Wave Life Sciences Ltd. ($WVE)

Hello, and welcome to the Wave Life Sciences RestorAATion-2 Clinical Data Update Conference Call. [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.

Thank you, operator. This afternoon, we issued a press release announcing a positive update from our ongoing RestorAation-2 trial of WVE-006 in alpha-1 antitrypsin deficiency. Our press release can be found in the Investor Relations section of our website, www.wavelifesciences.com. The slide presentation to accompany this call will be available on the website following the prepared remarks. Before we begin, I would like to remind you that discussions during this conference call will include forward-looking statements. These statements are subject to a number of risks and uncertainties that could cause our actual results to differ materially from those described in these forward-looking statements. The factors that could cause actual results to differ are discussed in the press release issued today and in our SEC filings, including our annual report on Form 10-K for the year ended December 31, 2025. We undertake no obligation to update or revise any forward-looking statements for any reason. Joining me today in Orlando is Dr. Paul Bolno, President and Chief Executive Officer, who will begin with opening remarks. Next, Dr. Kyle Hogarth, Professor of Medicine and Director of the Alpha-1 Clinical Research Center, University of Chicago will provide an overview of the current AATD landscape and unmet need for PIDV individuals. Dr. Chris Wright, Chief Medical Officer, will then present the RestorAATion-2 clinical data update before turning the call back over to Paul for closing remarks. Dr. Erik Ingelsson, Chief Scientific Officer, is also here with us today and will be available to answer questions. I'd now like to turn the call over to Paul.

Thanks, Kate. Good afternoon, and thank you for joining us for an update on RestorAATion-2, our clinical program for WVE-006, the first GalNAc-conjugated subcutaneously delivered RNA editing oligonucleotide for AATD. We're excited to be speaking to you from the ATS conference, where there is a significant appreciation for the limited treatment options available for the hundreds of thousands of individuals living with TIZZ-AATD. Through our engagement with the Alpha-1 community, we have heard many accounts of the challenges of living with AATD. One individual described it as a full-time, full body and full life disorder. Every set of stairs, every fragrance candle store, every emptying a vacuum bag is uncomfortable and potentially dangerous. Our discussions with KOLs and advocacy groups have also shed light on their work to improve detection of AATD liver disease, which can ultimately lead to cirrhosis in these patients. Our work at Wave is to help these individuals breathe easier and reclaim their lives. There is a clear and urgent need for new therapies, which address both the liver and lung manifestations of AATD and restore dynamic AAT production with a convenient and safe regimen, recognizing these patients have underlying liver disease. Earlier today, data from our RestorAATion-2 clinical trials were highlighted for the first time in a major medical meeting, and there is broad enthusiasm for the transformational potential of our RNA editing approach. By correcting the mutant transcript in the liver, 006 aims to address the root cause of both the lung and liver manifestations of the disease. RNA editing with 006 enables the production of endogenous native wild-type MAAC protein, which reaches the lung and protects against the protease damage that drives lung disease. Importantly, with RNA editing, we avoid creating bystander edits, meaning unintended base edits in the target SERPINA-1 transcript that creates a nonnative protein and avoid permanent off-target edits like indels, which could silence the protein altogether or has potentially other severe consequences. Publicly available data on DNA editing approaches also confirms that these off-target edits risk changes that include cancer-associated genes. Designed using our proprietary PRISM chemistry, which drives potency, specificity, stability, distribution and delivery, 006 has the potential to be the first treatment for AATD that enables patients to produce protective AAT protein when needed and address the root cause of the disease with a convenient and infrequent subcutaneously dosed therapeutic. With 006, our goal is to recapitulate an MZ-like phenotype as it's well established that heterozygous PIMZ individuals has significantly lower risk of both lung and liver disease. And the individuals have reduced levels of Z-AAT, which protects the liver from damage and are able to protect the lung with basal AAT levels above 11 micromolar, of which at least 50% is wild-type M-AAT and most importantly, are able to mount a dynamic AAT response during an acute infection. That combination Z-AAT reduction, protective basal levels with a meaningful proportion of wild-type M-AAT and a preserved acute phase response is the bar we set for 006. We are pleased to share today this is exactly the profile we consistently achieved. With only 3 months of treatment, 006 continues to deliver a compelling therapeutic profile, achieving all of our key treatment goals with both 200 milligrams biweekly and 400 milligrams monthly dosing. Z-AAT, the misfolded protein that drives liver pathology was reduced by approximately 70% with 200 milligrams biweekly dosing and 400 milligrams monthly dosing. Total levels of AAT reached 11.9 micromolar with biweekly dosing and 13.6 micromolar with monthly dosing, both above the 11 micromolar bar that has historically defined the proceptive level. Wild-type M-AAT reached 64% of total protein with biweekly dosing and 59% with monthly dosing, which recapitulates the M-AAT proportion seen in MZ heterozygous. This wild-type M-AAT is all canonical M-AAT and does not include bystander edited isoforms as seen with DNA editing. And we continue to see MZ-like dynamic AAT production with now 3 acute phase responses observed and a strong correlation supporting that AAT rose dynamically with CRP even in minor elevations throughout the study. 006 continues to be generally safe and well tolerated with no liver toxicities. Durability of editing remains impressive and supports the potential for monthly self-administered subcutaneous dosing. As Chris will elaborate on later, we are on track for regulatory feedback on an accelerated approval pathway for 006 in mid-2026. Now to speak more to the unmet need and treatment gaps remaining for individuals living with AATD, I would like to introduce Dr. Kyle Hogarth. Dr. Hogarth is a Professor of Medicine in the section of Pulmonary Critical Care Medicine at the University of Chicago. He is the Director of Bronchoscopy and is heavily involved in the field of advanced bronchoscopy and interventional pulmonology. He also runs the Alpha-1 antitrypsin deficiency Clinical Resource Center, one of the largest in the Midwest with over 250 patients and helps write the 2016 Alpha-1 antitrypsin deficiency clinical practice guidelines. Without further ado, I'll turn the call to Dr. Hogarth.

Thanks so much. I really appreciate this opportunity and bring everyone kind of up to speed on the broad understanding of what this disease is about and why a therapy like this is so interesting. As you know, alpha-1 is part of the SERPINA-1 family and the mutation in this, in particular, the Z mutation, which is our focus, can lead to both liver disease and lung disease, but both like completely different mechanisms. As the schematic that you are the drawings that you see on your slides, the healthy phenotype of M, you make plenty of alpha-1 protein. It leaves the liver with no difficulty. And the little scale picture on the side shows you make way more alpha than we need. It's actually the second most common protein the liver makes, implying its importance. And that's all to counter the amount of inflammation that goes on in the lungs from just your daily breathing. Now the ZZ phenotype leads to a misfolded protein that polymerizes and accumulates within the liver. And over time, that puts patients at risk for both fibrosis and cirrhosis. And it's unclear as to specifically which double Zs will develop this. So it represents a profound unmet need because we have at the moment, 0 therapeutics for alpha-1-related double Z genes in the liver and a lifelong fear of these patients for what level of liver disease they're going to develop. But because of that mutation and the accumulation in the liver, there's a reduction of the amount of alpha circulating and then you get flipped the scale, you get this balancing act problem of not nearly enough protection and then way too much destructive forces going on within the lung from the inflammation. And that manifests then as damage to all different parts of the lung, including the airways where you'll get more asthma COPD predominant phenotype, but then also, of course, emphysema with the direct parenchymal destruction. So when we look, of course, there's actually about 260 described mutations and counting, but the M and the S and the D are the big players, M is the normal. So hopefully, everyone's double M who's on this call. But the double Zs where our focus are the ones that are obviously of most importance. And as you will note, as you get worsening mutations present, the level of alpha-1 continues to decline. It's a broad range of levels within these proteins or within these mutations. But the double Zs are obviously consistently well below normal, but also importantly, well below the protective threshold of 11 micromolar. And that even in an acute phase response, the double Zs can never get into the normal level. This actually matters even less because the Z mutation has got a double problem of being less -- having less ability to bind to neutrophil elastase. So the Z protein by itself is a dysfunctional protein on top of being a low level and it further polymerizes in the lung is another additional risk. And when you look across survival curves, we move this little thing off to the side. I can see the curve better. speaking to the people directly. You'll notice the survivals of MMCs versus MM versus SZs versus MMs and then, of course, you doubleZs. And so looking at these slides, I think it becomes very clear that being a carrier has a beyond mild risk, and that's usually associated only with smoking. So carriers who don't smoke really have little to no increased risk for lung disease as opposed to people that start to accumulate mutations and reduce levels. And then, of course, looking at our double Zs, double Zs who have a much worse survival probability than our double Ms than normal population. This represents, obviously, from a disease perspective, the unmet need of trying to alter this natural history of this disorder. Now when you look again, there's lots of different ways to slice and dice this data looking at both MZs, SS, SCs and Zs. What I think you'll see on this -- this is obviously a slide with a lot of data -- but when you compare, obviously, everybody to MM and look at the risk for liver disease and the risk for chronic bronchitis and emphysema, and they're called out in the boxes, your MZs are barely above the odds ratio. The majority of that, again, is related to external factors such as smoking, vaping, et cetera. And then look at your double Zs where everything is shifted to the right in regards to the odds ratio for risk of fibrosis cirrhosis, risk of obstructive lung disease and emphysema. Double Zs have a profound increased risk for the problem -- both these problems developing as opposed to the MZ population, which barely has an increased risk and in some cases, actually crosses over the a no risk. And so this is all simplicity aside, this is what you remember from high school biology. Carriers are carriers. They're not interesting. It's only people that have 2 mutations that are going to be at increased risk. And of course, we've got both disorders. And by various estimates across the U.S. and Europe, there's about 200,000 people that are CZ, but less than 10%, that's roughly -- it's actually less than 10% are diagnosed and managed. So there's a profound unmet need on the diagnostic side, some of which is held back because of a perception of inadequate therapeutics related to plasma-derived therapy. That's been one of the biggest holdups when you talk to a lot of physicians about why they don't test. They don't feel like there's a management. There's no way to treat. So why bother? That leads to a problem of people developing lung disease typically at a younger age and on average, having to see 8 different physicians -- or excuse me, 3 different physicians over 8 years. And then because alphas as our COPD meds have gotten better are living a little bit longer, we are seeing an adult onset of liver disease now roughly at around 60 years, what has traditionally been a disease of children. And so there is an overlap. you look across the Alpha-1 International Registry, lung disease being the predominant phenomenon, but then obviously, liver disease, both in isolation and in the setting of lung disease being present. That is our problem. And it's a profound issue of both unmet need, like I already stated on the liver side with no therapeutics and then on the lung side, very limited treatment options. And so to put it into context because you're on this call saying, this is just a rare disease, not a rare disease. If you put it into the same rate of, say, that 100,000 double disease that are estimated to be the American numbers, again, that's an underestimate, but we'll stick to it. It's actually more common in both sickle cell and cystic fibrosis diseases that are usually something that people are quite familiar with and have seen. Now the key difference here is that both of those are extremely clinically obvious. They present in a very specific way, and then you draw the blood to determine that you are clinically correct. Alpha-1 presents is a disease that every lung doctor on earth sees every single day, which is COPD and asthma. So it's been hiding in the noise as part of the problem that it's had. There's been a lot of discussions about making sure people follow the guidelines appropriately and actually work up these lung diseases. This is not a rare disorder. It's just been rarely tested for. And going back to the core of the Z mutation, these folks actually on one level, make plenty of alpha-1. It's just all stuck in the liver. This is a biopsy of the liver of built up accumulated polymerized gumming up the system, if you will, alpha-1 protein stuck there. And the fibrosis is very common and often asymptomatic and then progresses on from F0 through F3, which is the worst form and you'll see where then you get clinically associated liver disease, both liver function abnormalities as well as a particular damage to the liver. And of course, if there's an additional insult, an inability to recover and continue to manufacture all the other things that the liver also needs to take care of. And this is, of course, by itself as a double Z regardless of any other external liver insults, whether that's various meds, whether that's alcohol, et cetera. And this obviously impacts quality of life. I don't think it should come as any surprise that having lung disease, I think it was already stated talking to patients who gave you very specific examples. But these are folks who do suffer from obstructive lung disease, asthma, emphysema, chronic bronchitis, bronchiectasis, basically the entire obstructive phenomenon. They get short of breath, they get winded doing exercise. On the liver disease side, obviously, there is this ongoing damage to the liver and actually an increased risk for hepatocellular carcinoma. There's also a rare manifestation within the skin and also an associated vasculitis. The issue is, is that we, I guess, technically do have a therapy for alpha-1, and it involves for the patient's rest of their life, every week getting a needle put into their vein and having someone else's plasma infused, and that's it. And if you have liver disease, I got nothing for you. And on the lung side, you just take inhalers and then every week forever, chain to an IV. And that's been the state ofthe-art for a very long time. And why do we do this? Because obviously, when we look at the 60 milligrams per kilogram dosing intravenously, it kept patients above the protective threshold. And this became the standard of care. This became what we treat currently. There's 4 plasma-derived products currently available in the United States based off of this. That's great. imagine from a patient's perspective, desiring something maybe a little bit better. And of course, the idea of going back to that scale where there's this deficiency of alpha-1, the imbalance where you have a whole lot more destructive forces. The idea, of course, of replacing it makes sense, built the scale back, right? So it's all about not just increasing alpha-1 levels generically, but it's increasing the amount of M protein. But you'll notice when you look at this little graph, you don't see anything reducing the Z protein, right? The Z protein is still the same levels, and it's still got its own issues of not being able to avidly bind to neutrophil elastase and it's still got its issues of polymerizing. So alpha-1, a huge component of the acute phase response. the bodily response to injury of any kind, whether that's an infection, whether that's a kidney stone, it doesn't matter. You get multiple elevations across multiple different proteins to essentially think about it as rallying the forces, if you will, if you want to make it very humanized. And obviously, lots of different things go up. But if you track the C-reactive protein is there in the red box, you'll obviously see that goes way up. That is a measure of inflammation. And you'll notice that alpha-1 also shoots up dramatically to help regulate all the inflammation going on because neutrophil elastase is one of the main responses to any amount of damage inside the lung. And as the name implies, elastin, elastase, the lung is made of elastin, you now have unregulated enzymes quite literally digesting the lung. Through multiple other inflammatory markers. And of course, this is why you have this acute phase response. Now what you'll see right here is that's in a normal person. if I'm an alpha-1 patient who was infused on a Monday and I, Friday afternoon have pneumonia, true pneumonia and have a ridiculous amount of inflammation going on in my lung, I'm depleting the alpha-1 that I got on Monday rapidly. And I have no ability to respond. I only got a meager amount of Z protein as a response. That's not good for our patients. And that's seen right here in this schematic. Again, when we give IV dosing, the levels go up, they come back down, they go up, they go back down. This is why it's weekly, and we've got lung protection. But now when I have that acute phase problem, I've already gotten rid of it, and I have this gap of time where I don't have any protection. This is also important. I mean, I used the example of the infused Monday and pneumonia on Friday, but alpha-1 is broken down in a one-to-one capacity to take down neutrophil elastase. So if there's a ton of neutrophil elastase, I said pneumonia, but even an exacerbation is going to increase neutrophil elastase. You're going to have this profound and rapid imbalance. And while the liver is trying to churn out a little bit more Z protein, which again isn't very good at binding and is also going to continue to do potentially more damage to the lung. These people are literally getting kicked while they're down. And the problem is there's a 0 indication to give extra infusions. So this has been our problem. And again, this represents state-of-the-art, the best we've had historically. So this is, of course, where other options come in. And this is where, of course, the excitement from today's data for people like me who are busy reviewing it and thinking about how we're going to be dealing with our patients, unbelievably excited. Now there's a lot happening across this whole space, as you're aware. On the lung side, there's a recombinant form of augmentation therapy, less infusions, higher levels, but conceptually the same as what we're already doing. There's a liver-only therapy, except to shut down that Z mutation are going to essentially make our patients a double null. And so yes, you'll help the liver, blood, you're going to leave the lungs completely naked. And then, of course, on the genetic-based side and potentially 2 birds stone here, our ability to modify the RNA and as the data is obviously was presented, ability to do it easily and monthly and subcutaneously. And then obviously, the potential for DNA-based editing, which has raises both some concerns and excitement all at the same time from a clinician's perspective. But I think this represents, obviously, for us in the alpha-1 world, an exciting time that people are finally interested in our disease. So thanks. Let me turn it back over to Chris.

Thanks, Dr. Hogarth. We appreciate you joining and sharing your perspectives today and truly grateful for all the work that you do for the alpha-1 community. As a reminder, WVE-006 is a subcutaneously dosed GalNAc-conjugated A toy editing oligonucleotide or AIMer, designed to correct the single G2A mutation in the SERPINA-1 transcript that causes ZZ-AATD. The corrected transcript translates into the healthy wild-type M-AAT protein, the same protein the cell would have produced if the patient did not carry the Z mutation. Two benefits follow. First, the cell makes less Z-AAT, allowing clearance of the misfolded protein aggregates that drive liver pathology. Second, the cell produces wild-type M-AAT, which is secreted into circulation and reaches the lungs where it performs its physiological role, inhibiting neutrophil elastase and related proteases that could otherwise damage lung tissue. Here, you can see serum AAT levels across the 4 major AATD genotypes. ZZ individuals, the people we hope to treat, produce only mutant Z-AAT and no M-AAT. Their serum AAT sits below the 11 micromolar threshold and they are at high risk for both lung and liver disease. Notably, levels of misfolded Z-AAT for ZZ individuals are underrepresented by turbidimetry assays, which have lower limits of quantification as high as 6 micromolar. In our RestorAATion-2 trial, we use a highly specific LC-MS assay with lower limits of quantification of 0.03 micromolar. With 006, our goal is to shift these ZZ individuals towards an MZ range with reduced Z-AAT, production of wild-type M-AAT and a dynamic acute phase response. Heterozygous MZ-AATD individuals have low risk of lung or liver disease and circulating M-AAT levels ranging from 57% to 71% of total with a mean of 64% based on an analysis of natural history study samples measured using the same validated assay as RestorAATion-2. Here, you can see the impact of RNA editing visualized. On the left is the same population we're treating in RestorAation-2, the ZZ genotype, producing exclusively Z-AAT, accumulating Z aggregates in the liver and not mounting a meaningful AAT response in the lung. On the right is the MZ-like profile we are aiming to achieve with greater than 50% M-AAT as a proportion of total, AAT levels that rise in response to acute inflammatory events and CRP elevations and with the potential for higher serum AAT over time as Z aggregates resolve and hepatocyte health improves. When a ZZ individual, as shown on the left, encounters an inflammatory stimulus, CRP levels rise. However, these individuals have a limited ability to increase circulating AAT levels when it's most needed. The result is that lung damage accumulates during exacerbations, the moments when protection is most critical. When an MZ individual, as shown on the right, encounters an inflammatory stimulus like a respiratory infection, 2 things happen in concert. CRP rises sharply and in close approximation, circulating AAT protein levels also substantially increase. That coordinated rise is one of the body's natural defense mechanisms, yielding more circulating AAT precisely when neutrophil elastase activity is highest. One of the best ways to limit exacerbations and the associated damage that drives disease progression would be to enable ZZ individuals to respond like an MZ or healthy individual, increasing circulating protective AAT protein when it's needed most. Even with augmentation therapy, individuals with ZZ-AATD experienced acute exacerbations on an average of 1 or 2 times per year. When this occurs, a rapid increase in AAT is needed to maintain a healthy protease activity balance. Healthy individuals, including MZ, mount that response within 24 to 72 hours of the stimulus. ZZ individuals on augmentation therapy may not be able to mount this response as they receive exogenous AAT on a fixed schedule. Between doses, levels decline and exacerbations further deplete tissue AAT. The result is that patients on augmentation therapy may be left at risk from the very events that drive lung damage over time. WVEs 006 mechanism allows the dynamic regulation of AAT. Endogenous AAT levels can rise during the acute phase response without the need for additional dosing, restoring the natural protective rhythm that healthy individuals exhibit. Now turning to the clinical results. RestorAATion-2 is our ongoing Phase I/II trial of WVE-006 in adults with ZZ-AATD. Our restoration program began with healthy volunteers in RestorAATion-1. This was a safety, tolerability and PK dose escalation study that proceeded through single and multiple ascending dose phases, ultimately evaluating up to 3 600-milligram doses of WVE-006 administered every other week. These data informed the starting dose of RestorAATion-2, our open-label dose escalation study of individuals with AATD who have the homozygous ZZ genotype. In RestorAATion-2, each cohort was designed to enroll 8 participants who began with a single dose of WVE-006 and then continued into a multi-dose cohort. Today's update includes data from both the single and multi-dose portions of the 200-milligram and 400-milligram cohorts, which have completed dosing as well as data from the 600-milligram single-dose cohort. Our 600-milligram multi-dose cohort is ongoing and data is anticipated in the second half of this year. Baseline characteristics in RestorAATion-2 were similar between cohorts with some minor differences in gender and liver fibrosis levels as reflected by elastography. Participants mostly had no or mild evidence of liver or lung disease as required by protocol with 1 participant having moderate liver disease. All participants were required to be between 18 and 70 have a ZZ genotype and be non-smokers for at least 1 year prior to screening. WVE-006 continues to be generally safe and well tolerated across all dose cohorts. There were no serious adverse events. All treatment-emergent adverse events were mild to moderate in severity. There were no treatment-related clinically relevant changes in laboratory parameters, including liver function tests and no clinically relevant changes in ECG or vital signs. This absence of treatment-related changes in liver function test is particularly notable as it is a key differentiator from approaches requiring LNPs for delivery. One participant in the 400-milligram cohort completed the single-dose portion and withdrew prior to the multiple dose phase. This individual experienced a moderate injection site reaction and had a history of multiple allergies. There were no other discontinuations due to TEAEs across the study. Before walking through the biomarker data, it's important to reflect on what we set out to achieve with 006. As we've discussed today, AATD is a multifaceted disease, impacting both the liver and the lung. An ideal AATD therapy should aim to address both manifestations of the disease, protecting the liver by reducing Z-AAT and protecting the lung by restoring M-AAT and its dynamic production during inflammation. Our results today support that these key program goals were achieved. Starting with the changes in M-AAT and Z-AAT at an individual level, you can see just how rapid and consistent the effects of 006 were across participants with everybody responding to treatment following just a single dose. On the top, you see substantial increases in M-AAT protein with corresponding decreases in Z-AAT on the bottom of the slide, consistent with the presence of significant RNA editing. We also observed significant increases in neutrophil elastase inhibition or FAAT across all 3 cohorts. Here, we show the substantial mean reductions in Z-AAT across doses and regimens. On the left are mean maximum reductions of serum Z-AAT from baseline across 3 single-dose cohorts. Following a single dose, we achieved dose-dependent Z-AAT reductions of 47% at 200 milligrams, 50% at 400 milligrams and 59% at 600 milligrams. With repeat dosing, these reductions deepened in the 200-milligram multi-dose cohort where participants received 7 total doses, 1 every other week. Z-AAT reductions reached 71%, up from 47% in the single-dose panel, as shown in the middle. Effects were similar with monthly dosing in the 400-milligram cohort where participants received 4 total monthly doses, Z-AAT reductions reached 68%, up from 50% following a single dose, as shown on the right. These robust reductions in Z-AAT across dosing regimens are particularly notable as our preclinical data support that Z-AAT reductions of greater than 50% improve liver outcomes, including reductions in Z-protein aggregation in the liver, which is the central driver of ATV liver pathology. Turning to mean M-AAT. We again see dose-dependent effects across our single-dose cohorts. On the left are mean maximum M-AAT percentages of total protein in the single-dose portion of our trial. Following a single dose, M-AAT as a percentage of total AAT reached 44% at 200 milligrams, 48% at 400 milligrams and 52% in 600 milligrams. In our multi-dose cohorts with just 3 months of treatment, we're delivering M-AAT as a percent of total AAT in the MZ range. With extended dosing, both our biweekly 200-milligram and monthly 400-milligram delivered similar M-AAT levels that were within the MZ natural history cohort range of 57% to 71% as outlined earlier. Importantly, these are percentages of wild-type healthy M-AAT, which is not included bystander edits. Looking at the individual responses and M-AAT percent of total on the top and the reduction of Z-AAT from baseline at the bottom, we again see consistent and durable responses. For the 200-milligram cohort, both single dose and biweekly on the left and for the 400-milligram cohort, both single dose and monthly on the right, we see editing sustained out to at least 3 months post dose. M-AAT as a percentage of total remains elevated and Z-AAT reductions persist well into the follow-up phase. This durability supports monthly dosing with data from our 600-milligram multi-dose cohort expected to further inform the dosing regimen. A long-standing goal in the community has been to ensure individuals living with AATD are protected with sufficient circulating AAT during exacerbations. In September, we showed data demonstrating that we've already achieved these goals with 006 as we were able to restore a ZZ participant's ability to respond to an acute inflammatory event with total AAT levels of greater than 20 micromolar, just 2 weeks after a single dose. Encouragingly, the magnitude and the 4-week duration of this response are also proportional to the levels anticipated for an MZ individual based on natural history. Today, we're excited to share a growing body of evidence supporting 006's ability to systemically restore dynamic production of AAT. In addition to the acute phase response we shared in September, we've observed 2 additional acute phase responses, which were driven by mild upper respiratory tract infections. These events once again resulted in dynamic elevations of AAT with proportional increases of 58% and 60% from pre-event. Furthermore, across our entire study, we see that CRP increases are strongly and statistically significantly correlated with AAT increases even in events of smaller magnitudes. What's particularly important here is what these events represent. Not every inflammatory event escalates to clinical attention, but these events are happening in the background, consuming AAT protein and driving cumulative tissue damage over time. That is why a dynamic endogenous AAT response matters. It protects patients not only during major acute phase responses, but also during the minor inflammatory events that accumulate. Collectively, our data support 006 as a differentiated potential new medicine for individuals living with AATD. We've observed robust RNA editing with Z-AAT reductions of up to 71% and restoration of M-AAT to an MZ-like range, potentially supporting both liver and lung health benefits with durability favoring a convenient monthly dosing regimen. We have a growing body of evidence supporting that 006 enables the natural inflammatory response with 3 acute phase responses observed and a strong correlation of CRP increases in circulating AAT increases. Importantly, 006 continues to be safe and well tolerated across all doses with no clinically meaningful liver toxicities observed to date. With the urgent need for better treatment options for patients and the compelling profile we've observed to date with 006, we're excited to advance our discussions with regulators and expect feedback on an accelerated approval pathway for 006 in mid-2026. We also plan to share data from the 600-milligram monthly cohort in the second half of this year. This will further help inform the optimal dosing regimen. In tandem with our clinical and regulatory progress, we're actively collaborating with global advocacy partners to increase awareness of AATD, shorten the diagnostic journey and incorporate community feedback in study protocols, consent forms and educational materials. With that, I'll turn it back to Paul for closing remarks. Paul?

Thanks, Chris. With our update today, we are generating a growing body of data, which support 006 as a fundamentally differentiated treatment option for individuals living with PiZZ AATD. With the ability to reduce the midfolded Z-AAT driving liver disease, restore wild-type M-AAT to protect the lungs and enable dynamic AAT response with a favorable safety and convenience, 006 has the potential to offer a differentiated proposition for people living with alpha-1, the physicians who treat them and for the payers to reimburse their care. AATD remains an area of high unmet need. Currently, only 10% of the 200,000 PiZZ individuals are diagnosed. Standard of care is weekly IV augmentation therapy, which only addresses lung disease and is not reimbursed in many markets outside the United States. And there are no therapies for liver disease. Despite the limitations of augmentation therapy and low diagnosis rates, the global AATD market today is approximately $1.7 billion. This market is expanding and projected to grow to $5 billion globally by 2031, driven by increasing rates of diagnosis, broader treatment uptake, including earlier intervention and better ex U.S. access as more effective therapies become available. WVE-006 is positioned to be a meaningful driver of [indiscernible] addressing both lung and liver disease with a safe and more convenient administration profile that extends the addressable population. Against the landscape of approved and investigational therapies for AATD, WVE-006 has the potential to be best-in-class. Approved augmentation protects the lung but requires weekly intravenous infusion does not address liver disease and cannot deliver a dynamic AAT response. Recombinant augmentation and development extends dosing intervals, but operates on the same protein replacement principle. Investigational therapies in development also come with several limitations. DNA base editing approaches target both lung and liver, but they introduce permanent DNA modifications, carry bystander editing risk and rely on LNP delivery, which is associated with liver enzyme elevation. The risk of irreversible off-target effects is particularly notable as DNA editing has been connected to editing in cancer-associated genes. Also in development are AAT siRNA approaches, which reduce Z-AAT. However, they do not restore M-AAT, potentially exacerbating lung disease through chronic AAT knockdown. 006 has the potential to offer individuals living with PiZZ AATD, a compelling treatment option, which addresses both lung and liver, restores dynamic AAT production, safe and well tolerated and is delivered subcutaneously with infrequent monthly dosing. For over a decade, we've been relentlessly committed to unlocking the broad potential of RNA medicines to transform human health. Today's results accelerate the already strong momentum of our potentially best-in-class pipeline and strength and differentiation of our platform driven by our lead RNA editing and RNAi programs. Building on our success in RNA editing, we're advancing our next candidate, WVE-008 to the clinic this year, which has the potential to address the 9 million individuals living with PNPLA3 liver disease. In RNAi, we are rapidly advancing multiple studies of WVE-007 across treatment settings, which are strategically designed to unlock its full potential in obesity and other cardiometabolic diseases. This quarter, we expect to initiate our high BMI Phase IIa trial, followed shortly thereafter by trials investigating 007 in combination data. Beyond our lead RNAi and RNA editing programs, we are continuing to push the boundaries of innovation through our bifunctional modality that allows us to both silence and/or upregulate or edit to treat diseases with a single construct in a single dose. We're also advancing a growing pipeline of new hepatic and extrahepatic candidates. With the substantial progress we've made, we believe we are well positioned and well capitalized to advance our pipeline of transformational therapies for patients. Before turning the call over to questions, I'd like to take a moment and thank all the individuals participating in our restoration clinical program, the clinicians involved in the study site staff. The Alpha-1 community inspires the work we do every day. And from everyone at Wave, we'd like to express our sincerest gratitude. With that, I'll turn it over to the operator for Q&A. Operator?

[Operator Instructions] Our first question will come from Samantha Semenkow with Citi.

Congratulations on all the progress. My question is for Dr. Hogarth. I wanted to expand a little bit on perhaps the last slide you shared in your presentation, Dr. Hogarth. I'm wondering how you're thinking about the emerging efficacy and safety profile that we're seeing here today for WVE-006 and comparing that to the emerging data from DNA editing therapies and the recombinant AAT replacement therapies. Just wondering how you're thinking about potentially utilizing these for your patients.

Sam, it's a wonderful question. However, I must say Dr. Hogarth is in the middle of 2 other -- he's actually going to an alpha-1 back and just stepped out. We're trying to see if we can bring him back in for questions. But if not, we're happy to find him. I think he's already gone to the alpha-1 foundation recept but I apologize. But we'll get -- we'll connect him with you.

Your next question will come from Steve Seedhouse with Cantor.

Yes, I'll ask you a question then Paul in that case. So it looks to me like the biweekly dosing does, in fact, make a difference compared to monthly dosing. And my question is, do you agree? Is that what you see in the data? And do you think it's, therefore, worth exploring 600 mg biweekly to maximize efficacy and sort of close the efficacy gap with DNA editing? Or is there sort of a safety tolerability concern with doing that going forward?

Thank you for the question, Steven. So on one hand, the short answer to the last question is no. So if you think about the safety study we ran up through 600, there's no questions. So going up to 600 biweekly, which is what we studied in the Phase I portion of healthy volunteer study. So there's not a question of safety. What's interesting, and again, the 600-milligram monthly cohort will teach us a lot in terms of exposure is, to your point, there's -- on the dosing, we actually had a nice dose response as we gave doses to that kind of initial period of continuing to build and grow and see that shift from Z to M. We also saw, and I think what you're looking at is a window early where biweekly looked that it was smoothing that line out and then continued. But when you stop and you look at the biweekly, it stays pretty relatively flat for well over a month and beyond after that period. So I think we're going to learn a lot about what happens on the monthly basis, particularly with what levels of exposure and how to balance those. And I think the 600-milligram monthly data will teach us a lot. I think to the question of what does one need, I think we have to step back and realize 2 weeks after a single dose, we could get 20 micromolar protein. And even in -- as Chris pointed out, the cases now of what we call mild upper respiratory that's a common cold. And what we saw though is we could get up to 16 micromolar. So what we've seen even at these doses is the ability to mount an impressive response to meet the needs of the patient. So I think the question is ultimately going to be what's that optimized dosing regimen. And I think we're in a good position to explore that.

Your next question will come from Samantha Semenkow with Citi.

Apologies for the -- so based on the data, it seems like the 600-milligram single dose is tracking a little bit below what we saw for the 400-milligram single dose. So I'm wondering if you think that's going to be a plateauing effect in that 400 milligram is maybe the go-forward dose? Or do you think in the multi-dose when we see it, there's a possibility we could continue to see a dose-dependent effect ongoing?

Yes. I think the -- actually, it was really nice that we did see a dose-dependent effect. 600 was more in the reduction of Z and more M. So 600 was higher. So we did see a dose response at 600. I think the question ultimately comes down to once you reach a steady state inside the cell, how much more benefit is extracted from that. And I think that, again, as we look at the 600 monthly, where we'll be able to look at the 400 monthly and look at that exposure relationship. Again, I think it will help us on that dosing regimen. I think as Steve pointed out earlier, 200 is interesting once it reaches a steady state, and it may very well be an interesting dose and frequency. But the last, I think, 600 monthly will be just one last piece in the puzzle in terms of modeling that dosing regimen. But we definitely infrequently is nice. And as we've been wonderful to be here at a conference and spend time with clinicians and as we've tested this thesis, this idea of really shifting these dosing intervals out has been well received.

Your next question will come from Yun Zhong with Wedbush.

And my question is also related to dosing. So while in the study, you only followed patients for 12 weeks. From the PD profile, do you think -- well, in reality, people will probably receive chronic treatment. Do you think more doses will eventually lead to higher editing efficiency and higher AAT -- total AAT protein being produced?

No, thank you. And it's a wonderful question because it's exactly what we saw both in preclinical models. It's well understood. To your point, this is only 3 months of dosing. And so as hepatocytes become healthier, they become more functional. We're actually rescuing hepatocytes and they'll continue to turn over and generate more protein. And with more protein and more editing comes the continued -- that sustained effect. I think that's coupled and importantly driven by, as both Chris and Dr. Hogarth mentioned, a profound reduction in Z protein. So with the reduction in Z protein very quickly and removing those aggregates, those cells are now -- that toxic insult to hepatocytes is now removed, so these cells can become healthier and those cells turn over. I think that's a valuable component in RNA editing where we think about durability with the ability to continue to get access to these cells as they're turning over so that you can begin to capture them and again, be able to recruit more cells that can get healthier and generate that over time.

Your next question will come from Salim Syed with Mizuho.

Great. Congrats on the data. Paul or Chris, maybe just one for us on the 2 additional patients in the 400-milligram multi-dose cohort that saw an increase in AAT. Could you quantify the 57.8% and 59.8% increase? Could you quantify that in terms of total protein so that I believe you guys said 20.6 for the 200 milligram. Could you give us a similar number for the 2 patients? What was the M-AAT in those patients as well?

Yes. So that was the update that I gave, which is we see about a 16 micromolar increase. So those are the examples that we continue to see that increase in that relative proportion, as we said, of M and Z, is the same.

Your next question will come from Joe Schwartz with Leerink Partners.

Great. I guess I wanted to ask about the 3 dynamic response events. They look very compelling, but still anecdotal. So I was wondering how important is it to make this a labeled feature in your view? And if so, how might you do this? And then the CRP-AAT correlation is pretty strong with an R of 0.73, but I think this means that around half the variance is unexplained. Do you have any thoughts on what's driving the rest of this data?

Yes. break these into 2 parts. They're very much related in terms of the question of like anecdotal and continuing to look at what's happening. So I mean, to your point, I think we were the first to show it last year. I think there were a lot of questions of is it anecdotal. It was robust. It was exactly as we'd expect. I think what was encouraging in the interim is we saw that happen in DNA editing. So an editing approach as we think about protein replacement therapy and editing is driving this adaptive response. That's what's supposed to be happening. And I think it's encouraging is we engage regulators as well on a path of, are you recapitulating an MZ-like phenotype with that responsiveness. That's a critical component across that because that is the response. Seeing 2 more, again, in the case of these were much more mild. These were cases of cold, and we see the 16 micromolar total. It had the same features to it. So again, the body of evidence is growing from an anecdotal response to it's behaving like it should. I think to your point on the correlations, that was something we were looking for levels where patients weren't kind of at the level because when patients have a kidney stone, they're coming to their physician for an evaluation of that problem. Being able to look across the study for patients who aren't coming in and having those fluctuations, it's doing exactly essentially what Dr. Hogarth drew for everybody and where we should see that in those responses at a low level, when we see those correlations, it gives us the conviction and confidence that, again, the body is being restored to what it can do in a normal situation. I mean there's always a degree of some variability to your point on that, which could be just around functional sampling. But I think when we step back and say, is it really achieving the key objective for these patients to mount the responses that they need to, to prevent lung injury. I think the answer is yes. And I think it gives us a lot of conviction going into the upcoming regulatory discussions around...

Your next question will come from Alec Stranahan with Bank of America.

Just a quick one for me. I guess as you're looking to gain regulatory alignment for the pivotal for 006, is your baseline expectation going in a biomarker-driven primary? And I guess, do you think functional AAT or total AAT would be more important here? And then maybe when you're thinking about future studies, given the good tolerability profile today, do you think there's room to go beyond the 600 mg dose, maybe to say, an 800 mg monthly or even bimonthly cohort?

Yes. So yes, I mean, the first question is a biomarker-driven approach principally driven as we think about that transition from M to Z, which is the hallmark of what an MZ phenotype is supposed to be with other biomarkers that will continue to look alongside. And to the last question that came up, the ability to see that relationship between CRP, AATD -- sorry, total AAT and AAT levels as it relates to those acute phase responses. So again, putting together the picture and the totality of the biomarker data that really recapitulates the MZ phenotype. I think the question you're asking in terms of doses, there's a certain level of exposure that, again, we can get to 20 micromolar, which is like where we talk about with the IV protein replacement therapy trying to have somewhat of a native to protect. And as Dr. Hogarth said, deplete the protein when they have the event at 200 milligrams, 2 weeks post a single dose, we could get to 20 micromolar protein. So I think we have to step out from the more phenomena that really is exemplifies what IV replacement therapy is supposed to do, right, pouring water into bucket with holes in the bottom and the hope that as you're depleting it, you're going to constantly fill it back up, versus editing where when you have that acute phase response, you mount the response that you need into the event for the period of time. And again, I think it's encouraging that when that's happened in places that we could mark in the study, we've actually seen the body rise to meet those occasions. So I think that dynamic event is well within the dose cohorts that are already being studied. What we're really going to optimize is a couple of the other questions came up is what the dosing interval could be that we could push that out more conveniently to patients. And if we think about a convenient subcu potentially self-administered therapy for these patients, that's monumental in terms of transforming how we care for them. And if we can do that safely without causing liver injury in patients who are susceptible to liver injury and exposing them to other risks, I think we're putting together, I think, a very important proposition for patients and their caregivers.

Your next question will come from Catherine Novack with Jones.

Just wondering, is it possible for us to back into the mean max M-AAT using the percentages given? Or are the mean max total and the percentage of proportion of M to Z taken at, I guess, multiple different time points. How should we be thinking about that?

It's dynamic. I don't know if you could.

Yes. So because each individual has a sort of different time course, that's why the mean max makes sense in terms of trying to understand kind of the effects of the drug. So you can't really do the bowel calculation, as you mentioned, just because it's not at a specific time point. It's the max value for any individual subject over the course of the treatment duration.

But it's reasonable to think in totality about the percent M over time.

Your next question comes from Madison El-Saadi with BRS.

Congrats on the data. Just wondering, what do you think is new here that is most likely to incrementally influence the FDA on their conclusion on the accelerated regulatory requirements? And then somewhat related to that, is it -- do you think that the required frequency of administration of the drug could actually decrease over time, as you pointed out, as new hepatocytes are generated?

Yes. I think on the last question is, yes, with the caveat that we have to study that. But the data suggests like as we look at where -- that was what was interesting about the 200 biweekly where we stopped and you could see the durability continuing. It does suggest that there's some level of -- as drug gets on board and over time, you've got that exposure. And then to your point, as we get more cells that are healthier, but then are getting dosed that, that could continue to extend that range. And we'll continue to look at that dynamic range. In terms of the agency and biomarkers, again, I think it's the range of biomarkers that support the MZ phenotype. So again, it will be that transition from showing we can move Z to M at the same levels that MZ patients have. And it will be this dynamic response. I think the dynamic response is so important in this because ultimately, that is the disease, right? It's a chronic disease of acute exacerbations. And so being able to mount those needs when patients have them at the appropriate levels that the patients need are great ways for us again to show that the biomarkers are doing kind of -- are possibly doing what they're supposed to do. And so I think relative to the approval pathway, I think we have the component there, and we're excited to engage.

Your next question will come from Cheng Li with OpCo.

Congrats on the results. So probably just going back to the dosing discussion. I'm just wondering if there's a scenario you can probably do like induction periods where you have slightly more frequent dosing followed by maintenance period where you can have like more extended dosing beyond monthly injection. Is that something like you can potentially consider for the pivotal study? And if I can just squeeze in one commercial question. I'm wondering how you're thinking about like patients already on like augmentation therapy and if you can encourage patients to switch to 006 once approved? And what is required for such like switching for patients?

Yes. No, thank you for the questions. And to the first question, I think the answer is yes. And I think the data suggests that. And as we think about that's something that's been done with other therapies, particularly in the siRNA space for a while to get to exposures. I think stepping back, I think this is where the 600 exposure question is going to get us a lot of learning in terms of those dynamics. But you're absolutely right that, that opportunity, as we look at the modeling following the 600 monthly will give us opportunities to think about how infrequent. We maybe had to push it out actually substantially longer with a certain level of exposure. So that's going to help inform those dosing regimens. In terms of commercial, we spend a lot of time with that because I think as we think forward, and it was a good portion of a number of our meetings today with the community, physicians and others associated with alpha-1. I think there's a lot of enthusiasm for thinking about kind of transforming this care from a hospital IV setting, to your point on augmentation to really transferring this back to patients where it could be self-administered and that they could have a subcu versus IV and now really thinking about how do you deploy that to patients with augmentation and Dr. Hogarth being a great example, but several other physicians who we've been working with do see this as a shift where augmentation protects you at that threshold, but we've got this ability to continue to provide that level of protection that's seen with augmentation in a way that's adapted. And I think what's so critical, and we hear this a lot, we heard it a lot over the course of this meeting, is really the fact that these patients are all underlying liver patients. I mean it's interesting we're talking to the foundation today, and they brought up a really great point that as patients -- as hospitals started to do liver scans both patients who are coming in for pulmonary issues, the underdiagnosis rate of liver disease was astounding, the patients that were just being picked up on fibro scanning. And so I think as we think about this as both a liver and a lung disease, it comes down and physicians are realizing that just because you infuse the protein, you're not protecting liver. In fact, you're keeping those patients exposing and making toxic Z protein. So the ability really to see physicians gravitate towards the shift in protecting both lung and liver is important. I will say to the prior question, there was a question on biomarkers. And I do think it's important as we do engage with the agency that the specificity of knowing that what we're calculating is truly wild-type M-AAT protein. We know with others, particularly in the DNA space that the vast majority of protein being made is actually a variant of the native protein. So we think about being able to have those conversations about a wild-type protein and levels of editing that are exquisitely specific, I think that's going to factor in a lot to the discussion as well.

Your next question will come from Ben Burnett with Wells Fargo.

I wanted to ask about the discontinuation case that occurred. I think you mentioned that there was an injection site reaction that led to that discontinuation. Was that the only adverse event that the patient received? And any other color you can provide about that?

That's correct. So the person had the irritation at the injection site. And because they had a lot of allergies, the sense was that it was best for them not to proceed with the multiple injections. But -- so that was sort of the long and short of it. There wasn't really much more going on there.

Your next question will come from Whitney Ijem with Canaccord Genuity.

Sorry if I'm being dense here, but I just want to follow up and make sure I'm thinking about this correctly. I guess as we think about longer-term dosing, I understand that there is a potential for kind of higher total levers over time as the cells turn over. Is there also a potential for higher percent M over time? Or should we be thinking about that as kind of a fixed percentage, but with higher AAT levels? And then second part of that is just, are you continuing to dose the monthly doses for 7 doses to match the 7 doses and the biweekly? And should we expect longer-term updates from those cohorts?

So the next update will be the 600-milligram monthly cohort, and that will be our update. To your point on longer follow-up, it doesn't just clear total -- if you think about it, to your point, it will -- you should continue to see more M. So as you free up cells that can release more M protein and free out dose, you can continue to drive that. I think what's encouraging, and I know the question is so hard because we're in this mindset of augmentation therapy of like can you give out more? Again, patients met 20 when they needed 20 micromolar total protein. And so I think we have to remember that so long as there's exposure inside the cell and to this point, if we push that frequency out as long, patients will be able to make protein that they need when they need it. And that's really, I think, probably the most important feature of editing in totality. And when we look at the levels that we're seeing, we're seeing levels that are in the MZ range. So the ability to correct these patients both at their baseline, but also to see them meet those dynamic responses, again, as we go to regulators. So really a combination of the profile that we're excited to take forward.

Your next question comes from Cassie Yuan with RBC CM.

Congrats on the progress. And Paul, you have already nicely pointed out and other analysts have alluded to that going from flat to MAD at each level or going up on single dose escalation, circulating in serum constantly improve, but it's also notable that total AAT does not always increase. So how should we rationalize the biology there? Or is it mostly correlated with individual baseline level of so more of arithmetic experimentation than biological? And related to that, with Sanofi inhibit data update also at the conference is showing every 3-week IV can now get us to steady-state trough functional AAT above 24 micromolar. Does that raise the bar for any player in the editing space?

No, thank you. And I think the last question is, no, I think the challenge on this kind of where -- what is raising the bar is remember, that's the threshold with which patients now get exposed to Dr. Hogarth's important point seeing these patients is that's kind of the threshold where they had an event that they'd be depleting the protein. So again, being able to flip the narrative that actually with editing, and it's really a critical component to editing, you actually increase the exposure into those events. Again, we could raise the 20 micromolar into the event, which is actually what the patient needed, right? And that could stay out over a month to provide that protective ability and then come back to baseline. And so the dynamic effect is really the underlying component of editing. I think as we think about the ability to do that infrequently, it also have the liver, right? So by pushing out the intervals so now it's, call it, monthly as a number of people have raised the potential for thinking about regimens that could be longer. You have to remember that, that protein replacement doesn't raise the bar, as we said, not just because it's broken down, but because it's still not protecting the liver. These patients are still exposed and still during those acute events are actually producing Z protein into that event, which is causing further injury to the liver. So the ability really to shift to cascade, to shift, and that's really the driver of editing, to shift Z protein to M protein. That dynamic is the dynamic that you see in MZ is a shift from Z protein to M protein. That's the critical feature. That's what we do. And I think that's why it provides a really competitive differentiation from the protein replacement therapies.

Your next question will come from Michael King with Rex Biomed LLC.

It's Mike from Rodman. I don't know how we got signed in as Rex Biomed, apologies. Pretty much all of my questions -- sorry about that, Paul. I'm not trying to throw a curveball here. Most of my questions about the dosing and pharmacodynamics have been answered. I'm just curious from the animal modeling that you've done, do we know how long it would take to begin to either stabilize or even reverse liver or lung damage. Could you move patients from F3 to F2, could you reverse the lung damage, et cetera, over time?

Yes. I think -- I mean it's been interesting here to spend time with folks who've been looking at various ways of measuring lung injury. It's not easy to do in the animal model, but the levels of exposure and the levels of correction we get to, to the point on creating the MZ phenotype lead on lung. I think what is important to this pharmacodynamic modeling is we are able to look, as Chris alluded to on the call, at what level of Z protein reduction actually starts reversing aggregate damage where you see that reduction in liver aggregates and liver globules. And in a 50% reduction in Z protein, we started to see that those dynamics shift in our preclinical models. So again, encouraging that we're seeing in excess of 70% reduction in Z. And so that ability both in the production of M, but really importantly for these patients because they're at risk of liver disease, being able to substantially reduce that Z protein should continue to shift that. And the advantage in that is, again, you now start making healthier hepatocytes, you start getting that turnover kinetics now with new hepatocytes that are corrected and aren't kind of saddled with decades of Z protein aggregation, you now get healthier cells that can make more protein. So it's highly encouraging as we continue to think about this profile over a longer period of time. I think the other thing that was encouraging, too, in the liver baseline characteristics is that physicians were more comfortable putting patients on who were at more advanced stages of liver disease as the study progressed. And I think the notion that people were feeling comfortable versus, again, I think LNP background, patients with liver disease who occupy a substantial component of alpha-1 antitrypsin felt comfortable putting liver patients into the study. And I think it's important as we think about long-term treatment of both liver and lung patients.

Your next question will come from Cha Cha Yang with Jefferies.

This is Cha Cha on for Roger Song. Congrats on your update. I was hoping that you can share more about what we can expect from your FDA feedback update in mid-2026, assuming this is alignment on using AAT as a biomarker, but anything else we should expect there?

I think that's right. We're looking to have some agreement around using the biomarker to move forward. And again, it's not just total, but it's also how much M you have and how much Z you can decrease because you want to impact both liver and lung. And so we're excited to have those discussions with the agency.

Yes. I mean, I guess the key for us is much like others coming out with a very strong plan for what the path looks for the filing so that we could actually start guiding to the subsequent studies, right? I mean the goal for us is to think about this as a commercial program. So the goal is what's that path look like to commercialization, both on an accelerated approval pathway, but importantly, how we think about continuing to make sure that we address both lung and liver on the path forward. So I think this will be the beginning, and we're excited to provide that feedback.

Your next question comes from Alex Nackenoff with Truist Securities.

This is Alex on for Danielle. Congrats on the update. Just a detailed question from us. Can you explain the discrepancy in the reporting of the 400-milligram SAD data? I believe in the last cut, you reported the mean value was 12.8 micromolar. And today, you're indicating it's 14. Does that include additional patients, which drove the mean higher or removing the 400-milligram discontinuation? Just curious if these numbers were calculated differently and how to rectify those.

You've hit it because we've included a fuller data set with more patients for this particular analysis, everything up until the date of the data cut versus before.

So we didn't remove -- last part, we didn't take any -- just to be clear, we didn't take...

Yes, we didn't take any patients out. The one discontinuation completed their entire single ascending dose portion and then stop before the multiple ascending dose. So there was no patients that were removed. Go ahead.

Your next question will come from Michael King with Rex Biomed (sic) [ Rodman & Renshaw Research ].

Just a follow up on the previous question about the FDA interaction. Can you -- and it goes back to my question about the clinical benefit. The accelerated approval could come on the -- potentially on the biomarkers, but is there a clinical endpoint or endpoints that you think you might have to achieve over time to flip that to a full approval? Or do you think the biomarkers could allow for a full approval under the regs?

Yes. I think what's interesting, I mean, obviously, the focus right now is the accelerated approval based on biomarkers. I think the work that's happening around other tools in terms of CT densitometry, being able to do noninvasive imaging of liver, both give us opportunities. And you'd imagine that the discussions continue around those. And what's wonderful is those aren't just Wave having those discussions. So the clinical community, the alpha-1 community is engaged too through CPAP and other channels about really thinking about alternative endpoints that do and demonstrate benefits to long term.

Thank you. There are no further questions at this time. I will now turn the call back over to Paul Bolno for closing remarks.

Thank you, everyone, for joining the call. I'm grateful to every employee for their dedication and focus on our mission and on the patients and families we serve. And thank you again to the ATD community for your continued support and partnership. Have a great night.