Good morning, and welcome to the Intellia Therapeutics Investor event. My name is Alan, and I will be your conference operator today. Please be advised that this call is being recorded at the company's request. At this time, all participants are in listen-only mode. Following the formal remarks, we will open the call up for your questions. I will now turn the conference over to Lina Li, Senior Director 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 conference call to discuss the results from the NTLA-2002 Phase 2 study. Earlier today, Intellia issued a press release detailing these data, which were published in the New England Journal of Medicine and will be presented at the American College of Allergy, Asthma, and Immunology Annual Scientific Meeting or ACAAI. This release, along with the accompanying presentation and slides from today's webcast, 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. Before we get started, 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 discussions 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. Joining me on today's webcast are Dr. John Leonard, our Chief Executive Officer, Dr. David Lebwohl, our Chief Medical Officer, and Dr. Danny Cohn, Internist in the Department of Vascular Medicine at Amsterdam University Medical Center, and the lead principal investigator of our NTLA-2002 Phase 2 trial. Also on the call and available for Q&A are Dr. Paula Busse, Professor of Medicine in Clinical Immunology at the Icahn School of Medicine at Mount Sinai, and Dr. Jim Butler, our General Manager of the NTLA-2002 program. As outlined on this slide, we will begin with introductory remarks from John. Then Dr. Cohn will review the NTLA-2002 Phase 2 data, followed by David, who will provide an update on our hereditary angioedema program, including a review of the recently initiated Phase 3 study, before opening the call for questions. With that, I'll now turn the call over to John. Thank you, Lena. Welcome, everyone, and thank you for joining the call today. At Intellia, our relentless focus on advancing our proprietary CRISPR-based gene editing platform and clinical execution has positioned us at the forefront of a new era in medicine. With three active Phase 3 studies expected by year-end, we are on track to bring forth the world's first-ever in vivo CRISPR therapies to patients. Back in August, we shared positive top-line results from the Phase 2 study of NTLA-2002. Today, we will be reviewing the full data set that we believe clearly demonstrates NTLA-2002's potential to be a functional cure by eliminating HAE attacks after a one-time treatment and removing the need for further treatment. With this potential product profile, NTLA-2002 could represent a total paradigm shift for how HAE is treated, addressing the desire of patients to live a life free from attacks and the ongoing treatment burden of chronic therapies. Before Dr. Cohn reviews these data in greater detail, I want to take a moment to reflect on the key learnings from the Phase 2 study. Both a single 25 milligram and 50 milligram dose led to deep reductions in attacks. The safety and tolerability profile observed continued to be highly encouraging and was consistent with its Phase 1 profile. As we anticipated, the 50 milligram dose led to a greater response compared to the 25 milligram dose across all measures of efficacy. An impressive eight out of 11 patients achieved a complete elimination of attacks, an unprecedented result for this disease after a one-time treatment. Overall, it's clear when looking at the totality of Phase 1/2 data, that the 50 milligram dose is the optimal dose to advance into the Phase 3 study. As previously announced, we recently initiated HAELO, the global pivotal Phase 3 trial, and expect to submit a BLA in 2026. We are full steam ahead in our efforts to bring what could be the world's first approved in vivo CRISPR gene editing treatment and a truly transformative one-time treatment for people living with HAE. With that, I am honored to turn the call over to Dr. Cohn, our lead principal investigator for the Phase 2 study and a global leader in the research, diagnosis, and treatment of HAE. Thank you, John, and good morning, everyone. Here are my disclosures. Hereditary angioedema, or HAE, is a rare genetic disease leading to frequent, severe, and unpredictable swelling attacks. NTLA-2002 is an investigational therapy designed to selectively target the KLKB1 gene with the goal of lifelong control of hereditary angioedema attacks after a single dose. Today, I will share results from the Phase 2 portion of the first human study. The primary efficacy endpoint was the number of angioedema attacks per month during the 16-week primary observation period. Key secondary endpoints included safety, the number of angioedema attacks per month during weeks five to 16, and the change from baseline in the total plasma prekallikrein protein level. Before I walk through the results, we thought it would be helpful to highlight the key differences in trial dynamics between the Phase 1 and Phase 2 portions of the study. For the Phase 1, this was a small, open-label study with the goal of evaluating safety, tolerability, as well as initial efficacy. Concurrent use of other long-term prophylaxis was allowed, and because there was no placebo control, attack reduction was measured relative to patients' baseline. In contrast, the Phase 2 was a double-blinded, randomized, placebo-controlled study, which enrolled a total of 27 patients. One notable difference was patients were required to wash out their chronic prophylaxis therapy prior to receiving NTLA-2002 or placebo. Following the 16-week primary observation period, patients were then allowed to resume prior therapy at the discretion of the investigator. Patients randomized to placebo are now being offered the option to receive 2002. The second key difference was the attack rate calculation. Unlike the Phase 1 study, where the rate reduction is relative to each patient's baseline rate, the Phase 2 attack rate reduction is the difference in attack rate between patients who received NTLA-2002 and those who received the placebo. The objective of Phase 2 was to further study the efficacy and safety of the 25- and 50-milligram doses and determine which dose to move forward into the pivotal Phase 3 trial. The data cut-off date for this update is April fourth, 2024, when 25 out of 27 participants completed the 16-week primary observation period. Here you can see the patient demographics, which include both male and female patients across a wide range of ages, from 18 to 76 years old. The enrolled patients had a range of baseline disease severity that is representative of the broader patient population. 17 of the 27 patients were previously on long-term prophylaxis therapies. Notably, five patients washed out of lanadelumab to enroll in the Phase 2 study, and four patients washed out of berotralstat. The mean baseline monthly attack rate was 3.6 in both the 25- and 50-milligram arms and 3.7 in the placebo arm. Starting with safety, we are very pleased to share that NTLA-2002 continued to be well-tolerated. The most frequent adverse events were headache, fatigue, and nasopharyngitis. There have been no serious adverse events, and all adverse events were either grade 1 or 2. There were also no clinically significant laboratory findings observed. Moving on to the first measurement of activity, kallikrein reduction. A single administration led to dose-dependent and durable reductions from baseline measures of plasma kallikrein. The dotted line at the 60% mark on this slide represents our minimum target level of kallikrein inhibition based on the leading approved chronic HAE therapy. While this level often results in clinically meaningful reductions in attacks, many patients on current treatments continue to experience breakthrough attacks, and all must contend with significant treatment burden. As shown here, the 50-milligram dose exceeded this target protein reduction, resulting in a mean plasma kallikrein protein reduction of 86% at week 16. Importantly, the deep reductions were sustained through the latest follow-up and highly consistent across all patients treated, as indicated by the very narrow error bars seen on this graph. Turning now to the attack rate reductions, a single 25- or 50-milligram dose of NTLA-2002 led to deep reductions in attacks for patients with hereditary angioedema. The mean monthly attack rates relative to placebo were reduced by 75% and 77% for the 25- and 50-milligram arms during weeks 1 to 16, and by 80% and 81% during weeks 5 to 16, respectively. NTLA-2002 led to reduced levels of attack rate reduction at both doses, with the 50 milligram once again outperforming the 25 milligram dose. Similar to the Phase 1 study, we expect these attack rate reduction percentages will continue to increase with longer follow-up. Next, let's look at the patient-by-patient view. Here you can see HAE attacks for each patient during screening, primary observation, and the post-primary observation periods through the latest follow-up. The colored lines indicate any HAE attacks that occurred in either the screening period or in the subsequent observation periods following administration with NTLA-2002. Each line portrays the incidence, duration, and severity of attacks experienced by the respective patient. On the left, you see the attack rate reduction from a patient's baseline during weeks 1 to 16. On the right, you see the change in plasma kallikrein through the latest follow-up. Now, let's zoom in on the patients who received the 50-milligram dose. As you can see, 10 of the 11 patients achieved a clinically meaningful reduction in attacks during the primary observation period. Remarkably, and the key differentiator for NTLA-2002, 8 of the 11 patients ceased to have any attacks after receiving NTLA-2002, despite a mean attack rate of 3.6 attacks per month prior to treatment. All 8 patients continued to be free of all attacks through the latest follow-up and did not require any further treatment. Further, only 11 patients in the 50-milligram cohort achieved clinically meaningful reductions in attacks in the post-primary observation period. The three patients who did not achieve a complete response in the 50-milligram arm reported frequent breakthrough attacks prior to enrolling in the study and while taking other standard of care prophylactic therapies, including berotralstat, Cinryze, and lanadelumab. While these patients did experience a clinically meaningful benefit from NTLA-2002, it is unclear at this time why these three patients did not have a complete absence of attacks, or if these patients will ultimately achieve complete attack control after a longer period of time, as we observed in the Phase 1 portion of the study. Given the absence of a biomarker to confirm that symptoms experienced by participants are all true angioedema attacks, we rely on patients reporting their symptoms and use of acute treatments. Notably, patients may take some symptoms for early signs of an internal angioedema attack, such as throat irritation or abdominal discomfort, which may or may not be angioedema attacks. In the 25 milligram arm, we saw four of the 10 patients, or 40% of patients, experience the complete response. In the 50 milligram arm, eight of 11 patients, or 73% of patients, experienced a complete response with no attacks at all during the 16-week period and beyond, and no subsequent treatment required after a single dose of NTLA-2002. This high complete response rate led to the selection of the 50 milligram dose level for further investigation in Phase 3. In summary, results of the Phase 2 study continue to demonstrate that a single dose of NTLA-2002 has the potential to be a functional cure for patients with HAE. We are proud to have our groundbreaking clinical data published in the New England Journal of Medicine, which is now available online. Finally, I would like to thank the patients. Thank you, Dr. Cohn. We appreciate your leadership on this trial and your conviction in the potential of 2002 to be a transformative treatment for patients with HAE. As Dr. Cohn mentioned, we have selected the 50-milligram dose to advance into the global Phase 3 trial. The 50-milligram dose led to greater kallikrein reduction and importantly, a higher number of patients who achieved complete elimination of attacks compared to the 25-milligram dose cohort, consistent with prior Phase 1 results. In our view, these results speak directly to the strong potential of 2002 to reset the standard of care for HAE. We have now advanced 2002 into the final stage of clinical development, where we hope to further demonstrate what we've observed in the Phase 1/2 study. We are actively screening patients in the HAELO Pivotal trial, a global, randomized, double-blind, placebo-controlled study. 60 patients will be randomized two to one to receive a single 50-milligram infusion of NTLA-2002 or placebo. Patients randomized to the placebo arm will be eligible for optional crossover to NTLA-2002 at week 28. The primary endpoint is the number of HAE attacks from week 5 through 28. A key secondary endpoint will be the percent of patients who achieve attack-free status during the same time period. Importantly, the data from the primary analysis will support our planned BLA submission in 2026. Ultimately, our goal for NTLA-2002 is to functionally cure people with HAE. As such, we're evaluating complete responder status in the Phase 3 trial. That is a treatment outcome in which patients are both free from attacks and untethered from requirements of chronic therapy following our one-time treatment. Looking ahead, we believe that if approved, there will be a strong demand for 2002. We recently conducted market research to get a better understanding of how 2002 could fit into the treatment landscape, and the results were loud and clear. Despite available treatments, HAE patients are seeking improved efficacy and convenience. In a survey with patients and caregivers, there were three key themes reported. First, many patients continue to have attacks even when taking existing therapies and therefore are seeking a further reduction in the frequency of their HAE attacks. Second, patients expressed a strong desire for treatments that are less burdensome, offer more freedom, and ultimately a better daily life. Third, access-related challenges such as health insurance renewals, delays, and denials of chronic treatments, have a significant negative impact on the quality of life for HAE patients. Across all three of these factors, we believe 2002 has the opportunity to reset the treatment paradigm for people living with HAE. What was previously an unimaginable potential to be free of chronic therapy and free of attacks, is one step closer to becoming a reality for the HAE community. In both the patient and physician surveys, there was high interest for 2002' s product profile. In a survey of over 190 physicians who treat HAE patients, we found that over 75% of these U.S. prescribers would offer a product with 2002 's target profile to all patients within three years of launch. And over time, we anticipate this percentage will continue to grow. For HAE patients who are typically diagnosed in their adolescence, they must contend with many decades of treatment. Their current options are limited to chronic long-term prophylaxis treatments, either regular IV infusions or injections, or a daily pill in exchange for lower efficacy or on-demand therapies once an attack has already begun. As such, patients need to plan their lives around the limitations of existing treatment options. When you walk in the shoes of a patient, we believe the option of a one-time treatment that could eliminate all attacks will be a compelling choice. We are now focused on rapidly enrolling the Phase 3 study, which we believe will demonstrate what we've seen thus far. NTLA-2002 can be a one-time treatment that offers the potential of a complete response for people living with HAE. We are grateful to the patients and their families who participated in our clinical study, and thank our investigators and Intellia colleagues for their continued efforts to advance NTLA-2002 to patients. With that, we'd be happy to answer any questions. In addition to Dr. Cohn, we are pleased to have Dr. Busse here with us today to share her insights as an expert physician in the HAE space. 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 touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw it, please press star then two. We ask that you limit yourself to one question before reentering the queue. At this time, we will pause momentarily to assemble our roster. Our first question comes from Luca Issi of RBC. Please go ahead. Oh, great. Thanks so much for taking the questions. Congrats on the data. I have a quick one, maybe David. How should we think about the data today versus the last time that it was presented? T he European Academy of Allergy, which was just a few weeks ago, you show a reduction in attacks in the low nineties versus today, you're showing a reduction in attacks in the low eighties or even upper seventies. What's the best way to rationalize why those numbers have come down just in a few weeks? Any thoughts there are much appreciated. Thanks so much. That the patients in Phase 1 were compared to their baseline rates, while in the arm changes in the placebo arm rates. David, can you just repeat that? Y ou were, there was a little bit of audio cut off there. T hanks, Luca. T o talk about some of the differences which Dr. Cohn started to talk about, is that in the Phase 1, patients were being compared to their baseline rate, while in Phase 2, they're being compared to placebo. So this comes out differently. The patients in Phase 1 came in, were able to be on prophylaxis, while in the case of the other study, the Phase 2, we did withdraw the prophylaxis prior to the patients coming on to the study. And part of being on a placebo-controlled trial is the patients don't know that they received the therapy. And in fact, in the data you've seen, they haven't at all been informed about what's going on. What we saw in the Phase 1, and the reason, one big reason it went to the higher, somewhat higher numbers, is that, the numbers of attacks went down over time as the patients realized that some of the things they were experiencing were not, maybe not HAE attacks. And Dr. Cohn mentioned some things like throat irritation would sometimes be interpreted as an attack, and the patients were taught to immediately treat those, before they even knew fully that it was an attack. And that's very smart for patients, but it does make it more difficult to interpret, these attacks. Maybe one other thought to add would be with the 98% reduction, that was with very extended follow-up, so the denominator of time grew. As we expect this pattern to play out again with this study as well, as we've seen all of the patients with continued follow-up to continue to have attack reductions. That's right. The most exciting thing about the data is the number of patients who had no attacks. Eight out of the 11 patients have no attacks. Adding that to the Phase 1, it's really 12 out of 15 now. So this is what we think patients are really looking for: a treatment, a one-time treatment with no additional burden of disease. ... in which they will be attack-free for their entire life without additional therapy. And that's what we're looking to get for all patients and the goal of our treatment. Our next question comes from Maury Raycroft from Jefferies. Please go ahead. Hi, congrats on the update, and thanks for taking my question. I have a follow-up to the last one based on the placebo response. The New England Journal of Medicine editorial mentioned that the intra-individual reduction of 16% attack rate occurred in the placebo group. How does that compare to historical Phase 3 placebo arms? And was this accounted for in your Phase 3 design and patient selection criteria? Cohn, do you want to address some of the particulars? I t's not unusual to have a decrease in the attack rate compared to baseline, also in placebo patients allocated to placebo. This was about 25% in the Phase 3 trial assessing lanadelumab, and we have seen comparable decreased numbers of angioedema attack rates also for garadacimab and donidalorsen. The next question comes from Mani Foroohar of Leerink Partners. Please go ahead. Thanks, Adrian. Congrats on the data. So the first question that I have, a two-part question. Question one is, can you clarify the difference in how an attack will be defined and adjudicated in the Phase 3 versus what we've seen in the Phase 1 and Phase 2 to get to apples to apples? And then I have, like, a quick follow-up. The answer to your first question is simple. It's the same. Great. And I'm looking at the patient response chart on page 17. You mentioned that obviously, as the denominator of time goes up, the attack-free patients have more and more follow-ups, so attack rates, so attack reduction rate evolves upward. Are there specific characteristics of the non-complete responders, especially patient one, that we should keep in mind? There's a little bit of incongruity between the depth of plasma kallikrein reduction and the attack rates for that patient, and I'm trying to understand if that's a something we keep in mind for baseline characteristics, or if that's just the variation in response that happens in relatively small patient populations. Thanks for the question, Manny. First of all, I'd say that there's an imperfect correlation between response and kallikrein reduction. That's not strictly one for one, and we've looked very, very closely at that. The other aspect as mentioned by Dr. Cohn, is really important to keep in mind, which is what patients experience and how they report what they're experiencing. What we've found and are continuing to find in this study, especially with the extended follow-up, is that when patients know they've received a drug, they're in a position to think differently about what they're experiencing, and report lower attack rates as time goes on. We've seen that uniformly in the Phase 1 study, and thus far as this study's playing out, we're seeing the same pattern. The next question comes from Terrence Flynn from Morgan Stanley. Please go ahead. Hi, thanks for taking our questions. This is Chris Yu on for Terrence Flynn. Just follow up the previous question. Two parts for us. For those three patients that did not get complete response, any similarities between them? That's one. And then second, did any of them receive rescue medication as a result of the attack? Thank you. So, first I'd like to remind everybody that the 8 of 11 patients that had no attacks is something that we shouldn't look past, as we see a handful of patients who are still probably equilibrating with respect to the therapy. But Dr. Cohn, if you want to speak to whether those patients received any therapy or differences in terms of how these patients responded. So these patients were from three different sites, but what they have in common is they have all used prophylactic therapies in the past and still had angioedema attacks during that long-term prophylactic therapy. In the other end, there is no way that there are no other similarities amongst these patients, except that they all had symptoms that could or could not have been angioedema attacks and were all treated early with on-demand treatment. And yes, the on-demand treatment, since we don't have any reliable biomarker, we won't know for sure if it was an angioedema attack. But all the symptoms resolved in the end, whether or not this was due to the on-demand treatment. The next question comes from Gina Wang from Barclays. Please go ahead. Thank you. I wanted to say thank you very much for the complete transparency of the data. T he slide 17 really lay out all the important information that we are interested. So for me, one puzzle is why certain patients, when we look at the attack rate, very high, we can debate, are these real attacks or not, but they still have some attack. But when we look at the kallikrein knockdown level, and we have a 91%, 89%, and you have another one that's about 78%. And then the other two, I look at all the eighty, pretty high level, maybe only one patient is a 46% knockdown. So can you help us understand, what... Why there is no clear correlation with this, and is that patient baseline characteristic? Is that baseline kallikrein the protein level? A nything you can help us understand. And another very quick question. Sorry, you said one question, but I, I do wanted to ask two doctors here. T hat with 70% attack-free rate, this clinical profile, what patient population you think it would be best suitable for this modality of a therapy? Maybe we can start with just the correlation of kallikrein. As you move to the higher dose, 50 milligrams, there's pretty similar reductions in kallikrein that we've seen at 25 milligrams. Y ou pointed to a patient within the 40s in terms of reduction of kallikrein. That's why we didn't choose that dose. So 50 milligrams, we think is definitely the way to go. We know from prior studies that patients, there, there's always a group that behaves a little bit differently. What we've seen in the Phase 1 study and what we're also seeing here is that that remainder set of patients, once they have information about the therapy that they received, may perceive what they've been considering attacks differently. But Dr. Cohn, maybe you can speak to that again. And then Gina's question relates to this profile, with eight of 11 patients having no further attacks. What patient would that appeal to? F irst of all, let's not forget that until the end of the data that we are seeing now in the primary observation period, all patients had been blinded during the entire follow-up. So since we, as physicians, have always instructed patients to treat as early as possible, I assume that these patients treated these symptoms just like they did in the past. I know that almost all of these attacks that were reported were internal attacks or alleged internal attacks. So there were no observations in these patients in which we can definitely conclude that these were truly angioedema attacks. I'm pretty confident that after the blinding, we will see that also these patients are likely to improve, but we will need to see that, of course, in the follow-up. Regarding the 73% complete response, that is unprecedented if we compare this to other trials. Also, to my first comment, I'm sure that after the blinding, as we observed also in Phase 1, this percentage is likely to increase. Dr. Busse, maybe you could say a word or two about patients in your clinic, patients you're familiar with in terms of a profile of the drug as it currently exists, and how attractive that will be, and to which patients. I n my opinion, all patients are eligible for prophylactic treatment. It's really a shared decision-making, and the reason I'm saying patients are eligible is that there is a huge burden of not only treatment, but of disease. P atients may be afraid to travel if they might have attacks. But I really think that peace of mind that you're not gonna have attacks in the future is a huge component. So in my opinion all patients are gonna be available for it. I wouldn't say based upon number of attacks per month or year, and in my population, really, there's... And this is happening worldwide, is that many patients are switching from, or most patients are switching from on-demand to long-term prophylaxis. And the problems that we have with long-term prophylaxis is that people are not getting complete relief. There's a burden of treatment, frequent injections, which may be painful, a daily pill, which is a constant reminder of you having hereditary angioedema without complete relief. And going in the future if we can get a therapy that's safe for kids as well and for women who are pregnant this is a huge game changer, in my opinion. One thing I'd like to point out is that one of my patients who is gonna, there's some of them are so excited, and they said they really have to change their mindset to living with a disease that they've had their whole life, to then not having this disease. So it's really, this is a game changer, in my opinion. T his is Danny again. I fully agree, and based on the experiences of the patients that have participated in the trial, I have heard really these touching stories about this patient, mother of a family, that for the very first time went to an amusement park with the family, which she didn't dare before because of the stress of angioedema attacks. Other patients now for the first time taking holiday trips where they are for the first time daring to leave the proximity of the hospital where they were receiving their on-demand treatments in the past, is really a game changer for these patients. Our next question comes from Dae Gon Ha from Stifel. Please go ahead. Great. Good morning. Thanks for taking our questions, and let me add my congrats to your data, as well. Going back to Manny's question, just one quick clarification. So for patient 1, 2, and 7, I was wondering if you can comment on anybody that's in the adolescent age. Just curious if the hormonal imbalance may have been exacerbating the attacks here. And then my actual question is, when you look at placebo patients, for those that have now started prophylaxis- What agents were they going on? And why wouldn't they go on Intellia 2002? Thanks so much. I can speak to the adolescent question. There were none. Patients need to be eighteen years or above to participate in the trial, and the second question, do you want to speak to it? So the placebo patients are being offered 20 or 2, and we suspect that all of them had either placebo or some many of the 25 milligram patients will receive the drug. Our next question comes from Kostas Biliouris from BMO Capital Markets. Please go ahead. Good morning, everyone, and congrats on the data. A two-part question from us as well. Did you observe any correlation between safety and reported response? For example, you mentioned that in 2 cases you had a temporary interruption of study drug and one patient had a grade 2 ALT response. Were those people responders or non-responders? And then I have a follow-up. Thank you. Dr. Cohn, is that something you can address, patients who either interrupted or? T here were 2 patients overall, in which the administration was just very briefly interrupted. One of these patients was my patient that reported back pain just very briefly. After we discontinued the infusion for no more than 15 minutes, the pain resolved spontaneously, and we could continue the rest of the treatment. I don't recall about safety and efficacy. This was none of these patients that reported. I don't recall by heart. There's no apparent correlation- No apparent correlation. Those patients and the response. Yeah. Thanks. Short answer, but thanks for the... You had a follow-up? The follow-up, which is relevant, is we know it takes about four weeks for the kallikrein levels to go down, but we don't really see any attacks in the four weeks, which is great. But I'm wondering, what helps patients during these four weeks that the kallikrein is still not low, but the eight patients that are still at actually did not get any attacks at all? Any thoughts around these four weeks? How can it be explained here? Thank you. Dr. Butler, you want to speak? S ure. So I get the observation. I n short, the steady state isn't reached or pseudo-steady state isn't reached until about four weeks or five weeks. But the reality is, if you look at the data, we probably get a very good reduction within the first week. So after probably seven days, you're seeing a significant effect that may have something to do with what we're observing with respect to the clinical efficacy. I'm not sure if all the patients, but a few patients received just very prior to the administration of the drug on the study day a dose of C1 inhibitor concentrate to avoid them having any attacks during the day of the infusion. So that may also account for the lack of angioedema attacks during the very first days after treatment. Absolutely. The next question comes from June Li of Truist Securities. Please go ahead. Hi, good morning. This is Marion for June, and congrats on the great data. So it appears that there is a really black and white response to therapy. So in light of functional cure, some of the patients respond really rapidly and cleanly, and some they don't. So I just want to understand, is there any relation to type of HAE, type 1, Type 2? And is there a way to reduce the number of these people in Phase 3 trial? Thank you. We haven't seen any correlation between Type 1, Type 2 and how the patients respond. I would say that like the Phase 1 trial, there are some patients who, as you say, immediately appear to have, reduction to zero in the attacks. And there are this very small set of patients that appear to more slowly reach whatever equilibrium they're going to get to. What we've seen in the Phase 1 study is with extended observation, essentially all patients have reached that point. We'll see what happens with these patients as well. But as Dr. Cohn has made clear, patients learn how to respond differently once they know that they've received the drug and are able to think about what they're experiencing and whether or not they it actually constitutes an attack. And there's a learning that takes place with that. That's, that's very clear. That's been true in all studies so far. In terms of the Phase 3 study, the approach will be, very similar to what we're doing here in Phase 2. We think that we'll get a very, good read on the drug's activity. We'll have extended follow-up in that, program as well. And, as was pointed out by Dr. Lebwohl's comments earlier, as excited as we are about the attack rate reduction, what we're most excited about is the high rate of complete responders. That's the paradigm change that really defines the drug. Dr. Lebwohl, you want to comment? J ust one other thing about the Phase 3 is we don't start counting attacks until the fifth week. So this issue of early attacks, which seemed to some extent in the Phase 1, will be reduced. And we do go out to six months. So this period where patients are having fewer and fewer attacks, if they have any attacks, will also be better addressed in the Phase 3. Our next question comes from Rick Bienkowski from Cantor Fitzgerald. Please go ahead. Hi, congrats on the data, and thanks for taking the question. I'm also trying to triangulate the strong reductions in kallikrein with the response in those patients that did not have complete reductions in attack rate. So was there anything about these patients' history of response to prior prophylactic therapies or responses to specific classes of prophylactic therapies that could be helpful in interpreting the responses seen here? Dr. Cohn, maybe you can speak to... I know you've seen some of these patients. Yes. You've had many of the complete responders and then a patient that maybe is a little bit different. What can you say about that? Exactly. So the three patients that reported attacks all used previously long-term prophylactic therapy. One berotralstat, one lanadelumab, and one Cinryze, and all these patients reported to a certain extent angioedema attacks also during this course of long-term prophylactic therapy. Our next question comes from William Pickering, from Bernstein. Please go ahead. Hi. Hi, good morning. Thank you for taking my question. A s others have noted, it looks like your drug can be a functional cure in a large majority of patients, while a smaller% may need to resume prophylaxis. So a ssuming that's representative of what we see in the Phase 3, how are you thinking about commercialization and ways to tie reimbursement to quality of response? Thank you. First, we're not sure that everybody's going to be in a position to resume prophylaxis. And I, I know Dr. Cohn can speak to the one patient represented in the New England Journal, where it was a brief resumption, and then the patient has stopped shortly after beginning it. In terms of commercialization, obviously, we'll complete our Phase 3 study. We'll get the data. We think that what we're seeing here in Phase 2 is gonna be quite similar to what we anticipate seeing in Phase 3. As has been noted by the physicians here with us, they think that the profile will be broadly attractive to all patients, regardless of the severity of their disease or the frequency of the disease. What we found in our research, talking to patients and physicians, is uniformly a desire for patients to be normal, if that's possible. What does normal mean? It means not having attacks, not taking therapy, and importantly, not living one's life with the fear that an attack is right around the corner, initiated by some exposure or, having to have, your access to insurance be determining what job you take or don't take. We've seen that, up and down in all the work that we've done. I f there are a small number of patients who don't respond, we'll learn whatever we can about them and take whatever measures we can to address that. Our goal ultimately is to have every single patient be a complete responder. There may be a small set of patients that, there's more work to do, and we'll see as the data matures. Our next question comes from Brian Cheng of JP Morgan. Please go ahead. Good morning. Thanks for taking our questions. Y ou talk about how some patients may be potentially over-reporting the symptoms or miscategorizing their symptoms as HAE attacks. Is there a strategy in place in the Phase 3 to better control over-reporting or misinterpretation of these attacks? How do you overall minimize this risk in the ongoing Phase 3? Thank you. Maybe Dr. Cohn can help us. I know you've talked about patients being trained to use on-demand therapy immediately at what the patient suspects might be an attack. How are we doing this in Phase 3, and how have you talked to patients even in the Phase 2 study with respond, with respect to that? So that will be similar in Phase 3 than in the current study, as long as patients are unblinded. What will be very interesting in Phase 3 is all patients will receive the optional crossover during the study. Afterwards, all patients will have been aware that they have received actual treatment, and that's when we will be starting to have the discussion with the patients if they can postpone their on-demand treatment use. As long as patients are still blinded to the initial treatment, we cannot ask them to postpone any treatments. We are judging all these attacks individually by the treating physicians. Also sometimes within our team, if we are in doubt whether or not to call this a true angioedema attack. But in the end, for Phase 2, it will be the same as in, for Phase 3, it will be the same as in Phase 2, where all patients report each individual attack and, their treatment. So in other words, once a patient knows that he or she's been treated, there can be maybe a slight hesitation in initiating therapy- Yeah. that is on demand, so that they can better understand what they're experiencing is or is not in fact an attack. Exactly. O ne very important observation, which I would like to highlight once more, is that most of these attacks reported were internal angioedema attacks, where there is nothing objective, which you cannot take a picture and send it to the investigator. So we really rely only on the patient's stories and their use of their on-demand treatments. ... The next question comes from Ry Forseth of Guggenheim. Please go ahead. Hi, this is Ry from Chattopadhyay's team. A question for the KOLs. How much long-term follow-up would physicians and patients in the HAE space need to get comfortable with genome editing? Or are you already comfortable with the safety profile? Maybe we could start with Dr. Cohn and then go to Dr. Busse. How long do you need to have follow-up on these patients before you offer to all your patients? W e have already observed, of course, in this program, as well as in the NTLA-2001 program, that there are no long-term safety concerns so far. The drug has been very well tolerated. There were no severe adverse events during administration, and actually already patients in my center are already in line for to receive treatment in the Phase 3 trial because there is a very high interest. Regarding safety, for the data that we have now, there is a lot of interest from my patients. Dr. Busse, what's the view from your side? From my side again, with the Phase 1 and Phase 2 data, with the safety that we've seen, I really, I'm not hesitant at all, and it really assures the patients who are wanting to go into Phase 3 that we have this data. So I don't really see it as a concern. Y es, sometimes when you say gene therapy to patients, they get a little nervous, but giving the fact that you have backup there data that really shows good safety is very reassuring. I'd point out that when we file, the drug for approval, we'll have several years of follow-up. It'll be the ongoing follow-up, the Phase 1 study, which we're now out to a couple of years. The Phase 2 patients will be followed, plus those patients that will have been retreated at the 50 milligram dose, that were treated either at 25 or placebo, and then we'll have the additional patients from Phase 3. So we'll have a strong safety cohort with several years of follow-up. Our next question comes from Steve Seedhouse of Raymond James. Please go ahead. Hi, this is Timur Ivannikov of Raymond James for Steve Seedhouse. Congrats on the data. Sorry if I missed it, but could you talk about the decision criteria for restarting patients on prophylaxis therapy? For patients one and thirteen, what was the baseline therapy, and when they restarted, was it the same therapy that they restarted on? Thank you. Maybe Dr. Cohn, I know the first patient is yours. Could this- Yeah. An unusual story, maybe you could- The first patient wasn't actually my patient, but I know that this was only for administrative purposes. It was for non-medical reasons that they briefly continued to use berotralstat again, but that had just to do with continued access, and it was not for a medical reason that it was continued. I don't recall patient thirteen by heart. It's not my patient, so I don't know what the reason was why this patient restarted with the long-term prophylactic therapy. The next question comes from Joseph Thome of TD Cowen. Please go ahead. Hi. This is Peyton Bohn for Joe. Thanks for taking our questions and also extending our congratulations. L ooking to the Phase 3 trial, how quickly do you anticipate enrolling this trial? Do you have any recruitment requirements for each region, given it's global? And have you seen any increased interest on the part of trial investigators to be a part of it, or from investigators that weren't part of the Phase 2 trial? And then for the physicians, in a similar vein, have you seen any change in enthusiasm for gene therapy for NTLA-2002, from either your colleagues or patients? And what do you think would sway patients or colleagues that are more hesitant on getting a gene therapy and, from the Phase 2 primary endpoint or follow-up? Thank you. T here were six questions there, if I'm counting right, but maybe I can speak to speed of enrollment of study, and then we can turn to, again, Dr. Cohn and Dr. Busse to, again, speak to the appeal of genome-based therapy and their colleagues that they interact with. With respect to the trial, we're enrolling. The study's up and running. We will continue to add sites as we've just begun here. You've heard from Dr. Cohn say he's got patients lined up at his center. What we're hearing is that there's similar levels of interest, whether you're in Europe or the United States. Your question with respect to enrollment across different regions, we're looking for a balanced enrollment in Europe and the United States. However, we expect that the United States will be the single largest enrolling country, where upwards of 30%-40% of patients we expect will be sourced from the United States. Thus far, based on the interest we have, we think the study will go extremely expeditiously, exactly as we saw with Phase 1 and Phase 2, where enrollment exceeded our own expectations. Dr. Cohn, maybe you can comment on your colleagues that you interact with at meetings who may not have treated patients like this. What's their level of interest and enthusiasm? The ultimate treatment goal of patients, as also written in the guideline, is to achieve total control of the disease and normalization of patients' lives. Given these results and the prospect that this can be reached with a single treatment is something that has also been encouraging my colleagues a lot, so indeed there is also interest from other colleagues that did not participate in the previous trials, and they also want to offer this treatment to their patients to achieve this ultimate treatment goal. I t's important to think about the guidelines, as you said, and recognize that we're really talking about a totally different category of response, where following a single application, potentially indefinitely, patients will not have to take any other therapy. Dr. Busse, maybe you could speak to the colleagues you interact with and their level of enthusiasm for the data and interest in participating. N o, I would say this is a treatment that we've been all waiting for. C olleagues as well as patients. So really i t's a one-time treatment. It can reduce... You don't need to have additional treatment. F ree from breakthrough attacks. R eally, this is something we've been waiting for. And I've had patients, like, waiting, asking me, "When is this gonna happen?" It's always wonderful to tell them that this is in the pipeline. The next question comes from Jay Olson from Oppenheimer. Please go ahead. Oh, hey, thank you for providing this update. We have a question for Dr. Cohn and Dr. Busse regarding the eight patients in the 50 mg cohort who were attack-free. How often have you seen HAE patients become attack-free in your practice, or is this considered totally unprecedented? And also, would you consider these eight patients to be cured, so they no longer need to carry on-demand therapy, or is there any reason to believe that there could be a risk that attacks might return? And then for the 25 mg cohort, some patients had attack elimination during the 16-week primary observation, but then, after 16 weeks, experienced a return of attack. So is there any reason why attacks may have returned in those patients, and are those patients also cured? Thank you. Maybe I can speak to the twenty-five- Yeah. which is, we are not pursuing that dose in Phase 3. I f you go back and look at the slides, you'll see that the level of editing was different, was less than what we had seen at the 50 milligram dose. And that's one of the key things that we were looking for, just to make sure that we're getting high levels of reduction in circulating plasma kallikrein. And that correlates with what we saw clinically. The word cure is something that's a loaded word, and Dr. Cohn and Dr. Busse, you can tell us what you think constitutes a cure. But to this question of unprecedented, can you think of any other drugs where, following a single dose, there's no additional therapy required, and patients remain attack-free who have HAE, or is this unique? So the short answer is no. There is no other treatment with a single dose, not requiring any additional treatment. What I meant with the 73% unprecedented. We observed lower rates of total absence of angioedema attacks in other Phase 3 trials. Indeed, the ultimate treatment goal is having a complete disease attack-free status. And yes, we achieved that with also some other forms of long-term prophylactic therapies. However, we recently published a cross-sectional study in my country, where all patients reported their use of long-term prophylactic therapy and disease control, and that was achieved only in a third of all patients. So yes, there is still a large group of patients that have uncontrolled disease and may benefit from better prophylactic treatment options, including naturally NTLA-2002. Dr. Busse, can you speak to the unprecedented or not nature of this, following a single application being attack free? No, I can speak to it. O ne important thing also to mention is that some of the therapeutics we have. Yes, patients can be attack free. However, they do have a lot, a huge burden too for treatment. P atients either inject once every three to four days or once a month, so it's a huge. And it's not without, pain at the injection site. So again, you may be attack free with some alternative therapies, but there's a huge burden of treatment that remains a huge burden of treatment. So if patients can have one treatment and be attack free, that's amazing. It's really, again, like I said before, it's a game changer in the treatment of HAE. Dr. Cohn, you want to add? T here was also the question whether or not we recommend to use on-demand treatment or to keep it at all times. I t's a little too early to state that patients can refrain from carrying their on-demand treatment. We also use to instruct them to use short-term prophylaxis. So prior, for instance, to dental surgery or other dental procedures, to use short-term prophylactic therapies. T he observation that one of my patients completely forgot about using short-term prophylaxis, whether needed or not, illustrates that they really are cured because they forget about their condition. They had a dental procedure which happened uneventful, fortunately. The patient only realized afterwards, "Oh, I should have discussed with my physician whether or not to use any short-term prophylactic therapy." So we have set the bar really high for the next treatment goal, which is forgetting about your disease after a single treatment. And we'll see how that evolves as time goes on. I would just emphasize Dr. Busse's point, which is, as we've done our own research, even for patients who are taking ongoing prophylaxis with currently available therapies, most patients, and the vast majority of them, would prefer not to have to do that. What they're looking for is the normality, normalness, that Dr. Cohn referred to, which is the ability to live their lives without thinking about their disease. David? Let me make one last point about why patients with other therapies may not achieve the benefit we're seeing with this drug. You have to recall the results we're showing. We're showing a 85% reduction in the prekallikrein. That's quite consistent. The difference of other drugs is they tend to be variable results and, in general, not getting that deeper reduction. That's the basis of why we're seeing these excellent results. This concludes our question and answer session. I would like to turn the call back over to Lina Li for final remarks. Thanks, operator, and thank you all for joining today's call and for your continued interest and support. Have a great day! The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.