Terrific. Okay. Welcome everyone, and thanks so much for joining us for our next session. I'm Steve Seedhouse on the biotech team here at Cantor. Thanks to everyone online for joining as well. It's my privilege to welcome Wave Life Sciences, our next participating company. I'm joined, of course, on stage by CEO Paul Bolno. Always exciting things going on at Wave, and looking forward to covering the recent progress and what lies ahead. Paul, first of all, would welcome any opening comments, but I'd love to start with the highest level of questions because we've been following this field, of course, in terms of RNA medicines and certainly RNA editing as well, where you're a leader for some time, and there's always great progress and always a lot to talk about. Just at a high level, sort of a state of the union, so to speak, on RNA editing, how far have we come over the past year? Just our understanding of how to make these medicines and things that you've learned. Would love for you to start at that high level, and then we can drill down, of course, into the specific programs, including your non-editing programs. Yeah. Well, one, thanks for having us. Welcome. I think it's an exciting time for RNA editing. We're seeing clinical data and translation. I think if we look back over the last year, a couple of things we can see. One, we're getting high-potent, specific, durable editing, which is exciting to open up the field. I think we saw that, we'll talk obviously more about AATD, but I think what was incredibly compelling as we looked at that data set is the inter-patient variability was super tight. Every patient had the correction of Z protein to M. We could look at that on a patient-level basis. To feel the confidence of a new mechanism and a new modality translating where you could see that level of specificity, we think is pretty exquisite. I think the evolution of the field, and I think that's probably the most exciting thing as we think forward about just RNA editing, in general, is I think alpha-1 antitrypsin was a great first exemplar for the field. Here's a protein, a single mutation. Can you correct that single mutation? Can you measure that and see that translate? Is a great way to see that test case and to drive the field forward. I think as we introduced last year, and we'll see that translate to the clinic this year with the CTA submission for PNPLA3, I think stepping back and saying, what more can you do with this particular enzyme? What's the opportunity set around editing with this enzyme? I think we're going to see gets a lot broader than I think the single-base corrections for these mutations like alpha-1. PNPLA3 was a great example where we showed last year, here's an enzyme, and then can you create a protein that lets that enzyme function at a natural level, taking patients who are homozygous at risk of liver injury. 9 million patients have the PNPLA3 mutation. If you can correct that, you can restore functional activity back in them. At that time, there was a lot of debate, and I think about this mechanistically, because when you have a new tool, it's really easy for people to say, do we need a new tool? What about the existing modalities, and is this really competing with other modalities, or is it providing a difference? At that point in time, we ran the experiment because, as you point out, we have other modalities. We can make potent siRNAs. We showed that if we knock out the enzyme, which is an approach that a number of companies were taking in the clinic at the time, that you don't actually make the disease better. You could actually make the disease worse, both on how the fat translocates and moves, fat disposition in MASH, but most importantly, the retinol pathway and inflammation, and that by taking out that normal functioning enzyme, you can actually worsen it, versus correction, where we showed you actually enhance both disposition of fat, but most importantly, improvement on the inflammatory endpoints. I think what we saw this year at EASL was reporting data on the siRNA space, showing that indeed, even clinically, you silence the enzyme, you see dose-dependent worsening. I think it's an exciting time as we think about real applications for these modalities more broadly in protein upregulation and protein correction, though I think ADAR is going to have an interesting moment of continued therapeutic area expansion. Beyond trying to think about extrahepatic, just within the liver about thinking about big opportunities, both on the correction space and upregulation space is going to be exciting. Yeah, that's a good flag on the sort of target selection and the ability to leverage what you can do with ADAR editing. Wave, of course, the company's been built around oligos more broadly and novel chemistries and improving on those chemistries and leveraging that into PK/PD advantages. I think RNA editing sort of is a field that's in its infancy from the standpoint of there is a lot of novel chemistry yet to be discovered and ways of improving on efficiency and sort of the nuts and bolts, the blocking and tackling of the editing reaction itself. How would you characterize sort of how the progress has been in the field over the last year or so, and is there anything that you would call out that sort of you've learned at Wave or that you're implementing from a rules and oligo design standpoint that's working? Yeah, one, it's working. We're seeing highly specific, durable editing. I think the chemistry enhancements that we made from first gen, when we published the original papers early on about how to design them to ultimately getting to AATD, to designing where we are now with PNPLA3. I think in each of these, we're continuing as a chemistry company to bring those innovations directly, not just to preclinical data, but ultimately to unlock those as clinical data. I think what's exciting about those chemistry enhancements, and we've seen this in some of the other modalities too, is they also provide, not just to your point on the PK/PD on the target itself, but they also open up the opportunity for us to think differently about other cell types and therapeutic areas so that you start pushing the bounds both, obviously with GalNAc delivery for the liver, but being able to think more broadly about extrahepatic editing and the opportunity sets that are there. I think, as you said, I think this field is evolving in a very similar way. I think the beauty, getting back to kind of our roots and why stereochemistry matters in making single drugs, is the principles that every data set becomes a learning opportunity, whether that's for siRNA, where Inhibin E was 18 months from our mouse data to human data. And we can apply that to other siRNAs and are doing that rapidly. I think the same becomes very much true for what we're doing with ADAR in terms of the design characteristics that then can translate across various sequences. Building those principles for correction, and now we're doubling down to kind of dig out those rules for upregulation. Kind of tackling the next frontier, I think, for ADAR editing, which is exciting. I always say it's a good time, we have our R&D Day in the fall, which tends to be where we like to share that opportunity on what else we can do. We shared a lot on the bifunctionals last year. I think there's more progress as we think about that opportunity set. Bifunctionals, not just an ADAR siRNA, dual siRNAs, and being able to really think about these modalities, the target space, trial efficiency, commercial efficiencies, and how we develop therapeutics where we can really get to the underlying drivers of the disease mechanistically and genetically, and then be able to have multiple tools that can address those problems in cells. Again, more opportunity as we think about our R&D Day this fall. That's great. Maybe just to walk through some of the leading programs, some of the programs most in focus for you and for investors, and we'll start with AATD. I think we're waiting to hear from you just on feedback from the FDA. I guess just a question, are you able to comment, have you had a meeting with the FDA yet? Do you sort of know what the phase III path in AATD looks like or still unable to discuss that? Yeah, as we said, we were granted an FDA meeting end of summer, this fall. We'll provide an updated guidance once we have written feedback. I think going into that, we had all the confidence that we'd have feedback similar to Beam. We also went in with a notion, we shared this going into the meeting about our strategy and how we're just thinking about the development future for AATD and being able to think about efficiencies. Are there ways to design studies where we can do one study that gets us to potential full approval with potential for interim analyses that can get us potential for accelerated approval and try to think about what are the learnings across the rare disease space around multiple trials, the efficiencies in operating and executing them, and are there better ways that you can do this in a single design? Yeah, we'll provide feedback once we have. Okay. Is it fair to say, before you sort of reached out to the FDA with your meeting request, did you have a good sense of what you wanted to do in phase III, initially, I guess based on, yeah, what you've seen out there in the public domain from other folks in AATD? Did you sort of go to the FDA with a proposal, like, "Here would be our ideal scenario"? I think it's safe to say we'd go into that testing ideas around what we want to see and what we want feedback around in terms of those endpoints designs. I think there's a lot of work, as you point out, across other studies that are evaluating things like CT densitometry and measurements and a variety of tools that we're going to be able to watch play out in the clinic. I think CT densitometry is a very interesting endpoint. We had a number of meetings with the Alpha-1 Foundation, who themselves were doing work on validating that as a potential endpoint, and they're still running some natural history studies there, but have a high degree of conviction and confidence. Other regulators use CT densitometry as a full approval endpoint. I think, coming into this, we had a lot of ideas of obviously how we're thinking about it. We're excited to get to the other side of that. Okay. Yeah, just on that point, how for demonstration for these sort of dual acting editing programs where you're affecting potentially liver and lung disease, maybe you can talk about the relative importance of some of those lung function endpoints and then also liver function tests and markers of fibrosis and sort of how this all meshes together into an overall therapeutic profile. It's great. We'll talk about the regulatory component, but I think just stepping back, I think we're just watching an evolution of the AATD landscape. I've spent a lot of time talking to the community and how we think about it, even clinicians and how they're thinking about it as we start thinking about these as commercial products. I think it's fascinating because we do think about and talk about it oftentimes as a lung patient and lung disease or a liver disease and a liver patient. I think we have to step back into the root and say for ZZ patients, you're on a continuum. You're going to be a lung and liver patient. It's just at what rate does the liver disease accelerate and at what rate does the lung disease damage occur? But mechanistically, if you've got a misfolded protein that's going to build up in the liver, it's going to injure the liver. If it's a loss of function because it's not getting to the lung, it's lung. It's less about either/or, and we saw that playing out in our current study as the study progressed and you look at baseline characteristics, we saw physicians getting more comfortable putting their F1, F2 liver patients onto the trial, and they were doing fine without changes in LFTs, which we think is an important differentiator as clinicians holistically think about RNA editing, where they don't have to think about it, is this my lung patient or my liver patient? I say that because the Alpha-1 Foundation, when we had met with them, had funded a study with pulmonologists just giving them access to ultrasound and just basically saying, these are classically patients who are being perceived as being lung patients. When they did ultrasound on them, they found about 30% of patients had to be referred to hepatologists for liver disease. They didn't have overt liver injury. I think it's just this opening and this realization that these patient continuums are real. I say that as we think about separately, here's the commercial population, here's how we think about the intent to treat patients. They're alpha-1 patients, and they're on that spectrum. I think RNA editing is a wonderful way to address that disease. As we think about the difference of getting to market, what does that regulatory strategy look like? Some of the endpoints around lung just make it easier in terms of a more direct way of running those studies. That's not to say that we're also in those designs testing the idea of being able to put hepatic patients on that we can follow and continue to collect those endpoints as well. That'll be some of the updates as we think about the trial design. We are thinking about the strategy of how do you get onto the market. But in all of our testing, clinicians and patients, they don't view themselves as defined as liver, lung, they view themselves as AATD patients. I think prospect-wise too, as we test this commercial capability in RNA editing. We're hearing from payers, too, that RNA editing is an exciting way to pay for therapy. You need a decade of durability on DNA editing to break even versus an RNA editor. I think as we're profile testing this across that community, we're pretty excited. Just on that point, as you think about competitively how you fit into this landscape, I guess tried and true or more familiar chronic therapy, including in this setting where I guess they're used to augmentation therapy, do you think you can slot in and be a much easier transition for payers and- Yeah, and as we talk to the clinicians, too. I think if you think about the utilization of protein replacement therapy, while it is the therapy that's available, it's not necessarily, and it has its liabilities. I think in general, and I think it's an important nuance as we think about editing, and I put in this category all the editors, editing versus replacement. That's a really important nuance to discuss because we'll continue to watch and see data that evolves on the protein replacement side. I think sometimes the mistake in thinking about editing is it's just a different version of augmentation, right? Are you producing the protein and just doing augmentation in a different way? And we have to remember that it's not just replacing augmentation, it's correcting those patients back to a functional phenotype. Augmentation, it's never really been studied. We talk about the nadirs of these proteins a lot, and that's the driver, and people will cite, is it 11, is it 15 as the nadir of where those proteins drop before reinfusion? But people forget the study on what actually that protein level is at a point of actual acute phase response. We don't know. Is it two? Is it zero? Right, when those patients are at their most vulnerable in a consumptive protein and injury is occurring, that dynamic is lost, right? I always say it's like pouring water into a bucket with holes in the bottom, and when you have an acute event, you're just putting more holes in the bottom of the bucket. The difference on correction is we have seen this now across the multiple editors, so it is encouraging, is what we are all doing is by correcting that transcript back, we are letting that dynamic take hold. We got over 20 micromolar of protein during an acute phase response, right? It is sustained out at a month, protecting that patient during that interval and coming back. So when we do think about this translation of actually protecting lung, and I think about this in the context long term of endpoints, the ability for editors actually long term to bio durable solution for fixing the underlying pathophysiology of AATD is really inherent to the editors versus the augmentation. Okay. In addition to the important regulatory update and maybe pivotal study plans accordingly, there is more data coming soon this year maybe. What expectations can you set for the 600 mg multi-dose cohort and- Yeah AATD study? More data this year, so that is not changing. I think for us, we have seen highly durable editing. We have said before, total shouldn't change unless you are having an acute phase response. We see adjustments on total, we are always going back to saying, are those patients having an acute phase response that is ultimately driving that production of total? You should see improvement over time and correction, durability, so there is ample ways for us to continue to see that impact of 600. But I think the most important part is feeding into our modeling for what the dose selection is going to be for the pivotal trial. So we will have multiple doses to be able to look at that PK and pharmacodynamic effect. 200 biweekly, 400 monthly, 600 monthly, and that will give us a very good assessment of what we think the durability range should be for exposures to ultimately guide the two, three trial design. Okay. Will it likely be in that biweekly or monthly? We think that, modeling now is monthly or less frequent. Okay. I think that will help infer that of where we think we need to be. Okay, wonderful. Maybe we can pivot away from RNA editing, and that was a great discussion, Paul Bolno, and thanks for that, and talk about the Inhibin E program, of course, which has also been in focus. Yeah First, how, I guess the obesity multi-dose cohort that you recently opened, and this is the first sort of important test in maybe a demographic that's more suited for the mechanism. How has enrollment been going in that cohort and what's the forecast for that? Yeah. Enrollment's going well. As we said, we'll continue to watch and say we've got potential to deliver data in this year. But I think the question for us will ultimately be where do we want to cut that data for what I know we know people are looking for, which is the evolution, not just the body composition, which we see that as a very strong deliverable for this program, but body weight. Phase II-A, for those who are unaware, it is a very thorough study. It's 160 patients. It's divided between diabetics and non-diabetics. That's important not because we think there's an efficacy driver between diabetics and non-diabetics, but we have other endpoints in this study that are powered to be looked at. So in diabetic patients, we expect them to have increases in liver fat. We have MRI-PDFF in the study. So again, the ability to look at the potent effect of Inhibin E silencing on liver fat as a potential endpoint in MASH. We'll have Hemoglobin A1c, diabetes. We can look at HDL triglyceride ratios for insulin sensitivity. We got a lot of questions early on of what about all these other cardiometabolic indication potential for Inhibin E? Are you going to study those? I think we've designed one study that will enable us to unlock all of those potential indications, obesity and cardiometabolic disease. I think our conviction remains in obesity. It's important to go back and look at a phase I healthy volunteer study with low fat. If you look at where our patients were relative on visceral fat, they had 1 L. Phase II, three studies have 5 L of visceral fat, and yet we saw as potent a reduction in visceral fat as you see with incretins in their studies, at 15%. We know 5%-10% is a threshold where you see outcome differences, so highly important. We also know, compared to others, we see with our Inhibin E program, getting back to your point on chemistry differences, potency, durability. We see reduction in subcutaneous fat. That's ultimately how you get to weight loss with fat reduction, is it comes from the subcutaneous compartment, and we see that. We saw a 3.3% reduction in waist circumference in this healthy population. That's a belt buckle. I do think it's important mechanistically why we're jumping to the phase II-A study, and we agree. I think that's how we're going to be able to benchmark to how do you get to the regulatory threshold of 5%. It is important in terms of de-risking the mechanism that we see potent reduction of activin translating to reduction of fat, visceral and subcutaneous, and ultimately translating in a safe, durable way. We're excited. I don't want to put words in your mouth, that you're not committed to having data available for that multi-dose cohort this year, but it's possible? It sounded like- Yeah, I think it says to your question on enrollment's delivering to where the study remains on track to deliver across the three-month, six-month. Have you decided when you would put the cutoff on follow-up to sort of take that first cut of data, or is that TBD also, depending on enrollment and depending on weights? It depends on enrollment, and I think ultimately, as we are evaluating whether or not we want to index on body composition, which I think we are still focused on how do we draw attention to that path to 5%, because we do know that that is a core area of focus for folks of always how do we see a regulatory paradigm. I think we see that in very much on the 5% pathway. We can model this to bimagrumab and see a clear path to 5%. I think we are also, as we said, going to have conversations this half with the agency around other endpoints, namely visceral fat and ways to think about body composition, which have measurable quantitative endpoints, and that will obviously inform things as well. Yeah, we will come back to that because I did want to ask you about that. Any other data from the SAD cohort, 600 mg or otherwise forthcoming as well? 600 is also on track, as we said, for this year. Yeah. I think our clear guidance there is we don't expect those baseline characteristics to be different than the other phase I patients. It's an important metric, again, for looking at suppression of activin, and we'll continue to follow those patients. But now with the phase II-A running and the intent to treat patient population, I should say the combination study expected to start imminently, meaning starting to generate that data in combination with incretins to unlock that data set, and maintenance will be coming soon thereafter. A lot of studies getting up and running and generation of data as we think about the second half. Let's park there for a moment because I am curious about just on the combo treatment with Inhibin E or for anything really, and also in the maintenance setting. These seem like two obvious areas where at some point there needs to be, or it'll just organically happen, that there's a path established for how to develop a drug in those settings. The entire market is going to be post-GLP-1 at some point, right, essentially. What is your understanding just on sort of will the FDA have a clear maybe guidance document even, or regulatory path for those studies and how they would be label-enabling for maintenance or combo setting? Is there any progress there, do you sense? Are you expecting in the coming years that that'll become clarified? Do you try to pave the way yourselves? Yeah, I think that that path will be there. We know, like every other area of cardiometabolic disease and cardiology, that combinations are inherent, whether it's hypertension, it's cholesterol, the idea of physicians having access to tools and then being able to think about how they sequence and utilize those tools. To your point, when we do our analysis of this market, I think the continuum for Inhibin E is there in monotherapy, it's there in combo, it's there in maintenance, and how physicians want to utilize it. I think it's very easy to see in the, at least in the mono, which I think will become a segmented marketplace. There's 30 million people in the U.S. who are sarcopenic obese patients. Right now, physicians have to make the decision on how to titrate an incretin where you're going to get 40% loss of lean muscle mass on the induction part in patients who you don't want to lose muscle. I think there'll be physicians who think very early on about, okay, this is the right opportunity. And there'll be patients who say, do I really want to lose lean mass versus losing fat? I think that's that population. To your point on the continuum, we know that patients are going to plateau. They're questioning, do I want to go up higher in my incretin to try to drive further fat loss, which is really what they surrogate for weight loss. Do you add incretins on top of that? As we saw pre-clinically, we can double weight loss when those are added. I think that becomes a place where there's high utilization in thinking about how to think about these therapies, and I do not think there necessarily have to be studies. As long as physicians have that and data that supports that there is synergy there, I think physicians will use it that way. I think the area that we see as most intriguing has probably been getting the less attention is this maintenance, kind of this tail part. As we spend more time, we know there's patients who've reached goal. They do not want to stay on their incretin longer. There's a lot of hesitancy to coming off because both financially as well as in time investment to get to whatever that treatment goal is. The goal is how do you sustain yourself there? I think the opportunity for a once a year dose medicine where you get your dose and you can come off your incretin and you may regain some muscle frankly, but you do not regain the fat back. If you think about what happens with rebound weight gain and weight cycling is you actually get more fat back than you started your study with at the beginning because the lean mass does not come back. The notion of giving patients that off-ramp and how to utilize this in that maintenance setting we think is also compelling. We do think about this as a whole continuum, to your point of patients on this journey will find themselves at one point in a way to utilize this mechanism. Our goal is to have the studies which are going to be all running this year as we go forward, that all paint a path to how you can get there in any one of those settings. Separate from a possible development path across that spectrum, as you note in obesity, of course, you talked about the visceral fat impact that is pretty clear with this drug, and there are even other inhibins that are replicating that result. It seems like a feature of the drug, and that 15% reduction, potentially clinically meaningful. That itself could manifest development paths in various cardiometabolic indications, as you noted. How well accepted or regarded is visceral fat by regulators and by the field? Is this, at this point, unclear biomarker, or do you think it's pretty widely accepted as a functional biomarker that is going to resonate well? I think if we stepped back and took a room at a physician meeting and said, "Would a reduction of 10% in visceral fat be clinically meaningful?" People would say, yes. The data on visceral fat is robust. On the other side, we know, if you look at the draft guidance on obesity from the agency, there is this focus beyond the 5% saying the recognition of fat being bad, lean mass preservation being good. I think the key is bringing those pieces together and having a conversation of how do you quantitate that, how do you divide that in this sort of study. I think those will be the conversations that we are seeing receptivity to those discussions. We're going to have those discussions. We know a number of the obesity patient advocacy organizations themselves are having that discussion with the agency. I think there's a moment where the pieces of long-term literature on this that are well-documented and well-defined are there, an agency that's receptive to understanding that. Bringing those paths together, it's probably one of the right time to be having how do we quantitate that. I say all of that with, and I think it's always important for us to reiterate it, not that we don't believe, because it is important with an Inhibin E, we tend to lump a bunch of, and I won't say we, I think the broader community tends to lump all RNAi together and say it's almost like a commodity. I think we do need to remember getting back to your early point on differentiation. This was the paper we put out three and a half years ago, where we compared to a, what would be considered a best-in-class TTR, and could show better duration, better durability, better potency. I think this happens to be with Inhibin E, one of those targets, to your point, visceral fat's the first fat that gets lost. Being able to see subcutaneous fat reduction, waist circumference changes, again, in a patient population that's otherwise healthy with no comorbidities, is important because I think it does distinguish the profile of our medicine from other Inhibin E programs where, yes, visceral fat stays there as an important indication. But it is important to lose subcutaneous fat and the ability to affect that change on that 5%. I think we can do both. I think in addition to potential molecule differentiation, if I may, I also think it's an interesting time because we've seen some of these other potentially predictive biomarkers, IL-6 and Lp(a), and we know they're risk factors, but with the wrong study and maybe the wrong molecule, it just hasn't panned out recently. Probably an opportunity for something like Inhibin E, just smart trial design, picking the right indication and being judicious. How do you think about that, and how do you think about really maximizing the value for this asset? You can't run 10 CVOTs. No offense. Exactly. Wave's a great company, but you can't. No, and we hear you on that, and we never want anybody to think we're going to do that. But I think stepping back, to your point on Inhibin E, what's nice is the CV outcome work had been done on the human genetics. If we think of that kind of maintenance, the long-range study on human genetics in the UK Biobank showed a 50% loss of function in Inhibin E translated to outcome measurements on cardiovascular outcomes, diabetes outcomes. So there's a good connection between this target to those indications. I think if we step back, and I think it's important for people to remember, the design of this phase II-A study was intentional beyond just racing to do obesity, and I think it is important for those listening to hear the intentionality on that study to make sure we are taking that opportunity to look at those other endpoints. Hemoglobin A1c in diabetics, where there's connection to genetics. You don't need an outcome study if you reduce that. Being able to look at other lipid changes. The way that study is designed on liver fat, lipid biomarkers, being able to look at Hemoglobin A1c, builds that compendium of cardiometabolic indications in ways that it's well-powered and well-designed to unlock. So we can be very intentional about how to think about the implications for this target beyond an obesity target. Terrific. If you have any thoughts in closing, would love to hear them, but also, we're looking forward to the R&D Day, of course, in the fall. Anything that you'd want to say to preview that, maybe we can close on that. If not, really appreciate the time, Paul. No, we appreciate it. Well, to that point, we do hope people tune in to our R&D Day. To your point, it's an interesting time, and I think as you pointed out on some of these indications, it's a fun time to be able to think about these tools and these modalities and how they work and how some of these targets really play well together. Beyond the individual targets themselves in this landscape, being able to think about bifunctionals and the way to think about these targets and the interplay amongst these targets is I think a unique opportunity that we've got. Terrific. We can wrap there. Thanks to the audience. Thanks to Wave and to Paul for the conversation, and have a great rest of the day, everyone. Thank you. Appreciate it.