Intellia Therapeutics, Inc. (NTLA) Earnings Call Transcript & Summary

Good morning, and 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. [Operator Instructions] I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.

Thank you, operator, and good morning, everyone. I'm pleased to welcome you to Intellia's investor call, featuring 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 on the Investors & Media section of Intellia's website at intelliatx.com. As a reminder, this call is being broadcast live and a replay of the event will be archived on the company's website. At this time, I would like to take a minute to remind listeners that during this call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for a 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 2002 interim data. Dr. Craig will then provide an overview of the current treatment landscape and unmet medical need for patients living with HAE. And finally, John will offer some closing remarks before we open the call for your questions. And 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. But 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 dosed 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. And importantly, with longer follow-up, NTLA-2002 continues to be well tolerated across all 3 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. 2002 targets the KLKB1 gene in liver cells, 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 2002. In the Phase I portion, which is the focus of today's call, single doses of 25 milligrams, 50 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 3 HAE attacks within 90 days prior to screening and were allowed to enter the study even if they're 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 2002 continues to be well tolerated. Consistent with the previous results presented last November, there have been no adverse events higher than Grade 2 reported in any patient across all 3 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 after 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 3 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% to 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 2002. For context, on the left, you see the attack rate for each of the patients in the 3 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 2002, which range from 5.6 to 14.1 months. Each line portrays the incidence, duration and severity of attacks experienced by the respective patients. As you can see, after a single dose of 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 9 patients who achieved greater than 60% kallikrein reduction remain 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 1 patient in the 25-milligram cohort, the lowest dose tested, who did not achieve the targeted kallikrein reduction post 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 2002 through the data cutoff date. The first 3 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 3 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 6 patients receiving HAE prophylaxis therapy prior to administration of 2002 have all subsequently discontinued their medication 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 3 dose levels tested. These data also lay the foundation for evaluating the 25-milligram and 50-milligram doses in the Phase II randomized, double-blind, placebo-controlled portion of the study. Most importantly, we continue to be quite excited for what 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 need that exists for people living with HAE. Dr. Craig?

Thank you so much, David. I appreciate the opportunity to be here today. So as noted, I wanted to give you a brief overview of hereditary angioedema and really how it affects people who have that disease. So 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 consultant as well as in research. And please note that I've also been consultant 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. Now one thing I don't want you to believe is that it only affects the face or it only affects the skin, but it also affects the GI tract or as an abdominal pain that can last for days with nausea, vomiting and diarrhea, but it also can affect the [ up ] airway and with that can lead to asphyxia. So you could see what devastation this could have on a patient. Most patients have about 2 attacks per month. Each attack last on an average of 3 days. So if you think about that, 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 was -- had HAE, is what I'll use for described hereditary angioedema, so 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 in quality of life. Really, she was kind of housebound unfortunately. Then she had her daughter, who I'll refer to as mom, in this case, a mother. She came right when a new drug suddenly came to United States. Now [ grant you to ] had drugs for 35 years in Europe. But in the United States, in 2008, we finally got the first 2 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 health care, which was very exciting to her. But then you have her child that came around when we had more drugs. So there were 3 other drugs approved, which I'll talk about in just a minute. And 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. So 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. And when you wait a long time before you get your medication, your response rate is much poorer. So 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 it's so uncomfortable, they don't use the medication. But it can be self-injected. So there is an advantage over Ecallantide. There's also 2 plasma-derived C1 inhibitor protein, so 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. Now both of these require IV administration, which is a deterrent of use in a rescue medication. But most people I have been able to train had to self-administer despite that, but it's not comfortable to have to give you an IV medication all the time. Next slide. So more recently, though, we really started focusing on prophylaxis, that is drugs to inhibit the attacks or to prevent the attacks. And there are good drugs out there that works very well, but some of them have major inconveniences with the use. So we have plasma-derived C1 inhibitor that can be given IV or subcu. The problem here is both of these, you 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 newer approved and/or more recently approved. It does work very well. It does require injections, though, every 2 weeks. You can give it once a month, but the efficacy drops significantly. And then there's 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. So 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, also drugs that are tolerated much better and maybe drugs that are -- really can be used infrequently, so we [ want ] maybe once in the cases of what we're talking about today. So that would be a big advancement in the field. Also, we want decreased drug burden, right, instead of using a drug twice a week, maybe more infrequently, also 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. And we know those both, one goes down as anxiety goes up when they have an attack. Next slide. So really, what I want to kind of focus on is before control and after control and how important that is for these people. So 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 in 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. So 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. And what I'm really hoping for is -- I'd like to use a 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. And I think that's what we really need in this space to allow people to be [ everything that's possible of being ]. So thank you so much. I appreciate the opportunity to give you an introduction to hereditary angioedema. And if you have a need to reach out, please never hesitate. Thank you again.

Thank you, Dr. Craig. We appreciate you 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.

[Operator Instructions] The first question comes from Greg Harrison with Bank of America.

Congratulations on the great data. How do you think the baseline attack rates in the trial so far represent the broader HAE population? And 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 will 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. But 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.

Yes. Thank you, John. Yes, Greg, so I think this is a population that does represent most of the people who have hereditary angioedema. So severe people have 2 or more or 1 or more attacks a month. Some people moderates, which account for the vast majority, maybe less than an attack per month, but more than 6 attacks per year. And so you're right in there with the majority of people. There's nothing to suspect that someone less severe like 3 or 4 attacks per month would actually fail therapy. But yes, I think this is very representative of HAE in general.

The next question comes from [ Yanan Daniat ] with Wells Fargo.

Congrats on the data. So 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 might -- what the proportion of patients need to be completely attack-free? And also in patients who continue to have occasional attacks, what level of reduction of attack is needed?

Dr. Craig, maybe you could tell us the characteristics of a drug that you think would be broadly used in this patient population.

Yes, so a drug that's infrequent, which obviously from the discussion that David presented, that's very compatible of 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 onetime infusion. And then you would want to have a -- you need to still have people carry rescue medication. Hopefully, from the data, it looks like rescue medication will be rarely needed but will be essential to carry. The -- initially, you would think just severe people would be -- people would be candidates for long-term therapy such as this. But I think what's happening and as we've gone through drugs that -- through the 2017 and in 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. So I think as drugs have come around and have been more effective and tolerated better, a greater portion of the population has moved towards prophylaxis. So 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%. So 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.

The next question comes from Debjit Chattopadhyay with Guggenheim.

This is Ry from Debjit's team. Given the washout of prophylactic therapies in Phase II, do you think 100% attack-free rate 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. Yes, so 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 rapidly. Most of them had no further attacks after treatment. And when you took away the prophylaxis, that was a late washout, you could call it. Again, there were no attacks. So 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.

Congrats on the data.

Thank you.

The next question comes from Liisa Bayko with Evercore ISI.

Just 2 quick ones for me. First, that one patient who did have the breakthrough attack, and I realize it was [ probably ] by sports injury, what was the level of kallikrein reduction? I know they were at the lowest dose, so I was just curious.

David, do you want to take that?

Yes. So the reduction that we've seen was about 40% in that patient. We talked about this in the poster actually for those who were at the meeting itself. And so we do think that may have contributed to the fact that they have these late attacks.

Okay. And any kind of understanding of why -- I know 25 is one of the doses you're going to take forward in Phase IIb, but why some patients may have a lower response than others?

What we've seen and also in our TTR experiences is, at the lower dose, there is a greater variability in the effect. And it's still, as you see, quite a profound effect even at this lowest dose, 25 milligrams, with an average of greater than 60% reduction. But you do see also that there's greater variability. And this is now being seen in 2 examples of gene knockout. And therefore, as you saw with TTR, we went to the higher dose. We're testing both doses here in HAE, but the variability may lead us to go to the higher dose, where there's very little variability.

Okay. And then just a question for the doctor. I was wondering in the context of just there's a pretty robust pipeline for prevention of HAE attacks and a question we get a lot from investors is just like with some of these less frequently dosed treatment options and quite what looks like pretty good ones where you'd have pretty significant reduction of attacks. Where do you see the role of gene editing vis-a-vis some of those other treatment options, things that maybe provide a pretty profound reduction in kallikrein at the same time quite -- and frequently dosed, say, every 3 months, every 6 months, less than 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, do you want to tell us how you see this fitting in?

Yes. So that is a good question. And right now, those drugs are still in Phase II or III that you're referring to every 3 months or every 6 months maybe. There are also some every month. The only one that's every month right now is lanadelumab, but its efficacy is down to about 76%. So 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 onetime treatment is very appealing to a subpopulation of those who will have HAE. I think the safety and efficacy is really what's going to drive the infrequent use of medications or medications that are infrequently used in the future. So I think it's going to be a while before we know whether those markets -- those other drugs are going to come to market, probably 3 years, maybe 4 years. But I still believe that if the data from Intellia continues to be like it is, it's going to be very appealing to people.

The next question comes from Luca Issi with RBC Capital.

Congrats on the great data here. Maybe one quick one for David. Can you expand on the dosing strategy? Obviously, strong correlation between knockdown and efficacy. And it looks like the 75 milligrams drive the strongest knockdown, the tighter air bar, safety seems benign. So why is 75 milligram not the go-to-dose going forward? So any color, much appreciated. And then maybe for Dr. Craig, assuming that the data holds up, what percentage of your patients would you ultimately put on this therapy?

David, do you want to address that?

Yes. So 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. And as you know, they do get a very good result. We have gone to 2 doses that get a better reduction than that, both 25 and 50 milligrams, where 50 milligrams is in the 80% to 90% range of reduction. When we looked at comparing 50 and 75, the difference is not really discernible at this point in terms of our results, it looks like a small difference in pharmacodynamics. And we do believe that the results we're getting with 50 milligrams are sufficient to get a very good kind of benefit and complete reduction of attacks perhaps that we're seeing already in the Phase I escalation. So we did choose those 2 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 and your own practice that you might imagine using the gene editing approach for.

Yes, John, difficult question to answer at this time, but I think as Phase III data becomes available, [ and they get more ] concrete on who would be on gene editing and who would not. As of now, I'm in an academic center, so I have referrals, so I get mainly severe people, not many people who are mild. So 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 2000-teens, 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. So I would say that probably some people are going to go towards traditional oral therapy, some to subcutaneous therapy, I think very few on intravenous. But I think gene editing is going to 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. So I would say maybe the majority.

The next question comes from Mani Foroohar with SVB Leerink.

A quick question. To what extent is the variability in baseline kallikrein level that drove some of that variability? Do you see more of that in one dose or another and that contributed in part to the greater variability? And then 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, whereas now there's much more willingness. So if you could 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 newly diagnosed patients that are going to be moving and less of a switch market?

Thanks, Mani. So David, maybe you could tell us if you've looked at baseline kallikrein levels and if that has any effect on patient response, and then we'll turn to Dr. Craig for the second question.

Yes, 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. So we don't think that's contributing to this. But we are -- yes, so -- and of course, in terms of attacks, all patients had gone to zero attacks after 16 weeks with only a single attack occurring in that one patient. So the -- we don't think that's a contributory factor to the kind of effects we're going to see with this drug.

And 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?

Yes. So this population is also very similar to the population you mentioned. There is -- once people get good control in their medication, they [ will worry ] about stopping it only because of memory of their past and how awful it was when you had frequent attacks. When Haegarda was approved, there was a large portion of people waiting for something. And then obviously, when the oral medication came approved, Berotralstat, same thing. I think the uptake is not going to be like a queue waiting, like in those 2 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 and then gradually through communication with other patients, that's where the uptake will be. I don't think there's going to be a huge group of people right up front. I think it's going to be more gradual and onset because there are some very good drugs out there.

Congrats again, guys.

The next question comes from Will Pickering with Bernstein.

Congrats on the data. For the Phase II in the U.S., I was wondering if you could provide an update on progress, activating sites and enrolling patients. It still looks like there's not any U.S. sites listed on clinicaltrials.gov. And then 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.

I'll say this about the Phase II site. It's -- as we shared in our last earnings call, not only have we started dosing, but we expect the study to be fully enrolled here in the second half for the sites. So things are going very, very quickly and very robust. 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. And for the second question, David, I think it 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?

Yes, thanks. No, we haven't heard back from any questions different from some of the things you're asking. So -- but very good response to the poster and of course, a lot of excitement about the results.

The next question comes from Joon Lee with Truist Securities.

Congrats on the progress and the results. This is Mahdi on for Joon. So could you please elaborate on why patients in 50 milligram 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 3 attacks at least in the past 90 days before the screening.

David, do you want to speak to the variability in attack rates? Remember, we had a total of 10 patients in this study. If you can talk about variability there?

Yes. So of course, we don't -- 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 were really waiting for this study, so they came in very early. But after this, we're going to get the patients, as Dr. Craig describes, as a more typical patient who has about 1 or 2 attacks a month or even less as being the most common type of patient. So it's really nothing special in terms of what we expect to see in future studies, there will be more -- a big number of the more typical patients joining.

And 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 high efficacy? In 25 milligrams, they have like 85% to 90% reduction in one case and the other one was 40%. So 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?

Yes. So I think what we've seen for all the patients over 60%, they go to zero attacks by the time 16 weeks are done. So 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 were at a heavy attack rate before, still are having some attacks right after the infusion. 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. But the great result is that they all go to zero attacks.

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 the resolution of the doses we've chosen for Phase II studies. So I think that that's behind some of the variability here.

The next question comes from Maury Raycroft with Jefferies.

I'll add my congrats on the update. I 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.

Yes. Thanks, Maury. So at the -- in the ATTR program, we did commit to the patients, we did not get as much knockdown as the others. This is the patient at the lowest dose, we've got an average of about 50% knockdown, that we would give them -- offer them a treatment when we establish the appropriate Phase II dose. And 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 could see, all patients really achieved zero attacks, including even the patient who had that -- the lower effect. So 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. But of course, we'll keep open to this as we see the results continue.

[Operator Instructions] The next question comes from Gena Wang with Barclays.

So congrats on the data. I will ask just one question. This question is for Dr. Craig. So wondering, regarding the attack-free duration, how long follow-up post the prophy withdrawal or will you have a definitive answer on a potential cure? And then do you see this genetic approach as 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. And at what point would you be convinced for patients who don't take prophylaxis to, in fact, take this therapy?

Yes, difficult question. So what is cure? 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. So 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. But 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, but they should always be prepared only because it could be a life-threatening attack with asphyxia. So 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.

And regarding on-demand patients?

So we've got an on-demand, I'm not sure about -- so you mean people who are mild or 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 if 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, because even if you only have 2 attacks per year, which are -- they can be extreme. But it also ruins your quality of life, having to wake up every morning, thinking this is the day I'm going to have my attack. So I do think, as time moves, more and more people who have more mild disease will move into having long-term prophylaxis.

The next question comes from Dae Gon Ha with Stifel.

I'll also stick with one, but congrats on the progress and with the data, great outcome. Can you maybe go into a little bit more detail on the abdominal pain that we saw in the safety? I think it was new from the last update. If you could characterize these observations, granted they're only Grade 1 in the 25 and 75 mg. And what exactly distinguishes an AE for an abdominal pain versus an abdominal attack?

David, can you address that?

Yes. When an adverse event is Grade 1, 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. So 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.

The next question comes from Brian Cheng with JPMorgan.

Maybe one question for 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, what would be the -- well, should there be a cutoff for attack rates? And what might that be for a Phase III program?

Yes. So traditionally, with CINRYZE and Haegarda, it was 2 or more attacks per month. And then when lanadelumab came about, it was 1 attack per month. And 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 2 attacks or more per month, that there would not be enough signal to show benefit. But it was, it's lanadelumab, and it is -- now we're far [ doubted ] from the Phase I here. So I do think that probably every 6 attacks per year is probably adequate to show signal. And less frequent than that becomes more difficult because of the time you have to observe patients. So 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 can do a study in 3 months if you're looking at 2 attacks per month, but you need a longer duration to ensure you're catching all attacks if you have less frequent attack rates. So I really think, David, probably is the one who should answer that more so than me. John, can David comment?

Go for it.

Yes. I think what we're thinking right now is to keep people able to think about it relative to previous therapies is to look at patients who on average -- have 1 attack per month on average. That would be the most likely standard we're setting. We haven't said exactly what our Phase III study will be, of course, but anticipate something in that range.

The next question comes from Kostas Biliouris with BMO.

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?

David, can you speak to the likelihood of having patients with less than a 60% knockdown at the 50-milligram dose?

Yes. It's just with 3 or 4 patients now in each of those doses. So it does make it difficult to give an exact number. But -- so I'll wait till we have more results to tell you that, but particularly having the Phase II results. But you could see, given the current results, it will be either all or almost all of the patients will be below 60%.

The next question comes from Joseph Thome with TD Cowen.

Congrats on the data. Maybe for Dr. 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. But is there a level of follow-up that you're looking for on a safety perspective to treat a broad proportion of your patients?

Dr. Craig, how do you think about the long-term effects of kallikrein knockdown?

Yes. So actually, we've had kallikrein knockdown with lanadelumab, and we've had that, I think, since 2017. But 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, there was some concern about an increased risk of hypertension, but the risk of hypertension was the same exact as the U.S. population. So I don't know if, in fact, that's really true. There's some in the office that talk about thrombosis, but it really hasn't been that concern with lanadelumab. So I think the target is very safe. And 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 families of patients, it appears to be a very safe target without any consequences.

The next question comes from Steve Seedhouse with Raymond James.

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 and up in a registrational study and if you think there's an opportunity to differentiate NTLA-2002 as the highest efficacy candidate therapy here in HAE? And real quickly also, were there any Grade 2 or higher elevations in liver enzymes?

David, do you want to talk about withdrawal of prophylaxis and whether or not they can be part of the endpoint, and any Grade 2 LFTs?

So the first one, that withdrawal of prophylaxis, so that will be patients who withdraw versus those who don't will have different results. I'm not sure that's the question...

I think he means that if patients are -- come into the study on prophylaxis and then withdraw, so maybe you could talk a little bit about the study design that we're thinking about with respect to prophylaxis.

Yes. Sure. Yes. 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. So that would be the plan. And we -- again, from what we know, we don't think that, that will have any effect on our ability to reduce attacks. We haven't seen any Grade 2 or greater elevations so far in the trial.

And our last question today will come from Jay Olson with Oppenheimer.

Congrats on these results. 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?

David, that one is for you.

Yes. 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?

Yes. 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 trial is sort of -- seems to be accelerating over time as you might think it might, based on the results that are coming in. So the trial, as we said, Phase II has not only started, but started in a very robust way with enrollment going very quickly.

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, and thank you, everyone, for joining us this morning. We appreciate your interest and continued support, and we look forward to continuing to keep you abreast of our future news and advancements. So 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.