Good morning, and welcome to the Wave Life Sciences First Quarter 2024 Financial Results Conference Call. [Operator Instructions] As a reminder, this call is being recorded and webcast. I will now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs. Please go ahead.

Thank you, Kevin. Good morning, and thank you for joining us today to discuss our recent business progress and review our first quarter 2024 financial results. Joining me today with prepared remarks are Dr. Paul Bolno, President and Chief Executive Officer; Kyle Moran, Chief Financial Officer; and Anne-Marie Li-Kwai-Cheung, Chief Development Officer. The press release issued this morning is available on the Investors section of our website, www.wavelifesciences.com. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to several risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings. We undertake no obligation to update or revise any forward-looking statement for any reason. I'd now like to turn the call over to Paul.

Thanks, Kate. Good morning, and thank you all for joining us on today's call. I will open with comments on our recent progress and continued execution on our strategy. Next, Anne-Marie will provide an update on our 3 ongoing clinical trials. And before opening up the call for questions, Kyle will review our financials. Chandra and Ginnie will also be available for questions. The start of the year has been marked by steady execution for Wave. First, we've continued to advance our 3 ongoing clinical trials towards key data updates. This includes our RestorAATion program, which is underway, evaluating WVE-006, our RNA editing candidate for patients with AATD; our potentially registrational FORWARD-53 clinical trial with WVE-N531 for boys with exon 53 amenable DMD; and SELECT-HD, our trial evaluating WVE-003, a first-in-class, allele-selective investigational therapy for patients with HD. We also continue to advance our INHBE lead clinical candidate for obesity towards CTA filing as early as the end of this year and expect to initiate a clinical trial in the first quarter of next year. Last month, we announced meaningful progress in our research collaboration with GSK as they selected their first 2 programs following achievement of target validation. Before diving deeper into each program, I'll pause to acknowledge an exciting leadership update. As announced this morning, Dr. Erik Ingelsson has joined Wave as Chief Scientific Officer. In this role, he will drive our emerging therapeutic portfolio strategy, including growing our genetics and genomics capability by identifying new, high-impact targets and leveraging our best-in-class multimodal platform to continue to advance novel RNA medicines. Dr. Ingelsson comes to us from GSK, where he most recently held positions of SVP, Head of Target Discovery, and SVP of Genomic Sciences, leading activities across all therapeutic areas. He was responsible for harnessing the latest…

Thank you, Paul. With our continued execution across modalities and multiple data sets planned for the months ahead, it's certainly an exciting time to be at Wave. I'll start by covering the progress we've made in RNA editing, where we are advancing our GalNAc-conjugated AIMer, WVE-006, in our ongoing RestorAATion clinical program for AATD. As a reminder, our clinical program is comprised of RestorAATion-1, which is a dose-escalation study in healthy volunteers; and RestorAATion-2, which is a Phase Ib/IIa open-label study designed to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetics of WVE-006 in individuals with AATD who have the homozygous Pi*ZZ mutation. We have rapidly progressed dose escalation in the RestorAATion-1 trial of healthy volunteers. And consistent with our last update, we've observed safety and pharmacokinetic data translating as expected for a GalNAc-conjugated molecule. Just last week, we were pleased to announce that our first CTA for RestorAATion-2 has been approved, and we expect additional approvals to follow. Using the data from healthy volunteers, we identified a starting dose level for RestorAATion-2 that's expected to engage target based on preclinical data. RestorAATion-2 is now underway and includes both single ascending dose and multiple ascending dose portions. And we have the ability to make adjustments with the dose level and frequency as the trial progresses and data emerges. We will be taking multiple assessments of serum M-AAT throughout the 3 dose cohorts, enabling us to quickly detect the potential presence of wild-type healthy M-AAT protein in the serum, which would indicate that WVE-006 is successfully editing RNA and represent the achievement of proof of mechanism. We are currently initiating clinical trial sites and remain on track to deliver proof of mechanism data from RestorAATion-2 in patients with AATD this year, which will be an important step as we work towards completing…

Thanks, Anne-Marie. We recognized revenue of $12.5 million in the first quarter of 2024 as compared to $12.9 million in the prior year quarter. This slight decrease was a result of lower revenue from our Takeda collaboration. Revenue from the GSK collaboration was relatively consistent in the current and prior year quarters. Research and development expenses were $33.4 million for the first quarter 2024 as compared to $31 million in the prior year quarter. Increased spending for our clinical programs as well as our INHBE program was the driver behind this increase, and was slightly offset by the decrease in spending in our discontinued WVE-004 program. Our G&A expenses were $13.5 million in the first quarter of 2024 as compared to $12.2 million in the prior year quarter. This increase was primarily driven by professional fees and other external expenses. As a result, our net loss was $31.6 million in the first quarter as compared to $27.4 million in the prior year. We ended the first quarter with $180.9 million in cash and cash equivalents. Subsequent to the end of the quarter, GSK selected their first 2 programs to advance the development candidates following target validation, triggering a $12 million payment to Wave, which is not included in our Q1 cash balance. We expect our current cash and cash equivalents will be sufficient to fund operations into the fourth quarter of 2025. As a reminder, we do not include any future milestone or opt-in payments under our DSK or Takeda collaboration in our cash runway, but we do have the potential to receive meaningful near-term milestone payments this year and beyond. Notably, over the past 12 months, we've achieved milestones representing $39 million in nondilutive cash from these collaborations. I'll now turn the call back over to Paul for closing remarks.

Thank you, Kyle. With INHBE rapidly advancing toward the clinic and meaningful data updates for all 3 of our clinical programs expected this year, we are well positioned to deliver program and platform value. Positive clinical data would validate our best-in-class editing, splicing and silencing capabilities and would serve to unlock our robust preclinical pipeline. Taking a look at our upcoming milestones, we plan to deliver the first-ever clinical proof-of-mechanism data for RNA editing with WVE-006 this year and share new preclinical data on our advancing RNA editing programs; submit CTA for our INHBE siRNA obesity program as early as the end of this year and initiate a clinical trial in the first quarter of 2025; deliver data, including dystrophin protein from our potentially registrational FORWARD-53 clinical trial in the third quarter; and deliver HD data from the multi-dose SELECT-HD trial with extended follow-up, along with all single-dose data in the second quarter. We look forward to sharing our progress with you along the way as we reimagine what's possible for patients and continue on our journey towards building a leading RNA medicines company. With that, I'll turn over the call to the operator for Q&A. Operator?

[Operator Instructions] Our first question comes from Salim Syed with Mizuho.

Congrats on the progress, guys. Paul, a few from me, if I can. For Dr. Ingelsson, can you just remind us, just given all the prior relationship with GSK, what data did he have access to that perhaps wasn't in the public domain that you could have potentially used in his decision-making to join Wave? So that's question number one. Question number two on DMD. If you could just remind us if there's any -- just given -- I don't know -- I don't think you guys have access to open label, but is there anything you can do in terms of patient identification or site prep or other exons of interest? How you're prioritizing that? And the third like -- can you do anything in advance of actually getting the data there to expand into other exons quickly? And then the last one just on Huntington's. Can you just help us, is it May or June, just given we're in the second quarter? And do you guys have access to any blinded safety data or the ventricular enlargement data?

Thanks, Salim. Why don't we work from back to front. So I think pretty quickly on the last one. I can't provide any other information other than we'll have data this quarter. I can say at this point -- and we are not in the possession of any data on the readout. So that's about as much as I could say about HD. But we're in the quarter and we are on track for delivering that data. Appreciate the question on DMD. As you know, we have done extensive work across other exons. We have now, across the 4 additional exons that expand that population, shown as good if not better dystrophin protein from these other exons. And the work is underway internally to assure that following -- and we have data, following the dystrophin data readout that will be poised to advance and actually accelerate those other exons. Acceleration comes in two paths. One, as you pointed out, we've identified and, as you're well aware, we can work with leading experts at our various sites, including additional sites, and have been able to start identifying sites that have patients and their proportion of patients with the other exons. And I think that's definitely helpful work to be able to bring forward these other programs extraordinarily rapidly since -- it's not only the sites, but having identified sites with patients. We are poised to also, as we think about the development plan, not just think about how to quickly bring them into the clinic, but actually reimagine an umbrella study that has at its core the confirmatory study for N531 if that data is positive. So bringing that to a potential full approval. But also thinking about that study with a common placebo arm as the basis for the umbrella…

Our next question comes from Joon Lee with Truist.

Congrats on the great additions to the team, looking forward to talking to him in the future. Regarding alpha-1 antitrypsin program, are you able to share what you saw in the RestorAATion-1 that triggered the advancement to RestorAATion-2? Were there any specific bogeys that you were looking to hit in healthy volunteers before you advance to the patients? And for the forthcoming RestorAATion-2, what would be considered a success and good enough for GSK to take it forward? And I have a quick follow-up.

Thanks, Joon. And I appreciate the congrats on Erik, and we will definitely be connecting him with all of you in the coming weeks. Secondly, on the transition for AATD from RestorAATion-1 to 2, as we said at the very beginning, the design of RestorAATion-1 really accomplish two important features to transition to RestorAATion-2. And that's namely safety, which continues to progress well; and secondly, PK transition. As you know from our preclinical models, we've established in the SERPINA1 model the ability to see substantial levels of protein. So we can characterize that in the preclinical model. Just for a basis, in the mouse preclinical model, those doses that we were seeing substantial levels of protein are a human equivalent dose of less than 1 milligram per kilogram, [ 0.75 ]. So if we think about that, a lot of our modeling went into establishing that first dose, as we said, to be a dose that we would anticipate engaging target and then continuing to build both dose and dose frequency to be big drivers for the RestorAATion-2. To your last question on thinking about what success looks like in RestorAATion-2 for GSK. The key for us there is to establish in this study, the dose and dose frequency with which to bring forward, obviously, a potentially registrational study. So as we think about this design, there's a combination of not just looking at protein levels but really looking at protein levels to -- and I think this is important as we think about the expansion beyond alpha-1 antitrypsin to our other GalNAc-conjugated RNA editing program, establishing that translation from prediction from animal models to humans, which for GalNAc and siRNA space is pretty well established. So I think it will do two things. One, for AATD, establishing a dose of frequency with which to move forward. I will say this is not an opt-in agreement. GSK has a license, so this transition is not as if there's a pause there. But importantly, and I think this is critical for Wave as we shared earlier, we have 4 other GalNAc-conjugated AIMers that we've generated data on. What we want to establish is that paradigm for preclinical, the clinical translation, and this study is poised to do that.

Great. Looking forward to the update there. And regarding the additional preclinical data, the head-to-head trial against -- not trial, study against semaglutide in mouse model, as you mentioned, is this something that we can expect at a medical conference? Or would it be something that you would share during a subsequent earnings call?

Thank you, and thank you for recognizing that. So before we had done a lot of comparable work, so it's nice to have an ongoing head-to-head study with GLP-1. So we are comfortable on weight loss similar to sema. That's an important update. And additionally -- and I think we've talked a lot about what we see as one of the advantages as part of a maintenance therapy regimen, which is this question of prior basal mechanism, we were surmising that you could blunt that rebound weight gain. Obviously, now we have data to demonstrate that, and we're seeing that. This is an ongoing study, and we do plan to share data, as you said, at upcoming meetings later this year.

Our next question comes from Steve Seedhouse with Raymond James.

This is Nick on for Steve. From the ClinicalTrials.gov entry for RestorAATion-2, it looks like the eligibility criteria involves some quantification of lung disease by spirometry and liver disease by FibroScan. We were just wondering if you plan to measure those changes from baseline FEV and liver stiffness throughout the duration of RestorAATion-2? And if so, do you plan to share those data in your first update?

Thanks, Nick. Anne-Marie, would you like to take that question?

Sure. Yes, we will be measuring these kinds of outcomes in the study. But for the duration of the study and the fact that these patients actually have very limited disease enrollment, you wouldn't expect to see much change over the course of the study.

Okay. And just as a quick follow-up. Just thinking about the nonhuman primate PK results for N531 that were shared at MDA, you have exposures reaching about 60-microgram per gram, it looks like the equivalent human dose and cardiac issues. Can you comment on the implications of cardiotoxicity with your PN chemistry? And secondarily, does this exposure profile make you inclined to pursue development in cardiovascular diseases?

Yes. And one -- I appreciate the question. So we've done exposure. Obviously, we've done a substantial amount of work in PN chemistry in multiple areas, whether that's in CNS and systemic. Obviously, safety has allowed us to continue to progress and we don't see the -- PN [ again ], itself is a neutral charge causing cardiovascular disease. But it does, as you point out, give us good exposure and, in this case, putting functional protein restoration in those potential tissues. So we do see that as a substantial advantage in DMD, where we know, particularly in the later stages, cardiomyopathy becomes an issue. So again, restoring dystrophin protein, functional dystrophin protein, not micro or mini dystrophin protein early, is an important component. So as you saw with 53% skip transcript in the skeletal muscle, that gives us a high degree of confidence based on the preclinical data. And we're seeing substantially more, not just in heart, but also in diaphragm. Interesting question, as you pointed out, as we think about other applications. So when we do think about particularly in the area of editing and upregulation, there are opportunities for us to be thinking about these other target tissues for a variety of treatments. So we look at this data as early supporting, obviously, the DMD and splicing, but the opportunity -- and with Erik coming on board bringing his experience, we are thinking more broadly about what potential tissues would be in play and how would we think about the diseases in those areas.

Paul, can I just add. I just wanted to confirm, we've never seen any data in tox that would indicate there's a cardiac tox issue. So these concentrations in the heart are all upside for us.

Our next question comes from Ananda Ghosh with H.C. Wainwright.

Thanks for the update. I have 2 questions on the INHBE program. The first question is, there was a report in PNS, I think, Regeneron published which mentioned that maybe beta E is linked to energy expenditure and improved insulin resistance. So are there data that kind of -- that you guys tested, these aspects in your animal model? And the second question is how much of innovation might be required to see a translation? And like how are you thinking about dosing, PK, et cetera, as you think about developing the programs?

No, it's a great question. Thank you. I'll take the last one first. If we think about demonstration of loss of function driving disease in publications, these are heterozygous carriers, so 50%. There's been data suggesting like even 40% or lower you see improvements. We've surpassed that, When we had our R&D Day, where we provided the update on both the target -- and our first generation is a while ago construct, not even the candidate, we had already surpassed 50% silencing and demonstrated that, that had a meaningful effect on phenotype. So we surpassed that. We continue to do that, as we said, with our clinical candidate now. We're in an ED50 of less than 1 milligram per kilogram. That looks improved over what the existing siRNAs are currently in the market. So we've got better potency, which is consistent with our NAR paper where we published in our siRNA format. So we see better potency against best-in-class siRNA and we see better durability, which is an important feature in this than the current best-in-class siRNA. So we put those features together based on our candidate and data, we have substantial knockdown that achieved what's been seen in humans and a durability profile now that not only looks -- the potential for twice a year, but once a year. So we think that, that sets ourselves up very nicely. To your point on improved insulin resistance, I mean, that has translated in humans, where there's an improvement and an outcome benefit in type 2 diabetes. That's been seen in both the Regeneron publication, on the UK Biobank data and [indiscernible]. So we do know that looking at the human data set for INHBE, that there is this advantage in improving type 2 diabetes as a function of improved insulin resistance. We've not currently looked at that. We've been focused on measurements that relate to weight, fat and muscle. But obviously, as we continue to build the preclinical package, I think we have multiple opportunities to really think well beyond obesity as a fat loss. And I think you bring up an important point. We need to look at obesity as a public health challenge, one that has cardiovascular implications and INHBE. Humans that have a reduction of INHBE have low triglycerides, low LDL, high HDL and they have this improvement in [indiscernible] resistance. So as we think about the totality of actually treating a substantial population with metabolic syndrome, I think the opportunity for this program extends well beyond just fat loss.

We'll take our last question from Joseph Schwartz of Leerink Partners. .

This is Jenny on for Joe. We were just wondering if you could give us any insight into GSK's process for choosing their 2 recent programs? Do they see any data? And how are they defining target validation?

Thank you. I mean there's not a lot I can share, unfortunately, around what's under their tent, but I can walk through the process and I think that would be helpful. So if you imagine, they have invested in these genetic activities, that's given them targets, and so if we think about INHBE as a good surrogate, targets that have strong genetic differentiation and potential, we can say based on the selection, these were in hepatology. As we said publicly, we've got targets across therapeutic areas beyond hepatic and across modalities. But in these cases, there's -- we generate programs that validate that target, that target biologically. And when that target's achieved, the threshold that we prove that concept, right, we've demonstrated that by impacting that target, we're recapitulating some biology that, that triggers, at their discretion, the ability to move that program into their pipeline. So that triggers the program nomination that takes away from those key opportunities that they have. And so all I can say is we've met that validation criteria on that translation. And the key now is really thinking about these as therapeutics that drive towards the clinic. So if we think about therapeutics -- and this is across modalities we're doing this work. And so there's a lot of ongoing work that I think, holistically, we really benefit from. So if you think about why we did this part of the collaboration, there's a lot of research and discovery efforts that we're doing across these various targets that are informing us in our strategy as we think about the pipeline creation at Wave.

I'm not showing any further questions at this time. I'd like to turn the call back over to Paul for any closing remarks.

Thank you, operator. Thank you all for joining the call this morning. We're excited to see many of you in New York at the RBC Conference next week, and we look forward to keeping you all updated on our progress. Have a great day.

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.