All right. Good morning still, yes, everyone. Thank you for joining us. My name is Whitney Ijem. I am one of the Biotech Analysts here at Canaccord. I am pleased to be chatting now with Wave Life Sciences, and President and CEO, Paul Bolno. Thank you so much for being here, Paul. Thanks for having us. Diving right in. Can you start with a high-level overview of who is Wave? What do you guys do? What are you trying to build over the next 5+ years? Yeah. Hopefully longer than even the next five years. If we look back over the last now over a decade at Wave, we are an RNA medicines company, and we are really at the precipice now of clinically validated programmable RNA medicines. I say that it is really important because we are now at a point across multiple modalities. Because when people talk about RNA medicines, you could say, "Well, are you an siRNA company, or are you a splicing company, or are you an editing company?" I think the real focus at Wave has always been that our opportunity, our chemistry, is across the whole RNA medicine. So multiple modalities, programmable with the opportunity that our cycle times are now 18 months from the time we pick a target to human data. We will talk about that in the context of obesity with INHBE for siRNA. Differentiated chemistry, but really now the convergence of that chemistry engine with human genetics. Again, when we talk about each of the therapeutic programs that are in the clinic now, they are all able to rapidly translate unique clinical genetic insights. Coming out of human genetic databases like UK Biobank and others, they are validated. Being able to partner that with a platform that can rapidly translate that to human data. We are at the point now where as we came into 2026, came in with $600 million that we said were going to be invested in continuation of making sure that the platform engine could deliver. We have got collaborations like we do with GSK that are delivering, and b e able to push our clinical programs forward. INHBE is in a phase II-A dosing study now in a population that is high BMI with comorbidity, so higher fat. We will be able to discern the impact and differentiation of the INHBE pathway for obesity. It will enable us to take alpha-1 antitrypsin forward, and we will have feedback from regulators on a path to accelerated approval for the first RNA editing medicine for alpha-1 antitrypsin deficiency, which we see is highly differentiated. Be able to bring forward the next novel RNA editing target that is built off of genetics, PNPLA3, for the 9 million patients living with PNPLA3 liver disease. Across the board, platform engine delivering on human genetics into clinical programs, and now with a pathway to potential accelerated approval for alpha-1. Perfect. All right. We are going to start with WVE-007 and dive into the science a little bit. I do not think anybody-- We all understand that obesity is a large market, so I am not going to dive into the patient numbers. Just going to how the drug works. Can you talk through the INHBE biology? Why mechanistically does that have an effect in potentially the desired effect of weight loss without muscle loss? Yeah. I think beyond just biology, I think it is biology with genetics. I think if we step back into why is INHBE an interesting target to pursue orthogonally for the treatment of obesity? I think we know biology of the incretins. We can put a whole bunch of different medicines in that category, which work by centrally decreasing appetite, slowing the GI system, and essentially through cachexia, which is why you get muscle loss and fat loss and other complications associated with that. INHBE, very different pathway. Came out of the UK Biobank, genetically validated target. These human loss of function. If we think about the PCSK9 for obesity, these are humans who walk around who have a 50% loss of function of this target, have low visceral fat, low subcutaneous fat, they have low LDL triglycerides, high HDL, they have better cardiovascular outcome benefits, better type 2 diabetes outcome benefits. When you look at the human experiment as like a lifelong maintenance, these patients do extraordinarily well and are differentiated. The question we ask from biology is, that is wonderful if you are born with it and are followed through, i s this a target that you can actually induce and drive? We showed in the DIO mouse model. These are obese mice, and that is an important distinction as we talk about the upcoming clinical data, the phase II-A patients in obesity with comorbidity. We saw that we could actually induce that. With a single dose, we could actually see weight loss similar to GLP-1s, all fat. The difference is the kinetics of that weight loss. Because when we will talk about incretins later, when you have 40% of your weight loss driven off of muscle loss early, you are going to get a very steep decline, and then that continues. What we see is a slower onset because you are actually building muscle, and we will talk about the human data where we saw that. You increase lean mass, but then you see that fat loss over time as well. We could see weight loss and monotherapy, single dose, with equivalency to the incretins. We show that it is orthogonal and compatible for combinations, so we did it in combination with GLP-1 and saw we could double the weight loss because the approach is further fat reduction. We will talk about that human clinical trial that will get started this half. A really interesting indication. Because in the preclinical data, we also showed that if you pretreat a mouse on an incretin prior to cessation of the incretin, if you take those two arms, both mice go back to hedonic eating. If we think about the pathway for incretins, you take that resistance to dieting off, right? Mice go back to caloric consumption. They regain their weight back above where they started. We see that in humans. What is important is that weight that comes back is all fat. You actually have more fat at the end than you started with. The beauty of pretreating with the INHBE program is if you take the brake off lipolysis, which is how this medicine works, then actually when that caloric consumption resumes, those mice are unable to store that as fat again. What you see is a stabilization of weight at that set point. We will be running that study too this half, initiating the maintenance study. We think across each of those preclinical data sets there is really highly compelling data that is translated into our human data that we continue to follow as we will start the next studies. Mm-hmm. Okay. One more just background question. Why did you choose to target INHBE, which is the key, versus the receptor ALK7, which is the lock? Lock. Yeah. As you point out, this is a protein that is made in the liver. It is a hepatokine. The signaling pathway is the hepatocyte sends this protein to the adipocyte for fat storage. That receptor, to your point, is ALK7. What is wonderful is, and again, this marries our chemistry so highly potent siRNAs. When we compare our preclinical data sets across the field, we have single-dose data with weight loss. Our peers, we look at competitive data sets, are all multi-dose data sets with prevention of weight gain. We know that we have got a highly potent suppressible way to do once or twice a year dosing that can suppress this ligand. The receptor, as you point out, is on adipocytes. It is on some other cell tissues. It has multiple signaling pathways that come through it, but beyond Activin E. Our approach in stepping back in biology is simplicity. If you have a single methodology that can suppress the target at that single cell type that is accessible through GalNAc and has the safety that comes with understanding the pathway with a single ligand, our view is to avoid the promiscuity that comes from a multi-targeted ligand receptor. We saw that too play out in our clinical data with specific knockdown, but also, again, exquisite safety through the highest dose cohort. Okay, got it. Can you speak to, I guess, key learnings from the phase I portion of the ongoing clinical study, in terms of weight loss, fat loss? Maybe how that sets up or relates to the phase II-A that is ongoing? Yes. As we step back and say phase I studies, you need to run a phase I study in obesity. These are patients with no comorbidities who are otherwise healthy. They have a higher BMI. We need to remember that you can have a higher BMI and be a bodybuilder as well. These patients have varying degrees of baseline levels of fat to begin with, but the purpose of a phase I study is safety pharmacology. Then we have the ability, because of DEXA, to assess body composition. I think what was exciting as these data come out, and I think it's hard when thinking people's minds, everybody has a phase II-A obese study, right? That's the benchmark that everybody's looking at when they do comparative data sets. I think what was exciting about the early data sets is we were seeing highly compelling data in a phase I, otherwise healthy population. What did we see? We saw exactly the biology translate, that we could get potent, durable silencing with a single dose. The lowest dose, which is the longest time point that we had cut at that time, was still 7.5 months with suppression of Activin E. Again, continuing to support the opportunity for once or twice a year dosing. It's a strong effect on the target. We saw that when you take that target down, what we saw in the models was translating. We saw an increase in that early time point, so the first three months of an increase in lean muscle mass, meaning as you broke down fat into free cholesterol and fatty acids, muscles could consume that. You could actually see an increase in muscle mass, which is highly important in this population because that drives insulin sensitivity, can actually project further ability to lose fat. Then we saw, as you point out, we saw substantial levels of visceral fat loss in this population, up to nearly 15%, which is clinically relevant. If we think about changes in outcomes, as you get to 5%, you start seeing changes in cardiovascular measurements, 10% increase in MASH. To already be achieving that in a healthy population with no comorbidities was exciting. Beyond that, and this gets to kind of what we project forward, is we think about, well, how do you continue to see health benefits and eventually weight loss comes from the total body fat reduction, subcutaneous fat reduction. We saw a substantial reduction in subcutaneous fat that was relevant and importantly, on the measurements that, how do patients measure themselves? Waist circumference. We saw a 3.3% change in waist circumference. Again, all in a phase I, otherwise healthy population. As we step back in terms of pharmacology translating very well, phase I population translating as we would expect to see with that slight increase in lean mass, which is important. But reduction, substantial reduction, in fat, again, really important. Then the last piece, as we think about this space, because it is in an obese, a large population, is safety and tolerability. And again, both safe and very well-tolerated. We did not see GI side effects, no change in liver function tests. All of the important things that you would want to see in a therapy that really could be life-altering. Again, all highly informative as we think forward to the design of the phase II-A study, which is dosing now, and where we would expect to then be able to benchmark against existing obesity therapies. Okay. Excuse me. Can you put that 3.3% change in waist circumference into context? Is that like a belt- A belt loop. A belt loop. Okay. It is a belt loop. Got it. All right. Just talking about expectations, because to your earlier point, I think investor expectations headed into the phase I data were maybe mismatched relative to what would be reasonable to show given the design of the study. To be clear, where do you want expectations to be headed into the phase II-A data? Yeah, I think we want to see continuation of the-- We have this wonderful way of thinking about it. If you think about just benchmarking, I am going to give you kind of the visual with my hand. If you think about where this study started, if we think about other phase II-A studies, the best comparison study is kind of the BELIEVE study, looking at bimagrumab and GLP-1. Bimagrumab is a medicine that, in their phase I, had more lean mass gain, because that is the mechanism of action of that medicine. Less fat loss in their phase I. When they went to their phase II-A study, at the end of that study, at a year, they saw a greater than 5% change in body weight. They saw all of that progress. Our view is exactly as you would expect in going from a phase I healthy volunteer study to a phase II study in patients who have more fat to lose, how do you project that? Exactly as we think about the characteristics, the design of the study that is dosing now, this study has entry criteria of BMIs of 35- 50. While that is important, the most important kind of co-variable is comorbidities. Allowing patients who have comorbidities, you are not excluding patients with high lipid levels, higher hemoglobin A1c. Those are all contributing factors to high fat, high visceral fat. What we see in those studies of GLP-1s, bimagrumab in these phase II-A is high levels of visceral fat, high levels of total fat. When you reduce that is how you change total body weight. Total body weight is really a function of losing. You do not want to lose muscle, so incretins, you will get that by losing muscle and fat. As long as you have fat to lose, you will lose weight. Where our study started was at the patient disposition was where patients were at the end of a year on all of those therapies. Already we know from our phase I study, that body composition profile where patients have been treated with incretins or bimagrumab for over a year. Again, as we go into this phase II-A study, we believe we have got the patient disposition, background characteristics. Importantly, we will also have the measurements. If we think about this as a cardiometabolic drug, yes, the obesity is going to be an important indication. We are set up to be able to look at changes in body composition, change in total body weight. We do believe based on all of our modeling from the phase I, II, between this study, and other studies, we will achieve a greater than 5% change in total body weight driven on fat. The opportunity ahead for this program is on all of the other metrics as well that this improves. We will be able to capture all of those in this study. Liver fat on MRI-PDFF, being able to look at hemoglobin A1c levels by having diabetics and non-diabetics, being able to look at changes in lipid profiles. As we think about the compendium of cardiometabolic indications beyond obesity as well, this study is designed to answer all of those questions with the biomarkers that are there and have the patient population that will be reflective of that we can study. I hear you on all that. Okay, this 5% BMI level continues to be the thing people are looking for. Yeah. Is that-- at the dose you're looking at, at the time point, with that the data will be at when we see it, should we not be thinking about that yet? Or is that a reasonable thing to be comparing whatever we will see to? Yeah. I think it's not unreasonable where people are thinking about what is a regulatory threshold at the end of a study that suggests that you're going to have an ability and a pathway for approval. We know that the FDA has set a greater than 5% change in total body weight at the end of a study for filing. Interestingly, there is an emphasis on the agency on all of the other parameters. We're kind of excited about that as well because it's not just delivering on the greater than 5% change in total body weight. We're seeing an agency that's also reflective of this kind of race to the bottom based on muscle mass loss and saying, "We'd like to see that also with improvements in body composition," meaning driven off of fat and not muscle. We believe we'll be able to deliver both. It's not a movement away from what's a regulatory endpoint, but the most important piece is what's going to drive outcomes. That is going to be driven off of fat reduction. We see that as a point of differentiation. Yes, I think we will be able to see that as part of the study. That is the design of the study. That is the plan on the patient disposition coming into the study, and that is what is seen with other programs that have similar pathways. But I think we are even more differentiated from, again, if we look at bimagrumab, higher lean mass, lower loss of fat, greater than 5% change in body weight at the study point. I do not see how we have less lean mass because that is not our mechanism, but greater fat reduction. If we are doing algebra, that should lead to greater changes in body weight. Mm-hmm. Okay, got it. Then you are also looking to start the incretin combination, and post-incretin maintenance studies. Which incretins, plural, or how are you thinking about that study? Yeah. We will obviously provide the design once the study starts. I think it is safe to say, recognizing that there are combinations using INHBE out there with other medicines like the tirzepatide study that our peers study in combination. It would be reasonable to assume that we would want to do a very similar design just to be able to differentiate our INHBE program, where we do see differences from others. I think that study is really set up for us to, I think, prove what combination is really able to do, which is provide continued fat loss, right, driven on weight loss. But fat loss on top of the incretin. This notion of having to continue to push incretin doses to try to get that offsetting fat reduction. Being able to do that in a way, again, with a once to twice a year medicine that is not adding, at least based on the monotherapy data, any additional safety signals. I think it is actually a wonderful medicine to think about in combination. Because with that once or twice a year, you are able to reduce the injection burden and then be able to think about that combination. I think the study that is going to start just after that is probably the one that people are not paying as much attention to. I think there is a lot of focus on monotherapy and the 5%. There are the next questions because others have done it on combination. Probably one of the most interesting studies that will start, then we do not have to be talking about market segmentation, is maintenance. If we think about patients now, we talk to clinicians, patients a lot, we talk to payers. This notion of a lifetime of therapy, and the biggest fear everybody has that we talk to is, "What happens if I stop?" Because what people do know is when you stop, the weight comes back. It comes back as fat. Those patients then are at increased risk potentially when they stop. This notion of what does maintenance look like for the therapy long term, we think is a very interesting indication. Again, you bring a once or twice a year medicine back where patients are going to their physicians for checkups. You reduce the risks of anhedonia, hair loss, GI tolerability side effects, long-term lean mass loss in both bone and muscle. When we think about the long-term treatment of patients and how do you keep patients at their goal, given the financial investment that payers are making, frankly, that patients are making, the opportunity we see that is probably the most undervalued, underappreciated aspect is actually elevating the maintenance aspect of this approach. That study will also start this half. As we came into 2026 with the capital that we had, we said the investment is going to be in unlocking those three pillars: monotherapy, combination, and maintenance. Got it. Okay. Last INHBE question. As discussed or alluded to in this discussion, investor enthusiasm for INHBE came out on the back of the last update, which we think is incorrect. Very incorrect, by the way. Curious if you can talk about if there has been any shift in strategic interest in this program or enthusiasm? I think what's wonderful is some of the greatest calls afterward. I think strategics have gotten this program from the beginning. There's strong genetics. It translates. I think there was widespread recognition that, and it's not unsurprising, where there's sometimes investor disconnect from actually strategic disconnect, right? In terms of where this mechanism works. I think there's a widespread appreciation on the strategic side that this is a phase I healthy volunteer study, and that the data that investors are gating to our phase II-A obesity trials. I get it. With all of the medicines coming out, everybody wants to put something in a spreadsheet and say, "Well, how does this compare to those studies?" I think we were getting a lot of comparisons, to your point, with a lot of the early enthusiasm that absolutely, at this early time point, the enthusiasm was a phase I study in that first time point, is very much comparing and delivering against the profile of phase II-A studies, kinetics with lean mass and otherwise. I think, clearly we're on a pathway. Our focus is delivering on this. The biology is being recognized and translating. The study, we believe, is set up to do that, and we continue to see support from the strategics who are interested in this program. There was just another large biotech company recently that announced that they were going to enter the INHBE space. I think there's strong support off of genetics. This is a very strong genetic target that is translating, and we're running the experiment to deliver that. All right. Did not leave a lot of time for AATD, which is the latest stage program, but we'll try to cover a lot of ground. Can you just briefly talk about what WVE-006 is? You're planning to speak to the FDA at the end of the summer. What will you be asking them on? What are the key questions? Yeah. To start with, alpha-1 antitrypsin deficiency, these patients have a mutation. Instead of being MM with two healthy copies of this protein, they have two misfolded copies. This protein ends up building up in the liver and damaging hepatocytes. These patients are at increased risk for liver damage. Because it cannot get out of the liver and effectively bind in the lung to protect during these acute phase responses that patients get, they end up with lung injury. If we think about longitudinally, there are about 200,000 patients in the U.S. and Europe who are at risk of lung and liver disease by having this ZZ mutation. What WVE-006 is an RNA editing approach. Again, not working on mutating DNA to repair it, but actually a reducible way of thinking about correcting the transcript. Highly specific, no risk of off-target or bystander edits, is able to recapitulate this protein back and convert it back to an M protein or a normal function protein. What is important about the population, this ties into the regulatory discussion, is MZ patients. These are patients who are heterozygous, are able because they have a normal copy of one of those transcripts and make one normal copy of the protein, have low risk of lung disease and liver disease. They are able to not have as much accumulation in the liver, and they have enough protein to protect their lung. This is for those who are following the protein replacement space, this discussion around 11 micromolar is this set point is there. I say with protein replacement, and we will talk about that in a minute. The other differentiation between RNA editing, I should say, editing in general in protein replacement is the idea of fixing the protein. Not having to pour exogenous protein in to put a level higher, so that when patients have these acute events that are consumptive of the protein, that there is protein there to do it. What we were able to restore, our clinical trial data demonstrated this. Two weeks after the single lowest dose in the study, we had a patient with over 20 micromolar of protein, is that we could restore that normal physiology back to these patients, meaning this is a chronic disease of these acute exacerbations. What patients really need is when they have this exacerbation, can they produce the protein they need to protect the lung? Going forward, the opportunity we have is a safe redosable format to be able to actually correct the underlying mutation, restore physiology, restore back that heterozygous phenotype. The discussions that we are going to have with regulators are really built around this pathway of, one, do we have a pathway to accelerated approval based on biomarker-driven approaches? Two, we are also going to use that as an opportunity to discuss how we might be at accelerated path to full approval. So, how we can design the study to most efficiently deliver both on the biomarker-driven approach, but start those discussions on aligning on what a registrational pathway would look like. Okay. There is a competitor DNA editor program out there that some people may be familiar with that already has agreed to the FDA on the pivotal plan. Should we expect your outcome, understanding that we do not know yet, but is it unreasonable to think that yours would look similar? I think as we talk about biomarkers, I think we are all using the similar approach, right? We are all looking at the ability to convert Z to M. W e would not expect that to be different. I think where there are opportunities for differences, since we do not have to have ongoing safety characterizations of what does it look like if you off-target edit a cancer-associated gene? What does that study need to look like over time? Or bystander proteins, and how are you measuring that? That is different than what we would need for RNA editing. It may be that if we do not need to show longer durability, that we may discuss shorter time frames to be able to demonstrate a biomarker-driven approach. So I think that is where the flexibility comes in. But the key similarity is the biomarker approach to a potential registration. Mm-hmm. Okay. Then two other programs, HD and DMD. You have talked about partnership discussions ongoing for those. I guess, can you characterize the level of interest in both of those programs at this point? Yeah. DMD, I think there is a lot of discussion on the commercial side and watching a number of programs. We are having discussions with companies that have commercial distribution partnerships in that space. But there is a lot to watch as we look at the regulatory environment that is pursuing and how the commercial space is evolving. HD, I would say those partnering discussions are a little bit different in the context that in that space, we are now, because of Roche terminating due to a number of things, potentially a signal in their early study on allele-specific, that WVE-003 now represents the only allele-specific therapy that could be administered quarterly in Huntington's disease. I think there's a large belief that wild type suppression or wild type maintenance with mutant huntingtin suppression, where we've seen the largest reduction in mutant huntingtin protein across any of the programs, is attracting interest in the setting now that there's a clear lane in that setting to bring it forward. Those conversations continue. Got it. Okay, perfect. Well, perfect timing because we are out of time. Thank you so much for taking the time this morning, and thanks everybody for listening. Thanks for having us.