Wave Life Sciences, Inc. (WVE) May 20, 2026 Conference Transcript

Hi, great. Thanks. Hello, everybody. Luke AC, Senior Biotech Analyst here at RBC Capital Market. And today's our great privilege to have WAVE as part of our 2026 Global Healthcare Conference. Representing the company, we have Paul Bolnow, Chief Executive Officer. Paul, thanks so much for joining us. How are you doing today? Great. And thank you for having us, Luke. I appreciate it. Absolutely. Absolutely.

We have a long list of questions here, but maybe before we jump and talk about some of the specifics, especially around your data obviously earl this week at ats and whatnot it would be great if you can maybe start big picture tell us a little bit more about what progress has the organization made over the last few months and what's ahead here for wave yeah no i mean in 2026 was set up to be an exciting year as we started and we really grounded the year on two key themes the first was going to be the investment we had been making in a differentiated si rna platform and that was led by our program with inhibiting we've made progress last year demonstrating that you know we could translate a novel human genetic clinical insight into the first obesity target that's really focused on solving the underlying body composition question of reduction in body fat preservation of lean mass and being able to do so in a once to twice a year injection and so it was exciting to see that as kind of the anchor product for si rna and deliver that data at the beginning of this year. And as we'll speak to later, really the progress we're making there in terms of getting the phase two A high BMI study off the ground. So that was kind of one anchor of strategy coming into this year. And the second core anchor was our leadership in RNA editing, really grounded with alpha-1 antitrypsin to bring that program in an accelerated way through the 400 milligram data with the goal of really saying that we could do this in a way that was less frequently administered and be able to have a meaningful therapy for these patients with ATD who suffer from lung disease and liver disease and really be able to treat the disease holistically. The goal being off the two programs that we can continue to build the underlying platforms, both in RNA editing beyond. So PMPLA3 on track to enter the clinic later this year to treat 9 million patients living with PMPLA3-related genetic liver disease and then continue progress across siRNA. So I think what we set out to do as we enter 2026, we're very much on track to continuing those activities, and we're excited to continue the progress.

Great, great. Just came back from Orlando, obviously, ATS, lots going on there. Maybe, again, before we go into specific, just maybe just recap a little bit what data you've shared there. Maybe just remind us why you're excited about that data. And then maybe if I may, can you just maybe remind us why GSK ultimately decided to pass on this program?

Yeah, so I mean, to deal with that last question the beginning i mean there was a decision last year that gsk made so this is well before any data um as we know is and shall we say i'm not authorized to speak on gsk on behalf of their um strategy but there were strategic shifts in the company in terms of particularly respiratory franchise in terms of larger focus on big diseases versus rare and you know as they kindly said in the quote you know we were better positioned to accelerate a rare genetic disease And so I think that was a good transition to happen before data. We're excited about the data. And I think really coming off of ATD, to your point, I don't think we are excited about It was, you know, ATS was a wonderful place to showcase the data for the first time. We had a late-breaking abstract that was presented by the clinical community really grounded on the data that we had previously shared, that we're doing something that's, you know, fundamentally interesting for these patients in terms of changing their outcomes by the profile that we're generating. And so I think there's excitement and enthusiasm for RNA editing. And yeah, so we're excited to bring that program forward.

Great, great. Again, maybe before we go into the data, I think the other big highlight at ADS was the data from Sanofi. And, you know, obviously post their transactions with networks years ago. And, you know, it seems to me that, you know, now augmentation therapy has a little bit of a better option that is maybe dose less frequently and drives kind of a higher pharmacodynamic effect in the serum with a higher level of alpha one does does that raise the bar for everybody in the space again appreciated your approach is totally different and you're tackling the genetic root cause of the disease and everything else but like that data was pretty reasonable so how are you thinking about where the field is moving i think in order to understand the field and the various programs it's just really important to take five steps back and just say, what are we all trying to do for these patients, right?

So oftentimes, sometimes it's not about the, how do you do it? Is it genetic root cause or is other, it's really, do you treat the underlying disease? And so if we step back and say, AATD is a disease of really starts in the liver, that's why everybody talks about, but it talks about the lung and that's because the protein secreted in the liver and because it's misfolded it doesn't isn't able to protect the lung from injury and so if we think about what alpha-1 antitrypsin deficiency particularly for zz patients is it's a chronic disease of acute exacerbation so we have to remember what are you trying to treat you're trying to treat these multiple acute exacerbations over time where there's this inflammatory event during that inflammatory event that protective protein that's supposed to protect you from the breakdown of that inflammation doesn't work. So what do patients have? They have, over this chronic period, they get repeat lung injury. Because this protein's misfolded, during those events where there's a stimulus, they're producing this misfolded protein in the liver, so they continue to accrete these aggregates in the liver that injure and damage the liver cell. So when we step back, and I think, you know, I think Dr. Hogarth did a wonderful job kind of articulating this. For the longest period of time, and hence when you talk about, it's interesting when we talk about the innovation right now in this space on augmentation is really going from once a week to every three weeks. It's not a dynamic shift. But it's really saying that the only treatment option physicians had was to infuse a plasma-derived protein to a level that they believed would be there to treat the disease. And this is where 11 micromolar, as you pointed out, this extension with Inhibrix, which is dimerizing this FC, enhanced a little bit of different protein, but could get to like 2024 at steady state. You have to remember, this is the protein replacement. So it's like pouring water into a bucket with holes in the bottom. The whole thesis was, could you get, because this is a consumptive protein, as soon as you have an event, you lose the protein. So physicians' fears actually were, I'm going to infuse my patient every week. If they have a pneumonia on a Friday, they're losing their protein. I've got to wait to get them back to get their next infusion. And actually, there's some infusion anxiety when I talk to some physicians who are like, now I've got to wait potentially from a payer two more weeks to give my patient another infusion because that's what they're going to pay for now is every three-week infusion. And so I think there's going to be a real debate in the field of the advantages of pushing those infrequent infusions out versus not. Obviously, for patients, less is more in terms of the time in a hospital. But IV hospital-based infusions. The real step change in editing, and I think this is really where we need to kind of divide the field, is really trying to address the disease. So yes, we do it by addressing the underlying genetics disease, but I step back and just say, you're really addressing the two components of the disease. If you can fix that protein, you decrease the accumulation of liver. And we saw 71% reduction in toxic Z aggregates. So the ability to actually remove that source of misfolded protein from the liver that damages the liver. You have the other key treatment goal, which is these patients create 50% of their protein in circulation. So that greater than a lot of micromolar is M protein. And we see 65%. And we actually did an analysis because there's a lot of questions sometimes of like, what is that ratio? We actually took the assay that's validated that we're using for our regulatory discussions. We ran a natural history cohort of, you know, what are MZ patients, this phenotype that is protected from lung and liver disease. And the mean was about 64% M protein. And there was a range of about 57 to 71% M. So clearly within the range of what we need to have the MZ phenotype. But the single most important aspect of this treatment is being able to recapitulate the natural physiologic response to these acute phase events. So in the 200, two weeks after a single dose, we could see we could get to over 20 micromolar of protein. So to your point on when we look at kind of where the state is in terms of protein replacement, we're achieving that endogenously when the patient actually needs it. And then, you know, everybody says, well, that was interesting. that was an event I think was really affirming at ATS with physicians is we saw two more opportunities where patients had acute phase events. These were much more mild. These were, as we said, mild upper respiratory infections is to translate that into English. I always say that's a common cold. So patients reported and we went back and saw actually when patients had their cold and they had their spike, we could actually see spikes of total AAT levels and, you know, in case up to 16. So again, what we're seeing is with editing, you're actually treating the underlying components of a fungal liver.

And definitely, yeah, the induction of expression is critical in that context. Maybe the other question, again, this is a never-ending debate around RNA editing versus DNA editing. You know, how does your data compare to Beam? And again, I think when I look at your data versus their data, one of the maybe, you know, differences is the ratio between M and Z is a little bit different between the ratio that you're showing versus the ratio that they're showing. So maybe you want to compare or contrast your approach versus them.

Yeah, I mean, I think stepping back, I think we both share the appreciation for what editing gets, right? If you can restore these dynamics, that's advantageous to patients. If you can really get that component of treating lung and liver, that's a step change, I think, for the field. I think where the separation between those two pieces come out is in what it is we're measuring. So I think it's really critical when we speak to the ratio, when we look at what the ratio as an MZ. We're measuring actual M, canonical M protein. So when you look at the percentage of M protein, the actual endogenous protein, it's consequential. It's 65% of that is the native protein. I think it's very hard. And I'll put the question to you back to that. Within how the data is reported, and I know it's very hard as people look at these numbers and appreciate that people try to dissect these numbers of what do they mean. dna editing has two components on one hand to try to drive the ability to create the protein there was this kind of hyperactive deaminase how do you push this protein and in so doing they drove what are called bystander edits so these are on target off target edits so these are creating variants of that protein that need to continue to be characterized so when the total gets reported as you're comparing within that total are isoforms of m there's m there's isoforms of z so there's actually off-target z edits and then there's z and so that total as you add that sum up becomes a very different component so when people are trying to compare we saw 14 micromolar of total protein all m all z in total you know the others can you know discuss how they report that totality but very similar in terms of that. And when we talk about percentage of protein, 100% of our M protein reported is the canonical native M protein. I think the other thing we have to remember in looking at these two different approaches is specificity on the off-target side. And I think that's the piece that is continuing as we come out of ATS is an important piece for us to focus on, which is RNA editing is exquisitely specific. When we look at transcriptome analysis going into the clinic, we don't see off-target edits. So the ability not just to look at not having the bystander edits, but avoiding permanent off-target editing in key components that, you know, I think physicians would be concerned about over time, and it's not to say that those can't be discharged over time, are critical, including, you know, the potential for editing of cancer-associated genes and what that means long-term for patients. So I think it's critical as we think about putting a profile together that meets the key treatment goals for patients with alpha-1 that delivers the dynamic response and does so safely and conveniently. So at this point in time, we can deliver a profile that doesn't have liver toxicities. We don't use LMPs in patients with liver deficiency and can deliver a safe infrequent profile that I think transform, you know, how patients look at care for alpha-1.

Got it. Super helpful. Maybe what's the latest thinking on dosing, I go, I appreciate the trial is still ongoing. We haven't seen all doses and all dosing frequencies yet, but it feels to me that maybe monthly is the way to go versus biweekly, at least at high level. And maybe are you thinking 400 milligram or thinking 600 milligram? Well, how are you thinking today at the go forward dose?

So I think what's this data was, you know, designed to deliver. And, you know, as we said, coming into this year, what was going to be the importance of this upcoming data set was the last data update had been biweekly. The question for us was that shift of, could this be a monthly dose or less frequently? I think we've crossed into the monthly dosing regimen. And I think to your point, we have a 600 milligram monthly dosing coming, which now gives us the ability to look at exposure differences between the 400, 600 that let us calculate and step back. Are there less frequent regimens? Are there different ways of dosing this that continue to protract the dosing interval out? And that'll be some of the data that we'll continue to affirm.

But I think we feel very comfortable that monthly dosing is a pathway way forward um which is i think important for these patients gotcha super helpful um i do want to pivot to inhibi but maybe last one on alpha one um tell us more about the regulatory uh path here have you had recent conversation with the regulators obviously your competitor is in record arguing that there's a path for et cetera approval based on biomarker i think they're not describing exactly what biomarkers they are but we can all think about total total protein as well mz m and disease as well? So like, are you planning to follow their path or what's your latest thinking on that side?

Well, I think the good understanding that we have is I think the path that we're both taking is very similar. And I think it's not necessarily following a path as much as I think that has been the path for alpha one. So I think there is a well-established path of biomarkers that are necessary for treating this disease. So I think the good news, if we're talking about M protein and how much percent within total, these are ranges that have very well described paths, right? We know what the MZ phenotype looks like. So again, a lot of our characterization of this natural history cohort is really establishing the biomarker precedence for saying, are we delivering on that? So at baseline, you need a certain level of total protein, because in order to talk about what percentage of your protein is canonical native protein, you have to have a basis for with which you're evaluating that. And we think there's consistency around looking at these MZ patients have this range of, you know, over 11 micromolar. So that's kind of the entry point. Within that, I think this idea of what percentage is the canonical native protein becomes the And so I think, again, talking about these biomarker strategies on a registrational path is the same approach that we'll be taking. And we'll have feedback middle of this year on the path to accelerated approval, what that study needs to look like. I think we have opportunities to think differently about that study in a medicine that's reducible, where you don't have to do longer follow-up to see test durability, which could be in question, safety, which could be in question. So the ability to think about, is there an opportunity to truncate some of those studies to the accelerated approval side? And then I think what's encouraging, again, coming off of ATS, where we've met with the Foundation, Alpha One Foundation, and others who are doing a lot of work right now in CPATH and with the FDA on endpoints for the clinical side. So not just thinking about what do you need for an accelerated approval, but what are the endpoints as we think down the road? And I think what we're seeing is CT densitometry is becoming more and more interesting for looking at lung function over time. And so I think these other tools that we'll have to be able to evaluate what's going to be necessary as part of a registrational pathway and being able to look at other non-invasive measurements for liver function to add liver into those indications, I think will be important as we think about those discussions that are upcoming.

Got you. Got you. That's super helpful. Maybe talk about Inhibi. I think obviously that pathway is a pathway that you and many other companies are pursuing in different ways, either with Inhibi or Inhibiol 7 or both and whatnot. I think we're seeing some pretty profound reduction in weight in mice. However, as monotherapy in humans, it doesn't look like those drugs are driving profound reductions in weight. What's the best way to kind of rationalize why the preclinical data is maybe not necessarily replicated in monotherapy in humans?

Well, I don't think we're in this. I mean, I think it was encouraging if we step back and say, well, what do models do? And how do they translate. And I think preclinically, our models differentiated very much from some of the others. So we saw single dose weight loss. Others had to give repeat doses to prevent weight gain. And so there was very different models recognizing that these are obese mice. And that's an important distinction. Our early clinical data that you're referring to is interesting. It's not that in my mind, it didn't translate. Actually, it translated extraordinarily well in patients with low BMI in phase one. And I think what happened is, I was thinking a lot about the discussions around the data, the comparisons everybody were making, which were wonderful, were being able to compare our phase one healthy overweight volunteer study with phase two, three high BMI clinical trials. And so to say that these things were looking similar and interesting, I think was a great starting point. I think highly encouraging, but that's not the patient population to do those comparisons in. And I think we've been consistent for a very long time that that was about establishing a profile while we go into the high BMI studies, where now we're looking at the similar patient populations, similar levels of visceral fat, similar levels of subcutaneous fat, ways to be able to actually do these direct comparisons. That population has a lot more in common with the DIO mouse model, which is an obese mouse model with fat to lose. So actually, that's why we're so encouraged about going into the high BMI phase 2A study because now we're in the appropriate population. We know that we take down the target extraordinarily well. We know we're on track for once or twice a year dosing based on following the biomarker. I mean, six months after a single dose, we saw a 15% reduction in visceral fat without inducing diet or exercise in these patients. So the ability to see that actually this target's doing what it's supposed to be doing and And now putting it in the appropriate patient population, I think, is highly encouraging. So this wasn't this study to definitively say, is inhibiting the target? This was the study saying, is it safe? Does it engage target? And do you see those impacts of hitting the target? And I think the answer to all three of those was yes. Now we can go into that patient population study and actually do the direct comparison. Yeah, yeah.

And you already mentioned, but maybe how should we think about regulatory? To your point, you're not going to start a trial. with patients with much higher BMI, hopefully those patients, we're going to see this magic 5% threshold reduction in weight that the regulators are focused on. So hopefully that's the case, and the rest is history. But should that not be the case, how are you thinking about what are the potential other endpoint that could lead to registration? Can reduction in visceral fat be potentially registrational, or are there other endpoints you're thinking about? What's your take?

Yeah, I mean, it's interesting. after the data, you know, all the questions of like, you know, well, what about cardiometabolic disease instead of obesity? And, you know, I always step back and say, we need to remember that obesity is a cardiometabolic disease, right? I mean, it is in a family of all of these. And what's the driver of the complications in obesity? It's visceral fat. That's the principal driver of pathology. And so we're able to see that there. To your point, I think what we see, which is what drives that is a whole bunch of other potential endpoints so to your point liver fat reduction we should see that we're measuring that with mri pdff so we're capturing that risk of type 2 diabetes so if we look at the study we're running and it's not just high bmi patients we're we're theoretically running two studies in tandem which is high bmi with diabetes and high bmi without diabetes so again being able to capture hemoglobin a1c another biomarker that actually by itself is a registrational endpoint in diabetes. So being able to capture, you know, those endpoints. Other lipids, which change in a function of, you know, driving an improvement in cholesterol, which you see in the human genetics we're capturing. So when we step back in the study, we are capturing the totality of what you would want to see for a whole variety of endpoints potentially in cardiometabolic disease. So we're kind of feeding two birds with one hand in the study that we're going to learn a lot about cardiometabolic diseases at a high level, of which a subset of that is obviously looking at obesity as an indication and some of the other endpoints. But I think it's as crucial as we do think about this, that you mentioned this 5% figure, and I think it is an important regulatory bar in terms of that's an accepted established. If we look at medicines like Bimagramab, which are principally lean mass builders, right? They're not focused. Phase one in our study, we actually had more fat loss than Bimagramab, slightly less lean mass gain. But nonetheless, when they moved from their phase one trial to their phase two of obesity study in high BMI patients, despite larger lean mass and less fat loss, they achieved a 5% body weight reduction. So I think our confidence when we see more fat loss, which is ultimately the driver of body weight reduction and preservation of lean mass. I think there's nothing that's changing our mind of being able to deliver that. I mean, I think that's important. But you brought up another point, which is, and I think where we should be talking about, which is if visceral fat actually does drive the majority of these diseases, the VMR, this visceral fat to lean mass ratio, and being able to look at actually quantifying in a very defined way, there's established mechanisms for doing that, is actually a really interesting tool to be able to say, what are your real risks of outcomes? And those are pretty well established in the literature. And there, I mean, if we look at our VMR, even in the healthy phase one study, our VMR was still better than the GLP-1 semaglutide when we did the direct comparison to the BELIEVE study. So I think the impact that we're having on FAD is substantial. I think it underlies the value of the target validation of the human clinical genetics to humans.

And now again, we just need to put it in the right population to see it work. got it got it that's helpful um maybe in the last few minutes i know we only have a couple minutes here left um what's maybe the latest thinking on dmd um i feel like that program is not getting maybe the attention that it deserves from investors and other holders like what's your latest thinking on whether you can get accelerator approval or not again we've seen a lot of the skippers for better or for worse the confirmatory trial obviously did not pan out favorably so is Is the Accelerate Approval Pathway still open? What are the timelines to your product? And just walk us through that part.

So nothing's changed from what we've heard on the pathway to Accelerate Approval based on biomarkers. But we would be remiss not to be continuing to watch that landscape with a number of companies who are actively going their regulatory interactions to see where they are. I think the other piece within this space is it's becoming a lot more crowded. And so I think as we watch commercially in that space, you know, we came into this year, as we said, with a strategy really anchored on siRNA with inhibiting and building the siRNA platform, editing with alpha one commercially. We think that there's a tremendous opportunity there and being able to build and grow that with our RNA editing programs. And as it relates to DMD, I think we've been, you know, having the conversations with those companies that have been engaged in the commercial landscape there to really think about that as opposed to building out into that. while we watch the regulatory landscape evolve and assure that we have a program. I think clearly we have a program that generates strong muscle exposures, generates strong dystrophin to the point on that as an endpoint. We had improvements in time to rise. I think those clinical measurements are gonna become more important to follow over time. And I think we'll continue to track that and work with companies in the space. But in terms of pathway, there's nothing that we've heard that's changed the timeline or trajectory there. Got you.

Super helpful. I know we're almost at time here. Maybe, Paul, stepping back big picture, what do you think is the most kind of underappreciated aspects of the wave story today?

I think sometimes we tend to underappreciate the fact that in two really areas of innovation and novelty, these medicines are translating. I think they sometimes get lost through the opaqueness of what's different because you're doing something that's new. It's not taking something that people have already established and saying, you can take it from a once a week to once a month, but you're really underlying and unlocking new biology in addition to driving that innovation. And I think what's important when we step back and look at characterizing each one of these opportunities, inhibiny is very much delivering the clinical picture of what it needs to do. Now it needs to deliver it in the right patient population. And the same thing with alpha-1 antitrypsin. It's delivering that transition in a way that it should, and we're excited to continue to advance that conversation through regulators and see that transition to being a potential commercial product.

Fantastic. Paul, we have a lot more questions but no more time.

So we appreciate you joining us here at RBC.

Thank you for joining. Thanks again. I appreciate it.