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

Hello, and welcome to Wave Life Sciences 2025 Research Day. [Operator Instructions] Also, as a reminder, this conference is being recorded today. I will now turn the call over to Kate Rausch, Vice President of Corporate Affairs and Investor Relations.

Good morning, everyone, and welcome to Wave's 2025 Research Day, Spotlight on RNA editing and RNAi. The slides that accompany today's presentation will be available following the call in the Investors 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 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, 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 2 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 2 cohorts of our Restoration 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-milligram subtherapeutic cohort had substantial target knockdown, supporting our preclinical modeling that the second 240-milligram cohort would be expected to deliver a therapeutically relevant knockdown. To confirm this, we plan to analyze all Activin E biomarker data as well as safety once the full expanded Cohort 2 reached day 29. Today, we are excited to share an Activin E target engagement update from the INLIGHT clinical trial. In the first 3 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 2 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 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 2 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 Pi*ZZ 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 a protein alpha-1 antitrypsin. This AAT protein protects the lung during inflammatory or infectious events, preventing lung injury that could lead to emphysema and 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 Z-AAT, 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 Z-AAT 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. 006 is an RNA editing GalNAc oligonucleotide that contains Wave's proprietary chemistry, including PN and N-3-uridine. It edits mRNA A-to-I in a highly specific manner to produce only wild-type M-AAT without biostatic edits and is administered by a convenient subcutaneous injection with potential for monthly or less frequent dosing. The goal of RNA editing is to increase wild-type M-AAT protein edit source and restore the physiological production of AAT needed to prevent lung damage during acute inflammatory response, while enhancing liver health by reducing the production and aggregation of Z-AAT, thereby addressing both key disease manifestations. With RNA editing, you create a wild-type transcript, which leads to the production of M-AAT, the healthy AAT protein in the liver. M-AAT then circulates to reach and protect the lung. Its production in the liver also replaces Z-AAT and allows for Z-AAT reduction and clearance of harmful protein aggregates in the liver. Across genotypes, those with 2 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 2 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 therapy 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 M-AAT 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 will recapitulate the MZ phenotype and overcome key limitations of protein replacement therapy. Typically in the disease state in patients with 2 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 MM individuals that have a preserved acute phase response, AAT protein increases correspondingly to protect the lung against the undesirable consequences of inflammation, ensuring the lung 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 testing. Restoration of the MZ phenotype requires achieving 3 criteria: one, keeping basal protein levels at or above 11 micromolar; two, driving 50% or greater circulating M-AAT with corresponding decreases in Z-AAT 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 M-AAT, while there was a corresponding 60% decrease in the mutant Z protein. These effects were highly consistent across individuals and persisted for up to 2 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. Dynamic effect was observed 2 weeks after a single dose of 006, supporting the rapid onset of the editing effect. Encouragingly, the magnitude and the 4-week duration of this response were also proportional to the levels we'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 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 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 acute phase response. Additionally, augmentation therapy do not have any impact on the liver manifestations of the disease, whereas 006 has demonstrated the ability to meaningfully increase levels of Z-AAT 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 interval. We selected 600 milligrams as our dose for this third cohort. 600-milligram 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 wholly owned clinical candidate, which is a GalNAc-conjugated RNA editing program for genetically defined liver disease. 008 builds directly on learnings from WVE-006. As you heard from Chris, we have demonstrated clinically efficient and consistent RNA editing, restoration of dynamic physiological response to stimuli, durable effects supported in infrequent dosing and a favorable safety and tolerability profile. PNPLA3 is a compelling target with strong human genetic 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 ninefold higher risk of dying from the liver disease compared to noncarriers. 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 NASH. The PNPLA3-I148M variant leads to a substantially higher risk of a range of liver diseases from MAFLD, MASH, alcoholic steatohepatitis hepatitis 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 and 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 modified. While MASH among noncarriers of the PNPLA3-I148M variant tends to be multifactorial and polygenetic 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 their more frequently abnormal weight, and they more often present with an 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 nonprecision 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. 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. PLNP3 expression on lipid droplets is dynamic. It increases in response to feeding and participate 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 store in the liver are mobilized and exported as well as in retinal 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 retinal 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 in lipid mobilization, reverse steatosis as well as inflammation ballooning and fibrosis. And 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 increased ballooning and in stellate cells, PNPLA3 knockdown versus fibrotic responses. Together, these findings support our strategy to restore PNPLA3 function with RNA editing rather than removing, 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 008. In the middle, RNA-seq results from 2 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 008. And 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 008. Here, we compare lipid accumulation after treatment with our PNPLA3 AIMer versus the PNPLA3 clinical reference siRNA in 2 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 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 008, we'll edit, not silence PNPLA3, which will restore its important functions in liver lipid homeostasis. The goal is to reverse steatosis inflammation, ballooning and fibrosis by correcting the causal carrier. 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, and we have now selected 008 as our development candidate using Wave's proven chemistry and AIMer design. Clinical planning is underway for a first-in-human study where we will leverage previously genotype populations to efficiently identify homozygous I148 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, 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. 006 and 008 are 2 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 expertise tissues. As we shared last year's Research Day, our AIMers achieved substantial editing in lung, heart, adipose and pancreas, all without any ligands as well as region-wide editing in CNS after ICD or intrathecal dosing in rodents or nonhuman primates. We will 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 008 towards the clinic. Now I'm very excited to transition to our obesity program, WVE-007, a GalNAc-siRNA that targets in INHBE. 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 agonists, other treatments that enable fat loss have been shown to curve 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 a type of fat that contributes to the development of type 2 diabetes and cardiovascular disease. We believe 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 two to fourfold with coding variant evidence in the upper part of that range. In the UK Biobank and other cohorts, heterozygous INHBE loss of function carriers exhibit a healthier metabolic profile with lower abdominal obesity by waste-to-hip ratio and lower visceral adipose volume, lower triglycerides, ApoB and fasting glucose and higher HDL cholesterol. We also had 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 in INHBE mRNA by at least 50%. We aim to recalculate the protective phenotype seen in these heterozygous loss of function carriers. Association 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 2 of the subunits dimerized to form the hepatikine, Activin E. Activin E gets released into circulation where it binds in a specific manner to ALK7 receptors and adipocytes, resulting signaling blocks adipose lipolysis, promoting abdominal obesity and increasing risk for cardiovascular disease and type 2 diabetes. By reducing hepatic INHBE mRNA with a GalNAc-siRNA, we lower circulating Activin E, decrease alpha7 signaling in adipose tissue and release the grade from lipolysis, which is expected to shrink adipocytes and reduce abdominal adiposity, thereby lowering cardiometabolic risk. 007 uses Wave's best-in-class siRNA format that incorporates backbone stereochemistry and PN 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 silencing [ 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 will go deeper on our siRNA platform and how it underpins our broader hepatic and extrahepatic pipeline. As we have shared previously, our preclinical data strongly support 007's ability to both potently and durably knock down inhibin E, 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-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 per kg and 40% at 10 mg per kg, while muscle was unchanged. These data support 007 as a single-agent option for healthy weight loss with visceral fat reduction in lean mass reduction. We also have robust preclinical data to support synergistic use cases with GLP-1 agonists. At 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 observed 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 DAO mouse models, a single INHBE siRNA dose achieves more than 70% reduction of circulating Activin E 1 month after dosing at dose levels where we observed a substantial fat loss, as I outlined in the previous 2 slides. When comparing the kinetics, weight loss within 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 in the mRNA and Activin E levels, we would anticipate increases in adipocyte lipolysis and reduction of adipocytes. 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 light lipolysis with better cardiometabolic health. RNA sequencing for 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, bind the acid utilization and beiging of white adipose tissue while downregulating adipose and fibrotic pathways. In visceral adipose tissue, we observed upregulation of glucose utilization, thermogenesis and lipid metabolism pathways, consistent with what we observed in subcutaneous fat and downregulating 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 dia. Additionally, histology demonstrates a shift towards 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 the 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 diseases. 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 siRNA -007 has the potential to be a best-in-class approach. 007 incorporates proprietary chemistry, including stereochemistry and PN chemistry, which increases potency and durability of silence. And 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 the visceral fat with no loss of muscle. Further, our preclinical data shows that our INHBE siRNA can double the weight loss compared with GLP-1s 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 INLGHT clinical study.

Thank you, Erik. As a reminder, INLGHT is a placebo-controlled single and multiple ascending dose study, randomized 3:1 active to placebo. With potential to escalate up to 5 single and 3 multiple ascending dose cohorts, it's designed as a safety, tolerability, PK/PD study, enrolling base cohorts of 8 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 milligrams and 8 participants. Then for subsequent cohorts, which are expected to be in the therapeutic range, we have the option to expand to 32 subjects as warranted by safety. With the favorable safety profile, we have fully expanded cohorts 2 and 3 to date and are currently expanding cohort 4 at a dose of 600 milligrams. 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 milligrams, 240 milligrams and 400 milligrams, respectively. These data include time points up to 6 months from our 75-milligram cohort, which includes 8 participants, 6 of whom received WVE-007 and 2 placebo. We also have 1-month follow-up data from our 240-milligram cohort, which includes 32 participants with 24 on 007 and 1 month of follow-up from our 400-milligram cohort, including 8 participants with 6 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 3 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 3 doses, starting as early as day 8 all the way through to day 29. Each active dose also showed statistically significant Activin E reductions compared to placebo at all time points from day 8 to day 29. Across the 3 cohorts at day 29 compared to baseline, we observed a 56% reduction for 75 milligrams, a 75% reduction for 240 milligrams and an 85% reduction for 400 milligrams. 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 3 cohorts, we had the opportunity to evaluate our initial 75-milligram subtherapeutic dose out to 6 months. I want to call your attention to this. Even out to 6 months, we continue to see sustained reduction at this low dose. As we look towards the future data from our 240 and 400-milligram 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 of 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. So what levels of weight loss do we expect to see in the INLIGHT study? On the right are the semaglutide's 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 3 months and 4.4% loss in fat mass around 5 months. The aim of the WVE-007 program is to observe fat loss competitive with weekly semaglutide by 6 months post single 007 dose. With the robust and durable Activin E reductions and favorable safety we are 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-milligram cohort with 3 months of follow-up. In the first quarter of 2026, we'll have 6 months of follow-up data from the 240-milligram cohort as well as 3 months of follow-up data from the 400-milligram cohort. Throughout 2026, we'll continue to have follow-up data for both these cohorts, and we'll also share data from the 600-milligram 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 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 relationship to single agent. Since then, we have expanded our novel chemistry toolkit, which has provided step changes in potency, durability, 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, the GalNAc conjugated siRNA following a single dose at 2 MPK. 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 least up to 8 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 per 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 PN variant allows 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 3-month duration study with a single 5 mg per kg dose of 3 different tissue targeting SpiNA variants in mouse experiments to silence SOR1 gene expression. On the far left, we are highlighting silencing in adipose tissue and middle panel is silencing in the heart and the far right is in skeletal muscle. In all 3 tissues, we observed approximately 75% knockdown after 1 month and the level of knockdown persisted for at least 3 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 physical chemical properties. On this slide, we're showing results from an 8-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. But 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 adipose. To the middle and the right, we show how we can alternate designs with key enablements to enable access to various combinations of liver and adipose tissues in the absence of any targeting line. Depending on the target and indication, we can deploy the designs that best fits the biology. Using PRISM, we can change the physical chemical properties of our oligos 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 addresses areas of high unmet need. In this case, we have been working on target 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 path 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. Also, the knockdown of this target reduces fasting serum triglyceride by 60% to 70% using the 2 SpiNA designs in a DAO model. Next, we set out to investigate cellular access and silencing in the kidney using with SpiNA with PN variants. Oligonucleotide primarily accesses proximal tubule cells owing to its role in reabsorption. But this is usually a nonproductive delivery, meaning that oligonucleotides do not modulate targets in those cells. Our initial studies with a single 10 mg per kg subcutaneous dose of our SpiNA design achieved a durable 50% knockdown in mice with 3 different SOD1 constructs, which persisted for at least 4 weeks. The panel on the right show all 3 constructs have 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 3 months after a single dose of 5 or 10 mg per kg. Protein reduction was also confirmed by immunohistochemistry and miRNAscope staining for oligo distribution. The knockdown was not only robust but also widespread, affecting primarily the cortex and outer medulla regions of the kidney. High magnification images revealed broad distribution and substantial protein reduction, which was sustained at least up to 3 months following a single 5 mg per kg dose. Here, we see decreased levels of light blue representing knockdown of solvent 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 AIMer optimization -- through AIMer optimization, we can achieve RNA editing in kidney. Following a single dose of AIMer-1 and AIMer-2, we see that we can achieve 50% editing of UGP2 transfer 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, optimal and transient cells. Now I would like to discuss an example of how we are applying learnings and chemistry optimization from across our platform to uncover new modalities. By using 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 cause editing or upregulating another distinct target with a single oligonucleotide construct. Additionally, because this oligo is loaded on to Ago2, we believe that this has the potential to further extend the durability of editing compared to an AIMer alone. We confirm 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 pink line compared to the UGP2 AIMer alone shown in 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 on to 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. Since AIMers 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 AIMer 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?

Thanks, Chandra. Before turning to Q&A, I'll recap the updates you heard today 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 milligrams with the subsequent multi-dose portion to be dosed monthly. We're on track to deliver data from the 400-milligram dose cohort in the first quarter of 2026 and from the 600-milligram 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 006. Turning to INLIGHT, the highly significant dose-dependent Activin E reductions observed post single dose are incredibly exciting, not just for 007, but for our entire siRNA capability. The knockdown observed in the 240 and 400-milligram 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 6 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 so from our entire team here at Wave, thank you. And with that, I'll turn the call over to the operator for Q&A.

[Operator Instructions] the first question is from Joon Lee MD PhD from Truist Securities.

Thanks for that impressive presentation. Your activin E target engagement, dose dependence, exceeding the DIO mouse model, very impressive. How much more than 75% knockdown of activin E and DIO model did you need to achieve the semaglutide like weight loss? And does the increase in fat burning through INHBE drive increase in hunger drive due to caloric burning? And are you measuring potential increase in caloric intake of these patients? And what are you doing to control for that? And I have a follow-up on the platforms, SpiNA platform.

Yes. 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. And so I think it's highly encouraging as we think, again, the 240 and 400 gives us a range to continue to suppress within there. So 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. And I think just on that concept, and I'll turn it over to my colleagues. I think that the most important take home from today is that we've essentially set the clock. The essential durability that we've seen off of the subtherapeutic dose of 75 milligrams, where we see sustained knockdown out past 6 months. And as you saw on those slides, we continue to see that slope of reduction continue and the fact that we can push that durability out even longer is highly encouraging. So 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 for discussion on the caloric intake.

Yes. So we have tracked caloric intake in the mouse models, and we don't see a shift between INHBE siRNA or the controls. What we -- what I did present today is that we 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 beiging of fat. So 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 to you, 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. And 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 withdraw study, actually the caloric consumption was mirrored in both mice. They both increased their caloric consumption on when removal of the downward pressure from the GLP-1 to actually go back and resume that hedonic eating, as many of you probably heard us refer to, that hedonic eating occurred across the control and the INHBE treating. So even despite that pressure, we saw that we could again take the brake off of lipolysis and not store fat post the cessation. So again, highly encouraging as we think about a different profile for obesity treatments.

Yes. 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? And sorry to keep going, but I have a quick follow-up after that.

Sure. I'm sure this is a question that's going to come up in the queue. So -- and 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-1s that these models do translate in the clinic. And so the effect of INHBE reduction, activin E reduction and weight loss in these models demonstrate that we do achieve those kinetic curves. And as you said, in preclinical models, it looks to be that there is a different slope or trajectory of that rate of decline. But we have a high degree of conviction that as you think about the 6-month time point, they do converge. And so 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 3 and 6 months, and we'll have the opportunity to see that. And as I said before, I think this is a target that probably many people have dialed into the call that have extensive experience on the genetics, human genetics, biology and the study of this target. I think what's incredibly compelling are 3 things. One, we have the potency that's required, meaning we're in the therapeutic range of production of activin E. 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 -- the target protein up are suppressed by duration. So we have that durability. And I think the third and most important thing in any obesity therapy and really any therapy in general is safe and well tolerated. And 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. But again, highly encouraging as we think about being able to continue to make these assessments over time.

Great. And then on the SpiNA platform. Looking forward to your progress there. But how does it sort of specifically for the muscle tropic oligos, how does it come to transferrin receptor-mediated delivery?

And, do you want to take that follow-up?

Yes. This is -- yes, the duration, as you can see what we showed here in the muscle, this is -- these are single small doses, which is very similar to a transferrin receptor antibody dosing too. So 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. So we have an advantage here through our SpiNA platform by increasing not only delivering, but we're also increasing Ago2 loading, which actually substantially increases its potency and durability. So that's...

I think just a 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, I think open up tremendous opportunity. So I think as we think about the opportunity in muscle more broadly, we don't have to sacrifice what others are showing with the conjugate to deliver to the tissue, but we can get that potent durable knockdown without that. And I think that's, again, highly encouraging as we think about the platform capability and future targets.

And 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. So -- but we don't have to -- it's not an either/or. We can use it when it makes sense. But 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.

The next question is from Joseph Schwartz at Leerink Partners.

Great. I have a question on 007 and maybe one on 008 as well. So I guess, given the early fat loss signals might be in a fairly low single-digit range after 3 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.

Yes. I mean I think it's about the data and as we've laid out nicely and Chris 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, you remember that slide at 1 month, you're in that like 1%, 1.5% range. And we all can acknowledge that in smaller studies, there's a high degree of variability at early points in time. But I think these moments in time at 3 months, 6 months and across doses will allow us to eventually. And remember, the follow-up goes out for these therapeutic cohorts out to a year. So I think we're going to have the ability to really to track what fat loss looks like with a completely novel approach to treating obesity that drives healthy sustainable weight loss. So I think, again, highly encouraging as we think about this sign. But yes, by 3 months, we'll get a sense of where we are on that trajectory across both body composition, body weight and other biomarkers.

Okay. Great. And then on 008, given 148M expression is enriched in MASH 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. And 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? And 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, and we've made strides to, as Erik pointed out in this discussion to derive biomarkers. But I'll let Erik talk holistically about that.

Yes. We haven't shared any details on this really, but there are good noninvasive biomarkers that we can apply early on. I think it's important one thing, Joe, to point out is that the variant per se is associated with increased risk across the whole spectrum. So it's from F1 all the way up to F4. It's just that it's more enriched and kind of a big segment of individuals in the later-stage MASH and especially lean MASH that don't really have any treatment options. But for proof of concept, it's also possible to go to a more -- all weight -- like all ranges of BMI or early stages or late stages. And we haven't really shared exactly where we're going right now.

Just to be clear on that. So it could treat all patients that have the mutation. And again, we're talking about MASH in this context. But as Erik also pointed out, there's a range of liver diseases associated with PNPLA3. And so thinking about it more broadly gives the opportunity for expansion to other indications in the future as well.

[Operator Instructions] The next question is from Steve Seedhouse at Cantor Fitzgerald.

Maybe just wanted to cover at the end there, that bifunctional RNAi, RNA editing approach, you just kind of slipped in at the end there, but it looks awesome. The PCSK9 LDLR application, in particular, that feels like not just a proof-of-concept experiment, but actually something that like I would want to see in the clinic. Now a pretty promising approach. So how close is that, in fact, to the clinic?

Well, we're not guiding yet today in the clinic. But as you point out, I think we have 2 independently really well-validated targets that should be developed. Obviously, PCSK9 extraordinarily well validated. And I think in the introduction and hearing lots of feedback and people are excited about what we could do with LDLR, there's always this discussion that goes, what about PCSK9 and how does -- and I think to the point that the team takes on is there's a lot we can learn about a platform. And 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 isoteric. It's not thinking about what can do, but actually, as you point out, how do we apply it to high-impact, high-value programs and medicines where hopefully, the outcome is how quickly can we move this forward. So a lot of work is happening to accelerate those programs. We see lots of translation from research data going forward. And there's lots of good things behind this, as Chandra shared in the kidney as well. But yes, these are 2 highly compelling targets and you put them together, you get a very highly compelling program in cardiovascular disease. So we're excited to continue to make progress there.

Great. Just maybe more near-term question then. So you announced today, I guess, that you're dosing up in a couple of these studies. So AATD going to 600 milligrams. And then in the obesity study, 600 and beyond, it looks like despite already obviously really good PD data. So can you just elaborate on those decisions, and it feels like the right call in AATD to try and maximize editing efficiency, but what are you seeing in the PK/PD data that inform those decisions?

Yes. 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 and 2, no efficacy gets left on the table. But most importantly, as you remember from the prior call, I mean, we see healthy levels of alpha-1 antitrypsin protein 2 weeks after a single dose of 200. So there's also the optimization of PK and what those dosing intervals like. Are they monthly? Are they quarterly? So to fully flush out the dosing interval. And 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 mean, I think as Chris alluded to highly encouraging that we can go above 600 and still have the DSMB allow us to go higher. So 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. So how much more is to be gained at going higher. But again, we'll learn more about duration of activity as well as continue to establish a profile for medicine. But again, we're highly encouraging from just the 240 and 400, let alone the 600 and where we can go from there.

The next question is from Yun Zhong at Wedbush Securities.

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-milligram dose cohort this month. And based on preclinical data, so given that the knockdown efficiency is still slightly below that 75 milligram that you talked about, is it reasonable to still expect some kind of a weight loss signal? And if that's the case, well, how much difference will -- maybe a higher knockdown efficiency translate into weight loss?

I think we have to be focused. 75 milligrams is modeled to be subtherapeutic as it's a Phase I study still needed to be dose low. I think to your point, highly encouraging to see durable, stable knockdown out at 6 months. So yes, actually stepping back, the answer -- short answer to your question is yes, we'll show weight loss data from the 75 milligram, and that was on Chris' slide at this Q4 time point will be 75 milligram as well as the 240 mg. We wouldn't be guiding this expecting to see something given the range was outside of the early reported data. But again, this is the first time INHBE has been developed in the clinic and we'll have long-term durable knockdown. So we'll get a good sense of that. I also look, whether or not we see other biomarkers that are interrogated beyond just weight loss itself, I think, will be helpful. But again, it's a 75-milligram cohort. So it will be, if anything, level setting for where we get to at 240 mg as that continues. That will be included.

I see. Okay. That's very helpful. Then on the 008 program, I think -- well, is it reasonable to expect that initially, you will be focused on MASH. And I think do you have any data to show whether those carriers they are showing any different response to current MASH treatment or other therapeutic in clinical development? And 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 narrowed down to that specific patient population?

Yes. Thanks. That's a great question. Yes, that is exactly the point of this. It's a disease-modifying correction of the causing mutation in these patients. And while you could kind of potentially have some effect of other medicines, it's going to be -- have lower efficacy than correcting the driving disease-causing variant.

The next question is from Salim Syed at Mizuho Securities.

On the color today. So Paul, Chris, I just want to -- because I know a lot of people are looking at a quantitative number, and 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 2, which is your therapeutic range of 240 mg where you do have 75% [ E ] reduction, that's kind of the target you stated here. The sema is showing 3 months on your chart, a 2.5% fat loss. So quantitatively, is that the bogey here? And 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?

Yes. 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. So I think finding a harmonization of benchmarks that we can use sustainably across programs where we could look into ranges of fat loss and be able to take those ranges and extrapolate them in a forward-looking way. Again, 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. I think to your point on where we are, I think the recognition is at the 3-month time point, you have this range of what we've seen preclinically where it does look like in the early point that kinetics on lipolysis versus what happens when you have chemical starvation and lose muscle and fat look different. And so 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. And so I think by the time we get to 6 months, I think we think we're over that hurdle on the normalization. But it just means where we're going to be to try to put in an exact moment of time relative to the GLP-1 and 3 months is something we're going to have to learn in running the experiment. I think 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. And I think as Chris alluded to today, we're clearly within the range. And so I think that's going to be helpful as we look at the subsequent experiments, both at the 240 and the lowest therapeutic dose as well as others and continue to follow this over time. And 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 6 months, but continue to see what that range of reduction looks like, both in terms of time and dose.

Okay. But we're getting 3 months, right? So I just want to be clear because the consensus is all over the place, like investors are all putting out different numbers. I just want to be clear to get consensus in a little bit, like people should really be thinking low single digits for this 4Q update.

Absolutely. I mean I think we were very clear on the numbers that we have put out that even if you were 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 that muscle. And so when we look at that degree of fat loss, I think we were very clear about the range of numbers. And as you pointed out, low single digits is what you see with fat loss within the GLP-1 space at the early...

And just to add to that, like the other things that you're bringing up like amylin or any -- basically any incretin medicine or any obesity medicine in development right now, they all have an orthogonally different approach. They're all kind of acting on appetite or GI versus we are acting directly on adipose sites. So it's a totally different approach, but the comps are always going to be like the fat loss and primarily the visceral fat, which is what increases the risk of cardiovascular disease and events.

The next question is from Cheng Li at Oppenheimer.

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 2. And just based on the patient baseline, whether the semaglutide from STAT1 is a fair benchmark? And I have a follow-up on 008.

I'll let Chris comment on that.

So the question was about the patient baseline compared to sema?