Good morning, welcome to the Intellia Therapeutics NTLA-2002 Interim Clinical Data Update 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 a listen-only mode. If you need assistance, press star, then zero. 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. Good morning, everyone. I'm pleased to welcome you to Intellia's investor call, featuring updated interim data from the phase I portion of the ongoing NTLA-2002 phase I/II study. On Sunday, Intellia issued a press release detailing these results, which are presented at the European Academy of Allergy and Clinical Immunology Hybrid Congress, held this past week in Hamburg, Germany, and virtually. 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. 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 that 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; Dr. Timothy Craig, Tenured Professor of Medicine, Pediatrics, and Biomedical Sciences at Penn State University, and also in the room and available for the Q&A is Dr. Laura Sepp-Lorenzino, our Chief Scientific Officer. As outlined on this slide, we will begin with introductory remarks from John, followed by David's review of the NTLA-2002 interim data. Dr. Craig will provide an overview of the current treatment landscape and unmet medical need for patients living with HAE. Finally, John will offer some closing remarks before we open the call for your questions. With that, I'll now turn the call over to John. Thank you, Ian. Welcome, everyone. Thank you for joining us today as we review new positive clinical data from the ongoing first-in-human study of NTLA-2002 in development for hereditary angioedema, also known as HAE. At Intellia, we're deploying the industry's broadest and deepest toolbox of novel genome editing and delivery solutions to advance a full spectrum of in vivo and ex vivo therapeutic applications. For genetic diseases, such as HAE, our in vivo approach leverages our CRISPR-based gene editing platform to selectively inactivate a disease-causing gene or precisely insert a gene to produce desired proteins. These latest data on NTLA-2002, our wholly owned investigational therapy for HAE, provide the strongest evidence yet that this approach may lead to a functional cure for this disease. Last year, Intellia presented groundbreaking initial interim data from the phase I trial of NTLA-2002. Today, we're pleased to provide an update on the safety and efficacy, including substantially longer follow-up on attack rate measurements. David will review the data in greater detail that at a high level, these data demonstrate unprecedented results, which embolden our view that NTLA-2002 could meaningfully change the future HAE treatment paradigm. After just a single dose, all patients experienced durable elimination of their attacks. We're thrilled to see the earliest dose patients are free of HAE attacks for approximately a year or more now. These remarkable attack rate reductions have been consistent even in patients with the most severe history of angioedema attacks. Importantly, with longer follow-up, NTLA-2002 continues to be well tolerated across all three doses. Overall, these data reinforce our belief that NTLA-2002 could be a best-in-class prophylaxis agent and also address the significant treatment burden that exists for HAE, despite currently available therapies. We are full steam ahead in our efforts to advance NTLA-2002, with patient screening and dosing ongoing for the phase II portion. As previously announced, based on the encouraging study interest from investigators and patients alike, we look forward to completing enrollment in the second half of this year. With that, I'll now turn the call over to David. David? Thank you, John. As a brief reminder, HAE is a rare genetic disease characterized by severe, recurring, and unpredictable inflammatory attacks in various organs and tissues of the body. NTLA-2002 targets the KLKB1 gene in liver cells to reduce the production of kallikrein protein, with the goal of achieving lifelong control of HAE attacks after a single dose. Here on this slide, you'll see a summary of the ongoing phase I/II study to evaluate the safety, tolerability, and activity of NTLA-2002. In the phase I portion, which is the focus of today's call, single doses of 25 milligrams, 50 milligrams, and 75 milligrams- ... were administered via intravenous infusion. HAE attacks and plasma kallikrein protein levels were measured for all patients. Next, you can see the inclusion and exclusion criteria. Notably, patients were required to have at least three HAE attacks within 90 days prior to screening and were allowed to enter the study even if they were receiving long-term prophylactic therapy. Here you can see the patient demographics, which include both male and female patients across a range of ages from 26 to 73 years old. Additionally, we had patients with a wide range of historical monthly attack rates interested in enrolling in this study. Starting with safety, we are very pleased to share NTLA-2002 continues to be well tolerated. Consistent with the previous results presented last November, there have been no adverse events higher than grade two reported in any patient across all three dose levels. There are also no clinically significant laboratory findings observed. Moving on to the first measurement of activity, kallikrein reduction. A single administration led to robust, dose-dependent, and durable reduction 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 is therapeutically meaningful to patients, many patients continue to experience breakthrough attacks, and all must contend with significant treatment burden. At all three doses tested, we achieved mean plasma kallikrein protein reduction of greater than 60%. As shown here, these deep reductions were sustained with a range of 67%-95% reduction through the latest follow-up. Here, we are pleased to report the HAE attack rate reduction for all 10 patients in the order they were dosed with NTLA-2002. For context, on the left, you see the attack rate for each of the patients in the three months prior to screening. The colored lines indicate any HAE attacks that occurred in either the screening period or in the subsequent observation period following administration with NTLA-2002, which ranged from 5.6-14.1 months. Each line portrays the incidence, duration, and severity of attacks experienced by the respective patients. As you can see, after a one dose of NTLA-2002, the number and severity of attacks dramatically decreased for each patient across all dose levels. Importantly, all patients then experienced durable elimination of their attacks that were sustained and long-lasting. All nine patients who achieved greater than 60% kallikrein reduction remained completely attack-free following the initial 16-week observation period. As mentioned earlier, 60% kallikrein reduction is a target level expected to yield a highly meaningful clinical response. There was one patient in the 25 milligram cohort, the lowest dose tested, who did not achieve the targeted kallikrein reduction post-NTLA-2002 administration. Following being attack-free for approximately a year post-treatment, this patient reported a single mild HAE attack after experiencing minor hand swelling precipitated by a sports injury. The event did not require any medical intervention or acute therapy. This patient has not reported any additional HAE attacks since the injury. Across all patients, a 95% mean reduction in attack rate was observed after a single dose of NTLA-2002 through the data cutoff date. The first three patients dosed in the study with the longest follow-up have now experienced attack-free durations of approximately a year or longer. Additionally, the reduction in HAE attacks has been persistent in patients with the most severe HAE symptoms. The three patients with the highest historic monthly HAE attack rates at the start of the study have all remained attack-free following the primary observation period. The longest attack-free duration in this patient group is now 11.5 months and ongoing. I would also point out that all six patients receiving HAE prophylaxis therapy prior to administration of NTLA-2002 have all subsequently discontinued their medications and have not experienced any HAE attacks since discontinuation. Altogether, the attack rate reduction data looks more and more compelling as we have extended follow-up for each patient. Additionally, we are seeing greater than 90% attack rate reduction across all three dose levels tested. These data also lay the foundation for evaluating the 25 mg and 50 mg doses in the phase II randomized, double-blind, placebo-controlled portion of the study. Most importantly, we continue to be quite excited for what NTLA-2002 could mean for people with HAE, their caregivers, and physicians. With these unprecedented results as a backdrop, I'd now like to invite Dr. Craig to provide an overview of the current treatment landscape and his perspective on the unmet medical needs that exist for people living with HAE. Dr. Craig? Thank you so much, David. I appreciate the opportunity to be here today. As noted, I wanted to give you a brief overview of hereditary angioedema and really how it affects people who have that disease. I do have multiple conflicts of interest with companies that have made drugs for hereditary angioedema. You can see this is the list of my conflicts. You can also see that I've worked with many of the companies in consulting as well as in research. Please note that I've also done consulting with Intellia. Next slide. What I wanted to do is give you some insight, what it's like to be a patient who has hereditary angioedema. These slides really show the changes of when a person has an attack compared to those changes when a person doesn't have an attack. One thing I don't want you to believe is that it only affects the face or it only affects the skin, it also affects the GI tract, whereas an abdominal pain that can last for days with nausea, abdomen, diarrhea, it also can affect the upper airway, and with that can lead to asphyxia. You can see what devastation this could have on a patient. Most patients have about two attacks per month, each attack lasting on average of three days. If you think about that's about 72 days of disability a year, which it's hard to maintain any employment or to get a good education when you have hereditary angioedema that's poorly controlled. Next slide. I really like this kind of description. This is a family description. I use the name grandmother, even though she wasn't always a grandmother, but is at this time. She had HAE, is what I'll use for describe hereditary angioedema. She had HAE since a young child. Prior to when we had medications available here in the United States, she did get fresh frozen plasma, but she needed to go to the emergency room to get that because it's an IV drug, and there's no way you can prescribe that to use in a home setting. She also was on androgens a little bit for prophylaxis, but androgens have a lot of problems with them, adverse effects mainly, especially limited in their use in children and females, but also on males as well. She had a pretty poor existence and quality of life. Really, she was kind of housebound, unfortunately. She had her daughter, who I'll refer to as mom, in this case, her mother. She came right when a new drug finally came to the United States. Grant you, they had drugs for 35 years in Europe, but in the United States, in 2008, we finally got the first two drugs other than androgens and fresh frozen plasma. Her mom did really good, or I should say, mom did really well. She was able to take a job where she had some international travel, which before then, she would never really go on a jet plane. She never went to school because she was afraid to leave home, but now she really entered a school program. She became a specialist in healthcare, which was very exciting to her. You have her child that came around when we had more drugs. There were three other drugs approved, which I'll talk about in just a minute. Really, this child didn't know what HAE was really about. She was on drugs. She had rescue drugs when she had an attack. She was on prophylaxis to prevent attacks. She did have an occasional attack, but compared to her grandmother, she had a much better quality of life. Next slide. These are the medications we have available in the United States. Now, I don't have a lot of time to go through each one, but I just wanted to give you some kind of idea on what it's like to be on these therapies. The first one is ecallantide. It does work. It's only for what we call on-demand or to treat acute symptoms. The problem is it can't be self-administered, so you would have to go to an emergency room or have a nurse come to your home, and that decreases the time to get your medication. When you wait a long time before you get the medication, your response rate is much poorer. It is a drug that works, but it has too much inhibition to really or too many problems to really use as a first-line therapy. icatibant, another drug that's used for rescue. Its problem is that 97% of those people who get it actually have a burn at the site, which some people feel is so uncomfortable, they don't use the medication. It can be self-injected, so there is an advantage over ecallantide. There's also two plasma-derived C1 inhibitor proteins. That's the protein these people lack, and you can actually give that. The first one was actually IV, and it was human-derived, but there's also a recombinant as well. Both of these require IV administration, which is a deterrent of using a rescue medication. Most people I have been able to train how to self-administer despite that, but it's not comfortable to have to give you an IV medication all the time. Next slide. More recently, though, we really started focusing on prophylaxis. That is, drugs to inhibit the attacks or to prevent the attacks. There are good drugs out there that work very well, but some of them have major inconveniences with the use. We have plasma-derived C1 inhibitor. It can be given IV or sub-Q. The problem here is both of these have to give twice a week. Again, with IV drugs, that's a deterrent. Subcutaneous injections are much easier, but again, giving an injection twice a week, it really inhibits a lot of people from using it. There's also a drug, lanadelumab, which is more recently approved. It does work very well. It does require injections, though, every two weeks. You can give it once a month, but the efficacy drops significantly. More recently, berotralstat has been approved. It's the first oral medication in this disease, and it's tolerating relatively well, but it only has an efficacy of about 50%, which limits its ability to really inhibit attacks on a regular basis. Next slide. You would say, do we really need new medications? We have many medications in this space already. Well, I'd say we do. I think we need drugs that have better efficacy. Drugs that are tolerated much better, and maybe drugs that really can be used infrequently, we want maybe once in the cases of what we're talking about today. That would be a big advancement on the field. We want decreased drug burden, right? Instead of using a drug twice a week, maybe more infrequently. Have a drug that can significantly improve quality of life, because that's the major thing that happens to these people, is the impingement of quality of life and the increased anxiety. We know those both, one goes down as anxiety goes up when they have an attack. Next slide. Really, what I really want to kind of focus on is before control and after control, on how important that is for these people. This is a young lady, obviously, before control. In the midst of an attack, you can see why she doesn't want to go to work, and this can last days, as compared to this next slide. You can see instead, a person who looks just like you and I do, can function, can go to work, can be productive, and can have a good quality of life with minimal anxiety, if we can keep her in this state and not allow her to have multiple attacks. Next slide. What do I think the future is? Well, in the past, initially, we focused on really treating attacks when they occurred. More recently, we've really focused on preventing attacks so that people can have a better quality of life. As I said, I do think there's a lot of room for new medications, less frequent dosing, better efficacy, tolerated much better. What I'm really hoping for is a, I'd like to use the word relative cure, since we're not really curing the disease, even if we have a medication that can last for years and years, but a relative cure. I think that's what we really need in this space to allow people to be everything that possible of being. Thank you so much. I appreciate the opportunity to give you an introduction to hereditary angioedema, and if you ever need to reach out, please never hesitate. Thank you again. Thank you, Dr. Craig. We appreciate your joining us today and providing your perspective on the level of unmet need that still remains for patients living with HAE. These are exciting times for Intellia, the field of medicine, and most importantly, the patients we aim to serve. Our company's mission is to transform the lives of people with severe diseases by developing potentially curative genome editing treatments. With these positive interim results, we see ourselves well positioned to bring forth NTLA-2002 as a potential functional cure for the treatment of 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 telephone keypad. 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 your question, please press star then two. Please limit yourself to 1 question. At this time, we will pause momentarily to assemble our roster. The first question comes from Greg Harrison with Bank of America. Please go ahead. Hey, good morning. Thanks for taking the question and congratulations on the great data. How do you think the baseline attack rates in the trial so far represent the broader HAE population? Do you think it's reasonable for the vast majority of patients in the real-world setting, the overall population to get to a zero attack rate? Thanks, Greg. We've tried to design the study in a way that it'll be broadly representative, and we think that the medication will have broad appeal, which we judge from the great interest in the drug and the ongoing study thus far. Perhaps we could turn to Dr. Craig and ask Dr. Craig how representative he thinks this patient population is thus far with the patients we're presenting here. Thank you, John. Greg, I think this is a population that does represent most of the people who have hereditary angioedema. you know, severe people have two or more or one or more attacks per month. some people, moderates, which account for the vast majority, maybe, less than a attack per month, more than 6 attacks per year. you're right in there with the majority of people. there's nothing to suspect that someone who has severe, like, three or four attacks per month, would actually fail therapy. I think this is very representative of HAE in general. Great. Thanks for taking the question. You're welcome, Greg. The next question comes from Yanan Zhu with Wells Fargo. Please go ahead. Hi, thanks for taking the questions, and congrats on the data. A question for the doctor: What would be a profile that could support wide adoption of a gene editing treatment by the HAE patient population? Such as what the proportion of patients need to be completely attack-free. Also in patients who continue to have occasional attacks, what level of reduction of attack is needed? Thank you. Dr. Craig, maybe you could tell us the characteristics of a drug that you think would be broadly used in this patient population. A drug that's infrequent, which obviously from the discussion that David presented, that's very compatible with Intellia's drug. You would want a medication that's easy to inject, and here, you don't have to worry about that. It's a one-time infusion. And then you need to still have people carry rescue medication. Hopefully, from the data, it looks like rescue medication may, will be rarely needed, but will be essential to carry. Initially, you would think just severe people would be candidates for long-term therapy such as this. I think what's happening as we've gone through drugs that, you know, through 2017 and then 2018, as more drugs became available that were better, we found more and more people wanted to move into long-term prophylaxis who had moderate attacks or a moderate number of attacks, so maybe attacks of 6 a year. I think as drugs have come down around and have been more effective and tolerated better, a greater portion of the population has moved towards prophylaxis. If you went back to, say, 2012, I had about 25% of my patients on prophylaxis. Now, in this day and age, it's about 75%. I do think the vast majority of people in a drug that's safe, well-tolerated, and infrequent dosing, especially with such good efficacy, would be candidates. Got it. Thanks for the answer, congrats again on the great data. The next question comes from Debjit Chattopadhyay with Guggenheim. Please go ahead. Morning, everyone. This is Ry from Debjit's team. Given the washout of prophylactic therapies in phase two, do you think 100% attack-free rates in subjects with greater than 60% kallikrein knockdown will happen sooner than week 16? David, maybe you want to comment on the response kinetics that we're seeing in these patients and what we know and what we're learning as we proceed. Thank you. Yeah, the prophylaxis washout in phase II, we expect to have little effect on the kinetics of the decrease in attacks. As you saw, the patients who had prophylaxis mostly went down to zero attacks very, very rapidly. Most of them had no further attacks after treatment. When you took away the prophylaxis, that was a late washout, you could call it. Again, there were no attacks. Our prediction would be in phase II, that the results will be quite similar to what we're seeing in this phase I portion for patients who achieve or patients who are treated at either 25 milligrams or 50 milligrams and achieve a greater than 60% reduction. Thanks for that, and congrats on the data. Thank you. The next question comes from Liisa Bayko with Evercore ISI. Please go ahead. Hi, thanks for taking the question. Just, two quick ones for me. First, that one patient who did have the breakthrough attack, and I realize it was, prompted by a sports injury. What was their level of kallikrein reduction? I know they were at the lowest dose. I was just curious. David, you want to take that? Yeah. The reduction that we're seeing was about 40% in that patient. We talked about this in the poster, actually, for those who were at the meeting itself. We do think that may have contributed to the fact that they had this late attack. Okay. Any kind of understanding of why, you know, I know 25 is one of the doses you're gonna take forward in phase II-B, but, you know, why some patients may have a lower response than others? What we've seen in also in our TTR experiences is at the lower dose, there is a greater variability in the effect. I mean, still, as you see, quite a profound effect, even at this lowest dose, 25 milligrams, with an average of greater than 60% reduction. You do see also that there's greater variability. This is now being seen in two examples of gene knockout. Therefore, as you saw with TTR, we went to the higher dose. We're testing both doses here in HAE, the variability may lead us to go to the higher dose, where there's very little variability. Okay. Just a question for the doctor. Was wondering, in the context of just, you know, there's a pretty robust pipeline for prevention of HAE attacks. A question we get a lot from investors is just like with some of these less frequently dosed treatment options and quite, you know, what looks like pretty good ones, where you'd have pretty significant reduction of attacks. You know, where do you see the role of gene editing, vis-a-vis some of those other treatment options? You know, things that maybe, you know, provide, you know, pretty profound reduction in kallikrein at the same time, you know, quite infrequently dosed, say, you know, every three months, every six months, once a year. I know there's a lot of things in development, I'm just curious on the relative role of gene editing in the context of those treatments. That's just a question we get a lot from investors and wanted to run that by you and how you're thinking about that. Dr. Craig, you wanna tell us how this, you see this fitting in? Yeah. That is a good question. you know, right now, those drugs are still in phase IIs or IIIs that you're referring to every three months or every six months, maybe. There are also some every month. The only one that's every month right now is lanadelumab, you know, its efficacy is down to about 76%. I think it's hard to tell which will actually come to market, the drugs that are being investigated now. I think, though, the concept of a one-time treatment is very appealing to a subpopulation of those who still have HAE. I think the safety and efficacy is really what's gonna drive the infrequent use of medications, or medications that are infrequently used in the future. I think it's gonna be a while before we know. Those other drugs are gonna come to market, probably three years, maybe four years. I still believe that if the data from NTLA-2002 continues to be like it is, it's gonna be very appealing to people. The next question comes from Luca Issi with RBC Capital. Please go ahead. Great. Thanks so much for taking my question. Congrats on the great data here. Maybe one quick one for David. Can you maybe expand on the dosing strategy? Obviously, strong correlation between knockdown and efficacy. It looks like the 75 milligrams drive the strongest knockdown, the tighter error bar, safety seems benign. Why is 75 milligrams not the go-to dose going forward? Any color, much appreciated. Maybe for Dr. Craig, assuming that the data holds up, what percentage of your patients would you ultimately put on this therapy? Thanks so much. David, do you wanna address that? Yeah. In terms of the dose, I think you see, and we put on our slides, that 60% is what the best agents are getting right now, a 60% reduction. As you know, they do get a very good result. We have gone to two doses that get a better reduction than that, both 25 milligrams and 50 milligrams, where 50 milligrams is in the 80%-90% range of reduction. We looked at comparing 50 and 75, the difference is not really discernible at this point in terms of our results. It looks like, you know, small difference in pharmacodynamics. We do believe that the results we're getting with 50 milligrams are sufficient to get a very good, the kind of benefit and complete reduction of attacks, perhaps, that we're seeing already in the phase I escalation. We did choose those two doses, 25 and 50, which we'll use to decide what dose to use in phase III. Dr. Craig, I think the second question was directed to you in terms of the proportion of patients in your own practice that you might imagine using the gene-editing approach for. Yeah, John, difficult question to answer at this time, but I think as phase III data becomes available and make it more concrete on who would be on gene editing and who would not. As of now, you know, I'm in an academic center, so I have referrals, so I get mainly severe people, not many people who are mild. The majority, like I said earlier, 75% of people are on prophylaxis now, where in the past, before all these newer medications that came in the 2000s, it was down to about 25%. I expect, though, that as time changes, those people, even with mild disease, might kind of drift towards going on prophylaxis, even though they only have rare attacks, because they won't have to worry about it. I would say that probably some people are gonna go towards traditional oral therapy, some to subcutaneous therapy. I think very few in intravenous. I think gene editing is gonna be a drug that a good portion of the population will choose to do because of that one-term treatment and no need for serial treatments. I would say maybe the majority? Got it. Super helpful. Thanks so much, guys. The next question comes from Mani Foroohar with SVB Leerink. Please go ahead. Hey, guys. Congrats on the data. A quick question: To what extent was there variability in baseline kallikrein level that, you know, drove some of that variability? Do you see more of that- ... in one dose or another, that contribute in part to the greater variability. Secondarily, more from a clinical perspective, how much switching do we see in this population? In some other genetically, driven genetically defined disorders, hemophilia, for example, we've seen a little more conservatism around switching to novel therapies, where notice there's, you know, much more willingness. If you can actually help us understand, sort of, is this, should we think of this as a population that will be relatively rapid adopters of new technology, or is this more new, newly diagnosed patients who are gonna be moving and less of a switch market? Thanks, Mani. David, maybe you could tell us if you've looked at baseline kallikrein levels and if that has any effect on patient response. We'll turn to Dr. Craig for the second question. Yeah, I think what you've seen in terms of response are obviously very consistent results, particularly as you get to the higher doses of 50 and 75 milligrams. We haven't seen any effect of the baseline kallikrein on that degree of variability, we don't think that's contributing to this. We are, yeah. Of course, in terms of attacks, all patients had gone to zero attacks after 16 weeks, with only a one attack occurring in that one patient. We don't think that's a contributory factor to the kind of effects we're gonna see with this drug. Dr. Craig, for you, I think the second question, addressed propensity to switch as new therapies come along. How do patients and doctors think about that? Yeah. This population is also very similar to the population you mentioned. There is, once people get good control on their medication, they're leery about stopping it, only because of memory of their past and how awful it was when you had frequent attacks. You know, when Haegarda was approved, there was a large portion of people waiting for something. Obviously, when the oral medication came approved, berotralstat, same thing. I think the uptake is not gonna be like acute waiting, like in those two situations, but I do think the transition will be gradual over time. I think really the newer patients coming in, who have not developed a loyalty, if you want to use that term, to a drug already, will be the ones that will be the best candidates. Gradually, through communication with other patients, that's where the uptake will be. I don't think there's gonna be a huge group of people right up front. I think it's gonna be more gradual in onset because there are some very good drugs out there. Great. That's very helpful. Congrats again, guys. The next question comes from Will Pickering with Bernstein. Please go ahead. Good morning. Thank you for taking my question, and congrats on the data. For the phase II in the U.S., I was wondering if you could provide an update on progress to activating sites and enrolling patients. It still looks like there's not any, you know, U.S. sites listed on ClinicalTrials.gov. A follow-up, I was wondering if there are any questions you got at the poster presentation yesterday that were worth sort of sharing with this audience. Thank you. I'll say this about the phase two site. It's as we shared at our last earnings call, not only have we started dosing, but we expect the study to be fully enrolled here in the second half of the study. Things are going very, very quickly and very robustly. We have broad-based interest, irrespective of geography. We're not going through individual sites and where they are and how many patients they have. We'll give the appropriate update subsequently. For the second question, David, I think there was just an open-ended question, if there's any interesting or informative questions that you've heard as a result of the poster presentation. Yeah, thanks. No, we haven't heard back from any questions different from some of the things you're asking. Very good response to the poster and of course, a lot of excitement about the results. Thank you. The next question comes from Joon Lee with Truist Securities. Please go ahead. Hi, good morning. Congrats on the progress and the results. This is Mandy on for Joon. Could you please elaborate on why patients in 50 milligrams dose cohort had some of the lowest historical attack rates compared to the other patients? For example, this patient 52 had no attack rates in the screening period, while based on the enrollment criteria, they must have had three attacks, at least, in the past 90 days before the screening. David, do you wanna speak to the variability in attack rates? Remember, we had a total of 10 patients in that study. You can talk about variability there. Yeah. You know, of course, we don't. You know, the patients aren't selected by the attack rates. They come in as they come to their physicians. I think those couple of patients with very heavy attack rates at the beginning are probably patients who are really waiting for this study, so they came in very early. After this, we're gonna get the patients, as Dr. Craig describes, as a more typical patient who has about one or two attacks a month, or even less, as being the most common type of patient. It's really nothing special in terms of what we expect to see in future studies. There will be more, you know, a big number of the more typical patients joining. Thank you. A quick second question is that, like, is there any understanding of why there is variability in lower doses? Why, at some cases, they have a high efficacy, in 25 milligrams, they have, like, 85%-90% reduction in one case, and the other one was 40%. What is the biological reasoning of this variability? David, how do you think of variability as a function of dose with respect to the knockdown? Yeah. I think what we've seen for all the patients over 60%, they go to zero attacks by the time 16 weeks are done. That means there's really, in some sense, not much variability in terms of the clinical results. You do see that some of the patients who had a heavy attack rate before still are having some attacks right after the infusion. You know, this, we don't completely understand why their attacks don't go down at the same rate as the other patients, but we are looking to understand that as we go on. The great result is that they all go to zero attacks. I think it may be helpful to. Thank you. It may be helpful to add that the level of knockdown is a function of the dose, and the degree of knockdown is more variable when you have incomplete knockdown, which is the basis of this dose-finding study that we've done. We've explored the lower doses ranging up through higher doses, and that serves as the basis for further resolution of the doses we've chosen for phase II studies. I think that that's behind some of the variability here. The next question comes from Maury Raycroft with Jefferies. Please go ahead. Hi, good morning. I'll add my congrats on the update. Thanks for taking my question. Just wanted to ask a quick one, on redosing. Wondering if you're having any initial insight into redosing in your ATTR program, and if patients getting 25 mgs in your HAE phase I and phase II, if those patients could be eligible for a redose, and whether you would incorporate that formally into your phase II? David, maybe you can remind where we are with redosing in the TTR program and speak to whether or not we're doing it here? Yeah, thanks. Thanks, Maury. At the in the ATTR program, we did commit to the patients who did not get as much knockdown as the others. This is the patients at the lowest dose, who got an average about 50% knockdown, that we would offer them a treatment when we establish the appropriate phase II dose. That has now happened. Those patients have all been retreated, and of course, we'll report on them at a later time, exactly what their results are. In this study, as you can see, all patients really achieved zero attacks, including even the patient who had that lower effect. In this case, it's not clear that we would that anyone needs to be offered retreatment, and so far we're not planning on it. Of course, we'll keep open to this as we see the results continue. Got it. Thank you. Just a reminder to kindly limit yourself to one question. The next question comes from Gena Wang with Barclays. Please go ahead. Excuse me, Ms. Wang, your line is open. Is it muted accidentally on your phone? We'll go to the... Just one moment, please. Ms. Wang, once again, I wanted to ask please go ahead with your question. Can you hear me? Yes, I can hear you now on this. Okay. new line. Thank you. Go ahead. Okay, good. Good. Congrats on the data. I will ask just one question. This question is for Dr. Craig. Wondering, you know, regarding the attack-free duration, how long follow-up post the prophy withdraw, do you have a definitive answer on potential cure? Do you see this gene editing approach, a once-and-done approach, for future potential on-demand patients? Dr. Craig, when would you be willing to start using the word cure, I think is the question? At what point would you be convinced for patients who don't take prophylaxis to, in fact, take this therapy? Yeah, difficult question. What is cure? You know, it depends on how you look at the disease. There are some people with hereditary angioedema who never have symptoms, despite having an abnormal gene and also having abnormal protein levels. Those people, do they have the disease or not? I say yes, because you never know what it would be like under a situation of extreme stress. I would say people will still have to have rescue medication, and should have it, should carry it at all times, just like with food allergy, with an EpiPen. You hope that nobody has an attack of anaphylaxis or food allergy, just like you hope nobody who's been treated will have an attack. They should always be prepared, only because it could be a life-threatening attack with asphyxia. I would say cure would not be the word I'd use. I'd say very well controlled, and again, that's what I would refer to it as, more so than a cure. Regarding on-demand patients? Regarding on-demand, I'm not sure about. You mean people who are mild, who are only need on-demand therapy because their attacks are so infrequent, would they be a candidate? I would say yes, they could be. I would feel that as things develop and more and more people are treated, and it looks the safety record is there and the efficacy is there, I think you'll find more and more people who have less severe disease moving into therapy. Even if you only have two attacks per year, they can be extreme, but it also ruins your quality of life, having to wake up every morning and thinking, "Is this the day I'm gonna have my attack?" I do think as time moves, more and more people who have more mild disease will move into having long-term prophylaxis. Thank you. The next question comes from Dae Gon Ha with Stifel. Please go ahead. Hey, good morning, guys. Thanks for taking the question. I'll also stick with one, but congrats on the progress and with the data. Great, great outcome. Can you maybe go into a little bit more detail on the abdominal pain that we saw on the safety? I think it was new from the last update. If you could characterize these observations, granted, they're only grade one in the 25 and 75 mg. What exactly distinguishes a AE for an abdominal pain versus a abdominal attack? Thanks so much. David, can you address that? You know, when an adverse event is grade one, it's really very hard to say much about it because this is something I think any of us could have on a regular day or if we eat the wrong food. It's really tough to say a lot about it. I think in terms of how things are judged as attacks, these are discussed with the physician in terms of adjudicating each attack, and that's what might distinguish an adverse event that's considered not related to their disease versus one that is their attack or is their disease. Great. Thanks so much. The next question comes from Brian Cheng with JP Morgan. Please go ahead. Hey, guys. Thanks for taking my question. Maybe one question for David, Dr. Craig. Given the wide range of monthly attack that we saw in this phase I, what would be the ideal cutoff and also background therapy for a potential registrational trial to best capture the efficacy signal and also just to balance the need for enrollment? Dr. Craig, in your opinion, Well, should there be a cutoff for attack rates, and what might that be for a phase 3 program? Yeah. you know, traditionally, with Cinryze and HAEGARDA, it was two or more attacks per month. When lanadelumab came about, it was one attack per month. Now we're looking at data that's less frequent than one attack per month, and there's still signal. That's what I would worry about initially when we went from the traditional two attacks or more per month, that there would not be enough signal to show benefit. It was with lanadelumab, and it is now with our data from the phase I here. I do think that probably every six attacks per year is probably adequate to show signal. Less frequent than that becomes more difficult because the time you have to observe patients. I really do think it's the company's commitment on how long they want to have observation and how much signal they want in the sense of, you know, you can do a study in three months if you're looking at, two attacks per month, but you need a longer duration to ensure you're catching all attacks if you have less frequent attack rates. I really think David probably is the one who should answer that more so than me. John, Can David comment? Sure. You want to. Go for it. Yeah, go for it. Yeah, I think what we're thinking right now is to, you know, to keep people able to think about it relative to previous therapies, is to look at patients who have an average, have one attack per month on average. That would be the most likely standard we're setting. We haven't said exactly what our phase three study will be, of course, but anticipate something in that range. Thank you, David. Thank you. The next question comes from Kostas Biliouris with BMO. BMO, please go ahead. Hello, everyone. Thanks for taking my question and congrats on the great data. One question on the 50-milligram dose: Based on your PK/PD modeling and the variability levels that you saw so far with 10 patients, what percentage of patients would you expect to have less than 60% kallikrein reduction in the 50-milligram dose under a large trial or in the real world? Thank you. David, can you speak to the likelihood of having patients with less than a 60% knockdown at the 50-milligram dose? Yeah. You know, it's just with three or four patients now at each of those doses. It does make it difficult to give an exact number. I will wait until we have more results to tell you that, for particularly having the phase II results. You can see, given the current results, it'll be either all or almost all the patients will be below 60%. Thank you. The next question comes from Joseph Thome with TD Cowen. Please go ahead. Hi there. Good morning. Thank you for taking my question and congrats on the data. Maybe right after Craig, do you have any concerns about the long-term knockdown of kallikrein protein as it relates to safety? It looks like to at least 14 months, the safety profile looks solid today. Is there a level of follow-up that you're looking for on a safety perspective to treat a broad proportion of your patients? Thanks. Dr. Craig, how do you think about the long-term effects of kallikrein knockdown? Yeah. Actually, you know, we've had kallikrein knockdown with lanadelumab, and we've had that, I think, since 2017. There's also a family that doesn't make kallikrein. It's a very small population, maybe 150, maybe a little more than that. Of those, depending on who you read and how you interpret the data, there was some concern about an increased risk of hypertension, but the risk of hypertension was the same exact as in the U.S. population. I don't know if, in fact, that's really true. There's some of the authors talk about thrombosis, but there really hasn't been that concern with lanadelumab. I think the target is very safe. I think we have data from other drugs, including berotralstat, showing that the target is safe and that with a family group, even though only 150 or families of patients, it appears to be a very safe target without any consequences. The next question comes from Steve Seedhouse with Raymond James. Please go ahead. Hi, this is Ryan Deschner on for Steve. Can you comment on how, if at all, removal of prophylaxis without recurrence of attacks could be included in a composite secondary endpoint in a registrational study? If you think there's an opportunity to differentiate, NTLA-2002 as the highest efficacy candidate therapy here in HAE. Real quickly also, were there any grade two or higher elevations in liver enzymes? Thanks. David, do you want to talk about withdrawal of prophylaxis and whether or not that can be part of the endpoint, and any grade two, LFTs? I'm not sure. The first one that withdrawal of prophylaxis, if that will be patients who withdraw versus those who don't, will have different results? I'm not sure. I think he means that if patients are coming to the study on prophylaxis and then withdraw. Maybe you could talk a little bit about the study design that we're thinking about with respect to prophylaxis? Yeah, sure. Yeah. In the phase II, as well as, what's likely phase III design, we would require patients to come off prophylaxis, and that's been standard. It allows you to better, more straightforward way, interpret the data that you're getting with the drug. That would be the plan. Again, from what we know, we don't think of that'll have any effect on our ability to reduce attacks. We haven't seen any grade two or greater elevation so far in the trial. Our last question today will come from Jay Olson with Oppenheimer. Please go ahead. Oh, hey, congrats on these results, and thanks for taking the question. Can you talk about the feedback that you received from KOLs, and how do you expect these updated results to impact the enrollment rate for your study? Thank you. David, that one's for you. Yeah. Sorry, what was it again? I missed that actually. What kind of feedback have you been getting from KOLs, and do these results impact the rate at which our current phase II study enrolls? Oh, yeah. No, it's been a remarkable feedback from investigators. A great deal of excitement as they, of course, saw the very initial results now with more extended results in this example. The enrollment of the trials is sort of on, seems to be accelerating over time, as you might think it might be based on the results that are coming in. The trial, as you said, phase II has not only started, but started in a very robust way with enrollment going very quickly. Great. Thank you. This concludes our question and answer session. I would like to turn the conference back over to Ian Karp for any closing remarks. Great. Thanks so much, Drew. Thank you everyone for joining us this morning. We appreciate your interest and continued support. We look forward to continuing to keep you abreast of our future news and advancements. Have a great day and talk to everyone soon. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.