Good morning, and welcome to Intellia Therapeutics' Investor Event. My name is Drew, and I will be your conference operator today. Following formal remarks, we will open the call up for a question-and-answer session. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. As a reminder, all participants are currently in listen-only mode. If anyone requires operator assistance during the conference, please press star zero on your telephone keypad. I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed. Thank you, operator, and good morning, everyone. I'm pleased to welcome you to Intellia's investor call, featuring new data from the ongoing NTLA-2002 Phase I/II study. On Sunday, Intellia issued a press release detailing these results, which were presented at the European Academy of Allergy and Clinical Immunology Hybrid Congress, held this past weekend in Valencia, Spain. This release, along with the accompanying presentation, can be found in the Investors and Media section of Intellia's website at intelliatx.com. As a reminder, this call is being broadcast live, and a replay of the event will be archived on the company's website. At this time, I would like to take a minute to remind listeners that during this call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. Please note that NTLA-2002 has not been approved by any health authority. With that said, joining me today on the call are Dr. John Leonard, our Chief Executive Officer, Dr. David Lebwohl, our Chief Medical Officer, and Dr. Hilary Longhurst, Senior Medical Officer on the Auckland District Health Board and Honorary Associate Professor at University of Auckland, New Zealand. Also in the room and available for the Q&A are Dr. Laura Sepp-Lorenzino, our Chief Scientific Officer, and Dr. Jim Butler, our General Manager for the NTLA-2002 program. As outlined on this slide, we'll begin with introductory remarks from John. Dr. Longhurst will review the long-term data from the Phase I portion of the study. David will then review next steps for the program, followed by John discussing where we see NTLA-2002 fitting in the HAE treatment landscape before we open up the call for questions. With that, I'll now turn the call over to John. Thank you, Ian. Welcome, everyone, and thank you for joining today's call. At Intellia, we are deploying the industry's broadest and most advanced toolbox of novel gene editing and delivery solutions to advance a full spectrum of in vivo and ex vivo therapeutic applications. For genetic diseases such as hereditary angioedema, or HAE, our in vivo approach leverages our proprietary CRISPR-based gene editing platform and LNP delivery system to selectively inactivate a disease-causing gene or precisely insert a gene to produce desired proteins. Yesterday, we shared positive long-term data from the ongoing Phase I study of NTLA-2002 in development for HAE. These unprecedented results from the initial 10 patients with average patient follow-up of over 20 months speak to the safety, efficacy and importantly, the durability of NTLA-2002's effect after a single dose. With eight of 10 patients remaining completely attack-free in the post-primary observation period, we believe these data reinforce the potential of NTLA-2002 to be a functional cure for people living with HAE. Dr. Longhurst, a leading HAE expert and our trial's principal investigator in New Zealand, will provide an in-depth review of the results in a moment. Before we review these data in greater detail, I want to take a moment to reflect on our goal to change the lives of HAE patients with NTLA-2002. Despite approved chronic therapies, HAE patients continue to seek improved efficacy and convenience. Ultimately, patients want to live a life free from their disease and untethered from chronic prophylaxis and rescue medications. With NTLA-2002, our aspiration is to have a durable one-time treatment with best-in-class attack rate reduction. We believe this target product profile will offer significant value to patients, caregivers, and the overall healthcare system, supporting the potential of NTLA-2002 to become a leader in the HAE market. We're full steam ahead in our efforts to bring NTLA-2002 to patients. We expect to report the top-line Phase II results mid this year, with the detailed results to be presented at a medical conference later in the year. Based on these data, we will select a dose to further evaluate in the global pivotal Phase III trial, on track to begin in the second half of this year. All of this will position us to submit a planned BLA in 2026 for NTLA-2002, which we anticipate will lead to the first-ever approval for an in vivo CRISPR-based therapy. Beyond that, we are in late-stage development for NTLA-2001 for ATTR amyloidosis, with one Phase III already actively enrolling and a second Phase III expected to begin by the end of this year. Intellia is undoubtedly leading the gene editing revolution, with well over 100 patients already dosed across these two programs and many more to come. With that, I will now turn the call over to Dr. Hilary Longhurst to review the data. Dr. Longhurst? Thank you very much, John, and I'm delighted to be here to present the results from this study. Here are my disclosures. Hereditary angioedema is a rare genetic disorder, which causes people to swell up. Frequently, this is massive swelling, massive angioedema, and can occur unpredictably in any part of the body. So these patients have quite a miserable time, in fear of unbearable pain, or of laryngeal angioedema, which could close their throat and kill them. There is a significant lifetime mortality in untreated patients. The symptoms result from a dysregulated contact pathway, which you can see here. K allikrein in the contact pathway, in the center there, is directly responsible for production of bradykinin, which dictates leakiness of the small blood vessels. W e hypothesized that by editing the kallikrein gene, the KLKB1 gene, we could reduce plasminogen, stop overproduction of bradykinin, and rebalance this pathway on a permanent basis with NTLA-2002. NTLA-2002 is a CRISPR-Cas9-based in vivo gene editing therapy, which was designed to be given systemically via an intravenous infusion as a one-off treatment, which we hypothesized will be a permanent cure of symptoms. The NTLA-2002 is comprised of a CRISPR, so this is a guide RNA mRNA, which potently and selectively targets the KLKB1 gene and a Cas9 RNA, which encodes the Cas9 endonuclease protein, which cuts the gene and inactivates it. All of this is formulated in a lipid nanoparticle, and this is engineered so that it targets the liver very specifically, thus improving specificity and safety potentially. So today, we're going to share the updated interim results on our first 10 patients from the first in-human study. So these are patients with Type 1 and Type 2 HAE. It's an open-label, single ascending dose design with the primary objective of safety and tolerability. But we did also, of course, look at pharmacodynamics and preliminary efficacy. The primary observation period was 16 weeks, followed by a long-term observation period of 88 weeks. In this Phase I part of the study, our patients were allowed to continue use of other long-term prophylaxis. But despite this, they had to have had at least three attacks in the three months prior to treatment, a nd I can tell you that unfortunately for our patients, at the current time, there was no shortage of people who fulfilled that criteria in New Zealand. The data cut-off date is the 12th of February this year, 2024. T his gives an additional year of observation over that which we recently published in the New England Journal of Medicine and which was originally announced at the EAACI conference in 2023. Patient demographics were pretty typical of a population of patients with HAE, which tends to come on in adolescence and then be lifelong. The age range was from 26 - 73. Six out of the 10 patients were receiving concurrent long-term prophylaxis, but of course, had an attack rate of at least once a month or up to almost twice a week. The mean monthly attack rate being 4.6, so just over once a week. It's not shown here, but these patients had a range of comorbidities, again, typical of one might find in a New Zealand or American population. So with the median follow-up time of 20 months to this data cut, NTLA-2002 is continuing to be extremely well-tolerated across all the dose levels that we've tested. The most frequent adverse events were infusion-related reactions, which were typically extremely mild, and all our patients received the full intended dose of NTLA-2002. You can see here that the adverse events are much what one would expect from people living in New Zealand in the last couple of years, and there have been no serious adverse events or clinically significant laboratory findings to date. We saw a dose-dependent reduction in kallikrein, ranging from 60%-95%, from baseline, and these responses have been durable, to- date, at all doses. The data points marked with an asterisk just represent the beginning of the new follow-up since the previous reported analysis. Y ou can see from the horizontal dotted line that all three doses surpass the reduction of 60% that we know is associated with good control of HAE from our previous data from approved kallikrein inhibitor treatment. Pre-specified attack rate analyses were planned at the conclusion of the 16-week primary observation period, and you can see that the mean reduction was 90%. Overall, we've got a reduction of 98%, and you can see that after the first 16 weeks, almost no one had an attack, so the reduction in attack rate is 91%. So in this slide, we can see the results, per patient results, of this treatment, each horizontal bar being one patient. Within the horizontal bars, you can see vertical lines of different colors, representing HAE attacks of various severity, and the duration, of course, is represented by the width of the bar. Y ou can see that, people had attacks prior to treatment, which is shown by this solid vertical line a nd for most people, attacks stopped, pretty immediately after treatment. There were two people whose attacks took some time to settle down, but after the 16-week period, you can see that everyone has been able to stop their prophylaxis and everyone has been pretty much attack-free. In fact, eight out of 10 of these patients are attack-free. I just want to talk a little bit about Patient 1. You can see that way out at about week 50, he had an attack. This guy is a keen sportsman. He got a football boot with studs in his hand, and the following day, he noticed that his hand was swollen in a manner reminiscent of an HAE attack. This didn't need any treatment, and the patient himself commented that in the past, his whole arm would have swollen up, so he was not bothered by this. If you look down to Patient 6, you can see that she had an attack. It was an abdominal attack. This was in the context of a long-haul flight, where she was going to meet a convention of other HAE patients, which is a hugely emotional and exciting experience for those of us involved in HAE. D uring the flight, her fiancé proposed to her. Now, given that emotional stress is a huge trigger of attacks, this lady then began to experience the beginning of an abdominal attack, and she treated it with some C1 inhibitor. So in summary, the results of this first-in-human phase one study continue to demonstrate that NTLA-2002 has the potential to be a functional cure for patients with HAE. In fact, the patients are talking about it as a cure for symptoms, which is, which is how it feels. NTLA-2002 has been generally extremely well-tolerated at all times, with only a Grade 1 or 2 adverse events. I t resulted in a dose-dependent and durable reduction in plasma kallikrein protein, along with, of course, that very pleasing, absence of attacks for the vast majority of people. F inally, I just want to thank the patients who, it's, it's not within our comfort zone to step up for first in human trials, but of course, everyone is extremely glad that, that, we decided to take this on. The study site coordinators and staff and Rebecca Ryan have been fantastic. F inally, thank you so much to Intellia for developing this amazing technology, which I'm sure will have some ramifications way beyond hereditary angioedema. Thank you. Thank you, Dr. Longhurst. We're very excited about these Phase I study results. What we see now is that the effect of 2002 was durable and continued to improve over time. Eight of 10 patients continue to be completely attack-free for 18-26 months, and all 10 patients are free of long-term prophylaxis treatment. These remarkable attack rate reductions were consistent even in patients with the most severe symptoms. At the same time, the data from these 10 patients continue to demonstrate a favorable safety profile. Overall, these long-term data support our belief that 2002 could be a one-time potential functional cure for this debilitating disease. In other words, patients would be both free of attacks and free from chronic treatment. We look forward to reporting top-line results from the randomized, placebo-controlled Phase II study mid this year. The detailed results evaluating the 25 mg and 50 mg doses are expected to be presented at an upcoming medical meeting later in the year. These data updates will provide clarity on which dose we'll move forward into the Phase III trial. As previously disclosed, we plan to initiate the global pivotal Phase III trial in the second half of this year. We expect the Phase III will be a small study of fewer than 100 patients and to enroll rapidly. Based on the landmark findings published in the New England Journal of Medicine, we are already seeing grassroots excitement about 2002 and the upcoming Phase III trial. We look forward to discussing the trial design in more detail once we have regulatory approval. Based on our current projections and assuming the trial is positive, we expect to file a BLA in 2026, which we anticipate will lead to the first-ever approval of an in vivo CRISPR-based therapy. With that, I'll turn the call back to John to review how we envision 2002 fitting into the HAE treatment landscape. Thank you, David and Dr. Longhurst. We believe NTLA-2002 holds the potential to completely disrupt the HAE treatment landscape. Treatment for this disease has significantly evolved in recent years. Patients have more choices today than before, including both on-demand therapies and chronically administered prophylaxis treatment. However p atients are still in need of more effective and less burdensome treatments, as most patients continue to have breakthrough attacks despite current chronic therapies. We believe NTLA-2002 is well-positioned to become a leader in the HAE market, which is expected to grow to over $6 billion by 2029. Based on market research with patients and physicians, the significant enthusiasm for NTLA-2002 is driven by three factors. First, many patients are seeking a further reduction in frequency of their HAE attacks. Even more important for patients would be a complete response, where patients are free from attacks and free from the requirements of chronic treatment. Second, patients are seeking more convenient therapies, and perhaps convenience is not really the right description for what we hope to offer patients in the future. Of course, moving from a daily treatment to weekly and then to monthly certainly describes an improvement in convenience. However, what we are pursuing is really a paradigm shift. We believe patients would be best served by a one-time treatment approach, which would thereby alleviate the need for a lifetime of injections, infusions, or daily pills. F inally, patients and their physicians are always seeking treatments that are safe and well-tolerated. On all three of these factors, efficacy, convenience, and safety, we believe NTLA-2002 has the opportunity to reset the treatment paradigm for people living with HAE. As research and treatment options for HAE have dramatically increased over the past 5+ years, we now understand the needs of patients better than ever. These insights will help guide and prioritize our future commercial efforts. We expect the earliest interest will come from the 15%-20% of patients who are inadequately managed on current prophylaxis treatments. This current dissatisfaction can be related to breakthrough attacks, the burden of current treatment, or the payer requirements to be maintained on a chronic specialty therapy. Next, there are 40%-55% of patients on long-term prophylaxis treatment who are considered generally well-managed, meaning they're able to adequately control the symptoms of their disease. This group of patients has expressed a strong willingness to switch treatment if it can deliver on either additional efficacy or improved convenience. Finally, there are approximately 25%-30% of patients who are only using on-demand treatments today. These patients have foregone currently available prophylaxis therapies due to the burden of chronic injections, infusions, or daily pills, but may now consider a first-in-class, one-time gene editing treatment. In addition to getting input from patients and physicians, we also conducted initial market research with payers. As you can see on this slide, we received positive feedback on NTLA-2002's target product profile. We know that on average, patients are diagnosed at 20 years of age, which means they will contend with many decades of high-cost treatments. For payers, this means a one-time treatment could be very attractive relative to the high lifetime cost of branded prophylaxis therapies, which cost close to or more than $500,000 annually in the U.S. and between $140,000-$450,000 a year in European markets. Of course, we will be working with payers to evaluate potential innovative payment models to support our one-time treatments. But importantly, we expect access conditions for NTLA-2002 to be similar to branded HAE prophylaxis drugs. All in, our market research indicates there's significant enthusiasm for a one-time treatment that will lead to an attack-free and/or treatment-free status. With these long-term Phase I results, we are seeing the target product profile of NTLA-2002 take shape. We look forward to sharing the Phase II data later this year and believe we are closer than ever to delivering on a potential functional cure for people living with HAE. With that, we'd be happy to answer any questions. Operator, you may now open the call for Q&A. We will now begin the question- and- answer session. To ask a question, you may press star, then one on your touch tone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Maury Raycroft with Jefferies. Please go ahead. Hi, good morning. Congrats on the update, and thanks for taking my question. We're still waiting for your Phase II data, but it will be good to hear your views on whether the 25 mg dose, where you're getting consistent, approximately 60% knockdown, if that could be sufficient to eliminate attacks. How that's informed by the Ionis donidalorsen data, where they're showing about 60% knockdown. I don't know if you have any perspective on that and just how you're thinking about that dosing decision based on your Phase II data for the Phase III study. Maury, thanks for the question. You know, as you can tell, we're very excited by the data that we've just shared in the last day or so here. A s we've, you know, been saying repeatedly, our objective is, you know, to get to patients who are not only attack-free, but are effectively treatment-free. We 've seen that with the majority of these patients, in fact, eight out of ten. So in terms of where we're going, we're making very, very significant progress. I think what we've learned is that more suppression is better. There may be diminishing returns at very, very low levels of kallikrein. But when we look at some of the data that's been recently produced, it's our sense that there's a trade-off for patients that are taking chronic treatments between convenience, you know, the repetitious dosing and the ultimate knockdown that they get with kallikrein. A s you can see from the data we've presented thus far, that doesn't exist with our therapy, where after a single application, we're able to get to very low levels of kallikrein, and you see the results we presented that go with that. So we look forward to sharing the Phase II results as they become available mid this year a nd that will set us up for the Phase III work that we expect to begin before the end of the year. So stay tuned. Got it. Thank you. Thanks for taking my question. The next question comes from Gena Wang with Barclays. Please go ahead. Thank you. Also wanted to add my congrats as well. Great data. So I have one question for Dr. Longhurst. So I know the at the primary observation period, we do see, say, two patient attack out of 10, but when we look at each patient, the first patient in the 25 milligram, it's already attack-free after that attack happened for, like, 50 weeks. T he second patient in the 75 mg cohort, that's also my rough calculation, is about 48 weeks. So how would you see this, you know, the close to 50 weeks attack-free after last attack? How would you define attack-free, and do you think that that should be, you know, the any concern for future potential attack coming back? Yeah, Dr. Longhurst, maybe you could address that. In essence, the question is, are we 10 out of 10 patients for, who are truly attack-free? At what point, belatedly in the observation period, a single isolated attack, does that even count as an attack? I think that this is a question that we're in the very fortunate position of having to think about, perhaps for the first time. But I will say that all 10 patients actually consider themselves cured. I think for patient two, he was actually attack-free after 16 weeks, and it was just that initial period. J ust to give you a bit of background, with hereditary angioedema, this patient was very, very severely affected and actually had a swelling that ruptured his kidney, so the, you know, where the ureter goes into the kidney, while he was waiting, prior to the treatment. So this is, you know, the sort of thing that he was undergoing. So I think that this patient, as his kallikrein levels fell, and he felt low level symptoms that were similar to the beginnings of an attack, but of course, he had no kallikrein. The angioedema couldn't be generated, and the attack didn't go anywhere. I think it probably took him a while to, you know, understand the new situation. I will say he has no symptoms of any sort now and has taken on a huge load of extra activities that he never would have considered previously. So I think that we. I I guess our new attack definition will have to give some sort of denominator, and I'm hoping it would be along the lines of a very, very low annual risk or a very, very low five-year risk for an attack. But, you know, clearly we want people to have no attacks, and, you know, it looks as if this might be possible. Thank you. The next question comes from Mani Foroohar with Leerink Partners. Please go ahead. Hey, congratulations as well from me. You know, clearly a path to best-in-class data here. A quick question in terms of the practicality of the market. Presuming that this profile continues through a pivotal and is approved by FDA, EMA, et cetera, is broadly available, how much concern is there amongst patients for a potentially irreversible genetic therapy? That's a debate that's had amongst investors, if perhaps less so amongst the physicians we've spoken to, that there might be some reticence to take an irreversible therapy, some reticence to have a gene editing approach. How real is this reticence among the patients, or is this more of a sort of Wall Street debate than a physician-patient debate? Mani, thanks for the question. Good to hear from you. Yeah, we presented the market research that we found, and obviously we're very interested in understanding this deeply. So we probed not only physicians, but patients themselves, and we've tried to characterize what we've learned. There's clearly different groups of patients in terms of how they think about this. But the takeaway that we've come to is that the majority of patients will definitely consider taking a drug like this. In terms of what other barriers and conversations they may have with their physician, I'll turn to Dr. Longhurst here in a moment, and maybe she can address some of the interactions that she's had with her own patients. But as we look at the market, we find that what patients want to have is a normal life, and that consists of no attacks, no treatments, and not having to adjust their lives in a way that they avoid those stimuli that lead to the presence of attacks. T hen, obviously, what comes with that is the ability to freely change jobs and not feel constrained somehow by the insurance plan that you may have at your respective employer. W hen presented with all of those characteristics, what we found is that the majority, in fact, the vast majority of patients, certainly here in the U.S. and in Europe, are very, very attracted to a drug with this profile. You know, obviously, we need to present the Phase III data and Phase III data to build on the data that we have here. But assuming all that holds, our expectation is that the drug will be welcomed by many patients. Maybe Dr. Longhurst, I can turn to you, and you could just describe some of the conversations you may have had with your patients in terms of a gene therapy, as opposed to some of the other approaches that are available. Sure. I think to summarize, I'd say that patients are hugely more go for it and wanting this sort of treatment than maybe doctors who are, you know, wanting to wait for more information. Although, I have to say, I feel pretty confident, and obviously, the authorities are much more conservative, as you would expect. I will say that we do have certain ethnocultural groups in New Zealand who we would expect to reject gene editing as a treatment. But when it comes down to it, we've actually included two patients from these ethnic groups who've actually been, you know, very keen to have the treatment. So yeah, I think patients are keen. One of the things I think has always, has already been alluded to is that when these patients are in huge fear of attacks and what the next attack might bring, and if you can control the attacks, that's great. But they then have the fear that that treatment that controls the attacks may be taken away, so they've got a concern if they want to relocate to another country, if they want to change jobs. S o the idea of having a one-off permanent treatment is, is hugely attractive, much more than I would have expected, actually. Maybe I'll turn to Jim Butler, our general manager of the program. Jim, can you, you know, build on this notion of and just think about the Phase II enrollment rate and Phase III interest as you guys prepare for Phase III later this year? What are you seeing? Yeah, sure, John. So what's been really interesting, and I think Hilary started to allude to this, is that as the patients have started talking with one another, we see a lot of, a lot of interest starting from that, from that perspective, and it drove a lot of our interest in our Phase II, and we're already seeing a lot of this, some of the word's getting out, and I think you see, we're already seeing a lot of interest in the Phase III. So, you know, more data to inform, obviously, but we're pretty optimistic that patients will be interested. Thanks. Great. Thanks for the question, guys. The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead. Hello. Congrats on the data, and thanks for taking our question. A question from me on, maybe the characteristics of the two patients who had an attack, and specifically, anything uncommon with their body weight, given that, you have a flat dosing and not dependent on, on the weight. Maybe these patients had a higher weight, so they got maybe perhaps lower dose than the others. In general, your thoughts around flat dosing, given that your peers are using weight-based dosing for gene editing, but you have been using flat dosing, which seems to work, perfectly well, by the way. Any thoughts on whether you have seen any correlation between weight, weight and, efficacy would be helpful. Thank you, and congrats again. Yeah, thanks for the question, Kostas. The weight-based dosing is something we've looked at throughout the course of this program and the highly related NTLA-2001 program. You remember that this is a modular approach, where the LNPs are essentially identical, with the exception of 100 nucleotides in the single-guide RNA. What we've learned is that the degree of editing is really quite independent of body weight within a given dose. So a simple way of thinking about this is really what you're treating is the liver, as opposed to exposure to the rest of the body. A s we've looked at the limits of that is within a given dose, patients at the lower or higher end of body weights tend to behave essentially in a bioequivalent fashion. That's what's behind, you know, the flat dosing approach that we've taken. That also translates into safety in the clinic. There's fewer things to decide and things that might go wrong. It's less confusing for patients. It avoids some of the payer challenges that might come with different doses, et cetera. Maybe Dr. Longhurst, we could just turn to you. Outside of weight, are there any other characteristics that you think might influence how some patients might respond to this drug or any of the other drugs that are used for the treatment of HAE generally? There were no clear characteristics, and in fact, our highest weight patient, 130 kg, had no attacks at all after treatment. Whereas patient two, I think, Patient 1, sorry, weighed around 75 kg, so he wasn't a large person. Patient 6 was a relatively small woman who I think also had a relatively low body weight. I do think people who've had very frequent attacks do tend to, or very, alarming attacks, tend to take a little bit longer to settle down, and, you know, that could be this mistaking early symptoms issue. But I don't have any strong impression because obviously everyone is essentially attack-free. Very helpful. Thank you. Congrats again. The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead. Great, thanks for taking our questions. Congrats on the very impressive data here. So, one quick one is on safety. I think, to be called a cure, it not only implies complete efficacy but also complete safety. So I'm wondering, for any of the AEs, is it true that there is no ongoing low-grade findings, and all of that is probably early and associated with dosing? T hen the quick follow-up is on the upcoming Phase II data readout. Can you remind us of the number of patients and also, perhaps more importantly, duration of follow-up? A lso given, I think, there is a little difference in terms of patients coming off prophy, the timing of that, compared with this data set we're looking at, can you talk about whether that could lead to any potential difference in efficacy findings within the follow-up? Thanks. I think I got the nested questions there, but maybe, David, you could just say a word about the safety profile. You know, what’s the duration of any safety events, and then we can address some of the other questions here. Yeah. What, what we've seen in safety with, this program, of course, 2001 having a very similar structure, that program as well, is that the events are only very early on that we've seen. We don't see anything beyond the initial, treatment. T he only thing we've seen initially that seems, that does seem to be related to LNPs is the, infusion reactions, these low-grade infusion reactions that have been seen. None of them have prevented the patients being treated. None of them have been, very significant, as, as we've heard. So the, the safety is really, quite good. In Phase II, there are 25 patients. The follow-up, we're, you know, we're not talking exactly about what the, the following readings will be at the time of the report, but, you will hear about that fairly soon. T hen- No patients have been on prophy first. Now, as you've seen, patients who are on prophy, patients who weren't on prophy, all of them, have remained attack-free. So that really hasn't had an effect. Of course, these patients on prophy, you know, came off it for various reasons, and they've been able to do without it at this point. I think it's really important to emphasize that last point, because the, you know, the, the paradigm shift that we're working towards here is patients become attack-free. They're treatment-free, which means not only they do not take prophylaxis, but they can dispense with even their on-demand therapy. That's what we're aiming for, and what you've seen here in this long-term Phase I follow-up is that we've been able to achieve that. So we're very excited about expanding on that database as the Phase II program, something that we'll talk about later on this year as we move to Phase III. So maybe we can turn to the next question. The next question comes from Luca Issi with RBC. Please go ahead. Oh, great. Thanks for taking our questions. This is Lisa, also Luca. Congrats on the data. I just wanted to touch on your use of lipid nanoparticles here as a delivery vehicle. You know, given the recent safety setbacks we've seen from Verve's editing program, which potentially might be attributed to lipid nanoparticle use. Just, you know, wondering overall how you are feeling about the overall safety profile of your lipid nanoparticles to date. T hen, as a follow-up, can you remind us of any differentiating features between your lipid nanoparticle and Verve? Thank you. Yeah, thanks for that, I think, very important question, Lisa. I think there's a common misconception out there that all lipid nanoparticles are created equally. That's a real, you know, flawed belief and just something that is really critical to understand. I mean, since this company was formed, we've focused on the in vivo approach, and with that, we've taken great care to build out an LNP modular system, for which we've reported on over 100 patients thus far, that has a safety profile that we see as unmatched with anyone who's been in the LNP systemic delivery space thus far. That has to do with how the LNPs, you know, the constituents of the LNPs... how they're assembled, how they're characterized, and how they're administered to patients. We're rapidly expanding on that database as we move through our Phase III program with NTLA-2001 for TTR amyloidosis. O bviously, we'll be expanding on that safety database when we present our Phase II data for NTLA-2002 and move to our Phase III program. But thus far, we're elated with the safety that we've seen, which corresponds to what we saw pre-clinically, which again, we think differentiates from what we've seen from others who have been active in this space. Thanks so much for taking our question. The next question comes from Mary Kate Davis with Bank of America. Please go ahead. Good morning. Thanks for taking the question, and congrats on the data. Looking at the 90% reduction in all attacks in the primary observation period here, how are you guys looking at the follow-up time post-administration needed to reduce attacks? M aybe of the breakthrough attacks that you've seen, would you consider these typically more or less severe or easier to control? Thanks. David, do you wanna talk about how attacks change through time, and then maybe we could turn to Dr. Longhurst after that, just so she could share some of her experience thinking about this. Sure. Just in general, what we know about the pharmacodynamics is that the levels of prekallikrein come down within the first month. So we certainly expect that after the first month, we reach a stable amount of prekallikrein and ultimately perhaps a stable amount of attacks. We've seen that's not always true, that Dr. Longhurst talked about, that the patients who come in with very frequent attacks have a somewhat different pattern. But in the end, at 16 weeks, as you saw, all patients have basically eight out of 10 patients have gone to zero attacks and a single attack in the remaining two patients. Maybe Dr. Longhurst, if you wanna... If there's anything to add in terms of how you think attacks may change through time, even independently of pharmacokinetics and pharmacodynamics. Any perspectives? Yeah. Well, I can talk about what we've seen and the two late attacks. One, you know, it was an abdominal attack. It was on a plane. There was all sorts of things going on, so very difficult to make any comment on that. T he other one was, you know, a provoked attack. It was a hand swelling. It certainly wasn't. It was a mild attack. On balance, I thought it was probably hereditary angioedema, but you know, if you get a football stud in your hand, it probably will swell up a little bit. So difficult to know whether it was normal or, you know, actually pathological. It was that sort of level. Those attacks are, you know, were both really difficult to comment on, but certainly nothing, not the massive angioedema that we would see in untreated patients. Dr. Longhurst, do you think patients may- That people- Dr. Longhurst, do you think that patients may think differently or how may perceive their attacks differently through time? Yes, I do. T his, I think there's two things. One is that people have lived with chronic fear and chronic pain, and when that's taken away, I think there are, you know, the brain gut axis actually takes a while to reset if you've had what can be a very traumatic, it's family trauma, because a lot of these people have had family members who've died. So you've had a very traumatic time, and it takes a while to settle down. F or example, Patient 004 used to have throat swellings. His uvula, which is the dangly bit at the back of the throat, used to swell up. O f course, that's, you know, potentially extremely dangerous. So if he experienced any symptom in his throat, he would immediately treat. I think it took him a while to get the confidence to know that, you know, he didn't have to treat. Nothing was going to happen. The next question- Does that answer your question? Sure. We can go to the next question. Thank you. Thank you. The next question comes from Rick Bienkowski with Cantor Fitzgerald. Please go ahead. Hey, good morning, and congrats on the great data here. I appreciated the detail around the three different groups of commercial patients that were split into the inadequately treated patients on prophylaxis, the well-managed ones, and patients that currently avoid prophylaxis. Could you remind us of the enrollment criteria of the Phase II, and if we should expect that patients from all three of these groups will be represented in the trial? David, for the Phase II, which again, we'll be reviewing later this year, maybe you could remind us what the entry... Are we having a broad-based set of patients that's reminiscent of all three groups that we described in our market research, is really the question here. Yeah. No, thank you. This, this trial would allow all three of those types of patients in. Patients who are coming off prophylaxis in the Phase II, you'll hear more about that, as well as patients who, who haven't been on prophylaxis. So really, a t broad enrollment, we do think this has potential to benefit all patients and, and as we say, hope to get to a normal life where they have no attacks and no prophylaxis. D o you think that that will also be true for the Phase III program you currently envision? The Phase III will be the same entry criteria. Thank you. The next question comes from Joon Lee with Truist. Please go ahead. Hey, congrats on the really impressive data, and thanks for taking our questions. I have a question for Dr. Longhurst, and it's a variation on Mani's question earlier. Is there any theoretical risks associated with deleting plasma kallikrein? W ere there any AEs of particular interest you would need to follow beyond the scope of the trial setting? V ery quickly, is re-dosing an option for NTLA-2002, like you did for 2001 a nd were there any immune reaction against Cas9 during the second dosing? Thank you. Well, before we have Dr. Longhurst respond to questions of is there a risk with having kallikrein levels that are too low, what we've shown with NTLA-2001, again, essentially an identical LNP, is that we are able to redose those patients, and that's been done successfully. That's not currently part of how we think about the NTLA-2002 program, but you know, as we go forward, I'm sure we'll think about all of the best ways to deliver the best care that we can imagine for these patients as we go forward. But Dr. Longhurst, can you say a word about kallikrein levels? Is there a point at which you worry if they may be too low and any adverse events that may result from that? Sure. So, we do know that there are people who are born without any kallikrein at all, so they've got a genetic absence of the PKK gene, and they, as far as we can tell, they live completely normal, healthy lives and, you know, their children are healthy. So I think the short answer is no. There are kallikrein inhibitors out there which are used chronically, and they've been very well tolerated. T he other thing to say is that actually we're not completely removing kallikrein, so we don't see the, you know, the laboratory changes that we would see on someone who was born without any kallikrein at all. So there was no way that we could tell from routine blood testing that these people had the treatment that they've had. N o, we haven't seen any, you know, serious adverse effects or indeed any special adverse effects of special interest. So we have, we've been very interested in potential for thrombosis or bleeding, which, I would say, is theoretically very unlikely to happen. But, and we just haven't seen it, so all good. Thank you. The next question comes from Joseph Thome. I n fact- Go ahead, sorry. I was going to say this sort of treatment would be more suitable for someone who had a thrombotic or bleeding risk than some of the current treatments that we use. I n my opinion. The next question comes from Joseph Thome. Excuse me, Thome, with TD Cowen. Please go ahead. Hi there. Good morning. Congrats on the data update, and thank you for taking my question. Maybe just overall on the efficacy profile and sort of overall benefit of the therapy. Obviously, post 16 weeks, when patients are, you know, coming off prophylaxis, the value proposition is really driven home. So how is that impacting your thinking for how long you want to follow patients in the pivotal study? M aybe with regards to the FDA interactions, how clear is the agency, in terms of how long they want patients followed before potential regulatory approval, as you did mention, this could potentially be the first in vivo gene editing, therapeutic approved. Thank you. David, do you want to address duration of follow-up in the Phase III program and how we're going to think about that and some of the regulatory interactions? Yeah. So the Phase III program will be similar to other Phase III programs. That's what's been happening. You know, that's what the regulators like to see, like to see six months of follow-up, and you'll be seeing our exact design, but we do think that's the right period. Now, there will be patients who are followed longer, you know, over the course of a trial. Some patients are enrolled earlier, some later, so we will have more than that six-month follow-up. In fact, we will not only, you know, the trials are usually designed for about two years, and in the case of gene therapies, we'll be following them for 15 years. So, I think we'll be able to show the value proposition of this over a very long period of time, that, you know, if we do achieve an attack-free state, we'll be able to show that it does exist for years a nd that's what we expect to see. You saw what the pharmacodynamics look like. We get to very low and very consistently low levels, really, in all patients, and that, that we think will be a big advantage over other therapies. Thanks, Dave. The next question comes from Ry Forseth with Guggenheim. Please go ahead. Hey, thanks for taking our question. For the NTLA-2002 Phase III study at fewer than 100 patients, would it be possible to do a statistical analysis of the nature of attacks at baseline versus on treatment to establish labeling claims around treating the severity spectrum of the attacks from mild to life-threatening? Well, before David talks about the statistics and what we're going to be able to extract from that Phase III trial, I would just make the point that our objective is to have the broadest possible label, not only for severity, but also for age. T hat is something that we've been working very closely with the regulatory agencies to get to a point of, of, you know, implementation for this trial. David, in a smaller study, typical of this class of, or, you know, this type of drug for a treatment of HAE, you know, can you say a word about what we hope to suss out of some of these findings? Again, we, we do think the label will be broad, and we, because we will include patients who have relatively infrequent attacks, to some patients, as you've seen in our Phase I, who do have frequent attacks. That's not usually tested statistically in these studies. It's really small numbers of patients in the studies, but in terms of who would be appropriate for the treatment, it will include that broad range of patients. Thank you. The next question comes from Brian Cheng with JP Morgan. Please go ahead. Hey, guys. Thanks for taking our question this morning. Just curious if you can provide a little bit more color about the two attacks, you know, in terms of their... And whether you have seen any spike of plasma kallikrein that you're tracking when these patients experience the attack. Also, have you looked into the driver of these attacks historically? Thanks. Maybe we can turn to Dr. Longhurst, and if you've looked, noticed any kind of relationship in these two patients that have had their single isolated attacks and kallikrein levels? So, Patient 1 actually had quite a small reduction in the kallikrein compared to the other patients. But he has been attack-free apart from this one attack. Patient 6, who had an attack, I'm actually trying to remember, but I think she had a very profound reduction in kallikrein. So no, I don't think there is any signal there. Yeah. J ust to add that, you know, we do measure the kallikrein before and after these attacks, and it remains very low in all cases. I think that's one of the key attributes of the approach, is that the levels are essentially invariant as a result of the treatment. Yeah. Thanks. Thank you, Brian. Do we have time for one more question? Yeah, Drew, let's... I think we have time for one final question, Drew. Okay, that question comes from Dae Gon Ha with Stifel. Please go ahead. Hey, good morning, guys. Thanks for squeezing me in here, and congrats from me as well. Just looking ahead on Phase II and potentially Phase III, I know we've touched on the breakthrough attacks, but I wanted to take a slightly different angle. For Dr. Longhurst, but also for Phase III, when you start including U.S. patients, what kind of site training and patient training are you looking to implement to make sure we're not including breakthrough attacks that might actually not be attacks, as Dr. Longhurst was saying? Particularly curious, as donidalorsen, we had that OASIS data, that best-in-class profile. Just trying to see if you can design this trial well enough to see that definitive differentiation. Thanks so much. Let's turn to Jim Butler, and then you can supplement that what Dr. Longhurst. She has clearly been advising us as we think about this, but how are you guys implementing some of this for the Phase III effort? Yeah, I'd say it's... I mean, as you might expect, we have a standardized approach, part of site training, right? To try to identify and adjudicate attacks. But ultimately, this is left up to the investigator, and they have to use their judgment, right? They're the ones seeing the patient. But we do, but, you know, we are careful to and mindful that, you know, we wanna be as thorough and consistent as possible. I think Dr. Longhurst could probably speak better to that as a clinician who actually sees these patients, because I suspect what we're doing globally will be very similar to what we've done with her. Yes. So I think it's actually one of the most difficult questions because you've got a subjective endpoint in most cases. So if someone does report a swelling, then I would want to see a photograph of it. But of course, for the internal attacks, there's often nothing to see, particularly if they've been treated. R eally, the way I address it is I have quite a long discussion, a long and ongoing repetitive discussion with the patients about the natural history of an attack, which is very low-level symptoms, which could be completely nonspecific. It doesn't have to be HAE. T hen if it's HAE, the symptoms will worsen. I actually ask people when they're contributing to a study, to try and hold off a bit longer than they normally would with their treatment, just to be sure that this is actually an attack. But that's a huge ask for many of these patients, and particularly if they've got things to do, places to be. Actually, I think we've learned a lot from those early attacks that happened, you know, in the first few weeks. This business of people feeling like an attack might be starting and then it going away. I think, now we know about that, we can advise the patients that when you're on active treatment, you know, this might happen. It doesn't tend to happen long term, but it might happen very, very early on. Really, it's an ongoing discussion with the patient to help them understand what their body's doing. And this huge, you know, if they've had active treatment, this huge transformation from, you know, not having this, you know, chronic, painful disorder. So it's, it's difficult and it's, it's a dialogue, but I think we're, I think we're getting better at it, actually. As one of my patients said to me, he always thought it was an attack or not an attack, but he now realizes that there's whole shades of gray. Thanks, Dr. Longhurst. I think with that, Drew, yeah, I think with that, I'll close us out. So thank you everyone for joining us. While we still have Dr. Longhurst, a special thank you for joining us. I think your insights were certainly very helpful to put some broader context on the patient perspective. So thank you for joining. F or everyone who joined the call, we look forward to giving you further updates as we progress later in the year. So until then, have a great week. Bye, everyone. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.