Okay, great. Good afternoon, everybody. I'm Kristen Kluska, one of the biotech analysts at Cantor. Really excited to be hosting Wave Life Sciences today. Joining me from the company is Dr. Paul Bolno, the President and CEO. Thanks so much for joining us, Paul. Really appreciate it. Thank you, Kristen. Excited to be here. Awesome. So maybe, you know, to start, we'd love to just see if you want to have any opening comments. I know Wave Life Sciences is much more than just a DMD-focused company, but for the purpose of our talk today, I thought it'd be great to really just dive into that program in particular. Yeah, no, look, we appreciate your time and actually the recognition that we're doing more than DMD. DMD is obviously an important therapeutic to develop, and we've got a lot to talk about today. But, you know, as we think about this year in general, we're coming up on our Q2 data for Huntington's disease. It'll be the first allele-specific silencing data, multidose data for the treatment of Huntington's disease. We'll have our alpha-1 antitrypsin data, which is actually, if we think about the growth of the company in RNA editing, over the year we'll be delivering on our alpha-1 antitrypsin patient data, which will really be the first demonstration of, you know, RNA correction of the alpha-1 antitrypsin protein. And then INHBE for obesity, which is a really novel target of a protective loss of function siRNA, with a potential CTA filing as early as the end of this year and going into the clinic beginning of next. So as you said, a lot on our plate, but our Q3 dystrophin data readout in DMD is going to, I think, be important in the exon skipping field. So we're excited to invest the time with you today in DMD. Okay, great. So as part of this symposium, we've asked the corporates to stick to a key theme, and the one we chose for you was, "With an arsenal of new approaches for DMD, why should patients still consider next-generation exon skipping therapies?" So let's jump right in. So we know that dystrophin is a large, complex gene that encodes the largest protein in the human body. So what is it about the way the gene is structured into repeating elements and the location of DMD mutations that really makes these exon skipping therapies possible? Thank you for this thematic topic because I do think, you know, as you said, why should patients consider, you know, exon skipping and the next generation of exon skipping? I almost substitute that with are. Why are patients and clinicians so focused on exon skipping? And I think it really thematically gets back to your initial question, which is the dystrophin protein and really understanding that. So as you pointed out, dystrophin is the second largest protein in the body, the largest gene. So a really critical protein. And when you have it, a protein that large, I think a lot of times people simplify dystrophin and just call it a mechanical shock absorber because I think it's the easiest way to think about a protein that protects skeletal muscle and cardiac muscle fibers. What's really important and critical is dystrophin is more than just a mechanical shock absorber. It's a lattice framework that's actually involved in a whole host of things beyond just providing protection from contraction and relaxation of the muscle fibers. But it communicates. It does things like, you know, traffic some of the ion channel receptors that are involved. It works on nitric oxide synthase. And so there is a complexity of that protein that was really designed to do a very large function in that in the absence of dystrophin, we see the repopulation of muscle cells with fat and ultimately the degradation of muscle, both in skeletal muscle and then ultimately cardiac muscle. So as we think about the disease progress, it gets back to this fundamental concept of, well, how do we restore functional dystrophin protein? And I think the benefit of really thinking about this space and, you know, to your initial theme of, well, why exon skipping, is this notion of, well, how did we get here as a field in terms of moving therapeutics forward? And when we come back to what originally brought us all into this field, starting with the original exon skippers and Exondys being the first, was really this notion that if you could fix the frame shift deletion, if you could restore the reading frame, and you could actually then build a fully functional dystrophin protein that only has a small truncation on the internal aspects. And what's important about that is if you look at the Becker patients that have the disease, you actually find they too have this small truncation in the internal complex. So this notion that we could go to the human clinical phenotype of a Becker patient and say, actually, this protein is found there, it demonstrates an improvement in clinical outcomes, that served as the basis for a lot of the initial accelerated approval discussions and where you had a clinically relevant protein with which you can measure. I think that's important, both in how we think about the evolution of the space, meaning Becker patients have typically lower limit levels of protein than where they have mild phenotypes of 5%-10%, so actually far greater a percentage of dystrophin than the current approved products. If you think about even NS Pharma, you're still upwards around 5%, but really moving exon skipping towards what the Becker phenotype is supposed to be, which is 5%-10% of this functional protein. What's been challenging in the field in trying to solve for this is there's been evolutions in micro and mini proteins and kind of redesigning, you know, can we build components of that protein that actually only have about 30% of that protein because that's what you could fit inside of the payload. And the challenge there is there's no human alternative. There's no human correlation with that protein. You don't find that protein in humans. So people go look back at Becker and say, well, can we design this? So again, to the thematic piece, what's exciting about exon skipping as a field, forget next generation, just why exon skipping is an important place to start, is that exon skipping by its nature restores and produces endogenously that functional protein both in size and in location to do what it's supposed to do physiologically. So I think that underlies our approach of saying, you know, what? That's exon skipping. What makes next-gen exon skipping is we say, well, how can we as a field continue to do better in terms of increasing that amount of protein to actually see better correlation and clinical outcomes with those, with that direction? Okay, thanks. And just on that note, thinking about other ways the field has improved since the first one throughout and things that Wave is considering, you know, what specific chemistry allows for the specificity, the durability, and then the delivery of these? Yeah, I mean, when we say, well, how do you build an exon skipping therapy? And again, if we go back to the beginning, there's a general chemistry that's been utilized in all of what we would call the first-generation exon skippers. Even among some of the new conjugate programs, they're still using the same underlying chemistry with just now a conjugate added to that. And I think the challenge with the Morpholino, the PMO backbone, has been, you know, very, very short half-lives. If you think about, I think NS Pharma's public half-life is somewhere around 1.5 to 3 hours after 24 weeks of dosing. So, you know, relatively short half-life. And that's due to the fact that the Morpholinos are a neutral molecule. So if you have something that's an entirely neutral drug, its excretion rate is extraordinarily high. So people decided that, you know, well, how do you solve for that? Well, you need to force it into the cell and hence, I think, a move to using conjugates to try to push whether it's cell-penetrating peptides, whether it's transfer. And we step back and really ask the question, underlying oligonucleotide backbone chemistry of, are there things we could do to improve protein stability, meaning is it around for a really long time? Increase uptake and intracellular uptake and trafficking, meaning not just is it getting into the cell, but is it able to get into the cell and into the right compartment of the cell, meaning the nucleus, and actually have high nuclear retention over time so that you could build copy numbers of transcript to build more protein. And so if we kind of think about kind of the various pieces of pharmacology, as we built this backbone, so mixed backbone that includes our PN chemistry, as we've shared around a number of our different programs, the phosphoryl guanidine, that gives us high intrinsic, not just stability, but also gives us a really strong retention and resistance to endo- and exonuclease degradation. So, meaning the drug is not only around for a while in the cell, but is able to do its work there repeatedly. And so we think about this translation. We took a very rational designed approach to, okay, here's what we want to do in design on the backbone. We want to improve its pharmacology, its retention, its half-life. And let's make sure we have ways. You know, at some point, I'm sure we'll talk about our prior experiences in DMD, and I think we've learned a lot from that. I mean, if we kind of step back to suvodirsen, which did not use the PN chemistry, our first generation had a very short half-life, very low muscle exposure, and negligible skipping, and protein. I think what was the advantage of the platform capability we built is the ability to say, well, what's the contribution of these new chemistries, these new additions on the backbone as it relates to what we can compare at the first? I think one of the other big decisions we made early on in the DMD space to make clinical decision-making was getting beyond the mdx mouse model. A lot of work in the field has been done off of an mdx model. This model has utrophin knocked in, so it has basically a corresponding protein that offsets the removal of dystrophin. So we've learned it's an interesting model for screens, but doesn't have a phenotype. So all of our work that drove towards the clinic was really predicated on the double knockout mouse. So here's a mouse that has no dystrophin and therefore is an accelerated phenotype of Duchenne muscular dystrophy in that they die very rapidly. They have cardiac, you could see, die of cardiopulmonary arrest. So what we're able to do is see the impact of a lot of these new chemical modifications in that double knockout mouse to see, you know, is it getting to the right compartment? Is it generating functional dystrophin protein? And the beauty of a phenotypic model means you don't have to try to extrapolate. So the fact that when we ran this early on, that we could see at the end of the study at 40 weeks an unprecedented 100% survival, not just at our therapeutic dose, that we, but at half of that, we were still at 100% survival. It gave us a really good insight that we were having a meaningful impact on this chemistry of getting to where it needed to be. What we could also then do is do additional work to see, well, is it functionally changing outcomes? And in this case being, okay, you have survival, but we saw that that was coming at a step restoration of tidal volume back to wild-type levels, meaning respiratory function was there. When we looked at the model afterwards and we looked at our clinical program in the NHPs, what we saw, which was pretty astounding, is our level of exposure and of skipping was folds higher in heart and diaphragm over skeletal muscle. Meaning we were extending that distribution. If you think about DMD, the ability to get beyond skeletal muscle to go to other tissues. And so if we think about the building blocks of chemistry, but how does that translate? And And ultimately in the initial clinical trial where we could look at, did we solve for the differences between suvodirsen and N531 in the clinic? What we saw really mirrored what we wanted to see in an improvement in pharmacology, which means we saw a half-life of 25 days instead of 18 hours, meaning, okay, the drug is available for a very long time, which could enable monthly dosing. We saw that it was getting high tissue concentrations, 42,000 nanograms. So if we think about the exposures that we're seeing with some of the conjugate programs at 650, we're at 42,000. So substantially more drug getting into the muscle than we saw even with suvodirsen. But then importantly, and this is really where the exon skipping is the parameter, is we saw 0% skipped transcript with suvodirsen. And that was really our barometer of continuing into the subsequent trial, which is we're getting a lot of drug into the muscle. It's there for a very long time. But is it generating functional, skipped transcript? And we saw there a 53% skipped transcript, which is the highest level of exon skipping seen to date. So when we put that together, I think what we've seen is that chemistry changes the ultimate pharmacology. I think really puts us in a really great position to leverage, as you said, next-generation exon skipping, which is how do we build on exon skipping with an improvement in pharmacology? Okay, thanks. So some might point out that the potential for exon skipping therapies only addresses a subset of the DMD population as a disadvantage relative to things like gene therapy, for example. So do you think that this is a misunderstanding of the market opportunity? And if so, why? And regardless, even if gene therapies do emerge, do you still see the potential for combination therapies and why? Yeah, I step back and think about precision medicine and what is the goal of precision medicine? And I think the goal of precision medicine, and I think exon skipping is kind of one of the ultimate examples of precision medicine, is if the goal is really to restore functional full-length dystrophin protein in the requisite tissues, then having a selective approach with individualized exon skipping formats that, albeit, and I think that's the drawback currently for patients who don't have exons that are amenable to exon skipping, is provide those patients that do the best opportunity to generate full functional protein and ultimately see that hopefully translate to a substantial clinical benefit. I think the goal of automatically racing to say, well, how do you get to more patients? In that case, sacrifice functional protein and functional dystrophin for mini or microdystrophin, which, you know, based on clinical outcomes, failed to meet its primary endpoint on that clinical translation of being a functional mini protein. I think that's short serving the patients who would be amenable to exon skipped transcript. And I think we see that as we talk to families that say, if there is exon skipping that's generating high levels of functional protein, we would want to be on that. I think the world is already, you know, living with combinations. We know, and I think it's just an interesting comparison. If you look at the field of SMA, the utilization of both gene therapy and splice correction is utilized in both of those. I think what's interesting there is that's in an area where there were no sacrifices that had to be made on the protein. So it's a very different environment. And so I think even now we're anecdotally hearing patients who are part of the original four gene therapy patients are actually on X, you know, some of them are already on exon skipping therapies. So I do think the world of combination or moving on, I think the more realistic opportunity is that with muscle turnover, actually the longevity of gene therapy for fixing protein correction is going to wane. And therefore these patients will need exon skipping. And so I don't think it's necessarily a misconception from the investors in the market as much as I think where patients have exons that are amenable to skipping, I think we will find this. Now, I think what becomes interesting is once you get past four or five of the exon skipped transcripts, now you get to much, much smaller numbers. I think there's the opportunity in front of us is to think creatively about how can you accelerate platform learnings. So, you know, what we were thinking about after this study on positive data, we would anticipate not just filing for potential accelerated approval, but as part of that confirmatory study, we had with suvodirsen alignment with regulators on running an umbrella study, utilizing a shared augmented placebo arm, which minimized the use of placebo patients that let us actually run a multiple exon study. I think that opportunity both for approval of other exons and then using kind of platform capability with regulators to say, beyond that, how can we get to the smaller exon populations to skip? I think that becomes in play as well. Yeah, I mean, look, the exon skippers collectively have led to over $1 billion in sales. So collectively they are, you know, very important. And by the way, our KOL feedback during this symposium has been very similar about, you know, keeping the need for these therapies. And a lot of physicians also anticipate, you know, potentially using both or combinations or different therapies depending on the age and other factors of the patient. So everything you said is essentially in line with what we heard. So you talked about. I'll jump in. No, no, it is interesting because I do think as you talk to KOLs, I mean, I think there's a real desire and thought process of, you know, how do we think about accelerating this? How do we think about moving more of these forward faster? So sorry. Yeah. Yeah, no problem. So you talked about, you know, what you learned from your first generation approaches. So let's talk more about WVE-N531. So your non-human primate data showed high uptake in skeletal, non-skeletal muscle, including the cardiac and diaphragm. So can we talk about like the disease course in humans typically looking as these muscles are all progressively affected? And And how does broad targeting really compare to, you know, what we see on the market now for exon skipping therapies? Yeah, no, and I think, you know, that that's important as we think about next gen, you know, I think there's two approaches. And what I think I was going to say about, you know, some of the KOLs is it's still about how do we get better exon skipping? And when I say better, I mean above 5% in that, you know, the goal was 5%-10%, which was really gets you into that Becker phenotype. So to your point, we want to restore that not just in skeletal muscle, but the observation that our skipping levels are higher in heart and diaphragm leads us exactly, as you point out, to that disease progression path, which is, you know, initially you see loss of ambulation. But what eventually starts to happen at about the same time as loss of ambulation is boys go on CPAP because of lack of respiratory volume and assistance with respirations. And over time you see, cardiac muscle decline and ultimately cardiomyopathies. And so as we think about kind of that continued downstream progression, there's a really important phrase that I think the community uses, the physicians, both physicians and patients, which is time is muscle. And that erodes over time. And that begins very, very early on. And so right now we're talking about some of the later stage aspects, which is heart and loss of heart and diaphragm muscle. So our view as we think about this continuum is how do we restore that, not just to skeletal muscle? So obviously this study will give us access to skeletal muscle. We'll continue to take measurements where we can look at forced vital capacity and ways of measuring lung volume. We'll look at ways of doing cardiac assessments. At this early time point, for this study, it's still very much skeletal muscle focus, but we'll be able to continue to look at that later. I think an additional observation we had from our clinical trial was accessing the satellite cells within muscle. And so these are the regenerative cells in muscle. It's the first example ever in DMD of a drug actually restoring dystrophin protein, or dystrophin potential in those compartments. And so if we think about that potential, and I think about shifting to the earlier side of the equation, which is not as we lose function, right? It's how do you actually build muscle over time? I think the really unique opportunity we have is the potential early diagnosis of DMD. I know the community has gone through great efforts to bring on newborn screening for DMD. I think if we have the ability to really identify patients much, much earlier in the trajectory, the ability to not just restore and fix skeletal muscle through exon skipping, but actually hit the regenerative cells and muscle over time could really change the dynamic in the course of the disease. I think the ability to hopefully, and you know, again, we'll be able to have the dystrophin protein assessment that's going to be highly informative in Q3. I think that serving as an entry point to really thinking about, you know, what does the next generation of exon skipping look like? Where we could hopefully be looking at much higher levels of exon skipping, but also where that exon skipping is occurring, satellite cells, heart, diaphragm, in addition to the skeletal muscle, I think could really take us in a different trajectory in the disease treatment course. Okay, thanks. Something that I think is very interesting, but perhaps underappreciated, is thinking about muscle stem cells in these patients. Your initial clinical data looked at the uptake in three patients. Maybe can you talk about the importance of understanding this and what it specifically means to increase dystrophin levels in these cells in particular? Yeah, I mean, one, as I said, you know, it wasn't a unique feature where we saw it in one patient. So it was. We've seen it in all the patients in that initial clinical study. So I think that to the point I was making earlier, I think what's exciting about the field is really thinking about, and as we've talked to some of the KOLs, I think there's a real interest in what does that mean? Because if you think about satellite cells early on, being able to restore and they become the repopulating cells within muscle fibers, you're now restoring within those cells the protein level that now goes on to repopulate these muscle fibers. There is interesting work happening on the basic science teams of people who really study this protein, dystrophin, of looking at how dystrophin is distributed along myofibers and how you can enhance that. And so by not just getting into the myofiber itself and producing dystrophin into the myocyte, but actually getting into the regenerative cells, it starts opening up the possibility for a much broader distribution of dystrophin within these muscle fibers. Okay, thanks. And then on the dosing regimen, do you see this as a potential advantage in terms of your regimen relative to standard of care? Absolutely. Actually, when we had our last discussion with a number of patients, really just understanding, you know, what the, where the burden of disease is. And one of the conversations we were having with folks were this idea of weekly IV infusions. And you don't really understand the burden of it until I realized that depending on who your insurer is, sometimes they will be shipped a month's worth of medicine. And sometimes even more with all the tubes, all the volumes of bags. And actually some got it even more frequently to the point where they had another refrigerator and had to balance that in addition to just the trips for IV infusion. And so we stepped back and said, at this point, this study is being run biweekly. And people are like, well, that's different. That's half the amount of time, effort, resources that we need. I think our half life of 25 days really has us now thinking that this is most likely a monthly IV infusion. And so I think the burden of that, that we could take off patients that have other things to focus on, I think is really important. And I think being able to do that without sacrificing dystrophin protein, because I think that is critical, is going to be highly important. Okay, thanks. And when you think about all these advantages combined, you know, a big focus about DMD has been on time of intervention. And, you know, agree with all of your efforts that if we can find patients earlier, I think no matter what therapy they're on, they're more likely to benefit. But in light of all of the advantages your program could potentially bring, do you think that there is an optimal time for intervention? And do you also think it has the potential to expand beyond what we're used to seeing with current exon skipping therapies? Yeah, I think there's different, what the benefit of intervention is at various time points. So I think, you know, there's an opportunity if we think about one extreme and then let's call it the non-ambulatory setting, where even being able to intervene with high levels of dystrophin protein and distribution to tissues like heart and diaphragm become life extending and quality of life extending if we think about improvement in respiratory function and cardiac function. So if we think about kind of the one extreme, I think there's advantages there. I think on the other extreme, if we think about being able to intervene very early and being able to intervene very early again with high levels of protein into the requisite compartments, so not just skeletal muscle, heart, diaphragm, but into those regenerative cells, I think now we could be looking at a treatment paradigm that looks very, very different than it is today in terms of preserving and letting muscle function grow, where potentially you can envision taking these children off the curve altogether, where they have a normal developmental life cycle simply because Dystrophin protein was never missed. And so I think about those two extremes a lot as we think about therapy. Obviously, most interventions right now occur at a stage where we're rescuing. We're coming in a little bit later than, you know, at the very beginning. I think with newborn screening, that potential really changes to think about what does intervention look like early. Yeah, and by the way, we spoke to both PPMD and MDA yesterday, and they listed that as one of the highest priorities for their organization. So I mean, you're right. It's just, it can make such a difference for these patients, and we've seen it firsthand amongst other neuromuscular conditions. So we're rooting for that too. So let's talk about the ongoing FORWARD-53 study. You've noted that it could culminate in potentially registrational 24-week dystrophin data. Again, the big catalyst is in the third quarter. So maybe can you help us understand the regulatory precedent? What assumptions you've built into this study around powering, sample size that could potentially lead to this? Yeah, I think we have powered this. If you think about the study design of both being a 24, having a 24-week time point and a 48-week time point, that mirrors the two data sets for the two existing commercial programs within the exon 53 space. So that's the VILTEPSO and NS Pharma, that's at the 24 weeks. That's where they saw about 5% dystrophin protein. And then you have Vyondys 53, so you have the 53, 48-week data set that was around a little over 1%. So those are the registration endpoints that were there. I think we focus very much on, for us, that we designed this study to see over 5% skipping. We think that that's really the requirement. That was the goal to drive the Becker phenotype. I call it both, while the regulatory thresholds we know in exon skipping have been remarkably low. I think we're still focused on, you know, what do we believe is the requirement and, you know, what does that commercial landscape look like to be competitive? This study is powered for greater than 5% dystrophin, so puts us within the range at both time points. We'll be able to see at this 24-week time point superiority. That would, you know, enable us if we come out of that successfully on the protein side, we'd have, you know, hopefully not just high levels of exon skipping, but now high levels of protein that are greater than the standard of care. We'd be able to continue that study on to the 48-week time point. That would give us another ability to look at both the accumulation of dystrophin over time, but also relative to existing programs. So that would be the plan, would be to submit off of this dystrophin data. Okay. And are there any other expectations you want to frame for investors around this readout, or that's really the main thing to focus on? I mean, I think for us, that's the main thing to focus on. We've already seen high levels of muscle concentration as early as six weeks after three doses. So, you know, if we think about the level of concentration we have in the muscle after just three doses of the drug, it's pretty consequential for us in terms of what we've already seen to date in the early studies. But I think the ultimate question that we know is still out there is the question of translation of skipped transcript of protein. And this study is really designed to answer that fundamental question of can we get to those protein thresholds that we think are going to be important? Okay. Obviously it's a very important readout for the sake of that program, but to your point, it's going to be critical to validate the platform, which you've noted you could potentially look at other exons to address up to 40% of patients. Let's assume that you have really good data and really good news. What are the next steps for Wave as it relates to both moving that program forward commercially, but then also looking at which opportunities make the most sense based on the amenability to the PN-containing oligo platform? Yeah. So as we think about the other exons, so 51, 45, 44, 52, I mean, we have said publicly that we've already generated constructs that have equivalent, if not higher levels of skipping and protein because there we can assess protein in vitro and myoblast, than our exon 53 program. So we've got very strong leads across the other programs. So what we would do, and we are, you know, after our experience with suvodirsen, I think our step back was we answered the questions of differentiation clinically. We're going to get the protein answer. And to your point, if that protein is successful, what we would be building as part of what would be a potential confirmatory study is what we had done already with suvodirsen. So we have the clinical trial design. We actually published on the statistical design for that with the FDA, actually, which was a really, like I said before, this augmented placebo design was kind of the first way of using kind of Bayesian designs on placebo groups so that we could take historical, natural history, existing placebo patients, test them against controls in our study, and be able to then augment our placebo arms so that we can minimize the number of placebo patients on the study. By harmonizing that, we could then plan to do the additional exons as part of that study. So the roll forward would be a study that would be the confirmatory study for exon 53, but would also serve to be the study for the other exons that we could then accelerate behind that to bring those forward as part of that trial. The goal would be to keep the other exon skipping amenable boys open to exon skipping therapies utilizing our chemistry. Is there any reason to think why certain exon targeting can be either easier or more difficult than what you're looking at right now? There's always been this discussion of texture within various exons. And I think that the challenge to date also, and I think a little bit of realism is they've been tested with different medicines, with different chemistries and different backbones to know how much of that is biologically driven versus how much of that is the oligo itself, right? The RNA medicine itself is difficult to tell. So I think, you know, the approach we're taking is, you know, with exon 53, we're seeing a lot more exon skipping than we've seen with other exon 53 programs at a much earlier time point. I think what we really would do is assess those other additional four exons with our therapy and then be able to assess over time, you know, what the impact of that is and then actually have a controlled way of seeing how different is that level of protein across those exons if we standardize the chemistry format that we're using across those. Okay, thanks. So Paul, there's a lot of shots on goal for your pipeline, a lot going on, but the question I wanted to ask you is why do you think that Wave, based on its valuation right now, is undervalued just on the potential of the splicing platform alone? Putting aside everything else going on, why undervalued just for the potential that this splicing platform can bring to the company? I mean, as you pointed out, if we step back and think about the aggregate of Wave, we've got HD, which, you know, as I think about, you know, in Q2, these are challenges. Both HD and DMD, I think, are viewed as challenging indications to go after. I think, and areas that we've had setbacks, despite, albeit, clinical data readouts in 2022 that showed that single dose, we were in the therapeutic range for HD, allele specific silencing of 35%. We showed 53% skipped transcript with DMD, but have to answer the dystrophin question. So, you know, in HD, we're talking about 60,000+ patients amenable to silencing. We'd tackle about 40% of HD with our SNP3 construct, substantially more by protecting wild type that we could get to in pre-manifest HD. But I think it's an area that I think a lot of people have discounted. I think to your point in DMD, the franchise that we can address is a $1 billion franchise that we're supplanting not with additional risk of conjugates and safety. Our approach is if we can have the same profile as the existing Morpholino backbone, but a higher level of dystrophin protein and change the dosing frequency from weekly to monthly, I think that's a compelling opportunity as we talk to patients and clinicians about switching the exon skipping field. Alpha-1 antitrypsin, another 200,000 patients that are amenable to our RNA editing franchise that we can grow beyond. And then our siRNA program that'll, you know, file the CTA as early as the end of this year, which addresses about 50 million patients with a protective loss of function silencing for obesity. And I think if we think across that portfolio, I think we've stayed focused on really doing and taking targeted clinical genetics that we think can translate and bringing them forward. I think the big learning between now and before is that we do have strong models that demonstrate that our constructs are translating. We have clinical data to suggest that they're translating. It's our job just to continue to deliver on the clinical data set and hopefully, bless you, that the market will get us from here to there as we deliver on those data sets. Okay, great. In the last few minutes, just wanted to open the floor to you. Any other key takeaways we should bear in mind into a very busy year for you? It is a busy year, but I think given, I always say we have, as many companies have, what I call like 2023, busy years where people don't always see it because it's around execution on clinical studies and data generation. I think the benefit as we think about 2024, 2025 is it's a year of data delivery. So we're on track to deliver our three clinical data readouts this year by transitioning INHBE into the clinic means we can generate clinical data in 2025. And so we stay consistently on a clinical data generation front where I think these will be important, meaningful catalysts over the next 12 months. Okay, great. Well, thanks for the thoughtful discussion, Paul. Really appreciate it. Thank you for your time, and I appreciate.