Good morning and welcome to the Way of Life Sciences 4th Quarter and Full Year 2025 Earnings Conference Call. At this time, all participants are in a listen-only mode. As a reminder, this call is being recorded and webcast. I'll now turn the call over to Kate Roush, Vice President of Corporate Affairs and Investor Relations. Please go ahead.

Thank you, Sophie. And good morning to everyone on the call. Earlier this morning, we issued a press release outlining our 4th Quarter and Full Year 2025 Earnings Update. joining me today with prepared remarks are dr paul bono president and chief executive officer dr chris wright chief medical officer and kyle moran chief financial officer dr eric ingelson chief scientific officer will be available for questions after the call the press release issued this morning is available on the investor section of our website www.wavelifesciences.com before we begin i would like to remind you that discussions during this conference call will include forward-looking statements these statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

Thanks, Kate, and good morning to everyone joining us on today's call. 2025 was a tremendous year for WAVE, marked by positive clinical data sets in obesity and AATD that further demonstrated the broad potential of our unique, differentiated RNAi and RNA editing capabilities. Entering 2026, we are building on the strong momentum with a focus across two priorities, accelerating development of our WVE-007 and IBN-E-Galnec siRNA program for obesity and rapidly advancing our RNA editing portfolio led by WVE-006 for AATD, followed closely by WVE-008 for PNPLA-3 I-148M liver disease. Today, I will start with WVE-007, which is designed to address the substantial need for better next-generation treatment options for individuals living with obesity. While GLP-1s have clearly defined the market and raised awareness of the disease, they require frequent dosing, carry tolerability challenges, induce muscle loss, and result in high discontinuation rates as well as weight cycling with patients coming on and off therapy. Inhibin-E silencing with WVE007 aims to lower serum Activan-E levels and improve body composition by reducing fat while preserving muscle. Compelling human genetic data support our confidence in this mechanism of action. Activan-E is a liver-derived hepatokine that signals adipocytes to slow or put the breaks on lipolysis. By removing these breaks, O7 aims to unleash fat burning without calorie restriction and without concurrent muscle loss. The current obesity treatment paradigm is focused on total body weight loss, which is not the best way to improve overall health and longevity. An ideal obesity treatment should primarily focus on improvements in body composition, meaning decreasing metabolically harmful fat tissue and preserving healthy functional muscle Next generation obesity therapeutic strategies must first and foremost reduce harmful visceral fat and also be able to decrease subcutaneous and liver fat while preserving muscle. This profile is exactly what 007 aims to achieve. Visceral fat is strongly linked to multiple metabolic disorders including type 2 diabetes, cardiovascular disease, NASH, and others. It is well documented that lowering the mass of visceral fat by more than 5% is associated with reduced risk of developing many metabolic diseases. Additionally, total fat loss has been shown to improve glucose tolerance, insulin sensitivity, and overall lipid profile, while simultaneously attenuating adipose inflammatory state and decreasing hepatosteatosis, which is the first step in the development of MASH. Preservation of skeletal muscle is not just about strength. Rather, muscle plays a central role in maintaining basal metabolic rate through higher glucose disposal, better insulin sensitivity, and improved overall energy balance. All of these benefits can be delivered by silencing of Inhibit-E. We chose to target the active In-E ligand through Inhibit-E silencing over its receptor OX7 for several reasons. Turning off protein production in hepatocytes, the upstream source with a Galnec siRNA, is the most efficient and durable way to impact this pathway. Suppressing active N-E rather than disabling a receptor that transduces signals via multiple ligands across different tissues is a more selective approach with lower risk of unintended consequences. This selectivity is especially important for us as we think about long-term safety as well as clinical and commercial translation. O7's unique ability to durably suppress N-E is driven by our proprietary chemistry and Spina siRNA design. While RNAi is a clinically and commercially proven mechanism, there are extensive human genetic data supporting inhibiting as a target. We believe our proprietary Spina designs distinguish us from others attempting a similar approach. With Spina designs, we've demonstrated an unprecedented 10-fold improvement in AGO2 loading and several-fold increase in exposure versus industry benchmarks. Together, these improvements drove substantial increases in potency and duration of activity. WVE-007 is our first FINA design, and our preclinical data for WVE-007 remains differentiated from any other competitor. Most importantly, we are now seeing our preclinical data translate in the clinic. In December, we shared interim data from an LIGHT study. In our lowest therapeutic dose cohort, just three months after a single dose of 007, we observed fat loss similar to semaglutide without the associated muscle loss. These improvements in body composition included substantial reductions in fat, including reductions in both total body fat and visceral fat, and importantly, muscle preservation. I want to remind you, this is a phase one study in otherwise healthy individuals with overweight or obesity, and average BMI of these participants was 32, meaning this population has less visceral fat and subcutaneous fat than typical obesity studies. The trial also didn't include any diet or exercise modification. Already at our single lowest therapeutic dose, we observed that 007 demonstrated robust and durable suppression of active in need, supporting once or twice a year dosing, and we shared a clean safety profile through our 600-milligram cohort. The ENLIGHT study is fully dosed through the 600-milligram cohort, and we are on track to announce six-month follow-up data from the 240-milligram single-dose cohort as well as three-month follow-up data from the 400-milligram single-dose cohort later this quarter. With continued fat loss and with stabilization of muscle or lean mass, we are looking to see continued improvements in body composition and fat loss beginning to drive weight loss. As mentioned earlier, the ENLIGHT population has lower fat to begin with versus typical obesity studies, and thus a better comparison will be made of individuals with higher BMI who have greater fat mass, both visceral and subcutaneous, which is exactly what we will be looking at in the Phase 2A multidose portion of ENLIGHT. This MAD portion will enroll patients with higher BMI and comorbidities and is on track to initiate in the first half of this year. Chris will speak more on that later. We are also excited about the potential for this molecule as both an add-on to incretins as well as for maintenance post as an incretin offering. We have generated a compelling body of preclinical evidence supporting these use cases, and we remain on track to initiate new clinical trials evaluating 007 in these settings in 2026. There is widespread recognition of the need for novel obesity mechanisms and therapeutics beyond incretins. A once to twice a year treatment which can reduce fat and preserve muscle with a favorable safety and tolerability profile has the potential to shift the obesity landscape. In RNA editing, we continue to lead the field with WVE006, our Galmec RNA editing oligonucleotide for alpha-1 antitrypsin deficiency. AATD is a uniquely compelling disease for RNA editing because it is a single gene disorder where correcting the mutant RNA transcript in the liver directly addresses the root cause of both the lung and liver manifestations of the disease. There are approximately 200,000 individuals in U.S. and Europe living with homozygous ZZ, AATD, with high risk of disease. AATD is a debilitating disease that impacts multiple aspects of daily life, from their ability to work and play with their children to even just walking to the mailbox. These individuals living with alpha-1 have been underserved and remain in urgent need of an effective therapeutic option. Current treatment options are limited to IV augmentation therapy that aims to address the lung with nothing currently approved for AATD liver disease. With our highly specific and efficient Galnec aimer design for RNA editing, we do not modify DNA and we do not require delivery with lipid nanoparticles or LNPs that may be associated with systemic and liver inflammation, potentially inducing hepatocellular stress and activating a hepatic acute phase response. We also avoid the irreversible collateral bystander edits and indels, which are associated with DNA editing. With OO6, we have shown that RNA editing can restore endogenous MAAT protein to therapeutically meaningful levels, reduce mutant ZAAT, and reestablish the body's normal physiologic response to inflammatory stress, something that is not possible with the current standard of care. Remember, AAT protein plays a protective role during inflammation or acute phase responses when it's rapidly consumed. A patient on IV augmentation risks lung injury if AAT protein levels fall too low during an event. In contrast, RNA editing is designed to restore an MZ-like acute phase response where AAT production rises to meet the demand. With our data demonstrating already over 11 micromolar of protein, greater than 50% editing, and an acute phase response at our lowest dose, we're advancing our regulatory engagement with full control of the program. We expect to receive regulatory feedback on a potential accelerated approval pathway in mid-2026. Additionally, we are on track to report data from the 400-milligram multi-dose cohort of the ongoing Restoration II clinical trial this quarter and report single and multi-dose data from the 600-milligram cohort in 2026. Building on our clinical success in RNA editing, we are advancing our second RNA editing clinical candidate, WVE008, a Galnet-conjugated AMER for homozygous PMPLA3I148M liver disease, and we are on track for CTA submission in 2026. In DMD, we remain on track to submit an NDA in 2026 for accelerated approval of N531 with a monthly dosing regimen. In addition, our research collaboration with GSK continues to progress, and GSK has now selected a fourth program to advance to Development Canada following achievement of target validation, which carries an associated milestone payment that was received in the first quarter. Under the collaboration, GSK can advance up to eight programs leveraging our PRISM platform with target validation work ongoing across multiple therapeutic areas. WAVE is eligible for up to $2.8 billion in initiation, development, launch, and commercialization milestones, as well as tiered royalties, and we expect to continue to receive milestone payments in 2026 and beyond. With that, I'd like to turn the call over to Chris to review our clinical progress with O7 and our RNA editing programs.

Thanks, Paul. Starting with our InLite clinical trial of WVE-007, the ongoing portion of InLite is a phase one randomized placebo-controlled single-dose study in otherwise healthy individuals living with overweight or obesity. The study is active at multiple clinical trial sites, including in the U.S., and is fully enrolled through four dose levels our three therapeutic dose cohorts are fully expanded with 32 participants in each cohort individuals received a single dose of wve007 and are then followed for up to 12 months with key assessments including safety tolerability pk active in e body composition is measured by dexa biomarkers and body weight the average bmi in the study is low compared to what is observed in typical obesity studies, and there are no diet or exercise modifications. With this backdrop, we are particularly excited with the positive interim data we shared last At three months in the lowest therapeutic cohort, a single 240 milligram dose of 007 led to an improvement in body composition characterized by a placebo-adjusted 4% reduction in total fat, 9.2% reduction in visceral fat, and preservation of muscle is evidenced by a 0.9% increase in lean mass. Notably, O07's placebo-adjusted reduction in total fat mass was on par with semaglutide at 12 weeks, while simultaneously preserving lean mass and driving greater reductions of visceral fat. The safety profile was favorable, and there were durable reductions in serum activin-E supporting potentially once or twice yearly dosing. Overall, these data demonstrate that a single dose of O07 can shift body composition towards less visceral and total fat while preserving muscle consistent with our preclinical findings and with the underlying human genetics. We look forward to evaluating the impact of this mechanism at a higher dose and over a longer duration later this quarter. With this data, we anticipate that the continued fat loss and stabilization of muscle mass will drive further improvements in body composition and weight loss. We are preparing to initiate the Phase 2A multi-dose portion of InLight, in which we expect to enroll individuals with higher BMI and comorbidities. Assessments in this multi-dose portion are expected to be like those in the single-dose portion. with additional inclusion of body composition measured by MRI and liver fat content as measured by MRI-PFF. We're excited to evaluate not only body compositions to demonstrate fat loss with lean mass preservation in the study, but also better understand the impact on liver fat, which could read positively for a MASH indication. Finally, we remain on track to initiate new clinical trials evaluating OO7 as an incretin add-on and as a post-incretin maintenance therapy in 2026. Now turning to our ongoing Restoration II clinical trial of OO6 for AATD. Our goal is to achieve three criteria. One, keeping basal protein levels at or above 11 micromolar. Two, driving circulating MAAT protein above the 50% heterozygous MZ threshold with corresponding decreases in the mutant CAAT protein, and, most importantly, three, restoring the physiologic response of serum AAT protein to acute inflammatory events. Last September, we delivered data from a Restoration 2 trial demonstrating that we have achieved these goals with O06. Most notably, we were able to restore a ZZ participant's ability to respond to an acute inflammatory event with a total AET levels of greater than 20 micromolar. Just two weeks after a single dose of O06. We are accelerating our regulatory engagement timelines now that we have full control of the program. We anticipate receiving feedback mid-2026, which will guide our path towards an accelerated approval. Now turning to our second RNA editing clinical candidate. We are advancing WVE-008 for homozygous PNPLA-3 I-148M liver disease. This PNPLA-3 variant is a well-established driver of NASH pathology, yet there are no approved medicines that directly address this biology. There are an estimated 9 million homozygous PNPLA-3 I-148M carriers with liver disease across the U.S. and Europe, who are at a nine-fold higher risk of dying from their liver disease compared to non-carriers. With O08, we aim to correct the I-148M variant using our leading RNA editing capability, which is expected to restore PNPLA-3 activity and lipid mobilization, reversing steatosis and fibrosis, and improving liver health. In our upcoming first-in-human study of 008, we plan to leverage previously genotyped populations to efficiently identify homozygous I-148M carriers, evaluate target engagement with circulating biomarkers, and assess early signs of efficacy using non-invasive imaging. We remain on track for a CTA submission in 2026. With that, I'll turn the call over to Kyle to provide an update on our financials.

Thanks, Chris. Our revenue for the fourth quarter was $17.2 million, compared to $83.7 million in the prior year quarter. For the full year 2025, revenue was $42.7 million, as compared to $108.3 million in the prior year. The quarter-over-quarter and year-over-year decreases were attributable to revenue recognized upon the termination of the Ticada Collaboration in October 2024. These decreases were partially offset by increases in revenue recognized under our collaboration agreement with GSK. Research and development expenses were $52.8 million in the fourth quarter of 2025, as compared to $44.6 million in the same period in 2024. Research and development expenses for the full year of 2025 were $182.8 million, as compared to $159.7 million in 2024. These increases were primarily driven by our rapidly advancing inhibiting program and RNA editing programs, as well as compensation-related expenses, including share-based compensation. Our G&A expenses were $20.9 million in the fourth quarter of 2025, as compared to $16.1 million in the prior year quarter, and $75.3 million for the full year of 2025, as compared to $59 million in 2024. These increases were primarily related to compensation-related expenses, including share-based compensation. Our net loss was $53.2 million for the fourth quarter of 2025. as compared to net income of $29.3 million in the prior year quarter. Net loss for the full year of 2025 was $204.4 million, as compared to net loss of $97 million in 2024. We ended the year with $602.1 million in cash and cash equivalents, which we expect will be sufficient to fund the operations into the third quarter of 2028. It's important to note the potential future milestone and other payments to us under the GSK collaboration are not included in our cash runway. I'll now turn the call back over to Paul for the closing remarks.

Thank you, Kyle. 2026 will be a year of strategic focus aimed at accelerating development of 007 for obesity and rapidly advancing our RNA editing portfolio. We are excited to build on our positive momentum and are energized now more than ever to unlock the full potential of our RNA medicines pipeline to transform human health. Looking ahead, we expect our next update to be data from our light clinical trial of WVE-007 for obesity, and additionally, expect this to be followed by data from our Restoration II clinical trial of WVE-006 in ATD. 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.

We will now move on to our Q&A session. For those of you who are joining us via Zoom, if you would like to ask a question at this time, please raise your hand by clicking raise hand at the bottom of your Zoom window. Once calls upon, please unmute your audio to ask a question. We are asking analysts to please limit yourself to one question per person. We'll pause just for one moment to allow for participants to enter the queue. We'll take our first question from Joseph Schwartz with Leerink Partners. Please unmute your line and ask your question.

Hi, this is Jenny Ogford-Jo. So thank you for taking our questions. I guess let's just do one on AATD. One of your major competitors recently aligned with the FDA on their biomarker-based accelerated approval framework. How closely does your regulatory strategy mirror what they've laid out for their biomarker-driven path? And are there any key differences? And have you had comparable alignment discussions with the FDA? Thank you.

No, thank you, Jenny. And I think what we all heard in the feedback from one of our recent peer companies from the agency is very much aligned with our thought process in AATD in the beginning, and frankly, fairly well aligned with the existing therapies that have been developed for AATD, which is a biomarker approach in a disease where the protein is the measurement therapeutically active substrate. And so we wouldn't anticipate a distinct or different conversation. I think for us, recognizing that the only protein we're making is the MAAT protein, and we don't have to deal with bystander-edited proteins and the functionality of that. I think we're in very good shape for a discussion on active protein and meeting the requirements that we see as the therapeutic threshold. So we are engaging with them. Obviously, we don't comment on individual conversations with the agency, but we do fully anticipate feedback by mid-2026 on a registrational pathway. I think it was also highly encouraging recently, and I'm sure many of you heard, on the plausible mechanism pathway, comments made by the head of the FDA as well as CDER on using those pathways specifically for ATDs. So I think it's a very good time for us to be approaching regulators on a pathway for That's really helpful.

Our next question comes from Salem Saeed with Mizugo Securities. Please unmute your line and ask a question.

Hey there, guys. Thanks for the question. Maybe just one for us on just the second quarter data. I think, JP Morgan, you guys mentioned that we should be expecting the 400 milligram multi and 600 milligram single in the second quarter of this year for inhibiting. It doesn't seem like it's listed in the slide or the press release. Has there been a change? Are we going to get that data, or what caused you to remove it from the catalyst slide?

Yeah, no, the data's on track. I mean, as we always say, the beauty of a single-dose study with exquisite durability is all the patients are dosed, so data just continues to accrete. So we'll focus on the upcoming data, looking at the impact of time on 240 and the 400, and there's opportunities, again, for data cadence over the course of the year. We're not guiding to each individual update, but as you said, all of these data timelines are all on track, given that all the patients in the study have been dosed. I mean, we have now over 100 patients on the study across multiple dose forward, so it does create a unique opportunity over the course of this year.

Okay, so we'll still get that data then, Paul, or is it something that you're still sort of deciding?

We'll provide the next update in Q1, and then we'll provide subsequent updates on catalysts at each time we provide the updates. So the next update on inhibiting is this quarter.

Okay. All right. Thanks so much, Paul.

Our next question comes from Steve Seithouse with Camden Fitzgerald. Please unmute your line and ask your question.

Great. Good morning. Thanks for taking the question. I wanted to actually expand on the alpha-1 antitrypsin deficiency expectations. So assuming you get alignment on an accelerated approval pathway and some AAT marker, either M or total, what are you hoping that the confirmatory trial requirement will be there, or what are you expecting? Do you already have sort of clarity on what the post-marketing requirements would be for full approval eventually?

It's a great question, Steve. I think that's the conversation that we want to have with the agency and align on. I think there's a number of ways of thinking about that that can be efficient, particularly in the design of subsequent studies that could roll into addressing some of those opportunities. And I think there's really two sets of development pathways. One is obviously respiratory. The other important feature of RNA editing, remember, is we see dramatic decreases in Z-AAT protein, which open up the opportunity for liver indications as well. So I think our goal is make sure that we focus on an accelerated approval pathway for AATD patients. These patients aren't liver and lung patients. These are AATD patients. And then ultimately establish the right pathway as it relates for both labeling for lung and liver, and we'll align with the agency on this. Thank you.

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

Hey, thanks for the updates and for taking your questions. Do you have an internal weight loss bogey for the forthcoming six-month data for the 240 milligrams and three-month data for the 400 milligrams to feel confident on achieving the 5% weight loss bogey at 12 months? And what sorts of outcomes data are you planning to generate to minimize potential payer pushbacks?

Yeah, thanks for the question, June. I mean, I think if we ultimately think about the pathway for greater than 5% weight loss, remember that threshold is after 12 months in patients that would be presumed to have an average BMI of 37 on an optimized treatment regimen. So in the low BMI phase one, otherwise healthy patient population at the doses we're in now, I think we'd like to see continued trajectory down on the weight loss curve. I mean, we had about 0.9% decrease in body weight with that increase in lean mass of preservation and decreased, substantial increase in fat. So with the expectation that total fat should continue to decline, we expect lean mass to stabilize. We would expect to see that change in total body mass, and that would just be a great indicator for us. And, again, we continue to follow that, all of which would signal incredibly favorably that in this study, and as we mentioned on the call, I think this half of the year, getting that phase 2A portion of the study in the MAD, in patients with allowing for comorbidities, which means the expectation for higher BMIs that are more aligned with other obesity studies, would put us in a wonderful position to be able to have a regulatory pathway on weight loss. I think the broader conversation that we all need to kind of be ready for, and I think this is what we're hearing too from our strategic partners as well, is that this addressing body composition piece is critically important. I mean, we hear time and time again, both from the clinicians, patient advocacy community and obesity, again, and strategic partners is scale weight versus body mass. And this notion that weight on a scale equating to actually healthy phenotype and actually what's driving obesity improvements in health outcomes is driven from fat reduction, lean mass preservation, and ultimately seeing that forward. So I think it's important that we look at the benchmarking for weight loss to be, can we cross those criteria for an approval of obesity? And we do believe that we will use that pathway.

But I think what's more important than that in terms of ultimately the therapeutic potential for inhibiting in the obesity landscape is really driving this improvement overall. body composition and that's how you get healthy outcomes thank you yeah our next question comes from alex ranahan with bank of america securities please go ahead and ask your question great thanks guys good to see the progress and thanks for taking our questions maybe one on on obesity it was interesting to hear your thoughts on the various activist strategies out there are there any specific AEs or other metrics you think we should pay attention to for say ELK7 or direct active NE modulators that you're maybe avoiding here with targeting inhibiting? And I guess longer term, given the better tolerability you're seeing so far, how does the duration of mass benefit that you could potentially achieve with 007 fit into your picture for addressing some of the comorbid conditions that these patients face? Thank you.

No, thank you. I'll break the question into, you know, the first piece. I mean, as we think about, as you mentioned, some of the myostat and other active pathways, I think as we're looking at our safety profile versus safety profiles of other medicines in that space, I think they've been distinct. So I do think what we're seeing in terms of not just driving fat loss, and we'll talk about that in the context of your what's ultimately going to improve the outcome for patients in that status, I think we see a very differentiated safety profile and efficacy profile as it relates to fat loss. As it relates to the, as you pointed out, some of the potential risks and if you're looking at OCC7, I think we need to continue to watch those programs over time. I mean, that's something that has to be evaluated is what is the downstream impact of this kind of multifaceted ligand strategy and what happens. And I think data will be accreting there and people will be able to observe what the impact of that is. I think it gets back to the very important point of why we selected inhibiting, which is specificity. I think as we all learned over a long time in obesity, that specificity and understanding pathways is important. And I think the inhibiting E access without seven in terms of driving improvements in outcome is established both in genetics, following patients over time, so in clinical genetics, and ultimately as we're seeing translated in our human studies. As you point out, and I think this is an incredible opportunity in thinking about areas for inhibiting reduction, and particularly activity reduction, I do think this opportunity is it's very well established that a 5% or more change in visceral fat does change outcomes, cardiovascular outcomes, diabetic outcomes. And so when we do think long-term about what's actually driving the benefits of when people say weight loss, ultimately what's driving those benefits is this reduction in visceral fat, which we've surpassed with now nearly 10% reduction in visceral fat at our lowest therapeutic dose at the earliest time point, and reduction in total body fat. So I think with all of that coupled with preservation of muscle, which ultimately as an endocrine organ is critical for sustaining, the profile of what's ultimately going to drive health outcomes is that benefit. And those outcomes are well established in the literature. I think when people step back and say, you know, what overall is important in medicine, I think those two things are really important. One, we have the health outcomes. And for those who try to think about, you know, what's going to happen with that preservation, I don't think people raise their hand and say, you know, I want a medicine that I'm going to lose 40 to 50 percent of my lean body mass at the expense of losing fat. And so I think ultimately, as an obesity therapy on health outcomes and other measurements, a reduction in substantial fat, particularly visceral fat, and preservation of lean mass over time creates an optimal therapy in the space and with durability of once to twice a year as we think about the commercial prospects. You really can change the landscape in the current setting. So as we think about maintenance and the opportunity for once, twice a year and the ease of administrating that, but we also think about the global billion patients worldwide living with obesity and how they get access to therapies. And when you change that dynamic where patients aren't having to go in for a weekly or monthly injection of a protein or stay on a daily oral pill that has to be coincidental with eating and has all of the other tolerability challenges, we think it opens up the global obesity landscape too. Very helpful. Thanks Paul.

Our next question comes from Madison Al Saadi with B Riley Securities. Please unmute your line and ask your question.

Hey guys, thanks for taking our question. It's nice to see you're adding MRI-PDFL to your planned Phase II Obesity trial. I'm just wondering what is the treatment delta you are expecting to get there, just recognizing I think that model of therapy, single glutide, gets around 30% to 40%. So curious where you think you may land on that scale from, say, glyph-1 to the FGF-2-1 mechanism, things.

Yeah, I mean, without, at this point, running, I mean, it was interesting in looking at comparator data, peer data on combinations, where they were seeing nearly a 78% reduction in liver fat. I think there is a substantial opportunity, as Chris pointed out in the call, for MASH as a potential indication as a monotherapy. So I think by enrolling a study where we have patients that allow for comorbidities, I think there is going to be a substantial opportunity for us on imaging to look at monotherapy data by itself in recognizing that there really is a powerful signal that's been seen with inhibitor reduction in weight loss. I think it steps back into, again, the overarching opportunity for the inhibiting pathway and really thinking about the substantial active knee reduction and driving outcomes, both for MASH and reduction of liver fat. And as we were talking about in the last class, we think about just lipid levels in general. You should see with this reduction in these patients with comorbidity, and this is really, I think, again, speaking about long-term outcomes and benefits to patients in cardiovascular disease, reductions in lipid profile, meaning reductions in cholesterol, LDL, epipholbin, A1C, and triglycerides.

Understood. That's helpful.

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

Hi, good morning. Thanks for taking my questions. Just one for me on the dose response and relationship between activity and fat loss. So clinically, you are seeing similar fat loss to a competitor with lower activity knockdown. You know, is there anything we're missing, or is it just small numbers? And then similarly, you know, do you have preclinical modeling data that shows that going from 75% to 85% knockdown is going to lead to better fat loss?

Yeah, I mean, I think one of the things that we've seen, and as you pointed out, you know, our study versus other studies that have come out is we actually have larger cohorts. So I think the dynamic effect that we're seeing with longer-term measurements of active NE, I think we feel really confident that both, and we'll talk about the dose response second, that we do see really highly durable suppressed active NE levels over time. And I think that's the most important feature of speaking to active NE reduction is not just do you knock it down, it's keeping it chronically suppressed. And so we have the long-term data that, again, to your point, differentiates this from other programs in the space. Secondly, going back to our preclinical data, yes, we have shared that we see a dose response on activity reduction driving, again, with suppression, driving further weight loss. Remember, that was the measurements we were using in our preclinical experiments were reduction in weight loss, and that weight loss driven by fat loss. So again, gives us continued support between the 240, and, you know, we've been consistent in saying the bookends that we think around the therapeutic activity, we believe, are modeled into the 240 versus 400 as being opportunities to look at that dynamic range on weight loss as we saw pre-clinically and translate that into fat loss in the clinic. So, yes, we would expect to see the impact of both time but also dose on fat reduction.

Got it. Thank you.

Thank you.

Our next question comes from Kang Lee with Oppenheimer. Please unmute your line and ask for a question.

Oh, hey. Thanks for taking the question. Congrats on the quarter. I'm just wondering for the upcoming in-light update, are you planning to share some additional like biomarker data for those like related to inflammation or maybe fibrosis and also are you planning to present the data at maybe a medical conference this year?

Yeah, we haven't guided to where we're presenting. It will be this quarter. So I think that's the most important update for consistency. In terms of data, we'll present the data. the expectation should be similar to last time in terms of looking at the key metrics of measurements. I think what's important and really where the opportunity sits to Chris's point on the call for the 2A portion of the study is since these are otherwise healthy individuals, and that's really why the BMIs are in this range of around 32, is because we've cut out patients that have a lot of the other features that you're measuring because those wouldn't be considered otherwise healthy individuals, and they don't meet that criteria. So, therefore, being able to look at some of the other markers that one can see in the study does present more of a challenge because they're otherwise healthy. I think the opportunity as we get into the phase 2A where we allow patients with comorbidities being higher hemoglobin A1Cs, other lipid characteristics, will give us more opportunity to be able to discern some of these other changes that are seen with inhibiting in a clinical context. But that will be in the subsequent 2A portion of the study.

Thank you.

Our next question comes from Whitney Ajem with Canaccord Genuity. Please unmute your line and ask your question.

Thanks for taking your question. This is Angela on for Whitney. Can you just maybe help us set expectations into the upcoming obesity and AATD readouts? So for 07, how should we all be thinking about what is good in terms of body count for fat reduction from the 240 milligram cohort at six months and then 400 at three months and then similarly for 06 in terms of what AT levels would you welcome to see from 400 mad thank you no thank you i mean i think the key criteria for us is we're already on that curve with the 240 where we're seeing fat loss similar to glp1's increased visceral fat higher fat visceral fat reduction than GLP-1s.

And lean mass preservation versus, remember, at that three-month time point, there was nearly a 50% reduction in lean mass on the GLP-1. So I think continue to see the profile of an improvement in body composition with, I think, continue to see the impact of that fat reduction. So that should happen over time, and lean mass should be stabilizing over time, which should be driving that total body mass curve down, so weight down. I think that'll be the opportunity of looking at the impact of time at 240. And then it was brought up by one of the other questions, which I think is an important one, is we're going to be able to look at the establishment of this dose response context. So what's the impact of time on that curve? And what's the impact of dose on that curve? And so the 400 will be equally as important looking at that early time point. So that'll be at the three-month time point, because again, we can compare it to the GLP-1s on the dose response at that early time point with a higher dose and suppression of activity and potentially decreasing in fat and be able to set the stage for what does that look like modeled over time based on the 246 months. So I think we've got an opportunity really to continue to watch those kinetics play out. And if we go back to our preclinical data, you know, that was really the slope of that weight loss curve was driven by exactly what we believe we're seeing in humans, which is mice have substantial reductions in total body fat. They had a slight increase in lean mass, and overall the mice lost weight similar to GLP-1s, and their curve was continuing. So I think the opportunity is to actually be able to model between our preclinical data and clinical data based on the human evidence coming forward in obesity. For O6 and ATV, I mean, I think it's important to remember that the arms race for more and more protein isn't necessarily what the requirement is if you're not doing IV protein replacement therapy. So I think the idea in editing has been to establish, do you have the therapeutic threshold to say that these patients are corrected to an MZ phenotype so that ultimately, and it is really important when we talk about editing to step back and say, it's a chronic disease of acute exacerbations. And therefore, the whole premise of this is how do you prepare a patient so that when they have that exacerbation, they can rise to meet that need. And as we saw, 20 micromolar, the lowest single dose, meant that those patients actually in the event are protected at levels that we're talking about for IV protein replacement, you know, to hopefully prevent that, where that nature could actually be lower in the IV protein replacement space. So I think we've already seen that we're at that threshold. I think the question going forward is going to be both durability, time, so opportunity to continue to see as liver gets healthier, are we producing potential for more M protein over time, which we think based on our preclinical experience should be seen so you can continue to see that protein get released to see increases in M, but ultimately continue to sustain the portfolio, I mean, the pattern of increased editing efficiency. So, I think that's the notion. We're going to be able to look at that at the 400 and see, again, duration. So, is this – this will be monthly. Do we think about the opportunity to think about, you know, medicine that could be quarterly or less frequently? Being able to model that is going to be important ultimately as we think about a therapy. And so, I think we're set up to be able to distinguish this as delivering on the profile that we believe is going to be requisite for the regulatory interactions for a potential accelerated registrational pathway.

Thank you so much.

Thank you.

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

Hey, guys. This is Craig on for Ben. I appreciate the opportunity to ask you all a question today. So, you know, appreciating the fact that 007 is a liver-directed agent, I guess based on your understanding of the biodistribution of that agent, would you expect any of it to find itself to muscles? and maybe just a quick second one here. Given that now you're exploring the benefit of O07 on liver fat, how do you see that coexisting with O08 over longer periods of time?

Yeah, I mean, I think to address the first one very simply, it's a galmic-conjugated siRNA. So it's an active receptor-mediated uptake in the liver. So that is the target organ for delivery. And based on our preclinical data, that's where the drug is distributed and exerts its impact on a simple basis. And the second question was, sorry, if you want to. Oh, how do these work? Yeah, I mean, I think what we have to think about in 08, and it's important to kind of step back separately from just thinking about 07 and the impact on liver fat and 08 in the constituency matches one indication for 08. if we step back and think about the PMPLA-3 indication, these patients are at risk of all told liver disease. So, the best way to think about PMPLA-3, and maybe, Eric, you can share, and we should double-click back on the indication, because I think it is important to really think about this as a genetic mutation for the liver disease in general, and all told liver disease, not just NASH, and where the ability to identify this mutation is found in 23andMe. It's a genetic mutation that can drive a whole variety of diseases, of which MASH is one. But, Eric, I don't know if you want to...

Yeah, just to build on that, I think this is the first approach that is directly, or rather, there are no approved drugs that are directly addressing the pathology in these carriers. So, it really corrects back the disease-driving variant in these carriers, And to Paul's point, it's not only MASH, it's across a whole set of different liver diseases. So it addresses directly the causal variants, so therefore it's kind of a unique approach, we think.

We think about this as having kind of two, and we shared some more on this, so it's a good opportunity for us to go back to research day. You know, there's this concept on lipid trafficking, and when we think about MASH and where that application is, But there's also an inflammatory component in these PMPLA-3 patients, which is why their response to injury drives this fibrosis and liver injury in general. And so the real opportunity in correcting this, and this is, again, why you want to correct it, not silence it, is restoring the functionality of this enzyme so that what you're able to do now for these cells is actually repair them. So not thinking about kind of symptomatic treatments that improve kind of one aspect of the disease, but actually fix the underlying pathology that allows these patients to go forward, not just focus on liver fat, but actually prevent fibrosis and downstream sequelae, where these patients who are homozygous are at a very high increased risk of really progressing not to cirrhosis and ultimately need transplantation. So I think the opportunity we really have is fixing this disease at the source. This is separate from thinking about how do we think about the opportunities beyond treating body composition as it relates to obesity therapies with 007. So if we think about 007, there are a whole host of things we can think about. If we think about visceral fat reduction and what the impact long-term is on visceral fat reduction, improving outcomes to patients, It's not just thinking about, you know, obesity in general, but thinking about visceral fat reduction downstream. Thinking about MASH is another indication because of the increased impact on reduction in liver fat. And so I think these medicines are very different in how they approach things and have any really focused on a pathway around fat reductions and the ability of O8 to focus on a pathology that's very uniquely driven off of a genetic mutation. Got it. Yeah.

Our next question comes from Roger Song with Jeffries. Please unmute your line and ask a question.

This is Chacha Yang on for Roger. I have two questions. One is, can you speak more to what you expect to see for 007's kinetics based on some preclinical PK data and what we should expect to see for the rate of fat loss, weight loss, and lean muscle mass change over the next six to nine months? And then just second question really quickly. Can you just remind us what trials and programs your 2028 cash runway will include?

Yeah, I mean, I think what we see on the curves, if you look at the animal modeling data, so, you know, you can follow where the GLP-1 curve on weight loss is, you know, where that's heavily predominantly driven on lean mass loss at the beginning and then continued fat reduction, you know, kind of gives you this, that increased slope in plateauing. And then where you see inhibiting, where you see this acceleration kind of into that curve. And so I think we're right on that tracking with the rate. We're all learning about the pathology, or I should say, we're all learning about the rates of that curve together. I think it is tracking, actually, very nicely to our preclinical experience. I always say mouse kinetics to human, there's always a separation, so we just have to continue to watch that play out. But I think we have a very good benchmark in looking at the GLP-1 versus inhibiting, and they're tracking as to be expected. So, again, high degree of conviction that with more time, you see more fat reduction. With higher doses, you'll continue to see more fat reduction. And as you point out, we'll have these periods at six months, nine months, and, you know, out to this patient study allows for follow-up out to a year. We're going to get the opportunity to really follow that in this lower BMI setting. I think what's going to be exciting about bringing on earlier now this higher BMI setting is going to be that we're going to be able to look at these things in tandem, right, be able to track these together and be able to see, again, in that higher setting, which is more akin to the animal model, does that happen faster? And so we'll be able to look at that and track that. But again, very good correlation between the DIO mouse and what we're already seeing in the clinic. So again, drive that conviction, remembering that we did see weight loss in the preclinical models. Your other point within this 2028 envelope is exactly as we point out, delivering on our core strategic priorities. We're going to deliver the 06 data. we'll have our regulatory interactions in the middle of this year. It was and why we said last year it was important for us to accelerate inhibiting. It funds the Phase 2A study so that we can continue to deliver this study in patients with a higher BMI. And it's inclusive of accelerating, who said this year, the study on both add-on and maintenance. And what's been interesting in some of our strategic conversations is we are getting, there are good conversations happening with the ability to access various ingredients in various designs and studies and so you know that that isn't incorporated into those savings in those studies but there's opportunities that exist as we think about those collaborations ways of thinking about retaining the asset but ultimately continuing to drive clinical data sets off of that so again delivering you know in our runway as we said at the beginning of this year the core strategic principles of 07 in obesity, O6 for alpha 1A, trypsin deficiency, and bringing also forward the CTA submission and the clinical trial for O8. So that's in the envelope.

Great. Thanks so much.

The next question comes from Michael King with Rodman and Renshaw. Please unmute your line and ask your question.

Hey, good morning, guys. Thanks for taking the question. Can you hear me okay? Okay. You know, I just want to maybe reflect more on 07. We're talking in very scientific terms. But if you think about the trajectory of the obesity space, you know, I look at it as kind of a war of one-upmanship, you know, that started between Lilly and Novo and then, you know, is going to be, I think, joined by the life of Pfizer and others, just trying to focus on body mass index or loss of body weight. You see, you know, the consumerism aspect of it with, you know, with Serena Williams and Charles Barkley losing, you know, 30-plus pounds or 50-plus pounds, respectively, of weight. So how does one communicate? And this may not be your problem to solve. It may be your strategic partner. But how does one communicate the benefit of loss of visceral fat and preservation of muscle, you know, apart from body weight when so much of the light in, you know, the obesity, you know, ecosystem is focused on body weight loss?

No, it's where we spend a lot of time. And it's frankly why we're extraordinarily excited about where inhibiny fits into this. Because I think, you know, athletes not aside, call it your normal person, right, who is, you know, going and wants to, to your point, there's a need or requirement. In their minds, they're saying, I need to lose weight, right? They're worried about either being obese or overweight, and they want to take a therapy. And if you look at this, I don't know anybody who is going to raise their hand and say, you know what, I wouldn't mind losing 30, 40, 50 percent of my lean body mass. because I'm going to look at a scale and it's going to go down when, you know, you could look and actually I'm reminded of this because I was actually talking to a KOL yesterday, and, you know, what she was reminding me of is we need patients who are leaner, not lighter, and the notion that, you know, she has patients who come into her office and she'll remind them, she's like, don't look at your scale, but if I told you, you know, they're coming in because they're saying, look, I want to lose like 40 pounds, and I want to lose this, and then she puts up a picture actually of like Michael Phelps, which is like, you know, if I told you you could be 200 pounds and look like that versus, you know, 150 pounds but have no lean mass, what would you – and inevitably, when people think about it in a real-world context, what they're really saying is they want to be leaner. They want to have high lean body mass, low subcutaneous and visceral fat, but they don't want to do it at the expense of muscle, and they're thinking about it more.

They can get their six-pack.

It's just as important, but it doesn't mean – so, like, you know, I don't want to take us into the swirly of, it doesn't mean you're not going to lose weight. If you lose subcutaneous fat and you preserve muscle, you will lose weight. So this notion that all of that has to not coexist with a regulatory pathway, I think is a false pretense. So you can completely exist within the regulatory paradigm, but if I actually see where regulators are going as well, they're indexing this, right? The guidance last year was on body composition. Bring us weight loss, but bring us body composition. Don't come where this race, and you pointed out, the race that's happening in this other kind of war, call it on the ingredients, is just like incremental loss of, it's at the expense of muscle. There's tolerability. There's weight cycling. There's this notion of a whole generation of people who are on a therapy and, you know, it's switching from saying, well, we should think about this like hypertension, you know, keep people on it for a long time. Seventy percent of people can't stay on the ingredients for a full year, right, with all of the other complications to it. So I think the notion of really reminding ourselves, why are we doing this? A once-to-twice-a-year medicine that can drive substantial fat reduction, preserve lean mass, so you get that opportunity on both, as you said, the perception side, the aesthetic, what do I look like kind of question. But most importantly, what's going to drive health outcomes benefit is the profile of what inhibiting and active in need reduction brings, but does so at a scale where, again, Again, safety tolerability, I think, is highly differentiated from the growing incretin class. I think maintenance will be a really fundamental opportunity here. The idea of what does the off-ramp for a chronic therapy look like, where somebody now has to look at the potential lifetime of sustaining themselves on an incretin therapy. That's why we're excited this year to get the maintenance study, which is give patients an off-ramp. You can have the sustained reduction. In fact, you can prevent and continue to sustain loss of muscle. You can have a once-to-twice-a-year maintenance therapy. And so I think there's an enormous opportunity on the maintenance setting. And I think we're hearing this echoed by all of the strategics that we're talking about that truly recognize that this inhibiting body composition maintenance is crucial. So, and not to be lost to realize that when we do talk about this as an obesity therapy, there are a substantial number of people who can achieve goal on the incretin therapy. They can't tolerate staying on it. They can't tolerate being titrated up on it. And so, we really do think about the therapeutic paradox. You know, we had one strategic say, you know, what would be really interesting is inhibiting is the basal state and then titrate the incretins around it so that, you know, you can preserve better tolerability and safety. So I think this really does fit within this paradox, but as you point out, I think it really is important for people to remember in the real world consequence, this really is delivering the profile that patients are looking for. Reduction in fat, preservation of muscle, ultimately allowing patients to be leaner, not lighter. Yeah, thank you.

We'll take our last question from Cassie Yuan with RBC Capital Markets. Please go ahead and ask your question.

Hey, Kim. Good morning. Thanks so much for taking our question, and congrats on all the progress. On inhibiting E here, I appreciate that you are amongst the most advanced in clinic today for this target, but it also seems like some of your competitors are speeding up by following signals in co-morbidities and subpopulations earlier in their studies. Could you maybe comment on how important is it to be the first to pivotal data for inhibi, and ultimately do you see the activity space, accommodating multiple players? And what do you think is going to be the differentiating factors amongst the players here for actively lowering therapies? Any color there on these dynamics? Much appreciated. Thanks so much.

I think, look, I mean, as you point out, obesity is a very large space, so it can accommodate multiple therapeutic companies. But as we've also seen in the creatine space, it's helpful to be a leader. And I think within the Inhibit E access, I think WAVE is well poised to be the leader for inhibiting e-silencing. I think our chemistry is highly differentiated. We saw that from driving single-dose weight loss in our preclinical studies, which is the only preclinical data to date that's shown dramatic decreases in sustained activity reduction tied to weight loss. So our chemistry translated to differentiated preclinical data, which ultimately, as we've seen, translate into the clinic in a highly differentiated way. I think what we're seeing across the inhibiting space with competitors are programs that look very similar across all of the peer companies. I mean, if you look at all the posters that were sitting there on other inhibiting programs at Obesity Week, they all looked remarkably similar. So I think there will be a separation between here's what we've been bringing to the table in a highly differentiated way to look at inhibiting with a once-to-twice-a-year therapy that drives a dramatic difference. And then there'll be everybody else. So I think it creates a very unique opportunity for us really to define the space and then sustain our leadership within that space. And I think it is important because I think we tend to think about siRNA as a commoditized space across indications. And I think we're hearing this from those who are experts in the field, recognizing that what the team has done in driving new chemistries forward has created a very unique space for us here. Now, we need to sustain that leadership, really, as you pointed out, defining what success is going to look like. And so, it's wonderful that we can see already this differentiation. Everybody's comparing us to, you know, GLP-1s at three months, you know, other inhibiting programs at these time points, that's where a little bit later. But we're doing this in a way where our BMI setting, to your point, we're looking at patients who are non-diabetics, right, who are low BMI, and we're already seeing these differences. is, you know, we're excited to go into the higher BMI setting because I think that's going to give us the opportunity to see even greater weight loss, fat loss, and then ultimately changes in other outcomes measurements. So I think we're really poised to not have to say we need to get into these settings to be able to see the efficacy. We can see it in this low setting and then only build on that from here, time, higher doses, and also in patients with higher BMI and comorbidity. So, the data should continue to mature as these studies move forward, both in the existing and late study, but also in the face-to-face study.

Thanks so much, Pops. Thank you. There are no further questions at this time. I will now hand the call back over to Paul Bono for closing remarks.

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