Hi, everyone. Just wanted to come on to welcome everyone to this session of our mid-cap executive insights virtual event. I am Jill Hall, Head of US Small and Mid-Cap Strategy here at BofA Global Research. We are very happy to host this event for another year. Great opportunity to hear from corporates across the small and mid-cap space. Our analysts have great coverage in this space, about 1,000 small and mid-cap companies in the U.S. Fortunate to hear from almost 20 of them between today and tomorrow. Feel free to reach out to me or to the corporate access team if you need help registering for any other sessions. We can definitely still add people, or if you need the schedule, as well as if you need help connecting with any of our analysts afterward, or getting onto distributions for their research, our small and mid-cap research. We also do a fundamental compilation of small and mid-cap research each day. With that, I will pass it over to Alec. Awesome. Thanks, Jill. My name is Alec Stranahan. I am a Senior Analyst covering biotech here at BofA. I cover 29 companies ranging from $40 billion-$400 million on the market cap scale. I would say Wave is probably one of the more interesting stories in my coverage, and it is my pleasure to be joined today by Paul Bolno, who is the President and Chief Executive Officer of Wave Life Sciences. Paul has been with the company since just about the beginning, and I know you will be able to feel his passion about their RNA platform and opportunities in obesity and elsewhere. Paul, thanks so much for doing this with us. No, thank you. Excited to be here. Yeah. Great. I have some questions to run through here to lead the discussion, but for those dialed in, if you do have a question, you can utilize the raise hand feature via Zoom, or you can email me separately. I have already gotten a couple questions come in, and I will be sure to relay those on your behalf. Paul, maybe just to start, Wave has clinical validation for the RNA interference and RNA editing aspects of your technology. But maybe just starting at a high level for those less familiar with the story and the technology platform, maybe you can run through what Wave was created to do and what is going on with the company currently. No, and it is a wonderful place to start because, as you said, when we kind of look at where we are today, it is easy to become fixated on some programs and clinical validation, and we talk about RNAi as if it is almost commoditized, and we talk about RNA editing as this innovation on the platform. But as you pointed out, if I reflect kind of back on now an over a decade investment that we have been making at Wave, it is fundamentally off of chemistry, and at the core essence of Wave has always been about how do we design differentiation on chemistry that can ultimately unlock the potential of RNA medicines. I say this both on the investment we made in stereochemistry and so making single molecules where we could really understand the fundamental pharmacology of how these medicines work, to the ability to extrapolate new modifications that continue to drive potency, durability, and differentiation as we see with our obesity program in INHBE. When I step back and say RNA medicines, we have a ubiquitous chemistry capability across all RNA therapeutics, across the different modalities. What is really exciting about that, and I think this is the opportunity that sits ahead of us, both with the pipeline that we are currently developing and as we have R&D data later this year, really extrapolating where we can take this forward, is the convergence between what you can do when you have differentiated chemistry and how that translates to the intersection with novel genetic targets. That is really enabling us to really approach new areas. Case in point, INHBE and novel genetic target in obesity that really addresses what we see as kind of the fundamental future of the next generation of obesity therapeutics. Alpha-1 antitrypsin, the first RNA editing program, that is an important program for alpha-1 patients, but also unlocking the power of RNA editing more broadly with PNPLA3 coming behind it. Again, here is an opportunity where silencing, as we predicted a little over a year ago, where we were saying that if you knock down this enzyme, you could make the disease worse. The idea that in editing that could actually treat the underlying disease. We were seeing that play out with some of the recent clinical data updates on RNAi and PNPLA3. Again, differentiated target, differentiated approach. I think as we think to the future, the opportunity we have in front of us beyond the existing pipeline to use the platform to unlock differentiated targets that really address new biology is pretty exciting. Yeah. No, definitely a lot going on at the company. Maybe just to level set here in the beginning, what is the benefit of RNA editing versus DNA editing, which I think is maybe a little bit more mainstream for generalist investors and you are also competing against some DNA editing companies, say an AATD. Maybe you could just speak at a high level on kind of the benefits of editing the RNA. Yeah. I think when we step forward, we say, "What is the target product profile for these patients who are living with a disease?" In this case, we are talking about alpha-1 antitrypsin deficiency, and how do we best address that? The opportunity we always say is we have different modalities and different ways to address diseases, so if we do not think that that is the best way to do it, we do not have to be doing it. So really, RNA editing came about because our view fundamentally is that a redosable medicine that does not permanently mutate DNA and put patients at potential risk for off-target edits and I will separate, we talk about this space in particular, alpha-1 antitrypsin deficiency. When we talk about off targets, people tend to immediately go to just, "Well, is it bystander edits, and can you address that through specificity?" The real risk to off-target editing that could lead to editing of cancer-associated genes that could take decades to materialize. In addition to what happens when you get bystander edits that create different proteins. So specificity is important. So, can you redose it and get access to new cell types? Can you get specificity that is exquisite? We have seen that in our preclinical characterization. We see that clinically with just beautiful crossing of our M protein and Z protein. So we know we are functionally converting that Z misfolded protein to M. Durability. So being able to do so in a way that is not putting a dosing burden on patients. When we think about access and market access to these patients on the other side, how accessible do we make it when you work with payers? When we think about the idea of, and I do not think we have ever seen the concept of a true one and done in a therapy, but if you take durability, you need over a decade of durability on a DNA editor with safe, durable, no loss of editing, to just break even from a payer on what you would get in terms of treating a patient with an RNA editor. When we think about being able to provide that, so potency, safety, durability, and access, we see RNA editing as providing those features. It is not dissimilar to what we are seeing in other therapeutic spaces. I think TTR has just been another great example of watching where RNA medicines have really unlocked the potential for an indication, and have maintained a competitive position. I think we see that same opportunity in front of us for alpha-1 antitrypsin deficiency. Great. Wave, I think, has a distinct advantage that within RNA, you can silence, you can edit, you could do a splicing. How do you decide which approach is best for a given disease? I guess, where does your proprietary chemistry maybe create the clearest competitive advantage? I think the wonderful thing about the chemistry is we can see that advantage whether we are talking about editing or RNAi or splicing. The opportunity that] the chemistry provides gives us, to your point, and I think it is a very good one, that we can think about to hammer everything. Now, the wonderful thing about having optionalities is we think about these as tools, is we can select, to your point, the right tool for the right job. I think there is no better example of that, frankly, than the program that will be going into the clinic later this year, which is PNPLA3. There are 9 million patients who have this genetic mutation. You can find it in 23andMe, so it is commercially available, like people can find out that they have the PNPLA3 mutation. Those patients are at a substantial higher risk of all told liver disease mortality. The ability to actually provide a fix to that is important. I say a fix because, for a while people said, "Okay, there's this mutation. If you can silence it, you can treat the underlying disease." As to your point, we can make RNAi and we can make editors. What did we do? We shared some of these data last year at R&D Day. We looked at the comparison between silencing the enzyme versus fixing the enzyme. There were differences in outcome measurements. We saw differences in the cell's ability to dispose of the fat that was inside as we think about MASH. We also saw differences, and we will be sharing more on this, on the inflammatory component of the disease. When we looked back and said, "Well, do you want to silence or turn off this enzyme?" Frankly, you need it, right? This is a disease where a heterozygous phenotype, so a 50% correction basically restores functionality back to those patients in terms of their survival advantage. The idea that we had was, well, yeah, absolutely. Here is a case where actually the correction actually fixes the disease. I think not only do we see that in our preclinical studies, but watching multiple clinical programs start to read out on the silencing front is conferring that same advantage that we have been seeing, that there is actually the real advantage in fixing and correcting that underlying mutation back to a normal functioning enzyme, as opposed to silencing it and taking that enzymatic function away. We are excited as that goes forward to be able to think about this really in redefining liver diseases. Here is a PNPLA3 mutation. We can look at it for these different indications, but really what underlies this is protecting these patients very early on from a substantial risk. 9 million patients is not an insignificant number of patients that can be addressed. Right. You have mentioned a few of the internal pipeline assets, and I want to go through them one by one. I think maybe a good question just to sort of lead into that is I think WVE-007, which is your obesity asset got a lot of attention, brought a lot of attention to the company when we saw the really encouraging early human data a few months ago. I guess, which program kind of has the best or the greatest potential to change how the market values Wave over the next 12-18 months? Yeah, I think over the next year, I think that it's the wonderful aspect of these two programs, right? I think they have, if we think about alpha-1 antitrypsin and we think about WVE-007, each has the ability to be transformative in its own way, right? I think in the case of the next near term period on WVE-007, I think a lot of what people will say is the initial enthusiasm, I still think sustains our enthusiasm in the program. I think the biology is really well understood. We have genetic data. We have human data, and we have the bridging between human genetics of patients. We have the bridging to treated patients, and we have the models in between. The medicine's doing exactly what it's supposed to be doing in a way that's differentiated as we've watched other silencing programs come forward that reinforces our differentiated chemistry. We're still looking at durability as we think about a once to twice a year dosing. We still see in the only clinical data set in patients who are otherwise healthy, so phase I patient population in low fat who sees substantial reductions in visceral fat that are clinically relevant, substantial reductions in total body fat. If we think about what's going to drive ultimately weight loss in general is total body fat, and change in waist circumference, which is actually an immeasurably meaningful way of looking at the impact of this medicine. I think as we think about the early data from the phase I population, and even that is being compared to phase II, phase III, I think we're highly encouraged that with dosing underway in the phase II-A monotherapy in the patient population, that is the intent to treat, right? These are patients with higher BMIs, higher levels of visceral fat, higher levels of total body fat. With and without diabetes is 2 other cohorts so that we can really elucidate the broader cardiometabolic areas for treatment, meaning diabetes, MASH, and others. It's pretty exciting, and I think we're poised now with that running to be able to accelerate and deliver these data, and then shortly from now initiate the combination study. Where I think there's probably an underappreciated application, because everybody's so focused on the frontline, and how are we going to win in monotherapy, I think the opportunity is very much there, and I think this is going to be a meaningful medicine combination. Do you have to keep pushing incretins in order to get a benefit or the add-on? I think we're seeing examples of add-on being a really great opportunity. I think the most underappreciated aspect long-term for treatment of these patients who are living with obesity, have been treated, are at steady state on regardless of what therapy they came into treatment on. I think the conversation we hear time and again against clinicians and patients, payers for that matter, is what does maintenance now start to look like in this population? To date, maintenance is really like a titrating back on incretin levels and how much regain can you stave off in order to keep people in a level. I think the really fascinating opportunity about maintenance for INHBE is actually the shift of how do you lock in and prevent fat regain? That's the challenge, right? If you titrate back your incretin, the weight that comes back is actually fat. As you come back, you would imagine a patient going back to baseline actually has more fat than they actually started their therapy with. The idea that we could shift to a maintenance therapy that could be once to twice a year, prevent that regain of fat back, and really stabilize patients now has us not segmenting a mark, but really thinking about how do you take any incretin patient and actually think about a forward-looking vision where they do not have to sustain on that and run all of the complicating risks to being on a sustained injectable or frankly oral, where we will see whether or not the orals in a real-world setting actually sustain the levels that they are seeing now. But we think maintenance is a really exciting way. At this moment in time, I do not think it is still getting the attention that we think it should, and I think as we start that clinical study this half, I think that is going to be an exciting new part of the story. So that is how we think about unlocking obesity, and we saw that there is a lot of value there. On the other side, alpha-1 antitrypsin, we are poised to have regulatory feedback on a path to accelerated approval, I think accelerates a different conversation with Wave, right? Which is one of how do we move into a commercial stream for a substantial number of patients, 200,000 patients in U.S. and Europe. Would be the first RNA editing program we think as we laid out as your first question in a way that is differentiated, I think from others. As we test that profile amongst the medical community, patient community, and payers, we think that is an exciting component in Wave that gets unlocked again in the second half as we think about going in next year and having this pathway to potential accelerated approval. So I really do think we are in a position as we look forward that the next 12 months is incredibly exciting across both assets. I think both have the potential to contribute substantially to a higher value than we are seeing today, with PNPLA3 coming behind that as a supportive asset that will continue to generate data in the next 12 months that unlocks that opportunity. As people will learn at R&D Day, the opportunity we have with bispecifics and other targets that sustainably deliver on that pipeline beyond the existing WVE-007 and WVE-006, I think is a really strong foreseeable future. Yeah, great. Those tend to be the two assets that I get most focus on from investors as well. So maybe we can touch on those, and then I do hope we get time to talk about PNPLA3, sorry, PNPLA3 as well at the end, because I know that is a large unmet need as well. But maybe starting on WVE-007 and obesity and cardiometabolic disease, and I think you covered a lot of it. But maybe we could just talk a little bit about the lessons learned so far from the phase I data. You showed reductions in total and visceral fat with muscle prevention, which is the holy grail when you think about a maintenance or even an upfront therapy. A lot of the total weight loss is actually from muscle and not fat with the incretins. If you're able to strike that balance with convenient dosing, it seems like a pretty actionable profile. I guess, how did investors sort of interpret those results through the dose escalation? I think we're going to get a higher dose as well later this year, and what have you learned about baseline BMI, the relationship between Activin E reduction and clinical benefit that's sort of helping you inform next steps for your clinical program? Yeah, I think one from, and I think this is great from a platform perspective, from preclinical data to human data, I think we're seeing strong correlations and translations of target engagement editing. As we predict our dose going forward, the fact that we're seeing that once to twice a year sustained at the lowest dose that we're going into, I think continues to speak to what we expect to see from where we think we would need to be from a dose. We're seeing what, 80%, 88%, 85% reduction in Activin E. Knowing that we've seen preclinically that once you cross the 70% threshold and sustain it, you start to see that reduction. We're well in excess of that. I think that's an important nuance too, because I think what it also affirms for us is this differentiation on chemistry. What we have seen in our preclinical data is it's the only preclinical data set that's seen single-dose reduction in body weight. Not prevention of weight gain or slowing of fat regain, but true reduction in body weight. I think that was important because it does demonstrate that with sustained reduction, and it's important to remember that the DIO mouse is an obese mouse model with excess fat. I think it's affirming for us that where there's fat that can be stalled, you'll see that reduction in lipolysis occur. I think that's exactly what we saw in the humans. In fact, to your point on the dose response, was really interesting, and we have to go back to these data and remind ourselves, because I also think people tend to become, let's say, fixated on BMI, and forget you can be a bodybuilder with a higher BMI, and you can be overweight or obese with higher BMI, and the main difference there is the amount of fat. I think what we've seen, which has been affirming for the mechanism is where there's higher fat, we see higher rates of decline, right? That played out actually in the clinic. If we think about the dose response, the update we provided at the 400 was actually probably one of the clearest data sets to prove this principle. Once patients had a higher level of visceral fat and total fat, those patients had reductions on par with where we saw the substantial decline in the 240 mg dose. I think what is key in this early study, and I think it is hard because in obesity it is an area, and I do appreciate that those who are evaluating these from the other side are looking at the incretin pathway, right? People come out and they are like, "Here is our phase II-A data. Here is how it looks in the phase II-A population." If we look at our peers who share data for INHBE around us, they are all looking at the phase II-A. We never saw the early phase I data. I think what was compelling is our phase I data was competitive where we were starting to benchmark our phase I population with the phase II-A population. People were going, "Oh, look, Wave saw 14 point whatever reduction in visceral fat, and that looks similar to this other company's reduction in visceral fat." Our reminder when we step back is, if you look at, because these patients had different starting rates of fat, our patients only had 1 L of fat to lose, and yet they could lose it remarkably in comparison to a comparator with 5 L of fat because they were a much larger population. Which again, will speak to what is next and why we have conviction in the program. But I think it really taught us that the medicine is doing exactly what we had modeled to do. It targets the cells, it is durable, it is potent, it is safe, and I think that is really important as we think about durability and potency in this population. Safety and tolerability looks exquisite. I think that opportunity on top of that is translating very well. Now, the next question that everybody has is, what about 600? I think we have been saying time and time again that, yeah, 600 should see we are probably at the blunter end of the curve. I would anticipate more Activin E reduction. But I would not expect that the baseline characteristics of those patients would be any different, and we know we have already suppressed that. I think we will see what we will continue to see around PK/PD. I think the most exciting, and we have been very clear on this, is now seeing what the medicines do in the patient population with higher BMI, higher total fat, higher visceral fat, and comorbidities. That is that comorbidities piece that allows that fat to be larger. I think if we think about our modeling, and we have shared this with a number of folks, if you look at the BELIEVE characteristics, which are pretty much good baseline surrogates for the baseline characteristics of patients in phase II-A obesity studies, they have much higher total fat, much higher visceral fat. If you look at where our studies started in relation to those studies, and I should give that, I do not know, it is like beer. But we started at a body composition profile that looked like where those patients end after a year on therapy and still saw that we could continue to bring that down. What's encouraging is as soon as we go to that population where we get to higher fat to lose with the comorbidities, we model that we're not in any way going. Do we think we're going to see greater than 5% changes in body weight? I think what's most important, and you pointed it out, is being able to see that improvement in body composition. I think that's an exciting conversation that's also happening this half where we're going to engage regulators around that more broadly. We know the other obesity patient groups are as well. I think there's a big conversation to be had really on starting to reframe a focus on body composition that irrespective of the 5%, and we're not trying to change the regulatory paradigm there. But we do think from a label perspective and a forward-looking perspective, that changing the narrative from pounds on a scale, as you point out, you can have up to 40% reduction in your muscle mass in that early time point. That's really accounting for weight loss with incretins. That's not a benefit. Those patients are losing an organ that plays a big role in insulin sensitivity, further weight loss, and muscle mass and stabilization. So the ability to really frame what long term is providing health benefits as we think about improvements in body composition, I think is going to be an exciting part of the story as we go through this year and into next year. Right. Yeah, and we know that in patients with higher BMI that have been exposed to other Activin E assets, you do see better activity, which is probably not inherent to those other compounds. It's probably just where you start determines where you can end up. And to your point, Paul, the phase II-A INLIGHT study, I think that's a BMI of 35-50, right? With or without type 2 diabetes. And you're going to be measuring the whole gamut, body weight, body composition, visceral fat, liver fat, HbA1c, lipids. I guess, which of these endpoints matters the most for establishing WVE-007? And which could actually open up expansion opportunities into, say, MASH or even diabetes? I think they're all important in their own way, right? I think in general, looking at that continued shift in body composition, right, reductions in total body fat, reductions in visceral fat are going to be very important. I think ultimately that translates to body weight because by stabilizing muscle, you're going to see weight as a function of losing fat, right? I think that's going to be a surrogate to looking at what we're going to have in addition to the drivers of what's causing that. Which we want to see the weight reduction, but coming off of total body fat. Then to add to your point, I think what's really important about this mechanism, and frankly, what's also driving, I think, the patient disposition at the beginning of the study is the concept that these patients can have comorbidities, right? When you start thinking about pre-diabetics and diabetics as two different cohorts, the ability to look and track hemoglobin A1c, and we go back to these humans who are walking around with a protective loss of function. They have improvements in hemoglobin A1c. They have better type 2 diabetes outcomes and cardiovascular outcomes. Why? Well, because of this improvement, they have lower triglycerides, they have higher HDL, in addition to these improvements in hemoglobin A1C. So I think we are going to look at being able to elucidate some of those cardiometabolic endpoints as we think about looking at those two different cohorts, and we will have the biomarkers to measure that. As you point out, by having MRI-PDFF in this study, particularly the diabetic patients that have comorbidities and a higher BMI, the likelihood of having higher levels of liver fat, as we have seen in the other studies, is quite substantial, and therefore, the improvements that we can see. If we look at our peers who have looked at liver MRIs, 44% reduction in liver fat is consequential. That is substantially as large as, and if not actually larger than some of the MASH studies. So I think the opportunity we are going to have here is there is the unlocking the obesity perspective in a differentiated program with a differentiated pharmacology, and we are going to have the opportunity to open up the broader cardiometabolic endpoints that are all part of this study. Hmm. Okay, great. With the approval of oral incretins, I would say the field is moving pretty quickly. Although we have not seen maybe as much progress as the clinical pipeline would have led one to believe two or three years ago. I guess, where do you expect WVE-007 to fit into this evolving landscape? Do patients get an injectable and then oral maintenance, or would an INHBE asset compete against an oral, or would it be complementary in combination? How are you sort of thinking about these synergizing together ultimately five, 10 years down the road? Yeah, I think if we do not think about the method of delivery, then we know that incretins are compatible and orthogonal to INHBE. So the same features apply to your point of whether it is monotherapy at the front end, combination with the oral, which is an interesting way of thinking about it because if the whole goal is to minimize patient number of injections, and you could be talking about one or two a year on INHBE and then on oral, and that could take down the frequent injection frequency from a weekly injectable down to a once or twice a year in combination with an oral. As I start thinking about maintenance and where we are, I think the difference is you talk to patients where you go into your physician's office and you get a shot, and then you don't have to think about it for the year without the tolerability challenges. Frankly, it doesn't negate all of the other safety and tolerability complications on incretins, whether we're talking about oral or injectables. The idea that you still go to a once a year injectable, we think is highly competitive with that as we talk to, again, physicians, payers, and patients. I think what's going to be interesting as the data continues to evolve and looking at some of the orals is what the impact ultimately is, right? Here's medicine that you got to take every day. Some depending on time base, some take whenever you'd like. But we know from other orals that are required daily, I think cholesterol and statins are just a great example of what adherence looks like on a medicine that doesn't have the same tolerability challenges causing nausea, vomiting. You start thinking to yourself, in the real world setting, when somebody's not calling you or you don't have an app, you're not in a trial where you're taking it on this frequent basis. The evolution of what real world data looks like when people miss a dose or miss two doses or start adjusting their doses titratably, versus how that looks in a maintenance concept, versus you go in, you get your shot, and you know you're covered for the period of time that your active Activin E is suppressed. We think that the INHBE profile is highly competitive against orals in that maintenance setting. Yeah. Okay. That makes sense. Maybe I'll pause for a moment. We're about 30 minutes in, and I'll see if anyone on the line has any questions on obesity, and then we can shift to AATD and the rest of the pipeline. Again, if you have a question, feel free to raise your hand. I can see it through our platform, and we can unmute you. Maybe while we wait, I did get an email question here on obesity. The question is kind of around the partnership opportunity, right? Obesity is a large market. There's a lot of potential here for you guys to go alone or to leverage the capabilities to run some of these large studies. Pharma has been focused on post GLP-1 maintenance, and that's not just U.S. Pharma. Also in the EU and areas like Japan as well. What's sort of your outlook on partnerships and would you look to develop this on your own or would you want to be strategic to run it with a partner? I think we always want to make good strategic decisions with any program that we're investing in. I think near term what we feel is, again, with a once to twice a year therapeutic study, I think there's value to be unlocked with the current data set. We've got the ability to show duration, safety, and efficacy in a patient population. I think as we think long term, as you point out, I think some of this to your earlier question about how do we think about the interplay between programs where AATD could be a program that has the potential pathway now to, let's say, accelerated approval and a commercial transition. How these assets start to interplay as we think over the next 12 months with data and value, being able to think about those strategic decisions. We do have interesting opportunities after value becomes unlocked on this program. There is, as you point out, continued strategic interest in this program. It's orthogonal. I think it's enticing when people think about combinations. I think the fact we don't have to add to the injection burden, we don't have to add to the safety and tolerability burden. As people think about combinations, which we're seeing in the obesity space, it is critical that this program's not adding the burden both on the administration or on the safety tolerability profile. In fact, may actually improve that in combination if you can come down in lower doses of some of the other therapies. So we're seeing people proactively come and have that conversation about how to think about combination. We're having conversations with folks, particularly in maintenance as well, where there are a number of companies that have been interested in obesity, and their whole debate is always how to get in front of it. Having the ability to come in and say, "Well, you don't have to build the market, you just have to move the market," opens up a pretty attractive set of discussions. So I think INHBE does provide that. I think the focus is also not losing sight that accruing and accreting data is critical. The focus of the company is making sure that we can deliver the data sets that are going to deliver a differentiated profile against the current programs. But I think equally important, and we're seeing this in a really nice way in our partnering discussions, is I think a real recognition that with INHBE, people didn't think about Wave for years as an siRNA company. I think INHBE has opened up conversations about the access that we've had as an siRNA therapeutic company where we've been years ahead of, I think, who people would view as a best-in-class siRNA company that's kind of defined the field. I think the ability that we accelerated a clinical program for a massive indication ahead in a way that's sustainably differentiated, I think, has really solidified our place as both an RNAi capability company platform more broadly, in addition to what we can do with INHBE specifically. Okay. Partnerships could sort of, reading between the lines, it could span the in-house pipeline, and it could also be kind of discovery platform type. Exactly, particularly the work that we've already shown at Research Day last year on extrahepatic siRNA. I think we're already there on that with durability. We continue to share our updates on bispecifics, the idea of can you dual target, and that's exciting as well. Yeah. Okay. Very good. I want to shift gears now and talk about alpha-1 antitrypsin deficiency for a little bit. Here, with the rights wholly owned to the program, you guys can kind of run with it. You've shown some deepening data, acute phase response, both Z and M protein production, which is important. I think we're expecting some additional data in the second half. I guess how should investors sort of be thinking about this program, and kind of the path to a pivotal study, as you approach the regulator? Yeah, I mean, I think the key for us is that the current data is supporting that this is doing exactly what it's supposed to be doing. It's going to the right cell type. It's converting Z to M. I think there's always times where you look at data and you're like, "Oh, wow." There isn't this kind of concern that some patients are better responders than others, and I think the clarity of really showing the data that every patient is seeing this really nice conversion, I think, is really important as we think about positioning this going forward. I think the opportunity that we've seen preclinically where we have longer follow-up and being able to really show what's happening, which as we saw in the humans, not just this M to Z, but that reduction in Z is consequential, right? We oftentimes are always in our minds thinking about alpha-1 antitrypsin and the lung side of the equation. Liver is really important, and I think when those data were also shared at EASL, we got a lot of interest from the hepatologists. As we think about kind of bringing together the alpha-1 treatment community on both the pulmonologist and the hepatologist who are thinking about reduction in liver burden and improvement in lung, I think both of those features become crucial. That's important because as you continue to treat, and this was the preclinical data we showed, you take that burden of that misfolded protein off the liver, you actually see liver regeneration. The beauty of liver regeneration is now you've got fresh hepatocytes that you can continue to correct. I think this is one of the underappreciated sides, that repeat administration is actually a feature in this disease, right? Because as you begin to correct the liver, and as the liver repairs itself and gets healthier, you've got the ability to continue to access new hepatocytes that are continuing to get fixed, continuing to be able to produce more protein. Over time, we saw that in the animal model where we often got the question of why do we think there's this kind of continued uptick as it gets later? Clearly, we went back and saw a reduction in that burden on those aggregates in the liver and that transition. You're seeing more protein get made. I think that really longitudinal piece of continuing to treat these patients is important. What to expect, I think the key for us as we come through this kind of regulatory window, and we'll provide those updates when they come, is really what we had imagined, and we wouldn't have any reason to believe otherwise, is that there's a path to potential accelerated approval based on biomarkers. That's how we foresee it. I think the opportunity, as you lay out ahead of us, is how do we think about the design of that study? I think we don't have to look to the design that others have because there's features we don't have to evaluate, right, that we don't have to concern ourselves with. Can we do that, whether it's with different number of patients or more importantly, a different time horizon with which we can look to evaluate that from what could be an interim endpoint for a biomarker driven, but are there opportunities for us to run a larger, longer study over time so we don't have to run two studies, one confirmatory and one that's an accelerated registration that gets us to a potential pathway to full approval faster, but not forgoing that you can have that interim look to get to the market faster. I think that's where we want to be creative in our discussions, and that will be part of an ongoing conversation. But I think that's what we look at as we think about the design and update to the next trial. Okay. Powering for early success at an interim, but having a longer tail on the follow-up to check the boxes. That's right. The discussions around, and we know the advocacy organizations have been having C-Path discussions on CT densitometry. As we think about aligning on what those potential endpoints could be, I think there's really a unique opportunity to be thinking about that long term that ultimately could potentially contract the time to full approval. Okay. I think data from the 600 mg monthly multi-dose cohort is also expected here in the second half. That's right. I guess what should investors focus on from the update versus what we already know about the asset, and how would that cohort reading out influence your study design either way? Yeah, I think our plan is we look at the kinetics of our current. We're getting high potent, and we could get, if we think about over 20 micromolar of protein shortly after the lowest single dose. Two weeks after that dose, a patient could get to 20 micromolar during an acute phase response. So what we do know is that editing happens, it's happening pretty quickly in terms of that response rate. It's potent. As we look at PK, I don't know if there's much more on that potency side. We'll see. As we said, the 400 and the 200 were similar in terms of total exposures because one was biweekly and one was monthly. We'll be able to look at some of that PK, which will probably inform more for us, how do we think about dosing intervals? What do we think the infrequency of administration needs to be? But we'll learn more about the PK. I think what we'll see in terms of the translation of more time, once you have cells that are exposed, is the impact more on time to generating protein than necessarily more drug. But clearly we're in the MZ phenotype, so we have what we believe we need to have for a biomarker discussion as we go into those discussions. Okay, great. Looking forward to that. Another update that you have in the second half will be putting WVE-008 into the clinic. That's your PNPLA3 asset, and this is not one that I get a ton of questions on, but when I was making up our model, and we do have a build for this indication, it was actually kind of interesting to see what actually the prevalence of the I148M variant is and just how important this is and actually the genetic validation that's already there in the literature. It's a pretty obvious application for your technology with a large end market. So it feels like next year this could actually become more part of the conversation as people look at Wave. I guess, what are you thinking about this program? How do you approach the initial clinical study here in the second half, and what is the first in human de-risking that you'd be looking for from the study? Yeah, I think, one, to your point, it is astounding. We had a liver patient come in recently and walk through her PNPLA3 journey. I think what's wonderful is it's an opportunity to grow. Patients are finding out that they have the mutation. We're experimental therapeutics on silencing. I think what we're seeing was a, particularly after EASL, a big shift from some of the clinicians that have been the voices of the silencing community shifting and saying, "Well, actually, we need to shift our focus to editing." I think it's a great opportunity for us to engage that community as we're getting this trial forward-looking ready. With the patient population, as you point out, that can be diagnosed just based on genetics, and those tests are already readily available. I think there's a lot that we can do in this case well before we get to the trial that actually gets things ready to go so that we can accelerate things pretty quickly. We'll share more on the trial design, typically when we start the study. I think the opportunity ahead of us, given that we know the patients, there's physician engagement to get these sites up and running, and they're excited about this potential opportunity, is we'll have the ability to look at biomarkers in that study. To your point, be able to get early reads on that target engagement and profile well in advance of seeing, as we think about a MASH study later, being able to look at more near-term endpoints that tell us that this is doing what it's supposed to be doing. I think on the heels of alpha-1 and the pharmacology learnings, I think we're able to take this very quickly over to PNPLA3, where we know a 50% correction actually fixes the mutation and opportunity for these patients. We don't have this acute phase. This is not an acute phase protein, so what's really nice is the enzyme, you correct it to 50%, you repair the disease. I think on some basis, it's a little bit more simplistic in its understanding of the disease biology. I think as we design the study, we've designed it in a way that we can de-risk it, we think, pretty quickly. I think as we think about 2027, while it seems like it's on the horizon and farther out, as we think about the back half of this year, getting this into the clinic and getting ready so that 2027, I think, does become an unlocking period for this particular program. Okay. Maybe last question, Paul, as we run up on time here, I think this will help wrap everything up as well, it is just around the cash balance. It takes money to make money, especially in biotech. How are you thinking about capital allocation, your cash runway, which I think is into the second half of 2028, what does that carry you through in terms of de-risking for the pipeline? Yeah, as we said, on our last earnings call, we have nearly $500 million in cash. That couple takes us into Q3 of 2028. The most important thing is, as you lay out, it takes us through these inflections. We are going to continue to drive WVE-006, so alpha-1 into the clinic on that pathway. We are going to deliver important data across monotherapy in the high BMI with and without diabetes. That cash covers the combo study and data there that unlocks that potential value and maintenance. We will see that data set. In addition to all of that opens up, I think it is important to your point on what are we going to see in the other biomarkers. I know there is a lot of questions that people always have about what about all the other cardiometabolic indications. Those are all in that, I think that is the wonderful thing about this phase II-A design that we did say, as you mentioned, it is an investment, but we invested in those biomarkers so that we do not have to run separate studies to be able to look at liver fat reduction, hemoglobin A1c reductions, lipid profile shifts, insulin sensitivity. Those will all be unlocked as part of the phase II-A study. I think as we think about those, in addition to bringing PNPLA3 into the clinic and delivering that data set that again differentiates that program, I think we've made the right investments in a very focused and deliberate way. We came into the year with a resolute focus that these would be the three programs that we'd be allocating capital to, and I think we've stayed very disciplined on ensuring that we can deliver the data sets across each of those. We're excited to deliver the data. Yeah, great. Well, looking forward to seeing the data. Thanks. Yeah. Thanks for the updates here and the great conversation. I think we'll have to end it there for the sake of time. Paul, really appreciate you joining us here for our conference. Thanks everyone who dialed in for your interest. Thank you for having me, and thank you everybody for dialing in. Thank you. Take care.