Hello, and welcome to Intellia Therapeutics conference call. My name is Betsy, and I will be your conference operator today. Please be advised that today's call is being recorded. I will now turn the call over to Jason Fredette, Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.
Thank you, Betsy, and good morning, everyone. We're very pleased to be speaking with you. Earlier this morning, we issued two press releases, one summarizing the top line data from our phase III HAELO clinical trial, and the other discussing our rolling BLA submission. These documents can be found in the Investors and Media section of Intellia's web site at intelliatx.com. At this time, I would like to remind listeners that the discussion today may include certain forward-looking statements. We 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 as required by law.
Joining me today are Dr. John Leonard, our Chief Executive Officer, Dr. David Lebwohl, our Chief Medical Officer, and Dr. Marc Riedl, Professor of Medicine and Clinical Director of the US HAEA Angioedema Center at UC San Diego Health, and a HAELO principal investigator. We also have other members of Intellia's leadership here for the Q&A session. With that, let me turn the call over to John to begin our discussion.
Thank you, Jason, and thank you everyone for tuning in. This is an exciting moment for Intellia, the entire CRISPR field, and for many of the people who are living with HAE. Before we dive into the details, it's important to remind ourselves of what led us to this landmark event. While the discovery of CRISPR occurred nearly 30 years ago, it was the breakthrough publication in science in 2012 that made clear its potential role in the treatment of an array of different medical conditions. That publication and related work led to the award of a Nobel Prize for our scientific co-founder, Jennifer Doudna. In rapid succession since that first insight, scientists in academic settings and in companies like ours gained key insights and laid the foundation for CRISPR-based treatments.
Some work on ex vivo approaches in which CRISPR therapy is brought to patients in the form of a bone marrow transplant. We set out in a different direction just a dozen years ago, recognizing early on that ex vivo gene editing would have certain challenges and limitations. We chose to focus most of our development efforts on an in vivo approach, delivering CRISPR directly to the area where it's needed, which in Lonvo-Z's case is the liver. Our mission has been to transform the lives of people with severe diseases by developing and commercializing potentially curative treatments. We also set a high bar for all of our programs. We didn't wanna just compete with available and emerging therapies. We set out to develop definitive answers to diseases, treatments that have the potential to provide best-in-class outcomes and to free patients from the burdens of the chronic medications.
Since our founding, we've come a long way in a very short period of time relative to other biotech pioneers. We were the first in the world to dose patients with in vivo CRISPR-based candidates and the first to advance into phase III. Today, we're proud to be presenting the world's first phase III data for an in vivo gene-editing candidate and to be advancing our BLA filing, bringing us closer than ever to realizing our ultimate mission. Intellia's pipeline is approaching several important and exciting milestones. We have two phase III assets that, if approved, will compete in multi-billion-dollar markets that are today served by costly chronic therapies. Lonvo-z is advancing toward a potential approval. Nex-z is following close behind, and a range of other proprietary and partner programs are in earlier stage development. Now let's share some background about HAE and lonvo-z.
David, would you guide us through this, please?
Sure. Thanks, John. As most of you know, hereditary angioedema is a condition that can have devastating consequences. As the name indicates, it's a disease passed down in the genes and results from an imbalance in the kallikrein-kinin system. This imbalance leads to unpredictable swelling attacks in various parts of the body, including the face, throat, abdomen, and extremities. Onset often occurs early in life, and despite the availability of several chronic medications, the disease burden remains significant for many. On this slide, you can see a common cycle of burden in HAE. Here in the United States, to prevent future attacks, a majority of patients are taking chronic long-term prophylaxis therapies, also known as LTPs. Despite this, research shows that most patients continue to experience breakthrough attacks. Some of these occur in the larynx and upper airway, which can have a fatal outcome.
The impact on patients' lives is significant. The unpredictability of attacks can cause huge anxiety. Family obligations are not always met, and social interactions and simple vacations are often minimized or avoided altogether. Our market research has shown these types of disease burdens are very real despite existing therapies. What's underappreciated are the many burdens associated with the treatments themselves. Most people with HAE are otherwise very healthy, and they would like to avoid taking medications, whether it be regular injections or daily orals, for the rest of their lives. These medications also present an array of financial concerns. LTPs and on-demand treatments are costly, and they often face intense and very regular scrutiny from payers. What does the impact look like in dollar terms? Well, here in the U.S., there are about 7,000 patients who are receiving treatment. More than 60% of them are on LTPs.
On average, diagnosis takes place at about age 20. As I mentioned a moment ago, those afflicted with HAE tend to be otherwise healthy, meaning they will likely be on medication, whether it be LTPs, on-demand treatments, or both for decades. As you can see on the right, the U.S. healthcare system is today spending about $4 billion annually on chronic HAE medications alone. That figure excludes doctor appointments, ER visits, and other costs that come along with the condition. As shown on the far right, the cumulative costs for the healthcare system add up very quickly. We're seeking to address these issues with lonvo-z, a one-time treatment that provides patients with the potential for a lifetime benefit. On this slide, you see the cascade that occurs in HAE. For most of us, the C1 inhibitor acts as a brake or a modulator for the kallikrein-kinin system.
People with type one and type two HAE have a deficiency in their C1 inhibitor, which creates imbalance and leads to debilitating swelling attacks. lonvo-z is designed to permanently inactivate the KLKB1 gene to reduce kallikrein and bradykinin and reset the system. In addition to its mechanism of action, lonvo-z was designed to be administered in a patient-friendly manner. Certain one-time treatments, including some gene therapies and CAR Ts, involve complex and costly inpatient procedures. In contrast, lonvo-z is a gene-editing candidate that's designed to be administered in an outpatient setting. Patients in phase III took a steroid at home the day before receiving lonvo-z. The next day, they went to the infusion center and received an additional dose of steroid, a short-term prophylaxis, and an antihistamine to minimize potential infusion-related reactions.
They then receive an IV infusion of lonvo-z lasting about two to four hours, and then they went home. What adds to our excitement about lonvo-z's potential is the prolonged benefit that's been observed over time. As many of you know, in phase I and II, 32 patients in total received a 50-mg dose of lonvo-z. We see here the course of all of those patients following their one-time treatment. 97% of those patients were both attack-free and therapy-free at the time of the data cutoff. In general terms, the longer we have followed patients, the better they have performed from an efficacy perspective, with an increasing percentage of patients becoming free of all attacks and all therapy. Why is this? Well, we believe it's because they are learning what their new normal is. This slide shows the mean change in kallikrein from baseline for those same 32 patients.
The reductions in kallikrein are deep and quite durable, with no waning of effect out through three years after a single dose. With that as a backdrop, let's now turn things over to Dr. Riedl to share our phase III data.
Thank you, Dr. Lebwohl, and thanks to Intellia for inviting me to present these results, which mark a significant milestone for the HAE community and for the field of medicine. HAELO is a placebo-controlled, double-blind, randomized phase III trial. Patients with type one and type two HAE were allowed to enter screening and required to wash out any LTP therapy during the screening period and prior to entering the run-in period where the LTP-free baseline attack rate was established. They were then randomized two to one to receive a one-time 50-milligram dose of lonvo-z or placebo. The six-month efficacy evaluation period started at the beginning of the fifth week post-dosing and ran through week 28. Patients in both arms were then offered a blinded crossover and are followed for another 18 months before entering the long-term follow-up study.
The primary endpoint compares the attack rate in both arms from weeks five to 28. There are also key secondary endpoints focused on the number of patients who are attack-free, severity of attacks, and quality of life. The protocol pre-specified that the primary analysis would occur when at least 60 patients reached week 28, and we're excited to share the results of this analysis with you today. The demographics are shown here. A total of 80 patients were enrolled, with 52 randomized to the lonvo-z arm and 28 to placebo. The trial was well-balanced in terms of key characteristics. About 70% of patients in both arms were female, and about half the population was enrolled in the U.S. As is common in HAE trials, a high percentage of patients had Type 1 HAE.
Approximately 70% of enrolled patients were on an LTP at study entry, with lanadelumab being the most common. Most patients in both arms reported that the severity of their typical attack was moderate, and the mean monthly attack rate was 3.5 for both arms during the study's run-in period. HAELO met both the primary endpoint and all of its key secondary endpoints with statistical significance. In the figure on the left, you see a mean of 2.1 attacks per month for the placebo arm versus a mean of 0.26 for the lonvo-z arm, equating to an 87% reduction. On the right are the percentage of patients achieving attack-free status for the efficacy observation period. 11% for the placebo arm and 62% for the lonvo-z arm. As a reminder, these patients were also therapy-free, meaning they took no other prophylactic or rescue medication.
Diving a little more deeply into the lonvo-z arm, we observed that 100% of the patients achieved a reduction in their attack rate from their baseline level. Again, on the left of this figure, 62% of those patients were entirely attack-free and therapy-free during the efficacy observation period after a single dose of lonvo-z. The remaining 38% achieved a significant reduction of 72% from their baseline but had not yet reached attack-free status for the entire observation period. It's also worth noting that while the protocol allows patients to resume any LTP of their choice following week 28, all patients who received lonvo-z at either baseline or crossover at the time of the data cutoff remained LTP-free. The results observed during the six-month efficacy evaluation period are impressive and were uniquely achieved following a single dose of lonvo-z.
We can further gain insights into how patients respond by examining attack rates as patients continued to be followed after the optional co-crossover. As Dr. Lebwohl showed in the pooled analysis of patients from lonvo-z's phase I and II trials, patients increasingly became attack-free and therapy-free over time. Some of those patients only became attack-free after being unblinded to their treatment and were then confident that they had received active therapy. The early crossover data on this slide is suggestive of the same phenomenon and may be more representative of a real-world setting. Here you can see the monthly attack rates over time. As a reminder, the primary analysis was triggered when at least 60 patients reached week 28. All 80 of the patients enrolled in HAELO remain in follow-up. To orient you, the lonvo-z arm is in dark blue at the bottom.
After receiving lonvo-z, patients experienced a rapid drop in attacks post-baseline that is sustained through week 28. These patients crossed over to placebo. While still technically blinded, they are now certain to have received lonvo-z. While the number of patients included in the post-week 28 data are limited as of this data cutoff, it's very encouraging to see that the mean monthly attack rates for all patients reaching week 36 are now near zero. This additional reduction in attacks are now near zero. This additional reduction in attack rates reflects further improvement from the 38% of patients who were not completely attack-free during the efficacy observation period. At the top in the placebo arm is gray. Initially, you see a placebo effect immediately following dosing that wanes over time to approximate baseline levels by week 28.
This is a phenomenon seen in other similarly designed phase III trials. At week 28, the line turns to teal as these placebo patient's crossover, and we see the attacks drop immediately and steeply. By virtue of the crossover, patients now know that they have received lonvo-z. As is the case with the lonvo-z arm, these early data show that virtually all patients, whether they originally received lonvo-z or placebo, are attack-free of attacks and other therapy by week 36, which is very exciting. Consistent with the phase I/II experience, lonvo-z had a favorable safety and tolerability profile in HAELO as of the data cutoff. All adverse events were mild or moderate, with no SAEs reported in the lonvo-z arm. The most common adverse events were infusion-related reactions, which again, were all mild and to moderate and were transient.
In summary, lonvo-z appears highly differentiated, given its ability to free most patients from both attacks and ongoing treatment with just one dose. The efficacy observed in HAELO appears highly competitive and attractive, with the primary and all key secondary endpoints being achieved. All patients in the lonvo-z arm saw some level of attack rate reduction from baseline, with most realizing significant benefit. The early data beyond crossover is trending favorably for both arms of the trial, and the safety and tolerability profile was favorable. With that, let me turn the call back over to Dr. Leonard.
Thank you very much, Dr. Riedl . We're very pleased with these results. The road to get here was expeditious, due in large part to the significant patient and investigator enthusiasm we have seen for Lonvo-z. We exceeded our target enrollment and were able to enroll all patients in HAELO within just nine months. It's also notable that 70% of our population was willing to discontinue their LTP treatment to enter the trial, including the leading LTPs. We're pleased that we were able to enroll patients from nearly 10 countries with a diverse range of ages, including many who were well-controlled prior to entry. Finally, HAELO is going to be the gift that keeps on giving.
The trial will formally be completed in about 18 months, providing us with the opportunity to share additional data readouts and important insights as we continue to follow patients through the crossover portion of the trial. Consistent with FDA guidance for CRISPR-based therapies, we plan to follow all patients from all of our clinical trials for 15 years to better understand safety and the durability of effect. The results are unparalleled. For the first time ever, we have shown the ability to free most HAE patients entirely from attacks and ongoing therapy for six months with just one dose. As you all know, cross-trial comparisons have inherent limitations and should be interpreted with caution. That said, we show some key findings here from Halo and from the phase III trials for all of the approved LTPs to date.
As we had expected, lonvo-z's profile is highly competitive in terms of its ability to reduce and eliminate attacks, with a very distinct difference being we were able to do it with just one treatment, and they were able to do it with ongoing chronic therapy, which, as David discussed, can come with a number of significant burdens. Our preparations for potential approval and launch are well underway. We've expanded our team with commercial leadership and field medical personnel, developed our launch strategy and distribution model. We've been engaging with KOLs, payers, and patient advocacy groups. We've identified our target treatment centers, and we recently initiated a rolling BLA with the FDA. We'll continue to leverage our regulatory designations to expedite timelines where possible as we seek to get this potentially transformative therapy to patients as quickly as possible.
Next up, in terms of our priorities, are the completion of the BLA submission, scaling our sales and reimbursement teams, and finalizing our pricing and contracting strategies. In summary, we are thrilled with the outcome from HAELO as we achieved all of our objectives for the trial. We look forward to presenting additional data at EAACI in June, and we'll plan to share additional insights over time as patient follow-up in the crossover portion of the trial continues. We're proud to celebrate this landmark event for gene editing and precision medicine, and our excitement continues to build as we work to complete our BLA submission and, if approved, target a commercial launch in the first half of 2027.
In closing, we'd like to extend our gratitude and thanks to all the patients, caregivers, and families who have taken part not only in the HAELO clinical trial, but in all of Intellia's clinical trials. Their participation has played a central role in advancing the fields of science and medicine. We also want to thank our HAELO study investigators, site coordinators, and staff members, as well as the HAE patient advocacy organizations for making this trial possible. With that, we're ready to begin our question-and-answer session. Operator, would you please open the line for questions?
We will now begin the question-and-answer session. To ask a question, you may press star, then one on your touchtone phone. If you are 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. We ask that you please limit yourself to one question. If you have additional questions, please rejoin the question queue. At this time, we will pause momentarily to assemble our roster. The first question today comes from Maury Raycroft with Jefferies. Please go ahead.
Hi, good morning. Congrats on the great data update, and thanks for taking my questions. Maybe one for Dr. Riedl. I'm wondering why you think no one has shown an attack rate higher than 62% before. Based on the interesting data on slide 22, how would you expect patients to respond to lonvo-z in a real-world setting when they know they are on active treatment?
Dr. Riedl, I know you've participated in many of these trials. Maybe you can speak to that.
Sure. Yeah, thanks for the question, and I think you're referring to the attack-free rate of 62%. It's a challenging endpoint, meaning that you basically have to be perfect, that no one reports any HAE symptoms at all. That can be a high bar in part because HAE symptoms are so variable. Most, really all studies have relied on patient-reported outcomes. By that I mean, we know HAE, for instance, causes abdominal attacks. If a patient reports abdominal pain suggestive of an HAE attack, the investigator has to adjudicate that.
We tend to trust our patients, and if they report that as an HAE symptom, we review it, but it may be reported as such even if there are other possible explanations for that abdominal pain. That's all to say that the symptoms are highly variable, and so any symptom that is suggestive of HAE or receives HAE treatment during the course of the study period will likely be recorded as an HAE attack. I personally think that's the reason that we don't see, you know, 100% attack-free in really any of the trials that have been done, even with very effective medicines. To answer, the other possibility is that we do see variability in how people respond to medications, and that's always possible in clinical medicine.
I think the patient-reported outcome measures are what make that attack-free a challenging endpoint. The second part of your question, you know, how will it perform in the real world? I can't predict the future, but what I can tell you is that nearly all of the HAE preventative therapies that we prescribe now have generally outperformed in the real world compared to the clinical trial. We see that in open label extension trials where the attack reduction and the attack-free status generally improves over time as people are on therapy. We can only speculate as to the reason for that, but I do believe people know they're getting treatment.
They get confidence that the treatment is effective over time, and because of that, we see the reported attack rate going down and longer periods that people are attack-free. Again, I can't predict the future, but I suspect that may be what we'll see here, given that we've seen that with other long-term prophylactic therapies.
The next question comes from Mani Foroohar with Leerink Partners. Please go ahead.
Hey, thanks. Take the question, guys, and congrats on the data. I have a couple of quick ones. One, a quick clarification. You mentioned a Grade 2 ALT elevation resolved in one week. Did that elevation initially occur upon dosing or later on in the course? And then I have a commercial question to follow up.
Yeah, Mani, thanks. I'll take it. As we said, the clinical chemistry panels have been really quite clean with respect to liver function tests in particular. There's balance with Grade 1s across the board, and there's only a single Grade 2 that's been reported anywhere in the trial. That occurred a couple weeks out after dosing and resolved spontaneously within a week. It was asymptomatic. No therapy was provided to the patient.
Great. I'll shift over to execution, launch planning, et cetera. I got a two-part question. One being what are your plans for OUS and preparing an MAA with or without a partner? Secondarily, when we think about the evolution of this data, presumably this then the attack rate will improve over time, apropos of Maury's question around patients being aware that they're on active therapy. How should we think about what will eventually be on a label that you would promote to both U.S. and OUS in terms of attack-free rate?
Maybe I'll start with the second question in terms of the evolution of data, and then we'll turn to Ed Dulac, our CFO, who can speak to outside the United States and plans for that. From the perspective of what's been provided by our own comments and Dr. Riedl's, we really look forward to following these patients for an extended period of time. Everybody's seen our pooled data from our phase I and II trial, and we've reached a point now where essentially 97% of patients have an attack-free, no therapy status. We're looking forward to updating that data in the future here. I'd be surprised if something like that, at least directionally, doesn't take place here.
We see early elements of that already in the crossover following the week 28. We'll look at that very carefully. We follow these patients, as we said, for another 18 months, so I think there's gonna be a wealth of data to talk about how these patients do and even with respect to where they come from with prior therapy. Labeling is something that typically relies on what's been demonstrated in the phase III trial, along with supplementary information that comes from the preclinical work, of course, and our early clinical data as well. As you know, we presented data that's out now over three years, and that'll be extended.
Just to reiterate a point that was made, we've yet to see a single instance of waning of effect, certainly as measured by editing or from a clinical point of view. Our hope, as time goes on is that the label will also evolve as we bring additional information to it. Of course, we'll be sure that the information is provided in the appropriate venues for physicians and their patients and their caregivers to evaluate. Maybe I'll turn to Ed. Ed, if you just wanna say a few words on where we stand with an OUS sort of approach and how things may play out.
Of course. Thank you, John, and good morning, everyone. As we've talked about before, I mean, these data will certainly help, and we're very excited about the possibility, not just in the United States, but outside of the U.S. As we run multinational studies, we are obligated and feel very strongly about getting this important therapy to patients outside the United States. That said, as you know, we built the infrastructure in the U.S., and we are considering multiple ways to get lonvo-z to patients outside the country. Collaboration and distribution agreements are the primary consideration of how we enable that possibility. There are potentially others. We haven't really disclosed our timelines and plans for MAA filings or in other jurisdictions, but we have, I think, things in place that would allow that to go fairly expeditiously.
First and foremost, we need to find the right partner and our distribution partner to make that a reality, and we'll come back to you with an update once we have one.
The next question comes from Alec Stranahan with Bank of America. Please go ahead.
Hey, guys. Thanks for taking our question, and great to see the positive outcome here in HAE. Maybe just double-clicking on randomization in the study. I noticed that 67% of the lonvo-z patients, and 79% of the placebo were on LTP at study entry. I guess I'm curious how you think about baseline LTP status and how this could maybe influence disease severity. Just trying to think through whether being more dependent on LTP at enrollment could influence attack rate during the observation period. Thank you.
Yeah, thanks for the question. We are really looking forward to presenting additional information at EAACI. If you look back at the study design that was in one of the earlier slides, you'll see that at the screening stage, there were a couple of steps, one of which was to establish a baseline. The other one was also to establish some understanding of where patients were coming from with respect to the individual therapies that they were receiving at that time and an assessment of the effectiveness of those therapies as judged by the patient. As we said, patients washed out of their therapy and established a baseline that was essentially free of any HAE pharmacotherapy, and they were randomized to placebo or to lonvo-z.
At this point, what we do is present the data, as Dr. Riedl went through, showing how patients respond to the absence of therapy. However, later this year, and that's in the not-so-distant future here at EAACI, it's just around the corner in June, you'll see a lot more information in terms of where patients came from with respect to the prior therapy. Our view of the protocol and the way it was structured was to have it be wide open essentially to at least with respect to prior therapy. Whether it's LTP on demand or as was the case for many of these patients, both of them taken as necessary together.
I think you'll be able to judge for yourself, and we'll certainly make it clear whether or not there was any effect on what patients were taking previously. I'll tell you that as patients came into the study, some of them were well controlled. They did well. Some of them were not so well controlled. They did well, as well as we reported out here today, and you'll get all the details come June.
The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
Good morning. Thanks for taking my question. You just spoke to some data that's gonna be presented at EAACI. Could you just walk us through what will be presented there and whether the entire 80-patient cohort data set will be released? Thank you.
Well, just to be clear, today we presented data on all 80 patients that came into the trial. And as we said, the analysis were triggered by the first 60 patients to go across. But the other 20 patients are all included in the data that you've seen here today. What will be presented at EAACI is essentially, you know, a complete data set with respect to all primary endpoints, which we've heard about today, and the list of secondary endpoints. You heard one of them today in terms of the attack-free rate. We'll give more information based on, as I just went through, with patient responses tied to the prior therapy, et cetera. It'll be a pretty complete rendition of what we know.
A lot of this will be done at pretty close to a patient individual level so that people can make an assessment, you know, along the lines of what is typically shown for these drugs. We'll see you at EAACI, Salveen.
The next question comes from Joseph Thome with TD Cowen. Please go ahead.
Hi there. Good morning. Congrats on the update. Maybe just in terms of the patients that you know achieved attack rate freedom versus that did not, did that have any correlation with the historical attack rate severity? I noticed, I think, 29% in the active arm had severe attacks before. Any information around that? Then maybe for Dr. Riedl, can you discuss maybe what proportion of your patient population, if lonvo-z was available today, would you consider potentially using this therapy on? Thank you.
Thank you. We'll come to Dr. Riedl in a minute. As we look at baseline, there's no relationship. I know Dr. Riedl has referred to some of this as the human factor, which you know runs through these different trials. One of the challenges with these studies is that some attacks are not strictly objective. When there's visible swelling, it's easy, but there's no biomarker to indicate that somebody's had an attack when it's not readily visible, and so we judge the behavior or what patients report. Again, back to that question you posed, there's just no relationship with where they came from or attack severity. What we've seen is good efficacy across the board. Maybe Dr. Riedl, we could turn to you.
I think the question was with respect to how you see lonvo-z fitting into your practice.
Thanks. You know, this is a good question, but it's a very difficult one to answer, and I'll be very honest when I say I will discuss, if this is approved, this treatment with every patient I have. I think, you know, the results we're seeing are on par with, you know, very competitive with any of the therapies that we're currently using. You know, my approach is to go through every treatment option, including this one, if and when available in the clinic. What I'll admit to is that I'm very I'm not very good at predicting which patients will choose which therapies and that speaks a little bit to the human factor that you just heard about. People have different priorities.
They have different value systems. They have different views of benefits and risks. I think that it's very likely that people that have either severe disruption from their life due to symptoms of HAE or struggle with the burden of treatments. I would just say burden of treatment is a real thing for these lifelong conditions, having to take medicine. I think those are patients that will look long and hard at this. In terms of, you know, what percentage will actually elect to have the treatment, I just don't have a good sense for that right now, to be totally honest.
The next question comes from Terence Flynn with Morgan Stanley. Please go ahead.
Great. Thanks so much for taking the question. Maybe Dr. Riedl, just to follow up on that last question, maybe you could just elaborate what % of your patients would you characterize as having, you know, issues with treatment burden or maybe have more severe symptoms that they struggle with? Just, you know, high level, recognizing you can't predict what % might ultimately go on lonvo-z, but maybe just-
What % fall into that bucket? Just one for the company, I know you're not gonna disclose pricing yet but based on the target profile that you're seeing here, maybe just talk to us about some of the inputs that you think are in play now given the profile you're seeing emerge. Thank you.
Yeah, I'll speak to that, then we can turn to Dr. Riedl. You're right, today's not the day to talk about pricing. We have not set one yet. Obviously, information like what we're sharing today is very important to that. Remember, some of the points we made along the way in terms of the long-term evolution of how these patients behave and experience the benefits of the drug following treatment. In the long-term follow-up that we've reported already back in November, out to three years for some patients, that's only gonna get longer, and that data set, you know, will be an important part of how payers and frankly, I think, physicians and patients think about using the drug. There's standard paradigms with respect to one and done therapies.
Ours is truly unique in that, in our experience, this one behaves differently with respect to the durability of the effect, and I think that's gonna be an important part of this. We're engaged, as we said, in the comments with payers, learning a lot. They're sharing our views, and I would characterize their enthusiasm based on what they've seen thus far, as high for the drug, and we think that this is only gonna add to that excitement. Dr. Riedl, just to restate the question, do you have any patients in your practice who don't have a burden of long-term therapy?
Yeah. Well, like I said, the burden of treatment is a real thing. You know, to answer the question, I have a subset of patients that are doing very well. As everyone here knows, we've come a long way with HAE therapies in the last 15 years or so. I have a subset of patients that are, you know, I would say, quite satisfied with their current treatment. It's probably the minority.
I would say certainly half and probably more than half of my patients we still spend time at their visits talking about either attacks that they're still having, symptoms they're having, or this burden of treatment and how it is difficult to stick with the regimens that they need to adhere to, how it is difficult to get their medication refilled and covered, and we commonly see interruptions in their treatment because of payer concerns or obstructions. Yeah. I would say still certainly a majority of patients there is room for improvement, so to speak. I think those are patients that will certainly you know have a look at this. I think the one and done concept is very attractive to the patients that we're discussing you know therapies with.
There is still need, and I think this has the potential to address some of those issues.
The next question comes from Whitney Ijem with Canaccord Genuity. Please go ahead.
Hey, guys. I'll add my congrats on the data. Just to follow up on the kind of discussion, Doc, for your patients, what are you hearing from patients, again, understanding that it's hard to predict what they'll ultimately do, but what are you hearing from them in terms of either pluses or minuses in terms of gene editing approach? Like, you know, you know, how many patients are kind of like asking about it actively and you know seem very interested to try it early versus, you know, how many patients and what are their concerns about from those that are maybe less enthusiastic or expressing safety concerns or whatever else you might be hearing. Just some more color there would be helpful. Thanks.
Yeah. Dr. Riedl, if you could address that. I think it'd be helpful to understand how many patients have even heard about it and where you think the patient population is with respect to the education process generally.
Yeah. I think this is a really important point. They do hear about it from us because we, at least in our center, we are always talking about what's coming down the pipeline in terms of therapies. I will say that not that many in my experience have heard outside of our visits, and I think there is an educational opportunity. I know Intellia and other companies work closely with the US HAEA, who is a very important driver of education and patient advocacy. I think we do have a lot to talk about with patients to make sure they're informed of options, again, assuming that at some point this is in the clinical setting.
To answer, you know, the question about questions that patients have, first of all, they're very interested when they hear about, you know, one treatment with long-term benefits. That's something that I think, again, speaks to the, I'll say it again, the burden of treatment is real, and I think they're very interested in potentially reducing the need for long-term medications to keep themselves healthy. Most of the questions we get, not surprisingly, are about safety, and I think long-term safety. As was said, I'm very I think it's very important, and I'll be very interested to gather more data as we go.
We're watching closely, of course, the phase I/II data where we have longer term safety and following these patients into the future will be really important. I think that's the big question most patients have. Of course, they wanna know how well it works, and I think we have very encouraging data we shared today on that. I think the long-term follow-up will be important and you know, so far so good on the safety front, but that's where most of our questions from our patient center.
The next question comes from Luca Issi with RBC. Please go ahead.
Well, great. Thanks so much for taking my question. Congrats on data. Maybe John or Ed, circling back to some prior questions, can you just maybe talk about payers and how they will be thinking about the pharmacoeconomic value of this drug? I know you're not disclosing pricing today, but this is absolutely one and done, so I'm assuming that the drug will come at a premium to the annual price of what's available on the market today. Do you think that this can drive some step edits where, you know, payers will first step and kind of look for annual alternatives, or do you think the payers will actually think about the total cost for patients over the many years and they'll be more receptive to your approach here? Any thoughts there are much appreciated.
Yeah. I'm gonna turn to Ed, but I would just preface the response by reminding everyone what Dr. Lebwohl brought up, which is these currently available treatments, certainly the market-leading ones, are extraordinarily expensive. As we said, you know, patients need to be treated essentially for lifelong consequences of the disease they have. From a purely pharmacoeconomic point of view, these are incredibly expensive patients, and that's just the drug costs. We're not even including the healthcare utilization, et cetera. As payers look at this, they see a very, very expensive patient population. Maybe, Ed, you can chime in on that another notch or two in terms of value-based agreements, I think, where, you know, step edits, et cetera, you know, is any of that coming into focus yet?
Thank you, and I appreciate the question. We've been talking with payers for quite some time, so let's just start there. I mean, we know this is an important stakeholder. We've been working with payers throughout 2025, and that work continues this year ahead of launch. As John alluded to in David's prepared remarks this morning, I mean, the value proposition of lonvo-z is incredibly strong. That chronic cycle that we're referencing, the cost of medications, the quality-of-life considerations, etc., it is not trivial to be an HAE patient despite existing therapies, and we think we have a great solution for that situation. When you look at that chronic premium price therapy, to your point, I mean, this is going on for years and decades. The cost adds up very quickly. Our conversations with payers have been or patient
Excuse me, payers have been very constructive. They will typically look at it as a, you know, a multiple of the average annual cost. You're absolutely right. We're very likely to be at a premium. We're not setting the price today, but we think for very good reason, just given the durability of the clinical benefit that we've seen, what benefit that will bring to patients and physicians, but also to payers in the healthcare system. We wanna make sure we strike the right balance. It is possible to go too far. To your point about step edits, we are very mindful that the more that we try to price aggressively, the more likely we'll face resistance.
I'll also say is there's a couple clear market leaders, and many patients have been on a product like lanadelumab, and so we're not as concerned about that step edit. We're looking to talk about this a little bit more as we get closer to launch. Very encouraged by the data and really, really like what we see on the value proposition so far with our discussions with payers.
The next question comes from Andy Chen with Wolfe Research. Please go ahead.
Hi. This is Emma on for Andy. Thanks for taking our question. Just circling back on the data, how should we think about the remaining patients that weren't attack-free? Do they still see a meaningful clinical benefit despite not being fully attack-free? Thank you.
Yeah. Thanks for the question. I would encourage everyone to look carefully at the slides that we presented. We did try to break out patients into two broad groups on the lonvo-z arm. Those that met the admittedly very high bar of already within that 28-week observation period achieving no attacks and remaining completely off therapy. That was 62%. Then there was 38% of the patients who had at least one attack somewhere in that window. In other words, if on the first day after week five, when we started the count, the patient had an attack and never had an attack thereafter, that patient fell into that 38% group. We will share more information at EAACI showing the characteristics of that group.
As we pointed out here, already they have an over 70% decrease with respect to their baseline attack rate, which if you stack it up against drugs already approved, that would be a very solid phase III performance for an entire patient population. Clearly that group is getting a significant benefit from therapy. As we said, as those patients, some of them, to the extent that we have them thus far, cross over and become aware that they've now received active drug because they've gotten both therapies, whatever in whatever order they were randomized to, now are certain that they received a drug. You see the so-called human factor, the extent that it's playing out here, being addressed. What we see is patients improving following week 28 when they have that additional information.
There's the time course over the initial 28 weeks and the nature of the attacks from those that are strictly objectively observed to those that become increasingly harder to characterize. Then there's the human factor that also plays out. That information will be available in June, and I will share this much. We very much like what we see.
The next question comes from Brian Cheng with J.P. Morgan. Please go ahead.
Hey, guys. Thanks for taking our questions this morning. Maybe for the investigator, can you talk about the excitement among those patients who are waiting for this agent in a real world, in your practice? Is there any wait lists at your practice waiting for lonvo-z to become available? Thank you.
Maybe we could step back. Thanks, Brian. And Dr. Riedl, I mean, even in the phase III trial, you remember that we were looking for 60 patients. We ultimately wound up enrolling 80, and we've shared in other venues that we screened over 40 patients in a single month early on. Did you have a waiting list to get into the trial at your site? Do you think there's patients waiting either at your site or elsewhere as you talk amongst your colleagues?
Yeah. I think how briskly the trial enrolled is sort of an indicator of interest, honestly. I think there is a lot of buzz amongst our patients about this. As you mentioned, it was a very competitive enrollment that moved very quickly at the various study sites. You know, in terms of a waiting list, we certainly have patients that are sort of want to know more when as the clinical development rolls out. Obviously, we don't, as it's been discussed, we don't know exactly what that's gonna look like yet. We obviously have been in discussions as a treatment center, as have many of my colleagues.
I do think there's a lot of buzz, there's a lot of interest among patients, and there are people that are sort of ready to hear more about the logistics of this, you know, if and when approved. Yeah, that I think we'll continue to discuss with patients, and we continue to get questions about the status of the treatment.
The next question comes from Jay Olson with Oppenheimer. Please go ahead.
Oh, hey. Congratulations on these landmark results and thank you for providing this update. Are there any patient baseline characteristics that might help predict which patients may become attack free? With these results, do you expect on-demand therapy would need to be carried by patients after receiving lonvo-z, even if it's just for peace of mind? If you could please talk about the ideal HAE patient population to be treated by lonvo-z, and especially if you expect more rapid uptake in naive patients or patients on certain treatments. Thank you.
I think that's a three-part question, Jay, and I'll leave the ideal HAE patient to Dr. Riedl, and I'm gonna guess he's gonna say patients have a lot to do with that to begin with. Again, from the standpoint of looking at individual patients as they come into the trial and knowing in advance that there's a high likelihood of a patient doing well, there's no clear indicators of that. What I can say is that everybody relative to where they started is doing better than they were to begin with. Again, that's information that we'll share as we give the updates at EAACI. But there's no single baseline characteristic that really gives us the information.
I just point out that 100% of the patients, as was indicated in the data presentation, did better off than their baseline, certainly at washout. With respect to on-demand therapy, I can only speculate, and it's early days, but remember that all patients who received drug, as of the data cutoff, and of course, we'll update this, were not taking long-term prophylaxis. One might imagine that the LTP side of the equation will decrease at some rate. We'll see what that looks like once we're out in the marketplace and things start to equilibrate and information becomes more pervasive.
That's a question mark that I think we'll be in a position to see a year from now and 1.5 years from now, et cetera, two years from now as things start playing out. With respect to how patients think about when they don't need to carry on-demand therapy, my guess is that's gonna be a discussion between that patient and his or her physician. I can tell you that from the phase I and II data, almost none of those patients are carrying on-demand therapy at this point and doing very, very well.
I think, you know, what we're seeing is the new new here with some questions that will come up, but I think they're all good questions and important ones that are very favorable, which is, how much therapy do I need to take, and do I even need to take it? We look forward to being part of the answer to those questions as the data unfolds. Maybe Dr. Riedl, do you think there's such a thing as an ideal HAE patient for this therapy?
Yeah, thanks. First I'm gonna push back a little bit on your on-demand response with due respect. The evidence-based guidelines continue to say all patients need access to on-demand HAE therapy. I think it will take a while for clinicians and patients to feel comfortable that they no longer need access to on-demand therapy. I expect even if it's not utilized that most experts in HAE will continue to recommend a prescription and at least a couple of doses of on-demand therapy available at all times. Let's never forget that even if an attack is extraordinarily rare, it could still be an airway attack that's life-threatening. I think on-demand therapy at least in the hands of patients isn't going away anytime soon.
That could change over the years, as you said. I think we will in fact see decreased use of on-demand therapy, but I think there's still a place for it as a safety net when rescues needed. In terms of you know the ideal patient, again, it's very hard to characterize this. HAE is highly variable. The way it impacts people is highly variable. Certainly, people that have a high burden of the disease, meaning they have very frequent, very severe, very disruptive and unpredictable symptoms, that's a patient that will be very interested in this treatment.
Certainly the patient who has difficulty with the burden of therapy that we've discussed and has trouble with adhering to the current treatments would be someone who's very interested in this therapy. I think, like I said, this is a therapy that, if available, we're discussing with really all patients. I think it's hard to know who will vote with their feet and elect the treatment. You know, the other reality is that sometimes there are certain bars that you know could be required by the healthcare system, and so we'll see how that rolls out. My view is always to try to keep this in the hands of the patients and the specialists in shared decision-making, but certainly the payers have something to say about that at times.
The next question comes from Jonathan Miller with Evercore ISI. Please go ahead.
Hi guys. Thanks for taking my question, and congrats on the results. I'd like to focus on a little bit back on the data for a second, especially the crossover portion of the curve. Obviously, we don't have a ton of patients, out, you know, multiple months after that crossover happened. Could you give us some more color on how long the window is for attack freedom in that curve that you showed during the webinar? Maybe what the dynamics are for the speed with which those attack free rates and that attack burden rate evolves after crossover. Do you expect this to be broadly similar to the phase II, or are there any special considerations here?
I'll give you a general answer and say that it's broadly similar to what we've seen in phase I and II. Really the best place with the information we're releasing today to look at this is that slide, I believe it's 22, that shows the rate at which attack rates decline following the crossover. On a patient-by-patient basis, that's something that we'll talk about as we tell more of the data at EAACI and subsequent to that. We'll be able to give you a lot more precision. As you can see, as a group, it's clearly improving.
The next question comes from Silvan Turkcan with Citizens. Please go ahead.
Good morning, I would like to add my congratulations also on this data. Just a quick question on manufacturing CMC ahead of filing. What is your progress here? What is that, your program with the FDA, what does that allow you to do? Are there any more hurdles ahead of you? Thank you.
Thanks for the question regarding the BLA. As we shared this morning, we've initiated the process. Part of the material's been submitted to the FDA. Much of the material is well along in terms of its generation. We frequently get questions with respect to the manufacturing, supply chain, et cetera. That's well established. The material that we used in the phase III program comes from the same suppliers and the same material that'd be used for a commercial launch. We think we're well-positioned. As was said earlier, we have some of these special regulatory designations, whether it's RMAT or participating in the CMC pilot program that the FDA has. We've had frequent and ongoing consultation with FDA.
They've been quite responsive and very, very helpful, and we've tried to be as transparent and as open-minded with respect to what they need as we can possibly be. We'll tell you when we finish the submission, but as we shared in our finishing comments, we wanna do this as expeditiously as possible and begin the process.
The next question comes from Myles Minter with William Blair. Please go ahead.
Hi. Congrats on the data. We might say this at IAC, but I'm just wondering what the magnitude of efficacy was in moderate to severe attacks, if you kind of take out that population that might be more prone to that placebo impact that you're describing in the overall data set. Any comments there would be helpful. Thanks very much.
We'll see at EAACI. We'll break all that material out for you so you can see it in a more complete fashion. As we said, across the board, patients all responded very, very favorably.
The next question comes from Yanan Zhu with Wells Fargo. Please go ahead.
Great. Congrats on the data. First, a very quick question. Are you going to show the swimmer plots like the presentation at EAACI? And then I was wondering for the attack-free endpoint, in the longer period following the crossover period, looks like the attack-free rate is further improving for the treatment arm. I think you explained why. My question is, in the longer term, where do you see the attack-free rate go? And at what point do you think it's fair to declare functional cure, and could that functional cure somehow be formally recognized as an endpoint? And if the doctor can comment on that would be great too. Thank you.
With respect to EAACI, we will show swimmer plots. You'll see patients through time, the types of attacks, the severity, et cetera, in standard fashion. You asked me where do I think the attack-free rate will go. We believe, you know, as I totally agree with Dr. Riedl, nobody has a time machine here. If past is prologue, we would expect, you know, the set of patients to continue to improve, and we'll report on how they do regardless. We look forward to sharing that. Functional cure is not a word in my vocabulary. That's for others to use. Maybe Dr. Riedl, if you wanna comment, does that ever come into play, and how might that be assessed?
Well, you and I agree. I don't love that term because I don't think we can say that yet. You know, we think about this, can we get to the point where patients go, you know, years without any symptoms, and we simply stop worrying about the attacks? I've thought about that. I think that's gonna be, you know, a little bit subjective for each patient and clinician. You know, is it five years with no symptoms? Is it 10 years with no symptoms, and we start to talk about that? I don't know the answer, but I also am very conservative in using that term, and I don't think we're there yet. That's what I can say about it.
This concludes our question and answer session. I would like to turn the conference back over to Jason Fredette for any closing remarks.
Thank you, Betsy, and thanks everyone for tuning in. We'll look forward to seeing many of you at the upcoming investor conferences and at EAACI. That concludes this call. Thanks.
The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.