Wave Life Sciences, Inc. (WVE) Earnings Call Transcript & Summary

Hello, and welcome to Wave's 2026 Research Day. [Operator Instructions] Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Good morning, everyone and welcome to Wave's 2026 Research Day. The slides accompanying today's presentation will be available following the event in the Investors section of our website at www.wavelifesciences.com. Before we begin, I would like to remind you that management may make forward-looking statements during today's presentation. These statements are subject to 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 our SEC filings, including our most recent annual report on Form 10-K and our most recent quarterly report on Form 10-Q. We undertake no obligation to update or revise any forward-looking statement for any reason. Today, you will hear from Paul Bolno, our President and Chief Executive Officer; Erik Ingelsson, our Chief Scientific Officer; and Chandra Vargeese, our Chief Technology Officer. We are also pleased to welcome Dr. Arun Sanyal, who will share his perspective on PNPLA3 I148M liver disease and the opportunity for an RNA editing correction approach. Following the presentations, our speakers will be available for Q&A as well as Chris Wright, our CMO. With that, I'll turn the presentation over to Paul.

Thanks, Kate. Good morning, and thank you for joining us today. Today marks our Eighth Annual Research Day. Each year, we use this time to showcase emerging programs in our pipeline, our platform capabilities and our recent innovations. As an organization, we are relentlessly focused on our mission of unlocking the broad potential of RNA medicines to transform human health. At Wave, we bring together deep genetic insights and our proprietary chemistry to rapidly advance a pipeline of transformational RNA medicines. There are thousands of known genetically defined diseases and understanding of how these genetic variations drive disease continues to deepen. At the same time, larger genetic studies and better tools for analyzing big data sets are rapidly expanding the number of strong genetic targets for common diseases. With our multimodal platform, Wave is uniquely positioned to leverage these insights. For most of the field's history, oligonucleotide innovation has advanced through sugar and backbone modifications. And even today, traditional oligonucleotides are made of a serial random mixture with potentially up to 1 million unique isomers in a single dose. Wave's founding premise was to bring rational drug design to oligonucleotides to solve for this, resulting in improved distribution and pharmacologic and safety profiles. With the introduction of controlling backbone stereochemistry, PN chemistry and modified bases, we've built the foundation for SpiNA design siRNAs and pioneered new modalities like RNA editing and bifunctionals. We've demonstrated clinical translation of our proprietary chemistry, RNA editing, allele selective silencing, and recently, our SpiNA design, further setting us apart in the field and demonstrating the differentiation of our platform. We've been developing a way to extend these innovations beyond the liver. And today, we will provide an update on our PN conjugates. We have established an oligonucleotide center of excellence for accelerating these innovations into better RNA medicines. The process starts with selecting targets with strong human genetic support, and we've built in-house systems to integrate large data sets into our discovery engine. Wave is uniquely situated to have options for choosing the right tool to silence, edit, or upregulate any given target, thereby enabling us to pair the modality that best addresses the target, including the ability to combine multiple modalities together. As you'll hear later, PNPLA3 is a perfect example of where RNA editing enables distinct advantages over siRNA. Using PRISM, we can leverage predictive modeling and rational design to optimize favorable pharmacology and safety profiles for our therapeutics. We've been compounding these learnings for over a decade and continuously improve the platform. The result is that we develop clinical candidates rapidly at no additional cost to standard oligo development and reproducibly with scalable, cost-effective manufacturing behind them. The most recent example of this process is our WVE-007 INHBE siRNA, which was 18 months from our first in vitro experiment to first human dose. Today we'll begin in RNA editing and highlight our PNPLA3 program. This program builds on our clinical success with WVE-006 for AATD. PNPLA3 liver disease is a similar story driven by a single base change and with strong human genetic support. We are pleased to be joined today by Dr. Arun Sanyal, who will discuss the unmet need for PNPLA3 I148M patients with liver disease and the opportunity for RNA editing. Erik will then discuss our WVE-008 program, which is advancing towards the clinic. And Chandra will then cover the foundation of our RNAi portfolio and how our SpiNA designs are enabling dramatic improvements in potency and duration of activity and how they're translating in the clinic with WVE-007 with a safe and well-tolerated profile. Next she'll speak about how we're using our chemistry to advance PN conjugates to unlock extrahepatic delivery and provide an update on our bifunctional modalities that provide the ability to silence, edit, and/or upregulate 2 distinct targets with a single construct. Now joining from the Liver Meeting in Denver, I'm delighted to welcome one of the most influential figures in hepatology, Dr. Arun Sanyal. Dr. Sanyal is a Professor of Medicine and Physiology and Molecular Pathology at VCU and Director of the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health. He has chaired the NIH NASH Clinical Research Network, served as President of the American Association for the Study of Liver Diseases and authored more than 500 publications. He's pioneered diagnostics and therapeutics for fatty liver and end-stage liver disease. And as recently as last week, he was awarded the American Liver Foundation's Leadership Award. Dr. Sanyal will share his perspective on PNPLA3 I148M liver disease and the opportunity for a genetic correction approach. And so without further ado, I'll turn the call to Dr. Sanyal.

Thank you, Paul. May I have the next slide, please? It's a real pleasure for me to give this talk. And we're going to talk today about PNPLA3, specifically a mutation at the 148 position that has been associated with more aggressive disease in the context of first steatotic liver disease, but now across a whole spectrum of chronic liver diseases. The first identification of PNPLA3 as a potential gene mutation linked to hepatic steatosis came from epidemiological studies with the Dallas Heart Study in 2008. Since then, there have been a number of landmark findings which have provided insight into how this leads to disease, what are its clinical associations. And we are now poised to really talk about how the mutation itself can be modified to change the trajectory of the disease and that's really going to be the theme of what I'm going to talk about. Next slide, please. Now one of the -- beyond linking this gene mutation to having excess fat in the liver, there are now data indicating that if you have this gene mutation, you are much more likely to have cirrhosis. So within cirrhotic populations, this gene mutation is enriched. And what is interesting is it is not just metabolic dysfunction-associated steatotic liver disease, but whether you talk about alcohol-related liver disease, even viral hepatitis, having this gene sets you up for liver trouble if your liver does get into trouble. Next slide, please. So what has occurred is that now with PNPLA3 as the very first sort of gene that was identified, we have a slew of genes that have been linked to steatotic liver disease. But PNPLA3 I148M remains the clearest genotype-defined MASLD target, where whether you look at common polygenic susceptibility variants, it is a central anchor of all of those. There are other protective genes that have been identified, and I think this is important that there are gene interactions. And so the evidence ladder, if you look on the lower right side of this slide, from starting with an association signal, we now know much more about the rare disease burden. We have understanding of disease biology, and we are getting ready to talk about functional and therapeutic validation of this as a target. Next slide, please. The global prevalence of PNPLA3, and this is another way of describing the same mutation across the world is quite variable. But you can see certain areas where there are -- where it is particularly overrepresented. And so if you look at Latin America, it is very, very overrepresented. But there are other areas such as China. And here in the United States, it's estimated we have about 18 million people who have or who carry this gene mutation. And similarly, in Japan and Mexico, many million individuals actually carry this mutation. So the public health relevance of today's conversation is underscored by the fact that there are many, many individuals, literally millions who actually carry this mutation. And when you think about the prevalence of steatotic liver disease in 1/3 or more of the general population and you layer these one on top of the other, that puts a lot of patients at risk from this mutation. Next slide. It is also the strongest genetic risk factor for progressive scarring. It's not just cirrhosis, but along the way to cirrhosis, as the liver gets more scarred, PNPLA3, again, across multiple etiologies has been shown to be a very important genetic driver of accelerated progression of fibrosis and accelerated development of cirrhosis. And once you get there, it is one of the strongest genetic risk factors for the development of hepatocellular carcinoma, which is one of the cancers where we have still not tamed the beast. And so that creates another opportunity for prevention of hepatocellular carcinoma or to actually flatten that curve. Next slide. Now if you look at individuals who already have established steatotic liver disease or MASLD, we see first that the impact of the mutation on the likelihood of developing a liver outcome is also age-related. So there is an interaction term with increasing age. Now if you look at our patients who already have advanced fibrosis, they are much older than people who have very early-stage disease. And so this is an important point. Now on the right-hand side, when you look at the disease allele and the risk of a liver outcome, and these are -- if you -- related to having advanced fibrosis, and then you're already seeing the data for the subhazard ratio for age over 60, you're seeing that in diabetics, there is an interaction as well. So all of these show that while there is a general impact on overall risk of liver outcomes, particularly in older diabetic patients, this is particularly relevant. And again, as you know, with more advanced fibrosis, there's an over enrichment of people with type 2 diabetes, which has been associated with accelerated disease progression also. Next slide, please. And having this mutation is associated with poorer mortality. So if you look at liver disease mortality, these are Kaplan-Meier curves, the homozygous people clearly are separated or differentiated from the heterozygous state. And similarly, if you look at cirrhosis-free survival time in people who did not have advanced fibrosis at baseline, once again, having homozygous I148M mutation is associated with much poorer outcome. So these provide a rationale that if you can convert somebody from a homozygous to a heterozygous state that you might actually improve their clinical outcomes, which would start looking like the curves at the top. So this is an important point. And so in this study, the gene mutation was associated with decompensation or composite endpoint after adjusting for age, gender, diabetes, and BMI, which we know are co-factors with which the gene interacts. And of course, these data are continuing to be analyzed. Next slide, please. Now if you look at -- we talked about obesity. Here, we have data with obesity and with ongoing alcohol. And in both settings, for the same degree of obesity or same degree of alcohol consumption, you are seeing an amplification of the risk of development of hepatocellular carcinoma if you have this gene mutation. Next, please. Now mechanistically, what is happening is that this -- the protein that is encoded by this gene sits at the surface of the lipid droplets. It's a triglyceride lipase. So it takes the triglyceride in the liver and modulates the function of how you break that triglyceride down to release fatty acids that can be used for cellular energy or for other functions or to be exported. And so this is a loss of function mutation. So when you get decreased function, you cannot mobilize your triglycerides. So at any given degree of fatty acid triglyceride flux through the liver, you start accumulating triglycerides. Now PNPLA3 gene is also important in the stellate cells, where it -- if you have the mutation, it impairs retinyl ester hydrolysis and thus accelerates collagen production by the stellate cells. And it's believed this is an important additional mechanism by which it contributes to increased fibrosis. It also attenuates proteosome autophagy. And so it leads to more fat. And when you start accumulating more fat, you also drive lipids into other apparent pathways such as ceramides, et cetera, which are altered and which can also contribute to additional inflammation and fibrosis. Next slide. Clinically, when you talk about treatment of NASH, there are data that NASH resolution with tirzepatide was weaker if you have the gene mutation. It's not that it's bad, it is just that less than what you would see in the CC carriers. And so this again provides an opportunity that if you can change a homozygous to a -- homozygous I148M mutation to a heterozygous state, you might be able to even improve the response to background GLP therapies. Although I will note that with semaglutide and some of the others and survodutide, which data will be shown at AASLD, the PMP -- those drugs worked regardless of the presence or absence of this gene mutation. This has been really shown in the context of tirzepatide. Next slide, please. So why is mutation correction really a cool solution for people who have this and have liver disease? One, that because it interacts with regulatory proteins and maintains lipid homeostasis, mutation correction, it would be expected to restore lipid homeostasis, reduce steatosis, and prevent liver injury. And because of its role through retinol homeostasis, mutation correction should be able to attenuate hepatic inflammation and oxidative stress and should be able to lower fibrosis and lead to NASH resolution. So with that, I think this is my last slide. Can we have the next, please? So I will hand it back over to Paul. Thank you.

Thank you. I'll hand it to Erik.

Thank you, Dr. Sanyal. So as I think you will agree, Dr. Sanyal has made an excellent case for why PNPLA3, one of the strongest genetically defined targets in liver disease. I'll now walk through how we are addressing it with WVE-008, our wholly owned GalNAc-conjugated RNA editing candidate. 008 builds directly on what we have already demonstrated in the clinic with WVE-006 in AATD. With 006, we have shown efficient and consistent RNA editing. We have demonstrated increased M-protein and decreased Z-protein, the levels seen in MZ individuals as well as restore the dynamic pathological response to inflammatory stimuli, supporting that our RNA editing approach is not only showing target engagement, but intended downstream treatment effects. The editing has been durable enough to support infrequent dosing and 006 has been generally safe and well tolerated. Together, these data establish Wave as a leading RNA editing company. They also give us a validated foundation to bring RNA editing to additional genetically defined diseases, starting with PNPLA3 I148M liver disease. As you already heard from Dr. Sanyal, PNPLA3 is a compelling target with strong human genetic evidence and a clear path to early clinical proof of concept. There are over 9 million people in the U.S. and Europe who are homozygous for PNPLA3 I148M and are living with liver disease. Homozygous carriers have a significantly higher risk of a range of liver diseases. These include MAFLD, MASH, and alcohol-associated liver disease and the extensive cirrhosis and hepatocellular carcinoma. As you can see in the survival curve to the right, homozygous I148M carriers have an approximately ninefold higher risk of liver-related death than noncarriers. Heterozygous carriers by contrast have about 80% of risk of liver-related death than homozygous carriers. This observation defines our therapeutic goal. We aim to edit at least 50% of PNPLA3 transcripts in the liver, restoring a functional heterozygous-like state that is associated with dramatically lower risk of liver complications. Our GalNAc RNA editing approach is uniquely designed to restore PNPLA3 function and fully address the genetic driver of disease. We believe it will be superior not only to PNPLA3 silencing, but also to non-precision approaches in MASH. Why edit rather than silence? The wild-type protein plays important roles in the liver to lipid and retinol metabolism. Multiple preclinical models highlight the potential liabilities of removing PNPLA3 altogether. To the left, in the iPSC-derived human liver organoids, silencing PNPLA3 worsens steatosis. In the middle, in primary human hepatocytes, silencing increases inflammation-induced liver cell death, and to the right, in hepatic stellate cells, a PNPLA3 siRNA worsens the fibrotic response. These findings are consistent with emerging clinical experience. As Dr. Sanyal noted, the emerging data from trials with PNPLA3 silencing agents have been disappointing with a recent trial that even showed dose-dependent increases in liver enzymes. The message is that functional PNPLA3 is essential for liver health, both for sustained fat metabolism and to avoid inflammation and fibrosis. This slide shows the mechanism. The I148M variant acts through a gain of function effect. The mutant protein builds up on lipid droplets and sequesters CGI-58, the co-factor of adipose triglyceride lipase, ATGL. This inhibits the lipase activity of ATGL, blocking lipid from being mobilized out of the liver. I148M also suppresses retinol metabolism, which worsens inflammation and fibrosis by promoting fat accumulation of fibrosis via activation of stellate cells. Silencing PNPLA3 can only partially address this biology, knockdown trades the PNPLA3 loss of function. ATGL activity is only partly rescued and retinol metabolism is not rescued. As a result, silencing may partially address steatosis while inflammation, ballooning and fibrosis persists. By contrast, correcting I148M with RNA editing is expected to restore full PNPLA3 activity and lipid mobilization. That would reverse not only steatosis, but also inflammation, ballooning, and fibrosis, treating across the stages of liver disease. This is the key rationale for RNA editing over knockdown. WVE-008 is a GalNAc-conjugated RNA editing oligonucleotide and AIMer. It incorporates Wave's proprietary chemistry and built on our learnings from 006. It is administered by subcutaneous injection with potential for infrequent dosing. In the left panel, you can see the dose response curve showing potent editing with 008. In the middle, you see results from RNA sequencing in 2 separate primary human hepatocyte lines, showing an ideal editing profile with strong on-target editing and no evidence of off-target editing elsewhere in the transcriptome, which gives us confidence in 008 specificity. In the right panel, you can see high liver tissue exposure in preclinical studies supporting excellent delivery and feasibility of durable infrequent dosing. Together, these data provide a strong foundational -- translational foundation as we advance 008 towards the clinic, building on the clinical success of RNA editing capability with 006 for AATD. Next, we looked at whether editing translates into a functional benefit on liver fat. We compared our PNPLA3 AIMer with a PNPLA3 siRNA using our best-in-class SpiNA format in 2 human hepatocyte models. In the upper world, you can see how PNPLA3 editing significantly decreased lipid accumulation in HEPATOPAC, 3D human liver cell culture model, homozygous for I148M. At the bottom, you can see that 008, again, decreased liver fat, this time in a monolayer culture of primary hepatocytes. These results reinforce the biological importance of preserving wild-type PNPLA3 function and the rationale for correcting I148M rather than silencing PNPLA3. For liver disease that progresses across the hepatic lobular cells, it's important that our oligonucleotide reaches all cells throughout the liver, not just in one region. Here, wild-type mice received a single subcutaneous dose of a surrogate PNPLA3 AIMer and liver tissue was examined a week after that single dose. The red signal shows the AIMer. You can see even distribution across all 3 zones of the liver, Zone 1, for periportal hepatocytes near the portal triad; Zone 2, intermediate hepatocytes; and Zone 3, pericentral hepatocytes around the central vein. This broad uniform distribution is a critical finding, this supports our goal of editing PNPLA3 throughout the liver, which is important for treatment of MASH and other PNPLA3-driven liver diseases. This data is also encouraging for our other AIMer programs such as our 006 program as uniform distribution of the drug is important for all liver diseases. Beyond hepatocytes, we also want you to understand whether our AIMers reach the hepatic stellate cells that drive fibrosis. Hepatocytes are only part of the story in PNPLA3 liver disease. As Dr. Sanyal described, the I148M variant also impairs retinyl ester hydrolysis in hepatic stellate cells or HSCs. HSCs are the main drivers of fibrosis in the liver, but it's important to know whether our AIMers reach these cells. In this study, wild-type mice received our target PNPLA3 AIMer. Desmin shown in green, marks the stellate cells and AIMer is shown in red. For the 2 overlap, you see yellow, which confirms that our AIMers are inside HSCs. As you can see, a substantial fraction of HSCs shows uptake. We then asked whether the AIMer actually edits PNPLA3 inside stellate cells, not just reaches them. In the panel to the right, you can see that we observed over 60% RNA editing in stellate cells. This confirms that the AIMers are active in these cells, not just present. These observations are critical because they suggest 008 could do more than correct PNPLA3 in hepatocytes. The data indicates that they also act directly in the cells to drive fibrosis, which gives us a direct antifibrotic mechanism on top of the expected benefit from reduced liver fat. To bring it all together, the PNPLA3 I148M variant is a well-established driver of steatosis, inflammation, ballooning, and fibrosis. Yet there are no approved medicines that directly address this biology. Preclinical and clinical data increasingly suggests that simply knocking down PNPLA3 is not the answer. Losing PNPLA3 function can make the very features we're trying to treat worse. Our approach is different. With 008, we edit PNPLA3 rather than silencing. The goal is to correct the variant that causes the disease and restore normal PNPLA3 function in 2 key cell types: Hepatocytes and hepatic stellate cells. Continuing -- by contributing to restoration of lipid mobilization and reduction of liver fat as well as restoration of retinol metabolism, which directly counters inflammation and fibrosis. Our preclinical data so far support each part of this approach with potent and highly specific editing with no bystander edits, reductions in liver fat in human hepatocyte models, even distribution across all 3 zones of the liver, presence and editing in hepatic stellate cells in addition to hepatocytes. Together, these data support 008's potential to reduce hepatic steatosis, inflammation, and fibrosis and to improve MASH resolution in people who are homozygous for PNPLA3 I148M. 008 also builds on our clinically validated RNA editing platform. If successful, it could be a first-in-class disease-modifying treatment for large genetically defined population with no targeted options today. In summary, 008 meets every criteria we set before advancing a program addressing PNPLA3 I148M liver disease into [indiscernible]. As we just outlined, there are strong supporting human genetics and a large addressable population of more than 9 million homozygous I148M individuals with no treatment options to directly target this driver of their disease. Our preclinical data support each element of the approach. We've demonstrated substantial highly specific editing that exceeds the threshold expected to shift these individuals towards the lower-risk heterozygous phenotype. We've shown restoration of lipid regulation and decreases in liver fat in human hepatocyte models. And we've shown broad distribution across all 3 zones of the liver as well as uptake in editing in hepatic stellate cells, which supports a direct antifibrotic mechanism on top of the benefit we expect from reduced liver fat. With strong preclinical data validating the translation of our best-in-class AIMer chemistry, we're excited to take 008 into the clinic. We will leverage previously genotype populations to efficiently identify homozygous I148M targets and accelerate enrollment, and we remain on track to file a CTA for 008 in the fourth quarter of this year. Now I'd like to turn the call over to Chandra, who will discuss our latest platform innovations.

Thank you, Erik. I'll begin with the foundation of our SpiNA designs and how they have enabled significant improvements over industry-leading siRNAs while extending our delivery to both hepatic and extrahepatic tissues. Next, I'll discuss how we are applying our best-in-class chemistry in RNA editing and RNAi to develop bifunctional oligonucleotides with the potential to address historically hard-to-target indications. For more than a decade, Wave has advanced RNA medicines through innovations in nucleic acid chemistry. We began with novel proprietary backbone chemistry, enabling us to rationally design to oligonucleotides and to study structural activity relationships in single well-defined compounds. Since then, we have expanded our toolkit with novel-based sugar and backbone modifications, optimizing sequence, stereochemistry, pharmacological, and safety profiles altogether. Our PN backbone modification improves cellular uptake, endosomal release, residency, nuclear uptake, and target engagement. Our novel base modifications such as N3U has dramatically increased RNA editing efficiency. Together, these advances have delivered step changes in potency, efficacy, durability, and delivery across hepatic and extrahepatic tissues. A hallmark of our platform is that insights from one modality informed others and helping us move quickly into new targets. Today, I want to spend a moment on stereochemistry. Stereochemistry is a foundational aspect of chemistry relating to the 3-dimensional arrangements of atoms. It has long been recognized that molecules differing solely by their stereochemistry have radically different properties. Given this, stereochemistry has been a central feature from several Nobel Prize in both chemistry and medicine. And this year's Nobel Prize in chemistry recognized the foundational breakthrough in asymmetric organic synthesis and molecular chirality. Critically, it should be noted that synthetic methods can be developed that overwhelmingly produce a single stereoisomers efficiently and without wasteful steps in separation, a principle we have built an entire company around. Chemically modified nucleic acids with chiral backbone, including RNA editing oligonucleotides and siRNAs exist as mixture of stereoisomers unless their stereochemistry is deliberately controlled. Why does this matter? The case of thalidomide targets the importance of characterizing chirality decades ago. The middle of this slide shows 2 stereoisomers with identical target engagement can have markedly different tolerability profiles, the same sequence, the same chemistry, and the same knockdown, but different liver enzyme responses. The field has learned this lesson with small molecules, and it applies to oligonucleotides as well. At Wave, we design and manufacture fully characterized single isomer RNA therapeutics. This capability is supported by a dominant IP portfolio and our unique ability to synthesize and screen stereopure oligonucleotides at scale. Controlling stereochemistry also enables rational structure-based design. For example, our siRNAs that -- for our siRNAs that means positioning the guide strand with the mid and PV domain of Ago2 to maximize Ago2 loading. A mixture of hundreds and thousands of molecules does not offer the same precision. As a reminder, SpiNA is our stereopure interfering nucleic acid design. By increasing Ago2 loading, it enhances RNA-mediated silencing, delivering greater potency and scalability than earlier designed siRNAs and industry benchmarks. The left panel here shows TTR mRNA silencing following a single dose of GalNAc siRNA. All constructs share the same sequence and 2 prime modification as the literature reference. Against this common background, SpiNA designs deliver substantially greater potency and durability of silencing than both the reference and our previously published constructs. The right panel shows corresponding reductions in TTR protein following a single dose. Here, too, SpiNA designs deliver an unprecedented improvement in potency and duration of activity. So again, what drives this? In our nucleic acid research publication, we showed that our earlier designs gain potency and duration mainly from Ago2 loading. But with SpiNA design, the shift is even larger. It comes from several fold increases in both pharmacokinetics shown on the left as liver tissue levels and Ago2 loading shown on the right. SpiNA delivers more than tenfold improvement in Ago2 loading versus the referenced siRNA. The SpiNA advantage extends even beyond TTR. Here, we evaluated PCSK9, our clinically validated cardiovascular target comparing 2 SpiNA designs with a construct based on the Inclisiran sequence and chemistry. Both SpiNA designs showed durable reduction in circulating PCSK9 protein compared to the reference siRNA at least through day 56 after a single dose. On the right, we also saw a corresponding increase in liver LDLR protein, which is a downstream effect that lowers LDL cholesterol. Together, these results give us confidence that SpiNA's gain in efficacy and durability reflect the impact of our chemistry rather than an effect specific to a single target. We will now describe applying our SpiNA design to a clinical target, INHBE. Our approach with the INHBE program relies on starting with the target with strong human genetics. What distinguishes our molecule 007 from others pursuing their biology is our SpiNA design, proprietary chemistry, and PN chemistry that enhance interactions with Ago2, stabilize the loaded RISC complex and improve liver exposure. As we just shared, these designs achieved greater than tenfold improvement in the Ago2 loading versus a reference siRNA. And we'll discuss momentarily, this approach has translated in the clinic. While our INLIGHT trial is investigating in other ways, healthy participants with a markedly lower BMI compared to other obesity trials, no diet and no exercise modification, this study provided us with a strong proof-of-concept approach. We demonstrated potent dose-dependent suppression of serum Activin E sustained through at least 7 months after a single dose, supporting once or twice a year dosing as seen on the left. The potent reductions translated to substantial reductions in total and visceral fat, reduction in waist circumference, stabilization of lean mass, all with favorable safety. Both our clinical data I just described as well as the preclinical data provide us with strong conviction for approach and our ongoing Phase II clinical trial. We can look to our preclinical data to demonstrate specifically the importance of baseline adiposity to this mechanism. As we shared previously, our INHBE SpiNA demonstrated substantial reduction in both total and visceral fat with the prevention of muscle -- with the preservation of muscle in DIO mice. In these DIO mice, in other words, mice with greater adiposity following a single dose of SpiNA, we also observed weight loss on par with semaglutide. However, when we looked at the impact of INHBE siRNA in lean mice, we see no effect on weight loss, as you can see on the graph on the right. These preclinical data support the potential to deliver an even more pronounced improvement in body composition in Phase IIa portion of INLIGHT, which includes individuals with higher adiposity or excess fat at baseline. In addition to our ongoing Phase IIa INLIGHT monotherapy trial, we are also making strong progress on our strategy to evaluate 007 in the combination and maintenance setting. We believe 007's orthogonal mechanism, ability to drive reductions in fat while preserving muscle, and favorable safety profile are well suited to both approaches. And we have shared compelling preclinical data, which supports both use cases. As shown on the left, we have observed approximately twofold greater weight loss as an add-on to incretins versus incretin alone. And on the right, they have demonstrated the ability to curtail weight regain following cessation of incretin. We believe the translation of SpiNA designs in the clinic unlocks opportunities for 007 across treatment settings and provide strong validation for our emerging pipeline. While GalNAc has transformed delivery to hepatocytes, reaching tissues beyond the liver has remained a major challenge for RNAi for more than a decade. Our approach starts with backbone. By modifying PN linkages to create what we call PN conjugates, we can tune the physical chemical properties of the whole molecule and in turn its tissue distribution. The heat map on the right illustrates this flexibility. We evaluated the same sequence with 15 different PN conjugates, measuring knockdown in kidney, liver, and white adipose tissues. Each conjugate produced a distinct silencing profile determined entirely by backbone chemistry. This flexibility lets us steer distributions to our different tissues and tune target engagement in each tissue. Rather than relying on a single fixed conjugate, we have a library of different conjugates and can match the design to the biology of the target. This slide illustrates how we put the flexibility into practice with results from an 8-week mouse study following a single dose. The far left panel shows the well-established activity of GalNAc, which delivers oligonucleotides to hepatocytes. It also illustrates the constraints of its cell and tissue-specific delivery. GalNAc does not enable silencing in other tissues of interest such as adipose tissue. The middle and the right panels show how non-GalNAc designs in PN conjugates enable silencing of up to 90% in adipose alone or in both liver and adipose tissue together. We achieved this by tuning physical chemical properties, allowing us to select a design that best fits the target and indication. Now I'll share how we have applied this to a historically elusive target, Target A. Target A is a cardiometabolic target supported by human genetics. Carriers of loss of function variants have a lower risk of both coronary artery disease and insulin resistance. This follows the same genetics first approach for INHBE. The unmet need is substantial. Insulin resistance drives type 2 diabetes, yet available insulin sensitizers offer either modest efficacy or meaningful safety concerns. Because this target acts in both liver and adipose tissue, our goal is to silence it in both tissues. That's what we observed. Deep knockdown in liver and comparably deep knockdown in both epididymal and renal white adipose tissues sustained for at least up to 3 months after a single dose. Durable silencing across multiple tissues with a single subcutaneous dose, a profile no one else in the field has demonstrated. And we have replicated similar data sets for other cardiometabolic targets requiring dual tissue targeting of liver and adipose. As we shared before, we have also extended SpiNA into kidney. Most oligonucleotides that reach the kidney go to the proximal tubule cells as a part of reabsorption, but that delivery usually does not affect the target. So through structural activity studies, we identified SpiNA variants with PN conjugate. That achieved 75% SOD1 mRNA knockdown in mice and a 50% reduction was sustained up to 3 months after a single 5 or 10 mg per kg dose. The images on the right confirm both broad oligo distributions and reduced protein, mainly in the cortex and outer medulla. They have also confirmed knockdown across many cell types, including proximal tubule, distal tubule, endothelial cells, and podocytes. Now let me turn to how we are using our best-in-class SpiNA capabilities to open up new ways of building RNA medicines. As highlighted earlier in the presentation, our GalNAc-conjugated SpiNAs achieved robust and durable silencing across multiple targets, including TTR, INHBE, and PCSK9. Using our unique chemistry design, we have built a single bifunctional SpiNA construct that silences 2 different transcripts at the same time in the same cell. This could unlock complex indications that require engaging more than one target. It also has practical advantages over combining 2 separate drugs. One molecule to manufacture with the potential to reduce cost of goods, 1 drug through development rather than 2 drugs and delivery to the same cell, so both targets are modulated together. Here, that approach is in action with 2 well-validated cardiovascular targets, LPA and PCSK9. In transgenic mice, a single bifunctional LPA/PCSK9 construct produced robust, durable reduction in both serum LPA and serum PCSK9 with activity comparable to each corresponding mono-SpiNA alone. Other dual siRNA approaches have sometimes shown reduced activity or durability compared with single target counterparts. Our chemistry preserves the activity of both arms, delivering performance on par with the current industry-leading designs and supporting potential once or twice a year dosing. And we continue to generate additional data with our bifunctional SpiNAs and look forward to presenting more data in 2027. As we shared last year, we're also using PRISM to combine SpiNA silencing and AIMer editing or upregulation into one oligonucleotide. The single construct engages both endogenous Ago2 and ADAR. It can silence one target while editing or upregulating a different target, which opens up complex indications that needs more than one target engaged. And because the construct loads up into Ago2, we believe it may extend how the longer editing compared to the AIMer alone. We confirmed this in vivo with a GalNAc-conjugated construct designed to edit UGP2 and silence TTR. Mice received a single subcutaneous dose at equimolar levels. On left, in mouse liver, the bifunctional construct achieved higher, more durable UGP2 editing than the UGP2 AIMer alone. As I noted earlier, we believe Ago2 loading may explain this. On the right, in the same mice, the construct silence TTR mRNA as robustly as the TTR SpiNA alone. Before turning to our bifunctional silencing and upregulating oligonucleotides, let me briefly explain what we aim to achieve with upregulation. Many gene transcripts contain regulatory motives that acts as built-in brakes. These motives recruit Decay machinery, shortening the life of the mRNA and limiting how much protein it produces. The gene is active, but its output is constrained. Our upregulators recruit ADAR to make a single A-to-I edit with the regulatory -- within the regulatory motive, destructing the break on the edited transcript. This stabilizes the mRNA, allowing it to persist longer and produce substantially more protein. Remember, we are not introducing a transgene, delivering a protein, or altering DNA. Instead, we remove a specific regulatory constraint to increase protein production from the genes' own transcripts while retaining endogenous localization and processing. For diseases driven by insufficient proteins rather than excess, this offers a novel way to address the underlying deficit. Here, we revisited our application of this approach to hypercholesterolemia by silencing PCSK9 while upregulating LDLR. These targets act within the same pathway. The goal is to increase the LDL receptor levels on the hepatocyte surface while reducing PCSK9-mediated receptor degradation. As we have shown previously, in primary human hepatocytes, our bifunctional constructs increased the LDLR protein to a level comparable to LDLR upregulator alone. In the same experiment, it achieved PCSK9 silencing comparable to PCSK9 silencer alone. Together, these results demonstrate the potential to address complex indications by engaging multiple targets with a single construct. Finally, we have brought silencing and upregulation together in vivo with results that demonstrate the potential for synergy. Using an undisclosed pair of targets, the bifunctional constructs maintained potent Ago2-mediated silencing of target X as shown on the right. Notably, the target X silencer or the target Y upregulator alone produced only a modest upregulation of target Y by themselves as shown on the left. However, the bifunctional construct, while effectively silencing target X on the right, also achieved a greater than fivefold upregulation of target Y, substantially more potent than either component alone. These findings illustrate the synergy we can achieve by pairing appropriate targeting targets in a single bifunctional construct, engaging 2 different modalities. Beyond the examples I've shared today, we continue to expand what is possible with RNA medicines with the goal of bringing innovative therapies to patients in need. With that, I'll turn it back to Paul for closing remarks.

Thank you, Chandra. As we reviewed today, Wave brings together deep genetic insights and proprietary chemistry to rapidly advance transformational RNA medicines. Our oligonucleotide center of excellence integrates large datasets in-house and applies rational design and combines a multimodal platform with our own manufacturing. We're advancing WVE-008 for PNPLA3 liver disease, an approach with strong support from human genetics and advantages over siRNA. Our SpiNA design is translating in the clinic and our novel PN conjugates are enabling extrahepatic delivery with potential to unlock new therapeutic targets. Finally, with our bifunctional modalities, we can simultaneously silence, edit, or upregulate 2 unique targets with a single oligonucleotide construct with potential to drive efficiencies in development and deliver value to patients, providers, and payers. Looking ahead, we continue to expect to deliver multiple milestones this year, including filing a CTA on 008, initiating a maintenance trial for 007, and for sharing data from the 600 milligram cohort of our Phase I INLIGHT trial as well as sharing data from our 600 milligram cohort of our RestorAATion-2 clinical trial of 006. I'd like to close by thanking Dr. Sanyal for joining us today and by thanking our team for their continued commitment and to our mission of reimagining what's possible for patients. And with that, I'll turn the call over to the operator for Q&A. And as a reminder, Dr. Sanyal has stayed on with us for Q&A.

[Operator Instructions] Our first question comes from Yun Zhong with Wedbush.

So it's a very interesting concept and very interesting data, of course. But my question to both Dr. Sanyal and maybe to the company is that for the clinical development plan, is that going to be a -- well, this is talking about the liver indication. Is it going to be the standard anti-MASH therapy targeting the typical MASH patients that have been enrolled in previous studies? Because theoretically, this is really should be preventive given the fact that the mutation increases patients' risk for MASH. And is preventive therapy, I know it's very challenging possibility at all. And also another question is, what's the current status of genotyping, please?

Yes. Perhaps I'll start with our approach and then Dr. Sanyal, I'll hand it over to you to talk about the biology more. But our general approach, to your point, I'll take the last part first, which is how available is genotyping for patients. And I think what's really important here, and we've had some of the foundations come in very recently, this is a mutation that's in 23andMe and is commercially available for genetic testing. So to Dr. Sanyal's point, this is a very prevalent mutation. And oftentimes, people don't or are unaware that they actually are walking around with it. And with the improvement in access to genetic testing, that number is continuing not just to grow, but people are actually coming and saying, to your point, what should I do with this mutation? Nonetheless, for drug development and while prevention is interesting, meaning correct the enzyme over time and prevent the chronicity of damage and the evolution of disease, there is the ability to develop this in a standard MASH way where you could look at improvement in steatosis and fibrosis. However, we'll also plan to use these genotype patients and establish a homogeneous population for the purpose of a clinical trial to evaluate it, but always have that ability to look at the broader market. Dr. Sanyal, I don't know if you have anything you'd like to add.

Yes. Maybe just a couple of points to build on what you said, Paul. First, that a drug -- this is a new area in the NASH space that we are entering. If you go into prevention, it takes a long time to show clinical outcomes and, therefore, you're creating a very long pathway. So the low-hanging fruit really are taking people who have established disease, but who are also carrying the mutation and, therefore, at higher risk of progression to cirrhosis as well as clinical outcomes. Despite the availability of GLPs, as you know, there are still a lot of nonresponders in terms of fibrosis. There are people who are intolerant. All of these, particularly if you have this particular gene mutation, may not get the kind of benefit that one might hope just with the existing drugs that are out there. And that creates, one, an opportunity to build on what is already out there and further enhance for this particular subpopulation. And then for those who are nonresponders, this really gives an entirely new way of managing these patients because if you looked at those Kaplan-Meier curves that we showed, if we can reduce the -- if you can bring the survival curve up to what you see with the heterozygotes, that's actually a substantial improvement in both liver outcomes and liver-related mortality. So that creates the rationale for why that probably should be the first thing to tackle and then deal with the more long-term issues of prevention. Also if you are otherwise healthy, having the mutation, the clinical impact of that may not be as significant as if you have underlying obesity and insulin resistance.

I'll turn to Chris for a couple of comments.

I'm just going to add to what Dr. Sanyal said was, is that preclinically, we have seen that we can reduce the levels of fat in hepatocytes. So we know that it has a direct effect there as well as on fibrosis and inflammation. And the other clinical studies of knockdown, you do see effects -- direct effects on fat levels. So I think it's not just that it's preventative, but that could be therapeutic as well.

Which is, by the way, consistent with the genetics, like the genetics is there across all stages of disease. It's not only to develop MASH or MAFLD in the first place or in liver disease, it's also in relation to survival. Dr. Sanyal showed those curves already.

Our next question comes from Joon Lee with UBS.

Just a quick clarifying question on Yun's question. Like so people with PNPLA3 mutation are born with it and get MASH and other complications. But can editing it as an adult be enough to reverse MASH? And how does PNPLA3 mutation actually rank compared to maybe other targets for MASH? And then just a follow-up question on INHBE. Is there a range of DIO models to test your hypothesis that higher BMI would indeed drive greater weight loss? In other words, would it be possible to generate mice with degrees of obesity by controlling for their diet to test for hypothesis that higher BMI in humans would indeed lead to greater weight loss for your INHBE program?

Yes, I'll take the last one first, Joon, and then hand it to Erik to follow-up on the PNPLA3 question and can also follow-up on the other one. But I think this is compelling where we know, and we've seen this now in human, even looking at 400 milligram, looking at a differentiation in humans with different levels of adiposity is it's very clear with increasing adiposity, you get increasing driver for fat reduction. That's something that we've always said is a core driver in achieving the weight loss off of fat loss. And I think what was interesting about these models is that's exactly what we've seen preclinically, correct, right? The DIO is an obese mouse model with high adiposity, and you can achieve weight loss similar to GLP-1s with that fat to lose. And in very lean mice, that lean diets, there is no effect. And so you do need that increasing adiposity. And again, it's translating in the Phase I where these patients do have increased adiposity versus a completely lean low BMI patient population, and we see an effect on 14%, 15% reduction in visceral fat, 5% reduction in subcutaneous fat, 3.3% reduction in waist circumference. So even in the human subjects, we're seeing that this change comes out with the increasing adiposity. I think will be compelling it. We've got a 2a study running in, as Chris mentioned in earnings, that are achieving those higher levels of adiposity. So we are going to be able to evaluate this in humans. [indiscernible].

Yes. So thanks, Joon. I think in terms of the editing as an adult and if it's enough to reverse MASH, I think we have evidence that, that would be the case across a couple of different levels, starting with human genetics, as we've talked about already, we know it is associated not only with developing MASH in the first place, but also survival in MASH and progression to cirrhosis and cancer, as Dr. Sanyal already pointed out. So genetics would support that it could be a reversible situation. The second thing is the preclinical. We've presented data today and before, both reversal of fat and of fibrosis, inflammation and fibrosis. I think that's also a second layer of evidence that it would be reversible in adults. And the third layer is the clinical data that already exists. You actually do see some reversal of the steatosis side of MASH. It's just the fibrosis that hasn't been possible to do with the total knockdown of PNPLA3. But we also think that actually restoring it back to wild type will be more efficient for the fat as well. So we think it's a superior modality, but there is some clinical evidence as well. So I think this is across both genetic, preclinical, and clinical data is pretty strong evidence that, that is reversible in MASH in adults. And then your second question was about how this variant ranks among different MASH targets. And I think Dr. Sanyal showed very nice overviews of that where this is that strong association. It was the first one really to be established through GWAS back in like around 20 years ago now. So it's like definitely the strongest genetically, and those are attractive because it's such a large population. It really allows for a precision medicine approach in a very large population of carriers.

Our next question comes from Alethia Young with William Blair.

Thanks for putting all this together today and having Dr. Sanyal on the phone. A couple of questions. One, the subgroup data, it seems to show a stronger risk association in patients with advanced fibrosis and diabetes. Do you think this suggests a greater dependence on the PNPLA3 biology? Or is it just kind of suggest that they're kind of identify high-risk patients? And can you use this for trial selection? And then my second question is, I'm just curious how much SpiNA like design carries over from one target to the next when you're kind of thinking about across TTR, PCSK9, or the same stereochemical pattern is working? Or do you need to kind of reoptimize as you go through each sequence?

Great. Maybe for the first question, Dr. Sanyal, would you like to take that?

Yes. I think there's no question there is an interaction between increasing age and type 2 diabetes and having the PNPLA3 mutation. Now there could be 2 potential sort of scenarios over here. One, that the PNPLA3 that when you have diabetes, you already have more severe insulin resistance, more severe lipotoxicity and already more aggressive fibrogenesis. And in that setting, having this, you could argue which one is the sub fire and which one is the catalyst. But the 2 together, they sort of synergize. And so if you take one of these away, you return things to sort of more of a baseline situation. And certainly, these could be used as enrichment factors for clinical outcomes. But I would suspect that based on the biology that the benefits of fixing the mutations would not be restricted only to those who have diabetes or are over the age of 60, although one could imagine stratification just if you had to show that there were differences in clinical outcomes that would help enrich for the clinical outcomes. I hope that makes sense.

Thank you, Dr. Sanyal. Chandra, do you want to do the SpiNA question?

Yes. So the SpiNA question you asked us about the sequence dependency. So the chemistry that we have developed, as I said, it's mainly looking at how the sequences dock onto the Ago2. And so this is actually sequence independent phenomenon. And we have translated our learnings from our TTR through our INHBE. And remember, we also have a clinical candidate declared for GSK. They're developing -- they have taken it for development. And so all this actually shows us that our technology is not sequence dependent at all [indiscernible].

Our next question comes from Samantha Semenkow with Citi.

Thanks for putting this together today. My question is with correcting this I148M mutation with 008. Is the therapeutic goal here reversal of disease? Or would prevention of further progression be enough for this market? And I guess what I'm getting at is, what do you need to show competitively in the clinic here to be used over some of the other obesity drugs, GLP-1s, and others that are in development?

Thank you, and I'll start and I'll let Erik. I think the short answer is both. And I think the opportunity we have on both the steatosis side and the fibrosis side give us a point of differentiation. As we've seen, there was a substantial investment in siRNA silencing to try to approach the disease with early data on the steatosis side, but again, not -- without being able to address the fibrosis side. So I think there is a strong therapeutic component to this, not just preventive. And to that point, a lot of the other mechanisms are out to really address and focus on the steatosis side by taking down that path. So again, mechanistically, and again, in patients that have this specific mutation, both is [indiscernible].

Yes, I'm not sure if I have so much more to add. I think, again, yes, both. And I think it would be a great drug if it could entirely stop progression because, typically, individuals with MASH and they do die more from the cirrhosis stuff. So even if it, within quotation marks, only put a break on it, it would be great. But we do think based on the biology and what we know at this point that there is also a potential to actually reverse and push it backwards in this basis. So both.

Our next question comes from Rick Bienkowski with Ladenburg.

This has been a really informative presentation. For Dr. Sanyal, you showed some evidence earlier that MASH resolution with tirzepatide is weaker in PNPLA3 carriers than in wild-type patients. I was curious to get your opinion on the RNA editing mechanism of action here. Would you expect to see resolution of MASH with an RNA editing monotherapy in heterozygous and homozygous patients? Or do you think the mechanism would really shine brighter here in a combination setting?

Dr. Sanyal?

So I think my answer would have to be a little bit speculative. So in that -- this kind of setting, first of all, these findings from the Phase IIb study have to be confirmed and validated in larger studies. But assuming that is so, I would imagine this could really potentially -- if there is a causal basis for those with mutation to have less of a response, then there could be a way to enhance the MASH resolution. And the MASH resolution over time would be expected to reduce progression to cirrhosis because the fibrosis progression does not occur in a vacuum. It is the disease activity or the steatohepatitic activity that drives the fibrosis progression. So to that extent, I think it could enhance the therapeutic benefits of a molecule like tirzepatide. And remind me again, there was a second part to your question as well, wasn't there?

I guess the second part of the question was about preclinically we've seen between 50% and 60% correction of the PNPLA3 transcripts. So do you think that would be sufficient for heterozygous and homozygous patients? Or is this one of those populations?

Well, I think if we can -- if you saw the survival curves, the heterozygote and the completely normal individuals with or the CC phenotype, they're not really that differentiated. But that is the premise, that when you switch this from a homozygous mutation to a heterozygous state, it's sort of the PNPLA3, you have to remember, one thing is a little bit weird and it's hard to wrap your head around that on the one hand, it's a triglyceride lipase, and having the mutation decreases triglyceride lipase activity. On the other hand, you need increased expression of the gene for the phenotype to develop. So that's a sort of interesting construct over there. And so, that has to be taken into consideration in terms of trying to understand whether a 50%, 60%, or more would be sufficient. You probably don't want to completely wipe out all triglyceride lipase activity because then you have no way to mobilize your triglycerides. So then you will essentially start accumulating triglycerides. And so more is not always better. And this is a little bit of a Goldilocks situation, I think, where you just want to hit it just right, not too much, not too little, get it right in the middle. And gene editing gives you that opportunity as opposed to gene silencing, which will wipe out all your triglyceride lipase activity, so then you cannot mobilize triglycerides or substantially impairs your triglyceride mobilization capabilities, which can have other unintended consequences.

And maybe if I could just add one thing. Thanks, Dr. Sanyal. I agree with all of that. And that's also why we set out 50% as kind of our bar for this development. Now just for the record, the 60% we showed today is that's in stellate cells and it's also for a surrogate AIMer for the mouse studies. Now in our human with the compound that we're taking into clinic, we've seen up to 85% editing in hepatocyte, just for the record.

Our next question comes from Amine Chaherli with B. Riley Securities.

Thank you so much for the comprehensive update and for bringing on Dr. Sanyal today. I just had a question with regards to 008. I guess, if you could talk about how you're thinking about demonstrating target engagement. And I guess, like how that kind of interacts with that genotype first enrollment approach that you've described? And then I just had a question about basically if you could just inform about the time course once the editing is established and whether clearance of the preexisting protein pool is kind of the rate-limiting step of the efficacy versus like just the editing itself?

No, it's a wonderful question. We'll obviously give more updates on the trial design as the CTA submitted and the trial initiates. But I think the premise really takes 2 approaches. One, because we can enrich and this is a study in PNPLA3 patients, the ability we have to start identifying those patients, right, and creating those relationships starts before the study goes. So we can actually start identifying patients with PNPLA3 mutations. Second, to your point on evaluating efficacy, there are biomarkers, and we've spoken this briefly in the past that we can identify to look at target engagement as well as other measurements we can use to look at editing and then have other approaches that we can look on physiology. I don't know, Chris, if there's anything you'd like to add to that.

You covered most of it. We're planning to ensure that we have a number of patients that are prescreened that have the actual genotype that we're looking for so that we can enroll them rapidly into the study. So I think just to cover from that perspective. And as Paul mentioned, and you can look at other sponsors trials where they looked at various lipid components to show that they were hitting their target. So it's possible to do that from a biochemical perspective or from biopsies, as you mentioned.

Our next question comes from [ Tessa Young ] with Jefferies.

This is [ Chacha ] on for Roger. So my question is for 008. My understanding for the ADAR-mediated RNA editing is that for the ADAR edit, you would generate the I148V (sic) [ I148M ] substitution rather than converting to wild-type isoleucine. So can you just share with us more data or how we're thinking about the functional activity of the edited protein with the valine in that position versus the wild-type isoleucine?