Good morning, everyone, and welcome to Wave 's 2025 Research Day: Spotlight on RNA editing and RNAi. The slides that accompany today's presentation will be available following the call in the Investor section of our website at www.wavelifesciences.com. Before we begin, I'd 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, we have an exciting agenda to cover, and our speakers will include Paul Bolno, President and CEO, Chris Wright, Chief Medical Officer, Erik Ingelsson, Chief Scientific Officer, and Chandra Vargeese, Chief Technology Officer. Following the presentations, all presenters will be available for Q&A. With that, let's get started. I'll turn the call over to Paul. Thanks, Kate. Good morning, and thank you for joining us today. Our call this morning marks our seventh annual Research Day. We dedicate this time each year to showcase our emerging pipeline and novel platform innovations, and today we'll speak to how they're translating in the clinic. Ultimately, all of the updates move us closer to our vision for Wave Life Sciences: to deliver high-impact medicines and reimagine possible for oligonucleotide therapeutics and human health. For over a decade, we've been committed to innovation, leveraging our best-in-class chemistry and genetic insights to build a leading genetic medicines company. By combining human genetics, clinically validated chemistry, and novel biology, we have built a multimodal pipeline of RNA medicines that continues to translate in the clinic. At Wave Life Sciences, we are leveraging AI from target discovery all the way through our development process to add efficiencies and unlock new targets to reach more diseases with our different modalities. Today, we are spotlighting both emerging and clinical programs from two modalities: RNA editing and siRNA. In RNA editing, we are pioneering this field to continue to make history, most recently with our positive clinical data update from our ongoing RestorAATion-2 trial. In September, we shared exciting translation of RNA editing with WVE-006 from the first two cohorts of our RestorAATion-2 clinical trial. These data included successful restoration of physiological or dynamic production of AAT protein at levels needed to prevent lung damage during an acute infection and represented a significant milestone for oligonucleotides. Building on this clinical success, today we will introduce WVE-008, our PNPLA3 aimer for liver disease. We are on track to submit a CTA filing for WVE-008 next year. In RNAi, our first siRNA, WVE-007 for obesity, is rapidly progressing as a novel approach grounded in human genetics that is designed to drive fat loss and preserve muscle. As we had previously shared in our INLIGHT clinical trial, the 75 mg subtherapeutic cohort had substantial target knockdown, supporting our preclinical modeling that the second 240 mg cohort would be expected to deliver a therapeutically relevant knockdown. To confirm this, we plan to analyze all active INHBE biomarker data as well as safety once the full expanded cohort 2 reached day 29. Today, we are excited to share an active INHBE target engagement update from the INLIGHT clinical trial. In the first three cohorts, we have observed highly significant dose-dependent activin E reductions following a single dose of WVE-007. These reductions in the clinic exceeded the activin E reductions that led to weight loss in our preclinical studies. The durability of effect supports the potential for once or twice a year dosing. We are incredibly excited about this program and its potential to disrupt the treatment paradigm for obesity by delivering fat loss while preserving muscle. Today's strong target engagement data sets us up for several clinical data updates with WVE-007 beginning later this quarter and throughout the first two quarters of 2026. We'll then take you through the latest innovations on our platform. With our novel chemistry, we are advancing our best-in-class siRNA, which builds on successful clinical translation of WVE-007, as well as advancing our extrahepatic delivery capabilities to achieve both siRNA silencing and RNA editing. We are also using our platform to innovate new modalities, including the capability to simultaneously silence and edit two unique targets with a single oligonucleotide structure. We are poised for significant sustained growth, and based on our recent experience developing WVE-007, our GalNAc siRNA, it's clear that we can rapidly accelerate the time from target identification to clinical translation. Across our entire portfolio, we are advancing a diverse, sustainable pipeline grounded in genetic insights with the potential to treat well over 100 million people in the U.S. and Europe. I will now turn the presentation to Chris for an update on WVE-006 in AATD. Chris. Thanks, Paul. There are approximately 200,000 people in the U.S. and Europe living with PiZZ AATD, which is often misdiagnosed and progresses over time due to accumulated tissue injury from unchecked inflammation. While it is one disease, alpha-1 antitrypsin deficiency impacts multiple organ systems with a predilection to impact lung and liver. AATD is caused by inheritance of a mutation in the SERPINA1 gene, which produces the protein alpha-1 antitrypsin. This AAT protein protects the lung during inflammatory or infectious events, preventing lung injury that could lead to emphysema, airway damage, or bronchiectasis. Damage in the lung occurs during exacerbations that induce an inflammatory acute phase response. Individuals who do not suffer from AATD produce increased levels of protective functional AAT protein during these events, thereby preventing lung damage. In the liver, mutant AAT protein, also called ZAAT, tends to aggregate into deposits, which cause liver cell dysfunction and death, resulting in fibrosis, cirrhosis, and liver cancer. While therapeutics are advancing in development, the approved treatment options for AATD today are limited. There's an immense new need for more effective and convenient medicines. Weekly IV augmentation therapy is the current standard of care. This approach targets lung disease, providing healthy circulating protein, but it does not significantly impact liver disease as the mutant ZAAT protein remains in the liver. In addition, IV augmentation therapy does not provide the dynamic increases of AAT expression needed during an acute phase response resulting from a lung infection or other acute inflammatory events. In those with one disease allele or healthy individuals, the AAT levels will increase to meet the need at the time of an infection. However, with IV augmentation therapy, there's no way to go but down unless an additional IV dose of protein is delivered to the patient. WVE-006 is a first and potential best-in-class treatment, which aims to address both lung and liver manifestations of AATD. WVE-006 is an RNA editing GalNAc oligonucleotide that contains Wave's proprietary chemistry, including PM and N3 uridine. It edits mRNA A to I in a highly specific manner to produce only wild-type M-AAT without bystander edits, and is administered via convenient subcutaneous injection with potential for monthly or less frequent dosing. The goal of RNA editing is to increase wild-type MAAT protein at its source and restore the physiological production of AAT needed to prevent lung damage during acute inflammatory insults, while enhancing liver health by reducing the production and aggregation of ZAAT, thereby addressing both key disease manifestations. With RNA editing, you create a wild-type transcript, which leads to the production of MAAT, the healthy AAT protein in the liver. MAAT then circulates to reach and protect the lung. Its production in the liver also replaces ZAAT and allows for ZAAT reduction and clearance of harmful protein aggregates in the liver. Across genotypes, those with two wild-type alleles have normal liver and lung disease risk, and they respond to acute events by increasing their AAT levels to prevent inflammation-related tissue damage. Those with two Z disease alleles have high risk of liver and lung disease and are known to not increase AAT in the context of an acute phase response. The MZ patients with one healthy M allele and one Z allele have low liver and lung disease risk and are able to increase their AAT levels in the context of an acute phase response. Since the approval of weekly IV augmentation therapies to treat lung disease, the field is focused on keeping serum AAT levels above a minimum threshold of 11 micromolar, in part because ZZ individuals do not produce any MAAT and have a limited ability to increase serum AAT levels during an acute phase response or exacerbation. However, with RNA editing, if you edit by at least 50%, keep AAT protein above 11 micromolar and, importantly, restore the acute phase response, the risk for liver and lung disease should be low, as this would recapitulate the MZ phenotype and overcome key limitations of protein replacement therapy. Typically, in the disease state, in patients with two mutant Z alleles, expression does not increase in the context of lung inflammation and the acute phase response. C-reactive peptide, or CRP, a measure of the acute phase response, can be highly elevated in relation to an inflammatory insult, such as pneumonia, but AAT does not correspondingly increase. In this context, inflammation remains unchecked and may lead to lung damage, causing emphysema and bronchiectasis. In the case of MZ or individuals that have a preserved acute phase response, AAT protein increases correspondingly to protect the lung against the undesirable consequences of inflammation, ensuring the lungs stay healthy. With our recent data from RestorAATion-2, it was very encouraging that we already achieved the key goals of RNA editing by restoring the MZ phenotype, even at the lowest single dose tested. Restoration of the MZ phenotype requires achieving three criteria: one, keeping basal protein levels at or above 11 micromolar; two, driving 50% or greater circulating MAAT with corresponding decreases in ZAAT protein; and most importantly, three, restoring the physiologic response of serum AAT protein to acute inflammatory events. In our September data readout, we observed AAT levels up to almost 13 micromolar. We showed 64% of AAT was wild-type MAAT, while there was a corresponding 60% decrease in the mutant Z protein. These effects were highly consistent across individuals and persisted for up to two months after the last dose, supporting infrequent dosing of monthly or less. Notably, we were able to restore a ZZ patient's ability to respond to an acute inflammatory event, in this case, a kidney stone. The participant exhibited a strong AAT response of greater than 20 micromolar. The dynamic effect was observed two weeks after a single dose of WVE-006, supporting the rapid onset of the editing effect. Encouragingly, the magnitude and the four-week duration of this response were also proportional to the levels you'd anticipate in an MZ patient based on natural history. Following our data last month, we've had multiple interactions with key opinion leaders in the field who've expressed their excitement about these data, as the ability of WVE-006 to restore physiologic AAT production represents a major paradigm shift from protein replacement therapies. IV augmentation therapy provides a bolus of AAT with the intention of keeping protein above the potentially therapeutic threshold until the next dose. If a patient experiences an acute inflammatory event, the circulating AAT is consumed without replenishment by normal physiology, and interim dosing may be needed to protect against lung damage. By contrast, with WVE-006 RNA editing, the levels of AAT can increase and remain elevated to meet the need of the body to protect the lungs, potentially protecting lung tissue from inflammation-mediated damage in a dynamic fashion consistent with the natural physiology of AAT and the acute phase response. Additionally, augmentation therapies do not have any impact on the liver manifestations of the disease, whereas WVE-006 has demonstrated the ability to meaningfully decrease levels of ZAAT protein. As we look ahead to the remainder of the RestorAATion-2 study, we're highly encouraged by our initial results and excited to advance the program, which is paradigm shifting and provides a potential new medicine to patients. With this goal in mind, we've made rapid progress through our RestorAATion-2 trial. We continue to dose patients in the 400 milligram MAD cohort and remain on track to deliver data in the first quarter of 2026. We've also initiated the single dose portion of our third and final cohort. Based on the continued favorable safety profile to date and the desire to optimize our assessment of efficacy, as well as dosing in people, we've selected 600 milligrams as our dose for this third cohort. 600 mg SAD and MAD data are expected in 2026. In tandem with our progress on RestorAATion-2, we continue to have discussions with our partner, GSK, about next steps for the program and planned regulatory interactions. With that, I'd like to turn the floor to Erik to review our next RNA editing program, PNPLA3. Thank you, Chris. Today, we're pleased to unveil WVE-008, our next fully owned clinical candidate, which is a GalNAc-conjugated RNA editing program for genetically defined liver disease. WVE-008 builds directly on learnings from WVE-006. As you heard from Chris, we've demonstrated clinically efficient and consistent RNA editing, restoration of dynamic physiological response to stimuli, durable effects supported in frequent dosing, and a favorable safety and tolerability profile. PNPLA3 is a compelling target with strong human genetics evidence and a clear translational path to early clinical proof of concept. There are an estimated 9 million homozygous I148M carriers with liver disease across the U.S. and Europe who are at a nine-fold higher risk of dying from the liver disease compared to non-carriers. As I will go over in the next few slides, we believe that our disease-modifying RNA editing approach to correct this variant back to wild-type function is going to be superior, not only to PNPLA3 silencing but also to generic non-precision medicine approaches in MASH. The PNPLA3 I148M variant leads to a substantially higher risk of a range of liver diseases, from MAFLD, MASH, and alcoholic steatohepatitis to cirrhosis, liver cancer, and liver failure. Longitudinal data shows that heterozygous carriers have about 80% lower risk of liver-related death compared to homozygous carriers. Therefore, our therapeutic goal is to edit at least 50% of PNPLA3 transcripts in hepatocytes, restoring a functional heterozygous state that is associated with a dramatically lower risk of liver complications and death, given the large addressable population and a clear genetic linkage. This is a setting where RNA editing is ideally suited to be both precise and disease modifiers. While MASH among non-carriers of the PNPLA3 I148M variant tends to be multifactorial and polygenic, to a large extent driven by obesity and type 2 diabetes, I148M homozygous represent a distinct subset of MASH with more severe disease biology with fast progression to end-stage liver disease. They're substantially enriched among lean MASH patients; that is, they're more frequently of normal weight, and they more often present with advanced fibrosis. Up to 25% of MASH patients are homozygous for I148M, with even higher representation in lean and later stage disease. The only treatment options are non-precision medicines for obesity-related MASH aimed at steatosis and early fibrosis, with limited efficacy for these I148M carriers. Importantly, there are no approved genotype-directed disease-modifying therapies for PNPLA3 I148M homozygous. WVE-008 is designed to directly address the genetic driver in these patients. PNPLA3 has an important role in the regulation of triglyceride storage and secretion, supporting the formation of triglyceride-rich VLDL particles that supply lipids to the peripheral tissues. PNPLA3 expression on lipid droplets is dynamic. It increases in response to feeding and participates in lipid remodeling and mobilization to meet cellular energy and structural needs. Additionally, PNPLA3 has an important role in retinal metabolism by hydrolyzing retinal esters to release retinol. In short, PNPLA3 is part of the liver's lipid metabolism machinery that determines whether fat is stored in the liver or mobilized and exported, as well as in retinol metabolism, disruptions of which can lead to inflammation and fibrosis. The I148M mutation impairs PNPLA3's lipase activity and exerts a gain-of-function effect that inhibits ATGL-mediated lipolysis. This promotes hepatic triglyceride accumulation and stellate cell activation. Additionally, PNPLA3 I148M suppresses retinol metabolism in hepatocytes and stellate cells, which increases liver fibrosis. Silencing PNPLA3 can partially address disease biology but is likely to leave residual pathology. ATGL activity is only partly rescued, and silencing will not restore retinol metabolism. As a result, silencing can partially address steatosis, but inflammation, ballooning, and fibrosis remain unaddressed. By contrast, correcting I148M is expected to restore PNPLA3 activity and lipid mobilization, reverse steatosis, as well as inflammation, ballooning, and fibrosis. This is the key rationale for RNA editing over knockdown and would explain why PNPLA3 siRNAs seem to have modest effect on steatosis but no effect on later stages of MASH. In line with this, multiple preclinical studies highlight potential liabilities of silencing PNPLA3. In iPSC-derived human liver organoids, PNPLA3 silencing worsens steatosis. In primary human hepatocytes, silencing increases ballooning, and in stellate cells, PNPLA3 knockdown worsens fibrotic responses. Together, these findings support our strategy to restore PNPLA3 function with RNA editing rather than removing it, aiming to improve steatosis, inflammation, ballooning, and fibrosis by preserving physiological roles important for liver health. WVE-008 is a GalNAc-conjugated RNA editor designed for subcutaneous administration with potential for frequent dosing. It incorporates Wave's proprietary chemistry and builds on learnings from WVE-006. On the left, you can see a dose response curve showing robust editing with 008s. In the middle, RNA-seq results from two donors at different doses yielded an ideal editing profile: strong on-target editing with no bystander edits and no off-target signals, as evidenced by lack of any other transcripts than the main PNPLA3 transcript, giving us confidence in editing efficiency and specificity of 008s. On the right, we demonstrate high liver tissue exposure with 008 in preclinical studies, supporting the feasibility of a durable and frequent dosing. Collectively, these data provide a strong translational foundation, building on our clinical success with 008 as we advance towards the clinic with 008s. Here, we compare lipid accumulation after treatment with our PNPLA3 aimer versus a PNPLA3 clinical reference siRNA in two different in vitro models. On the top, in the HepatoPac, a 3D human liver cell culture model, we observed significant decreases of lipid accumulation after editing, while the siRNA did not show a significant effect. On the bottom, in a monolayer culture of primary hepatocytes, we again see a substantial decrease of lipid accumulation increasing over time with our PNPLA3 aimer. In this model, we also see modest decreases with the PNPLA3 siRNA. Taken together with prior literature, it shows the biological importance of keeping wild-type PNPLA3 function and reinforces the biological rationale for correcting I148M rather than silencing PNPLA3. In summary, 008 meets our criteria for proceeding into clinical development: strong evidence from human genetics, a large patient population with no treatment options, the best and first-in-class opportunity, and an efficient path to clinical proof of concept. 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. Emerging preclinical and clinical data indicate that simply knocking down PNPLA3 is not the right solution. Loss of PNPLA3 function can worsen the very features we're trying to treat. Our approach is different. With WVE-008, we'll edit, not silence, PNPLA3, which will restore its important functions in liver and lipid homeostasis. The goal is to reverse steatosis, inflammation, ballooning, and fibrosis by correcting the I148M variant. WVE-008 leverages Wave 's proprietary, clinically validated RNA editing platform, giving us an efficient path to proof of concept in a large genetically defined population with no current options. Preclinically, our PNPLA3 editing restores functional PNPLA3 and decreases lipid uptake. We have now selected WVE-008 as our development candidate using Wave Life Sciences' proven chemistry and Aimer design. Clinical planning is underway for a first-in-human study where we'll leverage previously genotyped populations to efficiently identify homozygous I148M carriers. In an initial first-in-human study, we will enroll homozygous carriers and assess safety, tolerability, pharmacokinetics, and pharmacodynamic endpoints aligned to the mechanisms of PNPLA3 I148M. Our objective is a clear, early, go/no-go readout for a precision medicine approach in this large population at high genetic risk. If successful, WVE-008 has the potential to be a first and best-in-class treatment for homozygous PNPLA3 I148M carriers with liver disease. We're planning for CTA submission in 2026. WVE-006 and WVE-008 are two clinical RNA editing programs, both targeting liver diseases, but our Aimer platform is broader. By building on our proprietary Aimer chemistry and design, we can modify our chemistry to see substantial RNA editing across a range of extrahepatic tissues. As we shared at last year's Research Day, our Aimers achieve substantial editing in lung, heart, adipose, and pancreas, all without any ligands, as well as region-wide editing in CNS after ICV or intrathecal dosing in rodents or non-human primates. We'll continue to make progress on hepatic and extrahepatic editing, and we're currently building a diversified RNA editing pipeline, including a range of indications, while advancing WVE-008 towards the clinic. Now, I'm very excited to transition to our obesity program, WVE-007, a GalNAc-conjugated siRNA that targets INHBE. WVE-007 offers a novel, long-acting, muscle-sparing approach to treat obesity and its metabolic complications. Individuals living with obesity face markedly higher risk of a range of serious conditions, including heart disease, type 2 diabetes, and several cancers. GLP-1 receptor agonists have transformed obesity care. However, their impact is often limited by a loss of muscle mass, tolerability challenges, especially GI side effects, frequent dosing, and high discontinuation rates. Beyond GLP-1 receptor agonists, other treatments that enable fat loss have been shown to curb metabolic diseases. There are still large unmet needs. Our approach is to focus on healthy weight loss with substantial loss of fat, in particular visceral fat, which is the type of fat that contributes to the development of type 2 diabetes and cardiovascular disease. We believe WVE-007 can address important gaps in the current therapy for the more than 1 billion people living with obesity globally. Our INHBE program has a strong foundation in human genetics, which has been shown to increase the probability of successful drug development by up to 2- 4-fold, with coding variant evidence in the upper part of that range. In the U.K. Biobank and other cohorts, heterozygous INHBE loss of function carriers exhibit a healthier metabolic profile with lower abdominal obesity, body weight to hip ratio, and lower visceral adipose volume, lower triglycerides, ApoB, and fasting glucose, and higher HDL cholesterol. We also have favorable associations with liver traits, such as ALT and CT1, a measure of liver inflammation and fibrosis, and lower risk of type 2 diabetes and heart disease. Our therapeutic hypothesis is straightforward: by silencing INHBE mRNA by at least 50%, we aim to recapitulate the protective phenotypes seen in these heterozygous loss of function carriers. Associations of target engagement biomarkers with outcomes have also been shown to increase the probability of successful drug development. Therefore, we're very encouraged by evidence from multiple data sets showing that higher hepatic INHBE expression is associated with greater adiposity, insulin resistance, and MAFLD risk. Taken together, these data support that reducing INHBE mRNA should drive healthy weight loss and improve metabolic health. INHBE, or inhibin subunit beta E, which is the full name, is produced in the liver, where two of the subunits dimerize to form the hepatokine activin E. Activin E gets released into circulation, where it binds in a specific manner to ALK7 receptors on adipocytes. The resulting signaling blocks adipose lipolysis, promoting abdominal adiposity and increasing risk for cardiovascular disease and type 2 diabetes. By reducing hepatic INHBE mRNA with a GalNAc-conjugated siRNA, we lower circulating activin E, decrease ALK7 signaling in adipose tissue, and release the brake on lipolysis, which is expected to shrink adipocytes and reduce abdominal adiposity, thereby lowering cardiometabolic risk. WVE-007 uses Wave's best-in-class siRNA format and incorporates backbone kickstart chemistry and PM chemistry designed to enhance interactions with AGO2 and to improve silencing potency and durability. We have demonstrated the dramatic improvement of AGO2 loading, which is a crucial differentiator for us when we're trying to silence INHBE, a target that is hard to keep sufficiently and durably suppressed, presumably due to evolutionary pressure or the need to store energy efficiently. A bit later, Chandra Vargeese will go deeper on our siRNA platform and how it underpins our broader hepatic and extrahepatic pipeline. As we've shared previously, our preclinical data strongly supports WVE-007's ability to both potently and durably knock down INHBE, leading to impressive reductions in body weight and visceral fat while sparing muscle. In diet-induced obesity, or DIO mice, a single dose of INHBE GalNAc-conjugated siRNA produces clear dose-dependent weight loss. Importantly, the weight loss is all driven by fat reduction, especially visceral fat, without any loss of muscle mass. As observed in the middle and the right panels, visceral fat was reduced by 23% at 3 mg/kg and 40% at 10 mg/kg, while muscle was unchanged. These data support WVE-007 as a single agent option for healthy weight loss with visceral fat reduction and lean mass preservation. We also have robust preclinical data to support synergistic use cases with GLP-1 receptor agonists. As a monotherapy, INHBE siRNA achieves a similar magnitude of weight loss to semaglutide, but all coming from fat loss. When added on to semaglutide, we observe approximately twofold greater weight loss versus semaglutide alone. In the right panel, you can see that when GLP-1 treatment is discontinued, INHBE siRNA curtails typical weight regain seen in controls, supporting its use as an off-ramp and maintenance therapy. In our DIO mouse models, a single INHBE siRNA dose achieves more than 70% reduction of circulating activin E one month after dosing, at dose levels where we observed the substantial fat loss as I outlined in the previous few slides. When comparing the kinetics, weight loss with INHBE siRNA was similar in magnitude to semaglutide but occurred more gradually. Based on these data, we would expect a similar degree of activin E reduction to translate to healthy weight loss in clinic over time. In addition to weight loss, we expect meaningful improvements in cardiometabolic health, which is ultimately the main objective of any obesity medication. By reducing INHBE mRNA and activin E levels, we would anticipate increases in adipocyte lipolysis and reduction of adipocyte size. This, in turn, would lead to fewer pro-inflammatory macrophages and less fibrosis in visceral adipose tissue, as well as improved insulin sensitivity, changes that can contribute to lower risk of cardiovascular disease and type 2 diabetes. On the next few slides, I'll show data demonstrating what we're seeing with INHBE siRNA treatment, supporting the link of increased lipolysis with better cardiometabolic health. RNA sequencing from subcutaneous adipose tissue shows upregulation of genes and pathways related to insulin sensitivity, fatty acid utilization, and beiging of white adipose tissue. Concurrently, pathways involved in adipose remodeling and fibrosis are downregulated. These changes indicate better cellular energetics with suppression of fibrotic remodeling. As we can see, INHBE siRNA leads to an upregulation of genes supporting better insulin sensitivity, fatty acid utilization, and beiging of white adipose tissue, while downregulating adipose fibrotic pathways. In visceral adipose tissue, we observe upregulation of glucose utilization, thermogenesis, and lipid metabolism pathways, consistent with what we observed in subcutaneous fat, and downregulation of innate immunity, cytokine release pathways, and extracellular matrix remodeling. Together, these findings suggest increased glucose and fatty acid utilization, reduced inflammation and fibrosis in adipose tissue. As we presented at the ADA scientific sessions in June, histology confirms that a single INHBE GalNAc siRNA dose also leads to adipocyte shrinkage in DIO mice with a significant reduction in mean adipocyte diameter. Additionally, histology demonstrates a shift towards a less inflammatory state in visceral fat. Total macrophage staining decreases with a strong suppression of pro-inflammatory M1 macrophages, while anti-inflammatory M2 macrophages are maintained at the same level. Overall, this supports a transition from a pro to an anti-inflammatory state after INHBE silencing. Consistent with these immune cell changes, we see a 53% reduction of adipose fibrosis at day 56 after a single dose of INHBE siRNA, as shown by trichrome staining and quantified by image analysis. This decrease in fibrosis is likely the result of the shift towards a more anti-inflammatory state and will contribute to improved insulin sensitivity and better cardiometabolic health. To summarize, 007 has the potential to be a convenient therapeutic that drives healthy, sustainable weight loss while preserving muscle. Our approach is deeply rooted in human genetics, which strongly support that heterozygous loss of function carriers show less visceral fat and healthier metabolic profiles with lower risk of type 2 diabetes and cardiovascular disease. Mechanistically, INHBE silencing increases adipocyte lipolysis, shrinks adipocytes, reduces pro-inflammatory macrophages and fibrosis, and improves insulin sensitivity, all hallmarks of better cardiometabolic health. We've also shown that our clinical GalNAc-conjugated siRNA, 007, has the potential to be a best-in-class approach. 007 incorporates proprietary chemistry, including stereochemistry and PM chemistry, which increases potency and durability of silencing. Preclinically, we've demonstrated that a single dose of INHBE siRNA achieves potent, durable target engagement with more than 70% activin E reduction, with a semaglutide-equivalent weight loss, but all coming from fat loss, particularly visceral fat, with no loss of muscle. Further, our preclinical data shows that our INHBE siRNA can double the weight loss compared to GLP-1 receptor agonists alone and that it can curtail weight regain after GLP-1 cessation, supporting add-on and maintenance use cases. I'm now very excited to hand it over to Chris for an update on our INLIGHT clinical study. Thank you, Erik. As a reminder, INLIGHT is a placebo-controlled single and multiple ascending dose study, randomized 3:1 active to placebo, with potential to escalate up to five single and three multiple ascending dose cohorts. It's designed as a safety, tolerability, PK/PD study, enrolling base cohorts of eight participants that can be expanded up to 32 subjects per arm. Participants are healthy individuals living with overweight, with key inclusion criteria of A1C less than 5.9 and BMI between 28 and 35. In addition to safety, tolerability, PK, and activin E levels, the study has exploratory endpoints of body weight, body composition, and biomarkers. Our INLIGHT trial continues to progress rapidly through the single ascending dose portion of the study. INLIGHT is currently ongoing at multiple trial sites, including in the U.S., as we recently opened an IND. We began testing WVE-007 at our lowest subtherapeutic dose cohort, 75 mg, in eight participants. For subsequent cohorts, which are expected to be in a therapeutic range, we had the option to expand to 32 subjects as warranted by safety. With a favorable safety profile, we have fully expanded cohorts 2 and 3 to date and are currently expanding cohort 4 at a dose of 600 mg. Our independent data monitoring committee has also approved further escalation to a next higher dose in cohort 5. Today, I'm excited to share the target engagement data with you from cohorts 1, 2, and 3, which included doses of 75 mg, 240 mg, and 400 milligrams, respectively. These data include time points out to six months from our 75 mg cohort, which includes eight participants, six of whom received WVE-007 and two placebo. We also have one-month follow-up data from our 240 mg cohort, which includes 32 participants with 24 on WVE-007, and one month of follow-up from our 400 mg cohort, including eight participants with six on 007. I'm also pleased to note that to date, 007 continues to be safe and well tolerated with no discontinuations. We are delighted to share the robust target engagement we have seen to date. In this chart, we show the results for activin E decreases out to 29 days across the three doses and placebo. The percentage reduction of activin E from baseline is shown on the y-axis, with days on study on the x-axis. We observed no change from baseline to day 29 for the placebo group. However, we observed highly significant dose-dependent decreases from baseline across all three doses, starting as early as day 8 all the way through to day 29. Each active dose also showed specifically significant activin E reductions compared to placebo at all time points from day 8 to day 29. Across the three cohorts at day 29 compared to baseline, we observed a 56% reduction for 75 mg, a 75% reduction for 240 mg, and an 85% reduction for 400 mg. Based on our preclinical data, a greater than 70% reduction is expected to be in the therapeutic range for fat loss, and these levels were achieved in both the 240 milligram and 400 milligram cohorts. In addition to the highly significant and rapid dose-dependent activin E reductions we observed across our three cohorts, we had the opportunity to evaluate our initial 75 mg subtherapeutic dose out to six months. I want to call your attention to this: even out to six months, we continue to see some sustained reduction at this low dose. As we look towards the future data from our 240 and 400 mg cohorts, which are ongoing, we anticipate that this durability could extend even further, given the continued downward trajectory of activin E levels over the first 29 days. These data support a convenient dosing interval of once or twice a year. Our INLIGHT trial data indicates that we have exceeded the reduction of activin E needed to show fat loss based on our preclinical studies. As Erik previously reviewed, and as you see on the left, we demonstrated that meaningful weight loss in the DIO mouse model occurred when activin E was durably reduced by 70% from baseline. It's important to note that we expect consistent activin E reduction over time is necessary to achieve weight loss in the same range as semaglutide. This level of reduction in our clinical data is highlighted in the green on the right-hand graph. This substantial decrease with a long duration of effect will allow us to assess weight loss across multiple time points. The INLIGHT trial design allows evaluation of target engagement, blood-based biomarkers of metabolic health, body composition, and weight loss across multiple cohorts, with increased numbers of participants at higher doses as we expand each cohort. We look forward to following our cohorts as we progress with increasing doses and assessing these exploratory markers, as well as weight loss over time. What levels of weight loss do we expect to see in the INLIGHT trial? On the right are the semaglutide STEP 1 study results, where we separated the weight loss into fat in blue and lean mass in gray. From the fat mass loss perspective, which is most relevant to the INHBE mechanism, there is a gradual weight loss over time, with approximately 2.5% loss in fat mass by three months and 4.4% loss in fat mass around five months. The aim of the WVE-007 program is to observe fat loss competitive with weekly semaglutide by six months post-single 007 dose. With the robust and durable activin E reductions and favorable safety we're observing to date, we're incredibly excited to continue investigating 007 in INLIGHT and look forward to sharing multiple data sets, including target engagement, body composition, and weight loss over the coming quarters. Later this quarter, we expect to share the data from the 240 mg cohort with three months of follow-up. In the first quarter of 2026, we'll have six months of follow-up data from the 240 mg cohort, as well as three months of follow-up data from the 400 mg cohort. Throughout 2026, we'll continue to have follow-up data for both these cohorts and will also share data from the 600 mg cohort. With a mechanism focused on fat loss with muscle preservation, favorable safety, and potential for once or twice yearly dosing, we believe WVE-007 has the potential to be a transformational approach for obesity, and we look forward to keeping you updated on our progress. Now, to share an update on our platform innovations, including our best-in-class siRNA, I'd like to turn the call over to Chandra. Thank you, Chris. For over a decade, Wave Life Sciences has been extending the frontiers of RNA therapies through advances in nucleic acid chemistry. Our foundations began with novel and proprietary backbone chemistry, enabling us to apply principles of rational design to oligonucleotides and define structural activity relationships to single isomers. Since then, we have expanded our novel chemistry toolkit, which has provided step changes in potency, durability, and delivery across hepatic and extrahepatic tissues. We have a clinically proven platform with unprecedented capabilities in silencing, splicing, and RNA editing. A hallmark of our platform is our ability to take shared learnings across modalities and apply these learnings to subsequent targets for rapid drug discovery and development. Today, we are pleased to introduce SPINA, a stereopure interfering nucleic acid design that enables RNAi-mediated silencing by further increasing AGO2 loading, leading to improved potency and durability compared to our earlier siRNA designs and industry benchmarks. On the left panel here, you can see the dramatic difference in TTR mRNA silencing with GalNAc-conjugated siRNA following a single dose at 2 mg/kg. All siRNAs have the same sequence and 2'-prime modification as the literature reference construct with state-of-the-art siRNA chemistry. Compared to reference and our previous published siRNA construct, SPINA designs have substantially improved the potency and duration of silencing, and we have observed up to 95% TTR mRNA reduction at at least up to eight weeks after a single dose. We see similar differences in TTR protein and see unprecedented increase in potency and duration of activity with SPINA designs following a single 0.5 mg/kg dose of GalNAc siRNA. As a reminder, translation from preclinical experiments to the clinic is very well understood for RNAi, and we have just highlighted the exciting preclinical to clinical translation with WVE-007, our first SPINA design in the clinic with the potential for biannual or annual dosing. In our seminal NAR publication, we demonstrated that increase in potency and duration of activity compared to reference siRNAs was primarily driven by an AGO2 loading. However, the dramatic shift in potency and duration of activity of SPINA is driven by several-fold increases in both AGO2 loading as well as PK, with SPINA driving up to tenfold improvement in AGO2 loading versus reference. Now, I'll turn to some examples with our SPINA design to highlight how PM variants allow us to access new extrahepatic tissues, which in turn expands the scope of targets and indications amenable to RNA therapeutics. On this slide, we're showing results from a three-month duration study with a single 5 mg/kg dose of three different tissue targeting SPINA variants in mouse experiments to silence SOD1 gene expression. On the far left, we are highlighting silencing in adipose tissue, the middle panel is silencing in the heart, and the far right is in skeletal muscle. In all three tissues, we observed approximately 75% knockdown after one month, and the level of knockdown persisted for at least three months following a single dose. Additionally, as you may recall from last year, we shared that with siRNA designs, we are able to drive increases in potency and durability with tissue-specific delivery by optimizing physicochemical properties. On this slide, we're showing results from an eight-week mouse experiment using siRNA designs to silence gene expression. On the far left, we highlight the well-described impact of using GalNAc to access hepatocytes in the liver. This also highlights the limits of a conjugate, and it is cell and tissue specific, so it does not enable silencing in other tissues of interest, like white adipose. To the middle and the right, we show how we can alternate designs with PM variants to enable access to various combinations of liver and adipose tissues in the absence of any targeting ligand. Depending on the target and indication, we can deploy the designs that best fit the biology. Using PRISM, we can change the physicochemical properties of our oligonucleotides to deliver to numerous extrahepatic tissues and achieve potent and durable silencing with a single dose. Now, I would like to share with you an example of how we are applying these learnings and SPINA to develop first and potential best-in-class programs, which address areas of high unmet needs. In this case, we have been working on targets with strong support by human genetics for a disease with high unmet need, high expression in liver and adipose, and measurable biomarkers which offer efficient paths to proof of concept. In this slide, we show that we can achieve robust and consistent target mRNA knockdown and protein levels in the liver and in different adipose compartments utilizing both SPINA variants. Also, the knockdown of this target reduces fasting serum triglyceride by 60%- 70% using the two SPINA designs in a DIO model. Next, we set out to investigate cellular access and silencing in the kidney using SPINAs with PM variants. Oligonucleotide primarily accesses proximal tubule cells owing to its role in reabsorption, but this is usually a non-productive delivery, meaning that oligonucleotides do not modulate targets in those cells. Our initial studies with a single $10 mg/kg subcutaneous dose of our SPINA designs achieved a durable 50% knockdown in mice with three different SOD1 constructs, which persisted for at least four weeks. The panel on the right shows all three constructs at broad distribution, shown in red, across various kidney cell types. Now, to dig deeper into the cells that are accessible with SPINA and to confirm silencing activity, we collaborated with our partners at GSK to conduct single-cell RNA-seq analysis. This allowed us to map the knockdown effect at a cellular level, confirming broad knockdown across multiple cell types, including proximal tubules, distal tubules, endothelial cells, and podocyte cells. Building on these early successes, SAR studies helped to identify SPINA variants, which demonstrated an impressive 75% mRNA knockdown with a sustained 50% reduction lasting up to three months after a single dose of $5 or $10 mg/kg. Protein reduction was also confirmed by immunohistochemistry and mRNA scope staining for oligodistribution. The knockdown was not only robust but also widespread, affecting primarily the cortex and outer medullary regions of the kidney. High-magnification images revealed broad distribution and substantial protein reduction, which was sustained at least up through three months following a single $5 mg/kg dose. Here we see decreased levels of light blue staining, representing knockdown of SOD1 protein in treated samples relative to control. In red, we can also see broad cellular distribution of the oligos. In addition, we have demonstrated that AMR optimization, through AMR optimization, we can achieve RNA editing in kidney. Following a single dose of AMR 1 and 2, we see that we can achieve 50% editing of UGP2 transcript with broad distribution. Finally, single-cell RNA-seq analysis was performed by GSK to assess editing efficiency. These data show efficient delivery and editing in multiple cell types in the kidney, including distal tubules, mesangial, podocytes, principal, proximal, and transient cells. Now, I would like to discuss an example of how we are applying learnings in chemistry optimization from across our platform to uncover new modalities. By using the PRISM platform, we found a unique way to combine RNA editing and silencing modalities into a single oligonucleotide construct. This enabled us to silence one target while simultaneously editing or upregulating another distinct target with a single oligonucleotide construct. Additionally, because this oligo is loaded onto AGO2, we believe that this has the potential to further extend the durability of editing compared to an AMR alone. We confirmed the ability of the single construct to engage in silencing and editing in vivo using a GalNAc-conjugated oligo that is designed to edit UGP2 and silence TTR. As you can see in the graph on the left, in mouse liver, the single oligo construct shows a more durable level of editing, shown in the pink line, compared to the UGP2 AMR alone, shown in the light blue line, up to 28 days following a single subcutaneous dose. As we just shared earlier, we believe this improved editing durability could be due to the loading onto AGO2. Furthermore, as the graph on the right shows, in the same mice, the single oligo construct completely knocked down TTR mRNA, just like the TTR SPINA alone. Since AMRs have the ability to upregulate protein expression by stabilizing mRNA, we explored the possibility of using a single oligo construct to upregulate one target and silence the other. As you may appreciate, simultaneously silencing PCSK9 and upregulating LDLR offers an attractive therapeutic approach to treat hypercholesterolemia. Using our single construct oligo, we were able to achieve exactly that. As shown on the left, using a single oligo construct, we achieved the same twofold LDLR protein upregulation as an LDLR AMR alone. In the same experiment, the single construct oligo also silences PCSK9 to the same extent as PCSK9 siRNA alone. This shows how our approach can be used to upregulate and silence distinct targets using a single oligo. Beyond the examples I have shared with you today, we continue to push the boundaries of what is possible in the field of RNA medicines to unlock new targets and modalities with the ultimate goal of providing innovative therapies to patients in need. Now, for closing remarks, I would like to turn the call back over to Paul. Paul? Wow. Thanks, Chandra. Before turning to Q&A, I'll recap the updates you heard today and throughout the presentation. WVE-006 continues to advance in the RestorAATion-2 clinical trial, and as Chris shared, the single dose portion of the third cohort is now underway at a dose of 600 mg, with a subsequent multi-dose portion to be dosed monthly. We're on track to deliver data from the 400 mg dose cohort in the first quarter of 2026 and from the 600 mg cohort, both single and multi-dose data in 2026. We've selected WVE-008 as our next RNA editing candidate for PNPLA3 liver disease, which will build on the successful clinical translation we've observed with WVE-006. Turning to INLIGHT, the highly significant dose-dependent activin E reductions observed post-single dose are incredibly exciting, not just for WVE-007 but for our entire siRNA capability. The knockdown observed in the 240 and 400 mg cohorts exceeded the levels observed in preclinical models that led to weight loss. Knockdown was incredibly durable and supports dosing of once or twice a year. Based on these data, we believe that WVE-007 has the potential to achieve fat loss on par with semaglutide by six months post-single dose, and we are on track to report clinical data updates, including body weight composition, starting this quarter. We also continue to innovate our platform and have robust extrahepatic delivery capability for both RNAi and RNA editing and an emerging new modality that has the potential to unlock novel targets. Stepping back, our investment in RNA editing and RNAi to date has rapidly yielded multiple programs with WVE-006 and WVE-007 that have the potential to create immense value for both patients and shareholders. As you heard today, we are now expanding on the success of these programs and advancing the next wave to the clinic with PNPLA3, with more to come in both hepatic and extrahepatic. Finally, I would like to express our sincere gratitude to all the participants, study staff, and their families. They continue to inspire the work we do each day, and from our entire team here at Wave, thank you. With that, I'll turn the call over to the operator for Q&A. Thank you. At this time, if you would like to ask a question, please click on the raise hand button, which can be found on the black bar at the bottom of your screen. When it is your turn, you will receive a message on your screen from the host allowing you to talk, and then you will hear your name called. Please accept a mutual audio and ask your question. We will wait one moment to allow the queue to form. The first question is from Joon Lee, MD, PhD from Truist Securities. Please unmute yourself and begin with your question. Hey, guys. Thanks for that impressive presentation. Your activin E target engagement, dose dependent, exceeding the DIO mouse model, very impressive. How much more than 75% knockdown of activin E in the DIO model did you need to achieve that semaglutide-like weight loss? Does the increase in fat burning through INHBE drive increase in hunger drive due to caloric burning? Are you measuring potential increase in caloric intake of these patients? What are you doing to control for that? I have a follow-up on the platforms, SPINA platform. Thank you. Yeah, and thank you, Joon. I think it is important to note, hence the box shaded in green, as Chris shared, is that we are in the range from those DIO mouse studies. I think it's highly encouraging as we think, again, the 240 and 400 gives us a range to continue to suppress within there. I think it's highly, again, encouraging that we have the levels of activin E reduction clinically that we need to see to set the clock. Just on that concept, I'll turn it over to my colleagues. I think that's the most important take home from today, that we've essentially set the clock. The essential durability that we've seen off of a subtherapeutic dose at 75 mg, where we see sustained knockdown out past six months. As you saw in those slides, we continue to see that slope of reduction continue. The fact that we can push that durability out even longer is highly encouraging. In a lot of ways, the clock is set, and we expect this degree of knockdown to be sustained for a very long period of time, and therefore to be able to track together the level of weight loss that we can see relative to activin E reductions. I'll turn to Erik to have the discussion on the caloric intake. Yeah, so we have tracked caloric intake in the mouse models, and we don't see a shift between INHBE siRNA or the controls. What I did present today is that I actually do see some changes in some of the pathways in the fat directly, which indicates kind of an improvement of insulin sensitivity, fatty acid utilization, and basing off fat. There are changes to the metabolism, but we don't see anything in terms of caloric intake. Got it. I mean, I think that was actually going back, Joon, that was, I think, one of the most impressive features of what I call kind of parity of caloric intake, is if we thought about that rebound weight gain. I think that's an incredible opportunity as looking at INHBE silencing as an off-ramp to GLP-1s, is that when we did the withdrawal study, actually the caloric consumption was mirrored in both mice. They both increased their caloric consumption when removal of the downward pressure from the GLP-1 to actually go back and resume. That hedonic eating, as many of you have probably heard us refer to, that hedonic eating occurred across the control and the INHBE treating. Even despite that pressure, we saw that we could, again, take the brake off of lipolysis and not store fat post the cessation. Highly encouraging as we think about a different profile for obesity treatments. Yeah, you know, really appreciate that the weight loss is a little more gradual and takes a little longer than semaglutide. In mouse, it takes maybe 30 days longer. Extrapolating that to humans, I mean, any idea as to how long we would need to wait to see that kind of weight loss in humans? I'm sorry to keep going, but I have a quick follow-up after that. Sure, and I'm sure this is a question that's going to come up in the queue. I think it's an important one. Again, we're on this journey together to understand INHBE kinetics. I think we can feel highly confident based on the preclinical models that have translated with a positive control in the GLP-1 receptor agonists that these models do translate in the clinic. The effect of INHBE reduction, activin E reduction, and weight loss in these models demonstrate that we do achieve those kinetic curves. As you said, in preclinical models, it looks to be that there is a different slope or trajectory of that rate of decline. We have a high degree of conviction that as you think about this six-month time point, they do converge. This ability to watch that rate, we do think will come together. I think the question will be, what rate of decrease in fat do we see between the three and six months? We'll have the opportunity to see that. As I said before, I think this is a target t hat are probably many people dialed into the call that have extensive experience in genetics, human genetics, biology, and have studied this target. I think what's incredibly compelling are three things. One, we have the potency that's required, meaning we're in the therapeutic range of reduction of activity. Two, as Chris said and Erik, it is a combination not just of a single time point of reduction, but this feature of overcoming the natural compensatory mechanisms of pushing the program of the target protein up are suppressed by duration. We have that durability. I think the third and most important thing in any obesity therapy and really any therapy in general is safe and well tolerated. The fact that we can continue dose escalation gives us a high degree of conviction that the clock started. Medicine are in these patients. It's durable. We'll continue to follow it. Again, I'm highly encouraging as we think about being able to continue to make these assessments over time. Great. That Kohli on the SPINA platform, looking forward to your progress there. How does it, specifically for the muscle trophic oligos, come to transferrin receptor mediated delivery? Thank you. Chandra, you want to take that follow-up? Yes, you know the duration, as you can see what we showed here in the muscle, these are single small doses, which is very similar to a transferrin receptor antibody dosing too. What we are seeing is, again, uptake. One thing you have to keep in mind is that it's good to deliver a molecule, but the molecule also needs to, the oligo also needs to follow the mechanism. We have an advantage here through our SPINA platform by increasing not only delivering, but we're also increasing agonistic loading, which actually substantially increases the potency and durability. I think just to follow up to Chandra's point and maybe, Joon, what you were thinking in the back of your mind and others do when they see muscle is like if you were to take kind of a DM1-like construct and imagine what you could see. I think the benefit to deliver muscle without having to use transferrin with the safety liabilities and the others that are associated with it, but actually not forgo the distribution, the durability, and in fact, see potentially longer durability based on the siRNA constructs we have, open up tremendous opportunities. I think as we think about the opportunity in muscle more broadly, we don't have to sacrifice what others are showing with a conjugate to deliver to the tissue, but we can get that potent, durable knockdown without that. I think that's, again, highly encouraging as we think about the platform capability and future targets. Maybe just to add one more point on that is that just recall that our chemistry is compatible with ligands when very useful, such as GalNAc. We don't have to, it's not an either/or. We can use it when it makes sense. For transferrin to get to muscle, it doesn't make sense because we get there very efficiently, and we have shown that already with our DMD medicines. Great, great update all around. Thank you so much. Thank you, Joon. The next question is from Joseph Schwartz at Leerink Partners. Please unmute yourself and begin with your question. Great. Thanks so much for the presentation. I have a question on 007 and maybe one on 008 as well. Given the early fat loss signals might be in a fairly low single-digit percent range after three months of dosing of 007, I was just wondering if we'll be able to see the slope of response in patients similar to what you've shown preclinically as well as on the activin E biomarkers. That way, we might be able to appreciate how the effect could evolve with more time. Yeah. I mean, I think if it's about the data and as we laid out nicely and Chris Wright laid out a number of time points over a number of doses, I think we'll be able to plot those kinetics and what that slope of that trajectory begins to look like. I think as you get early, if you remember that slide, at one month, you're in that like 1, 1.5% range. We all can acknowledge that in smaller studies, a high degree of variability at early points in time. I think these moments in time at three months, six months, and across doses will allow us to eventually, and remember the follow-up goes out for these therapeutic cohorts out to a year. I think we're going to have the ability to really track what fat loss looks like with a completely novel approach to treating obesity that drives healthy, sustainable weight loss. I think, again, highly encouraging as we think about this sign. Yes, by three months, we'll get a sense of where we are on that trajectory across both body composition, body weight, and other biomarkers. OK, great. Thanks. On 008, given PNPLA3 I148M expression is enriched in lean-NASH patients who present later, I wanted to ask about your diagnostic and enrollment strategy to enroll these patients early enough in the sequelae that 008 can help. Also, can you talk about the biomarkers which you can track at various stages of development to gauge the degree of target engagement at different doses? What is your hypothesis about the dose levels that make sense to study in these patients? I'll hand it to Erik. We're not sharing yet, although we have biomarker data. As one would imagine, sometimes biomarker evaluation is competitive in this field. We've made strides to, as Erik pointed out in this discussion, derive biomarkers there. I'll let Erik talk holistically about that. Yeah, we haven't shared any details on this really. There are good non-invasive biomarkers that we can apply early on. I think it's important. One thing to point out is that the variant per se is associated with increased risk across the whole spectrum, from F1 all the way up to F4. It's just that it's more enriched in kind of a big segment of individuals in the later stage match and especially lean match that don't really have any treatment options. For a proof of concept, it's also possible to go to more all ranges of BMI or early stages or late stages. We haven't really shared exactly where we're going right now. OK. Just to be clear on that, it could treat all patients that have the mutation. Again, we're talking about MASH in this context. As Erik also pointed out, there's a range of liver diseases associated with therapy, so thinking about it more broadly gives the opportunity for expansion to other indications in the future as well. Great. Thank you. Please try and focus questions to one question and one follow-up. The next question is from Steve Seedhouse at Cantor Fitzgerald. Please unmute yourself and begin with your question. Good morning. Thanks, everyone. Maybe just wanted to cover at the end there that bifunctional RNAi RNA editing approach. You just kind of slipped it in at the end there. It looks awesome. The PCSK9 LDLR application in particular, that feels like not just a proof of concept experiment, but actually something that I would want to see in the clinic now. Pretty promising approach. How close is that, in fact, to the clinic? We're not guiding yet today in the clinic. As you point out, I think we have two independently really well-validated targets that should be developed. Obviously, PCSK9 is extraordinarily well validated. I think in the introduction and hearing lots of feedback when people are excited about what we could do with LDLR, there's always this discussion that goes, what about PCSK9? I think to the point that the team takes on is there's a lot we can learn about a platform. I think if you take anything from today's call on a research day, that the research day is incredibly translational. When we spend time thinking about something that could be a new platform in the case of these dual conjugates, it's not esoteric. It's not thinking about what we can do, but actually, as you point out, how do we apply it to high-impact, high-value programs to medicines where hopefully the outcome is how quickly can we move this forward? A lot of work is happening to accelerate those programs. We see lots of translation from research day going forward. There are lots of good things behind this, as Chandra shared, in the kidney as well. These are two highly compelling targets. You put them together, you get a very highly compelling program in cardiovascular disease. We're excited to continue to make progress there. Great. Just maybe a more near-term question then. You announced today, I guess, that you're dosing up in a couple of these studies. AATD going to 600 mg, and then in the obesity study, 600 and beyond. It looks like despite already obviously really good PD data. Can you just elaborate on those decisions? It feels like the right call in AATD to try and maximize editing efficiency. What are you seeing in the PK/PD data that inform those decisions? Yeah, I think as Chris shared, we're modeling up to 600 because it's the last and final dose to really max out where we are on the dosing curve. We can because of safety. Two, no efficacy gets left on the table. Most importantly, as you remember from the prior call, we see healthy levels of alpha-1 antitrypsin protein two weeks after a single dose of 200. There's also the optimization of PK and what those dosing intervals are like. Are they monthly? Are they quarterly? To fully flush out the dosing interval. Obviously, we're collaborating on this program. I think we'll learn a lot from 600 that ultimately enables us to say that that portion of the study is complete so the study can move on to the subsequent portion. As it relates to INHBE, I think Chris alluded to highly encouraging that we can go above 600 and still have the DSMB allow us to go higher. I think it's highly encouraging from a safety perspective to go higher. As you saw, we're doing a phenomenal job on activin E lowering. How much more is to be gained at going higher? Again, we'll learn more about duration of activity as well as continue to establish profile for a medicine. Again, we're highly encouraging from just the 240 and 400, let alone the 600, and where we can go from there. Great, thanks so much. The next question is from Yun Zhong at Wedbush Securities. Please unmute yourself and begin with your question. Hi. Good morning. Thank you very much for taking the questions. The first one is on the obesity program. I want to confirm that you're still going to report weight loss data from the 75 mg dose cohort this month. Based on preclinical data, given that the knockdown efficiency is still slightly below that 75% that you talked about, is it reasonable to still expect some kind of a weight loss signal? If that's the case, how much difference will maybe a higher knockdown efficiency translate into weight loss? Yeah, I think we have to be focused. 75 is modeled to be subtherapeutic because it's a phase one study still and needed to be dosed low. I think to your point, highly encouraging to see durable, stable knockdown out at six months. Actually, stepping back, the short answer to your question is yes, we'll show weight loss data from the 75 milligram. That was on Chris's slide at this Q4 time point, would be 75 as well as the 240. We wouldn't be guiding this expecting to see something given the range was outside of the early reported data. This is the first time inhibin E has been developed in the clinic. We'll have long-term durable knockdown, so we'll get a good sense of that. I also look at whether or not we see other biomarkers that are interrogated beyond just weight loss itself, which I think will be helpful. This is a 75 milligram cohort, so it'll be, if anything, level setting for where we get to with 240 as that continues. I see. That will be included. OK. Yeah, that's very helpful. On the 008 program, is it reasonable to expect that initially you will be focused on MASH? Do you have any data to show whether those carriers are showing any different response to current MASH treatment or other therapeutic clinical development? There are other agents, for example, working on fat synthesis modulation or fat metabolism. Do you expect your approach—I know it's a precision approach—will potentially generate something different, maybe better efficacy when it is narrowed down to that specific patient population? Yeah, that's a great question. That is exactly the point of this. It's a disease-modifying correction of the causing mutation in these patients. While you could kind of potentially have some effect of other medicines, it's going to have lower efficacy than correcting the driving disease-causing variant. OK, great. Thank you very much. The next question is from Salim Syed at Mizuho Securities. Please unmute yourself and begin with your question. Hey, guys. Thanks for the question and the color today. Paul, Chris, I just want to because I know a lot of people are looking at a quantitative number. You kind of put one out today, but not really on this obesity stuff that we're getting in the 4Q here. Just looking at cohort two, which is your therapeutic range of the 240 mg, where you do have 75% E reduction, that's kind of the target you stated here. The SEMA is showing three months on your chart a 2.5% fat loss. Quantitatively, is that the bogey here? Why should we not be looking at other things like Amylin or even like the Nomura oral data? Why aren't those the relevant comps here? Thank you. Yeah, I think we use SEMA because the GLP-1s have been the comp that we could use to model mouse weight loss and mouse fat loss to humans. I think finding a harmonization of benchmarks that we can use sustainably across programs where we could look at the ranges of fat loss and be able to take those ranges and extrapolate them in a forward-looking way. This is healthy overweight volunteers. As we move into subsequent studies, being able to try to create benchmarks on a new modality that let us look at ranges of fat loss, I think, is important. To your point on where we are, the recognition is at the three-month time point, you have this range of what we've seen preclinically where it does look like in the early point, the kinetics on lipolysis versus what happens when you have chemical starvation and lose muscle and fat look different. I think our view has been that we do expect to be on that curve of weight loss and particularly fat loss and then be able to see that normalize. I think by the time we get to six months, we think we're over that hurdle on the normalization. It just means where we're going to be to try to put a pin in an exact moment of time relative to the GLP-1 at three months is something we're going to have to learn in running the experiment. In order to have the conviction to even run the experiment, you need to believe that you have activin E reductions that are within the range. As Chris alluded to today, we're clearly within the range. I think that's going to be helpful as we look at these subsequent experiments, both at the 240 lowest therapeutic dose as well as others, and continue to follow this over time. I think by the middle of as we move into 2026, as Chris shared too on the slide, we're going to have a number of patients with therapeutic ranges of activin E reduction that are highly consequential and be able to look at not just where it is at six months, but continue to see what that range of reduction looks like both in terms of time and dose. OK, we're getting three months, right? I just want to be clear because the consensus is all over the place. Investors are all putting out different numbers. I just want to be clear to get consensus in a little bit. People should really be thinking low single digits for this 4Q update we're getting. Absolutely. I mean, I think we were very clear on the numbers that we have put out that even if you are in a GLP-1 for fat loss, again, we have to separate for other weight loss versus what we know about the degree of fat reduction. INHBE pathway, because it is, as Erik alluded to, working across actually what actually drives healthy weight loss, meaning preserving insulin sensitivity and all of the other cardiometabolic parameters of weight loss, is by reduction of fat and not muscle. When we look at that degree of fat loss, I think we were very clear about the range of numbers. As you pointed out, low single digits is what you see with fat loss within the GLP-1 space at the early time points. To add to that, like the other things that you're bringing up, like Amylin or basically any incretin medicine or any obesity medicine in development right now, they're all having a different approach. They're all kind of acting on appetite or GI versus we are acting directly on the edible side. It is a totally different approach. The comps are always going to be like the fat loss and primarily the visceral fat, which is what increases your risk of cardiovascular disease. OK, thank you so much, guys. The next question is from Cheng Li at Oppenheimer. Please unmute yourself and begin with the question. Oh, hi. Thanks for hosting the event and taking the question. Maybe a two-part question from me, one on 007. I'm just wondering if you can comment on the patient baseline in the cohort two, and just based on the patient baseline, whether t he semaglutide from STEP 1 is a fair benchmark. I have a follow-up on 008. I'll let Chris come in on that. The question was about the patient baseline compared to SEMA. Yeah. Yeah, we're looking at patients that are healthy with overweight. As you mentioned, we mentioned the BMI range and the A1C. They're non-diabetic and have an A1C range. I have a BMI range, I think, that's up to 28. I think the key is that they're similar, both CSAD programs across both, as you're pointing out, to the step one. This would be similar. OK, that's helpful. On 008, congrats on the preclinical data. It just seems like the RNA editing efficiency you show is around 60%- 70%. I'm just wondering if there's a ceiling for maximal RNA editing you can achieve or if there's something else you can further optimize by maybe increasing the load into the ADAR enzymes or any way to improve the RNA template design with potential learning from the siRNA modality. Thank you. Chandra, you want to? The RNA editing, if you look at it, when you look at tangle sequencing, which is the plot that we have on the left-hand side that you're talking about at 75%. When you look at the transcript, when we did the transcriptome wide analysis, we see about 85% editing. This is actually just the nature of the assay. We're not saturated. It's very similar to what we observed with WVE-006 as well. Got it. I Got it. I think that's something, to Chandra 's point, it's something that we learn now with human clinical data from the prior study, and being able to look at what occurred during an acute phase event is we learned that the drug is not substrate limited. There's plenty of drug. We had editing two months after the last single dose at the lowest dose, so there's plenty of drug on board. It's not substrate limited by the stability of the construct. We also learned that when you have the acute phase event and increased transcriptional activity, the enzyme is not substrate limited. I think those are two highly important features as we think again about what we continue to do in optimization, realizing that we did prove that ADAR is a catalytic enzyme in there to be edited. To Chandra 's point, our medicines are highly stable and durable. It gives us a lot of work that we can continue to do in terms of driving further optimization both in the liver and then importantly outside the liver. Got it. Thanks, and congrats again on the update. The next question is from Hsiu-Chiung Yang at Jefferies. Please unmute yourself and begin with your question. Hi, this is ChaCha on for Roger Song. Thank you so much for hosting this event and for taking our questions. I have two, both about your 007 program. The first one has to do with some of the safety fronts. I know you said no discontinuations. I'm hoping that you can give some color on the GI AE safety front. My second question just has to do with benchmarks as well to semaglutide. I know you talked about benchmarking to visceral fat loss. I'm wondering if you believe that the higher dose cohorts for 007 could achieve overall weight loss comparable to semaglutide. I think we have to think about fat loss, weight loss. I think we've got to stay focused on mechanistic activity, which is fat loss. Highly encouraging that the DIO mouse models were achieving weight loss similarities. We have to look at that as a model and mechanism. To the point on could and potential and forward-looking, particularly across doses, the models don't suggest that it's inferior to. I think that is always a possibility. The focus has been on optimization of fat loss relative to the fat loss I've seen with GLP-1 receptor agonists. That's what we'll continue to drive and explore. Higher doses, time, and the ability to recapitulate what we've seen in the animal models again are highly encouraging. As it relates to safety. Yeah, as we mentioned, we've been dose escalating without any issues from the safety perspective. It's been safe and well tolerated. The DMCs have been allowing us to proceed without any questions. All of the AEs that we saw were mild in terms of any drug-related AEs. Given the mechanism, you wouldn't really expect any GI symptoms. It is important to note when we think about the GI toxicities. Erik brought this up in terms of a lot of the category classes. It's not an increase. It's not working on either suppressing appetite or slowing the GI tract. As Chris just said, this is taking the brakes off of lipolysis. Again, highly encouraging that's a single subcu dose with long durability. Both on the preclinical studies as well as what we're seeing in the clinic, it's got a profile that has us encouraged for a long, durable medicine. I think the fact that DSMB could review the current data, let us go to 600, see the current 600, and enable us to go higher is, again, highly encouraging. Wonderful. Thank you. Yeah. The next question is from Catherine Novick at Jones Trading. Please unmute yourself and begin with your question. Hi. Good afternoon, everybody. Thanks for the great presentation. I have a question on 007. Can you let us know with the INLIGHT trial what is blinded to the sponsor? Obviously, you're sharing target engagement data while the study is ongoing. Is this unblinded separately and safety weight loss is still blinded? When a cohort finishes dosing, is anything unblinded at that time? Yeah, I think stepping back, it's important to realize what I said at the very beginning of this call. The short answer to your question is yes. We did an analysis here looking at activin E. Obviously, DSMBs can look at data, both blinded data and in preparation for those. The DSMB can continue to make their decisions based on evaluation of those data sets. No, I think it's really critical that this wasn't an unblinding of the totality of data sets, being able to even look at unblinded weight loss data, which I know some people are thinking. This was an analysis that, if you remember the last update, and I'll kind of go back to the beginning of what I wanted to reiterate, is a lot of the forward-looking pieces are predicated on being within a range where we've got a good model that enables us to predict where we're going to be. When we could model and say at the 75 subtherapeutic, we had substantial target engagement. I know there were a lot of questions of what range of target engagement were you seeing. How do you know that your 240 is going to be within a therapeutic range. We have a phenomenal team who's doing a lot of modeling. I think to see where we needed to be to be able to be on that trajectory to deliver weight loss data, we knew we needed to be within that range. Yes, we were modeling to be in that. This was a very specific cut at day 29 to do that assessment and assure that this 240, where we said we should be in that range, we can now switch that from where it should be in the range to we are in the range where we see it. Just to add, we will be unblinding for our three-month readouts and for our six-month readouts with regards to weight and the entire study and other measures, such as body composition and biomarkers, but not for the big nine measures. We were just looking at biomarker target engagement of activin E. Got it. Just one more. If you could give me any specifics about the timing of the data cut showing activin E knockdown, even though we have 24 patients in the 240 mg cohort at one month. Given that we know enrollment was complete before the end of July, is there a reason you don't have one month's data for all 32 patients in that cohort? How long after the three-month follow-up period do you anticipate it would take to analyze once the data are unblinded? Yeah, I mean, I think we haven't guided beyond where we can get to. Each one of these cuts, we were up and dosing and that's rolling forward. As we said, day 29s are the cuts of all patients who had that data at that time. This wasn't, these were the patients at this time of the cut of the day 29, full 32 on 240 that pulled that data together. I can't guide other than we'll have data this quarter on the sixth, sorry, the three-month follow-up of those patients, which will include then also the 75. Recall that the study designs so that you have a cohort of eight initially. If the safety and tolerability is acceptable, which has been in every case, you can expand the cohort. All those subjects are not enrolled at the same time. Maybe that gives you a sense of the flow of the study in terms of enrollment. OK, thanks. Thanks for answering that. The next question is from Bill Maughan, PhD from Clear Street. Please unmute yourself and begin with your question. Good morning. Thanks for the question. Just on the INHBE program, can you talk about the key remaining unknowns in the biology, given this is kind of the first foray into lowering activin E, whether there's a level of reduction that is too much, or whether long-term there may be some compensatory metabolic changes that may kind of offset some of the effect? Can you present it? Sure. Yeah, I think part of this is like relying on the human genetics. We know that under on target, there are really no concerns about decreasing it because there are also homozygote carriers of the loss of function carriers, and they're actually healthier. With regard to that, we also do pheno-wise studies where we look at these carriers across every known phenotype in human, and we don't see any increases of anything. That gives us some reassurances. We have obviously taken this through talks, and it's all both on and off target. It's clean. With regard to that, no really concerns about this mechanism with regard to decreasing it. I think we can decrease it, that there is really no limit to how much we could potentially decrease it. Okay, and Biology on the other side of inducing it, as you were saying, we have shown on the other side, as Erik shared, that we do think that we've shown across the pitch that inducing it impacts a whole bunch of features, right, beyond just fat loss, as Erik shared. When we think about other drivers of adipose inflammation and all of the features of what makes this, I think, really important cardiometabolic drug, I think we need to step back and think about the totality of it. Yes, it has an impact on fat loss and weight loss, and that's important. If we think about obesity as truly a public health disease and metabolic and why fat loss and muscle sparing is crucial, it's critical. I think that's ultimately what we think is going to be the biggest driving differentiator in this program, as for insulin sensitivity is saving muscle. That is important. Yeah, I think this is a largely new target since just a few years. Even today, with some of the data we've disclosed today, we're starting to put together the pieces how basically the increase in lipolysis is contributing towards the lower risk of cardiometabolic disease seen in these genetic carriers of the homozygote or the heterozygote loss of function carriers. I think the pieces we put together today with an increase in insulin sensitivity, a shift from the pro-inflammatory to the anti-inflammatory state and visceral fat and lower fibrosis, all of those things together contribute to the lower risk of cardiovascular disease and type 2 diabetes, to Paul's point, which is ultimately really the reason for any obesity treatments. OK. On PNPLA3, is that a validated enough target that you expect to be able to put forth an argument for accelerated approval? Do you expect to have to show functional endpoints? What might those be? Let my colleagues start. I mean, it's a very well-established target where the biology is well known. I don't think we would guide towards regulatory interactions at this point. To the question, it is a very well-known mechanism, yes. With biomarker, to Erik's point that we made on, I guess, one of the prior questions, we can have a biomarker-driven response in terms of then targeting the genetics, the biology through biomarkers, then ultimately through phenotypic analysis of the patients. Great. Thank you. The next question is from Madison El-Saadi, PhD from B. Riley Securities. Please unmute yourself and begin with your question. Hey, everyone. Thanks for taking our question. I appreciate the update. Lots of things one can get excited about. Maybe first, given the MASH or liver field pivot to these non-invasive tests, does this allow Wave Life Sciences to execute really end-to-end a phase two or even a future phase three in a 148 variant population just as an independent company? Yeah, I mean, I think we were excited when we saw the transition finally to looking at non-invasive imaging as endpoints. I think to the prior question and to this one, I think it's what obviously elevated the target in our minds that we've got a highly genetic correlation of it's in commercial genetic testing. It's a readily accessible genetic biomarker that drives disease. Being able to modify that with a biomarker and non-invasive imaging is something that we can fully deliver. Got it. And then secondly, Paul, has your view changed, I guess, on the future potential real-world use of 007? You've spoken about it in terms really independent of GLP-1 receptor agonists as a way to lower GLP-1 dose to improve the GI tolerability and then also as an off-round. Just wondering, as more data has come out, as you've learned more, if your view here has changed recently. No, I mean, I think on one hand, probably it's easier to have conviction with clinical data than preclinical data. I think having seen the range of knockdown, the durability translate, you do a lot of modeling when you try to go from a DIO mouse to human. I think the more data points we can have on actual protein reduction and durability of protein reduction, the more conviction you have. I think it absolutely is going to be a very important cardiometabolic medicine. I think where commercially the uptake starts and whether or not people begin to use it in advance with the evolution of just GLP-1 receptor agonists and where they go, particularly around generalization, I think there's easily for fat loss, muscle sparing, cardiometabolic improvement if the goal is to treat obesity. I think no doubt there's no wavering from our point that it can be very much a frontline medicine. Where it gets utilized in the initial piece, which I think is a very consequential market, is sustaining people on a GLP-1 receptor agonist where they're going to continue to learn to lose bone and muscle over time. 70% of patients can't stay on it. The ability to transition, as we did on maintenance, where you can move patients to a once, twice a year subcu injection and know that you're not going to get weight gain, you're going to sustain that benefit over time, I think is a phenomenal use case. I mean, for the US where GLP-1 receptor agonists are used. We have to look broader than that. I mean, there's over a billion patients worldwide living with obesity. When we think about what those treatment paradigms look like, I know we often look at this particular market and say, well, how are we going to intersect there? The ability of markets where people don't have access, I mean, you have large companies buying manufacturing CDMOs to try to keep up with demand and just individual marketplaces. The ability to think about how you can scale a once-a-year subcu GalNAc-conjugated siRNA opens up a massive possibility of how you think about the global treatment for obesity in a way that we believe this mechanism has the potential to address. Highly encouraged as we go on, we actually are set to deliver. As I said, the clock started. Medicines and patients, we're knocking down the target in these ranges. We're going to be able to follow this out over time. I think as we do that, I think that will be a huge opportunity as we think about the global obesity market. I think that's really how we think. How do we treat the over a billion patients worldwide living with obesity? I think we're really excited about all three use cases that we have presented. We hear a lot of that sentiment when we're out speaking to KOLs and the community as well, that there is really an opportunity in all of those three kind of potential paths forward. We're going to be guided by data to move forward now. I'll bring up one other point. I think that, as Erik just alluded to, we spend a time, obviously, our heritage has been in rare diseases. We spend a lot of time with the patient community. As we bring patients in, I think carefully about the number of patients who tell us when they watch ads on television advertising the weight loss potential of GLP-1s. They truly say, like, even if I achieve that level of weight loss, I still wouldn't be at a healthy goal in weight reduction. I think as we do think about what are the arrows in the quiver, as to Erik's point on talking to KOLs, that can actually enable patients to achieve true healthy weight loss that's going to drive protection for patients living with obesity, there very much is the need to think about a multitude of medicines that can be used together. I think the fact that we don't work on the GI system in terms of causing nausea, vomiting, distractibility, the fact that we don't cause anatomy because we're not actually driving appetite suppression to CNS, the fact that we've got a very orthogonal approach to doing this and can show that we have complete synergy with the incretin, so in this case, GLP-1s, I think does allow us to think about that middle use case, which is really about how do patients continue to be able to achieve those levels of weight loss if they need it. I do think that this orthogonal approach gives us a huge opportunity to think about all categories of how this medicine can be used. Got it. Understood. Really appreciate all the color. Thank you for the question. The next question is from Samantha Semenkow, PhD, from Citi. Please unmute yourself and begin with your question. Hi. Thanks very much for taking the question. Congrats on all of the updates you've presented here today. I just have a follow-up on one of the prior questions for your RNA editors, and I guess specifically for 006. What levels of optimization could you look at to help increase the maximum editing threshold? As you said, if that threshold is not substrate limited, is it then concentration dependent? Is that why we're seeing the editor respond when endogenous production of AAT increased in that one patient with the acute phase response? Thank you. Yeah, no, thanks for the question. I think the interesting thing on 006 independently, and I think that's some of what is intriguing. I know sometimes when I say this, I'll get nothing's easy in drug development. I think the difference between 006 and some of the other targets in editing in some ways is 006 is one of those where you've got this other kind of variable, right? What happens during an acute phase response? The other variability is increased transcription. That's what, as we shared again today, that's the biological rationale and mechanism for AATD is you get this response, this inflammatory response, CRP goes. You get this increase in transcriptional regulation. There is a different texture to how that happens. This gets to that target differentiation. It's when we have targets like PNPLA3 and others, as Chandra shared, we've got other features in terms of stability of showing good stable drug activity in editing. We do see a high degree of reproducibility across constructs, which I think, again, there's two metrics that we look for in kind of defining a platform: how much similarity is there to move from one construct to the other, and how do you impart those learnings. The other that I use a lot is how quickly, when you have a platform, does it mean moving from a target to moving to the clinic. We use that also as a barometer of the efficiency with which there's portability. I think we've been highly successful in that portability concept. Inhibin E was 18 months from our target work on the in vivo data to being in the clinic. I think we've been able to impart a high degree of that. Again, with PNPLA3, we've seen similar. I don't know if others have additions to the market substrate? The only thing to add is just the way we're thinking about this acute phase response. It's pretty well understood that increased expression at the RNA level, if you have more RNA, there's enough of the molecule and active enzyme to actually produce much more AAT. We don't believe that it's an enzyme or a molecule stability question. It's really that there's lower levels of RNA, and those go up in the acute phase response. We can convert that to AMP and increase the overall amount of AAT. That's how we believe it's working. As the prior question came up on the dose, moving that dose to the highest third cohort since we could is also about just looking at duration. How long? We know we've got a stable construct there. How long and then frequently do we need to administer the medicine to ensure that patients can respond? Got it. OK. As a follow-up to your last comment there, Paul, what is the residual amount of Z that you think is acceptable to support commercial uptake for WVE-006? I'm just wondering from a competitive perspective if you need to try to push Z down as low as possible. Therefore, maybe you would need to do optimization in addition to improving durability there. Thank you. Yeah, no, it's an interesting question because as we also know that Z has a high degree of variability, right? As you have success on freeing up, I also look at this as the sensitivity measurements of being able to analyze it in some moment in time. As you push up AMP, and then therefore Z comes down, we saw that dramatic. It was nice to see kind of that corresponding, which is what you want to see in editing, is your Z convert to AMP. There's another reservoir of Z, which is the aggregation over liver that's going to be various. It will be variable over time in patient depending on how much aggregates they have that eventually when you substitute AMP, you're going to free up Z aggregates. It is something that we'll have to watch for over time. We would expect to see if we continue to push AMP higher, that Z would go lower. That's the natural inverse relationship with the exception of the fact that as you do these measurements, if you're clearing Z aggregates from the liver, there will be periods of time until you've completely flushed the Z aggregates out that will confound that variable to know how low is low if you're continuing to clear aggregates. I know that seems circuitous, but you do have to look at the two reservoirs of Z. There's the hepatic reservoir, which is aggregates, and then the intracellular reservoir, which is the transcripts that are making the protein. We'll have to follow both of those over complete time to know you've fully flushed out the lower limit of Z. We do know that Z protein itself, and this is important, once it gets outside of the liver, has some residual function. I mean, we know there were companies that were trying to, and I think a lot of this had to do with the mechanism of doing it, to try to push Z protein out of the liver to restore some degree of functionality systemically. Those were kind of the small molecule disaggregators. It's not that Z itself has zero biological function. That's detrimental once it's freed out of the aggregates in the liver. Maybe just add one more thing. In advance of both for 006 and 008, that we're modeling our medicines for human genetics. In this case, just as a reminder, the MZ patients, AATD patients, they're more or less healthy. They have very low risk of liver disease and also of lung disease. That means that some Z circulating is OK, right? That's what we're trying to achieve. The same with PNPLA3, really, that the MZ, or in this case, it's a heterozygote. They have 80% lower risk of dying from liver complications than the homozygotes. That's the advantage of using gene mutants as our starting point for developing medicines. Got it. That's very helpful. Thanks very much. Thank you. The final question is from Craig McLean at Wells Fargo. Please unmute yourself and begin with your question. Hey, guys. Thanks for the opportunity to ask a question here. Just a quick one from us. I want to go back to the safety of 007. Given the mechanism of action, how you're putting the brakes on glycolysis instead to upregulate, let's say, lipid catabolism, can you share what you're seeing, if anything, in terms of serum glucose levels? Is this something that you've seen perhaps below a dangerous level in your patients in the study? Just to say the first, taking the brake off glycolysis, right, taking a brake off glycolysis. So it's a lipolip. It induces glycolysis to make sure everybody else is dilated. That's key. As Chris pointed out, we really haven't seen anything like that. I mean, we've been dose escalating up to 600 mg and potentially beyond, and we've not really seen anything except for mild events. Nothing really to speak of from that perspective. I don't think that the human data with individuals that have the mutations also would support that. There's not really any evidence of hypoglycemia or other things, even in the homozygotes. In any of the preclinical studies that we do that would ultimately push bounds and doses to go forward, it's a great question. It's something, obviously, you continue to follow all labs as you move a new mechanism forward. Got it. Thank you. Thank you. You're welcome. Thank you, everyone, for joining us today. We look forward to connecting with many of you in the very near future. Have a great day.