All right. Welcome, everyone, to Jefferies 2026 Global Healthcare Conference. My name is Roger Song, senior analyst covering SMID-cap biotech . It is my pleasure to have the next company with me, have a fireside chat, Wave Life Sciences, and then we have the CEO, Paul Bolno.
Thanks, Roger. It's great to be here.
Awesome. All righty. 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 then the pipeline. We're going to dive in after your remark.
No, look, one, we appreciate the time, and it's good to update. 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. With substantial cash on the balance sheet coming into last year, we recognized that we need to be very disciplined in where we apply that.
The core areas that we focused on at the beginning of the year, we're going to be delivering on INHBE 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'll start shortly thereafter, and then the maintenance study, which we think is a very compelling opportunity for that program. 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 EASL, which was well-received, really thinking about that program with regulatory update middle of this year on a path to accelerated approval. The third program, PNPLA3, 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 9 million people living with the PNPLA3 mutations that drive liver disease. This is a target that has been tractable through siRNA in terms of silencing, but it was always an enzyme that if you silence it, could theoretically make the disease worse. We actually had preclinical data that showed if you knock out the enzyme, you build fat, and you get, actually doesn't treat MASH. If you edit, you fix the protein, you do see improvement.
What we've been seeing since EASL is a number of siRNAs continuing to demonstrate the inefficiency target engagement, but that actually clinical translation of the [siRNAs] isn't translating, therefore, again, reinforcing the thesis around editing and bringing that into clinic. That's really the core thesis of where we've been investing, and we'll continue to deliver important, meaningful data sets there.
Excellent. All right. We do have a lot, but I think let's maybe just one by one, maybe focus on the INHBE for a moment, given that we are heading to ADA. You will be there, we'll be there.
Yep.
We'll host a dinner with you as well. What have you seen for the 200, 400, three months, six months? What you think is the most influential factors, maybe not seeing the weight loss you want to see, but actually is expected. Tell us a little bit more how you now, 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. I think this is the ultimate crux of this program.
Yeah.
I think stepping back, we have to remember what INHBE is and why it's so unique in this landscape for obesity. 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, they have type 2 diabetes outcome benefits. If we think about the kind of the genetics on obesity, it is a wonderful target, principally driven off of an important feature, which is called body composition, and thinking about reduction in fat and preservation of lean muscle mass. We're the first to show that you could recapitulate that human biology in obese mice.
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, and 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. Again, exciting to see the recapitulation of biology. We also were the first to bring it into the clinic and actually could see that. I'll say one very important feature as we talk about INHBE and the field of siRNA, there's both a platform component and a program component, and 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. W e could say we took a number of targets from Alnylam, made them, and could get better potency and better durability. There were a lot of targets where you kind of say, "Is that necessary? Is that going to give you less frequent dosing?" What was really unique about INHBE is this is a target that's under pressure. W hen we talked about the genetics, this is a target that human biology used over evolution to store fat and energy.
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. 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. 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. They showed multiple doses of a GalNAc-siRNA that could suppress weight gain. 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 pre-dosing, you prevent the rebound weight gain. Essentially, nature's drive to reconstitute in response to calories, fat regain, we could suppress that. You see stabilization. That's really important as we go now into our clinical data, where we were able to recapitulate that. 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 II-A study, are all the phase I 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. We see a 15% reduction in visceral fat, greater than 5.4% reduction in subcutaneous fat, 3.3% reduction in waist circumference, meaning patients were able to tighten their belt loops. 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 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 incretins, 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.
We were 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. Body composition's 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 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. 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 II/III study in patients who are obese, high BMI with comorbidities. We'll talk about that trial.
We do expect to see greater than 5% change in body weight, the best data that exists for that, we were talking to some of the physicians who were involved in the BELIEVE and bimagrumab study is, 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, our drug doesn't make lean mass, it just preserves lean mass. Yet, in the obesity studies that they ran in their phase II-A study saw a greater than 5% change in body weight.
I think it's just really important to contextualize what's mechanism. 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 cohort was clean, other than some irritation at the injection site, which is a great profile for obesity. 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. It'll be a substantial data set that we'll start.
Yeah. By the way, you're probably the only siRNA 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. The phase II is enrolling high BMI as a monotherapy. I believe that's the expectation. You say you're not backing from achieving the regulatory bar at this moment, right? 5% one year, that's still the bar. Also you want to do the combination with the incretin, potentially maintenance off incretin. How and when are we going to see those trials start and then data?
I think importantly, and we'll go through all three of those.
Okay.
Monotherapy data, that study's 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 phase II, III obesity study, BELIEVE's a great way of looking at it. You have much higher levels of visceral fat, but importantly, subcu fat. If we think about health is driven on your reduction in visceral fat. Body weight reduction is off of the subcutaneous compartment. Both of those are elevated in typical phase II, III obesity studies. What we'll also be able to evaluate beyond 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.
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 threefold improvement in ED50, so potency over on Arrowhead. They still in their phase II, phase III patient population, so the high BMI patient population, saw about a 44% reduction in liver fat. Again, with higher and at a much higher dose than where we need to be. 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 any outcome studies if you have a reduction in hemoglobin A1C. It becomes another mechanism for us to look at biomarkers, and then we'll be looking at other metrics for insulin sensitivity. The monotherapy study will give us a lot of information across this sphere. 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. To go on 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 weigh around 250 pounds.
They come in, and they're like, "I just want to be 170 pounds." She's like, "Why do you want to be 170 pounds?" She'll pull out this picture of Michael Phelps, and she'll say, "If I told you you had to be over 200 pounds, but you'd look like this, is this really healthy? Is this what you're looking for?" 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. 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.
I think right now the incretin space has kind of driven everybody to this least common denominator. 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 retacking 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. To that end, the second study in combination is really our opportunity to see how do you not have to push incretins right now. If you think about tirzepatide, 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 tirzepatide, and actually max on the fat loss side, get the benefits. Now patients can stay on it.
You don't need to push dose. 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. 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 INHBE, 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 get to.
The goal of having to keep somebody chronically on the incretin 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 INHBE. All three of those studies will be enrolling in succession. We'll start with the phase II-A monotherapy, shortly thereafter initiate the combination study, and shortly thereafter maintenance. Those three use cases will be running simultaneously.
Got it. 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. We'll give an update on that once we initiate.
By the way, Michael Phelps is not the expectation from your trial at this moment.
No. I say that in the it's been fascinating to have the conversations of what we ultimately mean in obesity care. For a while, I think there was such a leap from where historically I think obesity treatment was, when 4% would be success, and it was all 4% off of basically amphetamines, right? 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 phenomena. I think the idea of actually bringing that into 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? Sustainable being the key word and outcome for patients.
I think it's relevant is also about, on the regulatory side, I think a regulatory perspective. Right now we just saw, I think 2025, they have the updated guidance f rom FDA, still talking about 5%, but they do mention body composition, et cetera. Where are we now in the regulatory landscape? How far away we can actually talk about give a fat reduction X%, or the body composition, that kind of, or maintenance even?
No, 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. I think what's refreshing is that the number was followed by quality. This notion that I think what the agency was seeing is to this point of this race to the bottom, weight loss at the expense of what? 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. We know visceral fat, as you get to an increase about 5%, you start getting cardiovascular disease complications.
By 10%, those rates go even higher in terms of diabetes and MASH. We see a 15% reduction six months after a single dose in the healthy volunteer cohort. I think these conversations are important. VMR, as 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's talking about qualitatively on fat loss and muscle preservation and giving them a number on how to calculate it. It's published, so it wasn't like 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. 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 a number of other companies working on this notion of how do we collectively improve and quantify body composition. I think it will be an exciting time over this year as those discussions continue.
Excellent. Wrapping up the INHBE, we're heading to the ADA. You do have a poster there, but you haven't really said what kind of data will be there. We previewed this, we think may have 400 mg six months, may have the 600 mg. We'll see. How meaningful or difference 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 and the poster of those data. Different then, and I think we've done a reasonable job, too, of we're going to share new data of making sure we guide it to avoid unintended surprises. The key will be this will be the update of the data that we've seen. 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 phase II-A study. There's a lot of enthusiasm on clinicians to participate, U.S. investigators, and ex-U.S. investigators.
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. Again, we do see this ability to continue to build the differentiation strategy with INHBE, 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." Newsflash, after we had our early data at ObesityWeek last year, there were four posters of this target. What was really remarkable and gave us comfort is they all looked very similar 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. I think as we've continued to see that, and I think it's very important on our differentiation, we said this is not just INHB E for Wave, it's an siRNA platform with INHBE for Wave.
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. All right, we should move on to AATD Alpha-1. At the ATS, you just reported some updated data. I think I check all the boxes, dose response, dynamic response. 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 us an update mid-year this year.
We will. We said this summer's 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 total levels of greater than 11 micromolar. Others have said focus on biomarkers. I think there's a lot to unpack there. Our biomarker is 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. Z is very important for the liver, and reminder 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.
That's going to be important. This percent M, we did run samples to look at what percentage in an MZ patient population is M wild type protein at 64%. Obviously we can come in and say, "Here's what you want to see in terms of the % 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. Probably most importantly, and I think I can't emphasize this enough in AATD treatment, is AATD is a chronic disease of acute responses.
If we think about what happens to these patients, this will form the crux of a good part of the discussion, and it's 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. ZZ patients don't produce these protein into those events. We saw we could get 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. 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.
I think important notion is that's really because we often hear like, "How much more? How much more do you need in total?" 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. 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? 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. 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. I think the totality of that package is really the biomarker data set that we're going to have the conversation around.
Then it's really about design. Can we do this study without some of the feedback from others, was it a one-year study? We believe with the idea of repeat dosing. Are there ways for us to have conversations about shortening that timeline on the biomarker side? We'll come out of that meeting, I hope with a very good line up to what's next for the program as we think about the potential commercial transition.
Got it.
In the [accelerated groups].
Do you think that the 11 micromolar is still applicable here, given our genetic medicine? Also you are targeting specific for the M protein, which is wild type M protein.
Yeah, I think there's a rationale around the 11. I think that's clear. 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? You get to 20 during an acute phase event. The idea that this is a dynamic protein in response to acute phase events is really the underlying treatment. 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. 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 AATD, AAT protein, and then also percentage of the M protein. Can we just do the simple math using the percentage of 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, we have the mean max, but the total to your point, the percentage is the percent of M that's in the total.
Okay.
The total being the calculation of M and Z.
Okay. Got it. All right. In terms of the, I think the AATD space, you have some other modality, right? How you think about RNA editing to fit into this landscape, what kind of population you think are more suited to that modality?
Yeah, if we think about the profile, so a safe, well-tolerated RNA medicine, I think we can draw a lot of parallels to the TTR universe. That profile and coming out of ATS and EASL 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, 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.
The idea of clinicians of rendering patients unaddressable potentially with other medicines when the off-target, if we think about the bystander editing rate is nearly over 60%, the actual M protein is probably close to 38% on DNA editing, I think has physicians saying, there are unintended consequences to that. On the hepatology side, the fact that we have a GalNAc delivery means you're not delivering an LNP. LNPs activate CRP and the acute phase responses in the liver. The notion of these being liver patients is not irritating that.
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 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. As we think about use cases, we think there's a wonderful use case for RNA editing in the frontline setting for this disease.
Got it. Okay. Anything else that we haven't talked, but you want to impress on people?
I think the next thing, I know we always focus on what's in the clinic today and data. I do think PNPLA3 as we think about building on the next generation of RNA editing and what's going to be coming forward, 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. Those data I think will be really meaningful as we think about treating that broad patient population.
Excellent. All right.
Thank you.
Thank you, Paul.
Thank you.
Thank you, everyone.