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. At this time, all participants are in listen-only mode. If you require operator assistance, please press star then zero. Following the formal remarks, we'll open the call up for your questions. 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 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 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, 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'll now turn the call over to John.
Thank you, Ian. Welcome everyone, and thank you for joining us today as we review positive interim data 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 of 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 the 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 a disease-causing gene or precisely insert the gene to produce desired proteins. In a moment, David will present the updated interim data.
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 may offer people suffering from hereditary angioedema a functional cure for their disease. Across the 25-mg and 75-mg 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 three patients dosed, they have now been living free of HAE attacks for five to 10 months and without the need for chronic treatment. At the 50-mg 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 patients dosed 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 very pleased with the interim data from our 2002 phase I/II clinical study, which were presented this past weekend at ACAAI by Dr. Hilary Longhurst. HAE is a rare genetic disease characterized by severe, recurring, and unpredictable inflammatory attacks in various organs and tissues of the body, which can be painful, debilitating, and life-threatening. It is estimated that one in 50,000 people are affected by HAE. Despite the existence of chronic treatments, people living with HAE can still experience breakthrough attacks and face high treatment burden, which for many includes frequent injections and/or infusions to prevent or treat their attacks. 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 NTLA-2002's mechanism of action. For those of you familiar with our lead in vivo program, NTLA-2001, you'll notice that NTLA-2002 is also comprised of a lipid nanoparticle containing a guide RNA and messenger RNA. The only difference between these two candidates is the target site portion of the guide RNA. Intellia's ongoing phase I/II trial is evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2002 in adults with type 1 or type 2 HAE. The phase I portion of the study is an open-label, single ascending dose design with a minimum of three patients in each cohort evaluating 25, 50, and 75 mg. The phase II portion will include up to two dose levels in a randomized, placebo-controlled study.
For today's presentation, which builds upon the initial results we shared in September, I'll be reporting on all 10 patients enrolled in phase I. Here you can see the inclusion and exclusion criteria. Notably, patients were required to have at least three HAE attacks within 90 days prior to screening and were allowed to enter the study even if they were currently receiving prophylactic therapy. Next, you can see the patient demographics, which include both male and female patients across a range of ages from 26 - 73 years old. Here is the patient HAE attack history with a mean monthly HAE attack rate of 4.6 per month across all three cohorts. I will point out that patients in the 25- and 75-mg cohort had meaningfully higher historical attack rates of six to eight attacks per month. Starting with safety.
At all three dose levels, 2002 was 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 one and resolved within one day. There have been no dose-limiting toxicities, no serious adverse events, and no adverse events of grade three 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 mg 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 contend with significant treatment burden. At all three dose levels, we have already achieved our goal of greater than 60% mean kallikrein reduction. Now we are pleased to report the HAE attack rates for the patients in the 25- and 75-mg cohort who have all reached the end of the 16-week initial observation period.
In the screening period prior to the administration of NTLA-2002, patients in the 25 mg cohort had 1.1-7.2 attacks per month, and patients in the 75 mg cohort had 4.0-5.9 attacks per month. Following a single administration of NTLA-2002, the mean reductions in HAE attack rates at 16 weeks were 91% and 78% in the 25 mg and 75 mg 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 five to 16, we see the attack rate reduction is nearly 90% for both dose levels.
As we move to the next slide, we'll show you that with extended observation, all patients have now reached attack-free status as of the latest follow-up. Here we see a swimmer's plot of the patients in the 25- and 75-mg cohort. For context, on the left, you see the attack rate for each of the patients in the three months prior to screening. The colored lines indicate any HAE attacks that occurred in either the screening period or in the subsequent observation period following administration with 2002, which ranged from four 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 two months to more than 10 months. For all three patients in the 25 mg cohort for whom we have the longest follow-up, we see that they have remained attack free now for five to 10 months. We believe these interim data are an early indication that NTLA-2002 may offer people living with HAE a functional cure of their disease after a single dose. Finally, not all patients in the 50 mg 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 attacks. 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 two 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. 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 one-time 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.
We will now begin the question- and- answer session. To ask a question, you may press star then one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then two. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Brian Cheng with JPMorgan. Please go ahead.
Hey, guys. Congrats on the data, and thanks for taking my question this morning. John, as you said, in the 25 mg and 75 mg, you know, those cohorts had higher than average attack. 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? Based on the data so far, how are you thinking about when to best wean off prophylaxis? Thank you.
Why don't we turn to David? You know, I know we're thinking a lot about next steps. Maybe you could tell us how we're thinking about the phase II study.
Yeah. For the phase II, the main question in terms of number of attacks is to have enough attacks that you can see a signal. This has generally been in the range of one to two 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. We expect to have a range of attack rates, and we don't think there's particular limit we have to have that on that as we design the study.
Which ones? What do you think about
Yeah, on the prophylaxis. In Part 2, we will have patients coming off prophylaxis if they have been on prophylaxis. Generally you do that so that there won't be any, the drug will have been washed out of the patient before you start the new therapy.
We would make available therapy.
Yeah.
in the course of the trial should an attack
Of course, there are rescue therapy.
Which is the standard approach.
Yeah. This has been a standard approach to allow rescue therapies during the study itself, the study period.
Great. Thank you, guys.
The next question comes from Gena Wang with Barclays. Please go ahead.
Thank you for taking my questions. I have a very quick two-part question. First one is regarding one patient with all other AEs. Which dose was that patient? And also, for the 25 mg, you have a high standard deviation for the knockdown. Just wondering, when you look at the standard deviation, one patient certainly reached the 90% knockdown. I'm wondering which patient from 25 mg that reached that 90% knockdown.
Gena, I'm not sure I understood your first question about the. Can you just repeat the adverse event question?
Sure.
Clear.
I think that's the data slides. I'm not sure about the today's investor slides. The data slides, that was Slide 10. All other AEs, and I have a long list, were reported in one patient. You put all the AEs, adverse AEs occurring in two or more than two patients and put all the events there. Then in the footnote there is all other AEs were reported in one patient. Just wondering, you know, what dose was that?
Yeah. I could see the ambiguity there. Each of these events occurred only once, but it's different patients at different doses. It's not that all of these occurred in one patient. That's the question. They would have occurred at both dose levels.
I see. Okay. Very helpful.
The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
Hey, good morning, and thank you for taking our question. This is Elizabeth on for Salveen. Could you comment on the feedback from physicians and patients in the context of use just given their multiple modalities and development? Thank you.
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?
Yeah. 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. 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 at basically as quickly as we have the dose levels open. 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, that's one thing we've heard from the KOLs. The hope for a outcome of being able to dispense with, you know, what is an ongoing burden of care is something that is of great appeal. 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.
Thank you.
The next question comes from Joon Lee with Truist Securities. Please go ahead.
Hey, thanks for taking our questions, and congrats on the data. With this data, would you be looking at week one 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 mg and 75 mg doses? And related to that, you know, are you able to quantify the potential off-target risk as you go from 25 mg- 75 mg? And would the FDA require quantification of this? Thank you.
Maybe I can take some of that, Joon. You know, we'll do what the regulators require to measure attack rates, and there's 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. With that, you know, we'll certainly follow very, very carefully how these patients perform over time. As we accumulate that data, I would expect that in clinical trials, we'll put in place measurements that collect that information because it's what, you know, 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 you know what I would call adaptation. I think it's very complex. Where patients settle out, I think is gonna 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 suprapharmacologic, that are never expected to be achieved in human beings, which would encompass 25 mg and 75 mg and even doses beyond that. We feel really good about where we are from that off-target assessment in the preclinical work to justify these doses.
Great. Thank you.
The next question comes from Yanan Zhu with Wells Fargo. Please go ahead.
Hi, thanks for taking our question. This is Ohsung Kwon for Yanan. I have quick two-part question. Did you observe a correlation between individual patients', kallikrein level and their attack rate, and whether it's at baseline or during the study period? Is there a certain threshold on, kallikrein reduction that would translate to attack free? Thank you.
Kallikrein.
Yeah, 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 one knocks down those kallikrein levels, there is a decrease in the attack rates. You know, 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. We're well in excess of that.
We'll see with extended observation how much better the attack rates tend to be as we get to lower levels than that 60% reduction. Stay tuned.
The next question from.
All right. Thank you.
Thank you. The next question comes from Luca Issi with RBC. Please go ahead.
Oh, excellent. Thanks for taking our questions. 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? Thank you.
We're gonna 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. As that program moves forward, we'll share more details as they become available.
The next question comes from Joseph Thome with Cowen and Company. Please go ahead.
Hi there. Good morning, and thank you for taking our question. Maybe just a little bit on the pretreatment regimen as it stands right now. I see on day one, 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 eventual response? Maybe as it stands right now, are you considering any changes to the pretreatment regimen going into the phase II? Thank you.
David, I think the question was, does the pretreatment regimen influence response?
You know, we haven't seen any variation. You know, the main therapy for the infusion reactions has been dexamethasone with antihistamines. What we're seeing is really very effective. The infusion-related reactions are grade one or two and you know, just very short-lived. In addition, some patients have had some routine type of rescue therapy just to prevent any attacks happening in that period. Again, we haven't seen any difference from different things that people are using.
Okay, perfect. Do you expect to change that in the phase II at all or make any adjustments?
No. So far we are gonna keep that the same.
Perfect. Thank you very much.
The next question comes from Steven Seedhouse with Raymond James. Please go ahead.
Good morning. Thank you, and 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. Are you expecting basically patients won't have any need for future treatment or medical care for their HAE after this treatment? Thank you.
I appreciate your looking into that, Steve, 'cause I think it's a really important question. I don't know if that's language that'll appear in a 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. To the extent that they are, we think 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. Please go ahead.
Good morning. This is Mary Kate on for Greg. Thanks for taking our question. I guess in terms of your larger pipeline, maybe how did the results today increase your confidence in your larger in vivo CRISPR-Cas9 based platform? Thank you.
David, do you wanna think about how we think about the platform of modularity in general? It's two for two currently.
Yeah. We felt very good after the work with TTR. Again, the platform was just changing the 5 prime end, 20 nucleotides on the 5 prime end. Otherwise, the drug is really essentially the same as the TTR drug. The fact that we're seeing results that are almost overlapping in terms of reduction of biomarker is pretty remarkable. 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 a gene may work because we use the same type of lipid nanoparticle, mRNA and guide in order to create the site that the DNA is inserted to.
The two cases we're going forward with first is alpha-1 antitrypsin and with Factor IX for hemophilia. Again, it doesn't show that that's gonna work, but a piece of that is already working as part of the knockout program. We're very happy about what this shows for our program overall.
The next question comes from Dae Gon Ha with Stifel. Please go ahead.
Hey, guys. Good morning. Thanks for taking our questions, and congrats on all 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 know, you've cleared the 60% threshold on the pKal reduction. Attack rates, perhaps you guys are already maximizing in the weeks five to 16. What are your current thoughts on pKal reduction really maximizing on it, and where would that differentiation come in as we think about your two doses in phase II? Thanks so much.
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 gonna influence what we do in phase II and ultimately what we do in phase III. I think when we step back and think about what the product itself might be, you know, this is a regimen that we think potentially can offer lifelong improvement to patients, potentially a functional cure. You know, this is a condition that is typically diagnosed in adolescence 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 healthcare system.
We think we can improve on that. You know, we think we can improve on the efficacy. Of particular importance to patients is the immense burden of treatment. These are patients that are getting infusions or injections or have to carry, you know, prophylactic therapy or, you know, a treatment on demand with them as they live their lives. If we can free them from that, we think we will have reset the entire treatment category.
The next question. ... The next question comes from Jay Olson with Oppenheimer. Please go ahead.
Oh, hey, c ongrats on the results, and thanks for taking the question. I'm curious about your thoughts around dosing, especially since the 25 mg cohort, even though they had 64% kallikrein reduction, the patients seemed to do well in terms of attack rate. Does that change your view on the doses going into phase II? Thank you.
Well, sure. Mike Watson, David, you can amend them, I suppose. You know, these are small numbers, and I would bear that in mind. You know, obviously, we're very, very excited about the data that we have. You know, expanding the number of patients and following them for a greater period of time may tease out slight differences. We know from prior work that, you know, dipping below a 60% and maintaining people consistently below a 60% reduction in their kallikrein activity leads to pretty significant changes. We wanna improve on that, and we think that deeper reductions can do that.
To the extent that those two 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, 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.
Great. Thank you.
The next question comes from Raju Prasad with William Blair. Please go ahead.
Thanks for taking the question. Just out of looking at the summary plot, was wondering, 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 phenotypes that are out there? Thanks.
David, how representative are these six patients for reporting onto the HAE population in general?
Yeah. From talking to investigators, we have a pretty good range of most of the patients that you'll see, patients who are either having fairly frequent attacks, some of them moderate, some of them severe, and then patients having fewer attacks. 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. We'll have more patients to look at. We do feel like these are typical patients in the population.
The next question comes from Terence Flynn with Morgan Stanley. Please go ahead.
Hi. Thanks for taking the question. I was just wondering how much follow-up data on durability you think is sufficient to choose between the various doses, whether that's, you know, in follow-up data from the phase I trial or as you think out to the phase II, how much durability you think is gonna make a difference here? Thank you.
David, how does durability fall into our phase II thinking and ultimately phase III?
You know, the initial period is very important. What we've seen in each case is the events going to zero during this initial observation period, and that's always really part of the primary endpoint. As we go forward in the studies, we'll have patients with longer follow-up. You know, given the fact that what we think we're doing is a permanent reduction from everything we've seen, this will be a reduction to levels that will be maintained, as far as we know, for the patient's lifetime. We don't, you know, 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.
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, it would appear, and that gives us the opportunity to, you know, the room we need to choose doses. Patient number and time are gonna be key to what we can ultimately do in phase III.
The next question comes from Silvan Turkcan with JMP Securities. Please go ahead.
Good morning and congrats on the great data, and thank you for taking my questions. Just looking at your patient population in the swimmer plots. Half of your enrolled patients are not on prophylaxis and perhaps they should be. Are they more open to a one-time dosing? Because, you know, could you talk a little bit about why they choose, you know, 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? Thank you so much.
I think we lost half of what you said, but I think you were asking comment on the number of patients actually taking prophylaxis and whether or not patients who are on prophylaxis will determine how they use the product ultimately, David. I'm filling in some blanks. You were very hard to hear, but go.
Yeah, still not sure. I think.
You know, the reason a lot of these patients aren't taking prophylaxis, perhaps it's 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. In all I don't think, you know, I'm trying to think. It doesn't tell you a lot about what's gonna happen going into the future, except we do expect patients, because of the treatment burden, will 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?
Yeah. Thank you very much.
Thank you. The next question comes from Richard Law with Credit Suisse. Please go ahead.
Good morning, and congrats on the data. Since we don't reduce kallikrein levels to 100%, do you have any reason to believe there's breakthrough attacks are possible at some point in the future? 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? Thanks.
It's an interesting question. If kallikrein levels go to zero, will that obviate all attacks? My guess, and I emphasize the word 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, you know, permanent effect that approximates, you know, these very, very low levels that we're shooting for. That's the basis of, you know, doing this dose ranging study and following these patients over time. In terms of what we wanna learn between now and phase III, getting the dose right is really important. It's always true for every drug, irrespective of the modality.
As tempting as it might be to say we've got the answer with these six patients that we're reporting on today, I think that's premature. Yeah, 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'll give 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. It's the process that you know routinely is followed, and we're not deviating from those principles that all good drug development follows.
The next question comes from Swapnil Melekar with Piper Sandler. Please go ahead.
Hey, good morning. Thanks for taking my questions. Two-part question. One is, how far along are you in terms of selecting the two doses to move forward into the phase II trial? Then the second part is, the patient number three in 75 mg cohort, despite being attack-free for 3.9 months, why is that patient still on concomitant Berotralstat? Like, what's the decision-making criteria to take them off the background prophylactic therapy? Thank you.
With respect to your first question, we're very far along with choosing the doses. Stay tuned. As that information becomes available, we'll share it. David, it's my understanding it's the doctor's choice to continue, withdraw prophylaxis as the doctor sees fit. Is that correct?
It is the doctor's choice, but the decision is only made after 16 weeks. They do maintain their prophylactic therapy through 16 weeks. 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. Please go ahead.
Thanks for taking the questions, and let me add my congratulations. Most of the questions have been answered, but I just am curious. I know that I'm not an expert in HAE by any means, but I do believe there's a prodrome that a lot of patients experience, 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. Yeah. I think, you know, some patients getting the prodrome will, you know, may call that like an early attack often. You know, if they're having some symptoms, they will be most likely recording that. But, yeah, I think.
Hasn't been a focus for us just yet, Mike.
Okay.
that is something that we'll further explore with the KOLs who are helping us to design the study. Not something to report on today.
Okay. Just a quick follow-up and I'm just wondering. I know it's pretty early to think about registration-directed studies, but is there a population of HAE patients that are, you know, sort of, I'm thinking about maybe in, like, an oncology context where you've got patients who have failed all other therapies and are, you know, 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, you know, register the drug in a more heterogeneous patient population? Thanks.
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. If one's doing a placebo study in patients, whether they have mild, moderate disease or severe disease, with agents like this, we're likely to see an effect, you know, very, very quickly. Choosing some subset of those patients, I don't think it's going to hasten, you know, the approval or in any way. Our approach is try to make the drug available to the broadest set of patients, as we carry out the phase III program, whether they're severe or not.
We think about it, but I think the basic plan that we have following the existing paradigm should answer that question.
Thank you.
The next question comes from Tony Butler with Roth Capital Partners. Please go ahead.
Good morning. This is Tosh on for Tony. When we look at the patient-reported HA attack history, you know, the historical attack rate in the 15-week one cohort, I wonder if you have any thoughts around it, how, you know, these data should be considered when we have the 16-week, you know, evaluation available. Of course, any absence, as I understand, would be characterized as a 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. It's, again, it's a little hard to hear you. You know, there is this period of adaptation. When you think about it makes perfect sense. You know, you treat a patient and, you know, the moment that the infusion is complete, the patient's still a lot like what the patient was the moment before he got the infusion. There's a period of, you know, days to weeks as we're seeing, which is typical for all agents. I think some of it has to do with pharmacokinetics, some of it has to do with the pharmacodynamics, and some of it probably has to do with the patient, him or herself,
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. Across the board, for the small number of patients I'm 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, you know, regulatory purposes, which is, you know, from the time after the patients are treated immediately thereafter. I think we'll try very, very hard to characterize what we think represents the true state of the patient after some period of time. Those are regulatory discussions that way ahead. David, you wanna add to that?
Yeah. I think you're also asking what we expect to see at 50 mg. What you're seeing in the pharmacodynamics and the biomarker reduction is something that looks very similar to 75. I think you'll recall with TTR, we really had the same thing, that we were saturating at 55 mg-80 mg in terms of the TTR reduction. It looks like, you know, from everything we see, 50 will be similar to 75. As both 25 and 75 patients were able to reduce to zero attacks, we do expect a very good result with 50 mg as well.
Thank you. Appreciate taking my question.
The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead.
Good morning. Thanks for taking my question. 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 five to 16 is representative of the long-term effect? If so, how should we be thinking about these 11% of remaining attacks, especially in patients with a high number of attacks? Thank you.
David, do you think the 89% represents the final word where these patients are, or is there more to give?
We do think 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. This is a, you know, deeper reduction than has been achieved with the, you know, best available agents today. We think that could be valuable to patients. 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 a permanent reduction. We know this is, from everything we know, a permanent reduction.
We think we'd stay at those levels, and with that, perhaps, we could get a very high percentage or all patients to having no attacks. That would be our goal.
I think the 89% that we reported for these two dose groups reflects that adaptation phase. What we're excited about, Kostas, is the ongoing observation where if what we've seen thus far continues to be the case, if you think about it's eventually approach an asymptote, which gets very close to zero. These patients do have an attack or, you know, a few attacks immediately after therapy, which sorts itself out. You know, this is a lifelong condition. If what we're seeing here is representative of what's gonna 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.
that comes with extended follow-up and that's where the program's going.
Thank you. Very helpful.
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. 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.