Wave Life Sciences at Jefferies Conference: RNA Innovation Unveiled

On Wednesday, 04 June 2025, Wave Life Sciences (NASDAQ:WVE) presented at the Jefferies Global Healthcare Conference 2025, outlining its strategic advancements in RNA-based therapies. The company highlighted promising developments in its therapeutic pipeline, while also addressing challenges such as regulatory pathways and funding strategies.

Key Takeaways

• Wave Life Sciences is advancing its RNA editing platform, with significant milestones expected in collaboration with GSK.
• The obesity program targeting inhibin E shows potential for infrequent dosing and muscle sparing.
• Discussions with the FDA continue for accelerated approval pathways in the Duchenne muscular dystrophy (DMD) program.
• The Huntington’s disease program is progressing towards a pivotal trial, with collaboration opportunities being explored.

Financial Results

• AATD program milestones include up to $520 million in collaboration with GSK, with $2.3 billion in potential milestones for the broader RNA editing pipeline.
• The company is exploring collaborations to fund the Huntington’s disease program, aiming to offset study costs without reallocating capital from other initiatives.

Operational Updates

• The AATD program anticipates data releases for the 200mg multi-dose cohort in Q3 2025, and 400mg cohort data in the fall.
• The obesity program has completed dosing for the first two cohorts in the Phase 1 study, with data expected later in 2025. The study design allows exploration of dosing intervals up to twice a year.
• For the DMD program, Wave is in ongoing discussions with the FDA regarding accelerated approval, with plans for a confirmatory study leveraging clinical endpoints.
• The Huntington’s disease program plans to file an IND for a potential pivotal trial, utilizing natural history data on caudate atrophy.

Future Outlook

• Wave aims to leverage AATD clinical data to accelerate its RNA editing pipeline, targeting CTAs next year.
• The obesity program focuses on demonstrating single-agent activity and exploring combination therapies.
• In the DMD program, discussions with the FDA for accelerated approval continue, alongside the development of exon-skipping programs.
• The Huntington’s disease program seeks collaborations to fund the pivotal trial and monitor regulatory opportunities for mutant huntingtin knockdown as a surrogate endpoint.

Q&A Highlights

• In the AATD program, the CEO emphasized the goal of achieving normal protein levels and highlighted the importance of M protein for therapeutic comparisons.
• The obesity program addressed muscle sparing in weight loss and potential combination strategies with GLP-1s.
• For the DMD program, the FDA continues to recognize dystrophin as a surrogate endpoint, with confirmatory discussions including 48-week data.
• The Huntington’s disease program maintains its pivotal trial design, with ongoing FDA discussions about caudate atrophy.

Wave Life Sciences remains optimistic about its RNA platform’s potential to meet significant unmet needs. For a detailed account, readers are encouraged to refer to the full transcript below.

Full transcript - Jefferies Global Healthcare Conference 2025:

Roger Song, Senior Analyst, Jefferies: Welcome everyone to twenty twenty five Jefferies Global Healthcare Conference. My name is Roger Song, one of the seniors covers MidCap Biotech at Jefferies. It’s my pleasure to have the fireside chat with our next presenting company from Wave Life Sciences and CEO, Paul.

Paul, CEO, Wave Life Sciences: Thank you, Roger. We’re excited to be here. We have a lot to talk about going into the second half.

Roger Song, Senior Analyst, Jefferies: Yes. We have a few minutes to cover your pipeline, but we’ll try to do all the best to do that. But we’re going to learn a lot more in the second half and then from all of your pipeline. Maybe just a right start, you have a couple of pipeline, different modality, but all related to the RNA space. Maybe we’ll start with the ATD because that’s one of the lead program you have.

And you just guided. I believe you updated the guidance and say, okay, you will have the two hundred milligram data in 2Q and then you have a four hundred milligram later in the four. So tell us what you try to show us and what you expect to see from those two different cohort multi dose, single dose, higher dose, and then we can drill down a little bit.

Paul, CEO, Wave Life Sciences: Yeah, I think this is a continuation of the work that we have been doing and really establishing fundamentally a new category of medicine, So namely RNA editing and bringing the first RNA editing medicines forward, utilizing our unique chemistry and really being able to show that that indeed can translate to this. Last year, and so this is building on, so these data sets that we’ll have in q three really build on the data sets that we had in 2024. So we hit what we called proof of mechanism, meaning we demonstrated the first two patients that crossed forward into that cohort delivered therapeutic levels of alpha-one antitrypsin protein. We saw 11 micromolar of total protein. We saw about seven micromolar of M protein, which is the edited protein.

That just to be clear, alpha-one antitrypsin patients is zero at baseline. So it’s a great way, M protein, and a wonderful way to follow the ability to actually edit cells because the only way you get that production is by driving that efficiency. And we saw that out to day 57, which suggests the potential for monthly dosing. So a very exciting proof of mechanism that this could translate. The reason the data coming forward is going to be important and I think highly informative is now we not only have the full cohort of the single dose, but importantly the multi dose data set.

And I think what’s always been important about multi dose data sets where we’ve looked at our PN chemistry is usually we see higher cellular uptake and retention, so not just drug in but delaying drug out, which translates uniformly, we’ve seen, to better exposure, uptake, durability. And so the opportunity we’ll have with this cohort is it’s a substantial amount of drug. We’re going have two hundred milligrams with biweekly dosing in seven doses with a GalNAc conjugate. That’s a substantial amount of activity. So we’re going have a good sense of both in protein production, assessing durability and modeling.

And then behind that in the fall, we’ll also have the four hundred milligram cohort. So that’ll give us another opportunity to look at a dose response of four hundred versus two hundred, which will continue to give us ways of assessing the frequency. But excited about the upcoming data set.

Roger Song, Senior Analyst, Jefferies: Yeah, absolutely. I think the first data set already proved the concept, as you said. The protein, the production is coming from literally from your drug, which is very important. Get to the level of the heterozygous patient population. But you must keep asking me the question I’m going ask you.

You probably get the question all the time. Do you expect you will get to a higher level of the protection? And do you need to get to a higher level? Just put it down to the right to have a downstart.

Paul, CEO, Wave Life Sciences: It’s the more is more. It’s arms race to more protein. And I kind of step back and say, what’s the biological rationale around the mechanism? And I think to date, the challenge on this do you need more is really stemming from a period of time that the community, investment community, physician community has spent in IV protein replacement. So if we think about IV protein replacement, that’s been a weekly IV therapy.

Patients get infused. They have to come in every week. And that all is all predicated on this heterozygous level of 11 micromolar. And so that was all predicated there. There was this belief that if you can sustain that level of protein and come in, then you’re at this therapeutic threshold.

When the Inhibirex data was coming, and so now we were talking about a different form of the protein, that’s where there was this discussion of, well, now that this protein might be different, do you need more of it in order to have therapeutic activities? That’s where in the field, there was this discussion of, is it 11 micromolar? Is it 20 micromolar? Stepping away from IV protein replacement and really focusing on editing and correction, The value in editing and correction is twofold. One, by getting that transcript back to a normal level, you can produce a normal functional protein and therefore reach a steady state of protein that walking around a heterozygous patient would have.

And that’s where we talk about M protein. So you achieve so if we think about being able to get there, 11 micromolar, and particularly if you can achieve 11 micromolar of all M protein, now you have this baseline of normal protein that’s sitting there to protect individuals at baseline level. Importantly, with editing, when you correct the underlying transcript, what you’re now able to do is say, actually if you’re exposed to an insult, not verbal, you can suddenly start producing more protein. So now the endogenous machinery that’s normally doing its function is there. That’s why this is very different than IV protein replacement.

The benefit in once you can do both of those things means now you can fix the lung, you protect the lung. But actually, by taking on the burden of aggregating protein, you fix the liver. And so there’s really two aspects of this that distinguish it from IV protein replacement. So to look at that in the context of, Okay, with that as the background, how do you set up the therapeutic profile that you need to achieve? Coming into this data set, if you had asked and you did what is the target product profile that you want to see at the end of the study?

We would say, look, if we can achieve 11 micromolar or more and 50% of that was M protein, you now have the heterozygous phenotype and we hit that. So I think going into multi dose, I think the key is going to be where are we on that range between not just heterozygous but can you get to normal levels? That’s in that 11 to 20 range. I think of those as kind of the bookmarks. And then really where the focus is, is not on needing more, it’s how do we push out dosing intervals and play that out.

The one other feature that I’d say is when we talk about mprotein and it’s really critical because we’ve seen with other programs bystander edits, particularly in the DNA editing field. And when you install by stander edits, actually the vast majority of protein produced through DNA editing is actually bystander edited protein, there have been demonstrations that those isoforms have different degrees of productivity in terms of protection. And so I think if we’re really going to do comparative work to say, what is that therapeutic comparator, we really need to not look at the bystander edited total, but really look at apples and apples. What’s the M protein produced? How is that similar?

And how can that ultimately drive therapeutic effect? And I think we’re well poised to look at that at 200 and then really think about how infrequently do we need to give this to sustain them.

Roger Song, Senior Analyst, Jefferies: Yeah, got it. And then in terms of data readout, particularly for the multi dose, is that possible you can start to give us some functional data into the lung and the liver part?

Paul, CEO, Wave Life Sciences: We always look and measure it. I think with these patients in this study, the degree of the health is very too short a study, and patients are not sick enough to look at changes on functional outcome at this point in time. So really the driver in this is the biomarker and threshold levels of protein. And then we can continue to follow that out and in subsequent studies be able to evaluate. Sure.

Okay.

Roger Song, Senior Analyst, Jefferies: All right. Understanding this is a partnership with GSK, so what’s the next step for for six for this program?

Paul, CEO, Wave Life Sciences: So key for six is we’re not done yet. So we have that four hundred milligram cohort. There’s two things to think about alpha-one antitrypsin and its critical importance to WAVE. One is obviously it’s important to the patients who are developing this for and the relationship with GSK as collaborator and partner, which does bring in milestones that are related to that, over $520,000,000 in milestones still on the table for this plus IT royalties. But most importantly, the whole value driver between that and the rest of the GSK collaboration, has about another $2,300,000,000 in milestones, is to advance the rest of our RNA editing pipeline.

And the work that’s being done to have that pipeline translate to CTAs next year, moving clinical programs forward in a way where we can now, not dissimilar to how when siRNAs were accelerated with GalNAc, you could take advantage of clinical pharmacology from the translation of SI from animals to humans and then rapidly expand that. Our goal is to be able to take the human clinical data with GalNAc from alpha-one antitrypsin and rapidly de risk the pipeline beyond that. And so these data are really important. So we’ll have the 400. We’ll have the third cohort.

After that third cohort, this is not an option agreement. It’s a license. So it’s set up to streamline the transition where they pick up the next piece of the development and regulatory filings and 100% of the cost. And we continue to obviously have milestones in relation. To.

But those data continue to inform our ADAR RNA editing platform.

Roger Song, Senior Analyst, Jefferies: Yeah. We don’t have too much time to talk about the other gene editing program in the early But yeah, that’s absolutely the power of the platform and even more milestones associated Okay, let’s move on from the gene editing for ATD to obesity, right? That’s always the hot topic. So in HIBE, you are I think you say you will give us data later this year.

So how much data we should expect from that program?

Paul, CEO, Wave Life Sciences: Yeah. I mean, as we gave an update on last earnings with now having fully dosed the first two cohorts in the study, we’ll give updates on subsequent cohorts. We are poised to have the obesity data this year. So the two cohorts, the best way to think about them since it’s a phase one healthy overweight volunteer study is first cohort is by nature subtherapeutic. But it’s very easy to assess that the cohort above that was modeled to be therapeutic cohort.

So with those two cohorts moving, we are poised to have the data that we need to be able to assess the mechanism and weight loss with inhibin E. The study does allow up to five cohorts. So we have room for continued expansion and dose escalation as well as looking at dosing intervals. I think what’s intriguing about the single dose study is based on preclinical data, it looks to be once to twice a year dosing. So the way the protocol has been designed is each cohort.

So when you think about where we’ll be following patients out to, goes out to six months. And then we have an option to extend a cohort if we want out to twelve. So we don’t have to keep the study rolling on every cohort out to twelve months, but that optionality is built into it. This is important because between those two cohorts, it can enable us to have various dose response. So we can look at safety tolerability, which as we know in the obesity landscape, tolerability is important.

So we’ll be able to look at that in this assessment. For those unfamiliar with inhibin E, what’s critical is the mechanism. And if we step back to think about how do each of these features in the trial derisk the mechanism of action, inhibin E generated data of the UK Biobank data set as a protective loss of function. Patients who have a fifty percent, so heterozygous patients have a really favorable metabolic profile. They have low waist to hip ratio, so low visceral fat.

They have improved lipid profile, so low triglycerides, high HDL. They have beneficial cardiovascular outcome benefits. They have decreased risk of cardiovascular events and type two diabetes. So on longitudinal study of running the human experiment, the human experiment both on safety and efficacy and outcomes has been run, it’s really now about recapitulating that data. And so as we demonstrated in preclinical models, we can see weight loss single agent similar to semaglutide.

We can double the weight loss on GLP-1s in combination because it’s completely orthogonal in mechanism. And I should say that weight loss comes with complete muscle sparing because mechanism of action is a secreted ligand from the liver that binds to fat cells, so ALK7 receptor on the adipocyte, and drives lipolysis. So there’s no implication of it’s not chemical starvation, so you’re not getting catabolic events of consuming muscle for energy. So its whole mechanistic pathway is around fat loss. And so getting back to the clinical trial design, what’s nice is we can assess all of those same features we looked at in the various DIO mouse models, including the one where we stopped GLP-1s on stable mice, gave inhibin E, and then showed that all mice returned to hedonic eating except those treated with inhibin E while they consumed calories, stable on weight loss.

So we’ll be able to look at safety, tolerability, target engagement. And because Activin E is a secreted serum biomarker, you can measure it. We can look at target engagement and impact of an Activin E reduction tied to what will be the next measurement in the study, which will be percent body weight reduction. So we’ll be able to look at that. And I think what’s important there is a reminder that if we think about the GLP-one category and weight loss, forty percent of that weight loss is muscle loss.

So when we talk about percent body weight reduction, we’re really focused on that 60% of body weight reduction, which is true fat loss. And how do we drive that reduction in fat loss? We also have to all remember that when we cite percent body weight reduction, everybody jumps to the end of GLP-one studies after a year plus on therapy. So stepping back, thinking about the one, three, six month time point where you see about one and onetwo versus placebo, about four, and about 6% on the six month. And so that ability to look at those kinetics, be able to look at that correlation between target engagement, active knee, and body weight reduction is really what we’re set up to do.

And we’ll have both essentially a subtherapeutic dose and a therapeutic dose with the ability to assess target engagement and activity.

Roger Song, Senior Analyst, Jefferies: Yeah. I definitely can see a lot of the possibility for the profile using the induction or combination, maybe the long term maintenance given the dosing frequency, and then the muscle sparing, the aspects of

Paul, CEO, Wave Life Sciences: the As we step back and think about this, and our data is very different from what other siRNA companies and I think it’s critical because when we tend to think about some of these modalities, some of what we love to talk about with them as if they’re all the same, right? As if SIs are a commodity now, and it’s really just about target selection. While that could be true, there are certain targets where you can see differential activity. We go back to a paper that we published about two years ago where in NAR we showed we had 30 fold the AGO2 loading over best of state of the art of siRNA formats. We compare that to targets like HSD and saw better knockdown and better durability.

And I think at the time that publication came out, there was a lot of the so what? SIs are good. Are you going to make a longer acting TTR? How are you going to use this in the field of siRNA? And I think the opportunity we really had was the convergence of an interesting metabolic driven genetic target with a siRNA format that gives us uniquely and proprietary better knockdown and better suppression of that target, where actually inhibiting is the ideal place to actually differentiate the siRNA format and unlock it on a really high value target.

And I think the rationale in that is this is a target that evolutionarily nature’s designed to put pressure on to store fat. And so when you suppress it, there’s a natural inclination to get that target back and express. And so what we’ve seen, we’ve looked at other development programs in this space, is the need to do weekly siRNA delivery to get a separation of preventing weight gain. When you look at normal siRNAs, you’re not dosing them weekly to see effect. And so what was unique is we could see single dose activity that was highly durable, highly suppressive of the target itself, Activa and E, but importantly also then translated meaningfully to weight loss.

And I think when we think about that development cascade, it’s let us think fundamentally differently about how do we think about that marketplace. And so when we think about inhibin E, it’s interesting to hear you say, Okay, there’s three aspects. And I don’t disagree. Orthogonal combinations are interesting. You can see double the weight loss.

And how do you use that in a setting? But I do think in the field of obesity, this push to talking about double therapies, triplets, and I think there’s a certain threshold where the sustainability of that. And so when we think about the opportunity to have single agent activity on the front end with body weight loss and reduction, where you’re really obviating the need for GLP-1s and the risks associated with that when you can go on a once or twice a year subcu therapy, see fat loss that’s healthy and sustainable, muscle preservation. But being able to not just think about The US market I mean, if we think about an siRNA format that’s once or twice a year, the global billion patients worldwide suffering from obesity become amenable because you can think about ways of distributing that care. I think the other second opportunity we see is not building on that combination strategy, although it’s completely viable, is maintenance.

So the idea that taking the data we’ve already demonstrated that you can dose stable mice on GLP-1s and see that you don’t return back to rebound weight gain and weight cycling also becomes a highly interesting aspect of already going into an existing market. So we see those both as high value opportunities in advancing the program that all begin with the data from the second half of the ship.

Roger Song, Senior Analyst, Jefferies: Excellent. Okay. Yeah, I do want to use the rest of the time to talk about you have two more, right? Clinical program. So for DMD, so you report a forty eight week data.

It seems you are having conversation with the FDA to potentially file for approval. So maybe the question is what you need to show us or show FDA to be able to file for accelerated approval, and then what’s the confirmatory study discussion right now with all the going on within FDA.

Paul, CEO, Wave Life Sciences: So I know everybody talks about all that’s going on. We can say that nothing’s changed in interactions with FDA and on any of our programs to date. We did have the conversation already and I think that’s important that the filing discussion occurred on the six month data on dystrophin. And there was what we see is very consistent in the exon skipping world. There was not a change that dystrophin is still a surrogate endpoint in DMD.

I think the conversation that we’re having, impacts the design of a confirmatory study, is bringing the forty eight week data to the agency where we have the clinical data in addition. So it’s not just about dystrophin expression. It’s about return of muscle health, decrease in fibrosis, and the TTR data that we have and clinical activity. That data is important because thinking about endpoints of confirmatory study designs and using TTR lets us think about powering and running a study differently with onset of activity, what we need to see, and how we need to run that study to deliver that. And so that discussion that we’ll be having is really about the existing data on the clinical endpoints and utilizing those clinical endpoints as part of the future studies.

Roger Song, Senior Analyst, Jefferies: And then just one follow-up for the DMD. How’s the basket trial in terms of other axon, the conversation with the FDA? Is that still possible to do that?

Paul, CEO, Wave Life Sciences: Yeah. So to be really that was something that we had already had when we were developing suvodirsen in the past and actually had published on that study design with the FDA on using a common placebo cohort doing matching. So you take natural history matching and use essentially virtual placebo patients to minimize placebo patients in study. That was something that we had actually done in partnership with the FDA back with the suvodirsen trial. Our view is we’ll bring that forward as part of this study and really have that conversation in the context of the subsequent programs that advance.

Roger Song, Senior Analyst, Jefferies: Okay. Nothing changed there either, Okay, good. So last minute, I’m going to talk about Huntington. So this is also related to the regulatory. So it seems you are getting the feedback from the FDA.

You will file IND for the potential pivotal. So tell us what’s the current thinking, and then what’s the plan and the status of that?

Paul, CEO, Wave Life Sciences: Yes. So the current thinking of the design remains unchanged with the agency. I think we again, this is a conversation we had last year utilizing natural history data on track and predict HD where we showed caudate atrophy stays consistent across stages of the disease and actually gives a very clean way of following progression of patients that you can really measure meaningfully changing patients off of that course. So that piece of the pivotal trial design remains unchanged. I think it’s highly encouraging giving other companies recent conversations with the agency and the agency reflecting on the use of natural history in HD stays very much consistent with what we’re hearing.

I think our view remains on how do we power that appropriately. And as we’ve said before, how we think about collaborations as a mechanism to helping us fund that study as well without having to share the cost of that study without having to allocate capital away from some of the other programs so that we can advance this really important medicine. I’d add that the landscape from a regulatory environment in HD is interesting as we hear other companies are pursuing a discussion with the agency on accelerated registration utilizing mutant huntingtin with clinical data as a potential endpoint. I think while that would be surprising, we don’t see that as where the agency has gone in the past. We are positioned that if the agency changes its opportunity of thinking about mutant huntingtin as a clinical surrogate endpoint, then we would be poised to use our phase one, two existing data, which is a robust placebo controlled study where we did see more mutant huntingtin knockdown than any of the other formats.

So we’re well prepared should the regulatory landscape change in HD.

Roger Song, Senior Analyst, Jefferies: Yeah. One way or the other, you will be able to do that registration Okay. Good. I think the time is there, sure, when we have a good conversation. So thank you for being with us this afternoon.

Thank you everyone for listening.

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