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. Please be advised that this call is being recorded at the company's request. [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 event, featuring updated interim data from the Phase I/II clinical trial of NTLA-2002. On Saturday, Intellia issued a press release detailing these results, which were presented at the 2022 Annual Scientific Meeting of the American College of Allergy, Asthma & Immunology, also known as ACAAI, held this past week in Louisville, Kentucky. This release, along with the accompanying presentation, can be found in the investors and media convention 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 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 in 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 and Dr. David Lebwohl, our Chief Medical Officer. We will begin with introductory remarks from John followed by David's review of the interim results from our HAE program. John will then provide closing remarks before opening the call for questions at which time Laura Sepp-Lorenzino, our Chief Scientific Officer will also be available. I will turn the call over to John.

Thank you. Welcome, everyone, and thank you for joining us today as we review positive interim days from the ongoing first-in-human study of NTLA-2002. NTLA-2002 is our wholly owned investigational in vivo CRISPR Cas9-based therapy in development as a single-dose treatment for hereditary angioedema, also known as HAE. Here at Intellia, we're building a full spectrum genome editing company by deploying the industry's broadest and deepest toolbox for novel genome editing and delivery solutions. We're harnessing the immense power of CRISPR-based technologies for in vivo and ex vivo therapeutic applications, each with potential to revolutionize the future of medicine. For genetic diseases such as HAE, our in vivo approach leverages our lipid nanoparticle-based delivery system to selectively inactivate the disease-causing gene or precisely insert the gene to produce desired proteins. In a moment, David will present the updated interim data, but let me begin with how excited we are with these compelling results seen thus far in the study, which we believe provide early evidence that NTLA-2002 after people suffering from the hereditary angioedema a functional cure for their disease. Across the 25-milligram and 75-milligram cohorts where we have extended follow-up, all patients who received a single dose of NTLA-2002 have achieved and thus far maintained an attack free status. For the first 3 patients dosed, they have now been living free of HAE attacks for 5 to 10 months and without the need for chronic treatment. In the 50-milligram dose cohort, while the group has not yet completed their initial 16-week observation period, we're encouraged by the robust levels of plasma kallikrein reduction already seen in the initial 22 days following administration. We're also pleased that NTLA-2002 continues to be generally well-tolerated with a total of 10 patient dose and no serious adverse events or clinically significant laboratory findings. Altogether, we could not be happier with the progress we're making with the clinical study of NTLA-2002 and look forward to beginning the Phase II portion of the study in the first half of next year. With that, I will now pass the call to David, who will review the latest interim results. David?

Thank you, John. We're indeed pleased with the interim data from our 2002 Phase-I/II clinical study which we presented this past weekend at ACAAI by Dr. Hilary Longhurst. HAE is a rare genetic disease characterized by severe, recurring and unpredictable inflammatory attack in various organs and tissues of the body, which can be painful, debilitating and life threatening. It is estimated that 1 in 50,000 people are affected by HAE. Despite the existence of chronic treatment, people living with HAE can still experience breakthrough attacks, and [ save ] high treatment burden, which for many include frequent injection and/or infusion to prevent or treat their attack. As a brief reminder, 2002 targets the KLKB1 gene and is designed to reduce the production of kallikrein protein, which is a clinically validated approach for the treatment and prevention of HAE attacks. Here on this slide, you can see a summary of 2002's mechanism of action. For those of you familiar with our lead in vivo program 2001, you'll notice that 2002 is also comprised of a lifted nanoparticle containing a guide RNA and messenger RNA. The only difference between these 2 candidates is the target site portion of the guide RNA. Intellia's ongoing Phase-I/II trials is evaluating the safety, tolerability, pharmacokinetics and pharmacodynamics of 2002 in adults with type I or type II HAE. The Phase I portion of the study with an open-label single-ascending dose design with a minimum of 3 patients in each cohort evaluating 25, 50 and 75 milligrams. The Phase II portion will include up to 2 dose levels in a randomized placebo controlled study. For today's presentation, which built upon the initial results we shared in September. I will be reporting on all 10 patients enrolled in Phase-I. Here you can see the inclusion and exclusion criteria. Notably, patients who required to have at least 3 HAR attacks with 90 days prior to screening and will allow to enter the study even if they were currently receiving prophylactic therapy. Next you can see the patient demographics which include both male and female patients across the range of ages from 26 to 73 years old. Here is the patient HAE attack history with a mean monthly HAE attack rate of 4.6 per month across all 3 cohorts. I will point out that patients in the 25- and 75-milligram cohorts had meaningfully higher historical attack rates of 6 to 8 attacks per month. Starting with safety. At all 3 dose levels, 2002 is generally well-tolerated and the majority of adverse events were mild in severity. The most frequent AEs were infusion-related reactions, which were mostly grade 1 and resolved within 1 day. There have been no dose-limiting toxicities, no serious adverse events and no adverse events of grade 3 or higher observed to date. No clinically significant laboratory abnormalities were observed. This includes no significant elevation in liver enzymes. In summary, the 2002 safety and tolerability data reported to date is highly encouraging. Moving on to the activity data, which begins on this slide. A single infusion of 2002 led to robust dose-dependent reductions from baseline measures of plasma kallikrein. Mean plasma kallikrein reduction was 64%, 81% and 92% for the 25, 50 and 75-milligram cohorts, respectively. As expected, these deep reductions in plasma kallikrein were sustained throughout the observation period. The dotted line at the 60% mark on this slide represents the kallikrein inhibition of the leading approved chronic HAE therapy. While this level is therapeutically meaningful to patients, many patients continue to experience breakthrough attacks and all must [ contain ] with significant treatment burden. At all 3 dose levels, we have already achieved our goal of greater than 60% mean kallikrein reduction. Now we are pleased to report the HAE attack rate for the patients in the 25- and 75-milligram cohort with all reach the end of the 16-week initial observation period. In the screening period prior to the administration of 2002, patients in the 25-milligram cohort had 1.1 to 7.2 attacks per month. And patients in the 75-milligram cohort had 4.0 to 5.9 attacks per month. Following a single administration of 2002, the mean reductions in HAE attack rate at 16 weeks were 91% and 78% in the 25-milligram and 75-milligram cohorts, respectively. As has been seen in other HAE clinical studies, it's not uncommon to see some attacks occurring in the first month after the initiation of treatment. Therefore, when we look at weeks 5 to 16, we see the attack rate reduction is nearly 90% for both dose levels. As we move to the next slide, we show you that with extended observations, all patients have now reached attack free status as of the latest follow-up. Here, we see a swimmer plot of the patients in the 25- and 75-milligram cohort. For context, on the left, you see the attack rate for each of the patients in the 3-month prior 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 4 to 10 months. Each line portrays the incidence, duration and severity of attacks experienced by the respective patient. As you can see, after a single dose of 2002, the number and severity of attacks dramatically decreased for each patient. Of particular importance, all patients have achieved an ongoing attack-free status. Thus far, the duration ranges from 2 months to more than 10 months. For all 3 patients in the 25-milligram cohort for whom we have the longest follow-up, we see that they have remained attack free now for 5 to 10 months. We believe these interim data are an early indication that 2002 may offer people living with HAE a functional cure of their disease after a single dose. Finally, not all patients in the 50-milligram cohort have completed the primary 16-week observation period. However, based on the deep levels of plasma kallikrein reduction, we expect to see similarly high levels of HAE attack rate reduction and plan to present the data when available. We are highly encouraged by these data and excited for what this could mean for people with HAE, their physicians and caregivers. These results lead us to believe that 2002 can dramatically reduce or eliminate HAE attack. Further, we believe that 2002 will remove the significant treatment burden faced by people living with HAE. Looking ahead, we expect to select up to 2 doses to further evaluate in the Phase II portion of the study expected to begin in the first half of 2023. We anticipate including U.S. clinical sites as part of this study. And with that, I'll turn the call back to John for closing remarks.

Thank you, David. As you can see, observations so far from our Phase I/II clinical trial of NTLA-2002 continue to be very encouraging. Beyond the potential benefits of a onetime therapy, we believe these data highlight that NTLA-2002 holds the potential to improve patient outcomes over treatments currently available and in development for HAE. Moreover, these data continue to validate the modularity of Intellia's industry-leading genome editing platform and its potential to target a multitude of genetic diseases. 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 Brian Cheng with JPMorgan.

Congrats on the data. John, as you said, in the 25 mg and 75 mg, those cohorts had higher than average attacks. How are you thinking about the mean attack rate as you head into the Phase II? What would be a good mean attack rate for inclusion to gather more evidence? And based on the data so far, how are you thinking about when to best wean off prophylaxis?

Let me turn to David, I know we're thinking a lot about next steps, maybe you could tell us how we're thinking about the Phase II study?

Yes. So for the Phase II, the main question in terms of the number of attacks, is to have enough attacks that you can see a signal. And this has generally been in the range of 1 to 2 attacks per month in prior studies. We do think from what we see, the patients with a higher attack rates can be very effectively treated with our therapy. So we are going to look -- we expect to have a range of attack rates, and we don't think there's a particular limit. We have to have that on that as we design the study.

Question was what do you think about...

Yes, on the prophylaxis in the Part 2, we will have patients coming off prophylaxis as they have been on prophylaxis generally, you do that, so that there won't be any -- the drug will be -- have been washed out of the patient before you start the new therapy.

But we would make available therapy in the course of the trial should that attack...

Of course, there -- yes, this has been a standard approach to allow rescue therapies during the study itself, it's very clear.

The next question comes from Gena Wang with Barclays.

I have a very quick 2 part questions. First 1 is regarding 1 patient with all other AEs, which dose was that patient? And then also for the 25 milligram, you have a high standard deviation for the knockdown. Just wondering which patient reached, when you look at the standard deviation, 1 patient certainly reached the 90% knockdown. I'm wondering which patient from 25 milligrams that reached a 90% knockdown?

Gena, I'm not sure I understood your first question about -- could you just repeat the adverse event question? What's that?

Yes. So I think that's the data slides. I'm not sure about the -- today's investor slides, the data slides, that was Slide 10. There's all other AEs and I have a long list were reported in 1 patient. So you put all the AEs -- adverse AEs occurring over 2 equal of more than 2 patients and have put all the events there. And then in the footnote, there's all other AEs were reported in 1 patient. Just wondering what dose would that?

Yes. So I could see the ambiguity there. Each of these events occurred only once, but it's different patients at different doses. So it's not that all of these occurred in 1 patient. That's the question. And they would have occurred at both dose levels.

The next question comes from Salveen Richter with Goldman Sachs.

This is Elizabeth on for Salveen. Could you comment on the feedback from physicians and patients in the context of use just given there are multiple modalities in development?

David, you've had the chance to interact with some KOLs and patient groups. What are you hearing in terms of enthusiasm for this approach irrespective of state of their disease?

Yes, there's been interest in this. And you can see from the range of patients who have enrolled in the study with all different levels of disease, patients who are having less frequent attacks, patients who are having more frequent attacks, patients who've been on prophylaxis and have breakthroughs. And of course, some of the patients haven't been on prophylaxis yet. So we're seeing, in this study with our investigators, a very high level of interest in the study. You can see that it's been enrolling basically as quickly as we have the dose levels open. So we're very encouraged by the response of both the physicians and the patients so far.

I mean one of the recurring themes has been the fact that these patients live with incredible uncertainty, right, David, I mean it's one thing we've heard from the KOLs. And the hope for outcome of being able to dispense with what is an ongoing burden of care, something that is of great appeal. And so we're particularly excited about the extended attack-free periods here, which as you might imagine, we're watching very, very carefully as we continue to collect data.

The next question comes from Joon Lee with Truist Securities.

Congrats on the data. With this data, would you be looking at week 1 through 16 attack rate as your primary endpoint? Or would you be looking at some time after that where you're not seeing any more attacks in the 25 and 75-milligram doses? And related to that, are you able to quantify the of -- potential off-target risk as you go from 25 to 75-milligram and would the FDA require a quantification of this?

Maybe I can take some of that, Joon. We'll do what the regulators require to measure attack rates, and there are certainly paradigms that have been well developed over the years. I think what patients and physicians are looking for is not necessarily a number that's measured in the first few weeks, but what is the long-term consequence of therapy. And with that, we'll certainly follow very, very carefully how these patients perform over time. And as we accumulate that data, I would expect that in clinical trials we will put in place measurements that collect that information, because it's what is meaningful to those patients. As you might imagine, there's a period of adaptation that appears in these patients. And I think that's been seen across all modalities that we're familiar with, where over the first few weeks, there's a, what I would call, adaptation. I think it's very complex. But where patients settle out, I think, is going to be what is the ultimate determinant of how patients will make the decisions. In terms of the off-target, the paradigm we use is preclinically having a vast excess of LNPs, where we go and look at concentrations that are supra-pharmacologic that are never expected to be achieved in human beings, which would encompass 25 and 75 milligrams and even doses beyond that. So we feel really good about where we are from that off-target assessment in the preclinical work to justify these doses.

The next question comes from Yanan Zhu with Wells Fargo.

I have quick 2 part questions. Did you observe a correlation between [ regional ] patients kallikrein level and the attack rate? And whether it's base line or during the study period? And is there a certain stress on kallikrein reduction that would translate to attack rate?

Yes. It's a little hard to hear you, although I think you asked, is there a correlation between kallikrein levels in patients' attack rates. I don't know if you're asking in terms of pre-intervention or post-intervention. Clearly, post-intervention, there is. I mean what we've determined is that as 1 knocks down those kallikrein levels, there is a decrease in the attack rates. And that's what we're further exploring here, obviously, in the study as we look through different doses. You might remember what we pointed out in David's presentation that about a 60% knockdown is the benchmark that we're using for what we think is the best currently approved therapy out there, and we're well in excess of that. And we'll see with the extended observation, how much better the attack rates tend to be as we get to lower levels than that 60% reduction. So stay tuned.

The next question comes from Luca Issi with RBC.

This is Lisa on for Luca. Congrats on the data today. Just wanted to ask, since you reiterated in the press release, you have a plan to include U.S. sites for the Phase II for HAE. Can you provide us some color on whether you have had a pre-IND meeting with the FDA yet?

We don't go into detail with all of the regulatory interactions that we've had. We do have regulatory interactions as you might imagine. And we think we're well-positioned to put ourselves into U.S. sites here in the upcoming Phase II trial. And as that program moves forward, we'll share more details as they become available.

The next question comes from Joseph Thorne with Cowen & Company.

Maybe just a little bit on the pretreatment regimen as it stands right now. I see on day 1, you can take either IV or oral therapy. Is there a difference in the proportion of patients that take one or the other in their eventful response? And maybe as it stands right now, are you considering any changes to the pretreatment regimen going into the Phase II?

David, I think the question was did the pretreatment regimen influence response?

We haven't seen any variation. The main therapy for the infusion reactions has been dexamethasone with antihistamines. And what we're seeing is really very effective. The infusion-related reactions are grade 1 or 2 and just very short-lived. In addition to patients, some patients have had some routine type of rescue therapy just to prevent any attacks happening in that period. And again, we haven't seen any difference from different things that people are using.

Okay. Perfect. And do you expect to change that in the Phase II at all or make any adjustments?

So far, we are going to keep that the same.

The next question comes from Steven Seedhouse with Raymond James.

Congrats on the impressive results so far. My question is just on the nomenclature functional cure. I'm curious if you expect to eventually have that language in a product label? And are you expecting basically, patients won't have any need for future treatment or medical care for their HAE after this treatment?

I appreciate your looking into that, Steve, because I think it's a really important question. I don't know if that's language that will appear in the label. I think that's down the road yet. We use that language as distinct from cure, because what we're doing is intervening in the pathway in a way that's different from the underlying condition itself. The objective here, obviously, is to wind up with patients who are as normal as possible. And to the extent that they are, we think that, that constitutes a functional cure, but only time will tell as we go and make sure the outcomes for these patients, how close we get to that aspiration.

The next question comes from Greg Harrison with Bank of America.

This is Mary Keeton on for Greg. I guess in terms of your larger pipeline, maybe how does the results today increase your confidence in your larger in vivo CRISPR task-based platform?

David, do you want to think about -- how we think about the platform of modularity in general [indiscernible] currently?

Yes. So we felt -- obviously, we felt very good after the work with TTR. But it was -- again, the platform is just changing the 5 prime end, 20 nucleotides on the [ 55 end ]. Otherwise, the drug is really essentially the same as the TTR drug. And the fact that we're seeing results that are almost overlapping in terms of reduction of biomarker is pretty remarkable. So we think this is a very good sign for any of our ongoing work with knocking out a gene. It also increases the likelihood that knocking in the gene may work, because the same -- we use the same type of lipid nanoparticle mRNA and guide in order to create the site that the DNA is inserted to. And the 2 cases we're going forward with first is alpha-1 antitrypsin and with Factor IX for hemophilia. So again, it doesn't show that, that's going to work, but a piece of that is already working as part of the knockout program. So we're very happy about what this shows for our program overall.

The next question comes from Dae Gon Ha with Stifel.

Congrats on the progress. I guess I just wanted to get a little bit more thoughts on your next steps, particularly on differentiation. As we see it, you've cleared the 60% threshold on the peak kal reduction, attack rates, perhaps you guys are already maximizing in the weeks 5 to 16. So what are your current thoughts on peak kal reduction really maximizing on it? And where would that differentiation come in as we think about your 2 doses in Phase II?

Well, I think it starts with seeing how these results play out through time. Obviously, we're looking at early data here, although we're very, very excited about the preliminary information that we have as we continue to observe across the range of doses here, that's going to influence what we do in Phase II and ultimately, what we do in Phase III. But I think when we step back and think about what the product itself might be -- this is a regimen that we think potentially can offer lifelong improvement to patients potentially a functional cure. And these are -- this is a condition that is typically diagnosed in adolescents or early 20s. When you think about the cost of many of the best therapies out there, you're really talking about prohibitive expenses for the health care system. So we think we can improve on that. We think we can improve on the efficacy and of particular importance to patients is the immense burden of treatment. These are patients that are getting infusions or injections or have to carry prophylactic therapy or treatment on demand with them as they live their lives. And if we can free them from that, we think we will have restated the entire treatment category.

The next question comes from Jay Olson with Oppenheimer.

Congrats on the results. I'm curious about your thoughts around dosing, especially since the 25-milligram cohort, even though they had 64% kallikrein reduction. The patients seem to do well in terms of attack rates. So does that change your view on the doses going into Phase II?

Well, sure, Mike, Watson. David, you can amend them, I suppose. These are small numbers, and I would bear that in mind. Obviously, we're very, very excited about the data that we have but expanding the number of patients and following them for a greater period of time may cease out slight differences. We know from prior work that dipping below 60% and maintaining people consistently below a 60% reduction in the kallikrein activity leads to pretty significant changes. We want to improve on that, and we think that deeper reductions can do that. So to the extent that those 2 doses that go beyond 25 accomplish that, we hope that we can [ suss ] that out in our Phase II study, which will be the determinant of what we ultimately do in Phase III. David, do you have anything to add to that?

I think you have it all. The biggest question now is to have more numbers and then make a decision based with more patients.

The next question comes from Raju Prasad with William Blair.

Just looking at the summer spot was wondering, it looks like the majority of attacks are mild to moderate in nature. Just wondering how that compares with the HAE population in general? Or are there more kind of severe genotype that are out there?

David, how [indiscernible] these 6 patients were reporting on to the HAE population in general?

Yes. From talking to investigators, we have a pretty good range of most of the patients that you see patients who are either having fairly frequent attacks, some of them moderate, some of them severe, and then patients having fewer attacks. So it looks like we have pretty good set of the range as we go into Phase II, of course, we'll have a bigger range or more patients to look at. But we do feel like these are typical patients in the population.

The next question comes from Terence Flynn with Morgan Stanley.

I was just wondering how much follow-up data on durability you think is sufficient to choose between the various doses, whether that's in follow-up data from the Phase I trial or as you think out to the Phase II, how much durability do you think is going to make a difference here?

David, durability fall into our Phase II [ thinking ] in ultimately Phase III.

The initial period is very important. What we've seen in each case is the events going to 0 during this initial observation period, and that's always part of it is really part of the primary endpoint. As we go forward in the studies, we'll have patients with longer follow-up. Given the fact that we are -- what we think we're doing is a permanent reduction from everything we've seen, which will be a reduction to levels that will be maintained as far as we know for the patient's lifetime. We don't -- having a few months follow-up is very helpful. We don't expect there to be big changes after that period from any observations that we've had or from other programs. So we will look at all the data we get at the time of the Phase II to make those decisions about the Phase III doses.

I mean one of the things that's been quite helpful is that we have a pretty wide therapeutic index that would appear, and that gives us the opportunity to -- the room we need to choose doses. But patient number and time are going to be key to what we ultimately do in Phase III.

The next question comes from Silvan Tuerkcan with JMP Securities.

Congrats on the great data. Just looking at your patient population in the [ some ] parts. So half of the enrolled patients are not on prophylaxis and perhaps they should be. Are they more open to a onetime dosing [Audio Gap] could you talk a little bit about why they choose to be dosed here versus not being on prophylaxis to treat their medication? Is there an opportunity to just broaden the patient population beyond what's possible today?

We lost half of what you said, but I think you were asking how many times the number of patients actually taking prophylaxis and whether or not patients are on prophylaxis will determine how they use the product, ultimately, David. I'm filling in some blanks, it was very hard to hear, but.

Yes, I think the reason a lot of these patients aren't taking prophylaxis perhaps is not available to them in their country. Some of these patients were taking the prophylaxis that was available and apparently weren't receiving enough benefit that they stopped it or the burden was too high for them that they stopped it, which does happen in a number of patients. So that -- in all, I don't think -- I'm trying to think it doesn't tell you a lot about what's going to happen going into the future, except we do expect patients because of the treatment burden, we'll be very interested in this therapy, both in the clinical trials as we've seen, but also going forward, if we are able to get it approved for marketing.

Okay. Did that answer your question, Silvan? The next question comes from Richard Law with Credit Suisse.

Congrats on the data. Since you don't reduce kallikrein levels to 100%. Do you have any reason to believe there's breakthrough attacks possible at some point in the future? And also, what do you hope to learn in the next Phase II study that you're not learning here that can help you prepare for a pivotal study?

It's an interesting question. If kallikrein levels go to 0, we'll add [indiscernible] attacks. My guess, and I emphasize were guess is yes, since that's the enzyme that activates bradykinin, which is the ultimate final step in the pathway here. I think what we've learned is that already, you don't need to get to 100% reductions to have a profound and perhaps at some of these levels, even permanent effect that approximates these very, very low levels that we're shooting for, and that's the basis of doing the dose-ranging study and following these patients over time. In terms of what we want to learn between now and Phase III, getting the dose right is really important. That's always true for every drug, irrespective of the modality. And as tempting as it might be to say we've got the answer with these 6 patients that we're reporting on today, I think that's premature. And additional follow-up with these patients at these doses and the work that we do in Phase II, which will draw on what we're learning here, we will get the details once we finalize that protocol, the idea there would be to really lock in on the dose that we intend to study for Phase III. So it's the process that routinely is followed, and we're not deviating from those principles that all good drug development follows.

The next question comes from Swapnil Malekar with Piper Sandler.

So 2-part question. One is how far along are you in terms of selecting the 2 doses to move forward into the Phase II trial? And then the second part is the patient #3 in 75-milligram cohort despite being attack-free for 3.9 months, why is that patient still on concomitant better [ at like ] what's the decision-making criteria to take them off the background prophylactic therapy?

With respect to your first question, we're very far along, which usually the doses, stay tuned as that information becomes available, we'll share it. And David, my understanding is the doctor's choice to continue withdraw prophylaxis as the doctor sees it, is that correct?

It is a doctor's choice that the decision is only made after 16 weeks. They do maintain their prophylactic therapy through 16 weeks. So it's very possible this patient will decide and the doctor will decide to stop it.

The next question comes from Mike King with EF Hutton.

Let me add my congratulations. Most of the questions have been answered, but I just am curious. I know I'm not an expert in HAE by any means, but I do believe there's a prodrome that a lot of patients experienced. And I'm just wondering if there was any recording of presence or absence of prodrome or whether you'll measure those as a quality of life metric in your randomized studies?

David, can you speak to that?

Yes. I think some patients getting the prodrome may call that like an earlier attack often. If they're having some symptoms, it will be most likely recording that. But, yes.

I think hasn't been a focus for us this yet, Mike, but that is something that will further explore the KOLs who are helping us to design the study, not something to report on today.

Okay. And then just a quick follow-up. And I'm just wondering if the -- if you're -- it's pretty early to think about registration-directed studies, but is there a population of HAE patients that are sort of -- I'm thinking about maybe like an oncology context where you've got patients who have failed all other therapies and are in dire need, and there's a potential accelerated approval pathway. I don't know if that's something that you've contemplated? Or are you going to try to register the drug in a more heterogeneous patient population?

Well, we're always thinking about how to get drugs approved in a way that's meaningful and answers the regulatory questions. Inherent to HAE itself is typically a fairly truncated Phase III program largely because the treatment effects can be so profound. So if 1 is doing a placebo study patients whether they have mild moderate disease or severe disease, with agents like this, we're likely to see an effect very, very quickly. And so choosing some subset of those patients, I don't think it's going to hasten the approval in any way. And our approach is trying to make the drug available to the broader set of patients as we carry out the Phase III program, whether they're severe or not. So, we think about it, but I think the basic plan that we have following the existing paradigm should answer that question.

The next question comes from Tony Butler with ROTH Capital Partners.

This is Tash on for Tony. So when we look at the patient reported HAE attack history, the historical attack rate in the 50-milligram cohort, I wonder if you have any thoughts around it, how the data should be considered when we have the 16-week evaluation available. And of course, any [ sense ] as I understand, would be characterized as 100% reduction.

It was a little hard to hear you, but I think you were asking at what point can we conclude that the patients are attack-free. Again, it was a little hard to hear you. There is this period of adaptation. When you think about it, it makes perfect sense. You treat a patient. And the moment that the infusion is complete, the patient is still a lot like the patient was the moment before he got the infusion. And so there's a period of days, 2 weeks as we're seeing, which is typical for all agents. I think some of it has to do with pharmacokinetic, some of it has to do with the pharmacodynamics and some of it probably has to do with the patient, him or herself. But as all of that reaches a point of, let's call it, equilibrium as far as we can tell, it appears thus far that those patients reach a state that's fundamentally different from where they were before therapy. And across the board for the small number of patients are reporting on, they appear to be attack-free. We'll have to measure what happens, but we'll do it in a way that is meaningful for regulatory purposes, which is from the time after the patients have treated immediately thereafter, and I think we'll try very, very hard to characterize what we think represents the true stage of the patient after some period of time. That -- those are regulatory discussions at lay. David, do you want to add to that?

Yes. I think you're also asking what we to see at 50 milligrams. And what you're seeing in the pharmacodynamics and the biomarker reductions is something that looks very similar to 75 milligrams. I think you'll recall with TTR, we really had the same thing that we are saturating at 65 to 80 milligrams in terms of the TTR reduction. So it looks from everything we see, 50 will be similar to 75 -- and as both 25 and 75 milligrams patients were able to reduce to 0 attacks, we do expect a very good result with 50 milligrams as well.

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

Along the same lines, I'm wondering whether based on available data from prophylaxis therapies, you think that the 89% reduction you observed in weeks 5 to 16 is representative of the long-term effect? And if so, how should we be thinking about this 11% of remaining attacks, especially in patients with a high number of attacks?

David, do you think the 89% represents the final word on where these patients are? Or is there more to get?

Yes. We do think that, that percentage is enough of a reduction based on what we know from other therapies. We will be studying this, of course, in Phase II to figure that out a bit more and then decide what to do in Phase III. But the -- this is a deeper reduction has been achieved with the best available agents today. We think that could be valuable to patients. And of course, our ultimate goal is what John was talking about a functional cure, a place where we'd like to get where this is -- we know this is from everything, no a permanent reduction. We think it will stay at those levels. And with that, perhaps we could get a very high percentage of all patients to having no attacks that would be our goal.

I think the 89% that we reported for these 2 dose groups reflects that adaptation phase. And what we're excited about, Kostos, is the ongoing observation where if what we've seen thus far continues to be the case. If you think about it, it's eventually approaching [indiscernible], which is very close to 0. These patients do have an attack or a few attacks immediately after therapy, which sorts itself out. But this is a lifelong condition. And if what we're seeing here is representative of what's going to be the outcome for these patients, I think it's very exciting data where most of them will be able to, we think, abandon prophylactic therapy. And be essentially indistinguishable from people who don't have the condition. So that comes with extended follow-up, and that's where the program is going.

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, Andrew, and thank you, everyone, for joining us today. We appreciate your interest and your questions, and we look forward to talking to everyone soon. Have a great day now.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.