Welcome to the inaugural session of the 47th Annual Goldman Sachs Healthcare Research Conference. Pleased to be joined by Wave Life Sciences and Paul. First, Paul, for those in the audience and listening who may be less familiar with Wave today specifically, what do you think is the most important thing for investors to understand about the company and where it stands today? Well, one, thanks for having us. It's a great time to be connecting as we hit the midpoint of 2026. We're at what I would call a strategic inflection point on operating against what we set out as a strategy as we began 2026, which is, one, we see our platform chemistry translating into potentially meaningful therapies, starting with WVE-007 for inhibin E, coming off of our initial clinical data, seeing again in the siRNA space, our chemistry uniquely translate to a meaningful improvement in body composition in a phase I healthy volunteer study, and excited for the updates as we transition to the phase II-A high BMI study, which will be starting shortly. We'll spend more time, I'm sure, talking about that, but that's obviously a very critical component in our evolution. Second is the growth of our RNA editing platform, which is exciting, led by alpha-1 antitrypsin deficiency and the work we have there, and this summer being a key inflection as we engage regulators in a potential pathway to accelerated approval, being able to differentiate that program in the RNA editing field from other therapies for alpha-1 antitrypsin deficiency, and critically unlocking the platform capability for RNA editing, where we'll have WVE-008, the first RNA editing program for PNPLA3, a disease of nine million patients that will come into the clinic as we end this year. Again, lots of progress across siRNA, RNA editing, and we're excited to continue to do the work on the platform, and we're well-resourced to execute on those clinical trials. That's great. We'll get into individual programs here in a sec, maybe before doing so, investors often debate the value of a platform and breadth versus depth. You obviously have a few different RNA modalities. How do you think about the benefit of having RNAi, RNA editing, splicing, and emerging bifunctional modalities all under one roof? Yeah, I think when we step back and say, I think there's lots of different ways to define platform companies, right? You can become a platform company off of biology. When you build a platform company off of chemistry, the main value there is to really demonstrate that that capability is translatable. When we think about building an RNA medicines company, the goal and the premise has always been how do you unlock the power of emerging clinical genetics, right? Because I do think for our field and our industry, the biggest challenge is how do you find high-value, high-impact targets to make medicines for patients. The value of a chemistry platform is how do you unlock those genetics so that when those interesting, compelling, high-impact, high-value targets become accessible, that you can be poised to translate those innovations. Case in point, inhibin E going after a validated genetic target in the U.K. Biobank for obesity and cardiometabolic disease is intriguing on the RNAi side, and we'll talk about our differentiation on chemistry, where we're seeing that not just translate pre-clinically, but now in the clinic, again, given our unique and proprietary chemistry. Equally important, as we think about alpha-1 antitrypsin deficiency, PNPLA3-driven mutations for disease in liver, these are all opportunities not on the silencing side, but where actually, and we'll talk about PNPLA3 specifically, given some of the presentations at EASL that are reaffirming that siRNA is not the approach to take down the mutation, but correction is, to be poised to have a platform that can correct an enzyme lets us jump on that opportunity for those nine million patients and have a potential therapy. I think the key on the platform is really how do you drive differentiation. I'll step back and say, when we talk about inhibin E, I think the uniqueness of, again, the work that the team has done in that is special, and we'll see that later R&D day this year as we talk more about, to your point, this bifunctional capability, which is how do we interplay these modalities of either dual silencing targets or silencing and upregulation editing in one molecule. That's great. Maybe now turning to 007. Before getting into study design data, can you talk more broadly about biological rationale of inhibin E as a target in cardiometabolic, and maybe also what you've learned about it over the course of this last little bit? Yeah. One of the very important points, as we said, we like targets where there is human clinical validation for those genes, so that when we're working on a program, that there is clinical support that if you interrogate that target with a medicine, that you have a higher probability of that medicine translating in the clinic for patients. inhibin E is a wonderful example of that. It's like the PCSK9 for obesity in the sense that the UK Biobank data set has shown that there is very good translation of this target. People walking around with a 50% loss of function of this target have low abdominal visceral obesity, they have more lean mass, they have lower lipid levels, so lower triglyceride levels, higher HDL levels. Most importantly, the human outcome study has been run. They have a low risk of cardiovascular disease and a lower risk of type 2 diabetes. If we think about the totality of the evidence that says this is an important medicine for cardiometabolic disease, including obesity. The clinical genetics tell us that. I think stepping back and saying the translation from human clinical genetics to a medicine often entails a pathway of not having to be born with it, which is a great maintenance study. Ultimately, how do you create a therapeutic? This was our opportunity to really start to say, can we answer a fundamental question on our platform capability, opening up an opportunity unique to Wave, meaning can we take advantage of a target that the body has just a little bit of more biology of the target. This is a target that's the ligand's produced in the liver and hepatocytes and uniquely targets a receptor on adipocytes, ALK7, and we can talk more because there's always a lot of conversations around ALK7. The unique mechanism is actually the ligand communicating with that receptor. The target is the ligand. What it does is it actually kind of puts the brake on lipolysis. Evolution was always about fat storage when calories were not plenty, therefore the desire was how do you build and store fat? When you take the brake off lipolysis, you see that breaking down, oftentimes starting with highly vascularized fat like visceral fat, and then proceeding into the subcutaneous compartment, and we'll talk more about the ability of this in both subcutaneous and visceral fat. The key when you're developing a therapy is always will this translate? Can we uniquely translate this? So far, we've been unique in the sense that our chemistry is translated to the only single-dose reduction in body weight in the DIO animal model. We could give a single injection of the drug. We could see weight loss comparable to the GLP-1s all driven off of fat, so preserving lean mass. I think that's important as we talk not just about the importance of muscle as a stabilizer, a functional component of muscle, but muscle as an insulin-sensitizing organ. As we talk about cardiometabolic disease, this idea of fat reduction, lean mass preservation, and ultimately translating to healthier outcomes. We demonstrated that in the mouse model monotherapy and can show monotherapy reduction in fat leading to weight loss. We did a combination study. We know with the evolution, we'll talk more about that clinically, that the idea that you could get even more weight loss when you combine these with GLP-1s with that weight loss coming off of just fat. It gives you the opportunity to think about how do you preserve muscle sparing in the context of incretins. The last, which we think is a very compelling opportunity that we've demonstrated preclinically, is maintenance. As I said, that's also the compelling opportunity that's been seen in the UK Biobank clinical genetics, which is that if you knock the target out prior to cessation of incretins, you prevent rebound weight gain, even in the setting of higher caloric consumption. This idea that if you want to transition from incretins onto a muscle preservation, but not lose or drive that weight regain. Remember that weight regain that patients experience where their body weight comes back usually to or above where they started, is driven off of fat. These patients, from a health standpoint, actually accrete more fat after they stop than they had at the beginning of the study. The ability to think about this as a therapy where you can give a once to twice a year injection that sustains patients. I think when we think about these three use cases, it's a prime opportunity that we've been able to see that chemistry platform that you were referring to uniquely translate to Wave in seeing that. We've seen these data both in the preclinical studies now translate to humans, where single dose in a phase I healthy volunteer study, we could recapitulate that biology with a substantial reduction in visceral fat, about 15%, reduction in subcutaneous fat, about over 5.4%, and most importantly, a reduction in waist circumference of 3.3%, which is tightening of belt loops. We think about that in the healthy setting, which is a very different setting than people historically look at obesity studies. That data was, in our minds, very compelling in the translation of moving into obesity studies that looked like other larger obesity studies. Makes sense. Maybe you mentioned a little bit about this, the unique chemistry platform that you have. This is a target that many others, including some of the largest names in RNA, have tried and frankly, haven't even been able to get a molecule into the clinic, let alone continue through clinical development. Maybe just briefly, in terms of what allowed you to bring something potentially very compelling to the clinic. Absolutely. I mean, getting back to that concept of platform chemistry, we appreciate the question because oftentimes as portfolios mature, we spend more time saying, what's unique about the clinical data and driving the clinical opportunities in it, forgetting that probably one of the most fundamental criteria of Wave as an oligonucleotide chemistry company, I would say inhibin E is now giving us the opportunity to truly say that we have the potential of best in class in siRNA in this category, is Wave's unique chemistry, meaning with the phosphorodiamidite and our stereochemistry and control, the ability that, and we published this paper probably about three and a half years ago in NAR, we were able to compare it to, as you pointed out, some of the best oligonucleotides that are translating in the clinic and do head-to-head comparisons where we could see improvements in potency and improvements in durability. I think at the time where we were generating that work in the target space, a lot of the targets were kind of exploring of what more would you gain? You could gain more in terms of decreasing dosing frequency. I'm not discounting that. Those are important and interesting. It was really when we saw inhibin E where we said, here's a target that is under pressure, to your point, is eluding others because it needs that suppression. This would be a wonderful target, actually, to translate those chemistry innovations into strong differentiation in the clinic. This is a target that needs to be suppressed. Again, to your point, the ability to suppress that target didn't just translate in the preclinical animal obese models, but translated well even in the healthy volunteer studies in recapitulating that fat reduction, lean muscle sparing, and durability to the point where, again, in this space. It's competitive now where we can have a once to twice a year subcutaneous injection that can drive really meaningful improvements in body composition. Yep. Makes sense. Maybe on the data you've generated to date, obviously reduction, lean mass stabilization, there's a lot of focus on overall body weight. How do you interpret the data that you've had to say, maybe a little bit more detail than you've given, as well as what do you think it means moving forward for the molecule? Yeah. I think when we step back and really say, what does it mean? What does it mean in obesity treatment? I think we are seeing an evolution. We actually just came to this conference from our time at ADA, and I think in the meetings there and in the settings before it, I think there's a real fundamental shift in how we talk about therapies for obesity. We have had this compelling discussion about what does healthy weight loss mean. It means improving body composition. It means sustaining lean muscle mass, which does weigh more than fat, and shifting the narrative to pounds on a scale to what does improvement in body composition look like overall in terms of improving human health. When we think about that, and I'm often reminded, many people have heard this, but I just think it's the right way to visualize this. One of the key opinion leaders in this space, I'll give her credit, Angela Fitch, she has a very great analogy in her clinics, where patients who come in, they may weigh 250 or more pounds, and they come in, they say, "I want to lose weight. I want to be 170 pounds." She goes, "Why?" What is it about? I think it's because for a long time, that's the only way we had to measure what's happening to our bodies, right? You stand on a scale, and you watch the weights on pounds go down, and remember, those pounds are often driven by lean muscle mass loss. We saw that when we analyzed the BELIEVE data on the incretin comparator arm. In three months, 50% of that reduction was lean mass loss. That's the tool people have to see that, when these patients come in and say, "I want to be 170," and she'll hold up a picture of Michael Phelps and say, "If I told you were going to be over 200 pounds, but this is what you were going to look like, would you want that?" They go, "Yeah." I think it really changes the narrative visually of what people are really looking for and how important that lean muscle mass preservation is ultimately to human health. We move the conversation past pounds on a scale driven off of weight loss and really reframe the discussion to what does healthy weight loss look like. It is substantial. It means you need to lose substantial amounts of fat to drive that body composition. I think, hands down, I think the tools for that are getting better and more distributed. We're seeing scales now that people have in their homes that cost as much as body weight scales that actually enable people to measure their body composition. It'll be really interesting in the evolution of some of the incretins as people watch on that scale and see not the weight go down, but the lean mass changes that correspond to that. I think it'll allow us to kind of reframe and refocus the narrative on what's important, which is fat reduction. To your point, coming into that framing, recognizing that the clinical trial that we delivered first was healthy volunteers. I think it is important, we oftentimes use BMI, coming out of ADA, I can say BMI is uniformly viewed as not an ideal way to be talking about this space because you could be a bodybuilder with a high BMI, or you could be obese and unhealthy with a high BMI. It is important to think about not just high BMI, but our study excluded patients with comorbidities. It is the comorbidities that drive increase in fat, visceral fat and subcu fat, and that is what you ultimately want to see. In the phase I, even in these healthy patients, we saw substantial reductions in visceral fat, 15%. To put that in context, because I think we always talk about numbers, an increase in 5% - 7% in visceral fat drives a number of diseases. We could talk about cardiovascular disease risk of diabetes, as you kind of cross up to that near 10, you're talking about MASH. If we think about that change and seeing a 15% reduction in visceral fat in a healthy population, that is a really consequential shift for human health. We also saw, I think it's important when we get beyond what drives health outcomes, is the reduction in subcutaneous fat and recognizing that that's what drives change in body weight. That's the larger compartment. We saw a shift in declining subcutaneous fat by 5.4%, again, in these patients who did not have a substantial amount of fat to lose. That translated, I always say, what did that translate to as we think about what's meaningful to patients is that 3.3% reduction in waist circumference, meaning this was translating. Additionally, very important in the obesity therapeutics landscape is, this came with a safety profile that was extraordinarily clean. For these medicines, the only AEs were mild irritations at the injection site in some patients without dose dependency. Again, the important piece is safe and driving these meaningful changes in body composition. Again, reinforcing for us, the lowest dose, seven and a half months after that injection, we were still suppressing Activin E. The notion that you've got durability and infrequency, safety, most importantly, those improvement of body compositions in this phase I population, I think is incredible as we make that transition to the phase II high BMI patients with comorbidities, with and without diabetes, where the setting is more fat and will look more similar to other trials that have been run in this space, I think we're poised there to see meaningful differentiation. Maybe along those lines, as you're going into that patient population. Any expectations for what you're going to further learn about the program in terms of dose optimization, et cetera, as well as key differences in overall study design versus your phase I? Yeah. First is very different in terms of phase I. This is a shift in the population. This will be high BMI patients with comorbidities, with and without diabetes. As we model what that delivers and with all the waist circumference parameters that other studies have, that sets up the population where we would expect substantially increased levels of visceral fat and substantially increased levels of subcutaneous fat that would put it in baseline characteristics with other obesity trials. This study does have MRI and MRI-PDFF, and we'll talk shortly about liver fat reduction. By having MRI in this study, it does give us a way to ascertain a baseline whether or not we're meeting the body composition similarity. Again, this study will be poised to deliver that change. I think the with and without diabetes is equally important. What do we want to see in this study? We'll have two different doses that we'll be looking at, the 240 and the 400. That'll let us have the ability to discern how do we optimize that infrequency of administration in those settings. We'll be able to explore that on the PK side. On the PD side, one of the opportunities we have, so if we think about endpoints in this study, beyond just obesity and weight loss. We're obviously going to measure body weight reduction, body composition via DEXA and MRI, but we're going to have other endpoints in this study with which we can evaluate other opportunities, given that obesity is a metabolic disease. What are the other cardiometabolic diseases that are approached with this mechanism? One, the reduction in fat, which we've seen from others who've developed their assets. We still think we have a threefold improvement in ED50, but it was highly encouraging to see in this setting, a posted number of about a 44% reduction in liver fat. That's substantial compared to other MASH drugs. The ability to have that opportunity in this study to discern our own data set and what we can see is compelling as an endpoint to hemoglobin A1c. Again, looking at the diabetic patients let us evaluate what the impact could be on other biomarkers. Hemoglobin A1c is an endpoint that doesn't require an outcome study in diabetes, so we'll have that. We'll also be able to look at lipid levels, which again, the human genetic shows those improvements. We'll be able to discern those endpoints in addition to things like insulin sensitivity, looking at HDL triglyceride ratios. I think in totality, this monotherapy study is really poised to unlock the potential for inhibin E in obesity and other cardiometabolic diseases as a single agent, realizing that there's 30 million patients in the U.S. who are at risk of lean mass loss that need an approach to body composition improvement and fat loss and is uniquely poised to do that. I think the settings that will start beyond this, there's three trials that'll start on the heels of that. This study will initiate this quarter. The next study will be the combination study. This will give us the opportunity to really look at directly with an incretin. It's safe to say, given that others had looked at the combination with tirzepatide, that that would be a fair way to view this combination study. The ability there is really not to drive weight maxing at the risk of lean mass, but ultimately, how do these two features intertwine? The ability, potentially, at something like the low clinical dose of tirzepatide, to see that you can maximize fat loss without having to push the incretin from a tolerability perspective and a lean mass loss perspective. If we think about the idea that 70% of patients are intolerable to their incretin beyond a year, how do we think about these as keeping patients on meaningful medicines and maximizing body composition improvements? The third opportunity, which we're excited about, is maintenance, that's recapitulating exactly what we did in the animal model showing that we could dose inhibin E prior to cessation of the incretin and be able to have a way to sustain that weight reduction that patients have achieved, but do so without continuing the incretin to suppress lean mass, again, tolerability, have, I think, a unique way to drive adherence, which as we speak to payers is something that everybody's focused on, is the investment to get to a certain body composition and what's the risk to staying there. We know patients, they're investing financially in trying to stay there, the ability to work with patients on maintenance to be able to have an off-ramp to incretins is pretty exciting. Great. Maybe just briefly, you talked liver fat reduction, obviously looking at in T2D, but potential outside of just obesity or T2D kind of broader cardiometabolic opportunities. Broader metabolic opportunities, in particular, as you mentioned, diabetes, MASH, what was formerly called PCOS and going through evolutions. There's lots of ways to think about metabolically driven diseases that are driven off of, importantly, visceral fat. The opportunity where we have a potent reduction of visceral fat drives a whole host of cardiometabolic inflammatory diseases. Again, a unique approach where we're doing that, where the biomarkers are part of the study. I can't emphasize that enough that when one runs studies in obesity, people have in their mind the classic body composition, DEXA, and weight. I think the ability that we haven't missed the opportunity as part of the study to embed these other biomarkers and tools of measurement are going to give us that opportunity to unlock that potential as part of this study that's initiating. That will continue to generate data over time in a number of indications that we can unlock. Great. Turning to WVE-006, several different approaches for AATD. I guess maybe briefly before getting into the data and what you've seen to date, why do you think RNA editing is a compelling approach here, and maybe also briefly on your RNA editing platform? Yeah. RNA editing in general, we think is an interesting platform. It's compelling in that we don't have to work at the DNA level with permanent mutations. The ability to have a way to either correct a transcript or up-regulate a transcript opens up the potential to explore a number of therapeutic opportunities. AATD is a unique one in the context of correction, meaning you've got a single mutation on the transcript that if you can correct, you can restore the production meaningfully of healthy wild type protein. Focusing on the ZZ patients, which is where we do, these patients make no M protein. It gives you to evaluate how your medicine works, whether it's one, and first and foremost is reducing the Z protein. These patients may have two copies of Z protein, and that's what's produced. That protein gets stuck in the liver. It's also secreted, but it's the toxic folding of that protein which damages the liver. Therefore, by reducing that toxic protein, you ultimately enable liver repair. I say this because as we talk about editing versus other approaches, protein replacement therapy, we have to remember that alpha-1 antitrypsin patients are both lung and liver patients. These patients have both higher risk of liver disease as well as lung disease. When we think about lung disease, and we'll talk about this shortly, it is a chronic disease of acute exacerbation. What happens are we all have kind of steady state levels because it's an acute reactive protein that sit in the background. What really happens when we're exposed to an irritant is that you see your pneumonia, cold, kidney stone, that the body increases IL-6 and CRP. That's the acute inflammatory response that increases the transcripts that produce the protein. The protein then gets produced to protect damage from occurring. It's that chronic damage that happens over those acute exacerbations that injures tissues. The approach that editing has actually is to recapitulate changing these patients. If we think about patients on the spectrum of ZZ to SZ to MZ to healthy MM, as these patients have less Z and the ability to produce more M, they are protected in their various tissues. That's exactly what we saw pre-clinically, and that's exactly what we saw in the clinic, is that as we treated with WVE-006, we saw, and it was actually really beautiful when you think about the curves, that all patients were responding, and you could look at an individualized patient level and actually see that their Z protein substantially reduced, and they end up producing more M protein. We expect that as the liver continues to get better, those can continue to increase to higher levels. What's nice is we can recapitulate getting to that MZ-like phenotype, meaning reduction of Z, production of M, and importantly, having that acute phase response. For example, we did see that when patients had an acute phase response, they could produce total protein levels greater than 20 micromolar. This idea that you could generate that protection when you need it is really the fundamental aspect of what editing is supposed to do that safely in a way that you could redose it. As we know from clinicians and patients, reverse it, that if you stop the medicine, you haven't permanently altered the DNA of those patients. I think it's important because sitting on the other side, as you asked the question on replacement, there's the replacement concept, which is really focused on just the lung. That's infusing a protein in the background setting cell of a ZZ patient to try to be there to protect that tissue. The challenge there is these patients, when they have those events, it's a consumptive protein, so that protein goes away. I guess the best way to think about these two, as we do on either end of the pendulum, is one is depleting the protein during the event, the other is producing the protein in the event, which we think is a core advantage of editing in general. It's nice to see other editors also demonstrating those same features and phenomena. I think that's a core component of editing. If we think about DNA editing versus RNA editing, again, I do emphasize that the idea in liver patients to not have to use LNPs that can be pro-inflammatory in liver is an an advantage. We saw that as clinicians were putting patients with more advanced liver disease, F1, F2 on the study as the study progressed, is important. As I said, not being able to off-target edit. That's not about bystander editing. There's a whole concept still around creating the M protein versus bystander M protein, which is kind of thinking about that as an on-target/off-target. There's also the risk of permanent off-target editing that's irreversible, and that's a very real risk. As we think about this balance, having a reversible approach in RNA editing, we think is highly compelling. Great. Over the course of RestorAATion-one and two, what have you learned about PK/PD profile of the molecule and how has it informed kind of go forward plan here? I think as we know and said in the last trial, the 200 biweekly was looking at that dosing versus 400 monthly. It did give us the potential for, as we said, monthly dosing in this. I think what we'll continue to look for is whether or not there are opportunities on that dosing regimen. If you look at the curves at the end of those studies, we do see duration. As it's loaded onto cells and as we're continuing to see that activity, the potential for less frequent administration or other dosing regimens is in the evaluation. I think the key for us right now is staying focused on this potential for monthly dosing and where that sits in, generate those data, and continue to evaluate it. Great. You mentioned OO8 earlier. What initially drew you to PNPLA3 as a target, and why do you think RNA editing is the right approach here? PNPLA3 mutation, as we said, we like targets that have validation, it's got very strong genetics on the mutation of this enzyme drives an increase of disease. There's also very good genetic epidemiology data that shows that if you can correct it back to 50%, you improve the survival of these patients. Their risk of all-cause liver disease goes down. Very strong genetics in shifting these patients from the homozygous state to the heterozygous state. The question is, there's been a number of RNAi approaches, we demonstrated this work, we shared it at an R&D day in the past, that if you take this enzyme away, you can actually increase the risk of disease in these patients, meaning you could see increases in potential for liver fat, you could see increases in the inflammatory response that aren't addressed. That's really the ability of correcting the enzyme so that it can do its function, expel fat, improve the inflammatory response. When we did our own comparisons between these two, I think we're pretty good at making siRNAs given what we do with INHBE, we could really do that cross-comparison of modality to say, "Well, what's the right modality to treat this?" I think recently, coming off of EASL very shortly ago, I think what we're continuing to see is that the siRNAs are doing that. They are actually, as they're dose-dependent, potentially worsening the disease. Really shifting and reaffirming, frankly, from the human clinical data on the RNAi front, that correction is the right way to pursue this. We're excited to bring that data from our pre-clinical data that shows that potential now to the clinic where we can address this. It is a very consequential size. It's all-cause liver disease while we're starting and looking at things like MASH and others are doing that. There's a whole variety of diseases that these patients are exposed to, oftentimes it goes undiagnosed in the context that these patients go on to have liver diseases for other consequences, whether it's alcoholic cirrhosis and hepatitis to other liver diseases from infection, that they just have an exacerbated response. This is an identifiable mutation. It's in 23andMe, this is not an exotic mutation to look for and evaluate. Great. Maybe in our final minute, what do you think is the most underappreciated aspect of Wave Life Sciences today? Yeah. I think when we go back within each of these diseases we're talking about, there's that desire to see the next step. I think what's underappreciated is how important body composition is ultimately to the obesity landscape and how we believe we're best poised to address that with INHBE, both with our existing human data, again, remembering that the underappreciated fact is that was a phase I study and delivered results that very meaningfully should translate into the phase II-A. We're going to do that. We're resourced to deliver that 2A study, and the subsequent combo and maintenance. Additionally, AATD is an asset. We'll deliver those data, and then with the upcoming regulatory discussions, look for that pathway. Continue with PNPLA3 to unlock a very broad indication in the editing space. I think collectively, we're resourced to deliver a portfolio that's translating across platforms, across mechanisms to deliver high impact, high value diseases. Great. Well, that concludes our time today. Thank you, Paul. Thank you very much. for coming. We appreciate it.