who were able to join us for our 2025 research day on October 29th, where we shared the first-ever demonstration of active and E reductions in a clinical trial.

Speaker #3: Notably, with a single dose of WVE-007, our inhibin E galNAc siRNA, we were excited to show highly significant and durable reductions in human active and E that exceeded levels needed in preclinical models to drive meaningful weight loss and prevent rebound weight gain following cessation of a GLP-1.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: 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 007 at obesity week.

Speaker #3: 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.

Speaker #3: There was a clear recognition for the need for non-increase in 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.

Speaker #3: There is particular excitement in 007's potential as a maintenance therapy, which would allow patients to transition off chronic increase in therapies while at the same time preventing rebound weight gain, preserving lean mass, and sustaining cardiometabolic health.

Speaker #3: Reflecting on the rapid progress we've made in advancing 007 in our in-line 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.

Speaker #3: We began testing WVE007 in in-line at our lowest subtherapeutic dose cohort of 75 milligrams in each participant. 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.

Speaker #3: WVE007 was generally safe and well tolerated and our independent data monitoring committee has approved further escalation to a next higher dose in COLON 5.

Speaker #3: At research day, we shared highly significant dose-dependent and durable active and E reductions one month post single dose of the 007 in the first three cohorts of in-line 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.

Speaker #3: In addition, we had the opportunity to evaluate our lowest dose cohort out to six months and throughout the six-month follow-up period, we continued to see sustained reduction.

Speaker #3: 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 active and E reduction over time is necessary to achieve meaningful weight loss.

Speaker #3: As we shared at research day, Wave's unique spina design and proprietary chemistry enabled the achievement of the potent and durable suppression needed for the inhibin E target.

Speaker #3: In our DIO mouse model, we demonstrated that weight loss in the same range as semaglutide occurred when active and E was durably reduced by greater than 70% from baseline.

Speaker #3: The knockdown we've observed in the 240 and 400 milligram cohorts already exceeds 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.

Speaker #3: 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.

Speaker #3: Furthermore, we've shown that inhibin E 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.

Speaker #3: 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.

Speaker #3: 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 inhibin E reduction at three months in the 240 milligram cohort.

Speaker #3: And importantly, in the first quarter of 2026, we'll be able to assess six-month follow-up data from the 240 milligram cohort as well as three-month follow-up data from the 400 milligram cohort.

Speaker #3: In RNA editing, we continue to lead the field with WVE006, our galnec RNA editing oligonucleotide for AATD. 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.

Speaker #3: 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.

Speaker #3: 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 mAAT and have limited ability to increase serum AAT levels during an acute phase response or exacerbation.

Speaker #3: However, with RNA editing, our goal is to restore the mZ phenotype by achieving three criteria: keeping basal protein levels at or above 11 micromolar, driving 50% or greater circulating mAAT with corresponding decreases in mutant ZAAT protein, and most importantly, restoring the physiological response to serum AAT protein to acute inflammatory events.

Speaker #3: In September, we delivered data from our restoration two trial demonstrating that we have already achieved these goals with 006. We observed AAT levels of up to almost 13 micromolar.

Speaker #3: We showed 64% of AAT was wild-type mAAT with a corresponding 60% decrease in mutant ZAAT protein, and these effects were highly consistent and durable across individuals supporting infrequent dosing of monthly or less.

Speaker #3: Most notably, we were able to restore a ZZ participant's ability to respond to an acute inflammatory event with total AAT levels of greater than 20 micromolar just two weeks after a single dose of 006.

Speaker #3: Encouragingly, the magnitude and four-week duration of this response were also proportional to the levels you'd anticipate in an mZ patient based on natural history.

Speaker #3: Following our September data, we've had multiple interactions with key opinion leaders in the field who have expressed their excitement about these data. In particular, the ability of WVE006 to restore physiologic AAT production represents a major paradigm shift from weekly IV augmentation therapies.

Speaker #3: As we look ahead to the remainder of our restoration two 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.

Speaker #3: 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.

Speaker #3: Building on our success with 006, we are advancing WVE008, a galNEC conjugated RNA editing program for PNPLA3 I148N liver disease, as our next RNA editing clinical candidate.

Speaker #3: 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.

Speaker #3: They're an estimated 9 million homozygous I148M carriers with liver disease across the US and Europe, who are at a nine-fold higher risk of dying from their liver disease compared to non-carriers.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: We've shared preclinical data that corroborate this approach. We've demonstrated that 008 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 liver tissue exposure, which which supports infrequent dosing.

Speaker #3: 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.

Speaker #3: Turning to DMD and HD clinical programs, earlier this year, we shared data from Ford 53 and DMD, which supported WVEN531 as a potentially best-in-class and important new therapeutic option for individuals with exon 53-amenable DMD.

Speaker #3: 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 district and restoration therapy at 48 weeks.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: WVEN531 is also differentiated by supporting preclinical evidence demonstrating even greater access to heart and diaphragms compared to skeletal muscle. We remain on track to submit an NDA in 2026 for accelerated approval of N531 with a monthly dosing regimen.

Speaker #3: In HD, we are continuing to prepare for a global potentially registrational phase two, three study of WVE003 in adults with SNP3 and HD using caudate volume as a primary endpoint, and we are actively engaged in discussions with prospective strategic partners.

Speaker #3: Developed using our platform's FETCIFICITY 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.

Speaker #3: 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.

Speaker #3: 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 three doses.

Speaker #3: 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.

Speaker #3: 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 seven and a half years.

Speaker #3: 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.

Speaker #3: 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.

Speaker #3: We remain on track to submit an IND application for this phase two, three 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.

Speaker #3: Kyle.

Speaker #2: 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.

Speaker #2: 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 a rapidly advancing inhibine program and RNA editing programs.

Speaker #2: As well as compensation-related expenses including share-based compensation. Our GNA expenses were $18.1 million for the third quarter of 2025 as compared to $15 million in the prior year quarter.

Um, 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 US 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 pre-clinical and mouth perspective but also from a human perspective. Um, and what 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, um, findings that have have been seen in other heart failure, activities. So nothing that we would that would suggest any concerns from our standpoint.

Great to hear. Um, and on Huntington's have you had a pre-ind meeting with the FDA and any changes to uh their um comments on the use of MRI as a a reasonable surrogate for Huntington's and any any thoughts we've already recent, um, you know, backtracking by the FDA according to uh some of the some of the companies that use in in your peer group. Thank you.

Yeah, no. We appreciate the question. I know there's a lot of discussion 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 as a primary end point. I think there is a lot of concern Nation over the agency's perceived changes in the opinion. And, you know, to date. We haven't observed that, um, or found that, um, I think it is important when we think about coding. Um, you know, and I, I reflect on this relative to some of the discussions that are ongoing, um, relating to utility of Natural History studies in clinical trials. And I think it's important to note that, you know, when we use track and predict HD is 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,

That a 1% change in Kata, atrophy can translate to a 7 and a half year delay. In clinical disability, really does set the stage that small meaningful changes in cottage 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 product volume to Patient size of the Natural History. You know, some natural history studies like its role don't include, um, MRI imaging actually. If you have a larger Cottage at the beginning of that study, that could actually be attributable to a delay in clinical disability on seedrs 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 Cottage, 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 cottage volume within the same, Huntington's stage like stage 2 and stage 3 and Etc. Within the same stage are there variabilities in the quality volume. And how, how much

There can be, I think what we've seen is very steady, changes in coding. And actually, with the shift in the staging criteria. Now, actually coding is becoming a core component of that staging criteria and so actually you can assess stages and What patients have

What change in claw date at each particular stage? And I think that's why it's helpful if we think about other studies that are done in trying to benchmark.

Their size of cod, a volume relative to that. We could assess that in looking at, you know, those data sets externally. And I think.

If you had to bias a study towards larger context, let's say so that they would be accessible, that could be attributable to actually delaying and slowing clinical progression, not related to Central medicine.

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 huntingtin. I think looking at targeting engagement coupled with changes in anatomical, um findings is important. Um, you know, we actually

Throw people remember. But you know, the hfg meeting back in October, even the oral small molecules showed a lower reduction in 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 of brain volume production, so I think looking at targeting engagement relative to outcomes is going to be critical. And I think, you know, we remain have high conviction on an Alle specific approach to be huntingtin lowering and I think, post all of this have been actively engaged with our potential Partners. In terms of accelerating the study,

Thank you. We will take our next question from Changi with Oppenheimer. Please unmute your line and ask your question.

Hey, thanks for taking the question and congrats on the progress. Um, I have a question on the Obesity week poster, um, it just seems like some change expression changes actually happened pretty early, but some maybe happened later. So I'm just wondering by the time you report initial data in the fourth quarter, what kind of changes in those file markers are related to metabolism information and process you would like to see and maybe which file markers are more important and I have a quick follow up. Thank you.

Yeah, I'll let Eric 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 the protein happens fairly rapidly and is the same. Then, as you point out, that change over time drives the analysis, as we saw in the CIO models. Along that way, we are going to be able to track various biomarkers and metabolic health that correspond with that. I don't know, Eric, if you want to add to that.

No, I think that's a good summary. Um, there is a trajectory I think maybe worth just pointing out that on the Obesity week poster. Those are from liver biopsies and you know, obviously these are healthy individuals living with obesity and all way. So there will not be any delivered by please. 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.

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 you know greater than a year on the glp1 slot selling. Um but I think what's nice is we haven't seen that that

Hit that point yet. So I think we'll have an opportunity to continue to see um, what those that curve looks like for hypony over time. And the study is designed to assess that

Thank you, we'll take on that next question, from Salem, say from mizuho security, please unmute your line and ask your question.

Great. Uh, congrats on the progress um, following team, uh, just a couple from us. Um, 1 on Alpha 1, the trips in. Um, Paul just curious to get your thoughts around some of the DNA.

Editor, uh, ATV programs that we've seen some recent pre-clinical data on some discussion. There, obviously being able to reduce 20 micro molar, plus, uh, maintained. And just how how does that framework you're thinking at all? Do you need to be in that sort of range for an outside? The acute phase response? Um, and then the second question is just on DMD, um, I noticed in the press release, there's no more reference to the additional Exxon skipping program ctas for 2026 when if that was removed. Um it's no longer the plan. Thank you. Yeah. Start with the first 1. I mean I think as we've learned and trying to Benchmark pre-clinical the clinical

Data, recognizing a lot of that's driven in the server, A1 Mouse model that's high copy number. I think the absolute translations if we were to compare those data. Let's say DNA editing to DNA editing it beam. I think we've seen the, 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. Um on the DNA editing side. I think the what the opportunity is is whether or not that changes the target potential. And we've seen that across a number of DNA editing constructs both in a and not in a that off-target rates are consequential and can be detrimental. I think we've seen Vice in that create a parent 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, you know what data they're posting for clinically to differentiate distinguish? Let's say them from Beam on the DNA edit inside 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 MC phenotype levels? And as we've seen, it's not about getting higher. I think the

The real misnomer in this space is applying the recommended protein strategy, which is or 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

That actually protect your lung. And we've had a kol recently reminded that his biggest fear is a patient who's 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 subq Administration, we have. No bicep that ends. 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 aimer designs. Um, I think really meets the therapeutic need of patience with these diseases. Um, to your second question, I think on other axons, I don't think there's a fundamental change. We're ready to Pro progress. I think what we want to see is the continued progress that we're making on Exxon 53 and where we're allocating Capital to make sure that we progress on 53.

and,

Be prudent on the acceleration of other axons. I think, as we look forward to 2026, 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 ones and support them on a, once to twice a year, subq 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? Um, so yeah.

We'll take our next question from Steve seed. House with Cantor. Please unmute your line and ask your question.

Good morning. Um,

my question and congrats on. All the recent progress I wanted to ask

In the uh, ATV study obviously that is ongoing. And you have that 1 really profound example of the acute phase response. Are you able to uh, maybe gather more examples of that by protocol? You know 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 uh finding

That's an interesting question that, you know, it's 1 of the things that, you know, we obviously can can identify. So I think corresponding as we saw their CRP levels with changes in as lists, 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, you know, to your point as we come into the winter season, the opportunities that we have to be able to capture those events. Um, are there, I think with highly encouraging is at a basil 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, you know, we'll be able to identify them.

Okay. And then, um,

Just to inlight, I was curious. If you could um clarify or just guide us What proportion of that study, uh, enrolled in the US?

Versus xus and even if it's sort of relevant, would you expect any different in in the patient demographics? Or um, something that would affect? Um,

The uh, the results.

Yeah, I'll let Chris join in. Um, so obviously the study started X us and we provided the update during the last update. Um, that we now had the FDA IND acceptance to begin and begin at the highest dose so it's 600. Um, so proportionately, obviously, in the early setting. Its proportionately X you as with

The opportunity to come here. I wouldn't expect any changes, but I don't know. Chris know, that's right. So, as Paul said we're just starting up in the US now. So, um, we're going to be recruiting patients there, um, going forward. Um, and we know we haven't really changed our system criteria based on region. So you'd expect that, you know, all the subjects here would meet those criteria, just like the ones in the, uh, xus.

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

Our next question comes from Madison, Alphard with B Riley Securities. Please unmute your line and ask a question.

Hi, good morning everyone. Thanks for taking our question, a couple from us. Um,

On the single A ATV patient that experienced the acute phase response. I'm curious if there's any additional uh...

Insights uh or observations from that patient that you could comment on and then secondly I actually wanted to ask about your uh mind functional single uh nucleus nucleotide construct.

Curious, if you've optimized this construct, um, to avoid any type of intermolecular interference. And if you're seeing any off-target endos basically, where you're at in the optimization phase,

Thank you.

Exacerbation and down, I think it's important that, you know, to to this point that is the disease, you know, the disease are 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 is protected. But I think they responded exactly. As you would anticipate, an MZ patient responds to occur. Um,

I looked at Chandra just to confirm, but I mean, we did the work. We've shared some of those recent updates, and I think, you know, that was the piece that had me most excited about the fact that, you know, these five functional approaches to SI and editing.

could provide really compelling ways to treat diseases. I mean, as we share the opportunity to think about things like the combinations and actually watching. Aha, you know, pcsk9 reductions coupled with LDL upregulation is is a fascinating approach long term to effectively treat, um, cardiovascular disease, and with the distributes. 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, um, shows that there wasn't stirred hindrance across and I don't we haven't seen any um, because amrs are specific to the enzyme that they're working on in Dell's or bystander edits. But I'll let Chandra a firm look. We haven't seen anything to that effect.

Yeah, so this is, uh, the, the platform provides us an opportunity to be highly specific for both engrams, so that's the design principles, um, taking into consideration how our scene is, um, react with our ago too, you know, highly specific and, and see specific, uh, knockdowns and adding to that, the aimer that is also highly specific with recruiting need, or, 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 1 construct,

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

Our next question comes from Bill Moran from play Street, please go ahead and ask your question.

Uh, good morning and thanks. Um I just was hoping um you could comment on uh the recent data from surrept the Exxon Skippers that failed to uh

Fail to, uh, confirm that's in the confirmatory studies. Obviously, this highlights the, uh, the unmet needs in the space. But at the same time do you expect any difficulties and maybe, uh, changing FDA attitude towards, uh, District expression? As, uh, as a proper, uh, accelerated approval endpoint.

Yeah, I I think it it's it's critical as we share data very early on and looking at consistent disturbance expression across patients. If you remember 1 of the key highlights, both 6 months and the 48 weak data that we shared was not just an amplitude of how much protein I think there's been a lot of discussions about being protein levels. I think the narrative that was important for us to make sure people start pushing is how well distributed with that across patients. Because if patients don't have

Adequate amounts of protein levels. Then it shouldn't be unexpected if they don't continue to show benefits 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 in driving for us. We're going to have the opportunity, by the time we file in 2026, to continue to follow those patients who are on the open-label extension study and the...

Additional patients are being treated monthly to continue to see those clinical improvements. So, I think while we haven't seen any correspondence in the FDA changing on Derenne, we do recognize the importance of seeing clinically meaningful responses as an important part of our decision tree.

Thanks, and it might be a little early for this question. I know there's a lot of clinical de-risking left in your inhibit program, but do you have a view on the pricing dynamic in the obesity market? There seems to be this sort of sustained pricing pressure that you probably wouldn't expect to go away for a while.

No, and I think that's the unique opportunity that we have with inhibiting, and particularly the modality we're using to drive active and E reductions. So.

Beyond 6 months. So we're through that at the lowest up, therapeutic dose. So again, highly supportive of 1's to twice a year subq dosing. And if we think about the global greater than 1 billion people living with obesity, many of whom don't have access to glp1. If we think about the markets more broadly, the ability to expand where we don't have to have the manufacturing. As I say, is not as big a challenge as with, uh, the protein therapies. Um, 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, um where they still get the benefits in cardiovascular outcomes is the scene with the human clinical genetics and sustaining weight loss. I think there's a really unique opportunity to think about the true Global landscape for obesity and I think actually, hey galnac srna approach with our chemistry that drives durability. Um,

is highly disruptive as we think about the evolving obesity landscape, which is really dominated by similar increases. I mean, the 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 being out of obesity. Because so 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 retain 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. Please unmute your line and ask your question.

um,

Great. Um, thanks for the update. And thank you. I have a question. Um, great to see you at LBC week as well. So, uh, also a couple of questions relate to the inhibitory program; just interestingly, um, in learning a little bit more about the kinetics of the weight loss. I know you have the model. Uh, and then, uh, so any reason you have for...

To guide the 6 months versus earlier or longer, uh, for the substantial weight loss, similar to uh sagoti, uh, you know, maybe any insight from the human genetics. Um uh can give us a little bit more color around that and then also related to the uh, those response. Yes, in the diio, you see that those response for the weight loss? Just curious about your human dose, how should we think about your step up from uh, 240 to 400 and 600? What's the range of the corresponding dose to preclinical? And then is that possible? You can do those even higher than 600 is that necessary? Thank you.

Yeah, thank you. And I'll have Eric chime in on, on the other side because I think, you know, he'll have some valuable thoughts about kinetics too. But, you know, I think most importantly, you know, we do look to the modeling of our, our models, the Dio models translated well for glp1. 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. Um, so healthy, weight loss. So if we think about those kinetics, you know, we achieve in the Pio Mouse model, you know, up to similar levels of total body weight, reduction of glp1, but it's all back. 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 points. As we think about, you know, these first

It's three months into the six months. We're going to learn about the kinetics of inhibition 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 that you get this six 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 seems because it does look like you can continue to drive fat loss beyond that.

Where you have glp-1 weight loss. So I think the ability to kind of follow this over time. Much like you we all did with the glp 1 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 in a lot of ways

Of what we see with these revived 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 because we look at those genetics both on and 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. Um and Eric I love your opinion on that as it relates to dose. Um Roger you know, I think the ability that we do see this dose responsiveness in in the animal models, I think we're going to get an opportunity to evolve that as we settle on both Chris said, on the

Past call it, research, saying, as we reiterated on this call, you know, we are approved to go higher than 600. Whether or not we need to is a different story. Um, but I think the ability to continue to drive a do responsiveness of not just the totality of fat loss, um, but whether or not the kinetics happen faster in the do responsive way is something we'll be able to study in humans over the course of this study. Um, but with that, Eric, I don't know if you want to add on a couple of the points.

Yeah, I think you summarized it very nicely, but I just I guess to double click on a few things. So from the human genetics, then obviously we know that if you have a germ line, you know, loss of function variants from birth, then you, you have a substantially better card of metabolic profile in lower tattoo, diabetes risk and cardiovascular. So that's 50%, right? And then, we know from them from our invivo models that, if you can achieve more than 70% active in E reduction, we see that translate in the mouse models to

To weight loss and a better is all driven from fat and and especially as Paul pointed out, you know, as soon as this, uh, double effect from stuff like this tie, the, you know, the the uh, prevention of weight regain after sensation or glp wants all of those effects. And and we do observe that that kinetics looks a bit slower than cemig glutes, and that's why we're anchoring on on the 6-month time point. But again, this is a novel mechanism. We're we're work. We're learning together on, on, on the, on, on the kinetics of this, but we're all just to remind everyone. We're already in that range now. And it's 2:40 in the 400 Meg, uh, chords where in, in that range, where we would expect this to translate, to better for the metabolic health, and, and weight loss. And from Fat Loss.

Thank you. Our next question comes from Joseph Schwartz with Lance Partners, please unmute your line, and ask your questions.

Hi guys, 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 be 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.

Thank you. Um I'll I'll start with that last 1 because I think it's just an important 1 to get out of the way, is there. There's no inhibition for us to do anything related to inhibiting with GSK. So, inhibiting is a wholly owned wave program, um, and we have full control over that, not just clinically, but commercially, so it is a wave asset. Um, so move past that 1, um, as we think about the opportunities ahead, I think 1 of the things coming out of obesity weak. And hence our meetings with a number of Ko's who are incredibly excited about the profile, both not just the driver of fat loss without lean muscle mass loss. And and that profile as a monotherapy, particularly for 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. I mean muscle and bone, and the ability to drive healthy weight loss, um, 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 can 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's a huge need for this and these Therapies.

As we said in maintenance, 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 these studies.

Thanks, that's really helpful. Yeah.

Our next question comes from Yang, Chong with white brush Securities. Please unmute your line, and ask your question.

Right, uh, good morning. Um, so first question on DMD program, um, I wanted to check if you have had any interactions with the FDA on your 48, weak data and any additional Clarity that you are able to provide. In terms of uh 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've provided we've had updates with the agency that we've discussed our plans on as we think about filing. Um, 1 and as you point out, he was generating data not just Ole data on a monthly basis but ensuring that we have denovo, 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. Um and we'll continue to stay engaged with the agency as we advance those discussions.

Towards that file like to avoid surprises.

Okay, then on the Huntington's disease program, it's very encouraging to see or hear the FDA is open to accelerate approval pathway. Um, but you commented on the capital allocation? So I just wanted to ask uh, would you be able or would you be open to moving the program independently even without a partner? Would you prefer to have a partner before taking the next step? Thank you very much.

No, thank you. And and I think we've been consistent on this point. So, within HD. I think why, why we have conviction and why we have aligned with the agency as we're running a willpower for people to control study. And that's the as the designs advancing. I think what we're also having in conversations with

potential strategic partners with 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, a 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, you know, we would prefer to progress alongside another collaborator. Um,

Our next question, comes from Samantha smithco with City, please unmute your line, and ask your question.

Hi. This is Ben on foran. Thanks for taking the question. Um, go going back to obesity. Um, you shared in the R&D slides on the placebo adjusted Benchmark, based on some of gluta was approximately minus 2.5 percent. Um, are you expecting you'll see that in the upcoming data this quarter, um, for the 240 milligram 3-month data or is it possible? We'll need um more time to reset Benchmark just given what you kind of had, um, described earlier about the kinetics

Yeah, and I think that's what we were.

I mean if we if we go back to that slide I'll research day it was really important that what we're anchoring on is the 6-month data to that point. So that that curve continues and remember it's about 4.4% out at the 5-month time point with fatted fat loss for 7 blue tide. And I think that was key for us is we have the Benchmark of fat loss following the glp, ones 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 GOP ones, but I think it's really important as it relates to kind of a set point. And they, you know, what is a target range of fat loss to really look at 6 months and further than in the initial 6 months simply because as we said anchoring on pre,

Data.

There appear to be rates of kinetics that look apparently different, and I think it's important for us to assess that in humans. That's why we're not guiding to a specific target number for fat loss in this first 3-month data set, but rather looking at continued engagement and reductions in activity durability, which is going to be critical, um, and other biomarkers of.

Metabolic health as well as body composition. So we're going to have a number of features; we are measuring body weight, so it will be important, and not just med, but it really is important to look at that kinetics over time.

Given the IDMC, um, approved escalation.

Yeah, I mean the only thing now is given how I mean, we're at 85% reduction at the 400 million cohort and now have a, a 600 milligram forward. 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. Um, but at the end of the day, it's still about understanding, you know, not again leaving active 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 you know, already on planning what the next subsequent Phase 2 studies start to look like as it relates to studying this in obese patients as well as maintenance. So we have the coverage beyond what we think we need currently, and it's why we are confident about these subsequent studies.

Our next question comes from dazy with RBC Capital markets, please unmute your line and ask your question.

Oh, hi team. Thanks so much for taking our question to discuss the alpha. Um, congrats on auto progress. And we have another one on Heavenly. This is a circle link back on the X US versus US. You have a single site now, um, in Kishinev, Moldova, listed on clinicaltrials.gov, but you did mention that you have activated other sites, including the US at 600 mg. But can we assume that the second quarter of 2026?

Update in the 600 mg cohort is when we will start seeing data from the U.S. patients. Or is that update still going to be data from the Mulan patients? Thanks so much.

Yeah, no, look, we appreciate your question. One, just to make sure, because at one point you mentioned, like just to make sure that it's not confusing. This is Obesity. This is 007. Um, and it's beyond. Do we have sites in...

UK, Maldova, your Europe. And the update was moving beyond Europe to start in the US. So there's a number of sites that will be generating patience as we provide it on the call. The real shift is from Europe to the US. And as we said,

The U.S. is coming online at the 600 milligram cohort. That's what we shared at a research day because, one, the agency didn't have us. We started at a lower dose, but 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 at times.

Our last question comes from Leon Jones. Please go ahead and ask your question.

Hello, thank you so much for taking my questions. Um, just looking at your preclinical DIO mouse data that you showed at Obesity Week, do you think the reduction in macro features is simply due to a reduction in adipocyte size, or do you think there are other anti-inflammatory mechanisms involved?

Yeah, I'll let Eric add but it's not just reduction in that it's shift in macro flash minutes from an anti-inflammatory, a pro-inflammatory phenotype to anti-inflammatory. But Eric I don't know if you want to add anything.

Yeah, I mean in addition, exactly. So it's a shift um, from less pro-inflammatory, uh, to more larger proportion. And inflammatory is Paul said, we also do it with C with the RNA seek data, but we also see supportive evidence of that as well. There is a less inflammatory inflammation in both the subcutaneous and visual fat. So, so I think something is going on. It is probably partly driven by, uh, by at the site size, but there could be additional mechanisms that are all related to the like policies.

Okay, great. Thank you. And just a quick follow-up on DMD. Do you have any sense of the fda's opinion on muscle content addressed at this driven versus unadjusted unadjusted?

I think all of the conversations to date across the number of programs have been really exciting. I do think as we look at the new programs that come in looking at, actually the production of drooping 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 um the agency's opinion about that.

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

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