Good afternoon, everyone. Thanks so much for joining. My name is Will Pickering. I cover U.S. biotech at Bernstein. I'm very pleased to be joined today by Dr. Erik Ingelsson from Wave Life Sciences. Erik, thanks so much. Maybe let me hand it over to you for an introduction of the company. Yeah, thanks, Will, and thanks for inviting me. Yeah, Wave Life Sciences, we are an RNA therapeutics company. We're trying to transform the field of oligonucleotides using a combination of genomic medicine and proprietary chemistry. I think in terms of what we're doing, we're using a range of modalities, which I think sets us apart with some of our other oligonucleotide players in the field. We're using for various programs and various diseases. We basically can pick the modality that is the best fit. We use both ASOs, we use mRNAs, we use RNA editing, and also skipping modalities for different diseases. I think another part that sets us apart is a lot of proprietary chemistry with innovations on stereochemistry, on PM chemistry, and enterourea, most recently for RNA editing. That's probably also what kind of brought me to be more interested in Wave. I joined Wave now about one and a half years ago as a CSO. Before that, I had different leadership roles at GSK heading up discovery and genomics there over a period of five, six years. I think what really attracted me to Wave was both this combination of multimodal, a lot of proprietary chemistry platform, and also exciting clinical programs currently for in clinic. I'm sure we'll get to them. Excellent, excellent. One of the ones that I was hoping we could start with was the obesity program, your INHIBIN-E. Maybe could you just give an overview of that before I can ask some follow-up questions? Sure. This is our program on INHIBIN-E. It's an siRNA, GALAX siRNA program. It is founded in human genetics, which I think is one of the pillars that we use when we start programs and pick programs because of the higher probability of success for programs with human genetic evidence. In this case, it's been observed that carriers of a loss of function variants in the UK Biobank and elsewhere have a much healthier cardiometabolic profile. They have lower abdominal obesity, lower visceral fat on MRI, lower triglycerides, HbA1c, lower risk of cardiovascular disease and type 2 diabetes. Generally, a more healthy cardiometabolic profile and less visceral fat. The way it works is that INHIBIN-E is a liver-expressed dimer that homodimerizes into what's called activin-E that gets out into circulation. It's a hepatokine that's a circulating protein called activin-E. It binds to ALK7 on fat cells, which is the receptor, and then it acts as a brake on lipolysis. That's the natural kind of function of this protein. It's been selected for throughout millennia because throughout millennia, humans have gained by storing energy rather than losing energy, which is not the case in the current century, obviously. What we're doing then is we're modeling the human genetics approach, which is a loss of function approach of INHIBIN-E. We're using an siRNA to decrease levels of activin-E, INHIBIN-E, and then activin-E. That means that it releases the brake on lipolysis, or in other words, it increases lipolysis. Lipolysis is the breakdown of triglycerides into free fatty acids and glycerol backbone. It's basically what it does, or in very simplified, it increases fat burning directly on the fat cell. We think this is a very differentiated profile as compared to the current obesity paradigm because, as you know, the GLP-1 agonists and all of the increasing class, they're all going for appetite regulation. They have a lot of GI side effects. They have muscle loss and other tolerability and safety issues. In this case, we're going directly for the fat cell. It's a very differentiated approach. We think based on our preclinical data that we have a once or twice a year dosing approach. Our preclinical data, just if I go into that a little bit, shows us several different potential use cases. We have data for monotherapy where we are on par with semaglutide in terms of total weight loss, but it's all coming off of fat, as would be expected based on the biology, really. It burns fat, mostly visceral fat. We have no effect on skeletal muscle, and we get to the same weight loss in the DIO mouse model. We have an additive effect. If you add it onto semaglutide, we see double the effect from semaglutide alone. The third is a kind of an off-ramp. If you treat these DIO mice, when you stop with the GLP-1, the control group shoots back up with their weights and even overshoot where they started, whereas the ones that are getting the INHIBIN-E siRNA, they stay flat to basically prevent weight regain. That's like the off-ramp approach. We have those three use cases that we're working on, and we're currently now in clinic and focusing on the monotherapy as the first step here. We're phase one, so it's primarily safety, tolerability, and target engagement, but we also have measures of healthy weight loss. Is this your first siRNA in the clinic, is that right? Correct, correct. Wave Life Sciences has been around for, you know, we've been a public company for almost 10 years now. We've had multiple prior clinical trials, but it's been like other modalities. We have an allele-selective ASO for Huntington. We have an exon skip for DMD. Both have been in phase two. We have an RNA editing approach as well, but this is the first siRNA that reaches. Got it, got it. Was it like, oh, this indication or this target was so attractive that it made you want to do siRNA, or it was like Wave had a longstanding desire to get into siRNA, and then this was sort of your entree, so to speak? I think it's a little bit of both. We think it's a very attractive target based on the reasons that I just said. Like it's human genetics, it's fast to translation, it's a huge market, it's a big opportunity in a big unmet need, and we think we can have a unique approach. Also, on the other hand, since we have been working on siRNA, we think this is also a very good opportunity to show that because it's a hard target for the reasons that I mentioned. It's hard to kind of decrease because evolution has kind of tried to, and we see that with some competitors that have a hard time keeping this suppressed as well as we can do. We've shown in a paper in NAR in 2019 that we have a 30-fold higher AGO2 loading, which is the enzyme for siRNA, than what the Alnylam standard approach is. We do think we have a very differentiated chemistry. We've shown that on other targets before, such as CTFR or HSD17B13 and NASH targets. We've shown that, but this was a good opportunity to really show that in practice for the very hard target. You will be planning to present some single-assaying dose data in cohorts one and two in the fourth quarter, is that right? Yeah, that's right. Exactly. We've already, in our last earnings, just not a data release, but just presented a little bit from the 75 mg cohort, which was the first cohort of N of eight only. That's a subtherapeutic dose. We really just reported that we had seen robust target engagement and it's safe and tolerable. That led us into the dose escalation, then also expansion of cohorts. The second cohort is a 240 mg dose, and it's expanded to 32 patients, three to one active placebo randomization. We have the third cohort of 400 mg. What we'll present now in the Q4 catalyst or readout will be cohort one and cohort two, at least three months' worth of data for cohort two. In Q1, we'll get to the 400 mg. Got it, got it. What are you hoping to see in that fourth quarter disclosure? Is that 240 milligram dose high enough that you'll be able to get a read on the potential of this drug? Yeah, so based on what we have seen in the preclinical data, you remember I referred to this like semaglutide equivalent weight loss, but only from fat. Based on that, where we see decreases of activin-E levels to around 80%. What we have seen in the first subtherapeutic 75 mg cohort, based on that and PKB, the modeling, we're predicting that the 240 and the 400 mg dose ranges will be where we will start seeing some therapeutic effects. Yes, although it's a phase one trial, we're primarily focused on safety, tolerability, and target engagement, but we also have measures of healthy weight loss, weight, other composition, and biomarkers affecting cardiometabolic. Over the past few months, we've seen some other companies unfold turnover data in not this target, but in muscle-sparing targets like myostatin. I would say my general impression has been that while the quality of the weight loss has been good, it doesn't seem like they're necessarily getting incremental weight loss versus GLP-1. I guess just kind of your own reflections on what we've seen and the extent to which that has read through or not to Wave. Yeah, no, I think it's been fascinating to see this. I think it's a couple of things. I think it puts an emphasis on the skeletal muscle and the lean mass as being important. I think that's been helpful. FDA came out also with guidance earlier this year for future weight loss trials with a much stronger emphasis on the healthy weight loss and body composition. I think that's important. That kind of helps us as well. These alternative approaches are kind of emphasizing that. We agree with all that. I think where we're a bit different is that the motor mechanism and the way we drive weight loss, it's all through fat. It's all through releasing the break on lipolysis in the fat cells. We don't involve muscle at all. It's a little bit different in that sense. The Myostatin inhibitors, you know, they basically, what they're trying to do is to kind of circumvent the problem that is created by the GLP-1 agonists. GLP-1 agonists will reduce appetite. You lose both fat and muscle. By adding a Myostatin inhibitor, you can basically improve muscle growth or try to circumvent that kind of side effect or what you're not looking for with GLP-1 agonists, at least. Our approach is different in that it's going directly for the fat loss that you want to achieve rather than trying to solve for something that GLP-1 agonists are creating. It's a bit different. Yeah. Yeah. Any plans to test this in combination with GLP-1? Yeah, I mean, again, if you go back to the preclinical data, we have support from that, from the preclinical data that it would be an additive, as I said, with double the effect on SEMA when added to SEMA. Also, the off-ramp. Both of those two use cases will be part of future studies. It's not currently. We started with a monotherapy approach in the phase one just to show that we actually have a single effect from our drug. Down the line, such opportunities will be there. We haven't guided exactly when that will happen, if it's part of a MAD study or phase two. Please remind us of the timeline for the MAD disclosures next year. Right now the current study is basically SADs. It's like cohort one through five, and what we've guided towards so far is the third cohort. Beyond that, we haven't guided yet. Got it. Do you see INHIBIN-E approach as broadly applicable to patients that are obese patients seeking weight loss, or certain subgroups you would highlight as most useful? Yeah, definitely. Thanks for asking that, actually, because that's something just because we found it with human genetics, sometimes people perceive it as it's a kind of a precision medicine, a subgroup, or something like that. That's not how it works. Basically, this would be applicable to any obesity at all. The way the genetics was used was really just to find the target, to find a target, like define this mechanism, and then we're trying to model that with siRNA. You don't have to be a carrier of this loss of function or like any type of genotype. It would work in any genotype in any obese individual. You could envision that there could be scenarios where this would be extra attractive. For example, individuals that are at a higher risk for sarcopenia, if you're an elderly person, for example, where the muscle loss from GLP-1 agonists would be extra bad. If you have bad tolerability issues with GI from GLP-1 agonists, then you could see that as a subset which this medicine could be even more attractive. No, we're positioning it broadly in obesity. There's another company that's working on an siRNA and INHIBIN-E. Would you like to kind of compare and contrast your own drug with it? Yeah, sure. We know actually a couple of competitors that have been trying. I think generally what they've observed is that they have a hard time seeing the weight loss. If you line up our data, our preclinical data from DIO mouse with one of our main competitors, they've also released data. What they see is that they have to dose every week, and then it takes five, six weeks, and then you start seeing a little bit of separation of the two curves of weight gain. They can prevent weight gain, but it takes five, six weeks of weekly injections versus for us, we give just one injection and we see weight loss right away. It's a pretty dramatic difference in terms of potency and durability. I think that's an important raise point. What have I not asked about the obesity program that we should hit? No, I think you hit everything. I'm looking at, okay, yeah. Okay. Maybe we'll move on to alpha-1 antitrypsin. Again, I'll just give you a chance to give an overview of the program and then I can ask questions. Yeah, so alpha-1 antitrypsin deficiency, just as a reminder, this is a rare disease that affects both lung and liver. Current therapies, you know, for lung, there is augmentation therapy, which is basically protein replacement. It's basically just like putting in the protein to protect the lung. That's the goal of that. The liver part of it doesn't really have any treatment except for liver transplantation ultimately in the end of these. What our RNA editing approach is designed to do is to deal with both of those things in one medicine, basically. It converts, it basically corrects the mutation on the RNA level and then basically produces M protein, which is the healthy protein. These individuals that are homozygous for the CC mutation, they don't produce any M at all. They all have C at baseline. What we do with our medicine is that we're, again, converting that base and then creating healthy M protein. That goes out and protects the lung as it's supposed to do, but also decreases C accumulation in the liver over time. That's basically what it's designed to do. We had the first data release or four larger data released earlier this year, just a few weeks ago, where we observed several things and really showing that we are achieving already at this first dose level, 200 mg, what we're set up to do. That is to convert CC patients to MC patients, so heterozygote. Maybe take a step back and just remind why that is important. The CC patients, they have liver and lung disease. The MC patients, there are a slightly increased risk of COPD in older age, but they're pretty much protected. They also have a very small risk of liver, but they're pretty much healthy. That's why the MC kind of phenotype is really what we're trying to achieve with this therapy. The data we shared, we already at this first low dose hit 13 micromolar of total AATD and the kind of bars that have been set for protein replacement therapies are 11. We're hitting that already. We also saw around 65% conversion to M from C, like a dramatic decrease of 60% of C protein and increases of M from zero at baseline up to, depending on the SAD and MAD, but up to 7.2 micromolar in the MAD cohort. We hit that one as well. The third thing that actually has been maybe most exciting to a lot of our kind of, especially KOLs and those that are experts in this field, was that we, I guess we were lucky in a bit because we observed one individual that had a spike of ACD levels. We went back to the data and looked at that person. It turns out that person had a kidney stone. Unrelated to the drug, it's a non-drug related event, but it happened during the observation period. We happened to be able to take both CRP levels and AAT levels. What you saw was a spike of CRP up to around 40, and then exactly at the same time, AAT levels went up to around 20. It's basically showing that, again, this individual has this MC phenotype. It's responding exactly like AAT is supposed to do. We basically recreated the MC phenotype in protecting that individual from that event. I think that was a pretty big deal. Especially the KOLs have been very excited about that finding because it's the first time anyone has ever done that in any AAT medication, and it's something that the protein replacement can't do. What you do, you give protein and then it's consumed. It's basically a suicide protein if you want. It's being consumed, and if you are at your trough level and then you have a big event, you can have a larger event. 40 in CRP is not that high. If you have a 200, 300 CRP level of pneumonia or something, then if you're at 20 in AAT, you can't really respond. Versus if you have this endogenous regulation of the AAT, like the way we created, then you could easily see how you would respond even higher if needed. One of the questions that I got quite a bit after that data was on the dose response. Maybe you could speak to that. Yeah, yeah, exactly. We've seen a little bit of that as well. I think there's a little bit of a misconception on focus on the total versus the M. We think it's much easier to anchor on the M protein because the M protein is really like, that's the functional protein and we know it's zero in these patients. It's easier to make those comparisons. If you look at the M protein, depending on whether you include or not include that individual with that high response, if you don't include it because it's so high, it skews the statistics a bit, then you go from 4 micromolar in the SAD 200 up to 7.2 in the MAD. Multiple doses kind of almost doubles it. That's a pretty substantial dose response, I would say. It goes from around 4 to 5.3 maybe, 5.2 or 5.3 in the 400 to 400. A larger dose response on the MAD, SAD to MAD versus the dose. I think that's probably quite expected and a little bit in line with what we have seen with other modalities that we use with RP in chemistry, that they really kind of accumulate well in the tissue. Once you start giving more than one dose, you really see the dramatic effects on pharmacology. Great, great. The next disclosure will be the 400 MAD. Is that correct? Yeah, exactly. That's coming in Q1. I'm looking at the schematic. It looks like that one is dosed monthly as opposed to the 200 milligram MAD, which was dosed biweekly. How should we think about how those two data sets might look different or similar? Yeah, that's a good question. If you were just naively looking at the total numbers, it might sound like 200 every other week and 400 every month would be the same. Our PKP modeling doesn't really show that because what we saw is that what we expect is a higher, faster rise of AAT levels with the higher dose. Also, generally what we have seen with our medicines is that they accumulate in the tissue. I think stretching out the dosing over a longer period is likely to lead to more of a dose response. At some point, I also want to take a step back and just remind everyone that we're already at the MC phenotype and that really was the goal originally. At some point, it also becomes this trade-off of how high do you want to drive the levels, even if it's not needed by regulatory agencies, versus trying to stretch out the treatment instead. For patients, convenience would be better with a drug that you don't have to give as frequently. We'll learn a lot about that in the next, like now in Q1 for MAD and then in the third cohort. Right. One of the other things that jumped out at me when I was looking at the data was that the levels of Z protein at baseline for some of these patients were higher than I had seen in reference ranges. It seemed like it's around 10 versus 5, 4 to 6 is what I've heard quoted. I guess, any thoughts on why that might be and what are the implications for how we interpret the data in light of that? Yeah, that's a great question. I think the main reason for that is really that the majority of studies have used turbidimetry, which is like the traditional old way of measuring AAT levels. It's a method that was actually developed more than 100 years ago at this point. It's a clinical approach that you use with a very high lower limit of quantification, which makes it hard to really interpret because a lot of individuals will have under the low LLQ at the baseline. That makes it hard. It's not sensitive at all. That's not a way of expressing it. Importantly, it doesn't measure Z very well at all because it's an immune-based approach. The C have different epitopes. It won't really bind to C. It underestimates. There are actually several papers on this. We dove into this, as you can imagine, a lot when we saw that data. There's a lot of data on that and prior publications that have shown that generally there's a belief that the underestimation is two to three fold on C if you use that approach because it doesn't really pick up C that well. Now, if you go to the approaches that have used LCMS, like we did, some aspect-based approaches, then the C levels are more equivalent to what we have seen. We developed a separate assay for M and a separate assay for C with very high specificity and sensitivity. Different companies are using different approaches to report that data. At higher levels of total AAT and with a higher% of M, does the turbidimetry and the LCMS, do those things approach one another, or does there remain this kind of gap that we need to think about? Right. I think it's important to bear that in mind. The easiest comparison is really going to be with M because you know you start with zero and it's like the way you measure G. In that context, I would be remiss not to point out as well that one of our competitors is reporting M, but they are really doing M plus one. This is an approach in DNA editing where they get a lot of bystander edits. I think it's important to kind of just point that out, you know, again, apples for apples. If you take it for M, which is, you know, again, not true, they have themselves shown that more than 50% of their protein is actually bystander edited protein at different isoforms. Even if you do that, I think using M as a starting point is quite useful rather than the total. If you use total, then because it's underestimating C, that will give you a different fraction of M to total. Why does the M? If anything, it would actually be higher. If we were using M and then turbinometry AAT levels, it would be a higher fraction. Great. Got it, got it. You mentioned this competitor. Maybe let me give you a chance to compare and contrast RNA editing versus base editing. Yeah, yeah. I think both approaches have advantages as compared to protein replacement for the reasons that I already mentioned. I think getting at the center of the disease and treating both lung and liver in one go is a very attractive approach. I think there are a couple of things, both on the levels per se and M, I mentioned one already. It's the bystander edits. It's also the indels that you create. Those are some important things to bear in mind. Also, this particular competitor has really just released three individuals' worth of data on their highest dose, and it's a little bit hard to take versus for us. We see a very high consistency. We've released 16 individuals now and all have editing very consistently. I think it's a little bit hard for that reason to compare at this point exactly what the levels are. Stepping away from that, more generally on DNA versus RNA editing, I think there are some pretty substantial differences where we hear a lot from patients and providers as well that there's a lot of preferences for RNA editing and infrequent RNA editing approach rather than doing a permanent DNA edited. Because again, the indel risk, you have the delivery risk with LNP or AAVs depending on your approach, which comes with liver enzyme increases, et cetera, which is not ideal in a disease where liver disease is part of the disease. This is not even discussing the payer perspective, like who's going to pay for a one-shot very expensive DNA editing approach. That's even another separate story. Maybe a bit of a premature question, but thoughts on what the regulatory path could look like for this? Yeah, yeah. Obviously now with this new data coming, we kind of have a stronger incentive to engage now with regulators and starting to have that discussion. I think we, as I've said already, we think we're already there in terms of what we need to get to. We're recreating the MC phenotype already. Based on this data, we're strongly in to have discussions with regulators, but to do that together with our partner GSK. This is a partner program. They have a license on this. We're going to do that together with GSK. Yeah. Could you remind me of upcoming milestones related to that partnership? Yeah, we haven't broken out exactly which milestones, but the total milestones for this program is $525 million over the course of the whole program and has high teen royalties. That's what we've shared. Obviously, we also have, this is a part of a larger collaboration where there is up to $3.3 billion in total. Great, great. Maybe let me, I know you have a couple other clinical programs, but I thought maybe we could interrupt the flow and give you a chance to talk about some of your emerging pipeline. I know you have an R&D day coming up in about a month or so. Yeah, no, I'd love that. I think we already last year in the R&D day last fall started to talk about a couple of potential future clinical programs. One of them, which I kind of, we're doubling down a little bit more now and we're guiding towards filing CTAs in 2026, like in the upcoming year, is a program on PLMP3. This is also a genetic target. It's for liver disease and particularly MASH. These individuals that have this specific mutation, they're actually frequent. There are about 9 million liver patients who are homozygous with this specific mutation across Europe. A very large population. They're at a very high risk of liver diseases. For example, for liver-related deaths, they're nine times more likely to die from liver disease than the wild types. Those are the homozygotes. The heterozygotes are like maybe 1.5% higher. Here is a very good opportunity and very following the same blueprint as the AATD approach. It's a GALAX RNA editing approach. It's a much larger population. We need to try to recreate the heterozygote again that leads 50% editing. We have circulating biomarkers measurable. We can do the imaging in terms of early proof of concept studies as well. Yeah, very attractive program that we're now guiding towards starting clinically next year. How do you think about the broader range of diseases that are potentially addressable with RNA editing, or if you want to comment on any other technology? Yeah, no, yeah. In addition to that specific program, we have a whole preclinical portfolio. One of the focus areas right now for us is to kind of go beyond liver as well. That's a big one. We're working a lot on extrahepatic programs and approaches. We shared some of that already last research day and last year, but we're going to share more of that data this year. We have already been public about that we can, without specific conjugates, get into a lot of tissues that are hard to get into with oligo. We have really good uptake for siRNA and RNA editing into fat, muscle, heart, pancreas, lung, kidney, in addition to liver, obviously. We're doing that without any conjugates or delivery vehicles, which is a big advantage in terms of safety. Great. I won't ask you to front run your own R&D day anymore, but looking forward to hearing from that. Maybe we could go on to DMD, and if you want to talk about the construct, how it differs from the approved agents, then we can talk about the data as well. Yeah, yeah, yeah. Yeah, so this is an exon skipper for exon 53 amenable void. Just taking a step back, that's about 10% of the population in DMD. We have finished that. We reported out data in March on that one from the 48th week time point. Just like in summary on the data, we show very high and consistent levels of dystrophin. Just a step back in the DMD space, dystrophin is an approvable endpoint, accelerated approval. We observed both consistent across time because we had two time points in most of these voids, in addition also across patients. We saw around 8% or 7.8% dystrophin level, which is higher than any competitors. We also saw that eight out of nine of these voids had over five at their level, which is an important threshold because that is where you get into the Becker dystrophy phenotype, which is basically, again, what we're trying to achieve with this medicine. High and consistent dystrophin levels, and I think that's really important when we position ourselves against competitors. A second thing that we observed was, which was to me very exciting, and that was like we observed really a trajectory of muscle pathology. What we did with this was that we had six week biopsies in a few voids, and then we had six months and 12 months or 24 weeks and 48 weeks in the majority of voids. What we observed, and I think this is exciting and no one else has shown this for any DMD therapies, we saw that at the six week time point, we had a lot of uptake of our drug into the nuclei and in particular into stem cells. We get the drug where it's supposed to be. We saw high degrees of exon skipping, which we're trying to do, which is the target engagement. When we fast forward to week 24, we see an increase of stem cells, so more of a regenerative state of this muscle. A lot of stem cells, a lot of activity, and then dystrophin has started to come up already there, high already after 24 weeks. After 48 weeks, which was the last and third time point, we saw a maturation of the muscle. What we now see is that there are stem cells that are starting to decrease. All of the muscle looks much healthier generally. You see less fat. You see a statistical decrease of fibrosis in the muscle. You see less necrosis. Much healthier muscle. Also, this was kind of parallel with CK decreases, which is a muscle marker. The final piece of the data that was also very exciting to us was that we saw a statistically significant improvement of time to rise, one of the clinical measures. Overall, a very attractive package. This all together was safe and tolerable at the same level as the current existing exon 53 and 30. How did you do it? What's different about your drug versus the approved agents? I think it comes back to a lot of the chemistry actually. We haven't talked so much about that, but we have some quite unique parts of our platform. One is the stereochemistry, which is we can control all of the linkages in 3D space. This is different from what other oligotherapies or platforms are doing. If you think about a 20-mer, you can have two to the power of 20 different versions. It's more than half a million molecules really. It's a mix of that. That's what other oligotherapy companies are doing. We are controlling that already from the screening and the synthesis all the way through manufacturing. We know we have just one drug there, one molecule. I think that's one piece. Another piece is the PN chemistry. It was an innovation in terms of the backbone chemistry. I think those two things together mean that we can kind of get very, if you go and look at our PK data, we have very high levels of the drug there in the muscle that are much higher than anyone else does. I think that it gets to the right point, the right place. It starts exon skipping and it gets, importantly, gets into the stem cells. I think that's very important. What's your level of interest in other exons? We've seen some other companies turn over some fairly encouraging data outside of 44 and 51 as well. Yeah, we've been public about having early preclinical, like candidate stage programs for 44, 45, 51, 52. I think I would say 44 is a little bit of a separate beast for various reasons. I think that's also important to bear in mind when looking at other companies that are working in 44 specifically, because those individuals, those boats are fortunately a little bit more like Becker-like. They have much higher dystrophin levels at baseline, and they respond much more to exon skipping. For that reason, both important to remember when comparing, but also for us, it's a little bit different. It becomes harder for us to do a platform trial there versus 45, 51, 52. They have a very similar clinical trajectory, so again, much easier to see that as a kind of combined big platform umbrella trial with common control. Great, great. Maybe with the last few minutes, we could hit Huntington's. Oh yeah. You have a really unique program here that focuses on sparing the wild-type protein. Maybe just, yeah, I don't want to get too into the weeds too quickly, but you know, a quick overview of the program and why that wild-type sparing is important. Yeah, this is, again, I think it's nice that we're talking about all the programs because this is a fourth modality. This is an allele-selective ASO. It means a single strand approach. Allele-selective, the way we reach that is we basically leverage that there are genetic variants that are in phase on the same allele as the disease-causing KAG repeat in Huntington. That's what we're doing. We're basically designing an oligo that just binds one of the two alleles, the one that is causing disease. That's how we can be allele-selective and no one else has done that yet. We think that's very important because the wild-type protein, Huntington protein, has important neurological functions. For example, it's involved with celiac health. It's involved with regeneration of neurons. We think that's an important reason for why others have had problems in the past with Huntington development, that they're basically not, so while they're basically dealing with the gain of function part of Huntington by knocking it down, they're taking down also the healthy protein and therefore they create a loss of function situation. In terms of that, just to dig in on that a little bit more, if you look at the mice models, you know, if you knock out Huntington, the mice doesn't live, right? Which certainly is supportive. On the other hand, we've seen some competitor programs, including the one today, which don't seem to have any apparent safety effects from sort of this broad-based knockdown. Do you see some of those data points that we've seen in the clinic as challenging that hypothesis? Or how do you think about that? I think one important study in this space is the Tommy Nursten trial, which was the big Roche trial that ran for a much longer time. It might be something that takes longer really to observe, and also you need larger study samples to see that. I think it's a little bit hard to comment on a shorter time period where you would start seeing those negative effects of having a wild-type sparing. Could you comment on your plans to use the caudate atrophy as the potential endpoint? Yeah, yeah. In our data that we reported out last year from our MAD cohort where we saw a decrease of 46% of mutant Huntington, which is, by the way, still the highest Huntington decrease regardless of whether you're pan-silencing or allele-selective. You know, 46% knockdown of the mutant Huntington with no effect at all on wild-type, so like fully wild-type sparing. In that study, we also observed a statistically significant correlation of mutant Huntington decreases and slowing of caudate atrophy basically. This makes a lot of sense because it's known that the caudate is at the center of the pathogenesis in HD and it's also one of the first MRI measures that you can assess to look at progression of Huntington. We're excited about that and we've had discussions with regulatory agencies about that being an endpoint that we can use for accelerated approval. Great, great. Tremendous amount of progress at Wave Life Sciences over the past few years. I don't cover you guys, but I've enjoyed watching you from afar. As you look ahead into 2026, what are some of the developments that you're most excited about? Yeah, I think we've covered several of them, but thinking about the next catalyst. We just had the AATD readout, which was very exciting to us. We're now having a Q4 catalyst being the INHIBIN-E siRNA readout for cohort one and two. Following that in Q1, we have the next INHIBIN-E readout, with those with longer follow-up times and also with the higher dose, the 400 milligrams, plus the MAD cohort from AATD as well. Those are just near-term catalysts coming up in the next six months. As we go into the next year, we have a lot of exciting things coming on as well, including the PLMP3 story. Great. Thank you so much, Erik. Thank you.