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

Good morning, and welcome to Intellia Therapeutics' Investor Event. My name is Drew, and I will be your conference operator today. [Operator Instructions] 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 new data from the ongoing NTLA-2002 Phase I/II study. On Sunday, Intellia issued a press release detailing these results, which were presented at the European Academy of Allergy & Clinical Immunology Hybrid Congress held this past weekend in Valencia, Spain. This release, along with the accompanying presentation can be found in the Investors and Media section of Intellia's website at intelliatx.com. As a reminder, this call is being broadcast live, and a replay of the event will be archived on the company's website. At this time, I would like to take a minute to remind listeners that during this call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. Please note that NTLA-2002 has not been approved by any health authority. With that said, joining me today on the call are Dr. John Leonard, our Chief Executive Officer; Dr. David Lebwohl, our Chief Medical Officer; and Dr. Hilary Longhurst, Senior Medical Officer on the Auckland District Health Board and Honorary Associate Professor at University of Aukland, New Zealand. Also in the room and available for the Q&A are Dr. Laura Sepp-Lorenzino, our Chief Scientific Officer; and Dr. Jim Butler, our General Manager for the NTLA-2002 program. As outlined on this slide, we will begin with introductory remarks from John. Dr. Longhurst will review the long-term data from the Phase I portion of the study. David will then review next steps for the program, followed by John discussing where we see NTLA-2002 fitting in the HAE treatment landscape before we open up the call for questions. And with that, I'll now turn the call over to John.

Thank you, Ian. Welcome, everyone, and thank you for joining today's call. At Intellia, we are deploying the industry's broadest and most advanced toolbox of novel gene editing and delivery solutions to advance a full spectrum of in vivo and ex vivo therapeutic applications. For genetic diseases, such as hereditary angioedema, or HAE, our in vivo approach leverages our proprietary CRISPR-based gene editing platform and LNP delivery system to selectively inactivate a disease-causing gene or precisely inserted gene to produce desired proteins. Yesterday, we shared positive long-term data from the ongoing Phase I study of NTLA-2002 in development for HAE. These unprecedented results from the initial 10 patients with average patient follow-up of over 20 months, speak to the safety, efficacy, and importantly, the durability of NTLA-2002's effect after a single dose. With 8 of 10 patients remaining completely attack-free in the post primary observation period, we believe these data reinforce the potential of NTLA-2002 to be a functional cure for people living with HAE. Dr. Longhurst, a leading HAE expert in our trial's principal investigator in New Zealand will provide an in-depth review of the results in a moment. Before we review these data in greater detail, I want to take a moment to reflect on our goal to change the lives of HAE patients with NTLA-2002. Despite approved chronic therapies, HAE patients continue to seek improved efficacy and convenience. Ultimately, patients want to live a life free from their disease and untethered from chronic prophylaxis and rescue medications. Within NTLA-2002 our aspiration is to have a durable onetime treatment with best-in-class attack rate reduction. We believe this target product profile will offer significant value to patients, caregivers and the overall health care system, supporting the potential of NTLA-2002 to become a leader in the HAE market. We're full steam ahead in our efforts to bring NTLA-2002 to patients. We expect to report the top line Phase II results mid this year with the detailed results to be presented at a medical conference later in the year. Based on these data, we will select the dose to further evaluate in the global pivotal Phase III trial on track to begin in the second half of this year. All of this will position us to submit a planned BLA in 2026 for NTLA-2002, which we anticipate will lead to the first ever approval for an in vivo CRISPR-based therapy. Beyond that, we are in late-stage development for NTLA-2001 for ATTR amyloidosis with one Phase III already actively enrolling and a second Phase III expected to begin by the end of this year. Intellia's undoubtedly leading the gene editing revolution with well over 100 patients already dosed across these two programs and many more to come. With that, I will now turn the call over to Dr. Hilary Longhurst to review the data. Dr. Longhurst.

Thank you very much, John. And I'm delighted to be here to present the results from this study. Here are my disclosures. Hereditary angioedema is a rare genetic disorder, which causes people to swell up frequently, this is massive, swelling massive angioedema and can occur unpredictably in any part of the body. So these patients have quite a measurable time unfavorable pain or laryngeal angioedema, which could close their throat and kill them. There is a significant lifetime mortality in untreated patients. The symptoms result from a disregulated contact pathway, which you can see here. And kallikrein in the contact pathway in the center there is directly responsible for production of bradykinin, which dictates leakiness of the small blood vessels. And we hypothesized that by editing the kallikrein gene, the KLKB1 gene, we could reduce plasma time, stop overproduction of bradykinin and rebalance this pathway on a permanent basis with NTLA-2002. NTLA-2002 is a CRISPR/Cas9 based in vivo gene editing therapy, which was designed to be given systemically by an intravenous infusion as a one-off treatment, which we hypothesized will be a permanent cure of symptoms. The NTLA-2002 is comprised of a CRISPR. So this is a guidewire mRNA which puts potently and selectively targets the KLKB1 gene, and Cas9 RNA, which encodes the Cas9 endonuclease protein, which cuts the gene and inactivates it. And all of this is formulated in the lipid nanoparticle and this is engineered so that it targets the liver very specifically. That improving specificity and safety potentially. So today, we're going to share the updated interim results on our first 10 patients from the first-in-human study. So these are patients with type 1 and type 2 HAE. It's an open label, single-ascending dose designed with the primary objective of safety and tolerability. But we did also, of course, look at pharmacodynamics and preliminary efficacy. The primary observation period was 16 weeks, followed by a long-term observation period of the 88 weeks. In this Phase I part of the study, our patients were allowed to continue use of other long-term prophylaxis. But despite this, they had to have had at least 3 attacks in the 3 months prior to treatment. And I can tell you that, unfortunately, for our patients at the current time, there was no shortage of people who have built that criteria in New Zealand. The data cutoff date is the 12th of February this year, 2024. And this gives an additional year of observation of that which we recently published in the New England Journal of Medicine and which was originally announced at the EAACI conference in 2023. Patient demographics were pretty typical of a population of patients with HAE, which tends to come on in adolescents and can be lifelong. The age range was from 26 to 73, 6 of the 10 patients were receiving concurrent long-term prophylaxis. But of course, had an attack rate of at least once a month or up to almost twice a week. The mean monthly attack rate being 4.6, so just over once a week. And it's not shown here, but these patients had a range of comorbidities, again, typical of what one might find in New Zealand or American population. So with the median follow-up time of 20 months to this data cut, and NTLA-2002 is continuing to be extremely well tolerated across all the dose levels that we tested. The most frequent adverse events were infusion-related reactions, which were typically extremely mild. And all our patients received the full intended dose of NTLA-2002. You can see here that the adverse events are much what one would expect from people living in New Zealand in the last couple of years, and there have been no serious adverse events or clinically significant laboratory findings to date. We saw a dose-dependent reduction in kallikrein, ranging from 60% to 95% from baseline. And these responses have been durable to date at all doses. The data points marked with an asterisks just represents the beginning of the new follow-up since the previous reported analysis. And you can see from the horizontal dotted line, that all 3 doses surpassed the reduction of 60% that we know is associated with good control of HAE from a previous data from approved kallikrein inhibitor treatment. Prespecified attack rate analysis were planned at the conclusion of the 16-week primary observation period. And you can see that the main reduction was 90%. Overall, we've got a reduction of 98%. And you can see that after the first 16 weeks, almost no one had an attack. So the reduction in attack rate is 99%. So in this slide, we can see the results, per patient results of this treatment. Each horizontal bar being 1 patient. Within the horizontal bars, you can see vertical lines of different colors representing HAE attacks of various severity and the duration, of course, is represented by the width of the bar. And you can see that people had an attack prior to treatment, which is shown by the solid vertical line. And for most people attack stopped pretty immediately after treatment. There were 2 people whose attacks took some time to settle down. But after the 16-week period, you can see that everyone has been able to stop their prophylaxis. And everyone has been pretty much attack-free, in fact 8 out of 10 of these patients were attack free. I just want to talk a little bit about patient 1. You can see that way out, it's about week 50, he had an attack. This guy is a [ game ] sportsman. He got a football boot with studs in his hand. And the following day, he noticed that his hands were swollen in a manner reminiscent of HAE attack. This doesn't need any treatment, and the patient himself commented that in the past his whole arm would have swollen up. So he was not bothered by this. If you look down to patient 6, you can see that she had an attack. It's an abdominal attack. This was in the context of a long-haul flight where she was going to meet a convention of other HAE patients, which is a hugely emotional and an exciting experience for those that is involved in HAE, and during the flight her fiance proposed to her. Now given that emotional stress is a huge trigger of attack. This lady then began to experience the beginning of abdominal attack and she treated it with C1 inhibitor. So in summary, the results of this first in-human Phase I study continue to demonstrate that NTLA-2002 has the potential to be a functional cure for patients with HAE. In fact, the patients are talking about it as a cure to symptoms which is how it feels. NTLA-2002 has been generally extremely well tolerated at all times with only Grade 1 or 2 adverse events. And it resulted in a dose-dependent and durable reduction in plasma kallikrein protein along with, of course, that so pleasing absence of attacks for the vast majority of people. And finally, I just want to thank the patients who -- it's not within our [indiscernible] step up for first-in-human trials, but of course, everyone is extremely glad that we decided to take this on. The study site coordinators and staff and has been fantastic. And finally, thank you so much to Intellia for developing this amazing technology, which I'm sure will have some ramifications way beyond hereditary angioedema.

Thank you, Dr. Longhurst. We are very excited about these Phase I study results. What we see now is that the effect of 2002 was durable and continued to improve over time. 8 of 10 patients continue to be completely attack-free for 18 to 26 months, and all 10 patients are free of long-term prophylaxis treatment. These remarkable attack rate reductions were consistent even in patients with the most severe symptoms. At the same time, the data from these 10 patients continue to demonstrate a favorable safety profile. Overall, these long-term data support our belief that 2002 to be a onetime potential functional cure for this debilitating disease. In other words, patients would be both free of attacks and free from chronic treatment. We look forward to reporting top line results from the randomized, placebo-controlled Phase II study mid this year. The detailed results evaluating the 25-milligram and 50-milligram doses are expected to be presented at an upcoming medical meeting later in the year. These data updates will provide clarity on which dose we will move forward into the Phase III trial. As previously disclosed, we plan to initiate the global pivotal Phase III trial in the second half of this year. We expect the Phase III will be a small study of fewer than 100 patients and to enroll rapidly. Based on the landmark findings published in the New England Journal of Medicine, we are already seeing grassroots excitement about 2002 and the upcoming Phase III trial. We look forward to discussing the trial design in more detail once we have regulatory approval. Based on our current projections and assuming the trial is positive, we expect to file a BLA in 2026, which we anticipate will lead to the first ever approval of an in vivo CRISPR-based therapy. And with that, I'll turn the call back to John to review how we envision 2002 fitting into the HAE treatment landscape.

Thank you, David, and Dr. Longhurst. We believe NTLA-2002 holds the potential to completely disrupt the HAE treatment landscape. Treatment for this disease has significantly evolved in recent years. Patients have more choices today than before, including both on-demand therapies and chronically administered prophylaxis treatment. However, patients are still in need of more effective and less burdensome treatments as most patients continue to have breakthrough attacks despite current chronic therapies. We believe NTLA-2002 is well positioned to become a leader in the HAE market which is expected to grow to over $6 billion by 2029. Based on market research with patients and physicians, the significant enthusiasm for NTLA-2002 is driven by three factors: First, many patients are seeking a further reduction in frequency of their HAE attacks. Even more important for patients would be a complete response, where patients are free from attacks and free from the requirements of chronic treatment. Second, patients are seeking more convenient therapies and perhaps convenience is not really the right description for what we hope to offer patients in the future. Of course, moving from a daily treatment to weekly and then the monthly certainly describes an improvement in convenience. However, what we are pursuing is really a paradigm shift. We believe patients would be best served by a onetime treatment approach which would thereby alleviate the need for a lifetime of injections, infusions or daily pills. And finally, patients and their physicians are always seeking treatments that are safe and well tolerated. On all 3 of these factors, efficacy, convenience and safety, we believe NTLA-2002 has the opportunity to reset the treatment paradigm for people living with HAE. As for search and treatment options for HAE have dramatically increased over the past 5-plus years, we now understand the needs of patients better than ever. These insights will help guide and prioritize our future commercial efforts. We expect the earliest interest will come from the 15% to 20% of patients who are inadequately managed on current prophylaxis treatments. This current dissatisfaction can be related to breakthrough attacks, the burden of current treatment or the payer requirements to be maintained on a chronic specialty therapy. Next, there are 40% to 55% of patients on long-term prophylaxis treatment were considered generally well managed, meaning they are able to adequately control the symptoms of their disease. This group of patients has expressed a strong willingness to switch treatment if it can deliver on either additional efficacy or improved convenience. Finally, there are approximately 25% to 30% of patients who are only using on-demand treatments today. These patients have forgone currently available prophylaxis therapies due to the burden of chronic injections, infusions or daily pills but may now consider a first-in-class onetime gene-editing treatment. In addition to getting input from patients and physicians, we also conducted initial market research with payers. As you can see on this slide, we received positive feedback on NTLA-2002's target product profile. We know that on average, patients are diagnosed at 20 years of age, which means they will contend with many decades of high-cost treatments. For payers, this means a onetime treatment could be very attractive relative to the high lifetime cost of branded prophylaxis therapies which cost close to or more than $0.5 million annually in the U.S., and between $140,000 to $450,000 a year in European markets. Of course, we will be working with payers to evaluate potential innovative payment models to support our onetime treatments. But importantly, we expect access conditions for NTLA-2002 to be similar to branded HAE prophylaxis drugs. All in, our market research indicates there is significant enthusiasm for a onetime treatment that will lead to an attack-free and/or treatment-free status. With these long-term Phase I results we are seeing the target product profile of NTLA-2002 takes shape. We look forward to sharing the Phase II data later this year and believe we are closer than ever to delivering on a potential functional cure for people living with HAE. With that, we'd be happy to answer any questions. Operator, you may now open the call for Q&A.

[Operator Instructions] The first question comes from Maury Raycroft with Jefferies.

Congrats on the update. We're still waiting for your Phase II data, but it will be good to hear your views on whether the 25 mg dose where you're getting consistent approximately 60% knockdown if that could be sufficient to eliminate attacks? And how that's informed by the Ionis donidalorsen data, where they're showing about 60% knockdown with -- I don't know if you have any perspective on that? And just how you're thinking about that dosing decision based on your Phase II data for the Phase III study.

Maury, thanks for the question. As you can tell, we're very excited by the data that we've just shared in the last day or so here. And as we've been saying repeatedly, our objective is to get to patients who are not only attack-free but are effectively treatment-free, and we've seen that with the majority of these patients, in fact, 8 out of 10. So in terms of where we're going, we're making very, very significant progress. I think what we've learned is that more suppression is better. There may be diminishing returns at very, very low levels of kallikrein. But when we look at some of the data that's been recently produced, it's our sense that there's a trade-off for patients that are taking chronic treatments between convenience, the repetitious dosing and the ultimate knockdown that they get with kallikrein. And as you can see from the data we presented thus far, that doesn't exist with our therapy, where after a single application, we're able to get to very low levels of kallikrein and you see the results that we presented that go with that. So we look forward to sharing the Phase II results as they become available mid this year, and that will set us up for the Phase III work that we expect to begin before the end of the year. So stay tuned.

The next question comes from Gena Wang with Barclays.

I also wanted to add my congrats as well, great data. So I have one question for Dr. Longhurst. So I know at the primary observation period, we do see say, 2 patient attack out of 10. But when we look at each patient, the first patient in the 25-milligram, it's already attack-free after that attack happened for like 50 weeks. And the second patient in the 75-milligram cohort, that's also -- my rough calculation is about 48 weeks. So how would you see this the close to 50 weeks attack-free after last attack, how would you define attack-free? And do you think that, that should be any concern for future potential attack coming back?

Dr. Longhurst maybe you could address that. In essence, the question is, are we 10 out of 10 patients are truly attack-free? At what point if a patient does have an attack, belatedly, in the observation period, a single isolated attack does that even count as an attack.

I think that this is a question that we're in the very fortunate position of having to think about perhaps for the first time. But I would say that all 10 patients actually consider themselves cured. I think for patient 2, he was actually attack-free after 16 weeks, and it was just that initial period. Just to give you a bit of background with hereditary angioedema, this patient was very, very severely affected and actually had a swelling that ruptured his kidney. So the -- where the [indiscernible] goes into the kidney. While he was waiting prior to the treatment. So this is the sort of thing that he was undergoing. So I think that this patient, as his kallikrein levels fell and he felt low-level symptoms that were similar to the beginning of an attack, but of course, he had no kallikrein. The angioedema couldn't be generated and the attack didn't go anywhere. And I think it probably took him a while to understand the new situation. I will say he has no symptoms of any sorts now and has taken on a huge load of extra activities that he never would have considered previously. So I think that we -- I guess our new attack definition will have to give some sort of denominator, and I'm hoping it would be along the lines of a very, very low annual risk or the very low 5-year risk for an attack. But clearly, we want people to have no attacks. And it looks as if this might be possible.

The next question comes from Mani Foroohar with Leerink Partners.

Congratulations as well from me. Clearly a path to best-in-class data here. A quick question in terms of the practicality of the market, presuming that this profile continues through a pivotal and is approved but FDA, EMA, et cetera, is broadly available. How much concern is there amongst patients for potentially irreversible genetic therapy? That's a debate that's had amongst investors, if perhaps less so amongst the physicians we've spoken to that there might be some reticence to take an irreversible therapy, some reticence to have a gene editing approach? How real is this reticence among the patients? Or is this more of a sort of Wall Street debate than a physician-patient debate?

Mani, thanks for the question. Good to hear from you. We presented the market research that we found. And obviously, we're very interested in understanding this deeply. So we probe not only physicians but patients themselves. And we've tried to characterize what we've learned. There's clearly different groups of patients in terms of how they think about this. But the takeaway that we've come to is that the majority of patients will definitely consider taking a drug like this. In terms of what other barriers and conversations they may have with their physician, I will turn to Dr. Longhurst here in a moment, and maybe she can address some of the interactions that she's had with their own patients. But as we look at the market, we find that what patients want to have is a normal life. And that consists of no attacks, no treatments and not having to adjust their lives in a way that they avoid those stimuli that lead to the presence of attacks. And then obviously, what comes with that is the ability to freely change jobs and not feel constrained somehow by the insurance plan that you may have at your respective employer. And when presented with all of those characteristics, what we found is that the majority, in fact, the vast majority of patients, certainly here in the U.S. and in Europe, are very, very attractive to a drug with this profile. And obviously, we need to present Phase II data and Phase III data to build on the data that we have here. But assuming all that holds, our expectation is that the drug will be welcomed by many patients. Maybe Dr. Longhurst, I can turn to you and you could just describe some of the conversations you may have had with your patients in terms of a gene therapy as opposed to some of the other approaches that are available.

Sure. I think to summarize, I'd say that patients are hugely more go for it and wanting this sort of treatment, then maybe doctors who are wanting to wait for more information, although I have to say, I feel pretty confident. And obviously, the authorities are much more conservative, as you would expect. And I will say that we do have certain ethno-cultural groups in New Zealand who we would expect to reject gene editing as a treatment. But when it comes down to it, we've actually included 2 patients from these ethnic groups who have actually been -- they came to have the treatment. So yes, I think patients are keen. One of the things, I think, has already been alluded to, is that when these patients own huge fear of attacks and what the next attack might bring. And if you can control the attacks, that's great. But they then have the fear that, that treatment that controls the attacks may be taken away. So they've got a concern if they want to relocate to another country, if they want to change jobs. And so the idea of having a one-off permanent treatment is hugely attractive, much more than I would have expected, actually.

Maybe I'll turn to Jim Butler, our General Manager of the program. Jim, can you build in this notion of -- and just think about the Phase II enrollment rate and Phase III interest as you guys prepare for Phase III later this year. What are you seeing?

Yes, sure, John. So what's been really interesting, and I think Hilary started to allude to this, is that as the patients have started talking with one another, we see a lot of interest starting from that perspective. And it drove a lot of our interest in our Phase II, and we're already seeing a lot of this, some of the words getting out. And I think you see -- we really seeing a lot of interest in the Phase III. So more data to inform, obviously, but we're pretty optimistic that patients will be interested.

The next question comes from Kostas Biliouris with BMO Capital Markets.

Congrats on the data. A question from me on maybe the characteristics of the 2 patients who had an attack? And specifically anything uncommon with a body weight given that you have a flat dosing and not depending on the weight, maybe these patients had higher weights, so they got maybe perhaps lower dose than the others. And in general, your thoughts around flat dosing given that your peers are using weight-based dosing for gene editing, but you have been using flat dosing, which seems to work perfectly well, by the way. Any thoughts on whether you have seen any correlation between weight and efficacy would be helpful.

Yes. Thanks for the question, Kostas. The weight-based dosing is something we've looked at throughout the course of this program and the highly related 2001 program. You remember that this is a modular approach where the LNPs are essentially identical with the exception of 100 nucleotides in the single guide RNA. What we've learned is that the degree of editing is really quite independent of body weight within a given dose. So a simple way of thinking about this, is really what you're treating is the liver as opposed to exposure to the rest of the body. And as we've looked at the limits of that, within a given dose, patients at the lower or higher end of body weights tend to behave essentially in a bioequivalent fashion. And that's what's behind the flat dosing approach that we've taken. That also translates into safety in the clinic. There's fewer things to decide and things that might go wrong, it's less confusing for patients, it avoids some of the payer challenges that might come with different doses, et cetera. And maybe Dr. Longhurst, we can just turn to you, outside of weight, are there any other characteristics that you think might influence how some patients might respond to this drug or any of the other drugs that are used for the treatment of HAE generally?

There were no clear characteristics. And in fact, our highest weight patient, 130 kilograms, had no attacks at all after treatment, whereas patient 2, I think -- patient 1, sorry weighed around 75 kilograms. So he wasn't a large person. Patient 6 was a relatively small woman, who I think also had a relatively low body weight. I do think people who've had frequent attacks do tend to all very alarming attacks tend to take a little bit longer to settle down, and that could be this mistaken early symptoms issue, but I don't have any strong impression because, obviously, everyone is essentially attack-free.

Next question comes from Yanan Zhu with Wells Fargo Securities.

Great. Congrats on the on very impressive data here. So one quick one on safety. I think to be called a cure, it not only implies complete efficacy, but also complete safety. So I'm wondering for any of the AEs is it true that there is no ongoing low-grade findings and all of that is probably early and associated with dosing? And then the quick follow-up is on the upcoming Phase II data readout. Can you remind us of the number of patients, and also perhaps more importantly, duration of follow-up? And also given, I think there is a little difference in terms of patients coming off of prophy. The timing of that compared with this data set we are looking at. Can you talk about whether that could lead to any potential difference in efficacy finding within the follow-up?

I think I got the list of questions there. But maybe, David, you could just say a word about the safety profile, what's the duration of any safety events, and then we can address some of the other questions here.

Yes. What we've seen in safety with this program, of course, 2001 having a very similar structure of that program as well, is that the events are only very early on that we've seen. We don't see anything beyond the initial treatment. And the only thing we've seen initially that seems that does seem to be related to LNPs is the infusion reactions, the low-grade infusion reactions that have been seen. None of them have prevented the patients being treated. None of them have been very significant, as we've heard. So the safety is really quite good. In Phase II, there are 25 patients, the follow-up we're not talking exactly about what the following will be at the time of the report, but you will hear about that fairly soon. And then patients on prophy, first now, as you've seen patients who are on prophy patients who weren't on prophy, all of them have remained attack-free. So that really hasn't had an effect. And of course, these patients on prophy came off it for various reasons and they've been able to do without it at this point.

I think it's really important to emphasize that last point because the paradigm shift that we're working towards here is patients become attack-free, they're treatment-free, which means not only they do not take prophylaxis, but they can dispense with even their on-demand therapy. That's what we're aiming for. And what you've seen here in this long-term Phase 1 follow-up is that we've been able to achieve that. So we're very excited about expanding on that database as the Phase II program is something that we'll talk about later on this year as we move to Phase III. So maybe we can turn to the next question.

The next question comes from Luca Issi with RBC.

This is Lisa on for Luca. Congrats on the data. I just wanted to touch on your use of lipid nanoparticles here as a delivery vehicle. Given the recent safety setbacks we've seen from Verge gene editing program, which potentially might be attributed to lipid nanoparticle use. Just wondering overall how you are feeling about the overall safety profile of your lipid nanoparticles to date? And then as a follow-up, can you remind us of any differentiating features between your lipid nanoparticle and Verge.

Yes. Thanks for that, I think, very important question, Lisa. I think there's a common misconception out there that all lipid nanoparticles are created equally. That's a real flawed belief and just something that is really critical to understand. I mean, since this company was formed, we focused on the in vivo approach. And with that, we've taken great care to build out an LNP modular system for which we've reported on over 100 patients thus far that has a safety profile that we see as unmatched with anyone who's been in the LNP systemic delivery space thus far. That has to do with how the LNPs -- the constituents of the LNPs, how they're assembled, how they're characterized and how they're administered to patients. We're rapidly expanding on that database as we move through our Phase III program with NTLA-2001 for TTR amyloidosis. And obviously, we'll be expanding on that safety database when we present our Phase II data for NTLA-2002 and move to our Phase III program. But thus far, we're elated with the safety that we've seen, which corresponds to what we saw preclinically which, again, we think differentiates from what we've seen from others who have been active in this space.

The next question comes from Mary Kate Davis with Bank of America.

Looking at the 90% reduction in all attacks in the primary observation period here, how are you guys looking at the follow-up time post administration needed to reduce attacks? And maybe of the breakthrough attacks that you've seen, would you consider these typically more or less severe or easier to control?

David, do you want to talk about how attacks change through time? And then maybe we could turn to Dr. Longhurst after that, just so she could share some of her experience thinking about this?

Sure. Just in general, what we know about the pharmacodynamics is that the levels of kallikrein come down within the first month. So we certainly expect that after the first month, we reached a stable amount of prekallikrein, and ultimately, perhaps a stable amount of attacks. We've seen that it's not always true that, Dr. Longhurst talked about that, the patients who come in with very frequent attacks have a somewhat different pattern. But in the end, that 16 weeks, as you saw, all patients have basically -- 8 out of 10 patients have gone to zero attacks and a single attack in the remaining 2 patients.

Maybe Dr. Longhurst if you want to -- if there's anything to add in terms of how you think attacks may change through time even independently of pharmacokinetics and pharmacodynamics perspectives?

Well, I can talk about what we've seen. And the two later attacks. One, it was an abdominal attack. It was on a plane. There was all sorts of things going on. So very difficult to make any comment on that. And the other one was a provoked attack, it was a hand swelling. It certainly wasn't -- it was a mild attack. On balance, I thought it was probably hereditary angioedema, but -- if you get a football stud in your hand, it probably will swell up a little bit. So difficult to know whether it was normal or actually pathological, it was that sort of level. So those attacks were both really difficult to comment on, but certainly nothing, not for massive angioedema that we would see in untreated patients.

Dr. Longhurst, do you think that patients may think differently or how may perceive their attacks differently through time?

Yes, I do. And this -- I think there's two things. One is that people have lived with chronic swell and chronic pain. And when that's taken away, I think there are -- the brain gut axis actually takes a while to reset if you've had what can be a very traumatic, it's family trauma, because a lot of these people have had family members have died. So you've had a very traumatic time, and it takes a while to settle down. And for example, patient 004 used to have throat swelling, uvula, which is the [indiscernible] used to swell up. And of course, that's potentially extremely dangerous. So if he experienced any symptom in his throat, we would immediately treat. And I think it took him a while to get the confidence to know that he didn't have to treat. Nothing was going to happen. Does that answer your question?

Please go to the next question. Thank you.

The next question comes from Rick Bienkowski with Cantor Fitzgerald.

Congrats on the great data here. So I appreciate the detail around the three different groups of commercial patients that were split into inadequately treated patients on prophylaxis, the low managed ones, and patients that currently avoid prophylaxis. Could you remind us of the enrollment criteria of the Phase II? And if we should expect that patients from all three of these groups will be represented in the trial?

David, for the Phase II, which, again, we'll be reviewing later this year, maybe you could remind us what the entry -- are we having a broad-based set of patients that's reminiscent of the phase -- all 3 groups that we described in our market research is really the question here.

Yes. No, thank you. Is this trial would allow all three of those types of patients in patients were coming off prophylaxis in the Phase II, you'll hear more about that, as well as patients who haven't been on prophylaxis. Really, that broad enrollment, we do think this has potential to benefit all patients and as we say, hope to get to a normal life where they have no attacks and no prophylaxis.

And do you think that, that will also be true for the Phase III program you currently envision?

The Phase III will be the same entry criteria.

The next question comes from Joon Lee with Truist.

Congrats on the really impressive data. I have a question to Dr. Longhurst, and it's a variation on Mani's question earlier. Is there any theoretical risks associated with the leading plasma kallikrein. And were there any AEs of particular interest you been to follow beyond the scope of the trial setting? And very quickly, is redosing an option for NTLA-2002 like you did for 2001? And whether any immune reaction against Cas9 during the second dosing?

Well, before we have Dr. Longhurst respond to questions of, is there a risk with having kallikrein levels that are too low? What we've shown with NTLA-2001, again, essentially an identical LNP is that we are able to redose those patients, and that's been done successfully. That's not currently part of how we think about the NTLA-2002 program. But as we go forward, I'm sure we'll think about all of the best ways to deliver the best care that we can imagine for these patients as we go forward. But Dr. Longhurst, can you say a word about kallikrein levels? Is there a point that would you worry if they may be too low and any adverse events that may result from that?

Sure. So we do know that there are people who are born without any kallikrein at all. So they've got a genetic absence of the PKK gene. And they as far as we can tell, they've completely normal, healthy lives and their children are healthy. So I think the short answer is no. We -- there are kallikrein inhibitors out there, which are used chronically, and they've been very well tolerated. And the other thing to say is that actually, we're not completely removing kallikrein. So we don't see the laboratory changes that we would see on someone who was born without any kallikrein at all. So there was no way that we could tell for muting blood testing that these people had the treatment that they've had. And no, we haven't seen any serious adverse effects or indeed any special -- or any adverse effect of special interest. So we've been very interested in potential for thrombosis or bleeding, which is, I would say, is theoretically very unlikely to happen. But -- and we just haven't seen it. So all good.

The next question comes from Joseph Form -- go ahead, sorry.

Get this sort of treatment would be more suitable for someone who had a thrombotic or bleeding risk than some of the cover treatments that we use in my opinion.

The next question comes from Joseph Thome with TD Cowen.

Congrats on data update. Maybe just overall on the efficacy profile and sort of overall benefit of the therapy. Obviously, post 16 weeks some patients are coming off their prophylaxis the value proposition is really driven home. So how is that impacting your thinking for how long you want to follow patients in the pivotal study? And maybe with regards to the FDA interactions, how clear is the agency in terms of how long they want patients followed before a potential regulatory approval, as you did mention this could potentially be the first in vivo gene editing therapeutic approved?

David, you want to address duration of follow-up in the Phase III program and how we're going to think about that and some of the regulatory interactions.

Yes. So the Phase III program will be similar to other Phase III programs. That's what's been happening, that's what the regulators like to see 6 months of follow-up, and you'll be seeing our exact design. But we do think that's the right period. Now there will be patients who are followed longer over the course of the trial, some patients are enrolled earlier, some later. So we will have more the next 6 months follow-up. In fact, we were not only -- the trials are usually designed for about 2 years. And in the case of gene therapies, we'll be following them for 15 years. So I think we'll be able to show the value proposition of this over a very long period of time, that if we do achieve an attack-free state, we'll be able to show that does exist for years. And that's what we expect to see. You saw at the pharmacodynamics look like. We get to very low and very consistently low levels, really in all patients and that we think will be a big advantage over other therapies.

The next question comes from Ry Forseth with Guggenheim.

For the 2002 Phase III study at fewer than 100 patients, would it be possible to do a statistical analysis of the nature of attacks at baseline versus on treatment to establish labeling claims around treating the severity spectrum of the attacks from mild to life-threatening?

Well, before David talks about the statistics and what we're going to be able to extract from that Phase III trial, I would just make the point that our objective is to have the broadest possible label not only for severity, but also for age. And that is something that we've been working very closely with regulatory agencies to get to a point of implementation for this trial. David, in a smaller study typical of this class of -- this type of drug for the treatment of HAE can you say a word about what we hope to suss out of some of these findings.

Again, we do think the label will be broad. And because we will include patients who have relatively infrequent attacks to some patients, as you've seen in our Phase I, who do have frequent attacks. That's not usually tested statistically in these studies. It's really small numbers of patients in the studies. But in terms of would be appropriate for the treatment, it will include that broad range of patients.

The next question comes from Brian Cheng with JPMorgan.

Just curious if you can provide a little bit more color about the two attacks in terms of their -- whether that you have seen any spike of plasma kallikrein that you're tracking when these patients experience the attack? Also, have you looked into the driver of these attacks historically?

Maybe we can turn to Dr. Longhurst and -- if you look -- noticed any kind of relationship in these two patients that have had their single isolated attacks and kallikrein levels.

So patient 1 actually had quite a small reduction in the kallikrein compared to the other patients, but he has been attack-free apart from this one attack. Patient who had an attack, I'm actually trying to remember, but I think she was -- I think she had a very profound [ cap ] reduction in kallikrein. So no, I don't think there is any signal there.

And just to add that we do measure the kallikrein before and after these attacks, and it remains very low in all cases.

I think that's one of the key attributes of the approach is that the levels are essentially in variant as a result of the treatment.

And do we have time for one more question? .

Yes, Drew, let's say, I think we have time one final question, Joe.

Okay. That question comes from Dae Gon Ha with Stifel.

Congrats from me as well. Just looking ahead on Phase II and potentially Phase II, I know we've touched on the breakthrough attacks, but I wanted to take a slightly different angle for Dr. Longhurst but also for Phase III when you start including U.S. patients, what kind of site training and patient training are you looking to implement to make sure we're not including breakthrough attacks that might actually not be attack as Dr. Longhurst was saying, particularly curious as we donidalorsen, and we had that OASIS data that best-in-class profile, just trying to see if you can design this trial well enough to see that definitive differentiation.

Let's turn to Jim Butler and then you can supplement that with Dr. Longhurst as she has been clearly advising us as we think about this, but how are you guys implementing some of this for the Phase III effort?

Yes, I'd say it's -- I mean, as you might expect, we have a standardized approach, part of site training, right, to try to identify and adjudicated attacks. But ultimately, this is left up to the investigator, and they have to use their judgment, right? They're the ones seeing the patient, but we do -- we are careful to and mindful that we want to be as thorough and consistent as possible. I think Dr. Longhurst could probably speak better to that as a clinician who actually sees these patients because I suspect what we're doing globally will be very similar to what we've done with her.

Yes. So I think it's actually one of the most difficult questions because you've got a subjective endpoint in most cases. that if someone does report a swelling, then I will want to see a photograph of it. But of course, for the internal attacks, there's often nothing to see, particularly if they've been treated. And really, the way I addressed it is I have quite a long discussion -- a long ongoing repetitive discussion with the patient about the natural history of an attack, which is very low level symptoms, which could be completely nonspecific. It doesn't have to be HAE. And then if it's HAE, the symptoms will worsen. And I actually ask people when they're contributing to a study to try and hold off a bit longer than they normally would with their treatment, just to be sure that this is actually an attack, but that's a huge ask for many of these patients, particularly if they've got things to do, places to be. And actually, I think we've learned a lot from those early attacks that happened in the first few weeks, this business of people feeling like an attack might be starting and then it going away. So I think now we know that we can advise the patient that when you're on active treatment, this might happen. It doesn't tend to happen long term, but it might happen very, very early on. And really, it's an ongoing discussion with the patient to help them understand what their body is doing. And this huge -- if they've had active treatment, this huge transformation from not having this chronic, painful disorder. So it's difficult, and it's a dialogue. But I think we're -- I think we're getting better at it, actually. As one of my patients said to me, he always thought it was an attack or not an attack, but he now realizes that there's a whole shades of gray.

I think with that, Drew, yes, I think with that, I'll close this out. So thank you, everyone, for joining us. While we still have Dr. Longhurst a special thank you for joining us. I think your insights were certainly very helpful to put some broader context on the patient perspective. So thank you for joining. And for everyone who joined the call, we look forward to giving you further updates as we progress later in the year. So until then, have a great week. Bye, everyone.

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