All right. Good morning still. Yes, everyone, thank you for joining us. My name is Whitney Egem. I'm one of the biotech analysts here at Canaccord, and I'm pleased to be chatting now with Wave Life Sciences and President and CEO Paul Bolno. So thank you so much for being here, Paul. Thanks for having us. Diving right in. So can you start with a high-level overview of who is Wave? What do you guys do, and what are you trying to build over the next five-plus years?

Yeah, hopefully longer than even the next five years. But if we look back over the last, now over-decade at Wave, we're an RNA medicines company, and we're really at the precipice now of clinically validated, programmable RNA medicines. And I say that it's really important because we're now at a point across multiple modalities, because when people talk about RNA medicines, you could say, well, you're an siRNA company, or you're a splicing company, or you're 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 like 18 months from the time we pick a target to human data. And we'll talk about that in the context of obesity with inhibiting for siRNA. Differentiated chemistry, but really now the convergence of that chemistry engine with human genetics. And again, we talk about each of the therapeutic programs that are in the clinic now. They're all able to rapidly translate unique clinical genetic insights, so coming out of human genetic databases like UK Biobank and others, so they're validated. But being able to partner that with a platform that can rapidly translate that to human data. So we're at the point now where, as we came into 2026, came in with $600 million that we said we're going to be invested in continuation of making sure that the platform could, engine, could deliver. We've got collaborations like we do with GSK that are delivering. And be able to push our clinical programs forward. So inhibinies in a 2A dosing study now in a population that's high BMI with comorbidities. So higher fat, we'll be able to discern the impact and differentiation of the inhibiting pathway for obesity. It'll enable us to take alpha-1 antitrypsin forward and we'll have feedback from regulators and a path to accelerated approval for the first RNA editing medicine for alpha-1 antitrypsin deficiency, which we see is highly differentiated, and then be able to bring forward the next novel RNA editing target that's built off of genetics, PMPLA-3, for the 9 million patients living with PMPLA-3 liver disease. So across the board, platform engine, delivering on human genetics into clinical programs, and now a pathway to potential accelerated approval for alpha-1. Perfect.

All right. We're going to start with 007 and dive into the science a little bit. So I don't think anybody, we all understand that obesity is a large market. So I'm not going to dive into the patient numbers. So just going to how the drug works, can you talk through the inhibiting biology? Like why mechanistically does that have an effect and potentially the desired effect of weight loss without muscle loss?

Yeah. And I think beyond just biology, I mean, I think it's biology with genetics. And so I think if we kind of step back into why is inhibiting E an interesting target to pursue orthogonally for the treatment of obesity? I think we know biology of the incretins, and we can put a whole bunch of different medicines in that category, which work by essentially 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. Inhibiting E, very different pathway, came out of the UK Biobank, genetically validated target. These human loss of function, So if we think about like 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. So 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's wonderful if you're born with it and are followed through. Is this a target that you can actually induce and drive? And so we showed in the DIO mouse model, so these are obese mice, and that's an important distinction as we talk about the upcoming clinical data, the phase 2A 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'll talk about incretins later, when you have 40% of your weight loss driven off of muscle loss early, you're going to get a very steep decline, and then that continues. What we see is a slower onset because you're actually building muscle. We'll talk about the human data where we saw that, so you increase lean mass, but then you see that fat loss over time as well. And so we could see weight loss and monotherapy, single dose with equivalency of the incretins. We show that it's 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. So we'll talk about that human clinical trial that'll get started this half. And then a really interesting indication because in the preclinical data, we also showed that if you pre-treat a mouse on an incretin prior to cessation of the incretin, if you take those two arms, both mice go back to hedonic eating. 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's important is that weight that comes back is all fat. So you actually have more fat at the end than you started with. The beauty of pre-treating with the inhibiting program is if you take the break 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. And so what you see is a stabilization of weight at that set point. And we'll be running that study, too, this half, initiating the maintenance study. We think across each of those preclinical data sets, there's really highly compelling data that's translated into our human data that we continue to follow as we'll start the next studies.

Okay. And one more just background or question. Why did you choose to target inhibiny, which is sort of the key, versus the receptor ALK7, which is kind of the lock?

So, as you point out, so this is a protein that's made in the liver, it's a hepatokine. The signaling pathway is the hepatocyte sends this protein to the adipocyte for fat storage, and that receptor, to your point, is ALK7. What's wonderful is, and again, this marries our chemistry, so highly potent SIs, when we compare our preclinical datasets 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. So we know that we've 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's on some other cell tissues. It has multiple signaling pathways that come through it beyond active in E. And so 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's accessible through GALNEC 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 to play out in our clinical data with specific knockdown, but also, again, exquisite safety through the highest dose co-order.

Okay, got it. And so can you speak to, I guess, key learnings from the phase one portion of the ongoing clinical study in terms of weight loss, fat loss, and maybe how that sets up or relates to the phase two A that's ongoing?

Yeah, so we step back and say phase one studies, you need to run a phase one study in obesity. And so 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. So these patients have varying degrees of baseline levels of fat to begin with. But the purpose of a Phase I study is safety, pharmacology, and then we have the ability, because of DEXA, to assess body composition. And I think what was exciting is these data come out. And I think it's hard when, I think in people's minds, everybody has a Phase IIa OB 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. So 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 seven and a half months with suppression of active in E. So again, continuing to support the opportunity for once or twice a year dosing. It's a strong effect on the target. And 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 increase in lean muscle mass, meaning as you broke down fat into free glycerol and fatty acids, muscles could consume that, and 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. And 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, and so to already be achieving that in a healthy population with no comorbidities was exciting. But beyond that, and this gets to kind of what we project forward as 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. And we saw a substantial reduction in subcutaneous fat that was relevant. And importantly, on the measurements that, you know, how do patients manage themselves, waist circumference. So we saw a 3.3% change in waist circumference. Again, all in a phase one, otherwise healthy population. So as we step back in terms of pharmacology translating very well, phase one 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. And the last piece as we think about this space, because it is in a large population, is safety and tolerability. And again, both safe and very well tolerated. So we didn't see GI side effects, no change in liver function tests, all of the important things that you'd want to see in a therapy that, you know, really could be life-altering. Again, all highly informative as we think forward to the design of the 2A study, which is dosing now and where we would expect is then C 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 loop? A belt loop. Okay. It's a belt loop. Got it. All right. And all right. So just talking about expectations, because to your earlier point, I think investor expectations headed into the phase one data were maybe mismatched relative to what would be reasonable to show given the design of the study. So to be clear, like, how should we, where do you want expectations to be headed into the phase two 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'm going to give you kind of the visual with my Like, if you think about where this study started, if we think about other two A studies, so So the best comparison study is kind of the BELIEVE study looking at Bimagramab and GLP-1. So Bimagramab is a medicine that in their phase one had more lean masking because that's the mechanism of action of that medicine, less fat loss in their phase one. When they went to their 2A study, at the end of that study in a year, they saw greater than 5% change in body weight. They saw all of that progress. So our view is exactly as you'd expect in going from a phase one healthy volunteer study to a phase two study in patients who have more fat to lose, how do you project that? And exactly as we think about the characteristics, the design of the study that's dosing now, so the study has entry criteria of BMIs of 35 to 50. While that's important, the most important kind of co-variable is comorbidity. So allowing patients who have comorbidities, so you're not excluding patients with high lipid levels, higher hemoglobin A1C. Those are all contributing factors to high fat, high visceral fat. And what we see in those studies of GLP-1s, magromab, in these phase 2a is high levels of visceral fat, high levels of total fat. And when you reduce that, that's how you change total body weight. So total body weight is really a function of losing, if you don't want to lose muscle, so in Cretans you'll get that by losing muscle and fat. As long as you have fat to lose, you'll lose weight. Where our study started was that the patient disposition was where patients were at the end of a year on all of those therapies. So already we know from our phase one study that body composition profile where patients have been treated with incretins or Vimagramab for over a year. So again, as we go into this 2A study, we believe we got the patient disposition, background Importantly, we'll also have the measurements. So if we think about this as a cardiometabolic drug, so yes, the obesity is going to be an important indication. We're set up to be able to look at changes in body composition, change in total body We do believe, based on all of our modeling from the phase one, two, between this study and other studies, we'll achieve a greater than 5% change in total body weight driven on fat. But the opportunity ahead for this program is on all of the other metrics as well that this improves. And so we'll 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. So 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, that we can study.

I hear you on all that. And also, this 5% BMI level continues to be the thing people are looking for. So is that at the dose you're looking at, at the time point 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?

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. So 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 as also reflective of this kind of race to the bottom based on muscle mass loss and saying, you know, we'd like to see that also with improvements in body composition, meaning driven off of fat and not muscle. And so we're going to, we believe we'll be able to deliver both. So it's not a movement away from what's a regulatory endpoint, but the most important piece is what's going to drive outcomes. And that's going to be driven off of fat reduction. We see that as a point of differentiation. So, yes, I think we'll be able to see that as part of the study. That's the design of the study. That's the plan on the patient disposition coming into the study. And that's what's seen with other programs that have similar pathways, but, you know, I think we're even more differentiated from, again, if we look at the Magromab, higher lean mass, lower loss of fat, greater than 5% change of body weight at the study point. I don't see how we have less lean mass because that's not our mechanism, but greater fat reduction, if we're doing algebra, that should lead to greater changes in body weight.

Okay, got it. And then you're also looking to start the incretin combination and post-incretin maintenance Which incretins, or plural, or how are you thinking about that study?

Yeah, we'll obviously provide the design once the study starts. I think it's safe to say, recognizing that there are combinations using inhibiting out there with other medicines like the terzepatide study that are pure studying in combination. It'd be reasonable to assume that we would want to do a very similar design just to be able to differentiate our NIMME program where we do see differences from others. And I think that study is really set up for us to, I think, prove what combination is really, you know, able to do, which is provide continued fat loss, right, driven on weight loss, but fat loss on top of the incretin. So 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's not adding, at least based on the monotherapy data, any additional safety signals. So I think it's actually a wonderful medicine to think about in combination, because with that once or twice a year, you're able to reduce the injection burden and then be able to think about that combination. I think the study that's going to start just after that is probably the one that people aren't paying as much attention to. I think there's a lot of focus on monotherapy and the 5%. and there's the next questions because others have done it on combination. But probably one of the most interesting studies that will start, and I think then we don't have to be talking about market segmentation, is maintenance. If we think about patients now, and we talk to clinicians, patients a lot, we talk to payers, and this notion of a lifetime of therapy, and the biggest fear, right, 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, And those patients then are at increased risk, potentially, right, when they stop. So 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-to-twice-a-year medicine back where patients are going to their physicians for checkups. You reduce the risk of anhedonia, hair loss, GI tolerability side effects, long-term lean mass loss in both bone and muscle. And so when we think about kind of 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's probably the most undervalued, underappreciated aspect is actually elevating the maintenance aspect of this approach. And that study will also start this half. And so as we came into 2026 with the capital that we had, we said, you know, the investment is going to be in unlocking those three pillars, monotherapy, therapy, combination, and maintenance.

Got it. Last Inhibony question. As discussed or alluded to in this discussion, investor enthusiasm for Inhibony kind of came out on the back of the last update, which we think is incorrect, very incorrect, by But curious if you can talk about if there's been any shift in strategic interest in this program or enthusiasm.

So I think what's wonderful is some of the greatest calls afterward. I think strategics have gotten this program from the beginning. I mean, 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. This is a phase one healthy volunteer study. and that the data that investors are kind of gating to are phase 2A obesity trials. And 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? And 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 1 study, and that first time point is very much comparing and delivering against the profile of 2A studies, kinetics with lean mass. Otherwise, so I think, you know, clearly we're on a pathway. Our focus is delivering on this. The biology is being recognized and translating, and the study, you know, we believe is set up to do that, and, you know, we continue to see support from the strategics who are interested in this program. I mean, there was just another large biotech company recently that announced that they were going to enter the inhibiting space. So I think there's strong support off of genetics. I mean, 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. So can you just briefly talk about what wave 006 is? And 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. So to start with, so alpha-1 antitrypsin deficiency, these patients have a mutation. So instead of being MM with two healthy copies of this protein, they have two misfolded copies. So this protein ends up building up in the liver and damaging hepatocytes. So these patients are at increased risk for liver damage. And because it can't 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. So 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 O6 is, is an RNA editing approach. So again, not working on mutating DNA to repair it, but actually a reducible way of thinking about correcting the transcript. Highly specific, you know, 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's important about the population, this ties into the regulatory discussion, is, MZ patients, so 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. So they're able to not have as much accumulation in the liver, and they have enough protein to protect their lung. And this is, for those who are following the protein replacement space, this discussion around 11 micromolar is kind of a set point, is there. I say with protein replacement, and we'll talk about that in a minute. The other differentiation between RNA editing, I should say editing in general and protein replacement, is the idea of fixing the protein. So 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's protein there to do it. What we were able to restore, and our clinical trial data demonstrated this, I mean, two weeks after the single lowest dose in the study, we could get 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, and what patients really need is when they have this exacerbation, can they produce the protein they need to protect the lung? So 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. And so the discussions that we're going to have with regulators are really built around this pathway of, one, you know, do we have a pathway to accelerated approval based on biomarker-driven approaches? Two, we're also going to use that as an opportunity to discuss, you know, how we might be able to accelerate a path to full approval. So, you know, how do 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. And 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 don't know yet, but is it unreasonable to think that yours would look similar?

I think as we talk about biomarkers, I think we're all kind of using the similar approach, We're all looking at the ability to convert Z to M, and so we wouldn't expect that to I think where there are opportunities for differences, since we don't have to have ongoing safety characterizations of what does it look like if you off-target edit a cancer-associated What does that study need to look like over time? Or bystander proteins, and how are you measuring that? That's different than what we need for RNA editing. So it may be that if we don't need to show longer durability, that we may be able to discuss shorter time frames to be able to demonstrate a biomarker-driven approach. So I think that's where the flexibility comes in. But the key similarity is the biomarker approach to a potential registration.

Okay. And then two other programs, HD and DMD. You've talked about partnership discussions ongoing for those.

I guess, can you characterize the level of interest in both of those programs at this Yeah, I think, I mean, DMDA, I think there's a lot of discussion on the commercial side and watching a number of programs or having discussions with companies that have commercial distribution partnerships in that space. But there's a lot to watch as we look at the regulatory environment that's pursuing and how the commercial space is evolving. HD, I'd say those partnering discussions are a little bit different in the context that But in that space, we're now, because of Roche terminating due to a number of things, potentially a signal in their early study on allele-specific, that O3 now represents the only allele-specific therapy that can be administered quarterly in Huntington's And I think there's a large belief that wild-type suppression or wild-type maintenance with mutant Huntington suppression, where we've seen the largest reduction in mutant Huntington 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 and those conversations continue.

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.