Wave Life Sciences - Q1 2024

Transcript

Operator (participant)

Good morning and welcome to the Wave Life Sciences First Quarter 2024 Financial Results Conference Call. At this time, all participants are on a listen-only mode. As a reminder, this call is being recorded and webcast. I would now turn the call over to Kate Rausch, Vice President, Investor Relations and Corporate Affairs. Please go ahead.

Kate Rausch (VP of Investor Relations and Corporate Affairs)

Thank you. Thank you, Kevin. Good morning, and thank you for joining us today to discuss our recent business progress and review Wave's 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 Investor 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.

Paul Bolno (President and CEO)

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 three ongoing clinical trials. Before opening up the call for questions, Kyle will review our financials. Chandra and Ginny 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 three 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 two 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 for 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 methods and technologies in genomics to discover and validate novel drug targets and accelerate the development of next-generation medicines. Prior to GSK, he was Professor of Medicine at Stanford University and obtained his MD/PhD at Uppsala University. You will have the opportunity to hear directly from Erik in the very near future. Turning to our pipeline in RNA editing, our RestorAATion-2 clinical trial of WVE-006 for alpha-1 antitrypsin deficiency, or AATD, is now underway, and we continue to advance our wholly-owned RNA editing pipeline behind it.

WVE-006 is the industry's first-ever clinical RNA editing candidate, which aims to correct AATD-causing Z mutation to increase circulating levels of wild-type AAT protein and reduce mutant AAT protein aggregation in the liver. 006 is designed to address the root cause of AATD to provide a solution to patients with AAT lung disease, liver disease, or both. Other treatment approaches are often confined to either lung or liver manifestations, not both. The current standard of care treatment, weekly IV augmentation therapy, is limited to treating only lung disease. siRNA treatments in development are confined to treating only liver disease and could exacerbate lung injury. By targeting RNA, 006 differs from DNA editing technologies that rely on hyperactive, exogenously delivered artificial enzymes that can result in irreversible collateral bystander edits and indels.

In fact, in preclinical studies, the majority of edits observed using DNA-based editing were bystander edits that yielded isoforms of AAT protein with lower functional activity, while the indels have the potential to create loss of function variants. WVE-006 does not use complex delivery systems such as LNPs. 006 contains GalNAc conjugate, a highly specific and elegant delivery tool that is well-validated with multiple approved silencing therapeutics on the market. GalNAc enables the ease and convenience of subcutaneous dosing, effective and selective delivery to hepatocytes, as well as a high degree of confidence of preclinical to clinical translation since the entire dose is delivered reliably to the target organ. Our proprietary chemistry enables WVE-006 to effectively recruit endogenous ADAR enzymes and achieve potent and durable editing in preclinical studies.

We've shown AAT protein levels that exceed the thresholds for both MZ and healthy populations, and we confirmed the functionality of this protein with the neutrophil elastase assay. Additionally, we saw decreases of lobular inflammation and reduction of liver aggregates. WVE-006 also prevents increases in mitosis or turnover of hepatocytes, indicating improved hepatocyte survival. As Anne-Marie will speak to momentarily, we recently received approval for our first CTA for RestorAATion-2 and continue to make significant progress in our trial of WVE-006 with proof of mechanism data from RestorAATion-2 in patients with AATD expected later this year. Proof of mechanism for 006 would not only meaningfully de-risk our AATD program but would also serve as proof of concept for our growing pipeline of wholly-owned editing candidates, which are designed to either correct or upregulate mRNA in both rare and prevalent diseases.

GSK was early to recognize the potential of our differentiated RNA editing capability at our multimodal platform more broadly. Their leadership in respiratory medicine, development, and commercialization makes them an ideal partner for 006, and they continue to bring substantial value to Wave through their significant investments in deep genetic insights. The collaboration included $525 million in milestones related to 006, of which we received $20 million in the first quarter due to the advancement into the clinic. Development and commercialization responsibilities transfer to GSK at their sole cost after we complete our RestorAATion-2 study. Wave is also eligible for double-digit tiered royalties as a percentage of net sales of 006 up to the high teens.

Additionally, in the discovery part of the collaboration, GSK has selected their first two programs to advance following achievement of target validation, marking a transition to the next phase of the research collaboration and triggering a $12 million payment to Wave. Both of these programs utilize Wave's next-gen GalNAc siRNA format and target hepatology. The discovery component of the collaboration encompasses all of Wave's modalities, including RNA editing, and GSK is eligible to advance up to eight programs in total during the initial research term. For these eight collaboration programs, Wave is eligible for total potential milestone payments of up to $2.8 billion, as well as royalties on net sales. As a reminder, GSK pays 100% of the costs related to target validation for these partnered programs.

The collaboration also expands our wholly-owned pipeline as we are able to leverage GSK's genetically validated targets to advance up to three programs for Wave. Inhibin E was the first target we selected, and we plan to focus our remaining slots on high-impact targets based on strong clinical genetics, novel biology, with measurable biomarkers, and best-in-first-in-class potential. Our inhibin E program aims to be a next-generation obesity therapeutic. Using GalNAc siRNA silencing, we aim to recapitulate the protective phenotype of inhibin E loss of function heterozygous carriers who have a favorable cardiometabolic profile, including reduced abdominal obesity, reduced odds of type 2 diabetes, and coronary artery disease. Inhibin E mRNA is expressed in the liver with its corresponding receptor on adipocytes, which controls fat storage. Silencing inhibin E promotes fat burning or lipolysis and decreases fat accumulation.

While GLP-1s have become the standard of care for weight loss, these therapies come with several limitations, namely frequent dosing, loss of muscle mass, poor tolerability, and high discontinuation rates. With our Inhibin E program, we have demonstrated highly potent silencing with an ED50 of less than 1 milligram per kilogram in the diet-induced obesity, or DIO, mouse model and durable silencing following one low single-digit dose, which supports the potential for subcutaneous dosing intervals of every six months or annually. We've also demonstrated weight loss and reductions in fat mass with a preferential effect on visceral fat with no loss of muscle mass. The DIO mouse model has been used with many weight loss therapeutics on the market, including semaglutide, and there is a good precedent for weight loss translation into the clinic.

As the Inhibin E mechanism of action is distinct from GLP-1s, we also see the opportunity to use Inhibin E siRNA as a frontline or potentially maintenance therapy following GLP-1 weight loss induction. We now have emerging preclinical data to further support this use. In an ongoing head-to-head study in DIO mice, we observed that the weight loss effect from a single dose of our Inhibin E siRNA was similar to semaglutide. In addition, treatment with our Inhibin E siRNA upon cessation of semaglutide treatment curtailed expected rebound weight gain. We expect to share new preclinical data from our Inhibin E program later this year. We remain on track to file our CTA as early as the end of year and to initiate our clinical trial in the first quarter of 2025.

We believe clinical proof of concept can be achieved with just a single dose of our inhibin E siRNA in a study of healthy overweight volunteers. In DMD and HD, we are on track to deliver clinical data from each of these programs in the coming months. With our potentially registrational FORWARD-53 clinical trial of WVE-N531 in boys with DMD, our goal is to demonstrate that we can restore endogenous functional or Becker-like dystrophin to provide a meaningful clinical benefit for patients amenable to Exon 53 skipping. Significant scientific gaps on the functional benefit of micro or mini dystrophin remain, in addition to an unknown safety risk associated with AAV gene therapies. There is an urgent need to deliver more therapeutic options to patients, especially those which can achieve access to the heart and diaphragm, two areas where we have seen substantial distribution in our preclinical studies, including NHPs.

Our clinical data for N531 after only 3 doses every other week position it as potentially best-in-class. We've demonstrated industry-leading exon 53 skipping of 53%, muscle tissue concentrations of 42,000 nanograms per gram, the first clinical demonstration of uptake in myogenic stem cells, and a half-life which supports the potential for monthly dosing. We continue to make strong progress in our trial and remain on track to deliver 24-week dystrophin protein expression data in the third quarter of this year. In HD, we continue to advance our first-in-class allele-selective therapeutic, WVE-003. In this space of extremely high unmet need, as HD patients have no disease-modifying treatments available, there are approximately 30,000 patients in the U.S. with HD and over 200,000 at risk of developing HD. WVE-003 is designed to reduce mutant Huntington protein while also sparing healthy wild-type Huntington protein, which is critical to the health and function of neurons.

Having the ability to preserve this important protein is a clear advantage over pan-silencing approaches that non-selectively lower mutant and wild-type protein, especially as HD patients already start with a lower wild-type reserve. We have already demonstrated successful translation of our compelling preclinical data to the clinic with reduction of mutant Huntington and preservation of wild-type after a single dose in humans, and we are looking to replicate these biomarker data with the first multi-dose data from our SELECT-HD clinical trial in the second quarter. In addition, we will be looking closely to see if we can differentiate on safety signals seen by the pan-silencing approaches, including ventricular enlargement. Now, to discuss the progress we've made on our clinical programs in more detail, I'd like to turn the call over to Anne-Marie. Anne-Marie.

Anne-Marie Li-Kwai-Cheung (Chief Development Officer)

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 1b/2a open-label study designed to evaluate the safety, tolerability, pharmacodynamics, and pharmacokinetics of WVE-006 in individuals with AATD who have the homozygous PiZZ 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. We have the ability to make adjustments to the dose level and frequency as the trial progresses and data emerges. We will be taking multiple assessments of serum M-AAT throughout the three 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 the study and defining future dose and regimen. Turning to DMD, dosing continues in our fully-enrolled open-label FORWARD-53 trial for boys with Exon 53 amenable DMD. This phase II study is evaluating doses of WVE-N531 administered every other week with a primary endpoint of endogenous dystrophin expression, which will be evaluated after 24 and 48 weeks of treatment. The trial will also evaluate digital and functional endpoints, pharmacokinetics, as well as safety and tolerability. For dystrophin protein, we are looking for greater than 5%, which exceeds the level of standard of care, which is approximately 1%-5% with approved weekly exon skipping therapeutics.

We know KOLs are very focused on functional dystrophin restoration. Also, extended dosing intervals beyond the current weekly infusions would be very meaningful to patients and families. And ultimately, we think monthly dosing could be an option with N531. Our compelling preclinical data supports our excitement for this program and its potential to be transformative for patients. Specifically, in part A of our clinical trial, Wave N531 demonstrated industry-leading mean 53% exon skipping, which was driven by muscle tissue concentrations of 42 micrograms per gram, which is far above what other exon skipping companies have reported. We're also excited by the clinical evidence of myogenic stem cell or satellite cell uptake of Wave N531.

This is particularly notable as myogenic stem cells are the progenitor cells for new myoblasts, and we're not aware of any other clinical data for exon skippers or gene therapies that have been able to demonstrate myogenic stem cell uptake. Our preclinical data indicates that WVE-N531 concentrations in the heart and diaphragm exceed that of skeletal muscle, which could speak to the promise of addressing what remains a huge unmet need in DMD, impacting respiratory and cardiac involvement. In our FORWARD-53 study, we are monitoring cardiac and respiratory markers, whereas boys in our programs are earlier in the disease course and, as such, have normal baseline parameters. This is something we plan to explore in future studies. We look forward to the opportunity to build on this compelling data set as we plan to deliver potentially registrational 24-week dystrophin expression data in the third quarter.

If positive, these data would support our plans to file for accelerated approval in the US and would accelerate our clinical development plans to build a multi-exon DMD franchise beyond exon 53. As you may recall, we've generated data on compounds that would together address up to 40% of the DMD population, all of which utilize our PN chemistry and have demonstrated high levels of skipping and protein restoration in in vitro studies. Now, moving to Huntington's disease, or HD, where we continue to advance WVE-003 in our SELECT-HD study. WVE-003 is our first-in-class allele-selective candidate for HD designed to reduce toxic mutant Huntington protein while preserving the healthy wild-type Huntington protein. Preservation of healthy wild-type protein is increasingly becoming an area of focus due to its critical role in neuronal function.

New preclinical data in adult mice continue to demonstrate the need for a cautious approach in pan-silencing studies, as complete loss of huntingtin in mice has been associated with progressive subcortical calcification and neurodegeneration. In the multi-dose portion of our ongoing SELECT-HD studies, patients have been receiving WVE-003 or placebo every eight weeks. We remain on track to report data from this multi-dose cohort with extended follow-up, along with single-dose data in the second quarter. With multi-dosing, we are looking for durable mutant HTT knockdown of at least 30% with preservation of the wild-type protein. We will also be looking at safety and tolerability, including brain imaging.

In particular, we will be monitoring for signs of ventricular enlargement, which have been identified both with pan-silencing molecules in transgenic HD mouse models and in HD clinical trials of pan-silencing therapeutics such as Branaplam, an orally administered small molecule, and Tomanersin, an IT-administered antisense oligo, with additional SAEs of hydrocephalus reported in that program. If WVE-003 avoids such ventricular enlargement, it will be an important differentiator and clearly support the benefit of a wild-type sparing approach. Altogether, these upcoming data will form the basis for decision-making for advancement of our program, including supporting an opt-in package for Takeda. We are actively planning for the next steps that, pending positive data, would enable efficient and accelerated paths to bring WVE-003 to patients. In the HD community, we've seen growing support for shorter, more efficient development paths to registration and novel biomarkers such as imaging.

Specifically, the use of MRI imaging for caudate volume loss has recently been shown to correlate well with clinical outcomes in work conducted by IXICO on behalf of the Huntington's Disease Image Harmonization Consortium, which was founded last year to conduct an unprecedented harmonization analysis of more than 6,000 participant-visit MRI images acquired over 2,000 research participants. These markers are sensitive enough to enable highly efficient studies to allow us to establish the biological plausibility of the benefit of mutant Huntington knockdown with wild-type sparing. Here, we can think of confirmatory studies more in the range of 80 patient treatment arms. We've seen examples of imaging biomarkers used for accelerated approval in therapeutic areas such as multiple sclerosis. We look forward to delivering our HD data this quarter. With that, I'd like to turn the call to our CFO, Kyle Moran, to provide an update on our financials.

Ananda Ghosh (Analyst)

Thanks, Anne-Marie. We recognize 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 with the current and prior year quarters. Research and development expenses were $33.4 million for the first quarter of 2024 as compared to $31 million in the prior year quarter. Increased spending for our clinical programs, as well as our Inhibin E 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 equivalents. Subsequent to the end of the quarter, GSK selected their first two programs to advance to development candidates following target validation, triggering a $12 million payment to Wave, which is not included in our Q1 cash balance. We expect that our current cash and cash equivalents will be sufficient to fund operations into the fourth quarter of 2025. As a reminder, we did not include any future milestone or opt-in payments under our GSK or Takeda collaborations 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 non-dilutive cash from these collaborations.

I'll now turn the call back over to Paul for closing remarks.

Paul Bolno (President and CEO)

Thank you, Kyle. With inhibin E rapidly advancing toward the clinic and meaningful data updates for all three 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 a CTA for our inhibin E 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.

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 (participant)

Thank you. Ladies and gentlemen, if you have a question or a comment at this time, please press star 11 on your telephone. If your question has been answered and you wish to move yourself from the queue, please press star 11 again. We'll pause for a moment while we compile our Q&A roster. Our first question comes from Salim Syed with Mizuho. Your line is open.

Salim Syed (Analyst)

Great. Congrats on the progress, guys, and thanks for the questions. Paul, a few from me, if I can. For Dr. Ingelsson, can you just remind us, given all the prior relationship with GSK, what data did he have access to that perhaps wasn't in the public domain that he 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, even though it's 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 in the third can you do anything in advance of actually getting the data there to expand it to other exons quickly?

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? Thank you.

Paul Bolno (President and CEO)

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, I'm and we are not in the possession of any data on the readouts. So that's about as much as I can 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 four additional exons that expand that population shown as good, if not better, dystrophin protein from these other exons. And the work's underway internally to assure that following and we have gated following the dystrophin data readout, that will be poised to advance and actually accelerate those other exons.

Acceleration comes in two paths. One is, 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 for the other exons. So doing both the umbrella registration to bring multiple programs forward, but also rapidly identifying those for the expediency to assure that we have patients for those other studies. And that data looks extraordinarily promising for patients who have not been on other studies and are available for the other exons that we want to explore. As to your first question, we are excited to work with Erik. Erik's been engaged in the collaboration for a very long time at GSK. He was involved from the early time of initiation of the collaboration. And that really came from his role of SVP of genomic medicine at GSK.

So if we think about a lot of what we've been saying on calls for a while now of thinking about how to translate big genetic insights into medicines and GSK's investment in 23andMe, UK Biobank, and really building out a robust genetic medicine target discovery organization and thinking about how Wave played a role in translating those genetic insights into medicines with the most recent update up to programs transitioning. So we're well underway in that collaboration. I think it's safe to say that Erik brings, one, a robust understanding of our capability set. But two, is we're excited to have Erik inside Wave to be a real partner with our team as we think about the expertise we've built in RNA editing and upregulation and correction in siRNA and silencing and splicing and are really poised to translate those insights, one, with inhibinE.

Erik, coming before GSK, was professor of medicine at Stanford with a particular focus in metabolic diseases, including obesity. So brings a lot of expertise in where we currently are. But importantly, I think really brings the lens of helping us continue to build a sustainable portfolio of high-impact medicine. So I think he brings both what he's seen inside GSK. But we're really excited for him to work with us on the targets that we've seen and identified that are unique and high-impact and to help us rapidly translate those medicines into the clinic.

Salim Syed (Analyst)

Okay. Got it. Super. Thanks, Paul.

Operator (participant)

One moment for our next question.

Salim Syed (Analyst)

Thank you.

Operator (participant)

Our next question comes from Joon Lee with Truist. Your line is open.

Joon Lee (Analyst)

Great. Congrats on the great addition 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 bogies that you were looking to hit in healthy volunteers before you advanced 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.

Paul Bolno (President and CEO)

Thanks, Joon. I appreciate the congrats on Erik. We will definitely be connecting him with all of you in the coming weeks. Excitingly, on the transition for AATD from RestorAATion-1 to RestorAATion-2, as we said at the very beginning, the design of RestorAATion-1 really accomplished two important features to transition to RestorAATion-2. 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. And so we could 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, 1.75 of one.

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 the drivers for the RestorAATion-2. To your last question on thinking about what success looked 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 and 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 programs, establishing that translation from prediction from animal models to humans, which for GalNAc in the siRNA space is pretty well established. So I think it'll do two things. One, for AATD, establishing the dose-dose 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 four other GalNAc-conjugated AIMers that we've generated data on. What we want to establish is the paradigm for preclinical to clinical translation.

This study is poised to do that.

Joon Lee (Analyst)

Great. Looking forward to the update there. Regarding the additional preclinical data, the head-to-head trial against not trial, study against Semaglutide in mouse model, as you mentioned, is that 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.

Paul Bolno (President and CEO)

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 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.

Joon Lee (Analyst)

All right. Looking forward. Thank you.

Operator (participant)

Thank you, Joon.

Paul Bolno (President and CEO)

Sorry.

Operator (participant)

One moment for our next question. Our next question comes from Steve Seedhouse with Raymond James. Your line is open.

Nicholas Economides (Analyst)

Hi. Thank you. 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 in FEV and liver stiffness throughout the duration of RestorAATion-2. And if so, do you plan to share those data in your first update?

Paul Bolno (President and CEO)

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

Anne-Marie Li-Kwai-Cheung (Chief Development Officer)

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 a study.

Nicholas Economides (Analyst)

Okay. Thank you. And just as a quick follow-up, just thinking about the non-human primate PK results for N531 that were shared to MDA, you have exposures reaching about 60 micrograms per gram, it looks like, at the equivalent human dose in cardiac tissues. 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? Thank you.

Paul Bolno (President and CEO)

Yes. 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. We don't see the PN molecule itself as 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% skipped transcript in the skeletal muscle, that gives us a high degree of confidence based on the preclinical data that 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 Eric 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.

Kate Rausch (VP of Investor Relations and Corporate Affairs)

Paul, can I just add?

Nicholas Economides (Analyst)

Thank you.

Kate Rausch (VP of Investor Relations and Corporate Affairs)

I just wanted to confirm.

Nicholas Economides (Analyst)

Thank you.

Kate Rausch (VP of Investor Relations and Corporate Affairs)

We've never seen any data in tox that would indicate there's a cardiac tox issue. These concentrations in the heart are all upside for us.

Nicholas Economides (Analyst)

Okay. Thank you.

Operator (participant)

One moment for our next question. Our next question comes from Ananda Ghosh with H.C. Wainwright. Your line is open.

Ananda Ghosh (Analyst)

Hi, Paul. Thanks for the update. I have two questions on the inhibin program. The first question is, there was a report in the PNAS, I think, recently published, which mentioned that inhibin beta E is linked to energy expenditure and improved insulin resistance. So are there data that kind of you guys tested these aspects in your animal model? And the second question is, how much of inhibition might be required to see translation? And how are you thinking about dosing PK, etc., as you think about developing the program? Thanks.

Paul Bolno (President and CEO)

Yeah. 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 even 40% or lower, you see improvements. We've surpassed that. So we had our R&D day where we provided the update on both the target and our first generation, so this is a while ago, construct, not even the candidate. We had already surpassed 50% silencing and demonstrated that that had a meaningful full effect on phenotype. So we've surpassed that. We continue to do that, as we said, with our clinical candidate now. We're at an ED50 of less than a 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 NER paper where we published on our siRNA formats, where 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 two features together. Based on our candidate and data, we have substantial knockdown that achieves what's been seen in humans and a durability profile now that not only looks for 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 in an outcome benefit in type 2 diabetes. That's been seen in both the Regeneron publication on the UK Biobank data and Eli Lilly.

So we do know that looking at the human dataset for inhibin E, 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, 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 in humans who have a reduction of inhibin E have low triglycerides, low LDL, high HDL, and they have this improvement in insulin resistance.

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.

Ananda Ghosh (Analyst)

Okay. Thanks. Thanks very much.

Paul Bolno (President and CEO)

Thank you.

Operator (participant)

One moment for our last question. We'll take our last question from Joseph Schwartz with Leerink Partners. Your line is open.

Salim Syed (Analyst)

Hi, everyone. It's Jenny on for Joe. We were just wondering if you could give us any insight into GSK's process for choosing their two recent programs. Did they see any data, and how are they defining target validation?

Paul Bolno (President and CEO)

Thank you. I mean, there's not a lot I can share, unfortunately, around what's under their tent. But I can walk through process, and I think that would be helpful. So if you imagine they have invested in these genetic activities, that's given them targets. So if we think about inhibin E 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've said publicly, we've got targets across therapeutic areas beyond hepatic and across modalities. But in these cases, we generate programs that validate that target, that target biologically. When that target's achieved a threshold that we've proved 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 8 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 therapeutic 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.

Operator (participant)

Thank you. 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.

Paul Bolno (President and CEO)

Thank you, Emery. 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.

Operator (participant)

Ladies and gentlemen, that concludes today's presentation. You may now disconnect and have a wonderful day.