Welcome, everyone, to Jeffrey's 2026 Global Healthcare Conference. My name is Roger Song, senior in this cover of Simicap Biotech. It is my pleasure to have the next company with me, High Five Side Chat, Wave Life Sciences, and then we have CEO, Paul Bono.

Thanks, Roger. It's great to be here. Alrighty, so, Paul, why not you give us two minutes state of art for Wave? you have a lot kind of going on and then in terms of the platform and the pipeline so we're going to dive in after your remark yeah no look i one we appreciate the time and it's good to update and to your point where there's a lot going on i think we've come into the year with a very clear set of objectives of what we want to accomplish and with the resources to do that so with substantial cash on the balance sheet coming into last year we recognize that we need to be very disciplined in where we apply that. So the core areas that we focused on at the beginning of the year, we're going to be delivering on inhibiting for obesity and the other cardiometabolic indications, and deliver that across the three core principle use cases, meaning one, monotherapy, and we'll talk more about the initiation this quarter of the high BMI, patients with comorbidity, the with and without diabetes monotherapy study, the combination study that will start shortly thereafter, and then the maintenance study, which we think is a very compelling opportunity for that program. So that's all on track, and that's delivering those data within the cash envelope. Additionally, we came into the year to deliver on alpha-1 antitrypsin, and with the transition and data update both from ATS, which I really think reflects the pulmonary side of the disease, but importantly remembering that alpha-1 antitrypsin deficiency is both a lung and liver disease. The updated easel, which was well-received, really thinking about that program with regulatory update middle of this year on a path to accelerated approval. And then the third program, PMPLA-3, even, you know, we were excited about it kind of coming into the year. This is a program that will go into the clinic this year. This is for the nine million people living with the PMPLA-3 mutations that drive liver This is a target that has been tractable through siRNA in terms of silencing, but it was always an enzyme that if you silenced it could theoretically make the disease worse. We actually had preclinical data that showed if you knock out the enzyme, you build fat, you get actually doesn't treat MASH. But if you edit, you fix the protein, you do see improvement, and what we've been seeing since ESL is a number of siRNAs continuing to demonstrate the inefficiency target engagement, but that actually clinical translation of the SIs isn't translating, and therefore, again, reinforcing the thesis around editing and bringing that in the clinic. And so that's really the core thesis of where we've been investing. We'll continue to deliver important, meaningful data sets there.

We do have a lot, but I think let's maybe just one by one, maybe focus on the Inhibi for a moment, given we are heading to ADA. You will be there. We'll be there. So we'll host dinner with you as well. So what have you seen for the, you know, 200, 400, three months, six months? And then what you think is the most influential factors, maybe not seeing the weight loss you want to see, but actually it's expected. So tell us a little bit more how you know after a couple months and digesting the data, what's the current thoughts about that?

Yeah, no, we could spend a lot of time unpacking all of those points. And I think, you know, this is the ultimate crux of this program. I think stepping back, we have to remember what inhibiting is and why it's so unique in this landscape for obesity. And so this was always a human genetic target with a 50% loss of function in these people. I won't call them patients, people with a 50% loss of function. That's protective. They have low risk of abdominal obesity. They have low visceral fat, higher lean mass, low lipid levels. They have cardiovascular outcome benefits. and then they have type 2 diabetes outcome benefits. So if we think about kind of the genetics on obesity, it is a wonderful target, principally driven off of an important feature, which is called body composition, thinking about reduction in fat and preservation of lean muscle mass. We were the first to show that you could recapitulate that human biology in obese mice. So when we took the obese mice and we treated them, we could get weight loss similar to GLP-1s that was all driven off of fat, particularly a substantial reduction in harmful visceral fat and stabilization of lean mass. And we did see a slight increase in lean mass, and then that stabilized. So again, exciting to see the recapitulation of biology. We also were the first to bring it into the clinic and actually could see that. And I'll say one very important feature is we talk about inhibiting and the field of siRNA. There's both a platform component and a program component. I think the platform component is critical to understand that differentiation, particularly as we think about going into ADA and other meetings, where how our siRNAs are different than other siRNAs. And that comes down to chemistry. About three years ago, we published a paper in NAR looking at our unique chemistry as WAVE is a unique oligonucleotide chemistry company in RNA medicines, and demonstrated that we could see better potency, better durability when we compared that against industry standard siRNAs. And we could say we took a number of targets from anilum, made them, and could get better potency and better durability. There are a lot of targets where you kind of say, is that necessary, is that can give you less frequent dosing? And what was really unique about inhibiting is this is a target that's under pressure. And Nate, when we talked about the genetics, this is a target that human biology used over evolution to store fat and energy. So you can imagine if you start tipping the scales of reducing that, the body's going to have a high drive to see and reconstitute that protein. So it was an ideal target for us to do two things. One, validate our siRNA differentiation, and the other is bring that forward with a really meaningful program, in this case for obesity. And we saw in the human data and one in the animal data was the recapitulation of that in a very meaningful way, where we saw weight loss on single-dose data that suppressed that. All the other preclinical data sets were all multi-dose data sets, so they showed multiple doses of a GalNic siRNA that could suppress weight gain, and we were the first and really only to show weight loss in the preclinical models. We also had really interesting data on maintenance where we could show that we could dose prior to cessation of GLP-1s and then not have to subsequently dose and show that when you withdraw the GLP-1 following predosing, you prevent the rebound weight gain. Essentially the nature's drive to reconstitute in response to calories, fat regain, we could suppress that so you see stabilization. That's really important as we go now into our clinical data, where we were able to recapitulate Now, the important notion, and I think this is a very important feature of the clinical trial, is these data that we have subsequent to the start of this next study, which is the Phase 2A study, are all the Phase 1 healthy volunteer study. These are patients without comorbidities, meaning these patients don't look like patients who are in obesity studies, because they're not allowed to have all of the comorbidities which drive high levels of visceral fat, high levels of subcutaneous fat. I think what was exciting about those data is we saw a profound effect exactly as anticipated on fat. I mean, we see a 15% reduction in visceral fat, like 5.4% reduction in subcutaneous fat, 3.3% reduction in waist circumference, meaning patients were able to tighten their belt loops. So the medicine was doing exactly what it's supposed to do in a setting of patients who are otherwise healthy. I think, as you mentioned in the question of what about weight loss, I think it's really important that we think about kind of this evolution of what happens with body composition, not to exclude weight loss, but really to reframe the focus on body composition changing, meaning fat loss, muscle sparing, and ultimately where that leads to in total body weight. Right now, the only tool that people tend to use, and we think about this oftentimes with patients who are on increments, what drives them to use it is scale weight, standing on a scale and saying, am I losing weight? What we're seeing is an evolution, too, in measurements where people are getting scales that are as high quality as DEXA in the home and starting to track things like lean mass, fat mass, visceral fat, and we're at South by Southwest, and it was just amazing how many people and how prevalent this body tracking is becoming as just a feature of seeing what's happening and what you're doing. And so body composition is really important. I say this because when we actually did the analysis of what's called VMR, visceral fat, to mean lean mass ratio, meaning looking at that ability of loss of muscle and loss of prevention of loss of muscle and loss of visceral fat, we actually had a better VMR score than GLP-1s, meaning this effect on fat loss and muscle preservation was playing out. So we're excited to continue to see that trend. Nonetheless, to your question, we do anticipate achieving the thresholds that are in the regulatory constructs of in a phase 2-3 study in patients who are obese, high BMI with comorbidities, and we'll talk about that trial, we do expect to see greater than 5% change in body weight. And the best data that exists for that, and we were talking to some of the physicians who were involved in the BELIEVE and Pemagromab study, is, you know, here's a medicine that had less fat loss in their early studies than what we saw, higher lean mass production than what we saw, because it's a myostatin drug, and our drug doesn't make lean mass, it just preserves lean mass. And yet, in the obesity studies that they ran in their Phase 2A study, saw greater than 5 percent change in body weight. So I think it's just really important to contextualize what's mechanism, and we saw the mechanism of action in the translation here in a highly potent, safe, durable way, meaning we're still on track for once to twice a year as the dosing regimen, safety through the highest dose score was clean, there was some irritation at the injection site, which is a great profile for obesity. And now we're poised to really that transition, which will start this quarter, which is the high BMI patient study with and without comorbidities as both a non-diabetic and diabetic study. So it'll be a substantial data set that will start.

Yeah. By the way, you're probably the only SRNA is actually showing the monotherapy results in clinical, right, in terms of the overall visceral and then the liver and then overall fat reduction. Okay, so the phase two is enrolling high BMI and the monotherapy, and then I believe that's the expectation. You say you're not backing from achieving the regulatory bar at this moment, right, 5% one year, so that's still the bar. And then also you want to do the combination with the Inquitrin, potentially maintenance, you know, off Inquitrin. So how and when are we going to see those trials start in their data?

So I think importantly, and we'll kind of go through all three of those. So monotherapy data, that study is set up to do several things. One, it's indexed to do exactly, as we said, get to patients with and without the comorbidities, higher substantial levels of visceral fat, as we see. If you look at the baseline characteristics of any 2-3 obesity study, I believe is a great way of looking at it. You have much higher levels of visceral fat, but importantly, sub-Q fat. So if we think about health, health is driven on your reduction in visceral fat, body weight reduction is off of the subcutaneous compartment. And so both of those are elevated in typical phase two, three obesity studies. What we'll also be able to evaluate beyond kind of the standard metrics of DEXA, we'll do MRI to look at those various compartments, waist circumference, and body weight, are the other key elements. And you mentioned one very interesting one, which is liver fat reduction. I think what was intriguing to us in a medicine that we have a three-fold improvement in ED50, so potency over on Arrowhead, you know, they're still in their 2-3 patient population, so the high BMI patient population, saw about a 44% reduction in liver fat. So again, with higher and at a much higher dose than where we need to be. So I think it's really compelling as we now run a study in patients with comorbidities, meaning they'll have that. We're going to assess MRI PDFF levels of liver fat and be able to look at that in the monotherapy study. We'll also be able to look at the hemoglobin A1C levels in these patients with diabetes, which we know from human genetics is reduced. Well, hemoglobin A1C is an interesting endpoint in diabetes because you don't need to run out your new outcome studies if you have a reduction in hemoglobin A1C. So it becomes another mechanism for us to look at biomarkers. And then we'll be looking at other metrics for insulin sensitivity. So the monotherapy study will give us a lot of information across the sphere. And if you think about it, there's 30 million patients in the U.S. who can't tolerate lean mass loss, who are looking for approaches of reducing fat. And to go an aside on the body composition piece is there's this clinician we know very well, and she's got a multi-state obesity practice. And she'll oftentimes have patients who come in who are obese. They're around 250 pounds. They come in, and they're like, I just want to be 170 pounds. She's like, well, why do you want to be 170 pounds? and she'll pull out this picture of Michael Phelps and she'll say you know if I told you you had to be over 200 pounds but you know you'd look like this is this really healthy is what you're looking for and I think it's such an important notion because we spend a lot of time and I know we have to do it around metrics of talking about numbers and weight and pounds but I think if we think about ultimately what we're trying to achieve which is what is healthy weight loss body composition looking like I think that notion and framing that picture in your mind of what are you ultimately trying to achieve is really the differential. And I think right now the incretin space has kind of driven everybody to this like least common denominator. But we're spending a lot of time, including with some of the major companies in obesity. And I think what we're starting to see is this kind of re-tacking to the race to the bottom at the expense of lean muscle mass is not the goal. The goal is how do we improve body composition. So to that end, the second study in combination is really our opportunity to see how do you not have to push Right now, you know, do you need to go and, you know, if you think about, like, terzepatide, do you need to keep pushing the incretin doses to try to achieve that, or actually can you take some of the starting doses, five of terzepatide, and actually max on the fat loss side, get the benefits. Now patients can stay on it. You don't need to push dose, and really think about a world on a combination strategy that's about maximizing fat loss, preservation of lean mass, and keeping people on medicines. I mean, the realization is 70% of patients can't stay on an incretin past a year. So the notion of ultimately thinking about what obesity care looks like, this plays a critical role in that position. The last is probably what I think is the most interesting application, frankly, for the near-term commercial for inhibiting E, which is the maintenance setting, the idea that we have a potential once to twice a year injection that you can come off incretins, and this notion that patients reach a stabilization pretty quickly on where they're going to And then the goal of having to keep somebody chronically on the increase with the loss of muscle mass and all of the other complications that evolve after that, the ability to shift people to a once or twice a year injection as a maintenance therapy where they're already going to their physicians for care and really shift that narrative, we think is a very compelling use case for inhibiting E. And all three of those studies will be enrolling in succession. So we'll start with the 2A monotherapy, shortly thereafter initiate the combination patient study and shortly thereafter maintenance, and those three use cases will be running simultaneously.

Got it. And then when we will start to see some clinical data from those three?

Yeah, I mean, we'll guide to readouts. I mean, it's safe to say if you think about we'll have the same time points that we'll be evaluating. I think we haven't guided yet on where we'll do the first data cut. I think it's safe to say that we want it to be a meaningful data set, which is aligned where others see other data sets, so we're not kind of accelerating a certain piece of data versus having something that we know what people are going to want to do in terms of putting these different programs up against one another and seeing how they behave. So we'll give an update on that once we initiate.

By the way, the micro files is not the expectation from your trial at this moment.

No, but I think it's a very, I mean, and I say that in the, it's been fascinating to have the conversations of what we ultimately mean in obesity care. And for a while, You know, I think there was such a leap from where historically I think obesity treatment was when, you know, 4% would be success and it was all 4% off of basically amphetamines, right, medicines that were. And so the evolution, I think, in obesity was exciting, right? It got us talking about it as part of meetings. I mean, it's wonderful to have it be such a component of something like South by Southwest, a cultural phenomenon. So I think the idea of actually bringing that in the conversation has actually propelled us to have this other conversation of what do we mean by healthy weight loss? What does healthy, sustainable weight loss look like? And sustainable being the key word and outcome for patients.

I think the relevant is also about, on the joker side, I think a regulatory perspective. Right now, we just saw, I think 2025, they have the updated guidance from FDA, still talking about 5%, but they do mention body composition, et cetera. So where are we now in the regulatory landscape, how far away we can actually talk about liver fat reduction, X percent, or the body composition, that kind of, or maintenance even?

No, and I think you're absolutely right in that this conversation from the regulatory framework of coming off of a number, it's always nice to have a number because it at least gives a target and there's something unambiguous about having a number. But I think what's refreshing is that the number was followed by quality. And so this notion that I think what the agency was seeing is this, to this point of this race to the bottom, weight loss at the expense of what? And I think what it was elevated back to is a conversation of they want to see it dominated off of fat loss. That's the treatment for obesity is how to treat fat loss, and particularly harmful visceral fat. And, you know, we know visceral fat, as you get to an increase about 5%, you start getting cardiovascular disease complications by 10%. percent, those rates go even higher in terms of diabetes and MASH. We see a 15 percent reduction, you know, six months after a single dose in the Healthy Volunteer cohort. So, I think these conversations are important. VMRs, we talked about this visceral fat to lean mass ratio, actually we believe is a very compelling way to deliver on, in a quantifiable way, what the agency is talking about qualitatively on, you know, fat loss and muscle preservation and giving them a number and how to calculate And it's published. So, you know, it wasn't like, you know, we made a ratio and just said this is interesting. I mean, this is a published ratio that actually has clinical data associated with it. And so we do plan to engage the agency separately around VMR and really start the dialogue going from here's the guidance, how do we turn guidance into something that is useful not just for WAVE, but I think, you know, a number of other companies working on this notion of how do we collectively improve and quantify body composition. So I think it will be an exciting time over this year as that and those discussions continue.

Wrapping up the inhibitor, we're heading to the ADA. So you do have a poster there, but you haven't really seen what kind of data will be there. We preview this. We think may have 400 milligrams fixed months, may have the 600 milligrams. We'll see. But how meaningful or difference do you expect to show people if you have some additional data cuts compared to what we already see?

Yeah, I think we've been very clear that we've shared our data, and this will be the update in the poster of those data. So different than, you know, and I think we've done a reasonable job too. We're going to share new data, making sure we guide it to avoid unintended surprises. So the key will be this will be the update of the data that we've seen. I mean, our chance at ADA is not just for that data, but we've been engaging with clinician panels who are excited about the work that we're doing around body composition in expectation for the initiation and starting of the 2A study. So there's a lot of enthusiasm on clinicians to participate, U.S. investigators and ex-U.S. So the key for us is really setting the framework since we're going to have these three use case trials enrolling to keep the clinicians engaged on those upcoming studies. I think it's a good time for us to continue to drive that in comparison with the additional data sets. As you pointed out, what we're seeing is the separation on the siRNA world, where that preclinical separation is translating into clinical separation. We see in the clinic reductions in visceral fat oftentimes at higher doses, but those companies aren't seeing reductions in subcutaneous fat, waist circumference, and things that we've seen. So again, we do see this ability to continue to build the differentiation strategy within Hibini, which is really important. We know within the siRNA world, when there's an interesting target, you will oftentimes find three or four companies from China making an siRNA saying, we can do this target too. And newsflash, after we had our early data, at Obesity Week last year, there were four posters of this target. And what was really remarkable and gave us comfort is they all looked very similar to to the Arrowhead poster, right? They were all posters that showed repeat dosing and that if you did that you could slow weight gain and look very similar to our competitors. So I think as we continue to see that, and I think it's very important on our differentiation we said this is not just inhibiting for wave, it's an siRNA platform with inhibiting for wave. And I think we see that separation of our siRNA capability really demonstrating that we think that there's a strong differentiation from others there and we can continue to use that for other use cases.

Excellent. So we should move on to AATD Alpha 1. So you, at ATS, you just reported some updated data. I think I checked all the box, those response, you know, dynamic response. And then maybe what else you need to see, or if at all, before you think that's ready for the regulatory discussion. I believe you will have some update mid-year this year.

We will. We said, you know, this summer is going to be the feedback from regulators on the next steps on a path to accelerated approval. We believe we have what we need, and I think that's crucial. Others have come out of their regulatory meetings with guidance. I don't think there's anything that we expect to be different from guidance, which was, you know, total levels of greater than 11 micromolar. Others have said focus on biomarkers. You know, I think there's a lot to unpack there. Our biomarker is, you know, we can look at reduction of Z, and we've got a very good way of measuring that, and we see a substantial reduction in Z protein, and Z is very important for the liver, and remind ourselves when we talk about alpha-1 antitrypsin deficiency, it's a liver disease and lung disease, and those two things happen simultaneously for patients with the ZZ phenotype. So that's going to be important. This percent M, we did run samples to look at, you know, what percentage in an MZ patient population is M wild-type protein, it's 64 percent, so, you know, obviously we can come in and say, here's what you want to see in terms of the percent M in circulation, here's what we want to see in reduction of Z, meaning you're making that trade-off of the harmful protein going down and the good protein going up, and a total, and probably most importantly, and I think I can't emphasize this enough in AATD treatment, is AATD is a chronic disease of acute responses, and so if we think about what happens to these patients, and this will form the crux of a good part of the discussion, and it's, you know, really elegant that we've seen it, others have seen it, we saw it again in this study, is that when you have these acute phase events, that's when you need this protein produced, and so ZZ patients don't produce these protein into those events, and we saw we could get 20 over 20 micromolar of protein into an acute phase event that was what you'd expect for that level of CRP elevation, it was sustained out for a month, and then came down to baseline. And so, that dynamic response is probably the most important thing, really, in terms of the therapeutic threshold for treating these patients, is that it's not just about what you have at baseline. And I think an important notion is that's really a, because we often hear, like, how much more, how much more do you need in total? And that is a protein replacement mindset, the idea of you need to chase getting to, once you get to these higher levels of protein, because when you have an acute phase event with protein replacement, you deplete the protein. So the argument on replacement is always since the patient can't make it, how do you put enough in since it's a consumptive protein? And that's what physicians are worried about is I treat my patient with an infusion, three days later they have an acute event, they have no protein on board, and I've got to wait until their weekly infusion to give it. It's why some physicians are actually really hesitant about the Q3 weeks because now you've just pushed the interval out that patients can go in for their next infusion. This flips that narrative, right? Patients are corrected. So long as you can show they're at that MZ-like response rate, they should be able to mount these acute phase events, and that's what we saw in the clinic. So I think the totality of that package is really the biomarker data set that we're going to have the conversation around. And then it's really about design. You know, can we do this study without, you know, some of the feedback from others was it's a one-year study. We believe with the idea of repeat dosing are the ways for us to have conversations about shortening that timeline on the biomarker side. And so, you know, we'll come out of that meeting, I hope, with a very good lineup to what's next for the program as we think about the potential commercial transition.

Got it. Do you think that the 11 micromolar is still applicable here, given our genetic medicine, and also you are targeting specifically for the M protein, which is what type of M protein?

Yeah, I mean, I think there's a rationale around the 11. I think that's clear. Like, if we're using this as a benchmark for where are patients at these levels, that's a safe level. We're not using that, which is the advantage, as our therapeutic threshold, right, because you get to 20 during an acute phase event. So the idea that this is a dynamic protein in response to acute phase events is really the underlying treatment. So the key is, if you know you're at a steady state or a baseline level that meets that MZ-like phenotype, then you're going to be poised to be able to respond to these events when they happen. And I think that's really the ultimate opportunity for editing in alpha-1 antitrypsin.

One quick clarification for the data you disclosed at the ATS. You reported the total kind of ATD, AT protein, and then also percentage of the M protein. But can we just do the simple math using the percentage times the total to get to the M protein level, or that's something you seem to say it's a mean average or mean max?

Yeah, I mean, we have the mean max, but the total, to your point, the percentage is the percent of M that's in the total, with total being the calculation of M and Z. Okay, got it.

All right, so and then in terms of the, I think, the ATD space, you have some other modality, right? I think how you think about MRA editing to fit into this landscape, you know, what kind of population you think are more suited to that modality?

Yeah, I mean, I think if we think about the profile, so a safe, well-tolerated RNA medicine, I think we can draw a lot of parallels to, like, the TTR universe. That profile and coming out of ATS and easel is well-received by clinicians, right? It's safe. It's redosable. The non-permanent component of that is critical. We know off-target edits can off-target cancer-associated genes, and so the idea that you can permanently edit unintended consequences that you can't take back. The other thing that's really interesting when we think about use cases and order of uses is, you know, if we think about DNA editing with bystander edits, once you edit the bystander on DNA, now you've rendered those patients non-compatible with either RNA editing or next generation of DNA editing. And so the idea of clinicians of rendering patients unaddressable potentially with other medicines when, you know, the off-target, if we think about the bystander editing rate is nearly like 60, over 60 percent, you know, the actual M protein is probably close to 38 percent on DNA editing, I think has physicians saying, you know, there are unintended consequences to that. And on the hepatology side, the fact that we have a Galnec delivery means you're not delivering an LMP. LMPs activate CRP and the acute phase responses in the liver. And so the notion of these being liver patients and not irritating that. So as we think about the utility, we think the utility frontline for AATD patients with the ZZ mutation is very much in play, to a point where, again, the difference between protein replacement therapy and editing, again, why we're interested in frontline is we're not putting in a consumptive protein that you physicians have to worry, is it still going to be there when my patient has an event? We know if you can deliver editing, patients are going to produce protein into the event, which is the actual physiology of treating the disease. So, as we think about use cases, we think there's a wonderful use case for RNA editing in the front line setting for this disease.

Anything else that we haven't talked, but you want to impress on people?

Dr. I mean, I think the next thing, and I know we always focus on what's in the clinic today and data. I do think PMPLA-3, as we think about building on kind of the next generation of RNA editing and what's going to be coming forward, I mean, there's 9 million patients that have this mutation. And as we said, there's an important use case for editing versus silencing, and we'll be delivering that into the clinic later this year. And those data, I think, will be really meaningful as we think about treating that broad patient population.

Excellent. All right. Thank you, Paul. Thank you, everyone.