Wave Life Sciences Ltd. Q1 FY2024 Earnings Call

Good morning, and welcome to the Wave Life Sciences First Quarter 2024 Financial Results Conference Call. As a reminder, this call is being recorded and webcast.

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. 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 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 MD and 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. WVE-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, WVE-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. WVE-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 MM populations, and we confirm 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 mitoses for 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 WVE-006 would not only meaningfully derisk our AATD program, but would also serve as proof of concept for a 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 and development and commercialization makes them an ideal partner for WVE-006, and they continue to bring substantial value to Wave through their significant investments in deep genetic insights. The collaboration included $525 million of milestones related to WVE-006, of which we received $20 million in the first quarter due to the advancement into the clinic. Development and commercialization responsibilities transferred 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 WVE-006 up to the high teens. Additionally, in the discovery part of the collaboration, GSK selected their first 2 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 are in hepatology. The discovery component of the collaboration encompasses all of Wave's modalities, including RNA editing, and GSK is eligible to advance up to 8 programs in total during the initial research term. For these 8 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 cost related to target validation of 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 3 programs for Wave. INHBE 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 INHBE program aims to be a next-generation obesity therapeutic. Using GalNAc-siRNA silencing, we aim to recapitulate the protective phenotype of INHBE 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. INHBE mRNA is expressed in the liver with its corresponding receptor on adipocytes, which controls fat storage. Silencing INHBE 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 INHBE 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 1 low single-digit dose, which supports the potential for subcutaneous dosing intervals of every 6 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 in the market, including semaglutide, and there is a good precedent for weight loss translation into the clinic. As the INHBE mechanism of action is distinct from GLP-1, we also see the opportunity to use INHBE siRNA as a frontline or potentially maintenance therapy following GLP-1 weight loss induction. And 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 INHBE siRNA was similar to semaglutide. In addition, treatment with our INHBE siRNA upon cessation of semaglutide treatment curtailed expected rebound weight gain. We expect to share new preclinical data from our INHBE program later this year. We remain on track to file our CTA as early as the end of the 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 INHBE 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- and mini-dystrophin remain in addition to an unknown safety risk associated with AAV gene therapies and 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 WVE-N531 after only 3 doses every other week positions it as potentially best in class. We've demonstrated industry-leading exon-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 that 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 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 huntingtin protein while also sparing healthy wild-type huntingtin protein, which is critical to the health and function of neurons. Having the ability to preserve this important protein is a clear advantage over PAM-silencing approaches that non-selectively lower mutant and wild-type proteins, 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 the reduction of mutant huntingtin 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 PAM-silencing approaches, including ventricular enlargement.

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 the 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 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 the 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% to 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 WVE-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, WVE-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 WVE-N531. This is particularly notable as myogenic stem cells are the progenitor cells for new myoblast, 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. However, boys in our programs are early 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 U.S. 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 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 for HD designed to reduce toxic mutant huntingtin protein while preserving the healthy wild-type huntingtin 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 PAM-silencing studies as complete loss of huntingtin in mice has been associated with progressive subcortical calcification and neurodegeneration.

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 GSK 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.

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.

Our first question comes from Salim Syed with Mizuho.

Congratulations on the progress, everyone. Paul, I have a few questions. For Dr. Ingelsson, can you remind us about the data he had access to, especially considering the previous relationship with GSK? What information was available to him that might not have been in the public domain that could have influenced his decision to join Wave? For my second question on DMD, could you clarify if there's anything you can do regarding patient identification, site preparation, or any other exons of interest? How are you prioritizing that? Also, can you take any steps to expand into other exons before receiving the data? Lastly, regarding Huntington's, can you confirm whether it's May or June for the updates, and do you have access to any blinded safety or ventricular enlargement data?

Thanks, Salim. Let's start with the last question. I can't share any additional information right now except that we will have data this quarter. At this point, I don't have any data regarding the readout, but we are on track to deliver that data this quarter. I appreciate your question about DMD. We've conducted extensive work across other exons and have demonstrated comparable or better dystrophin protein levels from those additional exons. We are working internally to ensure that following the dystrophin data readout, we will be ready to advance and possibly accelerate those other exons. Acceleration can occur in two ways. First, as you mentioned, we've identified and are collaborating with leading experts at our various sites, including others, to find sites with patients, which will significantly aid in advancing these programs quickly since we are not only identifying the sites but also locating patients at those sites. Additionally, as we plan the development, we want to not only bring these therapies into the clinic rapidly but also envision a comprehensive study that includes a confirmatory study for N531, assuming the data is positive, which could lead to full approval. Moreover, we are considering that study to have a common placebo arm for other exons. This way, we are pursuing both the broad registration to advance multiple programs and ensuring that we can efficiently enroll patients for those studies. The data looks very promising for patients who have not participated in previous studies and are eligible for the other exons we want to investigate. Regarding your first question, we are thrilled to collaborate with Erik. He has been engaged in our collaboration with GSK for quite some time and was involved from the beginning as SVP of Genomic Medicine at GSK. A lot of what we've been discussing in our calls relates to how to translate significant genetic insights into effective treatments. GSK has made investments in '23 in the UK Biobank, working towards developing a strong genetic medicine target discovery organization, and Wave has played a role in this translation process, notably with updates on two transitioning programs, ensuring we are well underway with our collaboration. Erik brings a strong understanding of our capabilities and is excited to be with Wave as a true partner, particularly as we leverage our expertise in RNA editing, upregulation, correction, siRNA, silencing, and splicing to translate those insights, particularly with INHBE. Before his time at GSK, Erik was a Professor of Medicine at Stanford, focusing on metabolic diseases, including obesity, so he offers valuable expertise for where we are currently headed. Importantly, he will help us continue building a sustainable portfolio of impactful medicines. He has insights from within GSK, and we are eager for him to collaborate with us on the unique, high-impact targets we've identified and help us rapidly translate those into medicines.

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. I appreciate the congratulations regarding Erik, and we will certainly be connecting him with everyone in the upcoming weeks. Now, about the transition for AATD from RestorAATion-1 to 2, as we mentioned earlier, the design of RestorAATion-1 successfully accomplished two key aspects needed for transitioning to RestorAATion-2: safety, which is progressing well, and PK transition. From our preclinical models, we have demonstrated in the SERPINA1 model the ability to achieve substantial protein levels, which we can characterize in that preclinical setting. To give you a point of reference, in the mouse preclinical model, the doses that yielded significant protein levels correspond to a human equivalent dose of less than 1 milligram per kilogram. With that in mind, considerable effort went into defining that initial dose, which we anticipate will effectively engage the target, and then we will continue to optimize both dose and frequency as key drivers for RestorAATion-2. Regarding what constitutes success in RestorAATion-2 for GSK, our primary goal is to identify the optimal dose and frequency in this study that could support a potentially registrational study. This study design focuses not only on protein levels but also on translating findings from animal models to humans, particularly as we expand beyond alpha-1 antitrypsin to our other GalNAc-conjugated RNA editing programs, where this translation is well established. Essentially, it will serve two purposes: establishing the frequency of the dose for AATD moving forward. It's important to note that this is not an opt-in arrangement; GSK holds a license, so there is no pause in this transition. Additionally, as mentioned earlier by Wave, we have four other GalNAc-conjugated AIMers for which we've generated data. We aim to establish a paradigm for translating findings from preclinical to clinical settings, and this study is ideally positioned to accomplish that.

Great. I'm looking forward to the update. Regarding the additional preclinical data, is the head-to-head study against semaglutide in a mouse model something we can expect to hear about at a medical conference, or will it be shared in a future earnings call?

Thank you for your acknowledgment. It's encouraging to have an ongoing study directly comparing our results with GLP-1. We feel confident about our weight loss results being comparable to semaglutide, which is an important point to share. Additionally, we believe one of the benefits of a maintenance therapy regimen is the ability to reduce rebound weight gain, and now we have data to back that up. This is a continuing study, and as mentioned, we plan to present data 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, I appreciate the question. We've conducted significant work in PN chemistry across various areas, including CNS and systemic applications. Our focus on safety has enabled us to make ongoing progress, and we do not believe that PN chemistry, which has a neutral charge, is responsible for cardiovascular disease. However, as you mentioned, it provides us with valuable exposure, particularly for restoring functional proteins in targeted tissues. This is especially important for DMD, as cardiomyopathy is a concern in the later stages. Therefore, restoring functional dystrophin protein, rather than micro or mini dystrophin, is vital. The 53% skip transcript observed in skeletal muscle gives us considerable confidence based on preclinical data, and we are also seeing promising results in the heart and diaphragm. Your question about potential applications is intriguing. We are considering other target tissues for various treatments, particularly in the areas of editing and upregulation. We view this data as initial supporting evidence for DMD and splicing, and with Erik joining our team, we are expanding our focus to explore potential tissues and related diseases.

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.

We'll take our last question from Ananda Ghosh with H.C. Wainwright.

Thanks for the update. I have two questions regarding the INHBE program. The first question is about a report from Regeneron that suggested a connection between beta E, energy expenditure, and improved insulin resistance. Do you have any data from your animal model regarding these aspects? My second question is about the level of innovation that may be necessary for effective translation. Additionally, how are you approaching dosing and pharmacokinetics as you develop the programs?

No, it's a great question. Thank you. I'll address the second question first. Regarding the demonstration of loss of function driving disease in publications, these involve heterozygous carriers at a 50% level. There has been data suggesting that even at 40% or lower, improvements can be observed. We have already exceeded that threshold. During our R&D Day, we provided an update on both the target and our first-generation constructs, and at that time, we had surpassed 50% silencing, which had a significant impact on the phenotype. We continue to achieve similar results with our current clinical candidate, which has an effective dose of less than 1 milligram per kilogram, showing improvements over existing siRNAs on the market. Our data demonstrates better potency, as consistent with our NAR paper on our siRNA format. We see enhanced potency compared to best-in-class siRNA, along with better durability, an important feature compared to current best-in-class options. Combining these attributes from our candidate and results, we achieve substantial knockdown similar to what has been observed in humans, coupled with a durability profile that suggests the potential for treatment once or even twice a year. Regarding improved insulin resistance, we have observed benefits in humans, leading to positive outcomes in type 2 diabetes, as highlighted by the Regeneron publication on the UK Biobank data. Our analysis of human data for INHBE shows its advantage in enhancing type 2 diabetes through improved insulin resistance. Although we have not currently examined this aspect, our focus has been on metrics related to weight, fat, and muscle. As we continue enhancing our preclinical data, we believe there are numerous opportunities to address issues beyond obesity, which has cardiovascular implications and relevance to INHBE. Individuals with reduced INHBE levels exhibit low triglycerides, low LDL, high HDL, along with improved insulin resistance. Therefore, when considering treatment for a significant portion of the population with metabolic syndrome, the potential for this program goes well beyond 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 can't share much detail about what's happening behind the scenes, but I can explain the process, which may be useful. They have made investments in genetic activities that have identified potential targets. For instance, if we consider INHBE as a representative example, we have targets with strong genetic differentiation and potential. Our focus has been on hepatology, but we also have targets across other therapeutic areas and modalities. In these situations, we create programs to validate those biological targets. Once we demonstrate the impact on a target, we reach a threshold that allows them to decide whether or not to advance that program into their pipeline. This decision leads to program nominations and focuses on key opportunities. I can confirm that we have met the validation criteria for that translation. The important next step is to view these as therapeutics aimed at clinical application. We are conducting this work across various modalities, and there are numerous ongoing efforts that benefit us as a whole. This collaboration has involved extensive research and discovery across multiple targets, which shapes our strategy as we develop our pipeline 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.