Wave Life Sciences Research Day - WAVE LIFE SCIENCES INC

Hello, and welcome to WAVES 2026 Research Day. We ask that you please hold all questions until the completion of the formal remarks, at which time you'll be given instructions for the question and answer session. Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Roush, 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 investor 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 présentation. 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 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 Bono, our President and Chief Executive Officer, Eric Engelson, our Chief Scientific Officer, and Chandra Varghese, 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 the genetic variations drives 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 oligonocleotides are made as a stereorandom mixture with potentially up to a million unique isomers in a single dose. WAVE's founding premise was to bring rational drug design to oligonecleotids 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. We 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, PMPLA-3 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 inhibiny 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 PMPLA-3 program. This program builds on our clinical success with WVE-006 for AATD. PMPLA-3 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 PMPL-A3 I-148M patients with liver disease and the opportunity for RNA editing. Eric 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 WVE007 with a safe and well-tolerated profile. Next, she'll speak about how we're using our chemistry to advance PN conjugates to unlock extra-hepatic delivery, and provide an update on our bifunctional modalities that provide the ability to silence, edit, and or upregulate two 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. Sanyals 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 PMPLA3I148M 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 BNPLA-3 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, beyond linking this gene mutation to having excess fat in the liver, there are now data indicating that if you have this geneutation, you are much more likely to have cirrhosis. So within cirrhotic populations, this gene mutating 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 PNPL3I148M 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 in 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 it is particularly overly 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 a third or more of the general population, and you've layered 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 cirrhoses as the liver gets more scarred. PNPLA-3, 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 hepadocellular carcinomas 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 related to having advanced fibrosis, and then you're already seeing the data for the sub-hazard ratio for age over 60. You're seeing that in diabetics, there's 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 heterozygious state. And similarly, if you Look at cirrhosis-free survival time in people who did not have advanced fibrosis at baseline, once again, having homozoic I-148 mutation is associated with much poorer outcome. So these provide a rationale that if you can convert somebody from a homozygous to a heterozygious 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 a composite endpoint after adjusting for age, gender, diabetes, and BMI, which we know are cofactors, 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're 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 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 triglyceral 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 triglycide. So at any given degree of fatty acid triglycride flux through the liver, you start accumulating triglycyrides. Now, PNPLA3 gene is also important in the stellate cells, where if you have the mutation, it impairs retinal ester hydrolysis and thus accelerates collagen production by the stellates cells. And it's believed this is an important additional mechanism by which it contributes to increased fibrosis. It also attenuates proteasome autophagy. And so it leads to more fat. And when you start accumulating more fat, you also drive lipids into other aberrant 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 MASH, there are data that MASH resolution with terzapatide was weaker if you have the gene mutation. It's not that it's bad, 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 homоzygious I148M mutation to a heterozygues 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 cervodotide, which data will be shown at ASLD, you know, the PNPA, those drugs worked regardless of the presence or absence of these gene mutations. This has been really shown in the context of tirzapatide. 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 homostasis reduce steatosis and prevent liver injury and because of its role through retinol homeostases mutation correction should be able to attenuate hepatic inflammation and oxidative stress and should be to lower fibrosis and lead to MASH 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, Dr. Dirk. Thank you Dr. Sanyal. So as I think you will agree, Dr Sanyals just made an excellent case for why PLMP3 is one of the strongest genetically defined targets in liver disease. I'll now walk through how we're addressing it with WVE-008, our wholly owned gallium conjugated RNA editing candidate. 008 builds directly on what we have already demonstrated in the clinic with WBE-006 in AATD. With 006, we've shown efficient and consistent RNA editing. We have demonstrated increased M protein and decreased Z protein to levels seen in MC individuals as well as restored the dynamic physiological 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. He also gave us a validated foundation to bring RNA editing to additional genetically defined diseases, starting with PLNP3, I148M liver disease. As you already heard from Dr. Sandhya, PLNPP3 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 PLNNP4, I138M, and are living with liver disease, Homozygous carriers have a significantly higher risk of a range of liver diseases. These include methyl D, MASH, and alcohol-associated liver disease, and they extend to cirrhosis and hepatocellular carcinoma. As you can see in the survival curve to the right, homozygious I148M carriers have an approximately nine-fold higher risk of liver-related death than non-carriers. Heterocyclic caries, by contrast, have about 80% lower risk of liver-related death than homocyclocaries. This observation defines our therapeutic goal. We aim to edit at least 50% of PLNP3 transcripts in the liver, restoring a functional heterocyclus-like state that is associated with dramatically lower risk of liver complications and death. Our gamma-carni editing approach is uniquely designed to restore PLNB3 function and fully address this genetic driver of disease. We believe it will be superior not only to PLNP3 silencing, but also to non-precision approaches in MASH. Why edit rather than silence? The wild-type protein plays important roles in the liver's lipid and retinal metabolism. Multiple preclinical models highlight the potential liabilities of removing PLNB3 altogether. To the left, in IPSC-derived human liver organoids, silencing PLNV3 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 PLMP3 sRNA worsens the fibrotic response. These findings are consistent with emerging clinical experience. As Dr. Sangel noted, the emerging data from trials with PLMP2 silencing agents have been disappointing, with a recent trial that even showed dose-dependent increases in liver enzymes. The message is that functional PLMP3 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 CGI58, the cofactor of adipose triglyceride lipase ATGL. This inhibits the lipase activity of ATGL, blocking lipids from being mobilized out of the liver. I148M also suppresses retinal metabolism, which worsens inflammation and fibrosis by promoting fat accumulation and fibrois via activation of stellate cells. Silencing PLMP3 can only partially address this biology. Knockdown creates a PLMP2 loss of puncture. ATGL activity is only partly rescued and retinal metabolism is not restored. As a result, silencing may partially address steatosis while inflammation, ballooning, and fibrosis persist. By contrast, correcting I148M with RNA editing is expected to restore full PLMP3 activity and lipid mobilization. That would reverse not only steatosis, but also inflammation, balloning, and fibrosis, feeding across the stages of liver disease. This is the key rationale for RNA editing over knockdown. WV00A is a gallic-conjugated RNA editing oligonucleotide, an AMER. It incorporates WAVE's proprietary chemistry and builds on our learnings from 006. It is administered by subcutaneous injection with potential brain-frequent dosing. In the left file, you can see the dose-response curve showing potent editing with 008. In the middle, you see results from RNA sequencing in two separate primary human hepatocyte lines, showing an ideal editing profile with strong on-target editing and no evidence of off-targets editing elsewhere in the transcript film, which gives us confidence in 008's 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 translational foundation as we advance 008 towards the clinic, building on the clinical success of RNA editing capability with 006 for ATD. Next, we looked at whether editing translates into a functional benefit on liver fat. We compared our PLMP3-AMR with a PLMP-3-SRNA using our best-in-class SPINA format in two human hepatocyte models. In the upper row, you can see how PLMP2 editing significantly decreased lipid accumulation in hepatopac, a 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 PLM-degree function and the rationale for correcting IL-148M rather than silencing PLM degree. For liver disease that progresses across the hepatic lobular zones, it's important that our oral egonucleotide reaches all cells throughout the liver, not just in one region. Here, wild-type mice received a single subcutaneous dose of a surrogate PLMP3 AMER, and liver tissue was examined a week after that single dose. The red signal shows the AMER. You can see even distribution across all three zones of the liver, zone 1, very portable hepatocytes near the portal triad, zone 2, intermediate hepatocytes, and zone 3, very central hepatocydes around the central vein. This broad uniform distribution is a critical finding since it supports our goal of editing PLMP3 throughout the liver, which is important for treatment of MASH and other PLMP-driven liver diseases. This data is also encouraging for our other AMER programs, such as our 006 program, as uniform distribution of the drug is important to all liver diseases Beyond hepatocytes, we also wanted to understand whether our AMERs reach the hepatic stellate cells that drive fibrosis. Hepatocytes are only part of the story in PLMP 3 liver disease. As Dr. Sandel described, the I-148 mBarrant also impairs retinal ester hydrolysis in hepatic stellate cells, or HSCs. HSC are the main drivers of fibrosis in the liver, so it's important to know whether our AMRs reach these cells. In this study, wild-type mice received our surrogate TLMP3 AMR. Desmin, shown in green, marks the stellate cell, and AMR is shown in red. Where the two overlap, you see yellow, which confirms that our AMRs are inside HSCs. As you can see, a substantial fraction of HSC shows uptake. We then asked whether the AMR actually edits PLMP3 inside cell-like cells, not just reaches them. In the panel to the right, you can see that we observe over 60% RNA editing in cell-head cells. This confirms that the AMRS are active in these cells, not just present. These observations are critical because they suggest 008 could do more than correct PLNP3 inhibitor sites. The data indicates that they also act directly in the cells that 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 PLNB3-I148M variant is a well-established driver of steatosis, inflammation, ballooning, and fibroses. Yet, there are no approved medicines that directly address this biology. Preclinical and clinical data increasingly suggest that simply knocking down PLMP3 is not the answer. Losing PLMP-3 function can make the very features we're trying to treat worse. Our approach is different. With 008, we added PLMPT3 rather than sinusin. The goal is to correct the variant that causes the disease and restore normal PLMP2 function in two key cell types, hepatocytes and hepatic cell 8 cells. Continuing and contributing to restoration of lipid mobilization and reduction of liver fat, as well as restoration of retinal 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, models, even distribution across all three zones of the liver, presence, and editing in hepatic stellate cells in addition to hepatocytes. Together, these data support 008's potential to reduce hepatocephalosis, inflammation, and fibrosis, and to improve MAF resolution in people who are homocyclosed for PLNP3 I148 M. 008 also builds on our clinically validated RNA editing platform. If successful, it could be a first-in-class, deceit-modifying treatment for a large genetically defined population with no targeted options today. In summary, 008 meets every criterion we set before advancing a program addressing PLMP3 I148M liver disease in particular. As we just outlined, there are strong supporting human genetics and a large addressable population of more than 9 million homozygous I147M individuals with no treatment options that directly target targets the 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 three zones of the liver, as well as uptake and editing in hepatic cell A 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 aim in chemistry, we are excited to take 008 into the clinic. We will leverage previously genotype populations to efficiently identify homozygous I148M carriers and accelerate enrollment, and will 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, Eric. I'll begin with the foundation of our SPINA designs and how they have enabled significant improvements over industry-leading SA RNAs, 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 nucleotides 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 base, sugar, and backbone modifications, optimizing sequence, stereochemistry, pharmacological, and safety profiles all together. Our P and 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 inform the others and helping us move quickly into new targets. Today, I want to spend a moment on stereochemistry. Stereochemisty is a foundational aspect of chemistry relating to the three-dimensional arrangements of atoms. It has long been recognized that molecules differing solely by their stereochamistry have radically different properties. And this, stereochemistry has been a central feature from several Nobel Prizes 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-eriting oligonucleotides and siRNAs exist as a mixture of stereoisomers unless the stereochemistry is deliberately controlled. Why does this matter? The case of thalidomide taught us the importance of characterizing chirality decades ago. The middle of this slide shows two stereoisomas 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 structural-based design. For example, for our siRNAs, that means positioning the guide strand with the mid and PV domain of AGO2 to maximize AGO3 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 EGOTU loading, it enhances RNA-mediated silencing, delivering greater potency and durability 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' 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 gained potency and duration mainly from agotool 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 agotol loading, shown to the right. Spina delivers more than tenfold improvement in ego-to-loading versus the reference siRNA. The spina advantage extends even beyond TTR. Here we evaluated PCSK9, a clinically validated cardiovascular target, comparing two spina designs with a construct based on the inclicerant sequence and chemistry. Both SPINA designs show 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, LDL, or 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, inhibini. Our approach with the inhibini 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 risk complex, and improve liver exposure. As we just shared, these designs achieve greater than tenfold improvement in AgO3 loading versus a reference siRNA, and we'll discuss momentarily this approach as translated in the clinic. While our in-light trial is investigating otherwise 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 activity 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 our approach and our ongoing Phase II clinical trial. We can look to our preclincal data to demonstrate specifically the importance of baseline adiposity to this mechanism. As we shared previously, our inhibinase 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 inhibiting SARNA 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 2A portion of inline, which includes individuals with higher adiposity or excess fat at baseline. In addition to our ongoing phase 2a inline monotherapy trial, we are also making strong progress on our strategy to evaluate 007 in the combination and maintenance settings. 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 two-fold 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 incretine. We believe the translation of SPINA designs in the clinic unlocks opportunities for 007 across treatment settings and provide strong validation for emerging pipelines. 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 physicochemical 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 see our 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 eight-peak mouse study following a single dose. The far left panel shows the well-established activity of GalNAG, which delivers all of the nucleotides to hepatocytes. It also illustrates the constraints of its cell and tissue-specific delivery. GalNAg does not enable silencing in other tissues of interest, such as adipose tissue. The middle and the right panels show how non-Kelnack designs with PN conjugates enable silencing of up to 90% in adipose alone or in both liver and adipos tissue together. We achieved this by tuning physical chemical properties, allowing us to select the design that best fits the target and indication. Now, I'll share how we have applied this to 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 inhibiting. 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 epididymial and inguinal white adipos tissues sustained for at least up to three 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 cardiomerabolic 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 three months after a single 5 or 10 mg per kg dose. The images on the right confirm both broad oligodistributions and reduced protein, mainly in the cortex and outer medulla. We have also confirmed knockdown across many cell types, including proximal tubule, distal tubules, endothelial cells, and protocytes. 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 galnet-conjugated spinas achieve robust and durable silencing across multiple targets, including TTR, N-hebini, and PCSK9. Using our unique chemistry design, we have built a single bifunctional spinet construct that silences two 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 two separate drugs. One molecule to manufacture, with the potential to reduce cost of goods, one drug through development rather than two drugs, and delivery to the same cell, so both targets are modulated together. Here, that approach is in action with two well-validated cardiovascular targets, LPA and PCSK9. In transgenic mice, a single bifunctional LPA-PCSK9 constraint produced robust, durable reduction in both serum LPA and serum PCSK 9 with activity comparable to each corresponding monospina alone. Other dual-SARNA 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 spinners and look forward to presenting more data in 2027. As we shared last year, we are also using PROSEM to combine spinous silencing and AMER editing or upregulation into one oligonucleotide. The single construct engages both endogenous AGLE2 and ADAR. It can silence one target while editing or UPregulating a different target, which opens of complex indications that needs more than one target engaged. And because the construct loads up into AGO2, we believe it may extend the longer editing compared to the AMR alone. We confirmed this in vivo with a galnet 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 UGT2 AMR alone. As I noted earlier, we believe EGOTO loading may explain this. On the right, in the same mice, the construct silenced 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 motifs that act as built-in breaks. These motifs 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 up regulators recruit ADAR to make a single A2I edit within a regulatory motif, disrupting that 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 gene's 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 revisit our application of this approach to hypercholesterolemia by silencing PCSK9 while upregulating LDL-R. These targets act within the same pathway. The goal is to increase the LDL receptor levels on the hepatocyte surface while reducing PCS-K9-mediated receptor degradation. As we have shown previously, in primary human hepatocytes, our bifunctional constructs increase the LDL-L protein to a level comparable to the 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 ego2-mediated silencing of target X as shown on the right. Notably, the target X silencer or the target Y upregulator alone produce 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 five-fold upregelation 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 two different modalities. Beyond the examples I have 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 data sets in-house and applies rational design and combines a multimodal platform with our own manufacturing. We're advancing WVE-008 for PMPLA3 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 two unique targets with a single oligonucleotide construct, with potential 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 and light trial, as well as sharing data from our 600 milligram cohort. of our Restoration II 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. Sanial has stayed on with us for QAnon. Thank you. We will now move into our Q&a session. For those of you who are joining us via the QAnone webcast, If you would like to ask a question at this time, please raise your hand by clicking the raise hand at the bottom of your window. We would like all analysts to please limit yourself to one question per person. Once called upon, please unmute your audio to ask your question. Our first question comes from Yan Zhong with Redbush. Please unmute your line and ask your questions. Hi, good morning. Thank you very much for taking the question and thank you for the presentation. So it's a very interesting concept and very interesting data, of course. But my question to both Dr. Sanya and maybe to the company is that for the clinical development plan, is that going to be a, while this is talking about the liver indication, is it going to be the standard anti-MASH therapy targeting the typical MASH patient that have been enrolled in previous studies? Because theoretically, this really should be preventive, given the fact that the mutation increases patients' risk for MASH. And is preventive therapy, I know it's a very challenging possibility at all. And also, the question is, what's the current status of genotyping, please? Thank you very much. Yeah, 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. Sano's point, this Is a very prevalent mutation. And oftentimes, people 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 can look at improvement in steatosis and fibrosis. However, we also plan to use these genotype patients and establish a homogeneous population for the purposes 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 like that. Yeah, maybe just a couple of points to build on what you said, Paul. First, that, you know, this is, you Know, a new area in the MASH space that we're entering. if you go into prevention it takes a long time to show clinical outcomes and therefore you know 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 non-responders 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 non-responders, this really gives an entirely new way of managing these patients. Because if you looked at those Kaplan-Meier curves that we showed, if you can bring the survival curve up to what you see with the heterozygous, 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, you know, having the mutation, the clinical impact of that may not be as significant as if you have underlying obesity and insulin resistance. Thank you. I'll turn to Chris for a couple of comments. I'm just going to add to what Dr. Sanyal said, 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 in the other clinical studies with knockdown, you do see 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. The genetics is there across all stages of disease. It's not only to develop MASH or MAPL-D in the first place or any liver disease, it's also in relation to survival. Dr. Sanjog showed those curves already. Thank you. Our next question comes from Jun Li with UBS. Please unmute your line and ask your question. Hi, thanks for the webinar and taking our questions. Just a quick clarifying question on Yoon's question. So people with PMPLA-3 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 PMPL-A3 mutation actually rank compared to maybe other targets for MASH? And then just a follow-up question on inibini. 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 high BMI in humans would indeed lead to greater weight lost for your NABD program? Thank you. I'll take the last one first, June, and then hand it to Eric to follow up on the mpla3 question and can also follow up on 07 but but i think this is this is compelling where we know and we've seen this now in humans even looking at the 400 milligram looking at a differentiation in humans with different levels of adiposity is it's very clear with increasing adipocity you get increasing driver for fat reduction that's something that you know we've always said is is a core driver in achieving the weight loss off of fat loss and i think what was What's interesting about these models is that's exactly what we've seen preclinically, correct, right? The ZIO 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, fed lean diets, there is no effect. And so you do need that increasing adipocity. And again, it's translating into phase one, where these patients do have increased adipocyte 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. And I think what would be compelling is we've got a 2A study running in, as Chris mentioned at earnings, that are achieving those higher levels of adipocity. So we are going to be able to evaluate this in humans. Yeah, so thanks, Jun. 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 gene genetics, as we talked about already. We know it's associated not only with developing MASH in the first place, but also survival in MASH and progression to cirrhosis and cancer, as Dr. Sandel already pointed out. 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 inflammation of fibrosis. I think that's also the second layer of evidence that it would be reversible in adults. The third layer is the clinical data 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 PLNP3. Plus, we also think that actually restoring it back to wild type would 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 just across both genetics, preclinical and clinical data, it's pretty strong evidence that it's reversible in MASH in adults. And then your second question was about how this variant ranks among different match targets. And I think Dr. Sangel showed very nice overviews of that, where this is the strongest 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 it's also attractive because it's such a large population. So it really allows for a precision medicine approach in a very large population of carriers. thank you our next question comes from alethea young with william blair please unmute your line and ask your question hey guys thanks for taking my question and um thanks for putting all this together today and having dr samuel on the phone um a couple questions one um 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 plpna3 biology or does it just kind of suggest that you know they're kind of identify high-risk patients and can you use this for for trial selection um and then my second question is i'm just curious how much um spina like design carries over from one target to the next you know when you're kind of thinking about you know um across ttr or pcs k9 are the same stereochemical patterns working or do you need to kind of re-optimize as you go through each sequence great maybe for the first question dr sano would you like to take that Dr. Yeah, 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 two potential sort of scenarios over here. One that the PNPLA-3, you know, that when you have diabetes, you already have a 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 fire and which one is the catalyst, but the two 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 mutation 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, you know, that there were differences in clinical outcomes that would help enrich for the clinical outcomes. Hope that makes sense. Thank you, Dr. Chandra. Chakra, do you want to do the SPINA question? Yeah. So the SPina question you asked us about the sequence dependency. So, the chemistry that we have developed, you now, 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 inhibitor. And remember, we also have a clinical candidate declared for GSK. You know, they're developing, they've taken it for development. And so all this actually shows us that our technology is not sequence dependent at all. first women. Thank you. Our next question comes from Samantha Semenko with Citi. Please unmute your line and ask a question. Hi, thanks very much for taking the question and thanks for putting this together today. My question is, you know, with correcting this, the I-148N mutation with O-8, 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? Thanks very much. No, thank you. And I'll start, and I'll let Eric. 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 this disease with early data on the steatosis side, but again, without being able to address the fibro 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 fat. So again, mechanistically, and again, in patients that have this specific mutation, both is the operative. Yeah, I'm not sure if I have so much more to add. Again, yes, both. And I think it would be a great drug if it could entirely stop progression because, you know, typically individuals with MASH and they do die more from the cirrhosis step. 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 the stages, so both. Thank you. Next question comes from Rick Bianchowski with Leidenberg. Please unmute your line and ask your question. Good morning, everyone. This has been a really informative presentation, and thanks for taking the questions. For Dr. Sanyal, you showed some evidence earlier that MASH resolution with trisepatide was weaker in PNP-LA3 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 homozygious patients, or do you think the mechanism would have really shined brighter here in a combination setting? Dr. Sanya. So I think my answer would have to be a little bit speculative. So, you know, in this kind of setting, first of all, these findings from the phase 2B 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 fibcrosis progression. So to that extent, I think it could enhance the therapeutic benefits of a molecule like terzibetide. And remind me again, there was a second part to your question as well, wasn't there? Rick, your line is unmuted. If you'd like to go ahead. Right, thank you. I guess the second part of the question was about preclinically we've seen between 50 and 60 percent correction of the PNL-PLA3 transcript. So do you think that would be sufficient for heterozygous and homozygious patients, or just one of those populations? Well, I think if you saw the survival curves, the heterozoic and the completely normal individuals, they were the CC phenotype. They were not really that differentiated. But that is the premise, that when you switch this from a homozygous mutation to a heterozygious state, it's sort of, the PNPLA-3, 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 triglycereid lipase activity. On the other hand, you need increased expression of the gene for the phenotype to develop. so it's a you know 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 to mobilize your triglycerides. So then you will essentially start accumulating triglycarides. 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 triglycereids or substantially impairs your trigliceride mobilization capabilities, which can have other unintended consequences. And maybe if I could just add one thing. Thanks, Dr. Sonja. I'll 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, 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 in the clinic, we've seen up to 85% editing in hepatocytes, just for the record. Thanks for the question, Rick. Our next question comes from Amin Shaharli with B. Reilly Securities. Please unmute your line and ask your question. Hi, everyone. 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, you know, demonstrating target engagement in humans, 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, you know, once the editing is established and whether clearance of the pre-existing protein pool is kind of the rate limiting step of the efficacy versus like just the editing itself. Thank you. No, it's a wonderful question. We'll obviously give more updates on the trial design as the CTA is submitted and the trial initiates. But I think the premise really takes two approaches. One, because we can enrich, and this is a study in PNPLA3 patients, the ability we have to start identifying those patients and creating those relationships starts before the study goes. So we can actually start identifying patients with the MPLA-3 mutations. Second, to your point on evaluating efficacy, there are biomarkers, and we've spoken to this briefly in the past, that we can identify to look at targeted engagement, as well as other measurements we can use to look it 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. I think we covered most of it. We're planning to ensure that we have a number of patients that are pre-screened 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 come 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 Chacha Young with Jefferies. Please unmute your line and ask your question. Hi, this is Chacha on for Roger. Thank you for hosting this event and thank you for taking our question. So my question is for 008. My understanding for the ADAR mediated RNA editing is that for the A to I edit, you would generate the I148V 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-typed isolecine? Yeah, I can take this. So we actually looked at a lot of... These genotypes actually naturally exist. There's a lot of species that have the valine substituted for isoleucine. And so this is where we think that it's actually, you know, structurally, they're also very related. And so, this helps us to generate, of course, we are not converting back to the wild type, but we are actually making it to valine, which is actually a good substitution for isleucine, so that's where this is coming from. Again, it's supported by genetic data in lots of different species, in monkeys and even in bovine. You know, this is where it exists. And maybe, so if I can add, so that was the starting point, you know, both structure and conservation across species, et cetera. Now, so, that was a little bit of a bet, but now I think we've shown in a lot of preclinical study that it actually does revert it back to a functional protein, as we expected based on the conservation of the protein in the structure. to that point where we could look at it in comparison with other substrates. I guess IRNA is to look at comparable effects on the control side. So yeah, it was a great exercise both in understanding basic biology and translating that into a therapeutic. Our next question comes from Catherine Novak with Jones Trading. Please unmute your line and ask a question. Hi, Mornin. Thanks so much for taking the question. Just wanted to get a little clarity on the road and the timeline to proof of mechanism data in humans for PMPLA3. You know, the first in human data, I know you're focusing on genotyping, but will these patients also have clinically significant Maffold? And, you know, in what percent liver fat reduction would be considered meaningful? And then from a timing standpoint, you know, the duration of dosing, how many weeks do you expect to first efficacious data in the phase one trial? Thanks. No, thank you. And I think once again, once we're filed and initiated, we'll give more definition of where we're going to get to and on the various side of the trial. I think the thing to step back from, I think about the 30,000 foot view is the goal initiation is to look at this in an expeditious experimental way of unlocking the potential here, meaning how quickly can we identify in these patients with mutations and underlying disease, the ability to show high degree of editing, distribution, durability, change on biomarkers, change in physiology, all of which are going to allow us to de-risk the mechanism and then continue on the study. So I think to step back, speed and efficiency coupled with the ability To differentiate in this space will be the focus of the clinical trial. And I think interestingly enough, too, in terms of population enrichment, I think, as Dr. Sanyal presented, there are ways to think about populations that have large numbers of patients. And so it's not just a screening strategy. There's areas where we can run these studies, where we get access to a substantial number of patients to be able to run those studies. Our next question comes from Ananda Ghosh with HC Wainwright & Co. Please unmute your line and ask your question. Hey, thanks for the question and thanks for arranging this call. I think I have the first few questions are directed to Dr. Sanyal. So I wanted to know how well are these patients diagnosed currently? And with respect to the trial design, what is the sweet spot one should think about when one is thinking about the inclusion criteria for a POC trial? And also from the comorbidity point of view. So is there a way to kind of enrich homogeneous patient population if one has to design a POV trial? The other question is, what are the a good animal model to study steatosis in this disease. And strategically, this is for the company, strategically, how are you thinking about the developmental plan given the long timelines one sees in MASH trials? Thank you. Dr. Sano, do you want to take the question to start? Sure. So I think the proof of concept trial design, you know, we use individuals who have established steatotic liver disease and with criteria where they already have started scarring down their liver. so we have a well-defined natural history. So you can actually model how many patients you will need and how long you have to follow them to first show less progression to cirrhosis. If you win that battle, almost certainly in the long term, the clinical outcome will improve because without cirrhoses, you don't really get clinical outcomes. That's one of the basic clinical tenets of hepatology. Your second part of that question was, how many of these patients are currently diagnosed? But, you know, right now, probably a very small minority, but it's a self-fulfilling prophecy because the reason nobody's looking for them is, what are you going to do with that information? How will it change your therapeutics? And so third-party payers are not willing to pay for extra testing, you know, just to satisfy one's curiosity. Now, if it would modify your therapeutic approach, then there's a strong rationale for doing it. And the beauty is that we already have the technologies. These are widely available, commercially available. And to eventually, once, you knows, the clinical benefit is established, the scale-up could happen almost in real time, because doing genetic testing in other disease states is sort of a routine practice. For example, heart failure, lipodystrophy, other kind of situations, you know. So I think given that infrastructure already exists, this would be just another place to send a test. So I do not perceive that as any kind of a real significant barrier. And the proof of concept, of course, would be demonstration of improvement in steatosis. But we look at steatoses in multiple ways. It's not like there's one magic threshold that tells you yay or nay, and it's a thumbs up or a thumbs down. So you look at people who have more than 30% improvement in Steatosis, but it also depends where you start. Number two would be the proportion of people who drop below 5% steatosis, who completely wipe out their fat. And we know that 30% is good, but 50% improvement is better. And 70% is even more. And completely defatting the liver is probably ideal. So I think we'll look at the totality of the data and to make go-no-go decisions for further things. if it was my molecule. I'm, of course, only a consultant to WAVE. But I would look at the totality of the data. And of course we are going into fibrosis patients who have already started scarring down their liver. I would like to see some improvement in biomarkers of fibrogenesis to show that fibrogenic drive is also improving. That gives me the confidence that I'll hit all my clinical endpoints in a larger, bigger study. So, I mean, really the only thing I would have to add is that from the recruitment perspective, you know, as mentioned, we have a, there's a number of genetic databases for people that are already well-characterized. And so you can leverage those to pre-identify patients to move them forward into your study. And then maybe just to cover, you know from the MASH perspective, I think it's very well described kind of what approval pathway looks like for MASH. And you know it's like a year, year and a half long study and you can use surrogate endpoints to start with and get an accelerated approval. So you can move forward pretty quickly from that perspective and then follow up with a pivotal confirmatory trial following that. Thank you. Our next question comes from Alex Dranahan with Bank of America. Please unmute your line and ask your question. Hey, guys. Thanks for taking our question. Maybe just on the endpoints from the phase one, guess which of the non-invasive liver measures if you are measuring these which is liver fat ct1 alt etc should we focus on in the early data and i guess how quickly would you expect those markers to move um after dosing and then um just quickly sorry if i missed this but just the rationale um pursuing the cta route versus the ind route um any color there would be great thank you yeah so i think as paul mentioned earlier we will be looking at a number of measures and including MRI, but we'll, you know, as we file our CTA and initiate the study, we'll provide more of the details around the assessments and the timing from that perspective. To Dr. Sanyal's point, the ability, you Know, to look at these other biomarkers in conjunction also enrich in an early study the ability to differentiate mechanism and de-risk. And the last question. Oh, CTA versus I. This is something that, you know, I know a number of you, we have this conversation. We use CTA, I always say, in the broadest sense possible, in that these studies can be U.S. and ex-U.S., and so we'll provide a filing sequence, but we use C.T.A. just in general to mean the initiation of the trial. Our next question comes from Steve Seathouse with Hansa Fitzgerald. Please unmute your line and ask a question. Great, thank you. Interesting data on the inhibiting knockdown in lean mice, and my question is actually about the clinical study. I'm curious, in the high BMI cohort of ENLIGHT, are you protocolizing diet and exercise, and if so, how are you doing that? If not, do you think it's sort of not important with this mechanism? I'm just curious if any of the preclinical data that you've sort of generated recently has sort of informed that at all as well. Thanks. Yeah, so I think as we also mentioned at earnings, not only are we having a protocol for diet and exercise, it's a very standard approach that other anti-obesity medicines use, we're also evaluating measures up front from the MRI perspective to ensure that the participants have, you know, increased levels of adiposity. And that's what we're seeing. So that's really how we're managing that upfront to ensure the best, you know, the highest likelihood of success and, you know, kind of reproducing what we'RE seeing in the preclinical data in these higher individuals with higher adipocity. I think the other piece to add to that's your second part of the question, Steve, which is really interesting because we have run extensive models, multiple models across settings. And I think the fact that caloric consumption is not a driver mechanistically for this, I think it is an important notion. So again, standardizing things as part of these studies is always important to be able to compare and to run the clinical trials in a way that is benchmarked about how others have done it. But across all of the preclinical studies, that calori consumption piece has not played a role. And I'll say that in kind of two veins. One, if we look at the DIO mouse model, just the comparison with GLP-1, you know, I think what's kind of still astonishing that that is all that weight loss. If you look at The Two Curves, the slope of GLP1, where now we know looking at the Believe early data with semaglutide, 40% of that early initial weight loss is driven off of lean mass loss. So there's a very good mechanistic rationale when we look att the body composition in the DIO mouse that, you know, we're actually losing potentially even more fat, right, to get to that equivalent rate in weight loss. So I think that's encouraging. And again, independent of floor consumption. The other place where we see that directly, which I think is probably going to be one of the most interesting opportunities long-term as we think about maintenance opportunity for this mechanism, which is completely orthogonal to this weight loss component that, you know, I know folks are indexed on, but in maintenance, that driver at that point where the incretin was stopped, and because it is a preclinical experiment and you do measure caloric consumption in these mice, that we saw the opposite, right? These mice who were on incretins who had removed had a massive increase, right, in their caloric consumption and equivalently, whether they were on inhibity or not. And yet those who were treated when the break came off lipolysis didn't restore that excess energy in terms of fat. So I think across multiple preclinical settings, and again, we're seeing that caloric consumption is not the driver here. So again, the study in the 2A cross monotherapy combination of maintenance are all going to recapitulate, I think, a lot of this degree of high adiposity as a requirement in terms of seeing those changes. Our next question comes from Jenny Gonzalez-Amenza with Lyric Partners. Please unmute your line and ask a question. Hi, guys. This is Jenny on for Joe. Thank you for putting this together. It's been really helpful. Maybe just another question on biomarkers and early data in PNL, PLA3, maybe for the doctor and the team. Are there any other early and sensitive markers that we could see in these phase one data that would suggest or even definitively differentiate 008 on eventual fibrosis benefit, especially versus knockdown approaches, since you were talking about that being a potential differentiator. Thank you. Yeah, thank you, Jenny. Dr. Sano, would you like to start? Yeah, I think the low-hanging fruit really relates to quantification of the fat for a couple of reasons. One, it's directly in the biological pathway. So, you know, fatty acids it's coming to the liver. They are very toxic, so the liver cell packages it as triglyceride, which is sort of a storage form that is relatively safe. And of course, when you accumulate that, it's easy to see with MRI and quantify. You can quantify it with CAP score, etc., and you can see it under the microscope as well. So that is the obvious thing. And the ability to mobilize those triglyceride droplets is linked, that's where PNPLA-3 comes in. So if you facilitate the ability, you open the release valve, if you will, you know, then you should see a decrease in fat, and that should be an immediate readout. Now, the improvement of improving throughput of fat through the liver should be reducing lipotoxicity to the liver, so you would expect less liver injury. And so the next thing I would look at are the liver enzymes, which are markers of liver injury and to see whether they are actually declining. Then in addition to that, if you reduce these two, remember that this represents disease activity and injury. The injury activates fibrogenic drive. So there are now biomarkers such as ProC3, et cetera, that are more reflective of fibrogenous drive rather than the fibrosis burden itself. It takes a while to shift the actual fibrosis itself, but the fibrogenic drive can be cooled off. And so I think you can capture that also with these biomarkers. Another biomarker that is now sort of looking good and, you know, and more data are coming is the NIS2+. So this is based on microRNA 34A and YKL40. So it's again measuring a couple of things. 34A is very much linked to the metabolic disruption in the liver. So if you're restoring metabolic homeostasis, you might expect to see an improvement in 34A and YKL-40 is linked in the fibrogenic pathway. And there are now data showing that NIS2 plus reflects. It's a composite biomarker that tells you whether you have the kind of mash that requires pharmacologic treatment. So what we call at-risk mesh, it is a biomarker for at-risk mesh as a composite. And so there are some early data that with effective treatment, the NIS2 plus drops below the threshold for having. So more to come on this, but that's another potential biomarkers. And as you know, this biomarking space is very, very mobile and active. So everything I tell you today, there could be new biomarkings in play here. from now. But these are some of the best in class today that we can talk about. Yeah. And as Chris mentioned, we're embedding biomarker-driven studies in addition to being able to look at target engagement as a number of early signals as well. Thanks, Jay. Our next question comes from Michael King with Rodman & Renshaw. Please unmute your line and ask your question. Thanks for taking the question, guys, and putting this webinar together. It's been Super helpful. I wanted to see if you could address the topic of CIDEB. It was a target that was found at the Regeneron Genetic Center, and some phase one data, I believe, was presented at the liver meeting. A single dose of an antibody reduced liver fat to about 70%. So I wonder how you think about that incorporated into your thinking about development of PMPLA-3. And then I have a separate question, but I want to ask that one first. Yeah, I mean, I think there's a number of movements of ways of reducing liver fat. We know inhibini in the clinic substantially reduces liver fat as well. And, you know, we're exploring that through MRI, PDFF based on the clinical trial. But I think a lot of that has to do, as Dr. Sanyal was saying earlier, with this steatosis side of the disease. And I think what's really important for these patients who have PMPLA3 mutations is the fibrosis and inflammation component of the enzyme. So again, whether or not eventually these patients have the mutation, need the mutation and correct it, and then also get the benefit of having these other therapies, or in the case of the early data, these sensors epitide that show those patients are less responsive. I think these are things that will all, as this field continues to grow with therapeutic options, I think what's intriguing for us is the strong genetic correlation on the enzyme that it has this functionality on driving this kind of retinol inflammation pathway. I don't know, Eric, if there's anything to add. not really maybe not more than that these are different mechanisms and as far as i know there aren't interactions necessarily between the side of variants and tlmp3 variants so you would expect that this you know interesting targets but this is a independent mechanism and again uh there are so a very large number of homozygote carriers here where this is the exact like right way to treated because it's treating the direct cause of a liver injury in these individuals. Our next question comes from Ben Burnett with Wells Fargo. Please unmute your line and ask your question. Good morning. This is OPS on for Ben. Thank you for the little presentation. In light of 008, your bifunctional platform, and as you go into new indications, could you share what your thinking is when it comes to developing assets by yourself versus partnering? And specifically, what pieces of the platform and at what stage would you be open to partnering? Thank you. Oh, thank you. I mean, I think there's a variety of targets that have provoked conversations because they are interesting mechanistically and pathway-wise. And so I think the key is continuing to be able to bring interesting, innovative programs and products to the clinic, de-risk platforms, both on the RNA editing size that we've seen with Alpha-1 anti-trips and its applicability here. As we shared before, inhibity broadly is garnering interest and relative to what we can do with SPINA, particularly to Chandra's point, the fact that we're seeing the translation of candidates to our partners at GSK means the platform's now validated from an engine. So with Monica joining, one of the core focus has been, how do we think about the balance of a portfolio programs? And how do мы think about the platform capability and capacity more broadly and I think our view is to continue to drive optionality across the portfolio to optimize what's going to be best and most expedient for patients and an efficient use of our capital to de-risk and accelerate programs. Our next question comes from Cassie Yvonne with RBC Capital Markets. Please unmute your line and ask your question. Oh great, thank you for hosting another wonderful virtual research data. This is Cassie for Luca. Dr. Sanyo, and maybe also Paul on 008. Paul, you spoke of speed and efficiency in your clinical execution to bring therapy to patients. So if I may follow up and ask about comparing the expected disease progression and disease prognosis between PNPLA-3 patients in your prospective trial versus typical MASH or MSAD-LD patients. So, you know, as you touched on in MASH competitors, liver fat reduction, sphygmosphere, the MII are detected within 24 weeks or maybe even 12 weeks, but fibrosis improvement on histology generally requires a year or multiple years. But where does PNPLA3 patients fall on this timeline, given, Dr. Sanyo, you've talked about wanting to see fibrogens as improvement and also the prognosis, the first amongst patients with different baseline and comorbidities. Any comment there on that is much appreciated. Thank you. No, absolutely. And I'll start and then Dr. Sandel will hand it over. I mean, I think there's the first path for us is how do we get as rapidly as possible to finding that dose and editing efficiency, right? How do we gets to that ability to look at target engagement, change in biomarkers, and the medicine de-risking from a biology perspective, and then there's de- risking it from a pathology perspective. And so I think we're actively in the efficiency side, again, because we can identify these patients that have the mutation, as Dr. Sanyal pointed out, there's things we can do to enrich on pathology too, to optimize signal. I think we think about that study as having kind of two components to it to accelerate. And, you know, the first being as rapidly as possible, kind of de-risking the PMPLA-3 targeting, and then how do we unlock the potential as we think about then de- risking the pathological changes? And I think that is, we roll out the trial design on the other side. I think that's something that you'll see is the ability for us to think about those two pieces so that we can be efficient in de-risking the program. Dr. Sanyal, I don't know if you want to add on the pathology side and how we think about, you know, de-risking that. Yeah, I think you, Nova, basically agree with you. And in the early phases, of course, you get a signal for reduction in liver fat and fat is extremely mobile. So, you Know, there's all kinds of data going back 50 years that the fat can move in and move out of the liver within a matter of literally hours to days. So certainly within 12 weeks, one should expect to see a significant improvement in overall steatosis and markers of injury. And as we move forward, depending on how you select your population, that will determine the trajectory towards cirrhosis. So it is based on the relative numbers of F2 versus F3 population, you know, in terms of likelihood of progression to cirrhosis. So with the F3 patients, you would expect 7% to 10% over a matter of, you know. A year or two would progress to cirrhosis. And then so if you were to do a three or four year study, you would have about almost a quarter of these patients would have progressed to cirrosis. And, again, I think we are in a little bit uncharted territory, but if you look at the Kaplan-Meier curves for the clinical outcomes, then you would be able to see that, you know, first we have to show less progression to cirrhosis, and, you You know, you would want to see an effect size that would reduce the hazard ratio to at least 0.8 or greater. Greater is better, but it's very hard, given current data, to be absolutely certain where you land. But I would project somewhere between 0.5 and 0.80 is where we hope to land with this type of approach. Thank you. Our last question comes from Danielle Brill with Truer Securities. Please unmute your line and ask your question. Hey guys, this is Alex on for Danielle. Thanks for taking the question. Just a qualitative one on 008. I believe you said you're going to be initially investigating the efficacy of 008 in previously identified and genotyped homozygous I148M patients. Is there anything about these patients that led them to get genotyced in the first place? I'm just curious where on the bell curve do these patients fall versus a potential typical bucket of patients that you might recruit for future clinical trials as it pertains to disease severity, comorbidities, etc. Thanks so much. So what I would say just maybe to start from the last part of your question and move up is that, you know, we're designing the trial with inclusion-assisted criteria that allow us to best be able to detect, you Know, the types of differences we're looking for. So, you Now, obviously not too far, not too mild, but in that sweet spot where you can actually see a change. And so that's kind of irrespective of where the patient comes from, that they'll have to meet those criteria. So, and then to your earlier point, I mean, there's lots of different genetic databases out there that you could imagine, you know, either private or public where people just get tested and for different reasons, and it may not be for liver disease per se, but then, you know,, you do have all that information and you can utilize that to pre-identify individuals and you know again there may be other settings and um and liver clinics you know hepatology clinics where people have been genotyped over time because of the interest of the individuals there so so you know that's another way that you could potentially accelerate the approach versus just taking all comers and and hoping that they have you know the genotype of interest thank you thank you there are no further questions at this time i will now turn the call over to paul bono for closing remarks thank you everyone for joining us today and we look forward to connecting with many of you in the near future at the multiple upcoming conferences have a great day