Welcome, everyone, to Jefferies Healthcare London Conference 2025. My name is Roger Song, one of the senior analysts covering biotech in the U.S. It is my great pleasure to have the fireside chat with Wave Life Sciences. Good morning, Paul. Good morning, Roger. Thanks for having us. Absolutely. Okay, great. I think we have a lot to cover for Wave. Before we do all the individual program or pipeline, can you give us your state of the union? What Wave is focusing on right now, and then what's underlying technology to support all the development? Yeah, no, and one, thank you again for having us. It's wonderful to kind of come through 2025, where I feel like we're delivering on the expectations we set for ourselves, which was to build a fully integrated RNA medicines company that was truly capable of unlocking the broad potential of genetic medicines. When we say genetic medicines and genetic targets and biology, we really are working across the field. Whether that's with the leading programs in RNA editing, really unlocking the broad potential of where and what one can achieve by correcting and upregulating proteins like we're doing with alpha-1 antitrypsin deficiency with WVE-006, as well as PNPLA3, the new program for WVE-008. The chemistry is giving us that opportunity to demonstrate high potency, high specificity, and high durability. That same chemistry capability and leadership is extending now into siRNA with WVE-007. We're really now able to demonstrate unlocking novel genetic targets, in this case for obesity, with WVE-007 for inhibin E. I'm sure we'll spend more time speaking to that. When we think about the capability to unlock new modalities like editing, extend modalities like siRNA with inhibin E, as well as deliver best-in-class opportunities in splicing with DMD and allele specificity with HD, I think the opportunity we said at the outset was that chemistry matters in designing optimized oligonucleotides. I think as we look forward, and I think that's really been the demonstration in 2025 going into 2026, I think we're going to be resolute in terms of where we focus our attention. I think with the accelerating work that we're doing in obesity with WVE-007, that will definitely be a program that we'll be focusing on the expansion of and delivering across cardiometabolic diseases. With WVE-008, which for PNPLA3, we'll continue to extend that leadership both in silencing and editing. A lot of exciting work today. We're coming into a data-rich period as we think about Q4 and beyond, and particularly in 2026. It's going to be an exciting year ahead. Yeah, absolutely. Given the limited time, we also have to focus our conversation with the near-term priority. Nothing other program we did not spend too much time is less important because we talk about DMD a lot. We talk about Huntington a lot before. Now, absolutely, this year, earlier this year, we see the Alpha-1. You have exciting data, and you will have more data. We are going to talk about that. Before that, even more near-term, it is inhibin E, just like you mentioned, that all seven. Just can you give us a recap of what we have seen pretty recently, so the PD and the PK, and what we expect to see in also very imminently for the first weight loss endpoint? Yeah, for those familiar, and thank you, Roger, for setting it up, because I think it is important as we think about the data to come. When I say to come, there's Q4, but then there's also the extension through next year. Inhibin E is a really unique target. It's unique in the fact that within the field of obesity, it's grounded in human clinical genetics. It addresses probably one of the biggest concerns in the obesity space today, which is ultimately this transition from incretins to ultimately, how do you deliver fat loss that's healthy, right, versus lean mass loss? This is a target out of the UK Biobank. Humans who have this protective loss of function have low lipid levels, low abdominal visceral fat, low hip-to-waist ratio. Actually, the outcome studies have been run. They have improved cardiovascular outcome benefits and type 2 diabetes outcome benefits. What's wonderful about human genetics is it tells you that the human experiment's been run, and you can follow that over population in terms of safety and activity. The question is always, how therapeutically relevant is it? Are you able to actually induce those benefits that you see in the human genetics? It was exciting for the work that the team's done, and this really plays into the data that we had a couple of weeks ago, is the fact that we have shown that using our novel chemistry within siRNA, we're actually able to address this in a way that hasn't been seen before, meaning we showed in DIO mice that we could knock down inhibin E, the transcript. While others have shown that, we have continued to show that that durable knockdown and potent knockdown translates to durable, potent reduction in activin E protein, which is the protein made in the liver that goes to the adipocyte, and show that that reduction in protein translates to a loss of total body weight equivalent to GLP-1s, but all fat, so no impact on lean mass at all. We then showed that there is a threshold effect, meaning to induce this fat loss, you want to see greater than 70% reduction of activin E levels in those preclinical models. When you do that, that translates to that fat loss and fat reduction. In addition, and probably one of the most exciting preclinical experiences to come out of, and this was really evident during obesity week, was the impact not just on single-agent frontline taking down weight, but maintenance. The real opportunity near-term is the ability to show that we could dose a stable DIO mouse on a GLP-1. After dosing, when you either treat with placebo or pre-dosed with inhibin E, both mice groups go back to hedonic eating. You see this caloric intake rise. You see the PBS treated mice behave just like humans. They not only consume, but they go back to their baseline and above their baseline body weight. Those mice that are pretreated stay flat, meaning they're not able to translate that increased consumption of calories back into fat storage, meaning you now have the potential, and we've shown this preclinically, and we'll talk about the clinical data, for a once to twice a year sub-Q siRNA. It is looking more and more like once a year that has the potential for not just frontline weight loss, but ultimately maintenance and the ability to long-term get patients off of GLP-1s and incretins, which I think is an exciting proposition when we think about the long-term detriment of bone loss, muscle loss, hair loss, anhedonia, and a lot of the other features that we are seeing with incretins without losing the benefit of CV outcomes. To Roger's point, most recently, it is great to show activin E reduction in mice. Ultimately, this is a medicine for humans. We did see dose-dependent, statistically significant reductions in activin E levels. The subtherapeutic dose delivered exactly as we modeled from preclinical to clinical data. We saw the 75 mg cohort gave us a 55% reduction of activin E. That was sustained through six months, which was the end of the time point, and still looks like it's suppressed. Again, supporting the notion that it could be much less frequent than even twice a year, we believe once a year. What we did see on the therapeutic side is the 240 mg dose at day 29, which is the cut point for this, gave us a 75% reduction of activin E, and that was still declining. That means it's below the 70% threshold as we modeled for that dose. The 400 mg gave us an 85% reduction of activin E and still going down. Again, as we talked about the company's transition from chemistry delivering from preclinical experience into humans, we delivered again to our model in the human dose. As we look forward to Q4, the goal is now we'll have three-month data on the 240 mg cohort. That'll give us a sense of where that nadir may be on activin E. Again, continuing to look at what the minimum knockdown or the maximum knockdown is in supporting frequency as we think going forward. We'll also have the first opportunity to start looking at things like beyond target engagement and safety tolerability, be able to look at biomarkers of metabolic activity and lipolysis, being able to look at body composition on DEXA. We'll still look at total body weight. Exciting to get the first look at the first therapeutic, lowest therapeutic dose of 240, and then to look forward through 2026 as we have multiple additional time points. Yeah. Thank you, Paul, lay this out. Given this novelty, right, investors are very interested, right? A lot of people, I have a lot of conversation with people, but also we want to set the expertise correct or appropriately, particularly for the early day parts of the readouts. For Q, if we just focus on the weight loss, what you are looking for, and in the coming months, the next couple of readouts, what we focus on. Outside the weight loss, just like you said, the metabolic and the lipids, any other endpoint you want to orient people to also take a close look because that can be additional benefit for all seven. Yeah, and it's interesting because when we say weight loss, we spend a lot of time this year really reframing what do we mean by weight loss. Because I think we've been so preconditioned as a field when we hear weight loss to be thinking of pound-for-pound weight loss, right? I mean, I know everybody here and others are always thinking about, like, get up the Excel spreadsheet and be like, pound-for-pound, what's happening? I think what we really need to do is step back. I think the FDA did an interesting job at the beginning of the year, actually, in really framing what healthy weight loss looks like and really reframing this narrative from a pound-for-pound at any expense, meaning losing probably one of the most metabolically active organs in the body, muscle, which is involved in insulin sensitivity, is not a good thing. When you think about the number of perimenopausal, menopausal women on weight loss medicines who are at risk of osteoporosis and sarcopenia, the ability to actually preserve muscle mass and lean bone mass is critically important. I think we've seen a lot of the benefits of fat loss, but at the detriment of muscle, bone loss, and other complications. With a vast majority of patients not able to stay on drug and the others afraid to get off medicine to regain weight, I think really reframing what's the important piece, which is fat loss. To your point, as we think going forward, we're really benchmarking to the fat loss of GLP-1. How do we benchmark similarity across the fat loss? There, fat loss takes time, at least in the preclinical models. When we look in this question you're asking, Roger, of how do we think about the Q4 update on three-month data versus the Q1 update on six-month data, we're going to learn collectively as a community of what inhibin E kinetics look like in terms of the kinetics of only having fat loss. When we think about the GLP-1 curve, where essentially through starvation, cachexia, you're losing a lot of muscle mass, bone mass, and fat, that accelerates faster. We do think there's a kinetic difference in time between achieving fat loss and equivalency. I think we look at Q3 as the first, sorry, Q4 as the first opportunity with three months to really assess that kinetic curve, be able to look at the biomarkers that are engaging in terms of that metabolic activity, still measuring particularly DEXA and being able to look at body composition where we can look at changes in fat disposition and not miss the opportunity to measure, again, total body weight. As we move into the six-month time point in Q1, we do think that those kinetics, as we look at the preclinical models to clinic, should begin to translate. I think one opportunity that gives us a lot of conviction there is the fact that when we did look at the mouse model, there was equivalency in total body weight. If you think about what equivalency in total body weight means, it means you need to be losing more fat than muscle since it's more dense in order to have that equivalency. High conviction on the target, high conviction on translation. The real question is going to be time. Again, we want to manage the expectations in Q4 that it's really about understanding the mechanism and the pathway. Q1 is obviously an opportunity to look for where we get to imparity. Yeah. By the way, that's also your first therapeutic dose, right? You're also dosing higher and then the 400 mg and the 600 mg. That's also coming. To that point, and we're interested in the 400 mg. Q1 is going to give us the 400-mg, the higher therapeutic dose cohort at a three-month time point. One of the other opportunities we'll have there is to look at the rate of kinetics as an activin E-driven mechanism. It is a great point as we think about 400 mg higher dose as the speed of fat loss occur faster. As you pointed out, and it's great from a safety perspective, we've cleared 600 mg. That's expanding. There are 32 patients on each of the therapeutic cohorts. We're cleared by the DSMB to go higher than 600 mg. By the middle of next year, I mean, we'll have going through the first half, we'll have over 100 patients on therapy. We'll have a real opportunity as well next year to really stratify patients by activin E reduction and get a thorough understanding in humans of the ability to drive fat loss through an inhibin E mechanism. Yeah. Yeah. I think, as you said, we really look to feel is really look forward to these readouts. And we learn collectively how the kinetics works. At least for now, the biology is translating from the preclinical, but how eventually get to the endpoint, that's what we will learn together. Yeah, I think absolutely. A lot of this is driven on what I call the frontline therapy. What is that? If you imagine kind of two slopes in the weight loss spectrum, you have this front curve of what does fat loss look like and how do you drive that. The second is maintenance. When we think about this as a therapy that ultimately patients need to be on potentially for the rest of their lives, how do you do that? Really then the next piece, and we are planning underway, is now for running a phase two maintenance study. This idea of how do we generate the data on this off-ramp to incretins. Being able to generate that gives us a second look at a different set of kinetics, right? The first set is about how do you drive weight loss. The second, which is also tied very much to the mechanism, is how do you prevent the weight from coming back? That opportunity to be able to look at what happens to fat is tied very tightly into the mechanism of action for inhibin E. I mean, we think opens up a substantial market. I mean, when we think about what the GLP-1 and GLP-1 GIP revenues are on a quarterly basis to keep people on those medicines on either a weekly, and as we're learning now, potentially new medicines that are monthly, if we can shift that again to a once a year, twice a year sub-Q low-dose GalNAc- siRNA, the real opportunity, I think, for the global obesity market is how do you get to the billion patients worldwide in a sustainable way to deliver medicine? When we think about global health in the cardiometabolic space, I think this program has a tremendous opportunity really to address the global metabolic needs of the obese community. Excellent. That is a very important point in the dosing regimen and the long-term maintenance. Obviously, right now you are dosing still kind of early, and then you are single dose. How are you going to design the phase two to really capture the maintenance component? You just dose less frequent and then start to measure at kind of later point of the endpoint? Yeah, it's interesting you mentioned single dose. I mean, this was a study at the beginning when we saw mouse data that really the mouse data really suggested this was a potential once a year medicine. The phase one study is really set up as a single dose, but with a one-year follow-up. As we saw, the lowest dose already at 75 subtherapeutic, that's still down at six months. I think we're aligned on how we design the study to continue that follow-up period. We also designed it at very limited multi-dose follow-up, and that was just to generate more data. We can choose up to three cohorts to take into the multi-dose. Because we have the coverage and the time, we don't have to wait for the end of the phase one study to be complete to initiate the phase two studies. That is an important distinction as we think about it. I know a lot of people think, do you have to wait to the end of this and then the multi-dose? We do not. Given what we are seeing on durability and the fact that actually the recovery on cessation of GLP-1s is fairly quick, the ability to build that in on the back end of a study within the single dose range of a once-a-year therapy becomes fairly easy to study. Those studies, again, those designs are in plan. Those really reflect on, do you do it with a GLP-1 GIP? Do you do it with a GLP-1? I mean, there is a variety of ways of thinking about those designs. We have input from a number of folks who want to participate that are both on the clinical trial clinicians who have patients. I found that fascinating at Obesity Week. We were talking to a clinician. She was telling me she has 3,000 patients across her multi-sites that are going to lose coverage next year for their obesity medicines. They are worried. They are worried because they have invested the time on staying on therapy to actually get treatment. Now the real risk and fear is, are they going to go back to gain all the weight that got them there? The ability to start thinking about how we can apply that both in the clinical trial setting or with existing medicines that are in phase three, phase four, where we have been approached about potentially collaborating around those off-ramp studies, those are interesting to us, and those are all informing how we will design that study. Excellent. Okay, great. As expected, we spend most of the time on the inhibin E, but we do have a couple other programs, also very important. You have a data readout in the coming months and then into 2026. Maybe start with the AATD or the RNA editing kind of the angle of the story. What's the next catalyst for the AATD program? You recently nominated the RNA editing, the new candidate. How should we think about that? Maybe start with the AATD. Yeah, we'll start with the AATD. I mean, I think, again, as we said at the beginning, we built our programs off of innovation and chemistry. That's who we are at the heart of Wave. That's what differentiates each one of these programs from our peers. The investment in editing we made was how to design, particularly for liver editing, GalNAc conjugated editing constructs that are stable, durable, potent, and specific. We were excited to deliver data earlier this year that shows that we delivered that. We delivered at the lowest dose, potent editing, durable editing, stable editing, and specific editing. We think about that. There were a lot of questions of, would people need LNPs or other things to achieve superior editing? I think the clinical data has proven that we can deliver stable constructs as a best-in-class editing capability. What's to come? We will talk about what is unique about AATD, particularly the acute phase response and how just it is important. At its lowest single dose, two weeks after, we could show that we could actually fully correct a patient back to the MZ phenotype, meaning they could get over 20 micromolar of protein. That is sufficient back to near normal levels of total protein. Nearly 11 of that was M protein, so massively corrected back to the M protein and stable. They were protected for the month before they came down. Real demonstration that these medicines are active and doing what they need to do in clinical studies at the lowest dose. The data that will be upcoming is the 400 mg of the next dose cohort, which will tell us more about both what we gain in terms of durability. That is in a monthly cohort. Are we monthly or less frequent? What continues to happen on the editing efficiency with M protein? Got it. Are you any, because the last time we see the M protein and the total protein get to the level, is absolutely protective. Do you expect to see a little bit higher or deeper response for the production? Yeah, I think it's really important we say higher, deeper, what do we mean? I think there's a lot of going into data on RNA editing versus total protein replacement where anybody who's been following the space really needs to pay attention to the nuance of those two pieces. IV protein replacement therapy is like pouring water into a bucket with holes in it. You're constantly trying to sustain a level because the patients are inadequately able to produce a level of protein. People talk about, is it 15, is it 11, is it 20? That's all about pouring in exogenous protein to try to create a nadir that very well when a patient has an acute phase response, the bucket gets completely emptied. Nobody really knows how much protein is still actively there to protect patients. RNA editing takes the existing transcripts and converts them from Z to M. I think that was really the elegant data that we shared, that the response rate was every patient had a response between their Z protein to their M protein. I mean, it was beautiful when you graft both the increase in M tied to the decrease in Z. That is what RNA editing does. There is a little bit of confusion. I think sometimes when data comes, people are always like, is there going to be more total protein? You cannot make more total protein unless there is a setting where the patient has an acute phase event where they increase the transcriptional activity. As we saw, we can edit right away. There is a narrative that we keep hearing on the RNA editing space that somehow ADAR is constrained and these enzymes do not work. Anybody who knows a lot of biology knows that that's not true. Actually, the data that we generated actually was the first human data ever that actually proves there's no substrate limitation to the enzyme. You put more transcript in literally two weeks after a patient walked out of injection at the lowest single dose, they could mount a near normal response of total protein. They could go to 20 micromolar. They could generate from zero to, again, nearly 11 micromolar of M protein. That's not an enzyme that's constrained. That's an enzyme that just needs substrate to edit. That happens during that transcriptional upregulation to an acute phase event, which is the biology of AATD. As we look at the data that's upcoming, I always say, and we've said this for now a couple of years, total protein is not the right index for what happens with editing. Following M protein is the right index. Those patients have zero M protein at the outset, right? They're ZZ patients. Purely what these medicines do is take you from Z to M. If you track the M protein, that gives you high insights into the editing efficiency of what's able to be done. That's what we'll be looking for as we think about the 400 mg is what happens to driving the M protein levels. How do we think about the durability and sustainability of the construct? Again, how infrequently do we need to ultimately be giving this potential medicine? Yeah, I think that the benchmark set is really not the only bar for the genetic medicine to produce this physiological response or production of the M protein. Okay, good. We really run out of time, but why don't you do this? You give us your priority in the coming months and into 2026. What are the programs you want to highlight to people to focus on for Wave? Yeah, I mean, I think clearly the focus, and we see this in the time today. We've seen this in the last time in the last several weeks and months is delivering the first human data ever sustainably on inhibin E and really tie that to where do we see the really disruption in translation for patients living with obesity. I think we've got a very compelling path forward to treat patients with that. Q4 update, where are we on that path to fat loss? Q1, obviously, where are we with six months of treatment and continuing to push the dose? We'll continue to see the dose response across that for weight loss. As you pointed out, we'll have the next data set for editing. I think what's really important there is when you have a platform, you're able to rapidly translate a genetic insight into a medicine. I mean, inhibin E was 18 months from mouse study to first human clinical data. We have Alpha-1 antitrypsin data. We delivered PNPLA3. We'll go in the clinic next year. What's exciting there is that's a medicine for potential 9 million patients with homozygous mutations that are at risk of liver disease, MASH and other liver diseases. It's a very specific one. It's one that the siRNAs are not able to treat. If you knock down this mutation, actually you're unable to actually fully repair liver. We're seeing this translate in a number of the siRNA programs that are being stopped. What's unique is if you fix that protein, you're now able to traffic lipids appropriately, and that restores function. Again, being able to take everything we've done with AATD and now apply it to a new enzyme that's on a cell. The PNPLA3 mutation ultimately opens up the possibility for a really large patient population, substantially larger than alpha-1 antitrypsin deficiency. We're excited to bring that to the clinic next year and continue to build on our success across siRNA and editing to open up a broad range of genetic diseases that we have the potential to treat. Awesome. Right on time. Great. Thank you for this morning. I thank everyone. Thank you.