Beam Therapeutics Inc. ($BEAM)

Good morning, and welcome to Beam Therapeutics Conference Call. [Operator Instructions] Please be advised that this call is being recorded at Beam's request. I would now like to turn the call over to Holly Manning, Vice President of Investor Relations and External Communications.

Thank you, operator. Good morning, everyone, and welcome to Beam's conference call to review top line clinical data from the Phase I/II trial of BEAM-302 in patients with alpha-1 antitrypsin deficiency. You can access slides for today's call by going to the Investors section of our website, beamtx.com. With me on the call today with prepared remarks are John Evans, our Chief Executive Officer; Dr. Amy Simon, our Chief Medical Officer; Dr. Jeff Teckman from St. Louis University; and Dr. Giuseppe Pino Ciaramella, our President. Before we get started, I would like to remind everyone that some of the statements we make on this call will include forward-looking statements for purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual events or results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in the Risk Factors section of our most recent annual report on Form 10-K and any other filings that we may make with the SEC. In addition, any forward-looking statements represent our views only as of today and should not be relied upon as representing our views as of any subsequent date. Except as required by law, Beam specifically disclaims any obligation to update or revise any forward-looking statements even if our views change. With that, I will turn the call over to John.

Thanks, Holly, and good morning, everyone. At Beam, our vision is to provide lifelong cures for patients suffering from serious diseases. We believe base editing uniquely positions us to fulfill that vision through onetime durable genetic medicines that correct disease at its root cause while delivering predictable and reproducible outcomes. One year ago, we established clinical proof of concept for our onetime in vivo base editing therapy BEAM-302 in alpha-1 antitrypsin deficiency or AATD, and accomplished an incredible milestone for the field of genetic medicine, delivering to our knowledge, the first ever genetic correction of a disease-causing mutation in DNA. Today, we're excited to share a compelling and robust data set from 29 AATD patients treated with BEAM-302 in the ongoing Phase I/II study. These updated data further strengthen our belief in the best-in-class and first-in-class potential of this onetime therapy and pave the way for the advancement of BEAM-302 into pivotal development. Beam was founded on a simple but powerful idea that making precise, single base changes in DNA could fundamentally change how we treat many serious genetic diseases. Base editing allows us to correct mutations without creating double-strand DNA breaks. Our goal is to translate that capability into onetime genetic medicines that durably and predictably restore normal gene function. We believe that predictability is not just a scientific advantage. It's a strategic one. Predictable outcomes can streamline R&D, reduce development risk, support regulatory efficiency and ultimately build confidence among physicians, patients and payers. Over time, we believe that impact can ripple across the entire health care ecosystem. That same predictability also allows us to build a scalable platform for developing multiple genetic medicines. Many of the core components of these therapies can be reused across programs, so that once we demonstrate success in one setting, we can apply those capabilities to additional diseases with greater efficiency. In that way, we're not simply advancing a single therapy. We're building a repeatable engine for developing multiple genetic medicines over time. Our liver-targeted in vivo portfolio is a clear example of this platform in action. Now with 3 core programs that are in or nearing clinical development, BEAM-302 in AATD, the focus of today's discussion, as well as BEAM-301 for glycogen storage disease Ia and BEAM-304 for phenylketonuria, all leverage our LNP delivery capabilities, enabling us to apply the same core technologies across multiple programs and moving them forward efficiently through emerging regulatory pathways. Today's data further underscores the strength of our industry-leading in vivo liver-targeted precision gene editing technology and our ability to efficiently and rapidly execute to advance to pivotal development for BEAM-302. Before turning the call over to Amy to walk through the results in detail, I'd like to briefly highlight a few key takeaways from the data set we are reporting this morning. First, treatment with BEAM-302 continues to demonstrate robust and durable efficacy with more patients at higher doses and longer follow-up. In the single-dose 60-milligram cohort where patients have follow-up out to 12 months, we observed meaningful increases in both total and functional AAT, achieving steady-state mean levels of 16 micromolar and once again, with all patients above the 11 micromolar protective threshold that is associated with lung health. In addition, treatment resulted in substantial reductions of approximately 84% in mutant Z-AAT, the toxic protein responsible for the liver manifestations of the disease and that in circulation can also contribute to lung disease. Most importantly, these patients now produce corrected M-AAT for the first time as seen in a clear shift in circulating AAT protein composition to approximately 94% corrected M-AAT, consistent with correction of the underlying genetic mutation. All of these findings are consistent with AAT profiles seen in MZ genotype carriers, people who do not have severe AATD nor progressive disease and are not at elevated risk for lung or liver disease without secondary factors like smoking or obesity. Second, we now have strong evidence that AAT production is inducible following BEAM-302 treatment during periods of inflammation when it is most needed as expected from BEAM-302's mechanism of action. In one patient, AAT levels increased to approximately 30 micromolar during a respiratory infection and critically retained the corrected AAT composition of approximately 95% M-AAT, suggesting the edited gene does indeed function under normal physiologic regulation following treatment with BEAM-302. This is the strongest induction result yet observed after a genetic treatment in AATD showing that treatment with BEAM-302, not only elevates basal AAT levels to a new floor similar to carrier levels, it further provides a dynamic capacity in the body to generate even more AAT whenever it is most needed. Restoring the AAT acute phase response in these treated patients offers a fundamentally different treatment profile from that seen with augmentation therapies and shows the power of precision-based editing to correct all aspects of this disease. Third, BEAM-302 continues to demonstrate a well-tolerated safety profile across the single dose cohorts with Grade 1 transaminase elevations being the most common adverse event. Based on the strength of both the safety and efficacy data, we have selected 60 milligrams as the optimal biological dose for our pivotal cohort, which we plan to initiate in the second half of this year. Taken together, we believe these findings reinforce the potential for BEAM-302 as a best-in-class and first-in-class onetime treatment for AATD. With that, I'll turn the call over to Amy to go through these BEAM-302 findings in more detail.

Thanks, John. Alpha-1 antitrypsin deficiency, or AATD, is a serious genetic disorder caused by mutations in the SERPINA1 gene, which affects the production of alpha-1 antitrypsin, or AAT, a protein made in the liver that is secreted into the bloodstream to protect the lung from inflammation and damage. The most common severe form of AATD results for mutations in the Z allele, known as PiZ, which is caused by a single G to A point mutation in the SERPINA1 gene. This results in the extraction of a pathogenic variance of AAT known as Z-AAT that misfolds and aggregates in the liver leading to liver damage and disease such as cirrhosis, and you'll hear more about this from Dr. Teckman shortly. The Z-AAT made in the liver is poorly secreted into the circulation and less effective in inhibiting neutrophil elastase, leading to total circulating levels of AAT that are 10% to 15% of normal in homozygous PiZZ individuals. As a consequence, the lung is left unprotected from neutrophil elastases and other damaging proteases that can cause progressive lung destruction, resulting in early onset emphysema. So in this disease, it is caused by too much abnormal AAT that gets stuck in the liver and too little AAT that gets out in the circulation. The current standard of care for AATD for patients with lung disease primarily consists of treatment for emphysema, such things as bronchodilators, inhaled steroids, oxygen therapy and with severe cases requiring lung transplantation. The only approved treatment today, plasma-derived AAT or augmentation therapy requires weekly intravenous infusions to achieve static levels of AAT, lacking the natural upregulation of AAT, so important during infection and inflammatory processes such as respiratory infections. While augmentation has been shown to slow lung disease progression, it does not stop it, nor does it prevent ongoing liver damage and has no impact on the Z-AAT aggregates in the liver or circulation. Treatment for liver disease is limited to supportive care as there are currently no approved therapies. In severe cases, liver transplantation remains the only option. The PiZZ genotype accounts for over 95% of severe AATD cases. And despite affecting more than 100,000 individuals in the U.S., only about 10% of people living with this disease have been diagnosed. As shown in Slide 12, clinical genetics provides critical information on a wide range of AAT levels and highlights why reaching the protective threshold of greater than 11 micromolar for AAT in circulation is critical for decreasing disease risk related to AATD. Patients with the severe PiZZ genotype have 2 copies of the disease-causing mutation, leading to a high risk of developing both emphysema and liver disease. These patients have very low levels of AAT between 3 to 7 micromolars shown in orange. All of their AAT is in the mutant Z-AAT form, which is much less effective and can form polymers in circulation, leading to lung inflammation and injury. In the middle are individuals with just 1 mutant PiZ copy referred to as MZ or SZ individuals. And in this case, the majority of these individuals had AAT levels above 11 micromolar. On the right-hand side of the slide, you can see how these genotypes correspond to lifetime risk for emphysema and liver disease. People with the PiZZ genotype are greater than 30x more likely to develop emphysema, and greater than 20x more likely to develop liver fibrosis or cirrhosis. Conversely, an SZ or MZ individual's risk is only marginally greater than a person with no mutation, and disease in these individuals requires the presence of additional risk factors, such as smoking or obesity. These genotype characteristics are important as they help define what the critical goal posts are for efficacious AATD treatment. Any treatment that can achieve carrier range or better levels of AAT greater that 11 micromolar protective threshold along with further upregulation of the gene during inflammation would eliminate risk of progressive disease and would represent a functional cure of severe AATD. Our base editor consists of 2 components, an mRNA encoding an adenine-based editor protein and a guide RNA that directs it to the precise location of a Z mutation in the SERPINA1 gene. Both are encapsulated in a lipid nanoparticle or LNP for delivery to the liver. Once in the liver cells or hepatocytes, the base editor precisely and directly corrects the misspelling, so it changes the A base into G base, converting the disease-causing PiZ mutation back to the normal functioning PiM form. By correcting the root cause of AATD at the most proximal source, the DNA, we believe that BEAM-302 has the potential to deliver on the critical aspects of a onetime transformational genetic medicine. First and foremost, our goal at BEAM-302 is to have a person make corrected and properly functioning M-AAT that gets into the circulation so that it is above the protective threshold of 11 micromolar, which as described earlier, is informed through genetics and was clinically accepted as the basis of augmentation approval. Second, BEAM-302 aims to treat the full spectrum of AATD disease manifestations by significantly reducing mutant Z-AAT levels as much as possible to prevent aggregates in the liver and blood that can lead to ongoing organ damage. Finally, AAT needs to be available in a dynamic manner, meaning that during periods of inflammation or infection, AAT levels need to be able to increase in order to combat lung destruction from unopposed proteases generated from inflammatory cells such as a neutrophil elastase protease. This is not possible with existing therapies like augmentation. With those goals in mind, we designed a robust Phase I/II trial to assess early safety and efficacy of BEAM-302 and enable dose selection in patients across the spectrum of AATD. The dose escalation base of the study is structured in 2 parts. Part A includes patients with lung disease to establish an understanding of the safety in patients without clinically evident liver disease, followed by Part B, which includes patients with mild-to-moderate liver disease with or without AATD-associated lung disease. As of the February 10, 2026, data cutoff, we have treated a total of 29 patients across both Part A and Part B, representing a meaningful update from our proof-of-concept data last year where we presented data from 9 patients. In Part A, we have completed a 15 mg cohort with 3 patients dosed for 12 to 18 months of follow-up, a 30 mg cohort with 3 patients, each with 12 months of follow-up, a 60 mg cohort with 6 patients followed for 5 to 12 months, a 75 mg cohort with 9 patients followed for 2 to 9 months and a multi-dose cohort evaluating 2 doses of 60 mg given 8 weeks apart, which included 3 patients followed for 84 days or 28 days after the second dose. In Part B, we completed a 30 mg cohort with 3 patients followed for 4 to 5 months and dosed 2 patients in a 60 mg cohort. The first patient had 3 months of follow-up and the second patient was dosed after the February 10 data cut and is included in the safety data throughout the DLT period, but excluded from the efficacy data. Turning to safety. Single-dose BEAM-302 demonstrated a well-tolerated safety profile at doses up to 75 mg. Importantly, the safety profile was consistent in patients across all single-dose Part A and Part B cohorts. In the 26 patients treated with single-dose BEAM-302 from 15 milligrams up to 75 milligrams, no serious adverse events, dose-limiting toxicities or Grade 3 or higher adverse events were observed. All treatment-emergent adverse events were mild to moderate. Grade 1, asymptomatic transient elevations in ALT and AST were observed within the first 28 days in some patients. In addition, Grade 1 and Grade 2 infusion-related reactions were observed and all resolved within a day. In the multi-dose cohort evaluating 2 doses of 60 milligrams in 3 patients, we observed a higher rate of events following the second dose of BEAM-302. One patient experienced Grade 4 ALT and Grade 3 AST increases within days of the second dose, which were asymptomatic and resolved without treatment. The Grade 2 ALT increase occurred in another patient, which also resolved without treatment. No clinical signs of liver dysfunction or bilirubin increases were observed in any patient. Transient Grade 2 IRRs occurred in all patients. Turning to efficacy. Treatment with BEAM-302 led to durable increases in total AAT into the MZ carrier range at single doses of 60 milligrams or greater. Here, we show steady-state mean total AAT levels by dose, which is the mean of each patients total AAT levels measured by an LC-MS assay from day 28 to the month 12 visit or until the patient's last visit is earlier than 12 months. In the 60 mg cohort, where we have now just 6 patients with follow-up out to 12 months, we observed a steady-state total AAT mean of 16.1 micromolar. In addition, all patients consistently and durably demonstrated mean steady-state total AAT levels above the 11 micromolar protective threshold. In the 75-milligram cohort with 9 patients and follow-up out to 9 months, we observed a steady-state total AAT mean of 14.4 micromolar. Increased total AAT in circulation was functional as demonstrated by a functional AAT assay based on neutrophil elastase inhibition. The full change from baseline in total AAT was comparable between the 60 mg and 75 mg single dose cohorts, suggesting near saturation editing at doses greater than or equal to 60 mg. BEAM-302 was designed to increase total AAT by inducing the expression of corrected M-AAT while at the same time, stopping the expression of mutant Z-AAT. As shown here, mutant Z-AAT was durably and significantly reduced by 80% at steady-state compared to baseline in the highest dose cohorts. As a result, newly produced corrected M-AAT comprised the majority of total AATs in circulation with 94% M-AAT in the 16-mg cohort and 91% M-AAT in the 75 mg cohort. This exceeds the AAT profile seen in people with the MZ genotype with 80% M-AAT and 20% Z-AAT in circulation do not have disease unless there is a second injurious insult. Moving to Part B, patients with AAT-related liver disease show similar efficacy trends as Part A patients without liver disease. In the 30 mg Part B cohort, 3 patients achieved a steady-state mean total AAT of 12.5 micromolar, of which 75% was newly produced M-AAT, representing a 51% reduction in mutant Z-AAT. In the 60 mg Part B cohort, only 1 patient was efficacy evaluable at the time of the data cutoff. That patient achieved a steady-state mean total AAT of 17.2 micromolar and similar to the 60 mg part A cohort, 95% was newly produced M-AAT, driven by an 86% decrease in Z-AAT. In the multi-dose cohort, we observed an efficacy profile consistent with a single-dose 60 mg cohort. The 3 multi-dose patients achieved a mean of 16.5 micromolar of total AAT at day 84, which was 28 days following the second dose of 60 mg of BEAM-302. In addition, the mean Z-AAT reduction was 80% and the newly produced M-AAT was 93% of total AAT. Together, these early data suggest that a single dose of 60 mg BEAM-302 has achieved near saturation editing. As I highlighted earlier, one of the goals of therapy with BEAM-302 is to restore the physiologic control of AAT during inflammation, which is when lungs require higher AAT levels to maintain protection against tissue-damaging proteases. Here, we show strong evidence of inducibility of AAT in a patient who experienced a respiratory infection roughly 8 months after treatment with BEAM-302. This patient was dosed with 60 milligrams of BEAM-302 in Part A and achieved steady-state mean total AAT of about 16 micromolar through month 6. At an unscheduled visit around month 8, patient presented with a respiratory infection, resulting in elevated CRP and a concomitant increase in total AAT to approximately 30 micromolar. After the infection resolved, their total AAT levels trended back down along with their CRP values by their month 9 scheduled visit. Importantly, the patient maintained consistent AAT composition of 94% M-AAT before, during and after the respiratory infection. This case study shows clearly that there are 2 distinct assets at AAT protection offered by BEAM-302 treatment. First, the achievement of a new basal AAT level above the protective threshold achieved within 28 days after treatment. Second, the ability to produce significantly more proactive M-AAT on demand during periods of inflammation or infection. In summary, we are encouraged by these robust and comprehensive BEAM-302 clinical data now in 29 patients and follow-up out to 18 months. These data demonstrate that a single 60-milligram dose of BEAM-302 led to durable correction of a PiZ mutation, resulting in increases in total AAT to mean of 60 micromolar, above the therapeutic threshold of 11 micromolar and into the MZ range. Production of corrected functional M-AAT in circulation for the first time and significantly decreased mutant Z-AAT by approximately 80%. Treatment with BEAM-302 enabled production of corrected and functional M-AAT that was under normal regulatory control as shown by the increase in AAT that occurred in response to inflammation in a patient with a respiratory tract infection, enabling the body to naturally regulate AAT as needed. And importantly, BEAM-302 was well tolerated with an acceptable safety profile at all single doses tested to date in 26 patients. Based on the strength of safety and the efficacy profile of BEAM-302 in single-dose cohorts, 60 milligrams was chosen as the optimal biological dose for the pivotal trial, which we plan to initiate in the second half of this year. Pino will provide more details about the next steps for pivotal development shortly. Taken together, we believe these data demonstrate the potential for BEAM-302 to be a transformative onetime treatment for AATD that could meaningfully impact both the lung and liver manifestations of the disease. With that, I would like to turn the call over to Dr. Jeffrey Teckman. Dr. Teckman is a Professor of Pediatrics and Biochemistry at St. Louis University School of Medicine and a recognized world leader in alpha-1 antitrypsin deficiency. His over 30 years of research and clinical care has focused on the mechanisms of liver injury in AATD and improving the diagnosis and clinical management of patients across the disease spectrum. We're pleased to have him with us today to provide a clinical perspective on the disease, the needs of patients living with AATD today and how emerging genetic medicines could reshape the way this disease is treated in the future. Dr. Teckman, over to you.

Thank you, Amy. It's a pleasure to be here. On a personal note, I've been working on alpha-1 antitrypsin deficiency for a long time. When I first started, we didn't even know how this disease worked in the liver, let alone, a concept that we would have cures on the horizon. And it's very exciting to see how much has happened. I think the question to first start with is why alpha-1 antitrypsin deficiency now? There are a lot of conditions. There's a lot of interest in biologic treatments. Why this disease? Well, first of all, there's increased awareness in the liver disease and the hepatology field. There has been a lot of talk about "steatotic liver disease," our new word for fatty liver disease, steatotic liver disease. And there's a recognition that metabolic genetic liver disease like alpha-1 antitrypsin deficiency actually caused steatotic liver disease. And as more people with steatotic liver disease are being evaluated, there's more testing going on for specific causes like alpha antitrypsin deficiency. The lung disease of alpha-1 is well known, but not -- the patients are not fully diagnosed. And the treatment options, while they exist are suboptimal, there is protein replacement as we'll talk about but it does not return people to wild type. It's very expensive and it's burdensome to patients. What's also unique about alpha antitrypsin deficiency is the patient community is highly centralized. There is a very active foundation, the Alpha-1 Foundation. They have national meetings. They have a registry. They have a therapeutic development network, and they're a major mover in research and treatment and in lobbying for alpha antitrypsin deficiency. So these factors together really make this a great time to be developing treatments for alpha-1. Next slide. So just as a background reminder, the alpha-1 gene, the SERPINA1 gene has hundreds of variants. M being the normal wild-type allele, which is MM is 96%, 98% of the population in the United States and Europe. The Z allele is by far responsible for 90% to 95% of disease. People sometimes also talk about the S allele, which is the intermediate disease allele, which also when present with Z especially, it could be related to disease. But really, the vast majority of disease are individuals who were ZZ. Next slide. As you might recall, the liver disease in alpha-1 is a storage disease and the lung disease is a serum deficiency. That's why it's called alpha-1 antitrypsin deficiency because it was originally identified as a serum deficiency, but the liver has too much. Next slide. So this is just a schematic of alpha-1 protein processing in the liver. On the left side, you see a normal wild-type MM individual. That's the endoplasmic reticulum of the hepatocyte, the little black wavy lines are nascent polypeptide chains of AAT protein, and it folds into its secretion-competent conformation. That's the little knot. And then it's secreted into the blood in huge quantities. So the adult liver makes 2 grams per day of alpha antitrypsin. On the right side, a ZZ individual is still synthesizing the same number of nascent polypeptides, but they do not fold efficiently into the secretion-competent conformation. So only 15% of the peptides reach a secretion-competent conformation are secreted. The rest accumulate in the ER of the hepatocytes. Now most of those polypeptides are degraded by proteolysis pathways within the hepatocytes. But for reasons we're not totally sure, some accumulate and form these unusual, what we call polymers of protein, which are highly cytotoxic to the cell. And so again, you have the situation where the liver has too much, but the serum has too little. Next slide. So these are photomicrographs of human ZZ liver. On the left side is H&E. On the right side is what we call Periodic Acid-Schiff with digestion or PAS with digestion. So the PAS stains glycogen and glycoproteins red purple and the digestion washes the stain out of glycogen. And so if you have an accumulation of glycoproteins in the cell, which is shown there by the inclusions, what we call globules. So that shows the accumulation. Sometimes those are what 100% made up of Z protein in the polymerized conformation. Sometimes those accumulations are larger than the nucleus. So it really is very toxic to the liver cell. Next slide. So what's the risk of liver and lung disease? And it is complicated. So let me just walk you through the slide for a second. So if you look at the top and from left to right is the odds ratio, that's shown at the very bottom. And you see the line there on 1. So that's the same risk as MM individuals. So at the very top, you see MZ. And MZ individuals have a modest 1.7-ish odd ratio increase of liver disease and cirrhosis. We think of MZ being a genetic modifier of other liver diseases. Most of those people have other kinds of steatotic liver disease, NASH, other things like that. The risk of lung disease in MZ, again, it shows there, it is between 1.5 and 2. But really, that's just smokers. Nonsmokers who are MZ appear to have no increased risk of lung disease. If you again, if you go down a little further on FZ, so the cirrhosis risk for lifetime for FZ might be odds ratio of 3 over MM individuals, so increased, and emphysema, again, between 1.5 and 2. So at the bottom in ZZ, the risk of fibrosis cirrhosis lifetime, the odds ratio is more than 20%. So significantly increased over the general population. And likewise, with emphysema, somewhere between 30 and 40 odds ratio increased risk compared to MM individuals. So what's really interesting about the data is that we appear -- in this treatment, you appear to be able to make people at least MZ, if not better. So that would eliminate 95% of the risk, which is incredible and very exciting and something that we're anxious to see how it turns out with further study. Next slide. So this just sort of says over time, over a lifetime, because what's interesting also about this disease is it affects different people, different ages differently. So on the vertical is the incidence of medically significant disease in the ZZ individual at a certain age and then you have age from left right across the bottom. So early in life, ZZ babies and children can develop liver disease. But it's only about 20% of ZZ individuals have enough disease to come to medical attention in childhood. And then the risk of liver disease in young adulthood and new onset liver disease is very low, but it goes up later in adults and again, become significant as a lifelong risk. With regard to lung disease, you do see an increased risk of childhood asthma but not emphysema in ZZ children. The lung disease really starts to become evident in the 30s and older. And then again, the lung function decline in alpha antitrypsin deficiency is greater than the MM individuals general population. No, not everyone has -- who's ZZ has accelerated lung function decline. But it is well known that it is higher. And really even if you're a nonsmoker. Next slide. So I wanted to go back and touch on how the American Association of Liver Disease, AASLD, which is the worldwide leader in liver disease science. So just in the last couple of years, we've changed the way we look at "fatty liver disease." And it's not just a nomenclature change, but it's really a recognition change. So we call it steatotic liver disease overall. And this, again, is the official sort of scheme, which not only shows metabolic dysfunction associated with steatotic liver disease, so that's individuals with obesity, high lipids who then develop MASLD as well as alcohol, but it's also recognized that increasingly that monogenic diseases like alpha antitrypsin deficiency, you see in the red circle on the right, contributes to the steatotic liver disease group of patients. And so this has really led to an increased focus on diagnosis because it's on clinical grounds to a hepatologist, just history, physical exam, basic lab tests, you can't differentiate alpha antitrypsin deficiency from MASLD or alcohol, you really need to test for it specifically. And that's being increasingly recognized, especially as treatments are rolled out, it's going to be tested for even more. And we've seen that in a lot of rare diseases where when there's no treatment, the testing is modest. But when new treatments are available, there's a huge spike in testing. And we saw that actually in alpha antitrypsin deficiency in the late '80s and in the '90s when the protein replacement for the lung disease became available. There was a dramatic increase in diagnosis. And we went from just a few hundred people on replacement therapy to thousands and thousands on replacement therapy in just a decade as a result of more treatment. Next slide. So as we said, the liver currently has no approved treatment to supportive care and liver transplant if liver failure becomes untreatable. And the lung disease does have the protein replacement, which is an intravenous product. It's fairly burdensome and it doesn't do anything for the liver, right, because the liver is a storage disease and the lung disease is a serum deficiency. So this really brings up how the patients are really ready for new treatment options. And there seems to be significant interest among patients on IV replacement therapy to move to something more permanent such as a DNA-targeted treatment, which would be equal, if not better, to the protein replacement. I think one of the key concepts which has been touched on is the alpha antitrypsin protein is an acute phase reactant. So it can increase 3 up to 5 fold in serum with inflammation. So -- and that seems to be very important in the pathology -- pathophysiology of preventing damage because if you get inflammation of the lung and pneumonia, then you make a lot more alpha antitrypsin to protect those tissues from injury. And that's part of the normal physiology. People on IV protein replacement don't infuse more when they're sick. They just have that same dose. So they don't get that boost. And we see that in some of the data, that there is an acute phase reactant boost, which will probably be much more effective at protecting the lung. And not require weekly infusion. So there's -- there seem to be a lot of interest in patients for this kind of intervention. Next slide. So again, just touching on the community, the Alpha-1 Foundation, their registry, their therapeutic development network, their funding of research and their support with government. I personally have been to the FDA a number of times as part of delegations from the Alpha-1 Foundation to discuss therapeutic development to discuss how these treatments should be evaluated and how important it is to treat both the liver and the lung. So these are very exciting developments. I think the community is going to be very excited about the data that we've been discussing. And I think we're very, very excited to see, not only improved treatment, but cures for this disease. Next slide. So again, in summarizing our key takeaways, alpha antitrypsin deficiency has a wide range of presentations over a full lifetime, from infantile liver disease to emphysema in older adults. It's way underdiagnosed but increasingly being recognized, not only in lung disease, but also in liver disease as a result of increased focus on steatotic liver disease. There certainly is unmet need. Even though there are treatments, they're suboptimal. And these are very exciting developments. And we look forward to the next steps.

Thank you, Dr. Teckman. It's a pleasure to have you here with us today. As we disclosed in January, on the heels of significant regulatory engagement over the course of last year, we have reached alignment with the U.S. FDA on a potential accelerated approval pathway for BEAM-302. To support the future BLA submission, we anticipate enrolling approximately 50 additional patients to be treated with BEAM-302 in an expansion of the ongoing Phase I/II study. The primary endpoint is expected to be based on AAT biomarkers evaluated over 12 months. Continuing our track record for efficient and rapid execution, we're moving forward with multiple parallel efforts to maintain momentum in the ongoing Phase I/II trial in preparation for initiating the pivotal cohort, which we expect to do in the second half of 2026. To start, now that we have selected 60 milligrams as our optimal biological dose, we plan to enroll additional patients in an expansion of Part A as well as continue to enroll patients in the 60-milligram cohort in Part B. This allows us to not only grow our safety database, but also to provide new sites in the U.S. with BEAM-302 experience prior to initiating the pivotal cohort. At the same time, we're actively working to complete the pivotal protocol amendment. And recently, we completed site activation at multiple U.S. sites. This builds on our already extensive global site network spanning 12 sites and 6 countries. At Beam, our commitment to lead in innovation for the AATD community extends far beyond one program. In addition to our focus on advancing BEAM-302 to patients as efficiently as possible, we continue internal R&D efforts for future life cycle management. We're also deeply involved in the advocacy and research communities and serve as a member of C-Path's CPA-1 consortium in collaboration with the FDA to accelerate AATD research by identifying clinical efficacy endpoints. And as a collaborator with Alpha-1 Foundation and Alpha-1 Europe alliance to educate about gene editing and obtain a critical input on clinical trial design and patient experience. As we look ahead to the rest of the year, 2026 is shaping up to be a milestone-rich period for Beam, with multiple value-driven catalysts on the horizon across our growing clinical portfolio. First, we remain focused on advancing our lead programs, including progressing BEAM-302 towards pivotal development in the second half of this year, following the data that we shared today. Second, we expect to continue advancing the pipeline with key development milestones across several programs that leverage the same platform capabilities. And finally, we are doing this from a position of financial statement with a balance sheet that we believe supports the execution of our commercial, clinical and development plans over the coming years. To close, at Beam, everything we do is driven by our commitment to patients. The promise of base editing is not just about innovation. It's about transforming lives and enabling people to live the lives that were meant to live. And we are deeply committed to our vision of developing onetime life-changing therapies for patients. I'd like to thank the entire Beam team for their tireless efforts and exceptional teamwork in advancing this program from inception to today. I'd also like to acknowledge that these findings today will not be possible, wherein not for the individuals whose lives we aim to change, people living with AATD. We'd like to thank all of our partners, including the investigators, the clinical site staff, our clinical development and manufacturing partners, the Alpha-1 Foundation and other advocacy organizations around the world, and above all, each of the patients and caregivers who have taken part in our trials and made today possible. Operator, please open the line for Q&A.

[Operator Instructions] Now first question in queue coming from the line of Cory Kasimov with Evercore ISI.

This is Adhi on for Cory. In the multi-dose cohort, how should we interpret the absorbed transaminase elevations? Are these events primarily a function of cumulative LNP exposure through repeat dosing? Or there is any residual concerns around the safety profile that could impact the future dosing strategies as well?

Yes. Thank you. Great question, and I'll pass that to Amy.

I think with one event such as that and the fact that it has very swift onset and a very rapid resolution along with some cytokine increases, we think it's likely driven by the inflammatory response to the second load lipids. However, given that I've mentioned, it's just a limited number of patients, we're not entirely sure. But I think what's important is the LFTs resolved very quickly back to normal, and there was no evidence, for example, that the patient had symptoms, required any intervention. And in the end of the day, I think that this is something that we think we didn't see with the single dose, which is very reassuring. And we've now dosed, I want to remind people, 20 patients at the 60 mg and 75 mg doses with really just very consistent Grade 1 elevations in LFTs. And I also just want to note that seeing Grade 1 elevations of ALTs or even Grade 2 are not really predictive of more severe events in the future, such as things like DILI. So I think from that perspective, we feel very reassured at this point in time with our single-dose and our optimal biologic dose chosen of 60 mg times 1.

And our next question coming from the line of Maury Raycroft with Jefferies.

Congrats on the great data. Wondering if you can talk more about just explanations for why the AAT levels at 60 mg are higher than your last update, increasing from 12.4 to 16.1. Is it due to higher baseline AAT or dynamics with longer follow-up, maybe a combination of both. And do you have a good understanding of the rate of AAT levels reaching steady-state after dosing. And do you think that could continue to improve with longer follow-up?

Sure. There's a lot in there. I mean I think maybe the first comment I'll make, and then I'll invite Amy to expand on it is, there's obviously a very significantly updated data set since last year. So we went from [ n of 3 to now n of 6 ] with much longer follow-up plus obviously expanding on the other dose areas as well. So I think we commented last year, actually we felt that the few patients we had at 60 were probably a little on the low end and I think you've seen that sort of normalize here. In terms of how the overall data set has matured, I mean, I think that we see a lot of stability in the levels that we're achieving and that is quite consistent with the mechanism of action of the drug.

Yes. I mean I do think that over time with more patients, we are seeing probably in the mean baselines that are more kind of what had been reported in the literature. So instead of having baselines of around 5, we're kind of up in the range of about 6 micromolar at this time. And I will say that once people hit day 28, they tend to kind of remain fairly stable from day 28, you can see all the way out now to as far as month 12. What we don't know yet is will the people who are at the lower doses, let's say, the 15 or 30 mgs, which are not close to kind of editing saturation, will they continue to increase over time because of the potential theoretic survival advantage that the cells that have corrected M-AAT would have over those that still have Z-AAT. But given the slow turnover in the liver of a T half-life of maybe 365 days, those drifts upwards over time in AAT levels may take a little time to see. In other words, 1 to 2 years, maybe kind of more along the line to what we need to see. But we're very pleased that we're seeing very strong steady-state levels and people maintaining those gains now in a durable manner.

Our next question coming from the line of Samantha Semenkow with Citi.

Congrats on all the great data and all the progress. I have a question for Dr. Teckman. Dr. Teckman, it would be great to just have your thoughts on what is most important here from an efficacy and safety standpoint in your view for a gene editing therapy specifically. When you look at the emerging profile for BEAM-302, how compelling does that mean 16.1 micromolar in total AAT. There's a few other additional gene editing therapies in the pipeline, and I would love to get a sense on whether you think pushing that total AAT higher, if that's possible, would impact your view on the BEAM-302 profile as we see it thus far?

Dr. Teckman?

Yes, good question. And I think something that I've been thinking about and others have been thinking about. I mean certainly, there's some element of a continuum there. So more probably better. On the other hand, the curve of that line, it's not straight, right? I mean it's actually a curve. And as we talked about and at the level that we're seeing, it's at least MZ and that eliminates 95% of the risk. And plus, it's better than that because MZ people half the protein they're making is Z. And in this situation, we see that really almost everything in the liver at that dose is converted and then you have the acute phase reactant response preserved or restored. So higher levels give some better protection? Possibly. But this seems pretty good. With regard to future treatment, hard to say, but this looks pretty exciting. The -- it's commonly -- I mean we've discussed this at the FDA going back a decade, what should the target be and a lot of people have said, well, if you make people into carrier better that you've eliminated the vast majority of disease. So yes, I think it's pretty exciting.

Our next question in queue coming from the line of Eric Schmidt with Cantor Fitzgerald.

Some of the main values you've produced here are really impressive. So congrats on that. I guess I'm wondering if there are any patient-specific factors that either lead to better or lesser gene editing efficiencies or whether maybe there's limited variability? And then as a follow-up, Pino mentioned that sites have already been activated in the Part C pivotal portion of the trial. I think some would probably claim that, that means the trial has already started, but what else are you guys waiting for to give us the green light on the go ahead there.

Sure. Maybe I'll take the first one and Pino can clarify on the second one. So I think the -- I don't think there's much to say yet on patient-specific factors. Generally, if anything, the results have been quite consistent across all types of patients and particularly now, not missing the point that the Part B and Part A patients, that's probably the biggest factor we were already controlling for in the trial, where a Part D patient has known significant liver burden. But as you've seen in the safety and efficacy of the 60-milligram dose has been comparable there, which is very exciting. So by and large, very consistent, frankly, across the full range of spectrum of patients in this disease. Pino, in terms of the site network and then the path to getting the trial open.

Yes. I invite Amy to comment as well. But fundamentally, we've made a protocol change, and we're in the process of the IRBs and the sites to review that and to improve it. Obviously, we submitted that to the FDA as well. And they don't necessarily need to provide the input, but it's obviously always helpful to provide a little bit of time for them to comment if they choose to do so. So fundamentally, it's just the process of activating all the sites, making sure that we review this, we get the approval. In the meantime, we are continuing, as I mentioned, some additional Part A treatment as well as Part B, and I think that will provide basically almost like the training ground, if you will, for some of the U.S. sites. So they will be ready for the pivotal trial. Amy, anything else that I may have missed.

Yes. Just to clarify, just so people know the footprint that we're using is global, and that footprint is the exact same footprint we've used for the Phase I/II study. So when we talk about site activation for the pivotal, these sites have already been open for the Phase I/II study and now we'll just wind up conducting the pivotal with, as Pino mentioned, an amended protocol. And so the good news there is a lot of these sites have already had experienced dosing people, kind of figuring out how to do the study, and this allows us to move superfast because we don't have to then go to new sites that haven't been familiar with BEAM-302 or that then we have to wait for sites to come on board and contract, et cetera. So I think we're going to be able to move very fast using our existing global site network.

Our next question coming from the line of Brian Cheng with JPMorgan.

Can you tell us a little bit more about how the additional 50 patients will be split across the lung and liver phenotypes in the expansion portion? And we know there's also a change in the way how you analyze total AAT here. Previously, you used turbidimetry and then here you use mass spec. Just curious if there's any potential influence in how we interpret total AAT levels.

So to answer your first question, I believe you wanted to know how the breakdown would be in the pivotal study for patients. And in that study, what we're requiring is that everybody have evidence of emphysema. So they don't necessarily have to have abnormal pulmonary function test, but they have to have at least CT scans and emphysema. They do not have to have liver disease, but they can have liver disease. And so what we're hoping here is we now have a pivotal cohort that is a spectrum of disease. So those with lung disease with and without as well liver disease. So it won't be divided into a Part A, B or altogether. And we feel that our studies that we've done in Part A and B really assure us, to John's point, that the safety and efficacy should be the same, whether or not you have liver disease. To get to the second point, we are using LC-MS because it's the preferred assay by the FDA to assess total AAT in circulation and enables us to test the AAT composition. So with turbidimetry, you can only just look at AAT. But with LC-MS, we can look at this composition of M-AAT, Z-AAT. And that's very important because it's not just the total AAT matters, but what is it made of? And so from that perspective, that's why we're switching to this. Now in general, the values tend to be similar. But again, you would have to have each assay compared to each other. It's not enough to say like our LC-MS assay versus turbidimetry done at another hospital. So we have our own validated assays, and we tend to do our assay side by side, and turbidimetry will have a role because it's a very quick turnaround time. So we need that for things like eligibility and other things. But as far as endpoints go, it's going to all be LC-MS based.

Our next question coming from the line of Yanan Zhu with Wells Fargo Securities.

Congrats on the data. So I have a question for the doctor and a very quick follow-up regarding an earlier question for the company. For the doctor, could you talk about what proportion of your AATD patients are candidates for this gene editing treatment? And how many of them do you think would be interested in proceeding if you prescribe? For the company, the quick follow-up is on the Grade 4 liver enzyme question asked earlier. I was wondering, can you talk about the time course of this event? And how is it similar or different from the other Grade 4 liver enzyme elevations seen by gene editing peers?

Great. I'll start out. This is Jeff Teckman. Yes, I think there would be a lot of interest from patients. I think that like with a lot of new therapies, the use would expand over time. Most alpha-1 patients come to medical attention because of lung disease, at least in the past. And so there's a significant group of lung disease diagnosed patients. And as we said, there is treatment with protein replacement, but it's suboptimal and a lot of lung physicians don't even use it. I talked to a patient last week who probably would benefit from it, but his doctor told them not to be on it because he didn't like it or something. So I think a new thing that's not going to be weekly infusions and burdensome, but is really going to return people to an excellent defense of the lung, I think people will be very interested in that. And I think there will be interest in people, especially as time goes on and it becomes more established, be interested in people from switching from infusions over to a one and done that really would be superior, at least that's our initial impression of the data. With regard to the liver, I think that it's extensive and would -- more study would help us understand the impact. But there are a lot of people who are going to be diagnosed more frequently coming up. And again, if we have something to offer them, that is going to be powerful, and it's going to drive diagnosis. I mean speaking to the liver doctor, I mean, we test just as an example, for Wilson's disease all the time, even though Wilson's is 10x more rare than alpha antitrypsin deficiency, but it has a treatment and if you can give it to people and save their life. So we send billions of Wilson's treatments for the 1 out of 1,000 that comes back positive. In this case, there will be way more people with alpha-1 that we would identify and then bring the treatment to bear. So I think it's patients, especially over time, as we establish better data, are going to be very interested.

In answer to the second part of the question about the time course for the Grade 4 LT elevation, this is very rapid. The LFT started to increase within 2 days. They probably peaked within 5 to 7 days and were within normal limits even by the next visit at month 4. And so this is a very rapid up-down. And as mentioned, the patients had no symptoms, was followed as an outpatient. There were no changes in bilirubin. And so again, I think this time course is more consistent with what one might see and what has been seen before with LNP dosing. You asked about contrasting it a little bit to what's been seen, and I think you're referring to the Intellia data with some Grade 4 elevations. And from what we can tell from what's out in the public domain, it seems like those are occurring later in time and being picked up about 1 month post dosing or so. And so I think this is quite distinct from that. I will point out as well that, as you can imagine, there's been no impact to efficacy either. So we don't think this is something that's like an antibody-mediated type of thing. We think this is more of a response by the body that you might see when you got a lipid load like after a COVID vaccine, et cetera, so more of an inflammatory response that's transient.

Our next question coming from the line of Mani Foroohar with Leerink Partners.

A couple of quick ones. One, we've seen a lot of dynamism in response to inflammatory insults, at least one patient you presented today. How should we think about what that might imply in terms of functional outcomes and clinical profile in a larger, longer pivotal study? And then I have a quick follow-up.

Well, I think -- I mean, just to clarify the question, I think -- I mean, clearly, we do think this is a dynamic mechanism. The gene is quite dynamic. It's one of the central parts of the acute phase response to inflammation. And I think you actually said it well in the question. I think we think it's a fundamental part of the value proposition of the mechanism of action of this drug to, I think as we said, not only get you to a new floor, but have you be able to respond over time. We will know when there is an induction event because we're also monitoring CRP, right? So we're looking at inflammation in real time. So you can tell the difference between a patient who's giving you the read on their new basal level over the long term, which gives you a sense of what the levels have been changed to after therapy versus when someone is having an inflammatory event and the spike that happens as a result of that.

Maybe just one point of clarification. The 16 micromolar steady-state level importantly does not include the 30 micromolar spike that has been seen. So just to give you a sense, that 16 is really very much basal, a steady-state level measured over several months without incorporating the acute response.

Our next question coming from the line of Michael Yee with UBS.

This is Matt on for Mike. I wanted to ask one for the doctor, maybe an add-on to a prior question. And could you just talk about how you use IV augmentation therapy now, what the weekly burden looks like for patients. And I'm curious whether new or longer-acting recombinant augmentation could change that? And then just overall, how does that compare to a onetime therapy like gene editing from a patient perspective?

Sure. So I'll just say, I'm a liver doctor. I'm very familiar with the lung disease. So I don't prescribe -- personally prescribe protein replacement for alpha-1, but I'm very, very familiar with it. The -- until recently, it's all purified from human plasma. And yes, people have to have IV started or they have to get a port and it's disruptive to travel and things that people want to do. And again, I wouldn't underestimate what the problems with the therapy are. Like I said, it helps people, but it doesn't return people to wild type and such that many people in the pulmonary field don't use it because they don't feel that the risk-benefit and cost ratio is even worth it. I don't agree with that, but that is a strong opinion among lung doctors -- some lung doctors. With regard to the recombinant or long-acting, that might actually be a bad thing because as we've said, when you're sick, you need more alpha-1. It gets used up. So we didn't really talk about this the actual physiology. But -- so when alpha-1 antitrypsin protein does its job, which is to inactivate neutrophil proteases. So when neutrophils are moving through tissue as part of their attack against bacteria, they use proteases to open the pathways in the tissue. And alpha-1 is present in the fluid between cells and in serum to inactivate that so that, that effect doesn't spread as well as when neutrophils phagocytose, and there's some leakage of proteases. So again, alpha-1 is there so that it protects. So when you have an active infection, you use up and when alpha antitrypsin protein, its mechanism is it binds -- it's a suicide binding to a molecule of neutrophil elastase, for example, or other neutrophil proteases. So you use it up. So if you have the long-acting, I mean, it's great that it has a long half-life in circulation. But if you get -- if you're getting infusions once a month instead of once a week and then you get an infection, your next infusions is for 3 weeks, you're suddenly unprotected because you used up all the alpha-1 that you've got. So the acute phase reactant response and restoring that theoretically would be a major advance in lung protection. Again, we have to see the data. But I mean, people have thought about this and hoped that there was something that would restore the acute phase response in this disease for a long, long time. And there are even people who are on protein replacement, who in the past, especially would hoard it and then try to infuse more when they were sick because they felt like they -- when they got sick that they had a step down in their lung function. So I think this is important, and I don't think the long-acting replacement is going to nearly match at least if these results are borne out, the infusion is not going to be as good.

And our next question coming from the line of Luca Issi with RBC.

Congrats on the progress here. Maybe, John, kind of high level, any quick thoughts on the competitive landscape here? I'm wondering what was your reaction to GSK return the rights to Wave. But maybe on the other side, also your thoughts on YolTech which I believe in China showed more than 20 micromolar of total protein, I believe it just 45 milligrams. So any thoughts there, much appreciated. And then maybe super quickly, Giuseppe, on the regulatory side. Again, I appreciate there's a path here for accelerated approval on AAT biomarkers. But what's the bar here that the FDA is looking for? Do you need to show all patients above 11 micromolar? Do you need to show a specific ratio between MN Z? Like any additional color on what the FDA is looking for here, much appreciated.

Yes. Thanks for the question. So I'll take the competitive one as you noted. So we think we're in a very strong position. This is going to be a huge indication. We have a very clear first-mover advantage. We're now up to almost 30 patients and moving directly into a pivotal trial now with alignment on the FDA for the path to market. So that puts us several years ahead of everyone else. There obviously will be more players, as you noted. I think the RNA editing field, I think we await more data to see if those agents can produce the kind of profile we're seeing here. I think we clearly believe that this will be a best-in-class relative to that, but look forward to seeing more. And then for future DNA editing agents, obviously, I mean, YolTech, a couple of patients reported in China. We have to wait for more there, only one of which was at the level you described. Other DNA agents moving into the clinic over the course of this year, we would probably get some data in a year or so. I think we have a very strong lead over them. I think the most important thing is the fact that as Dr. Teckman was commenting on the risk levels, we think we've done what we needed to do to get rid of the risk of disease. So it doesn't clearly, to me, leave any room for a lot of improvement that would be detectable in any kind of reasonable clinical experiment you can do. I mean I think we've -- that's the whole point of getting the carrier here is unless someone is a smoker or something like that, you're not going to see any progression in the disease whether you're -- where we are now or anywhere else that people can try to get to. So bottom line, I think it puts us in a very strong position. The other thing competitors talk a lot about, as you know, is bystander editing and variant. I think we are very confident, as we've shown before in our preclinical data that the variant acts completely normally relative to the normal protein. And I think we have a lot more data now in the clinic building up that we can share over time. So that, I think, will also not be a source of competitive advantage over time. In terms of the pivotal cohort, maybe I'll pass that one to Pino to address.

Yes. Look, in terms of what is approvable, there is no real sort of hurdle specifically in terms of the levels or MZ ratio that the FDA requires, certainly not expressed to us. I think the way we handle the conversation with the FDA, we shared the data that we shared with you in last year. And basically, we asked the question, if you saw this in the pivotal trial, will this be approvable? And the answer is yes. So the data that you see today is very consistent with that, and we do believe that there is approval. Obviously, in the pivotal trial, we will need to see consistent sort of responses to this data. And if we do so, we do believe that, that is approval.

Our next question coming from the line of Alec Stranahan with Bank of America.

This is Matthew on for Alec. Congrats on the data. First one from us, I guess, just curious the percentage of bystander or passenger edits. Is it similar to the previous update at 60 milligrams and sort of how do those pan out at 75 milligrams in the multi-dose cohort? And then maybe a quick one, double-clicking. Curious whether you're seeing those with higher AAT at baseline have more pronounced increases in total AAT or the proportion. Just trying to dig in there a bit.

Yes, maybe I'll handle that. So I think, again, nothing different clinically than we've seen preclinically in terms of the editing profile and the outcomes. And that's true at 60, 75 and multi-dose 60. So again, those are all quite comparable. And then just your -- I guess, your question about baseline and just sort of patients higher or lower baseline. We do think that, that's probably physiology, right, that a patient who lives at the high end of maybe their baseline is going to be a higher outcome after editing versus low and low. But it's very small end, so you'll obviously be learning more over time about those nuances.

Next question in queue coming from the line of Whitney Ijem with Canaccord Genuity.

This is Angela on for Whitney. We'll add our congrats. Just curious, are there -- has there been any discussion with regulators in terms of wanting to see an acute phase response in the pivotal? Will there be any endpoints related to that? And then I guess, at this point, are there any more conversations that need to be had with the FDA? Or did they have all the feedback in terms of getting the pivotal started?

Yes, I'll take that. The answer to your second question is, no, we don't need to have any further interactions. I think we have clarity on what it takes to do the pivotal trial and what would be acceptable. And there was no specific conversations around needing to see an acute response in pal. However, we'll keep on monitoring, and we do believe that on average, we're expecting to see that just by virtue of the fact that people are exposed to various infections and so on. So we think it will be part of that data set, but it's not a specific requirement.

Our next question coming from the line of Myles Minter with William Blair.

Congrats on the data. My question is actually for Dr. Teckman. I was just wondering whether you're aware of the SPARTA trial that's going to read out at the end of the year for a double dose of AAT augmentation therapy. I know it's measuring lung function and liver with a doctor. I understand that. But if that did show functional superiority with higher dose, does that move the 11 micromolar sort of bar that we're looking for, for efficacy associated with serum AAT levels that's the target here. Just curious if your thoughts there.

Right. So you're referring to the double-dose trial, which has been going on for a while. So yes, this is the -- the dose of augmentation -- protein augmentation therapy was arrived at almost 40 years ago. And the reasoning behind that has sort of been reworked and the thought -- part of the thought behind why augmentation doesn't return people to wild-type is that the dose is too low. And also, when you talk about the dose and the levels reached, people are -- obviously, you give it and it goes down over time until the next infusion, right? So it was natural to somebody finally do a higher dose. It's hard to get payers at this point to pay for higher dose or double dose. I think there has been some preliminary evidence that released from those trials, which might probably better, but it doesn't return the acute phase reactant thing. So I think there's more to do there. There's still the infusion burden. Infusion would be longer, it would be more expensive. And the other thing we really didn't touch on so much is that there is this data and idea that the Z protein polymers are actually damaging to the lung. So in the liver, it's definitely a storage disease. There is evidence that there's polymer deposition in the periphery in blood vessels and in the lung. And there's evidence that these little polymers are chemotactic for neutrophils and alpha-1 emphysema is known to be more neutrophilic than the usual emphysema. So there's some evidence that this actually is a thing. So getting rid of the circulating Z, 95% as was shown, that might also help the lung as well. And of course, protein replacement doesn't do that. So I think the protein placement has helped some people over the last 40 years, but I think it's ready to be replaced by better things. I don't think it's going to continue on with some of these new treatments, which are going to be so much better.

Our last question will come from the line of Patrick Trucchio with H.C. Wainwright.

This is Annabel on for Patrick. Congrats on the data. I guess I was wondering if you could comment on what drove the numerically lower AAT, the 14.4 versus 16.1 micromolar at the 75 versus 60-milligram cohort? And what drove the lower number instead of just a plateau? And then on the side of near saturation editing at 60 milligrams, do you have any direct measurement of editing efficiency in the liver? Or is this inferred from circulating protein biomarkers?

So I'll close with that here. So I think the -- on the latter, it's all inferred. We don't have editing rates yet. We'll pick that up over time with biopsies. But I wouldn't read too much into the 14.4 versus 16.1. I think that if you look at the aggregate AAT levels across 60, 75 and the multi-dose 60, you look at the percent M we're all in that sort of low 90s, 90, 95. You look at the Z reduction, we think that those are more comparable than not, and they certainly overlap statistic significantly. So I don't think we're picking up any real signal there. Most likely, obviously, with more follow-up, we'll learn more over time.

And I will now turn the call back over to Mr. John Evans for closing comments.

Thank you very much. So yes, I want to thank you all for your time. It's an exciting day. We're so pleased to see this continue to mature and really looking forward to partnering with the community to getting this to patients as quickly as we can. I want to thank Dr. Teckman for joining us and for the great and insightful commentary and help along the way, and we look forward to sharing more of this with you as this moves forward. Thank you very much.

Ladies and gentlemen, this concludes today's conference call. Thank you for your participation. You may now disconnect.