Intellia Therapeutics, Inc. Aktie

Let's get going. Thanks for joining this session with Intellia Therapeutics. My name is Alec Stranahan. I cover SMID Biotech here at Bank of America. And I'm pleased to be joined by Ed Dulac, Chief Financial Officer of Intellia. Thanks for being here, Ed.

Thanks for having us. Great conference again. Really productive day. I look forward to the discussion.

Great. Yes, another year in Vegas. Maybe just to start, you've had some recent updates. Maybe if you just want to kind of level set and step through the most important ones, whether that's lonvo-z or the next few studies we started.

A lot has happened at the company over the last few months. I think most notably, what you're referencing is we presented top line results from our Phase III HALO study in HAE, we couldn't be more excited. And so we've been thinking about commercialization, what that would mean for the product, but also for the company, have been thinking about this for quite some time. So to have top line data and just to provide a high-level overview, we showed essentially all patients get a meaningful clinical benefit. 62% of these patients at the end of the 28-week primary observation period are already attack-free and therapy-free, super important outcome. Those are as good or better than anything that's ever been reported. And from an attack rate reduction, we're at the very high upper 80%, which again is as good or better than anything that's been reported.

So we think there are limitations with the Phase III placebo-controlled study in HAE, we can talk about, but we're encouraged by the crossover data that we shared. And once patients know that they're on therapy, they think about their disease differently. I think that bodes well for longer-term follow-up, which is what we also showed in our Phase I/II study. So I really like the profile. The team is highly motivated. There's a tangible energy at the company right now, and we're preparing for the rest of the process to hopefully have a commercial launch in the first half of next year. From a nex-z perspective, that's our TTR program. It's been a very interesting 6-month period. We were on clinical hold for a period of time. We cleared that in roughly 3 months for the polyneuropathy indication. We call that study MAGNITUDE-2. So we did that at the end of January. And then about 4 weeks, 5 weeks later in early March, we announced that we're off clinical hold for the larger opportunity, which is MAGNITUDE is the study name, but that's in cardiomyopathy.

So we are going through all the approval process with various multinational regulators, but also from IRBs and the clinical study sites that are participating. So we're now screening patients. And what we've indicated on PN, which is the smaller of the 2 opportunities, we'll complete enrollment in the second half of this year. And for CM, we have made substantial progress. Before we were on hold, we got up to 650-plus patients. We continue to follow them. They're accruing events, but we're now back to screening and enrolling patients, and we'll provide an operational update towards the end of the year.

Okay. Great. Well, maybe we can step through each of these. Maybe first starting with lonvo-z and HAE. You alluded to the Phase III top line that we showed 87% attack rate reduction, and I think placebo was closer to 62%. So a pretty meaningful improvement and patients were entirely attack-free on a single dose of therapy. I guess, can you speak to where those figures come in versus your expectations and sort of how this stacks up versus competitor data?

Yes. And I'll spend a minute on this because I alluded to it. And this is not unique to what we're doing in HAE. But if you run a placebo-controlled randomized study like we did, these patients are required to wash off their therapy. So if they're on LTP therapy, they have to come off that therapy. They have to have a specific number of attacks actually go on to attacks to be able to eligible to go on to a study. Then once they're enrolled, they run the risk of being randomized to placebo. That is not a comfortable position for an HAE patient to be in. And what happens is that in that 28-week period, these patients are blinded. They don't know if they're on active drug or not. And their whole ever since being diagnosed, their whole existence is around surveilling their body at the first sign of an attack using an on-demand therapy. If that happens in a study, regardless if it's actually an HAE attack, it counts as an attack.

And so there's going to be limitations. It's very hard to see data that's going to be numerically greater than what we had. This is the behavioral human component of things, but we're very, very happy with the data. So going into this data set, we were just mindful the market leader has mid- to upper 80% attack rate reductions. We've matched or exceeded that. And from an attack-free status, we have not seen anything more than 44% from that market leader. And the best ever produced is 60%, 62%. So we're right where we want it to be as good or better than all the existing therapies.

But we also like to think what we're doing -- we're having -- we're playing an entirely different game, right? It's important to get patients attack-free. But in our case, we do that after a single outpatient 4-hour infusion, and they may never have attacks and never require chronic drug therapy again. That is a profound statement. There are many benefits for patients, but we also see a very strong value proposition with physicians and ultimately with payers that we've been doing work with since last year.

Great. Right. So it was 87% attack rate reduction, 62% entirely attack-free, which that latter number was even above what you would expect with the competitors.

Yes, it's a really good outcome. And I think could potentially get better once patients know they're on therapy and then longer-term follow-up. So we'll be in a position to share that from our Phase I/II study later this year. We will be patients out to 4 years at this point. And then we will be excited to share likely next year more mature data from the Phase III study.

Okay. Yes. And I think in that 38% of patients that were not fully attack-free, they still achieved meaningful attack rate reduction and it actually improved in the crossover period, right? And the data later this year that you alluded to is that the EAACI presentation. I guess what else should we sort of learn about this group that we didn't get in the top line? And how does that maybe inform real-world expectations?

Yes. So we're still working through exactly what we'll present, but the EAACI meeting will be held in Europe, I think, in Turkey this year. It's June 12 through the 15th. And we'll get much more granular in terms of patient-specific swim lane type information. We'll also be more articulated around how patients were doing on their prior therapy. This is a bit unique in our study design. Not only do we have attack rate reductions from baseline, we actually understand how these patients were performing on their prior therapy. These are data that we have not yet shown. I think what you'll end up seeing is that even if they have not yet gotten to attack-free status, they have received substantial clinical benefit with the potential that, that improves over time. So super exciting information that we'll have at EAACI.

I think to double down on your point, the crossover data. So once patients get to that primary observation period at week 28, they have an optional opportunity to cross over. At the time of our February data cut, there were 20 patients in that placebo group, all of whom opted to get a crossover. They are still technically blinded, but they actually know that they've gotten therapy, right? They either got it initially or they got to that crossover. Now they are completely confident they have active therapy. That changes how they think about their disease. It changes how they act on their disease.

And what you see already in the first few weeks of follow-up, small patient numbers, but you see a very significant reduction once they know that they're on therapy. And we think that speaks to the real-world experience, which, again, to go back to our Phase I/II data, we presented 32 patients that now know they've gotten therapy, 31 out of 32 as of that data cutoff last August has gotten to an attack-free status and therapy-free status of various durations. So we're really excited to play that movie out, share longer-term follow-up. The thinking is that the vast majority of these patients will be both attack-free and chronic therapy free, which is a very unique value proposition in this market.

Great. And I guess as you're packaging up the data and having initial payer conversations, one question we've been asked is like how do you justify the price vis-a-vis the value proposition if you're reimbursing for this medicine versus what's currently available? I guess how do you -- how have those initial conversations gone? And how are you sort of framing the lifetime value of a onetime therapy here?

Yes. This is -- I love talking about this because the value proposition is so clear. So you have patients with HAE. First of all, there's a trend towards LTP use in the U.S. At least 60% to 70% of patients are using LTP therapy. Patients do have options. They are accustomed to switching. They will switch either convenience or greater clinical benefit. We think we're going to bring both to that conversation. So we really like the market research and what we're seeing from a patient's perspective. We can talk more about physicians, but your question is more on payers. They see the value prop, right? Today, the average annual cost of treating patients is not inexpensive. If you think about premium LTP therapies that are $650,000, $700,000 or more, that's an annual cost to them. They still have to carry and often use on-demand therapy. There's still doctors' visits, there may be ER visits.

So the average annual cost for these payers today to treat HAE is every bit of $750,000 per year. So when you show up with a therapy that has the promise of one infusion, a very simple to administer infusion, doesn't require hospitalization, all these patients go home. And you couple that with majority of patients getting a profound and durable clinical benefit, they see the possibilities, what that can mean from their payer perspective. And so the conversations we've had have been what's the right price for an average -- for a onetime treatment. And they will typically think of a multiple, 2x, 3x, 4x, 5x the average annual treatment cost. So I'm not going to set price here today, but that gives you a range of what we talk about. And I think our value proposition is very strong. We definitely don't want to leave value on the table. We've got a company to run. We've got shareholders to reward, and we think we've got a really strong position.

That said, if you want to get very aggressive on price, and getting into the $4 million, $5 million range sort of precedented, but high end of the range, you're going to face resistance, right? Step edits, other administrative burdens. We want to reduce the friction and make this as easy as possible for patients to have interest, prescribers to write that prescription and then payers to pay for this. So we've done a lot of work here. We're doing it all again now that we have the definitive Phase III data that will be part of our label. And so far, it's been a very constructive conversation. They see a very short payback period and potentially the transformational nature of what lonvo-z will bring.

Great. And when you talk about the patients, is there a particular profile that you saw more apt to enroll in the study? Or is there maybe a patient population that you think would choose a commercial onetime treatment?

Yes, there's lots to unpack in that. So we've got lots of market research that says really good things. I think the best indicator of demand is how patients actually behave. And so if we just take a step back, we ran initially a 60-patient study in HAE, right, placebo-controlled, everything that we talked about earlier. We had more than 40 patients show up in a single month to enroll in that study, right? And what you now have seen, which is what we've known for quite some time is 70% of our Phase III population, not surprisingly, are on existing LTPs. Half of those patients come off lanadelumab. That's the market leader, right? So there's clearly unmet need, including on some of the leading therapies. We think that's very encouraging.

But I don't want to ignore the 30% of patients that are on on-demand therapy only, right? We look at this total addressable market as very broad, both existing LTP and at least a portion of on-demand therapy patients who really resonate with our profile. And so as we think about post approval, who's likely to show up, I think it could come from certainly existing LTP therapy use, but I wouldn't ignore the on-demand side of the equation. And what we've seen is we've got young patients, we've got older patients, but all seem to really resonate with this potential to not have attacks and not have therapy. Clearly, the patients who are on good LTPs but are still having breakthrough attacks, both the number of those attacks and the severity if they're moderate to severe, they're obvious candidates. They're going to be super motivated to engage with the physician, have the conversation. And so we look at about 25% of this market being switchable sort of early adopters, if you will. We think that helps the initial adoption.

But you're going to have a much bigger camp, roughly half of the patient population that understands what's available to them, the new options included, but is more of a watch and wait, right? They see it, they hear it. They may know someone who's had the experience, but they want to make sure it's super safe, they want to make sure that this is now demonstrated in more of that HAE community, and then they're very likely to consider a switch. So we see roughly 3/4 to 80% of the market switchable, and we think we see a nice adoption curve over that first few years as a result.

And when you think of the drivers of the demand kinetic if lonvo-z is approved, is it a highly motivated patient population where you might see kind of a pull-through demand from the patient level? Or is it more of the prescriber assuming that access is not a barrier kind of making that ultimate decision?

HAE patients are pretty well educated. They're well informed. There is a clear advocacy group. Everyone knows everyone. It's a very tight community. So there's lots of good communication. That's exactly what you would want when you're introducing a therapy, high degree of awareness, still a high degree of unmet need and a sophisticated purchaser, if you will, that understands what's possible. That conversation is clearly had with the physician. They are still very heavy handed in the prescribing. But it is much more of a partnership dynamic in that conversation. What are we solving for? What are we trying to achieve? And so when we speak to patients, they love the profile. Physicians interestingly also respond to the profile. Today's therapies are either orally administered or self-injected at home. There isn't a financial incentive that we're sort of working against with physicians.

And in many respects, they not only have to get prior authorization for these expensive therapies, they have to reauthorize at least annually and increasingly every 6 months because payers want to make sure that these patients are getting the benefit from these therapies. If not, they want them redirected. So I think there's a lot of tailwinds that we see that when we enter into that conversation, we want to make sure a physician is educated, we've had medical field force in the field for quite some time talking about gene editing, talking about the clinical data. We want to make sure they're highly educated. Patients have an advantage here just based on the advocacy group. But collectively, they'll make that treatment choice, and we want to make sure we're very much a part of that conversation.

Great. And maybe just thinking towards approval, you've -- I believe you've initiated the rolling BLA. What are sort of the 2 or 3 most critical operational items between now and the BLA completion? And then when do you start scaling the commercial infrastructure?

Yes. So we've been -- the BLA is a known thing. We know exactly what we have to do. We've had RMAT designation for a while. We've participated in the CDRP program. It's a special pilot program for manufacturing CMC considerations. We've taken full advantage of that, hence, our kind of speedy initiation into a rolling BLA submission. So what is ahead is completing that submission and what we've indicated that will definitely be done before the end of this year. Hopefully, we can accelerate that. And then we'll know PDUFA date and those sorts of things. Alongside that, we've already built the foundational leadership team last year in 2025 related to commercial brand leads, pricing and market access expertise, all those things that you'd want to see.

And now it's a question of how do we build and at what time and in what quantity the field force related to the actual sales force, but also the reimbursement field team. So that's on the horizon as well. We've already started to do some of that. That will be more back-end weighted. And then we clearly need to ultimately talk about our pricing and contracting strategy and thinking a lot about this. at some point, we're going to have to declare our intentions and what our final price is. So those are some of the big milestones leading up to what we expect will be approval in the first half of next year.

Okay. Okay. And obviously, U.S. is the first stop. It sounds like this is something that you're going to be equipped to handle on your own. When you think about the ex U.S. opportunity, I guess, how large is that opportunity? And is that sort of a geography that you'd want to partner and just kind of keep the U.S. piece for yourselves?

Yes. In many ways, we're following what I would say is probably the playbook for a U.S. domiciled company. There's a lot of value in the U.S. market, as we all know. And honestly, we're a small company doing this for the first time. HAE is almost a perfect indication for us. It's not going to be a huge field force requirement. Other companies have talked about the size of their footprint. We're not going to be any really any different there. So we really like to set up in the U.S., but the company has a philosophy, and we feel very strongly about gaining access outside the U.S. treatment practices are different, price point is different.

We are not able to operationalize that ourselves at this point in time. So partnership is our preferred, right? And so we think about large, medium-sized companies that have the existing call point and the infrastructure to help accelerate that, and we're looking now with our Phase III data to find that ideal partner. But there are also distributors that are capable of doing cell and gene therapy that's been demonstrated, and it may be a combination of those things. But we have run multinational studies. It is very important for us for many reasons to go outside the U.S. Right now, our preferred path is partnership, and we'll think about what comes next after that.

Okay. And then one more question on lonvo-z, and I do want to talk about ATTR. I guess when you speak to physicians or payers even, I guess, maybe potentially, and you can let me know if this has popped up in your conversations. Are there any questions around kind of the longer-term durability or the benefit sort of beyond the trial period? I guess, what is sort of the longest followed patient showing in your study? And how are you, I guess, communicating the durability piece?

Yes. So in HAE, and I'm going to probably bring in TTR might be a good segue. But for HAE, if you go back to the data we most recently presented, that was not Phase III. This is the pooled analysis of the 32 patients from Phase I, Phase II. I believe that was an end of August 2025 data cut. The longest patient is out 3 years, right? So we're sitting here now getting to that point in 2026. We will be in a position later this year to fast forward that movie another 12 months. So we will have patients on the Phase III dose or greater for at least 4 years by the time we're at the time of approval and probably then some. There are similarities to how that program is in terms of LNP, the CRISPR machinery to TTR. We have even longer follow-up. We're already at 4 years. We're now going to get to that 5-year point. And by the time we're launching, we'll be at 5-plus years.

So we look at this in totality in terms of the safety database that we have, in terms of the durability of response. And I think it's safe to say everything we publish indicates that you get rapid reductions in the desired protein depending on HAE or TTR. Every patient gets that benefit. They get it very quickly, and they do not go backwards. We have no waning of effect, which is super important for a onetime therapy that I think has to have a strong value proposition. That durability of effect is important. So the short answer is we're already at 3 years in HAE. We're already at 4 years in TTR. We are going to build on that. And then obviously, we're going to follow Phase III patients into a much more mature state as well, and we expect to see a similar result.

Yes. I think you've committed to at least a decade, if not more, of follow-up, right?

It's 15 years for cell and gene therapies, but even our own studies in HAE, like this is a 2-year study. So we'll formally follow them. We'll put them in more of an extension, and we'll continue to monitor them, but yes.

Okay. Great. Maybe shifting gears here to ATTR amyloidosis. For MAGNITUDE-2, this is your PN study. It's off clinical hold. Full enrollment, I think, is expected by the end of this year. I guess what sort of protocol modifications were accepted for PN? And how do you expect this to maybe extend to the CM study as well?

So we're off hold on both. I will say what's common across both studies is the following. There are 2 potential paths here, right? When you're on clinical hold, ideally, you find the root cause. What's the smoking done, like what's causing the problem. We have hypotheses. We're still doing work on that, but we haven't really pinpointed the exact cause. So the other path, which is the one we're on and where we have alignment with the agency is more monitoring. And so to take a step back, we saw liver abnormalities in a very small, less than 1% of the population in the CM study, right? And that led to a temporary pause in clinical hold that we've subsequently got off of. What we -- and those -- if they do occur, they occur usually between week 3 and 5. So very consistent with immunological reaction, almost without exception, that's exactly how these patients perform, the ones that do have this, and they usually self-resolve without intervention.

But what we've agreed to with the agency is to monitor more frequently. So now we have biweekly every 3 or 4 days, blood draws during that window of like 3 to 5 weeks. And then for patients that get to grade 2 or greater transaminase elevations, they will be administered a short course of steroids. So that's sort of what we primarily agreed to across both studies for PN and CM. In addition, there's exclusion criteria. And what we wanted to make sure is that regardless of it's the PN or CM patient, if they have a preexisting condition, think about viral hepatitis or NASH, anything that might predispose them to liver injury, we want to probably exclude those patients. We don't think in practice that's going to really increase our screen fail rate. It's going to probably have a very modest impact, but abundance of caution, focused on patient safety, we've agreed to do those things.

What's been unique to MAGNITUDE, which is CM, this is a much older patient population, right? So things like cardiac stability, are they stable on their meds before they come into the study? Do they have symptomatic bradycardia that we need to sort out? Those are the types of things that we're now screening for. Again, we don't think it's going to have a big impact. And then for patients that have an ejection fraction less than 25%, they are now excluded. That's not going to really change our screen fail rate, and we still see a very large addressable patient population. So we need to now operationalize that. We are screening patients and then enrolling patients. We need to make sure those mitigation strategies are successful. And as I mentioned earlier, we'll be in a position later this year to give an update on how things are progressing, what's our best sense of time lines for CM.

Okay. And I guess in terms of benchmarks for TTR reduction in PN, I think tafamidis has established a pretty strong benchmark here, it's obviously established in CM. I guess what does the nex-z Phase III need to demonstrate on TTR reduction depth, the durability, any other clinical endpoints to justify sort of surfing the market leader here?

I appreciate the question. We focus so much on safety. We forget about the clinical benefit side of things. At the end of the day, it is the combination of those things which determines is there a product and what is the ultimate potential of that opportunity. What I would say is you got to look at our Phase I/II data. And I know there's a lot of focus on TTR reductions, 80%, 90%. That's a little abstract. I would think the closer connection here is almost the LDL cholesterol. Most people appreciate lower is better. So when you look at our Phase I/II patients, which half had New York Heart Association Class III and 1/3 had hereditary forms. Those are more difficult to treat patients. We had a really profound benefit on TTR. So from baseline, within 30 days post infusion, almost every single patient, and there's a very narrow range around this, are at 19 or 20 micrograms per milliliter, okay?

Remember that number, 19 or 20. When you compare that to a drug like vutrisiran, which is approved in this space, they have 50 or more. So we have almost 1/3 less TTR. This is a disease of a toxic protein. You don't want to have it. You don't want to have it for very long. So our ability to lower TTR quickly, substantially less than what is available today and very consistently over a long period of time, that results in a differentiated clinical profile. So what we've shown in Phase I is not just the ability to slow disease progression. Tafamidis works, slows disease progression, acoramidis works, slow disease progression, siRNAs works, slow disease progression. What they don't really do is halt disease progression. And in our case, in a subset of patients, reverse that. We've seen that in PN and CM. We do think that is possible. So we're mindful of the safety now with the TTR post clinical hold. But when we talk to our investigators, they understand that risk. They also see the very strong possibility of having a highly differentiated clinical benefit and that combination, they're very excited about. So we're curious to see how this plays out once we're fully up and operating, but there's a lot to play for here, particularly when we're talking about TTR levels as low as quickly and as consistently, that is not a profile that exists today.

Okay. And when we think about the read-throughs between PN and CM, PN seems like the one that's going to get over the finish line first. Are these the same physicians that are treating these 2 patient populations? Does a hit in PN actually increase physician comfort in CM either on safety or efficacy or the balance?

Yes, it's a good question. We -- in a model in a conversation, we talk like there are 2 different flavors. There's a lot of mixed phenotype. It's not that clean and simple. And so there are a lot of patients that have a PN diagnosis that are seen by a cardiologist. So there's a degree of overlap. So this experience really matters. The patient populations are pretty different. I mean one of the things we didn't touch on, PN tends to be a younger patient population. They're probably more resilient to some of the side effects that we've seen and considerations on the safety side with CM. And you see that almost in our collaboration with the FDA, they were much more comfortable coming off more quickly with fewer considerations on PN and CM. But I still think there's a lot to learn, right? It is the same product. It's the same dose. So we won't have nearly the patient experience. We've increased the study size from 50 to 60. So we'll have that body of evidence in PN.

But when physicians have that experience and they know how the drug operates, it is valuable in part because there's overlap between the CM and PN patients that they treat. Ultimately, we're going to have to enroll a good number of patients. We still have roughly 550 patients on CM to get to our target of 1,200. And I think that allows us to demonstrate that the mitigation strategy that we've agreed to with the agency is, in fact, working as intended. So ultimately, that's going to be required, but it will be an early positive sign if we have success in PN.

Okay. And maybe last question just around the safety profile and sort of the read across for the pipeline. I appreciate we're still sort of figuring out what were the drivers. I think this is uncharted territory in terms of the average age in ATTR, which could be like 70, 75 years old, which is -- yes, really uncharted ground for gene editing. Is there anything like the LNP that would be shared across your clinical programs? Or any sort of read across to, say, HAE from what we're seeing in ATTR?

Yes. I think a couple of things. I mean the LNP are essentially the same, right? Even the mRNA, which is the CRISPR machinery is the same. The only thing that's really different is the guide RNA. And so there's a lot of optionality there. And maybe we can go into different diseases as a result of that. But I do think we touched upon a few of these things. We've seen consistent knockdown of proteins, right? We're essentially knocking out these genes that are causing the problem and you're seeing the desired effect. That's been true in HAE. It's true in TTR. Where I thought you were going is, is there still the same value proposition in an elderly patient population, right, who may not have 20, 30, 40 years of therapy. And what I think is very interesting is that look at the study, every time you wait another year to run a Phase III study, patients are better served, more diuretic use, more SGLT2 inhibitor use, the standard of care is just improving. That's a great thing.

What it results in, though, are patients who are 75, 80 years old that are no longer just living 2 or 3 years. In fact, you've got 80-plus percent of patients making it to 3 years and maybe dying from something else. And so the value proposition I still think is there. And while there's less dosing frequency with available therapies and maybe that improves, I still think a onetime intervention is a very familiar paradigm for a cardiologist. And when it comes with a benefit that can be 4, 5-plus years, I still think if you've got this right risk-benefit profile that we talked about earlier, there's still plenty of opportunity. This is already a big market. There's more coming, better diagnosis rates. I still think it doesn't have to be a zero-sum game. There could be multiple modalities, but we really like what we're seeing with nex-z, and we need to complete the Phase III study to prove that out.

Okay. And maybe last question in the last minute, just around the cash balance vis-a-vis pushing through the next steps of derisking. How are you feeling as the Chief Financial Officer around the cash position? And what sort of -- how does that carry you through lonvo-z approval, et cetera?

I'm just happy to get a finance question. Thank you for that. We just raised a little bit of money on the back of the top line data, which was part of the plan. Sitting here today, we've got about $700 million. So that role -- the conservative guidance, if we forget about lonvo-z, we're going to build all this infrastructure. We never see a dime from lonvo-z. We still have enough cash to get us into 2028. That's a good place to be. What is much more fun is how will lonvo-z transform our P&L and our capital needs. It's possible that we require far less and/or from different institutions, maybe not just the good old equity that we do in biotech, but I think it can transform our P&L a little bit with a premium-priced product with a high margin can really change how we think about our capital needs. We require probably far less or potentially none for the foreseeable future, which is an exciting possibility. So it's up to us to make that happen. A lot of work to do, but we're super enthusiastic about what's ahead.

Yes. Good position to be in for sure. Well, I think with that, we'll have to end it there since we're out of time. But Ed, thank you so much for the great conversation, and thanks, everyone, for your interest in Intellia. Thank you.

Thank you.

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 2 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 website 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 unless 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 U.S. Hereditary Angioedema Association, Angioedema Center at the University of California, San Diego and the 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. So 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 want to 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. And 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 2 Phase III assets that, if approved, will compete in multibillion-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. So 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 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. health care 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. And as shown on the far right, the cumulative cost for the health care system add up very quickly.

We're seeking to address these issues with Lonvo-z, a onetime treatment that provides patients with a 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 break or a modulator for the kallikrein-kinin system. People with type 1 and type 2 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 onetime 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 received an IV infusion of Lonvo-z lasting about 2 to 4 hours, and then they went home. What adds to our excitement about Lonvo-z's potential is a 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-milligram dose of Lonvo-z. We see here the course of all of those patients following their onetime 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 3 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 1 and type 2 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 2:1 to receive a onetime 50-milligram dose of Lonvo-z or placebo. The 6-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 5 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 prespecified 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. And 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 6-month efficacy evaluation period are impressive and were uniquely achieved following a single dose of Lonvo-z, but we can further gain insights into how patients respond by examining attack rates as patients continue to be followed after the optional 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 treatments 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. Then 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 0. 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 of the placebo arm -- 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 patients cross over, and we see the attacks drop immediately and steeply. By virtue of the crossover, patients now know that they have received Lonvo-z. And 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 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 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 we're able to enroll all patients in HAELO within just 9 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. And 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. And 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, we have shown the ability to free most HAE patients entirely from attacks and ongoing therapy for 6 months with just 1 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 HAELO 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 time lines 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 field 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?

The first question today comes from Maury Raycroft with Jefferies.

Congrats on the great data update. Maybe one for Dr. Riedl. I'm wondering why you think no one has shown an attack rate higher than 62% before. And 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. Yes. Thanks for the question. And I think you're referring to the attack-free rate of 62%. So it's a challenging endpoint, meaning that you basically have to be perfect that no one reports any HAE symptoms at all. And that can be -- it's a high bar in part because HAE symptoms are so variable. And most -- really all studies have relied on patient-reported outcomes. So by that, I mean, we know HAE, for instance, causes abdominal attacks. And so if a patient reports abdominal pain suggestive of an HAE attack, the investigator must have to adjudicate that. But 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.

So 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. So I personally think that's the reason that we don't see 100% attack-free in really any of the trials that have been done even with very effective medicines. To answer the -- and the other possibility is that we do see variability in how people respond to medications, and that's always possible in clinical medicine. But I think the patient-reported outcome measures are -- make that attack-free a challenging endpoint. The second part of your question, 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 think -- I do believe people know they're getting treatment. They get confidence in that 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. So 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.

Congrats on the data. 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 follow-up.

Many 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 a 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 of weeks out after dosing and resolved spontaneously within a week. It was asymptomatic, no therapy was provided to the patient.

Great. And I want to shift over to execution, launch planning, et cetera. I got a 2-part question. One being, what are your plans for OUS and preparing an MAA with or without a partner? And then secondarily, when we think about the evolution of this data, presumably the attack rate will improve over time, I propose Maury's question around patients being aware 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 has seen our pool data from our Phase I/II trial, and we've reached a point now where essentially 97% of patients have an attack-free no therapy status, and 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. But we'll look at that very carefully.

We follow these patients, as we said, for another 18 months. So I think there's going to 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 3 years, and that will be extended.

And 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. And 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. So maybe I'll turn it to Ed. Ed, if you just want to 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. And so we've 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.

And so collaboration and distribution agreements are the primary consideration of how we enable that possibility. There are potentially others. And we haven't really disclosed our time lines 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. But 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.

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.

Yes. 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, but 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. Then 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.

So 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 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.

So 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. But 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.

You just spoke to some data that's going to 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?

Just to be clear, today, we presented data on all 80 patients that came into the trial. And as we said, the analysis are triggered by the first patient -- 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 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. So it will be a pretty complete rendition of what we know. And a lot of this will be done at pretty close to a patient individual level so that people can make an assessment along the lines of what is typically shown for these drugs. So we'll see you at EAACI, Salveen.

The next question comes from Joseph Thome with TD Cowen.

On the update. Maybe just in terms of the patients that achieved attack rate freedom versus those that did not, does 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? And 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 the therapy arm?

Thank you. We'll come to Dr. Riedl in a minute. As we look at baseline, there's no relationship. I know Dr. Riedl referred to some of this as the human factor, which 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 indicate that somebody has had an attack when it's not readily visible. And so we judge the behavior of what patients report. And 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.

Yes. Thanks. This is -- it's a good question, but it's a very difficult one to answer. And I'll be very honest when I say, I discuss -- I will discuss if this is approved, this treatment with every patient I have. I think the results we're seeing are on par with -- very competitive with any of the therapies that we're currently using. And so 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. And 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 treatment. And I would just say burden of treatment is a real thing for these lifelong conditions having to take medicine. So I think those are patients that will look long and hard at this. But in terms of 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.

Maybe Dr. Riedl, just to follow up on that last question. Maybe you could just elaborate what percent of your patients would you characterize as having issues with treatment burden or maybe have more severe symptoms that they struggle with just high level, recognizing you can't predict what percent might ultimately go on Lonvo-z, but maybe just what percent fall into that bucket? And then just one for the company. I know you're not going to 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.

Yes. I'll speak to that, and then we can turn to Dr. Riedl. You're right. Today is not the day to talk about pricing. We have not settling yet. Obviously, information like what we're sharing today is very important to that. Remember some of the points 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 and the long-term follow-up that we've reported already back in November out to 3 years for some patients. That's only going to get longer, and that data set will be an important part of how payers and frankly, I think physicians and patients think about using the drug.

There are 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 effect. And I think that's going to be an important part of this. So 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 going to 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?

Yes. Well, the burden of -- like I said, the burden of treatment is a real thing. To answer the question, I have a subset of patients that are doing very well. And as everyone here knows, we've come a long way with HAE therapies in the last 15 years or so. But -- so I have a subset of patients that are, I would say, quite satisfied with the current treatment. But 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.

So yes, I would say still certainly a majority of patients there, there is room for improvement, so to speak. And so I think those are patients that will certainly have a look at this. I think the one-and-done concept is very attractive to the patients that we're discussing therapies with. So yes, there is still a need, and I think this has the potential to address some of those issues.

The next question comes from Whitney Ijem with Canaccord Genuity.

I'll add my congrats on the data. Just to follow up on the kind of discussion, 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 how many patients are kind of like asking about it actively and seem very interested to try it early versus 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.

Yes, Dr. Riedl, if you could address that. I think it would 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.

Yes. I think this is a really important point. So 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 so I think there is an educational opportunity. I know I know Intellia and other companies work closely with the U.S. HAEA, who is a very important driver of education and patient advocacy. So 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 the question about questions that patients have, first of all, they're very interested when they hear about 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. And so 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. So I think that's the big question. Most patients have. Of course, they want to know how well it works. And I think we have very encouraging data we shared today on that. So I think the long-term follow-up will be important. And so far, so good on the safety front, but that's where most of our questions from our patients center.

The next question comes from Luca Issi with RBC.

Congrats on the data. Maybe John or Ed, circling back to a prior question, can you just maybe talk about payers and how they will be thinking about the pharmacoeconomic value. I know you're not disclosing pricing today, but this is obviously one and done. So I'm assuming that the drug will come at a premium to the annual price of what's available in the market today. So do you think that this can drive some step edits where payers will first step kind of 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, much appreciated.

Yes. I'm going to 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. And as we said, patients need to be treated essentially for lifelong consequences of the disease they have. So 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 health care utilization, et cetera. So as payers look at this, they see a very, very expensive patient population. But maybe, Ed, you can click in on that another notch or 2 in terms of value-based agreements, I think, step edits, et cetera. Is any of that coming into focus yet?

Yes. 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. And 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, et cetera, it is not trivial to be an HAE patient despite existing therapies, and we think we have a great solution for that situation. But when you look at that chronic premium priced therapy, to your point, I mean, this is going on for years and decades.

The cost adds up very quickly. And so our conversations with patients have been -- or excuse me, payers have been very constructive. They will typically look at it as a multiple of the average annual cost. So you're absolutely right. We're very likely to be at a premium. We're not setting the price today. But we think for a 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 health care system.

So we want to make sure we strike the right balance. It is possible to go too far. So to your point about step edits, we are very mindful that the more that we try to price aggressively, the more likely we will face resistance. But I'll also say is there's a couple of clear market leaders and many patients have been on a product like lanadelumab. And so we're not as concerned about that step edit. So we're looking to talk about this a little bit more as we get closer to launch, but 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.

This is Emma, on for Andy. 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?

Yes. Thanks for the question. And it's -- I would encourage everyone to look carefully at the slides that we presented. We did try to break out patients into 2 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%. And then there was 38% of the patients who had at least one attack somewhere in that window. So in other words, on the first day after week 5 when we started the count, the patient had an attack and never had an attack thereafter. That patient fell into that 38% group. So we will share more information at EAACI showing the characteristics of that group. But 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.

So clearly, that group is getting a significant benefit from therapy. And as we said, 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 we are certain that they received drug, you see the so-called human factor to the extent that's playing out here being addressed.

And what we see is patients improving following week 28 when they have that additional information. So 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. And then there's the human factor that also plays out. So 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 JPMorgan.

Maybe for the investigator, can you talk about the excitement among those patients who are waiting for this agent in the real world in your practice? Is there any wait list at your practice waiting for Lonvo-z to become available?

Maybe we could step back. Thanks, Brain. 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? And do you think there's patients waiting either at your site or elsewhere as you talk amongst your colleagues?

Yes. 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. And as you mentioned, it was a very competitive enrollment that moved very quickly at the various study sites. So 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. And obviously, we don't -- as has been discussed, we don't know exactly what that's going to look like yet. But we obviously have been in discussions as a treatment center as have many of my colleagues. So I do think there's a lot of buzz. There's a lot of interest amongst patients, and there are people that are sort of ready to hear more about the logistics of this if and when approved. So yes, 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.

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? And then 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? And then also, 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?

I think that's a 3-part question, Jay, and I'll leave the ideal HAE patient to Dr. Riedl, but I'm going to guess he's going to say patients have a lot to do with that to begin with. But 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. And 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. But I'd just point out that 100% of the patients, as was indicated in the data presentation, did better off than their baseline, certainly a 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. And so 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. So 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, 2 years from now as things are playing out. With respect to how patients think about when they don't need to carry on-demand therapy, my guess is that's going to be a discussion between that patient and his or her physician.

I can tell you that from the Phase I/II data, almost none of those patients are carrying on-demand therapy at this point and doing very, very well. And so I think what we're seeing is the 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. So 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?

Yes. Thanks. First, I'm going to 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. And I think it will take a while for clinicians and patients to feel comfortable that they no longer need access to on-demand therapy. So 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. So 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. But 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 rescue is needed.

In terms of the ideal patient, again, it's very hard to characterize this. HAE is highly variable. The way it impacts people is highly variable. And so 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.

So I think, like I said, this is a therapy that, if available, we're discussing with really all patients. And I think it's hard to know who will vote with their feet and elect the treatment. The other reality is that sometimes there are certain bars that could be required by the health care 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.

Congrats on the results. I'd like to focus in a little bit back on the data for a second, especially the crossover portion of the curve. And obviously, we don't have a ton of patients out multiple months after that crossover happened. But 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 and 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. And 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. So we'll be able to give you a lot more precision. But as you can see, as a group, it's clearly improving.

The next question comes from Silvan Tuerkcan with Citizens.

I would like to add my congratulations on the 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? And are there any more hurdles ahead of you?

Thanks for the question regarding the BLA. As we shared this morning, we've initiated the process. Part of the material has 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. And the material that we used in the Phase III program comes from the same suppliers and the same material that we use on a commercial for commercial launch. So we think we're well positioned.

As was said earlier, we have some of the special regulatory designations, whether it's RMAT or participating in the CMC pilot program that the FDA has. So 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. So we'll tell you when we finish the submission. But as we shared in our finishing comments, we want to do this as expeditiously as possible and begin the process.

The next question comes from Myles Minter with William Blair.

Congrats on the data. You might say this at EAACI, 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.

We'll see at EAACI. We'll break all that material out for you so you can see it in a more complete fashion. But as we said, across the board, patients all responded very, very favorably.

The next question comes from Yanan Zhu with Wells Fargo.

Great. Congrats on the data. First, a very quick question. Are you going to show the swimmer plots like presentation at EAACI? And then I was wondering for the attack-free endpoint in the longer period following the crossover period, it 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, that would be great, too.

With respect to EAACI, we will show swimmer plots. So you'll see patients through time, the types of attacks, the severity, et cetera, et cetera, in standard fashion. You asked me where do I think the attack-free rate will go? We believe -- I totally agree with Dr. Riedl, nobody has a time machine here. But if past this prologue, we would expect the set of patients to continue to improve, and we'll report on how they do regardless, and 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 want to comment, does that ever come into play? And how might that be assessed?

You and I agree. I don't love that term because I don't think we can say that yet. We think about this, can we get to the point where patients go years without any symptoms and we simply stop worrying about the attacks. I thought about that. I don't -- I think that's going to be a little bit subjective for each patient and clinician -- is it 5 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 quite -- we're there yet. So 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 has now concluded. Thank you for attending today's presentation. You may now disconnect.

Speaker 0

Hello, and welcome to Intellia Therapeutics' Fourth Quarter and Full Year 2025 Conference Call. My name is Drew, 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, operator, and hello, everyone. Earlier this morning, we issued a press release outlining recent business updates and our fourth quarter and full year financial results. This document can be found on the Investors & Media section of Intellia's website at intelliatx.com.

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. 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 unless required by law.

Joining me on this call are John Leonard, our Chief Executive Officer; and Ed Dulac, our Chief Financial Officer.

With that, I'll turn the call now over to John to begin our business discussion.

Thank you, Jason, and thanks to all of you who have tuned in for today's call. We'll begin with a brief recap of our 2025 accomplishments and we'll then review the status of our Nex-z program in ATTR amyloidosis. After that, we'll provide updates on the significant progress we've made with Lonvo-z, which is being developed as a potential onetime treatment for patients with hereditary angioedema or HAE. And we will close with Ed's financial review.

First, let's take a step back to the origins of Intellia Therapeutics. This company was formed over a decade ago based on the belief that we could help revolutionize medicine utilizing CRISPR gene editing. From the outset, we designed our gene editing product candidates to reset the treatment standard in our disease areas of interest. This new standard would raise the bar by conferring highly competitive and durable efficacy for patients via onetime treatment that is administered in an outpatient setting.

We believe our 2 lead candidates, Lonvo-z and Nex-z, fit this profile. Now with up to 3 years of patient follow-up, we have yet to see any waning of effect in serum kallikrein or TTR levels in the extended follow-up of our Phase I and II trials. Even more encouraging, the observations of improvement in clinical and disease measures that we track in the Phase I and II trials also have not waned. Given these clinical data and our preclinical work showing the edits we make are permanent in edited cells and in all subsequent generations of those cells, we expect patients to benefit for many, many years, if not their entire lives.

And both Lonvo-z and Nex-z are administered in an outpatient setting. After a simple prophylaxis regimen to reduce the risk of infusion-related reactions, patients visit a clinic where they receive an IV infusion over the course of 2 to 4 hours, and then they go home. And so a decade plus after our founding, it's for good reason that our excitement is building as we approach the world's first Phase III data readout for an in vivo gene editing candidate by mid this year.

Now for some reflections on 2025. Simply put, it was a time of both accomplishment and resiliency for Intellia. With Lonvo-z, we rapidly enrolled HAELO, our Phase III clinical trial in HAE, and we did this well ahead of schedule. Until the clinical hold in October, we achieved similar enrollment success with Nex-z. At the start of the year, we were expecting to have enrolled about 550 patients with ATTR amyloidosis with cardiomyopathy in our MAGNITUDE Phase III clinical trial by year-end, and we had not yet begun enrollment in MAGNITUDE-2, our Phase III trial for patients with polyneuropathy. By October, just 10 months later, we enrolled more than 650 patients in MAGNITUDE, and we're already approaching full enrollment in MAGNITUDE-2. We and many others believe this type of enrollment enthusiasm is a good indicator of a product candidate's commercial potential.

In late October, after elevated liver transaminases and total bilirubin were observed in a magnitude patient that met the trial's protocol-defined [ pausing ] criteria, we suspended enrollment in MAGNITUDE and MAGNITUDE-2. Shortly thereafter, the trials were placed on clinical hold by the FDA. Our team immediately took action to address the hold, working in concert with external experts, our clinical sites, investigators and regulatory authorities.

In late January, we were pleased to announce that the FDA lifted the clinical hold on MAGNITUDE-2. We aligned with the agency on certain study modifications. These include addition of supplementary liver laboratory tests in the weeks following patients' enrollment and dosing, and guidance that patients receive a short-term steroid regimen if elevated liver transaminases are detected in the weeks immediately following dosing. The rationale for this is that the LFT elevations appear to be consistent with an immune-mediated reaction.

We also have modified our screening criteria to exclude the enrollment of patients who may be the most susceptible to a potential liver injury. These include patients with significantly elevated liver enzymes at screening and those with a history of NASH or autoimmune hepatitis. We expect these new criteria will help to safeguard patients while also having a minimal impact on our screen failure rate.

As a reminder, we've already enrolled 47 patients in MAGNITUDE-2. As part of the protocol amendment, we also proposed, and the agency accepted, that we increase the trial's target enrollment from 50 patients to approximately 60 patients. This allows us to accommodate patients who had already been identified for screening prior to the hold.

Since MAGNITUDE-2 is being enrolled outside the United States, we are now working through the relevant local regulatory processes to resume patient screening, and we're confident we can complete enrollment in the second half of this year. At the same time, our FDA engagement is ongoing as it relates to MAGNITUDE. As we've mentioned in the past, MAGNITUDE and MAGNITUDE-2 are very different trials enrolling very different patient populations, and we are considering these factors in our ongoing work. While nothing is done until it's done, we've made a lot of progress in our effort on this front.

And given the positive Phase I data that's been presented for Nex-z, including the encouraging post-hoc mortality data derived from a contemporaneous and well-matched cohort of nearly 1,800 patients that we shared at AHA this past November, we continue to believe strongly in this candidate's potential to benefit patients with ATTR amyloidosis.

Now let's move on to Lonvo-z in HAE. We completed enrollment in the HAELO Phase III clinical trial with 80 patients in September, just 9 months after we dosed our first patient in the trial. This is due in large part to the tremendous amount of interest we have seen in Lonvo-z among those with HAE and the treating physicians.

This interest is also reflected in market research we recently conducted and shared at JPMorgan in January. In late 2025, 104 U.S. patients and caregivers were surveyed by a third party. They were shown a target product profile based on data from our Phase I and II trials on a blinded basis and were told the data was from a gene editing candidate. They were then asked if they would be likely to take the treatment if it were to be approved. 99% of the patients responded they would at least be somewhat likely and nearly 2/3 said that they would be extremely or very likely to take it.

The interest also carried over to prescribing physicians. When 151 U.S. health care providers were presented the same target product profile and then asked if they could identify a patient in their practice to whom they would prescribe the drug, 92% of them said yes. These HCPs reported they were managing the care of more than 4,000 patients collectively, which would represent about 60% of the entire treated patient population in the United States. When asked how many of these patients would they prescribe Lonvo-z to, that number came out to about 2,200 patients or 54% of the patients under their care.

So what's driving this interest? Well, it's because a substantial unmet need still exists despite today's available HAE therapies. At ACAAI in November, we presented data from another 100 patients who were surveyed, about 90% of whom were on long-term prophylaxis therapies, otherwise known as LTPs.

The results shed further light on the burdens that many patients continue to face: the burden of their disease and the burden of their chronic treatment. The results show that nearly 70% of patients were concerned about having to take LTP and/or on-demand medications for the rest of their lives. Nearly 60% were concerned about the unpredictable nature of their HAE. And most patients also are concerned about the logistical and financial burdens of the disease.

Also striking was the fact that only 20% of surveyed patients reported they were attack-free for the past 12 months. This 20% figure contrasts with the clinical data we presented in November from our Phase I/II pooled analysis showing that 76% of patients who were at least a year beyond the 50-milligram dose of Lonvo-z were free from both attacks and ongoing therapy for at least 12 months. We're looking forward to presenting more insights from this patient burden study at the [ QUAD AI ] meeting that is taking place this weekend in Philadelphia.

And so our march continues toward top line data by the middle of this year and a planned BLA submission in the second half of this year. We've been asked from time to time what our expectations are for this readout. When looking at the Phase III data for approved LTPs, the best attack reduction rates have been in the 80s, and the very best attack-free rate we have seen from an LTP is approximately 60% of patients. And of course, these results were achieved only with chronic therapy.

In our placebo-controlled HAELO trial, we believe the Lonvo-z arm will be highly competitive with those numbers, with the added and unique benefit that is a onetime therapy. And as was shown in the pooled analysis that was presented at ACAAI, Lonvo-z could perform even better outside of a placebo-controlled trial and in the real-world setting where patients know they are on active treatment.

As I've laid out, it's going to be a big year for Intellia with many meaningful milestones. We look forward to updating you on our progress along the way.

I'll now hand the call over to Ed, our Chief Financial Officer, who will provide an update on our financial results for the fourth quarter of 2025.

Thank you, John. We do indeed have a big year ahead, particularly as it relates to Lonvo-z and what will be the world's first pivotal readout for an in vivo CRISPR-based gene editing therapy.

As we look toward a potential launch of a product that we believe would have a highly attractive profile for patients suffering from HAE, we've made a lot of headway with our team and our thinking in terms of commercial readiness. We have scaled our field medical team, ramped up our engagement with treating physicians and patient advocacy groups, engaged with payers, and developed our launch strategy. This year, we plan to continue building out our sales and reimbursement field teams, finalize our distribution models, identify our U.S. treatment centers and finalize our pricing and contracting strategy.

It is, of course, premature to get into any specifics about our planned go-to-market strategy or pricing. However, those of you who know the HAE space are well aware that LTPs carry ultra-orphan price tags. Given the average U.S. patient with type 1 or type 2 HAE is diagnosed at about age 20 and that patients also tend to require on-demand prescriptions, the cost of lifetime treatment tends to be measured in the multimillions of dollars.

Given this backdrop, we believe a onetime treatment like Lonvo-z could deliver significant savings to patients and payers, greatly reduce or eliminate many of the social, emotional, treatment and quality-of-life burdens that are experienced by patients, and reduce burden on physicians given their need to repeatedly process time-consuming prior authorizations that are required for patients to remain on today's available therapies.

Finally, from a broader company standpoint, if approved, the commercial success of Lonvo-z could fundamentally change the future capital needs of the company. With about 7,000 patients receiving treatment for HAE in the U.S., Lonvo-z anticipated margin profile and our overall expected cost structure, if we were to achieve a mid-single-digit market share in a given year, the resulting cash flows would likely enable us to fully fund our entire operations. More on that topic when we get to BLA submission and potential approval.

I'll now review the Q4 financials. Cash, cash equivalents and marketable securities were $605.1 million as of December 31, 2025, compared to $861.7 million as of December 31, 2024. We believe this cash balance will be sufficient to get us into the second half of 2027 and beyond several important milestones, including the restart of enrollment in MAGNITUDE and the completion of enrollment in MAGNITUDE-2 this year and the launch of Lonvo-z next year.

Collaboration revenue was $23 million for the fourth quarter of 2025, compared to $12.9 million for the prior year quarter. The increase was mainly driven by revenue that was recognized related to the termination of our license and collaboration agreement with [ SparingVision ] and an increase in cost reimbursement related to our collaboration with Regeneron.

R&D expenses were $88.7 million for the fourth quarter of 2025, compared to $116.9 million during the prior year quarter. The decrease was primarily driven by reduced employee-related expenses, stock-based compensation, research materials and contracted services, partially offset by an increase in clinical trial expenses related to Lonvo-z. Stock-based compensation expense included with R&D was $10.5 million for the fourth quarter of 2025.

G&A expenses were $33.1 million during the fourth quarter of 2025, roughly flat from the $32.4 million spent during the prior year quarter. Stock-based compensation expense included within G&A was $6.2 million for the fourth quarter of 2025.

And finally, net loss for the fourth quarter of 2025 was $95.8 million, down significantly from $128.9 million for the prior year quarter.

With that, we are ready to begin our question-and-answer session. Operator, would you please open the line for questions?

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

Congrats on the progress. I'm going to focus on HAE. A lot of questions on how the study could read out. The question, the Phase I/II data was generated primarily ex U.S., whereas the Phase III trial includes U.S. patients. Do you anticipate any differences in baseline patient characteristics such as BMI or background prophy use that could impact the reproducibility of results, especially as it relates to the control arm? I guess, how should we think about what to see in the control arm?

Maury, thanks for the question. It's correct that the Phase II work and Phase I work was done outside the United States. The Phase III trial is done globally in some of the same countries and especially in the United States.

As we look at the patient populations in the Phase III group versus the Phase II group, they're largely overlapping. It's not skewed in any way towards one demographic or particular characteristic. In fact, it was designed to represent what is a pretty standard patient population for patients suffering from HAE with a range of severities and a variety of different drugs. In fact, many of them taking the market-leading drugs.

I think it's important to note that, especially when you think about the United States, patients to come into the trial needed to stop taking whatever drugs they were, wash out, get a baseline read on their attack rate and then go on to a placebo double-blind phase of the study. So we think that that's indicative of patient interest, that they're willing to go through all of that to participate in the trial.

But from a comparability of data perspective or at least from a patient population point of view, what you've seen for the Phase II patients is largely representative of what we expect to see demographically for U.S. -- for the Phase III trial.

The next question comes from Mani Foroohar at Leerink.

This is Lili Nsongo on for Mani. Maybe just 2 questions from us. So one, on HAE, can you maybe give us a little more color in terms of how you think about the commercial strategy there, especially as it relates to the type of patients that you expect to be the one the most amenable to gene therapy, meaning the ones that are the youngest or the ones that are the sickest? If you could give us a little color there.

And then second question on the TTR program. Thinking about the resolution of the hold, how do -- how should we be thinking about timing? And has your understanding of the underlying event that led to the patient death evolved?

Thanks, Lili. I'll start with some comments about the TTR program and then hand it over to Ed who can speak about your questions with respect to HAE. With the TTR amyloidosis program, Nex-z, as you know, the polyneuropathy study is off clinical hold and we're going through all the operational things to resume accrual. That's going very, very well. And as we've said, we expect to have that study fully accrued by the end of the year. And as we make progress there, we may be in a position to update guidance on that progress later this year.

With respect to MAGNITUDE, which is the cardiomyopathy study, it's a bigger study. There's a lot more data in the patient population, although they have the same drug and the same underlying gene, there's just many other factors to take into consideration. And we've been working through that with the FDA. So it's a long list. We've been making excellent progress. I think we're very, very far down that road. The hold is not lifted until the hold is not lifted. I want to make that point. But I think that the progress is substantial, that we've made.

With respect to the patient that you referenced, I just want to remind you that this is a patient who had a very complicated clinical course. It's true that he had LFTs that increased to Grade 4 for transaminases and had a bilirubin increase. The patient ultimately died from a ruptured duodenal ulcer, which may or may not have been related to his treatment. It may or may not have been there when the patient was originally coming to medical attention. He did present with abdominal pain, which is a little unusual for pure transaminase elevations.

So we're never going to really know exactly what happened to him. But he's an outlier. As you might imagine, the work that we're doing with the FDA is to give the trial, patient participants the best ability to receive the drug in the safest possible circumstances, and that's what we're working on. And as we have more information, we will obviously update everybody and bring you up to speed.

So Ed, maybe you want to say a few words about how we're thinking about HAE.

Yes. Thanks, John. I think the question was more about the commercial strategy, and we'll be in a position as we get through the year to share increasingly more details. I would say, generally, we just start thinking about this market as not about the modality per se. You mentioned a question about gene therapy. We have a gene editing approach that so far to date has a very simple-to-administer profile and long-term durable effects. So we think that will play very well.

When we talk to patients, they're not really concerned about the modality. What they're really concerned about is the treatment effect and the outcomes from the product. And so as we look at our target product profile, we feel like we're playing from a position of strength. We've got this long-term, durable effect. And quite frankly, we're the only therapy that can provide both freedom from attacks and freedom from drug therapy. So we like the profile we're playing with.

And we also see that as we think about going to market and the strategy there, we are looking for how do we make sure that physicians are educated, how do we put the infrastructure required to do that. And so we've been working for the past year or so, thinking about the commercial team that we have now in place, we've had field medical team for the last year or more looking in the field, educating physicians on the therapy that we have, gene editing, the aspects that are important to treating physicians. We've been engaged with payers for quite some time and we're encouraged by what we see there. And we have our overall launch strategy plan in place.

So we're already playing from a position of strength from an operational perspective. This year, the focus is really going to be on scaling the field force and the reimbursement teams that we have at the company. We'll be looking to finalize the distribution model that we've been thinking carefully about, and we'll have identified a number of treatment centers that we think will be very relevant.

Things like pricing will come with time. We feel like we have a very strong value proposition, and we'll be thinking about contracting strategy as well. So stay tuned for more information, particularly after the top line data. But overall, we feel really good about the prospects we have in HAE.

The next question comes from Alec Stranahan at Bank of America.

Maybe on the PN study, now that that's restarting, do you think an interim analysis would be possible here? And curious what you think about the 9-month endpoint on NIS for the [indiscernible] study.

I am not going to be in a position to comment on other people's studies. I would contrast the work that we're doing just based on our own extended follow-up for Phase I patients, and we presented that data previously. What we've seen in that data, which I think was very encouraging, is that patients with these very, very deep TTR reductions largely do not progress.

And many of them, in fact, there was a cohort of patients in that group that had failed patisiran, i.e., progressed on the drug, who actually improved relative to their baseline. So that thinking goes into the design of the study and the patient number of the study. So remember, the target population was 50. We've increased that to 60, as I said in my comments, to accommodate some of these patients that were waiting just as we meet -- met the stopping criteria in MAGNITUDE.

An interim analysis is possible, and that's not part of our current thinking. But as the study progresses, et cetera, we can always reconsider depending on how we're thinking about what we see in the behavior of the patients. But right now, it's -- the endpoint is set for 18 months.

The next question comes from Joseph Thome and TD Cowen.

Congrats on the progress. Can you comment a little bit on your CMC readiness for the Lonvo-z potential approval and launch? And if there were any manufacturing changes between the Phase II and the Phase III? And then maybe a little relatedly, have you aligned with ex U.S. regulators that this package would also be sufficient for approval outside the U.S.?

Thanks for the question. Let me make a comment overall with respect to BLA preparation and readiness for the Lonvo-z program. As you might imagine, we've been working on that submission for some time now. The preclinical work has been completed and that's being written up or has been written up in many circumstances. The CMC work, and here, our team has just done a wonderful job of getting to readiness in a very, very robust fashion. We're in a position of complete preparation with respect to that. We have completed the work necessary.

I would point out that in our Phase III trial for HAELO, we're actually using the material that will be the same sort of commercial material. There's no necessary comparability tests or things like that at the end of the study to change manufacturing sites or anything like that. The material we're using now is what you're going to see in the marketplace. So we feel that we're really in an excellent state of preparation.

Really what we're waiting for at this point is the maturation of the Phase III study. As we said, we've completed enrollments. We over-enrolled substantially. We said we'll share those top line data here this year. And the team is ready to light that up and include it into a submission that will be going in the second half of this year.

I'll just add, Joe, I mean, we have a network for Lonvo-z of CDMO providers that have been long established primarily in Europe for the product. And these are all, as John mentioned, commercial scale processes that are all been validated. So we are already operating at a very high level and very well equipped for commercial launch.

The next question comes from Luca Issi with RBC Capital Markets.

This is Shelby on for Luca. Maybe on HAE, did that program come up at all in your discussions with the FDA around the clinical hold? And then maybe also in your conversations with payers so far, have they given you any sense of what the efficacy bar is to avoid any pushback on coverage? Any color there is much appreciated.

I can say a word about our dealings with the FDA. First of all, just to comment, the FDA has been super engaged. It's the same review team that we've been working with throughout the program, and we're really appreciative of the work that they've been doing.

They've been treating, in their meetings with us, HAE and the TTR programs as distinct. In fact, largely the PN and the CM programs are, I think, viewed as somewhat distinct because of the patient populations there. And so that has not been a matter for discussions or submissions that we've made to the FDA.

I don't know, Ed, if you want to say a word about payers in Lonvo-z?

Yes, I'll say generally, the discussions that we've been engaged with payers so far have been very encouraging. Payers appear to recognize the unmet need with the current therapies that are available in HAE. These are high-priced products, as we talked about in our prepared remarks. And they see the value of a onetime therapy like we're presenting with them in Lonvo-z. And so we haven't talked price specifically, but we have had really good positive feedback.

I mean as we -- as John mentioned, the current standard in terms of attack rate reductions is in the 80%, and we're looking at 60% as the largest number we've seen to date in terms of attack-free rate. So that's kind of the efficacy bar. We expect to be very competitive on those figures. And when we layer in the value proposition, broadly speaking, keeping in mind, these patients are very young, they have many years, if not decades, of fairly high-priced, expensive drug therapy, this is a win for many different stakeholders. We see patients responding well to the profile. We see our physicians responding well to the profile. And we see that payers understand the value proposition that we will be bringing forward with Lonvo-z.

The next question comes from Jonathan Miller with Evercore ISI.

I want to go back to the mechanism of liver injury that you were talking about earlier. If it is immune-related or immune-mediated, is it reasonable to expect that affected patients are going to have ongoing liability for as long as the edited gene product is being translated? And sort of the same question, if you're excluding patients with liver risk, that might reduce enzyme spikes, that makes sense. But does that not -- it likely doesn't reduce the rate of immune reaction to edited protein. Is that fair to say? And if that's true, is it possible to screen patients for reactivity ahead, for edited peptides, ahead of dosing?

So thanks for your question. As we've said in our comments, we do believe that the process is most consistent with an immune-mediated reaction. It has the hallmarks of that. The pattern resembles that, the patients that have seen this, which is a very small number of patients participating in the study, behave in a very stereotypical fashion in terms of timing, the appearance of LFTs, et cetera.

That's why we've taken the approach of, MAGNITUDE-2, and we'll see how it plays out for MAGNITUDE, of using steroids that would be triggered by an LFT rise that's something defined in the protocol. Steroids are well known to work with a broad set of immune-mediated processes. They're usually very well tolerated. And especially in this case, we would expect it to be a very, very short-term use of them.

With respect to some long-term susceptibility, we just don't see that in the data. As we shared on prior calls, the patients that have had any of these rises have occurred within this window of 3 to 5 weeks typically. And we do not see anything that resembles that subsequently. So as far as long-term susceptibility, I don't think that's going to be an issue.

As you might imagine, if we could identify patients in advance that are going to have this, with a very, very high likelihood, we would take actions to probably screen them out or take other actions. We don't have that information just yet. And so the approach that we're taking is to make sure that we're carefully following the patients and intervening very, very quickly if something should arise.

Remember that of all of the patients that experienced, with the exception of this gentleman who passed away from a very, very complicated, somewhat unrelated clinical course, every other patient has had a rapid decline in those LFTs and has recovered essentially with no therapy. And so in most cases, I think it's going to be just not a particularly meaningful concern. And that number of cases in which we would actually use steroids, I think, is going to be very low single digits.

The next question comes from Andy Chen with Wolfe Research.

This is Emma on for Andy. Can you elaborate a bit more on why the FDA was comfortable lifting the hold in PN then not CM, just given they're the same products so we would think safety would be the same? And are there specific factors that differentiate the FDA's view across the 2 indications?

Well, I don't -- I'm not going to be able to articulate all of the FDA's thinking because I'm not privy to it all. But I think I would summarize it as they view the patient populations as somewhat distinct. You're correct in that they're receiving the same drug and it's the same gene that is being edited. Patient populations have different characteristics.

The PN patient population tends to be younger, sometimes several decades younger than those with cardiomyopathy. The typical age presentation for patients with cardiomyopathy is into the 70s or beyond. Remembering cardiomyopathy tends to be a disease of aging, I would say, and most of these patients have a wild-type gene. The patients with cardiomyopathy have polypharmacy, many of them have other ongoing medical problems, which tends not to be the case with the patients with peripheral neuropathy.

And so I think that set of demographic characteristics is probably driving a lot of the thinking, plus we've had actually very good safety profile thus far in the patients treated in the PN study. So as I said earlier, there's a lot of data to go through in the cardiomyopathy patient population. We are very, very far down that road. The hold will be lifted when it's lifted, but I think we've made a lot of progress with respect to working with the FDA.

The next question comes from Salveen Richter with Goldman Sachs.

This is Mark on for Salveen. Congrats on the quarter. So from your conversations with regulators, do you expect that additional mitigation strategies would be necessary beyond what you've already implemented in MAGNITUDE-2 in order to resolve the MAGNITUDE study clinical hold? And also, we just want to confirm that, in addition to the patient who passed away, there were only 2 other instances of liver enzyme elevations? Or were there other patients who saw such elevations?

We've said previously that the incidence of Grade 4 elevations was less than 1% in the entire patient population of MAGNITUDE. And I'd work with that number. And that's part of the thinking that we're addressing with the FDA. And we're thinking very, very broadly about how to deal with those patients, as I said in my prior remarks here.

We're up and running with the polyneuropathy study, going through the operational aspects to get the study accruing. With respect to MAGNITUDE, I think it's premature to say exactly where we're going to sort out, but there's many, many points of commonality between the 2 patient populations and some of the assessments. But when we get to a final readout here, we'll take everybody through exactly what's the same. And if there are differences, we'll point them out so that it's very, very clear.

The next question comes from Yanan Zhu with Wells Fargo Securities.

I think maybe also question is a little similar to the prior one, but maybe asked differently, do you think this Grade 5 AE in the CM study, how might that have been impacted with the mitigation strategies that you have proposed for the PN study? I understand you may have additional proposals for the CM. But do you think those 2 proposals would have changed the course or prevented this Grade 5 AE case?

And then separately, I was wondering, Argo Biopharma issued a press release for their QUAD AI presentation last night. Have you had -- wondering your thoughts about that data. And would that introduce any new considerations in the competitive landscape for Lonvo-z?

So thanks for the questions. I'm not in a position now to comment on the Argo reference.

With respect to the patient who passed away in the MAGNITUDE study, remember, we're working on the mitigation strategies for the CM study, and those are not yet finalized. You're asking me if what we're doing in the PN study would have either prevented that or changed I think you said the course of the patient's clinical course.

It's not clear that the patient would have been screened out in advance, although I think knowing what we know now and investigators knowing they may have -- will interrogate patients more carefully in terms of other medical issues that they have and somebody with [indiscernible] disease, if, in fact, it's active, would be something that we would not want to have come into the study.

But with respect to the actual LFT rise, what would be different is that it would be detected earlier and, of course, steroids would be begun substantially earlier than having the patient develop the full-blown transaminase elevations that happened in the case of this particular individual. Would that have changed going to the hospital and the rest of the clinical course? We can only speculate, and I'm not going to do that. But things would have been handled somewhat differently, and I think that's important.

The next question comes from Brian Cheng with JPMorgan.

In the MAGNITUDE-2 trial, can you give us a bit more color on how frequent the added supplementary liver blood test will take place after dosing? And is it fair to assume that [ added ] liver blood test will also be part of the trial modification that will take place for the MAGNITUDE trial?

I would start by saying that we already introduced some additional blood draws into MAGNITUDE-2 when we put the clinical trial on hold. It's important to remember, and I think it's sometimes get lost, but these trials are ongoing. What we're not doing is actively accruing patients. That's the one part of the study that is on hold. But in terms of ongoing clinical evaluations, clinic visits, all of the standard assessments that are part of the protocol, that's happening. We're collecting endpoints as we go from the 650-plus patients that were enrolled in MAGNITUDE. So things are moving, and I just -- I don't want that lost.

And as we put the trial on hold, for those patients who had just been dosed and had not passed through that window yet, we did implement measures that included additional screening of LFT. So that's already in the protocol. And if that changes or not, we'll see when we finalize that those -- any protocol modifications with the FDA.

In terms of the number of assessments, think of it as a couple of additional assessments in the weeks immediately after dosing, essentially weekly early on and then biweekly, or I should say, semiweekly, I guess, for weeks 3, 4 and 5. So we have a really good [ bin ] sampling through the time when patients are most at risk.

The next question comes from Silvan Tuerkcan with Citizens.

Congrats on the quarter. I just want to circle back to the prior question on maybe Argo's data in [ ADARx ]. I appreciate you can't comment without seeing the data. But maybe on a high level, what can you tell us about the delineation or how you would want to position this once-and-done gene editing versus some of these more spaced-out, potentially adults every 6 month [ silencing RNA ] technologies that may be coming to the market? And do doctors already appreciate the difference here?

That's an important question. And I think one part of this that gets lost is what is the so-called burden of care. And it's -- the burden of care is not just getting an injection, whether it's every 2 weeks, every 4 weeks, every 6 months, et cetera. It's also what patients need to go through to get access to these drugs and how they constrain life choices to do that.

Think of it this way. If a patient needs to get prior authorization once or twice a year, that is a burden. There's risks associated with it. There are sometimes delays associated with it. And then the next year, you do it all over again. And the year after that, you do it again. And these doctors are also engaged in this.

And if you ask the patients how they feel about that, they view that as an inherent risk to get access to the drug and continued access to the drug. And so it's -- attack rates are important and attack-free rates are critical for the actual outcomes of these patients. And as we've said, we think we have a very, very attractive profile that you can look at what we've seen from the pooled analysis.

But the ongoing constraints that patients deal with, including maybe not changing jobs because they lose their insurance, is something that gets lost in all of these data, but it is top of mind for patients when you go and ask them.

Yes, I'll just add on top of that. I mean we don't really talk about the emotional, social aspects. There's financial aspects, the prior authorization. I mean again, these patients are pretty young and have oftentimes decades of drug therapy that's required. When you speak to them, it's very clear, they prefer not to have HAE and they prefer not to have drug therapy.

So we are going to be the solution for the market for that, and we like what we see in terms of the large market. It's a highly informed, well-educated patient population. There is a trend towards [ LPP use], and we do see it as a switchable population for the most part. So we've got a lot of tailwinds here.

I would say, without knowing the data that people are referencing, I do want to remind folks that study design does matter. And so there's pretty stark differences between an early phase study, Phase I or Phase II, that, depending on how patients have come on to the study, are they on the LPT or are they not, in addition to the open-label nature, really has a way of changing the numerical responses as people would report them.

And so we had our own pooled analysis going back to November of last year from our Phase I/II study. That's the benefit of patients knowing they're on therapy, and you see very different outcomes, very high attack-free rates and very high attack rate reduction.

So that's not necessarily the case in the Phase III study. As we've talked about before, when you're in a randomized placebo-controlled study, patients are risking, coming off their existing LTPs, they are risking going on to a study where they may or may not receive active treatment. And that can lead to behaviors often seen in HAE patients that lead to additional attack rates being reported in that primary observation period.

So I think we're very careful about how we think about our Phase III data that we'll report out. But as we said before, we're very encouraged by the pooled analysis that we shared in November, we think that's the best representation of what the real-world profile of Lonvo-z will look like in the market.

The next question comes from Myles Minter with William Blair.

This is Jake on for Myles. Is it your current stance of the liver enzyme elevations you're seeing from Nex-z are specific to the editing of the TTR gene with no read-through to the rest of your pipeline? And maybe could you sort of dig into the underlying biology that would lead to that hypothesis? And does the evidence of these liver enzyme elevations being immune-mediated sort of influence your analysis of that question?

Thanks for the question. It's not something I'm going to be able to speculate on at this point. You're essentially asking me what are the molecular events that might be driving this. The simple answer is, at this point, we really don't know. Of course, we edit the TTR gene. That's the entire therapeutic hypothesis here. Whether or not that by itself or some other factor is what's driving this is not clear.

As you might imagine, we've looked extremely carefully at the patients in the trial for any trends of evidence that would help us sort that out. And on a going-forward basis, we're going to continue to look for clues that may help us sort this out. If we could identify some aspect of a patient that said this is the person who's going to have this, obviously, we would take action to address that. But we don't know that yet.

So as we step back a click or 2, we see all the hallmarks of something that's immunologic. And that's why we're proposing -- well, implementing, in the case of polyneuropathy, and we'll see how MAG-2 -- sorry, how MAGNITUDE sorts out the use of steroids, which is time tested, it's well known to be broadly applicable for immunological processes, and physicians tend to have a lot of experience with those drugs, which they can use safely. And when it's used, we would expect it to be a very, very short course, in most cases, probably substantially less than even a week.

So we'll see what we learn as we go forward. But to your broader question, does it speak across the entire pipeline? We don't think so. There's different genes, different edits, different patient populations, different demographic characteristics. And as we reported elsewhere, whether you look at our Phase I work or Phase II work or the Phase III work across the HAELO study, we just don't see this phenomenon. There's been no Grade 3s or Grade 4s that have been observed at any point in those studies.

So we think that we're dealing with something that's primarily playing out in the CM patient population, and we hope to be off hold so we can test the strategies that we're putting in place to get to what we think is a very, very attractive efficacy profile when we complete the study.

The next question comes from Terence Flynn with Morgan Stanley.

I was just wondering if you can remind us on the payer mix in HAE in terms of commercial versus Medicaid, and then how to think about timing of any Medicaid coverage in the event of approval?

And then on the expense side, your comment about if you achieve mid-single-digit market share in a year, the cash flow could fully fund your operations. Is that assuming expenses are at steady state? Or is that assuming that expenses ramp from here? Just want to kind of understand what the underlying direction is for the expenses when you make that kind of a statement.

Maybe you can help us look down the road a little bit for how you think about the expense profile and then maybe speak to the commercial Medicaid mix of carriers.

Yes. Thanks, John. Thanks, Terrence. So from a cost perspective, we're not giving long-term cost guidance. But if you look at where the business is in 2025, it's a pretty good year. I mean we undertook a restructuring with a very thoughtful plan. We kind of ratcheted back R&D, have become much more focused there, but still very active on the R&D front. But we did that to create capacity for the build that we were going to need to do on commercialization.

That started in 2025. So the mix of the business has already started to shift in that direction, and that will continue. As you heard in the prepared remarks, we've got still some final build-out capabilities that we need to do for 2026 to be prepared for a first half 2027 launch.

So roughly speaking, we've been guiding for around $400 million in net cash use over the last 12 to 24 months. And I think that's a reasonable number to be thinking about going forward. We'll have a little bit more investments on the sales and marketing side, but we've got a really good handle on what the needs of the business are beyond that. So we're not going to be substantially higher than where we are today. And that allows us to kind of feel really comfortable about, while we have much higher expectations for Lonvo-z,, a little bit goes a long way for a company our size. And from an operational perspective, this is an opportunity that we can definitely do ourselves, and we've been very thoughtful about the approach that we're taking. So that's behind the commentary this morning.

From a commercial split perspective, roughly 70% of the opportunity is commercial payers for Lonvo-z.

The next question comes from Mitchell Kapoor with H.C. Wainwright.

Mike on for Mitchell. Congrats on the on the quarter. What are the gating factors to get the ATTR studies back up and running? And for ATTR-CM, what have you had from regulators on the path forward?

The gating factors for PN are really local operational issues at sites, and we're engaged in that currently. There may be IRB submissions or some local regulatory considerations. All of that is happening, and we would be expecting to be actively accruing patients in the not-so-distant future. As we've said, we expect to have the study fully accrued by the end of this year. And as we make progress, we'll provide updates as appropriate.

With CM, the gating factor is having -- receiving a letter from the FDA that says you're off hold. And as we've said, we've been very, very actively engaged with respect to addressing any questions, supplying information, et cetera. I think that we are very, very far down that road. But until we receive a letter that we're off hold, we should just wait and see. As soon as we get that letter, should we receive it, we will bring everybody up to date as quickly as possible.

And then we'll go through a similar process that we are with PN, where it's local operational issues to make sure that if there's any changes to the protocol, they're able to do that, dealing with IRBs to the extent that that's needed. And any -- outside the U.S., any additional regulatory submissions that may apply to any particular country. And once we're off hold, should we get off hold, we will tell everybody exactly how that's proceeding at the appropriate times.

And the last question comes from Jack Allen with Baird.

Congrats on the progress over the quarter. I wanted to ask on the MAGNITUDE-2 peripheral neuropathy protocol amendments. Have you discussed with the FDA any impact as it relates to the comparability of the data set pre and post the implementation of those protocol amendments? Is there any risk that the FDA views the protocol amendment as creating a differentiated data set given the change in protocol?

I can't speak for the mind of the FDA, but I would point out that the interruption in time was actually quite brief. When you think about clinical holds generally, we are at the upper end -- and by that, I mean, shorter time frame, to get our clinical hold. In the case of PN, it was 3 months.

The evolution of the patient population, things like new therapies, et cetera, really doesn't come into play. And remember that of the target patient population that we started with, which was 50 total patients, we already had 47 at the time that we went to hold. So we are very, very close to the accrual finish line. And from the standpoint of patients who came in before the hold and after the hold, I think the differences, if any, are likely to be de minimis.

This concludes our question-and-answer session. I would like to turn the conference back over to Jason Fredette for any closing remarks.

Thanks, Drew, and thanks, everyone, for joining us. We look forward to seeing many of you at the upcoming TD Cowen, Leerink and Barclays events that are taking place in Boston and Miami. That concludes the call.

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

Good morning. Thanks for joining us for another session at the 44th JPMorgan Healthcare Conference. I'm Brian Cheng, one of the senior biotech analysts here at the firm.

On stage we have Intellia Therapeutics. I'll now pass the mic to their CEO, John Leonard for a short presentation, followed by a live audience Q&A. John, the stage is yours.

Thank you, Brian. I appreciate the opportunity to give you a sense of where we are, Intellia Therapeutics as we begin the new year here. This is our forward-looking statement. It's available on the website. If you want to examine it further. So Intellia has been a leader in the CRISPR medicine space since its outset in 2014. We've been leaders in many respects, but have emphasized work in vivo treatment of genetic diseases. From our outset in 2014, here we stand on the verge of completing trials that will lead to some of the first approved agents for in vivo use of CRISPR therapeutics.

We have 3 Phase III trials that are ongoing. We'll talk a little bit more about that in a minute. Across the board, from the outset, we've closed over 600 total patients, and we're accumulating, I think a very vast safety database. We have expanded follow-up on patients going all the way back to the beginning where patients have now been followed for in excess of 4 years. And we've had 5 landmark publications. First one with a very first report of humans edited with CRISPR for transthyretin amyloidosis, a second gene, which is KLKB1 for hereditary angioedema, the second group of report. And then 2 follow -- or 3 follow-on article showing the clinical consequences of those edits, whether in angioedema or the 2 different indications for transthyretin amyloidosis and cardiomyopathy and polyneuropathy is something we're very proud of and hope to build on that legacy.

As we look at the pipeline as it exists today, we're well into the clinical phase of the company. Two programs are late-stage clinical work the wholly owned hereto angioedema product, lonvo-z. And then our partnered program with Regeneron, nex-z for the treatment of transthyretin amyloidosis. We're also partners with Regeneron for the work with hemophilia B. It's a program that they lead. And then we have a robust research effort that we're not going to talk about today, but we'll bring forward what we think will be, again, paradigm breaking products not so distant future.

So let's focus on where we are from a clinical point of view. As I said, we're in late-stage Phase III work. Both of these programs have breakthrough profiles and these are large important markets. And we think that we compete very well within them. First product is lonvo-z for the treatment of HAE or hereditary angioedema. This is the first and to our understanding only product that, at this point, has the potential to be able to offer patients of not only freedom from attacks but freedom for any additional therapy probably over the course of their life. We have completed the enrollment of our Phase III program called HAELO.

We have several very favorable regulatory designations for the review submission. And I want to point out that although the target enrollment figure was 60 for this trial, we overenrolled it to 80 because of the vast and very quick interest that appeared, and we were able to accommodate those patients. We'll talk more about that in a moment. We have some important milestones coming up this year, which we'll talk about. And importantly, for the marketplace, which is currently in excess of $3 billion, we see that growing, doubling by the end of the decade. With respect to nex-z for the treatment of transthyretin amyloidosis, again, this is an agent that we think resets the paradigm for treatment in this disease. It is the first agent to not only stabilize but potentially reverse the clinical course of these patients following a single dose of the drug.

We're well into our Phase III programs, although they are in clinical hold. We'll talk a little bit more about that in a minute. And again, this is a large and growing market that we look forward to participating in. Here is the list of progress over 2025 and a look ahead to important milestones for this year. We were able to present extended follow-up from our Phase I/II work in HAE, which we did towards the end of the year. As I said, we completed, in fact, overenrolled the Phase III HAELO trial. And as we look ahead to 2026, we anticipate presenting top line data by mid this year, submitting a BLA in the second half and look forward to a commercial launch of the product in the first half of next year.

With respect to the TTR program, nex-z, also, we presented long-term follow-up on patients for both indications of cardiomyopathy and polyneuropathy. We had very robust and rapid enrollment in our MAGNITUDE trial for CM with over 650 patients enrolled and enrolled the preponderance of patients for the polyneuropathy indication in MAGNITUDE 2. The top priority for the year is getting off clinical hold and resuming the enrollment and hopefully regaining the momentum that we had coming to the end of the year.

So let's talk a little bit more about lonvo-z, as we call it, for the treatment of HAE. Many of you may know something about the disease. It's a genetic illness, typically diagnosed when patients are younger, oftentimes in adolescents or in the 20's. Patients suffer lifelong attacks related to the missing protein that leads to pretend and angioedema throughout different parts of their body. That can be life-threatening when it occurs in the larynx and many patients have experienced that over the course of their disease. There are treatments available and certainly, progress has been made over the last several years. But in fact, most patients achieve only partial control, and they make all kinds of modifications in their lives to adapt to not only their disease, but the therapy is necessary is treated.

We think that, that, along with some of high cost of these agents and the difficulty accessing them with insurance represents a major opportunity for us and a lot of those. So with respect to the market, again, despite the fact that there's agents approved, we believe it's absolutely right for disruptive innovation. We'll show you some of the clinical results that we think mirror that. We expect this marketplace to get to the point of about $6 billion by the end of the decade. In the United States, there's about 7,000 or so patients actively treated. Many of them currently on prophylaxis and the U.S. represents the lion's share of the marketplace.

Now with respect to treatment that exists today and what patients actually experience, despite on-demand therapy despite various forms long-term prophylaxis. You actually go and ask patients, how you're doing and what level of attack you've experienced? Fully 80% of them have experienced tax in the last 12 months. In other words, only 20% would say that they're actually attack-free with their disease control. And the majority of those patients, about 90% of them are actually taking long-term prophylaxis. That contrasts with the data that we've been accumulating in our Phase I and II work, and I'll show you some of the pooled analysis that we presented recently that shows fully 76% of the patients that we've had who have been followed for at least 12 months remain attack-free and also long-term prophylaxis free. And that's a very significant difference in the lives of these patients, we think represents a major opportunity.

That is a set of patients that we will continue to expand and follow the -- extend the follow-up and increase the number of patients who will pass that 12-month follow-up period, which we think will continue to support and perhaps even improve on these statistics. What you're looking at here is a pooled analysis that was presented at the college meeting in the fourth quarter last year in November. And what this represents is any patients from a Phase I or II program who's received a 50-milligram dose of the drug. 50 milligrams is the Phase III dose. What you see in the upper portion are patients who have been attack-free for at least a 6-month period. And in fact, of the 24 patients there. Many of them have been attack-free for at least 7 months all the way up to the 12 months that I talked about.

What you see is attack cease, and they don't come back in these patients. that middle group with the 7 patients there are patients who have less than 6 months follow-up since their last pack. The blue shows me tack free prophylaxis-free interval for those patients, and we expect that several of those patients may move up to that upper category. Of the 32 patients on this chart, there's only one patient who has not achieved attack-free status following a single dose of the drug. That's that patient on the bottom, who despite that, still had a 60% reduction in attacks from his baseline on prior therapy, which is a significant improvement. And as we're learning, as we follow that patient, he certainly has HAE, but there's good reason to believe there's another condition contributing to what's actually linked to a swelling attacks and we'll present more on that later this year.

With the safety profile of the product and the combined efficacy that we talked about, it remains a very attractive profile. What you're seeing here is that the primary adverse experience that patients have will be an infusion reaction typically at the time of infusion. And other than that, there are nuisance sorts of things that patients experience around the time of infusion. From the point of view of chemical abnormalities, it's a very clean profile with literally a single case of Grade 2 transaminases in this patient population. I would point out that there's interest in the TTR program. As we look across Phase I, Phase II and our Phase III program, the entire HAELO study, there's no incidences of Grade 3 or Grade 4 transaminases.

If you ask patients what do you want, given that incidence of a low instance of attack-free status, fully 99% of patients when confronted with a lonvo-z Phase II profile, emphasizing the fact that it's a gene-editing product will be likely, extremely likely or very likely to want to take the drug if it's offered to them. And of that group, fully 2/3 are extremely or very likely product. We think that is indicative of what the demand is at the patient level, again, despite the fact that existing therapy is available to them. And if you look across the board and look at what those patients were taking, it really doesn't matter which agent that they're on.

We have interest in taking a therapy in the form of lonvo-z is across the board. You can ask the same sort of question to a group of physicians here in work that was completed in just the last 2 months. Again, with the lonvo-z Phase II profile and a gene editing product of the 151 surveyed physicians asked can they identify a patient in their practice that they would prescribe the drug to fully 92% of them say, yes, I can identify patients. And when you ask them, how many patients do you manage in total? And how many patients do you think would benefit the drug that you would be willing to prescribe to? About 2,200 of the over 4,000 patients that they care for, they think would be appropriate to treat.

And you see some later commentary there, whether it's a game changer, how highly they would prioritize its use. And of course, they respond to what is the compelling set of clinical results that we presented. What you see here is the schematic for the Phase III program that we call HAELO. This is a program where patients wash out of whatever therapy they may be taking. So they are essentially, if we say, naked with respect to the prophylaxis, on-demand therapies made available to them, randomized 2:1, that's drug to placebo. And then over a 28-week interval, we count the number of attacks. Primary endpoint is HAE attack rate reduction. And then among the various other endpoints that we look at will be the attack-free rate along the lines of what I presented in that pooled analysis.

This is data that we expect to share by mid this year. And again, I would emphasize that we enrolled 80 patients. The target number for this trial was 60. There was great interest and given the long washout period, we had to think very carefully about what the screen failure rate, which turned out to be very low. And so we got this very high number of patients. But I think it's indicative of the interest in the product. And I would point out that in a single month, 42 patients presented themselves to be screened. Most of those patients in the United States.

So where are we with commercializing the product. We've made a lot of headway with our team and our thinking that the core team in place. We're out in the field with our RSDs actively engaging with KOLs. We've been talking to payers and understanding that marketplace. And we think we have a good idea of where we want to go and how we want to do it. and have been building the necessary relationships as you would expect in a rare disease group that's highly connected. The to-do list for this year is on the right, scaling our field team, finalizing contracting models, distribution in pricing.

So all of that is well in hand, and we're very excited about where we are and where we're going. So let's turn to nex-z for the treatment of TTR cardiomyopathy and polyneuropathy, the two standard indications for TTR amyloidosis. This is also a disease that has very significant morbidity and mortality associated with it. Patients with the cardiomyopathic form experience symptoms of heart failure, which can be quite severe. And of course, there's a mortality associated with it that is quite significant. There is a large patient population worldwide. And what's very interesting about the cardiomyopathic form of the disease is that most of these patients have wild type -- the wild-type gene in contrast with polyneuropathy, which is primarily the heritable form which suggests that the cardiomyopathic form is primarily a disease of aging.

So when you think about patients over time, I would expect that in addition to the higher recognition of the condition, the actual number of patients that have the underlying condition, that's only going to expand. With respect to therapy that's currently available for these patients, it certainly improved the prognosis of patients with the underlying disease. But what we see is that it only slows progression. The point for these patients. The end stage is unchanged, except for the rate at which they get there. And if you look at the actual rate of failure, even in the first year after beginning therapy, it's quite significant. And given the recurring nature of these therapies, it's subject to issues with adherence, all of which we think we can address with a onetime dose.

The marketplace, as I said in my opening comments, is large and growing. You see that doubling to in excess of $16 billion by the end of the decade. I would draw your attention to the orange segment of that. which is the knockdown category, which nex-z would participate. That is where most of the growth is taking place. And again, when you talk to patients in terms of what they're looking for, patients with a mortal illness, want a cure if they can find one. They want something that's convenient to take and something that they will deal with permanently when they realize that this is a condition that comes from within. So to speak.

We believe that the drug is approved is not only an important opportunity for the care of patients. I think it would be very helpful in the care of what that physicians are offering. But importantly, it will be resource sparing for the health care system when we consider the high expense of other agents in this category. What is the basis of the excitement? And what is the basis of the clinical data that we'll see here in a moment. It is the profound, rapid, deep and durable reduction in TTR. TTR is the pathogenic protein. It's been demonstrated in a variety of different analyses that the level of TTR reduction correlates with clinical progression or the absence thereof.

What you're looking at are patients here in both the CM on the left or the PN indication on the right, what you see is that very rapid and deep and sustained essentially unchanging level of TTR. These are not percentage reductions. These are absolute values. And what patients reach is typically on the order 17 to 19 micrograms per ml of blood, which are the lowest levels that have been reported in patients and significantly superior to what we've seen with other agents that are approved. This is 36 months of data. We do not have a single instance of a patient losing that effect over time.

And as far as we can tell, it's should be permanent, at least for many, many years and potentially life on. This is the important data that was presented at the American Heart Association last November. And what you see are the matching of this Phase I cohort that was in the cardiomyopathic slide that you just looked at, matched with a group of patients from the same site for contemporaneous who are not receiving silencers or stabilizers with a high degree of match and then look for mortality over the 3 week -- or 3 months -- I'm sorry, 3-year observation period. And that's represented here.

In blue, you're seeing incidence of mortality in patients who have received nex-z. And that contrast with the 1,800 patients that were followed again, on a matched basis of the National Amyloidosis Center in the U.K., what you're looking at essentially a 70% reduction in mortality in this analysis. Again, it's not prospective randomized study. But nonetheless, I think it's indicative of what the level of TTR reduction may promise as we carry out our Phase III work. I would point out that, that incidence of mortality when thought about in terms of number needed to treat would be about a number as low as 4 in this particular analysis to save a life over 3 years of observation, which is, I think, an outstanding number.

With respect to the safety profile in that set of patients, you see that here. Most of the adverse events are related to the disease that they have, the underlying cardiac failure there is an incidence of infusion-related reactions and a low level of transaminase elevations. I would point out in the MAGNITUDE study, this is, again, Phase I carried out the MAGNITUDE study where we have the over 650 patients enrolled, we've had transaminase elevations. That study is currently on clinical hold. On Friday of last week, we presented additional information on the one patient that triggered that clinical hold. That patient who had elevated transaminases and bilirubin that triggered the whole ultimately succumbed to septicemia due to a perforated duodenal ulcer that the patient developed over the approximately 10 days that the patient was in the hospital.

If you look across the Phase III study, the incidence of grade 4 transaminases is less than 1% across that entire study. And at this point, we're working through the clinical hold with the FDA, and we're actively engaged in that process with them. So as we look at where we are on hold, I said that we've enrolled over 650 patients. The target number is 1,200 last year before we went on hold. We had a very rapid and robust and actually increasing enrollment and the 650 patients was our target for the end of the year, we achieved it by the end of again, indicative of the high level of interest of the physicians and the patients that are participating in the trial.

And if you look at MAGNITUDE 2, the Phase III trial for polyneuropathy fully 47 of the intended 50 patients were enrolled at the time that we went on clinical hold. The study continues as we speak. We're not accruing new patients, but we're collecting data on all the patients those 650 patients. They contribute endpoints, safety information, et cetera. All of that's being collected as time passes here.

So wrapping up, we like where we are. We're very excited about the prospects for lonvo-z. We think that this has the potential for just revolutionizing the HAE marketplace. And as I said, it not only deals with the underlying disease, but should be able to obviate ongoing therapy for the vast majority of patients over time. And with nex-z, we're excited about the benefit that we think there's very strong signals of and the work that I just went through with you, and it's a matter of getting back on clinical hold. As I said, we're very back off of clinical hold. And as I've said, we're actively engaged with FDA as we speak.

From a capital point of view, we're in a strong position, and we're able to fund operations into mid-2027 at this point. So Brian, I'm happy to take some questions. And I think Ed going to -- our CFO is going to join us.

Great. Well, thank you so much for joining us. So let's start -- kick off the Q&A. [Operator Instructions].

John, maybe just kick off with some questions on lonvo-z. As we think about the HAELO trial reading out sometime later this year. How should we think of a win scenario? What do you want to see from the trial? In your slide, you pointed out there are endpoints of interest. One is attack rate and the aerie attack-free rates. So can you kind of frame what a win scenario looks like relative to those endpoints that you pointed?

Yes. No, it's an important question. The way that these products are evaluated at the level of the FDA is an attack rate reduction. And that's how these studies are set up to run. We would anticipate an attack rate reduction that's highly competitive with any of the agents that have been reported, probably well into the 80% or so from baseline. I think that, that in the real-world scenario may even underestimate what actually happens as we went through in that pool analysis, all those patients are not blinded, but ultimately know that they've been treated I think the real driver in the marketplace and what patients are ultimately looking for is not just an attack rate reduction, but an attack-free life that in which they're able to abandon long-term prophylaxis.

And we would expect that we will have a very high percentage of that. When we compare ourselves what we've seen already to what's currently out there. The best in class is on the order of 60%, Takhzyro, the leader in the marketplace is down in the 40s somewhere, we would expect that we should be able to handle at. I don't know if, Ed, do you want to add some color to that? Any other thoughts?

No. You said it well, I think the attack-free status, the fact that it comes with no additional therapy is also significant importance. And so John did a good job outlining the data that we've seen from our patient surveys and market research and what you see is the vast majority of patients still have a high unmet need. The vast majority are still having attacks. And so to the extent that we can have a onetime therapy, it's very easy to administer, with an attack-free status also accompanied by the absence of additional therapeutic intervention like long-term prophylaxis.

That's a profile that we think not only speaks to patients, but we're finding physicians resonate with that as well, and we haven't talked about it much today, but payers are responding favorably to that profile.

And just on -- in terms of the top line, have you decided on what we could see at the time of the top line and what could investors expect?

Yes. I would anticipate at this point that we would share the primary endpoint, attack-rate reduction, probably some insights into that attack-free drug-free interval that we've been talking about here as well as some top line safety data, whatever we think is particularly relevant. And that would be the base case.

Okay. Just kind of stepping back into the competitive landscape, right? There are acute treatments there are prophylactic options. How do you think about lonvo-z? How do you think about the opportunity itself?

Well, we think the market, as I said in my comments, is right for disruption. I mean it's clear that we've made advance -- I'm talking about the field in general in terms of treating the disease, and that's a wonderful thing. But I think we hold in our hands something that is tantamount to a functional care for these patients for many of them. And when I think about what patients are looking for, when you just ask them, they want to be free of their disease. And it's not just being free of attacks. They want to be free of the medicines that they take to do that. And I think it's important to understand that the disease is more an attack. It's how you order and organize your life to avoid things that stimulate that to put yourself in positions where you may not be able to take your medicine.

And importantly, these are medications that are extremely expensive that require insurance authorization on an ongoing annual and sometimes even semi-annual basis. And that leads to a behavior with respect to how they treat their workplace, their jobs, and if you think about their lives as how fully it might be lived, in fact, these are lives that shrink in terms of what patients would like to do. So given the opportunity to potentially a bean and all of that, that's what the market is looking for. And we think that represents a very significant opportunity for Intellia.

Ed, I think you noted some feedback that from payer, you must have done some research on that front. How should we think about just the payer access side of things and as you start to prepare towards the commercial launch?

Yes. We're not going to talk too much about that as we get closer to launch in the first half of '27, we may say more. I'll just build on what John said and some of what has already been presented. We see a large growing market opportunity of the 7,000 or more patients in the U.S. that are already being treated on therapy, you're seeing a trend toward long-term prophylaxis use. So we think that's a tailwind for us as well. In a prevalent pool of patients like HAE, which is a genetic disorder, the ability to switch patients is really important.

When you have new therapies being introduced, some of which have been in the last several months, you can see that desire to switch for new therapies that add incremental benefit. So when we look at that backdrop, we're very encouraged about what we see with a one-time therapy. And so when you layer in now this prospect of becoming drug-free and attack-free, it's a very strong value proposition. As we talk to payers, it's not lost on them that drug therapy is very expensive today, right? Some of these lean therapies are well in excess of $650,000. So that's already part of the treatment paradigm. And for what is otherwise a relatively young and healthy patient population, this ongoing annual process of prior authorizations continuing to take therapy.

They are a patient for life. A payer also looks at that and looks at the amount of resources that are required to manage this patient population. So they see a lot of benefit in reduction in health care resource from a onetime therapy that admittedly will be a premium price, but one that we think delivers value to patients, to physicians and actually to payers substantially so.

As we think about your plan towards filing later this year. Are there any gating factors towards the filing, assuming HAELO is positive?

We're really in a good position at this point. I mean the basic thing that we need to do is complete the data collection of these patients that are being observed in the HAELO study. And as I said, they've all been dosed, so we're just collecting the event rates here. We've -- as you might imagine, all the preclinical work is done, it's been written up. We've templated a lot of the material that will come from the clinical program. but probably most importantly, on the CMC side, which sometimes is a bugaboo for programs. That work is completed.

What we're using in the Phase III work is essentially the commercial form of the product. So we should be in a very good position to rapidly turn this around and go to the FDA. And as I said, we have several regulatory designations that are very favorable as well.

Great. Any questions from the audience?

Can you talk about the steps or the engagement with the agency with respect to the clinical hold and maybe outline what information or any statutory time lines for that process? And then maybe just in concert, just comment on the overall status of your partnership with Regeneron.

So that's a TTR nex-z question. And just to make that clear for the audience. We're actively engaged with the FDA. They submitted a variety of questions to us, many of which we anticipated. I think there are questions that any person or group running a clinical trial would expect to analyze, and we've been doing that. That data has been presented with them. So it's an ongoing discussion. There is not a mandated time to which people go off clinical hold. It's a decision that's made by the agency. We're providing them with everything that they've asked for and are happy to do that as efficiently as possible.

So in terms of just clinical holds in general, if you look at it from a historical point of view, on the order of 3 months or so would be a very, very fast turnaround for most companies that have been in clinical hold and the bulk of them fall within 3 to 9 months historically. With respect to Regeneron, they are our partners, as I said. They're involved in the process. There are partners that see all the data. We rely on each other, and we've drawn their expertise and have been actively doing that.

I think there's another question in the front.

John, what are your thoughts on international commercialization?

Maybe, Ed, you want to address -- are you asking generally or for a particular product?

Sorry. For lonvo-z.

For lonvo-z. Yes.

Yes. I'd say as a company, we're committed to getting outside the U.S., but as a small biotech building the infrastructure for the first time, not surprisingly, we've been focused on the U.S. So have foundational leadership in place, a lot of the enabling activities that you would expect ahead of commercial launch. We've had that plan for quite some time, and we're executing very well. That, of course, continues in 2026. We are running our studies outside the U.S. we want to make sure that we gain broad access to the therapy and the profile that we're very excited about. We can do that in a number of ways.

We could decide to build it at some point, not currently in the kind of short to mid-range plan, but we're also pro-collaboration. Just had a question on Regeneron, that would be an obvious place to look. And so we're looking for a partner that's like minded has the capabilities to help us extend the reach beyond the U.S. We haven't made that determination yet, but it's definitely in our thinking for the next couple of years.

So in the deck, you present at additional color on the grade 5 case. So any sense of the cost of the liver tox here based on the work that you've done in the past couple of weeks, was it related to subset? Any additional color that you can give today?

Yes. I mean the patient I mean, I can tell you a clinical course, which I think is helpful to understand. This is a patient who was in the study. 82-year-old man received drug a little over 3 weeks later, reported abdominal pain to his treating physician. Physicians said go to the emergency room, and they'll take a look at you. While he was there, he was observed to have an elevated transaminase, use them into the hospital for observation.

Over the course of the time that he was in the hospital, the hospital, which took excellent care of him as far as we can tell. His caregivers provided him with some steroids. About a week into his stay, he deteriorated, was evaluated, he have air in his abdomen, he went to surgery and was told they have a 2-inch perforation of his duodenum tied to duodenum ulcer that was also found. Patient never really recovered from that. He had a very rocky course thereafter had episodes of hypoperfusion, septicemia and ultimately, the family withdrew support.

So that's what happened to him. I mean he did not die of liver failure, which I think has been misunderstood by some observers here. It's very unlikely in our judgment that what the patient experience in terms of liver injury as manifested by the transaminase elevation was attributable to that other underlying process, but the death was attributed ultimately to the sepsis resulting from the peripheral ulcer.

Since the clinical hold, can you just talk to us about the level of engagement you have seen from investigators and clinical sites. How confident that enrollment will pick back up? How do you think about the phase as well after the clinical?

Yes, it's an important question. I mean the -- as I said in my comments, the study is continuing. I mean, we're collecting data on the patients who are in the study, they contribute endpoints, safety information and all of that is ongoing. The part that's not proceeding until we get off of clinical hold is the accrual of additional patients. The investigators remain fully engaged. As you might imagine, we have a very active outreach to them and tried to keep them fully aware of where we are to the extent that we can, and that's also true of patients.

I would point out that at the end of last year, the enrollment was only accelerated. I mean we're really very pleased to see the rate at which patients were coming in, and we had changed our guidance because we had -- it was very clear that we were going to exceed what we anticipated at the beginning of the year. It will be a process, assuming we have clinical hold. Studies done under the IND. It really comes down to starting with the FDA. And then depending on IRBs and any changes that may be necessary to the protocol, it's playing that out. It will not go immediately back to what it was, but we would expect that, given the enthusiasm we've seen that we would be able to continue enrolling the study and finish it.

Great. Well, thank you so much for your time, and that's all time we have. Thank you. one.

Hello, and welcome to Intellia Therapeutics Third Quarter 2025 Financial Results Conference Call. My name is Rocco, and I will be your conference operator today. Please be advised that today's conference is being recorded.

I will now turn the conference over to Jason Fredette, Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed, sir.

Thank you, Rocco, and hello, everyone. Earlier this afternoon, we issued a press release and filed our 10-Q outlining our recent business updates and our third quarter financial results. These documents can be found on the Investors and Media section of Intellia's website at intelliatx.com.

At this time, I would like to take a moment to remind listeners that during this call, Intellia management may make 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 unless required by law.

Joining me on the call are John Leonard, our Chief Executive Officer; and Ed Dulac, our Chief Financial Officer. With that, I'll turn the call over to John.

Thanks, Jason, and thanks to all of you who have tuned in for today's call. In terms of the agenda for today, we'll begin with the status of our nex-z program in ATTR amyloidosis since that is obviously top of mind for all of you. We then will provide an update on the significant progress we have made with lonvo-z, which is being developed as a potential onetime treatment for patients with hereditary angioedema or HAE, and we will close with Ed's financial review.

First, for nex-z. Since the start of 2024, we've been enrolling patients in MAGNITUDE, our Phase III clinical trial for ATTR amyloidosis with cardiomyopathy. And we've been enrolling MAGNITUDE-2 for patients with hereditary ATTR amyloidosis with polyneuropathy since the start of 2025. Both trials have advanced rapidly, which we believe demonstrates patients' interest in a potential onetime treatment option.

On October 24, a patient was admitted to the hospital after reporting abdominal pain to his principal investigator. This is a patient with ATTR cardiomyopathy in his early '80s who enrolled in MAGNITUDE and received a dose of nex-z on September 30. The patient's labs showed that his AST and ALT levels exceeded 3x the upper limit of normal and that his bilirubin exceeded 2x the upper limit of normal. These levels triggered a protocol-specified pause on patient dosing and screening for MAGNITUDE in the interest of patient safety. We decided to also pause patient dosing and screening in MAGNITUDE-2 as a precaution.

On October 29, the FDA notified us verbally that it had placed a clinical hold on MAGNITUDE and MAGNITUDE-2. We are now awaiting the FDA's formal clinical hold letter. We were very saddened to learn that the patient passed away last night. We have been advised by the treating physician that this is a case with complicating comorbidities, and the case is being further evaluated.

Since learning of this case, we've taken a number of actions in the interest of patient safety. For instance, we've mandated that clinical sites collect additional labs from patients in the initial weeks following dosing to detect potential liver elevation sooner. An internal team has been closely reviewing the blinded safety data, baseline characteristics, among other factors, to identify potential contributors to the liver-related events seen in MAGNITUDE.

We've been working with the trial's independent data safety monitoring committees as we consider other potential monitoring and risk mitigation strategies. And of course, we are engaging with global regulatory authorities and other stakeholders to understand their perspectives, concerns and requirements so we can develop a plan that would allow us to resume enrollment as soon as appropriate. Not surprisingly, given the clinical hold, we are unable to maintain our milestone guidance for nex-z, and we expect to provide an update once we finalize the plan with regulators.

Simply put, a lot has transpired over the past couple of weeks and in recent hours, and there is still much work ahead. There's a lot of focus on the safety profile of nex-z at this stage as there should be. That said, we continue to believe in this product candidate's potential to address important unmet needs for patients with ATTR amyloidosis. This is based on a few key factors.

First, ATTR amyloidosis is a disease with high mortality. While undeniable progress has been made in this treatment, current therapies only slow its advance and most patients continue to face progressive morbidity and mortality. Second, we've enrolled more than 650 patients in MAGNITUDE and 47 patients in MAGNITUDE-2. To date, Grade 4 liver transaminase elevations have been reported in less than 1% of all patients enrolled in MAGNITUDE. Each of these cases has been observed approximately 3 to 5 weeks following randomization and dosing. There have been no Grade 4 liver transaminase elevations in MAGNITUDE-2. And third, we are highly encouraged by the data from our ongoing Phase I clinical trial of nex-z. On Monday, in a late-breaker oral session at the 2025 AHA Scientific Sessions in New Orleans, we will have the opportunity to share longer-term data for nex-z that we believe demonstrates its potential to improve various disease measures and mortality.

Let's move on to lonvo-z, which is being investigated in our ongoing HAELO Phase III clinical trial for HAE. Over the course of 2025, we've made considerable progress in this trial. Enrollment was completed in September, less than 9 months after we dosed our first patient. This puts us on track to share top line data by mid-2026, submit a BLA to the FDA in the second half of 2026, and prepare for an anticipated commercial launch in the U.S. in the first half of 2027. We believe lonvo-z could completely redefine the HAE treatment landscape. We aim to reset expectations and the standard of care for patients living with this debilitating disease by completely eliminating attacks and the need for other HAE medications for a majority of patients, all with one dose.

This Saturday, at the American College of Allergy, Asthma & Immunology Annual Scientific Meeting in Orlando, we will be presenting longer-term safety and efficacy data from all of the patients who received a 50-milligram dose of lonvo-z in our Phase I/II clinical trial.

I'll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results for the third quarter 2025.

Thank you, John, and good evening, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our clinical pipeline and build important capabilities required for future success. Our cash, cash equivalents and marketable securities were $669.9 million as of September 30, 2025, compared to $861.7 million as of December 31, 2024. During the third quarter, we raised approximately $115 million from our ATM facility. When combined with the benefits of the restructuring initiatives we implemented in early 2025, this enables us to extend our cash runway into mid-2027 and through lonvo-z's anticipated commercial launch in the U.S. for HAE.

Collaboration revenue was $13.8 million during the third quarter of 2025 compared to $9.1 million during the prior year quarter. The $4.7 million increase was mainly driven by cost reimbursements related to our collaboration with Regeneron Pharmaceuticals. R&D expenses were $94.7 million during the third quarter of 2025 compared to $123.4 million during the prior year quarter. The $28.7 million decrease was primarily driven by employee-related expenses, stock-based compensation, research materials and contracted services, offset by an increase in the advancement of our lead programs.

Stock-based compensation expense included within R&D was $12.2 million for the third quarter of 2025. G&A expenses were $30.5 million during the third quarter of 2025 compared to $30.5 million during the prior year quarter. Stock-based compensation expense included within G&A was $7.4 million for the third quarter of 2025. Finally, net loss for the third quarter of 2025 was $101.3 million, down from $135.7 million for the prior year quarter. We continue to expect a year-over-year decline in GAAP operating expenses of at least 10%. And as stated before, our cash runway is expected to fund operations into the middle of 2027.

With that, we are ready to begin our question-and-answer session. Before we do, we would like to let you know in advance that we will be unable to answer some of your questions given a variety of factors, including the fact that we are still awaiting the FDA's clinical hold letter and a more thorough evaluation of the patient's case. We appreciate your patience and understanding.

Operator, would you please open the line for questions?

[Operator Instructions] Today's first question comes from Gena Wang with Barclays.

I'm really sorry to hear the unfortunate event. I know you are still collecting tons of data, but just wondering if any initial hypothesis of the reason for liver enzyme elevation since this is a 1 month after dosing. Is that because of lipid nanoparticle Cas9 or age-related or disease? Any initial thoughts that would be fantastic. And the related question is, you shared the color on Grade 4, less than 1% in ATTR cardiomyopathy. How is that rate for ATTR polyneuropathy and the HAE patient population?

So Gena, thank you for the question. At this point in time, we can only speculate, which we're not going to do in terms of what's the source of the liver function test abnormalities. As you pointed out in your question, we've seen across the entire study with over 650 patients enrolled, an incidence of less than 1%. This particular case is distinct from what we've seen. It was a very complicated clinical course with other comorbidities that may have had some influence in the outcome of the patient. Of the other cases that have occurred, all of those cases have either resolved or resolving and no one is in the hospital.

And our next question today comes from Maury Raycroft with Jefferies.

Maybe one more on the patient. I know you can't say much, but you mentioned the other comorbidities. Can you say what those were and also potentially whether the patient was managed in the United States or ex U.S.? And then, yes, I guess, if you can't answer those, if you could talk about just potential risk mitigation strategies that you could implement going forward.

Yes. At this point, Maury, we can't go into the comorbidities. I can only say that the patient had a very complicated medical course, and these other comorbidities may have influenced the ultimate outcome along with the hepatic abnormalities. We're not commenting on geography. I can only assure you that the patient received what we believe to be excellent medical care, and we have no reason to believe that there was any shortfall in taking care of the patient.

With respect to risk mitigation strategies, that's ongoing work. As you might imagine, we're doing as comprehensive analysis as we're able to do, looking at all of the data we've collected, coming up with any potential hypothesis. The ultimate goal would be to find a way to exclude patients who may be at risk, should we identify it or impose interventions that could deal with the liver function test abnormalities if they do occur.

And our next question today comes from Alec Stranahan with Bank of America.

I guess, how many ATTR patients are currently within that 3- to 5-week post-dose window on the study right now?

I can't give you precise numbers, but it's -- the vast majority of patients have passed through it. And with each passing day, there's a smaller and smaller set of patients who have yet to go through it.

And our next question today comes from Mani Foroohar with Leerink Partners.

My condolences, a tough outcome for the patient for sure. So let me dive in a little bit on a hypothetical that I've received from a number of clients, which is if this hold were to remain for an extended period of time, what does that mean for the ongoing OpEx spend of the company? i.e., I know it extends the duration to whenever we get a potential pivotal outcome for the study. But does it change the total amount of spend over the course of the study? Is your spend at a normal level during this hold or at least some activities interrupted? How should we think from a financial modeling perspective, recognizing that, that, of course, is a secondary concern to the moral obligations for the patient?

Thanks for the question. It was a little garbled, Mani, but I think you were asking how does the hold play into the financial runway of the company and how do we manage through it. I think there's going to be a two-part answer. Ed can speak to the runway and how we currently view it.

As you can imagine, our priority is going through the data and coming up with the best possible path forward. And that is job one at this point, and it's something that we're working very, very hard to do. The goal is to be up and running as soon as appropriate so that we can regain what was a very substantial momentum as we said. We had enrolled over 650 patients, and that's I think just a really stellar record. But maybe, Ed, you can say a few words about the runway and how we're thinking about this may impact that.

Of course. Thanks, John. Yes, I would say we -- it's premature to be too precise with any guidance. But as we sit here today, based on the information we know, as we indicated, the time lines and the plans for lonvo-z are unabated. So we continue to operationalize that study as we have been. While we are on clinical hold and therefore, unable to enroll new patients or screen for patients, as we reported, we do have now more than 650 patients in MAGNITUDE and we have 47 patients on MAGNITUDE-2 that still remain on study, are still being managed according to the protocol. So the appropriate follow-up. So that will continue as we work our way through our clinical hold.

Maybe to your point, the only thing that changes is the incremental cost of dosing per patient. So in many ways, near term as we work our way through the clinical hold, you could argue we're going to spend a little bit less money. We'll still have program management fees related to CRO costs and our own internal work, but the incremental cost per patient will not occur during this time, and we will reassess what the time lines look like once we have a clearer path on getting off clinical hold.

And then we don't talk much about it, but we do have research priorities within the organization, and that continues. So again, sitting here today, we don't see a substantial shift in the operating needs or the cash needs for the company, and we'll look to reevaluate that in a collaborative effort, including with the regulatory authorities in the weeks and months to come.

And our next question comes from Yanan Zhu with Wells Fargo Securities.

Sorry to hear the update about the patient. I was wondering, when you talk about comorbidities, is there any liver-related comorbidities? And then additionally, when you talk about less than 1% of the enrolled patients have Grade 4 enzyme elevation, could you -- are you able to disclose how many cases of Grade 4 liver enzyme situation has happened and how many are still resolving?

Thanks, Yanan. The 1% applies to the more than 650 patients. I remind you, this is an ongoing placebo-controlled double-blinded study. And what's attributed to what in precise numbers by case, et cetera, is not possible for us to get into. But you should think of this as less than 1% across that number.

With respect to the comorbidities, it's not something we can get into at this point. I can assure you that there's an ongoing evaluation where we'll get more information that I think will be very helpful to understand the clinical course that this patient experienced. And we'll present that information at the appropriate time once we have it. But until that information is in our hand, I think it's premature to discuss.

And our next question today comes from Troy Langford with TD Cowen.

My condolences on the unfortunate update today. I guess just to kind of follow on to some of the other -- some of the previous questions. Is there anything that you all can do preclinically to try and disprove any sort of causation between nex-z treatment and the safety event? And then I know you all can't say that much, but is there -- if you all can provide any sort of color on potential time lines or next steps with the FDA around reinitiation of the study, I think that would help a lot.

Yes. I can't speak for the FDA, and we're certainly waiting for the letter that we expect to receive from them, the hold -- clinical hold letter. And that will be obviously very influential in how we think about -- going about getting back the protocol up and running. With respect to preclinically evaluating, it's hard to know at this point. But as I said before, we're looking at every source of information that we have to see if there is some way that we can identify patients who may be at increased risk. And when we find that information, I'm sure we'll be talking about it in a way that will be meaningful, but only when we're convinced that we have that information well in hand.

And our next question today comes from Brian Cheng of JPMorgan.

Ed, earlier this year in January, I remember that you said that the ATM would be used at an opportunistic time. And looking at your 10-Q, $128 million this quarter was executed through the ATM. What changed your mind here in executing the ATM? And is the ATM your path going forward in raising additional cash?

Brian, thanks for the question. And Ed, do you want to talk about how we think about the various tools for raising funds?

Yes. So we've often talked about ATM as not a primary strategy, but a tool within the toolkit to raise capital for the company. We're not going to comment on specifics going forward, but we do believe in having options. And so whether it's traditional equity that's often done in biotech, including the use of the ATM, you should expect us to continue to have that available to us and potentially circumstances dependent to utilize that strategy. But there are others for a company like ours that is approaching Phase III data and has a BLA filing. And so whether it's collaborations that we could consider, debt structures or more creative financing opportunities, I do believe we have the balance sheet to get to those milestones and multiple options to consider to improve the balance sheet in the future.

And our next question today comes from Jay Olson at Oppenheimer.

We're sorry to hear this news. Since you mentioned there are no Grade 4 liver transaminase elevations in MAGNITUDE-2, can you just talk about any notable differences in the baseline characteristics for MAGNITUDE versus MAGNITUDE-2? And any particular changes you may be considering to the enrollment criteria?

The primary difference is the indication itself. Patients in MAGNITUDE-2, as I'm sure you know, have polyneuropathy, which is a manifestation of TTR amyloidosis. And in MAGNITUDE, it's cardiomyopathy as the primary manifestation. Other than that, the differences tend to be really minimal, and I would think of it as on a continuum with respect to the drug as a whole.

And our next question today comes from Salveen Richter with Goldman Sachs.

I was just wondering if we step back, whether you could just help us understand the steps from here apart from the FDA letter.

Well, central to the way forward is the FDA letter and coming to terms with what they'll require. But you can imagine that we're already working very hard with all of the information that we've accumulated. We're looking clinical information, preclinical information, manufacturing, et cetera. All of this is part of a very, very comprehensive analysis to see if there is any indication of a particular thing or a characteristic that puts patients at risk.

While we do that, we wait for the FDA and the information that it requests. And as that information -- as that letter becomes available to us, we'll think through what we need to do and we believe we'll have the tools to address what we imagine may be things that are of interest to them, and we will work very, very closely with them to come up with the best possible plan that we think is an appropriate way to mitigate risk.

And our next question comes from Jack Allen of Baird.

I also wanted to pass along my condolences, a tough update here. Stepping back, I was hoping you could help remind us of the differences in the construct as it relates to the ATTR candidate as compared to HAE. I believe they're using different LNPs, but could you help me understand that, and then also obviously targeting different genetic diseases as well?

Yes. Thanks for the question. As we've shared elsewhere, the LNP is the same. That is the lipid constituents, the mRNA is the same. It's the guide RNA that differs between the two. but that leads to a totally different sort of outcome in patients. So ultimately, the patients themselves are different. The disease that they have is different and the gene that is targeted is different. So we view lonvo-z and nex-z as absolutely distinct from each other and the patient experience thus far aligns with that.

And our next question comes from Silvan Tuerkcan with Citizens.

My condolences as well to the clinical team. My question is do you add any additional liver monitoring in the lonvo-z trial in HAE? And I'm asking because if the percentage is less than 1% on 650 patients, if you do the math, less than a patient in the HAE trial, right? So any chances you can pick up slight liver increases there before there's a potential launch?

Well, first of all, the lonvo-z HAELO trial is completely enrolled. And as we said at a prior update, that patient population is fully enrolled, and they've all passed through this initial window for the patients randomized in the primary evaluation part of the study. The monitoring that we have is not as intense as what we have in the nex-z trial. But again, our experience to date has been quite distinct. And if there were an issue that we would expect to be able to see it with the monitoring that we do have.

I would say that an additional aspect to point out is that on Saturday, as we said in our comments, we'll be presenting at the AACI meeting, the combined pooled experience that we have of all patients who have received a 50-milligram dose for lonvo-z, and you'll be able to see the same not only clinical performance, but safety performance that we're seeing ourselves.

And our next question today comes from Jonathan Miller at Evercore ISI.

My condolences as well to the family of the patient and to you guys, tough update. I guess I would love to dig further into the comprehensive analysis that you said you were doing. Obviously, you're going back over the individual patient. But how deep are you going across both the nex-z and the lonvo-z patient populations thus far? And can you maybe put some guidelines around what sorts of cases you would consider to be possibly fitting the pattern versus the sorts of cases you would be excluding? I'm thinking of patients who have subclinical liver enzyme elevations that might fit a timing pattern. How do you adjudicate whether you think those are part of this signal or not?

The first point I would make is that the lonvo-z experience is distinct from what we see with nex-z. But with respect to nex-z, you're correct in that we'll have more information coming from this particular patient, which I think can be potentially very illuminating in terms of understanding the patient's clinical course. But other than that, when I say comprehensive analysis, I mean comprehensive. And we're looking broadly. We're looking deeply and the sorts of things that you're raising are all on the list of things for us to consider.

And our next question comes from Whitney Ijem with Canaccord.

This is Angela Qian on for Whitney. I also want to express our condolences. So we understand you'll be increasing the monitoring of lab values after dosing. But can you give us a little bit more color on how often the lab values are being monitored previously? In this one patient, the levels were discovered when he had abdominal pain. But in the other patients who did have elevations, how was that discovered?

We've always monitored in the window, and that's how we are aware of what we've seen thus far. We've not only picked this up as a result of more intense monitoring. But what we've done as more information has become available to us is move to at least weekly monitoring for the first few weeks after a patient has been exposed to the drug to see if we're able to actually characterize the full course of what happens when it happens. Again, it's occurring in less than 1% of all of the patients that have been enrolled in the trial. And the notion there is that if there's information that can be acted on that, that's in the hands of the physicians who are caring for these patients.

And our next question today comes from Luca Issi with RBC Capital Markets.

This is Shelby on for Luca. Maybe a quick one on HAE. We appreciate that you don't see a lot of read-through here, but do you think the patient death in TTR could hurt the potential commercial opportunity for this indication? Any color there, much appreciated.

I can only speculate at this time, I think between where we are today and completing the readout of our Phase III trial for HAELO, there's a lot of time and information to be accumulated that will characterize the benefit risk profile for lonvo-z. Again, I would point you to a presentation that will be given on Saturday, just a couple of days from now, where the combined experience of all of the patients, 32 that have received 50 milligrams and the efficacy profile, along with the safety profile is there for everyone to see. And we think that, that is largely going to be representative of what we think we'll see in our Phase III or clinical use of the product more broadly. So until we get all of that information, I don't think we're going to be in a position to talk about the commercial opportunity. But thus far, we very much like what we see.

And our final question today comes from Myles Minter with William Blair.

Sorry to hear about the update. It's a straightforward one. Do you have a cause of death? This is a cardiomyopathy trial. You will have deaths in the trial, unfortunately. Just wondering whether this was a CV-related event or as it seems maybe something beyond that?

If I heard you right, I'm sorry, it was a little garbled. We'll give the information once we have all of the final material in hand. There are some things that are being done after the death to give us additional insights. And at the appropriate time, we'll share all of that.

Thank you. And that concludes our question-and-answer session. I'd like to turn the conference back over to CEO, John Leonard, for closing remarks.

So thank you all for joining us. We will look forward to speaking with you again when we have meaningful updates to share.

Thank you. This concludes today's conference call. We thank you all for attending today's presentation. You may now disconnect your lines, and have a wonderful day.

Good morning, everyone, and welcome to Intellia Therapeutics conference call. My name is Jamie, and I will be the conference operator today. Please be advised that this call is being recorded at the company's request. [Operator Instructions]

At this time, I'd like to turn the conference call over to Jason Fredette, Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.

Thank you, operator, and hello, everyone. This morning, we issued a press release and filed an 8-K regarding a safety event that occurred in our MAGNITUDE Phase III clinical trial of next-z. Those documents can be accessed on our website, intelliatx.com, and the 8-K also can be accessed at sec.gov.

Before we get started, please note that during this call, Intellia management may make forward-looking statements. We ask that you refer to our SEC filings, which are available at sec.gov for a discussion of potential risks and uncertainties that may be related to those statements. All information discussed on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law.

With that, let me turn the call over to Dr. John Leonard, Intellia's Chief Executive Officer.

Thank you, Jason, and thanks to all of you who have joined us on short notice. We will address the safety event, and we'll then open the call to questions.

On Friday, we learned that a patient was admitted to the hospital after reporting abdominal pain to his principal investigator. This is a patient with ATTR cardiomyopathy in his early 80s, who is enrolled in MAGNITUDE and received a dose of next-z on September 30. The patient's lab showed that his AST and ALT levels exceeded 3x the upper limit of normal and that his bilirubin exceeded 2x the upper limit of normal. This patient's labs triggered a protocol-specified pause on patient dosing and screening for magnitude to ensure patient safety, allow time to assess the situation and consider potential mitigation strategies. Although it was not required by protocol, we also decided to pause patient dosing and screening in MAGNITUDE-2 for patients with ATTR polyneuropathy. The patient is being closely monitored and is receiving medical intervention.

In addition to pausing dosing and screening, we've taken a number of other actions over the last 2 days. We've been consulting with clinical investigators and external experts to ensure optimal care for the patient and further assess the event itself. We've now mandated clinical sites to collect additional labs from patients in the initial weeks following dosing to detect potential liver elevation sooner. We're working with the trial's independent data safety monitoring committees as we consider other potential monitoring and risk mitigation strategies. And of course, we are engaging with global regulatory authorities and other stakeholders to finalize a plan that allows us to resume enrollment as soon as appropriate.

As of today, more than 650 patients with ATTR-CM are enrolled in MAGNITUDE and 47 patients with ATTR-PN are enrolled in MAGNITUDE-2. Of those patients, more than 450 are estimated to have been dosed with next-z.

As for our other investigational product, lonvo-z, we are not pausing our Phase III HAELO study, which is a study of a different drug for a different patient population. We announced the completion of patient enrollment in HAELO in mid-September. We'll be reporting longer-term safety and efficacy data for lonvo-z from our Phase I/II trial in early November at the 2025 American College of Allergy, Asthma and Immunology Annual Scientific Meeting.

So that's the extent of the situation as it stands today. We're working as diligently as possible to ensure patient safety and despite this recent event, we continue to believe in next-z's potential to address important unmet needs for patients with ATTR amyloidosis. In fact, we will be sharing longer-term data from our Phase I trial at AHA 2025 in early November, which includes what we believe will be a compelling update on various disease measures and on mortality.

With that, our Chief Medical Officer, Dr. David Lebwohl and I can now take some questions. Of course, as you might expect, we will be unable to answer some of your questions today given the recency and the fluidity of the situation, so we ask for some patience on this front.

Operator, would you please provide the instructions?

[Operator Instructions] Our first question today comes from Maury Raycroft from Jefferies.

Maybe just starting off, you mentioned that you are consulting with investigators from the study. Can you provide some perspective on just initial responses from investigators and whether it could be age related. I don't know if you can talk about other patients in the study who are in their 80s or anything else with potential baseline characteristics that could be contributing to this that you can comment.

Thanks, Maury. It's early days, in fact, early hours, I would emphasize here. And at this point, it's just premature to comment on any sort of predictors or patient populations at risk. Obviously, we're looking into that. And we're assembling a set of questions to pursue with our DSMB and related parties.

Our next question comes from Gena Wang from Barclays.

So maybe I wanted to ask, you dosed the patient on September 30 and October 24 have the event basically 1 month apart. I recall you also had a previous event, also Grade 4, I think, in the previous 8-K release. So maybe if you can comment on these two events, how similar in terms of the timing and the onset? And given the prior experience, have you thought about what could be the reason because we understand both lipid nanoparticle and RNA, they should be gone within a few days. So maybe if you can lay out what could be the possible reason versus the comparison of this case versus the last case? And also what is the initial thought in terms of scientific rationale behind it, why it will be a delayed response?

Yes. Thanks for your question, Gena. You're right in that it's about 24 days between the time that the patient was dosed and when we became aware of the finding. There are similarities between the cases, the one you referenced in this particular one in that timing is similar. That prior case presented with an increase in transaminases. This patient has increased transaminases as well as a total bilirubin increase.

And so I would say, while the pattern is similar, it appears that this patient has a more pronounced manifestation of the particular findings. And that's the key difference. We'll see how the patient's course goes. As we said earlier, the first patient that you referenced did very well. You say symptomatic, spontaneously resolved and required no intervention. This patient had symptoms and as we said, is being observed and has medical intervention.

As far as theories here, we can only speculate at this time. You are correct in that LNPs have a class effect where typically early following administration, and I'm talking in the first couple of days, one can see some very modest, small increases in transaminases. This, we think, is different from that. And as for the exact reason why that's occurring, we don't know that answer at this point. We're assembling hypotheses, and we'll do our best to determine what we can actually learn to risk mitigate as we go forward. But at this time, we don't completely understand what's going on.

Our next question comes from Mani Foroohar from Leerink.

This is Lili on for the team. So from what we know so far, granted, these are the early hours, but what we know so far regarding the underlying mechanism, is there any reason to think that this could potentially extend to other programs, including lonvo?

Our current view on that is that it's -- what we're seeing here in the TTR program does not apply to lonvo-z. We've presented data from our Phase I and II program, which has been presented in various forms, and we'll have an update here, as I said in my prepared remarks. I would emphasize that the lonvo-z program treats different patients at a different gene. And at this point, we think that these findings are isolated to the TTR program.

Our next question comes from Joseph Thome from TD Cowen.

Maybe on the protocol-defined pausing criteria, I guess what specifically triggered that? Because as Gena mentioned, there was the prior Grade 4 elevation in transaminase. I guess, was this the bilirubin or was it that it was symptomatic? And are the protocol-defined pausing criteria the same between the 2001 and 2002 programs?

Thanks for the question. The trigger for this particular protocol was the combination of exceeding the threshold for transaminases, coupled with exceeding the threshold for total bilirubin, and that's what triggered the pause. Stopping criteria, I believe, are the same for the 2 different protocols.

Our next question comes from Alec Stranahan from Bank of America.

This is Matthew on for Alec. Maybe just double-clicking on the previous question on read-through to the pipeline platform. Can you just maybe speak to the differences in LNP drug product and dose between the 2 studies and why you think the HAELO study is fine moving forward?

Well, first, I would emphasize that we have data on HAELO that we presented. And as we said in our remarks, we'll give an update on the patients we've already presented and add additional information on patients that have been follow-on dose either from the placebo group or the 25-milligram dose from the Phase II group. So you'll see a larger data set.

Again, I would emphasize that we do not see at this point that this is an LNP effect. The LNP characteristics when one looks across programs and across different forms of LNPs typically have findings that are isolated to the very first couple of days following dosing. What we're seeing here is something that's occurring 3 to 4 weeks after the dose. So it appears to be a delayed response to something.

Our current thinking is that, that's most likely to be tied to the specific gene target and not inherent to the LNP irrespective of the gene target. Again, the patient populations are different. What that may contribute is something that we hope to learn as time goes on.

Our next question comes from Brian Cheng from JPMorgan.

Maybe just one. Has the patient liver enzyme and bilirubin been elevated since it's a 1 month apart in the observation. Do you know how long it's been elevated in your observation?

The patient came to our attention when he had abdominal pain and contacted his primary investigator who referred him to emergency room where he was evaluated and blood was drawn. That corresponds to 24-day point that I shared in my -- shared with the group here in my prepared remarks. That is the first notice that we have of his having crossed these thresholds. And that was just, as we said, Friday afternoon. We'll collect additional information as the program proceeds, but the patients just recently come to our attention.

Our next question comes from Jay Olson from Oppenheimer.

Can you tell us if this case meet the criteria for Hy's law and the current status of this patient? Any signs that the transaminase levels are coming down? And any other -- you mentioned the age, but were there any other notable baseline characteristics for the patients like viral infection, et cetera?

We're still collecting information on the patients. And so we'll get a more complete picture as time goes on with respect to serologies and things like that. As you pointed out, the patient was in his 80s. Clinically, the patient is stable. Our last report was last night, he's playing cards with the nurse who's assigned to him. The patient has elevated transaminases and the bilirubin and they've crossed the threshold, which would meet the traditional definition of Hy's law.

Our next question comes from Terence Flynn from Morgan Stanley.

Maybe just two for me. I was wondering, first, if you could talk through what the next steps are, you believe, to get off hold and essentially start redosing and rescreening patients. And then for the HAELO study, I was just wondering, I know you've completed enrollment, but how many patients are yet to be dosed? Like how many have you dosed and how many are yet to be dosed?

Yes. Thank you. First, I want to make sure that you and the audience understands that we are not on hold. We have in the protocol a specified pause mechanism, which is what we're talking about. This is something that the company has chosen to do. This is not coming from regulatory agencies. Of course, regulatory agencies reviewed our protocol with us before we began the program. So they're aware of the rules we've imposed. But I repeat, we are not on clinical hold from any regulatory agency.

With respect to HAELO, we reported in September that we completed enrollment of the study. All of the patients randomized to the drug and placebo arms have been dosed and we're several weeks into the study.

Our next question comes from Salveen Richter from Goldman Sachs.

You talked about aggregating hypotheses here and how you do believe it's tied to the specific gene target for TTR. Could you just comment on what other hypotheses might be at this point?

Thanks, Salveen. I can only speak in terms of broad categories because that's the stage that we're currently at. We're looking to see if there is some demographic indicator. There was an earlier question about that. We have a very small data set to look at here. So it's going to be difficult to come up with a clear indication as far as we can tell at this point. But we're looking for any kind of baseline indicator that might suggest that a particular patient is at risk. One can imagine the broad category of an immunological response and that's something that we hope to learn more about as time goes on. But that is a very, very broad category with lots of potential ways to imagine that could be potentially involved.

I would remind us all that of the cases that we've discussed previously, patients had an increase in the transaminases that occurred in a very similar time frame. Those patients were asymptomatic. The event resolved very quickly. Patients returned to baseline. They were well and continuing the study essentially unaffected. So we'll see how that plays out here, but that would suggest that there's a self-limited course.

Our next question comes from William Pickering from Bernstein.

I have two, if I may. One was just across your lonvo-z trials, are you able to share the total number of patients that have been dosed with drug at this point? And if available, the total number of patient years of follow-up. And then second was just plans for engagement with the agency on this, if any?

Yes. I'm not going to be able to give you a detailed analysis of the total duration of patients on lonvo-z and how many have been treated. You will get that as an update at the upcoming allergy meeting here in November, where you'll see the full duration of follow-up from patients that were in the Phase I and Phase II trials with the complete safety profile and the efficacy information that we have. Again, all of the patients in the HAELO study have been dosed. The target patient population was 60. We've overenrolled that somewhat. And I'll remind you that patients are randomized 2:1 drug to placebo. So you can make an estimate with that.

As far as the agency goes, this is an international trial, multinational trial. We're going through the steps that you would normally imagine. We've begun that process and are laying out whatever findings we can share as we get them. Our own recommendations, as I said in my prepared comments, something about additional monitoring. And we'll be working with our DSMB to come up with a plan that we would hope to present to the agency.

Again, I would remind everybody, we are not on hold. This is a self-directed program tied to the protocol itself. And we've had RMAT designation with the agency. So we would expect that we will have rapid and active engagement, and we look forward to that. The goal is to have enrollment begin as soon as appropriate, and we want to make sure that, that's done in the best possible way.

Our next question comes from Jack Allen from Baird.

So forthcoming as it relates to the update. I guess I just wanted to ask briefly on some of the prophylactic measures you have post dosing in place right now as it relates to the existing ATTR program. What kind of steroid regimen are you giving patients afterwards -- after they receive treatment? And how might you revise that regimen moving forward? I know it's still early days, but I'd love to hear any context you have here.

Yes. Thank you for acknowledging it's early days. In terms of actions we will take, I think it's premature to discuss that. But with respect to what's currently in place, the regimen for patients is very straightforward. They receive a dose of dexamethasone the day before the treatment and then the day of infusion, which is done as an outpatient. Patients receive another dose of dexamethasone in antihistamines. And that's it. There's no subsequent steroid administration that's in the protocol or designed as necessary or appropriate based on anything we've seen thus far. That might be something that's discussed. But again, I'd say it's early days to imagine that, that's going to change until we have a more complete plan.

Our next question comes from Yanan Zhu from Wells Fargo.

I was wondering, can you talk about your criteria for on pausing the trial? And also what regulators might consider with regard to whether to put a trial on hold in -- in this realm of liver toxicity AE?

So the criteria for pausing are the ones I shared in the prepared comments. It's exceeding a threefold increase of the upper limits of normal in the transaminases coupled with greater than a twofold increase in bilirubin. We -- this patient surpassed that. There's no alternative explanation readily available to us to indicate something other than the drug. And so with that in mind, this patient meets those criteria, and we initiated the pause, as we said, both in MAGNITUDE where the event occurred and then also applied it to MAGNITUDE-2, where it's the same set of patients, although with the polyneuropathy manifestation as opposed to cardiomyopathy.

As far as regulators, I can only speculate what they might think. We have very strong relationships with the regulators. We're very forthcoming with information. We've worked with them as we put the program in place, including this protocol. Again, I'm sure that they will understand that this is a self-imposed pause so that we can take whatever actions we think may be appropriate. Those are yet to be determined. I don't know why they would need to apply clinical hold because we're effectively not screening or enrolling patients at this point in time until we have the clinical course established for the protocol going forward.

Our next question comes from Joon Lee from Truist Securities.

It's nice to hear that the patient is stable and hopefully recovers fully. Anything you can share about the underlying medical condition of the patients such as BMI, MASH, viral infection? And are you screening out patients with preexisting liver disease in the TTR program?

Operator, I think we may have lost John.

David, this is John. Can you hear me?

Yes. Go ahead, John, sorry.

Yes. So I don't know what happened with the sound. I'm sorry about that. The patient, as I said, has a high BMI, whether or not that has any relevance to this is something to be determined. As far as other pre-existing risk factors or concomitant medications, it's not obvious that any of those would be contributory to what we're seeing here. Of course, we'll collect additional information and consider whatever information we learn and see how that may apply to thinking about this case or the case that we discussed previously.

And our next question comes from Mitchell Kapoor from H.C. Wainwright.

I wanted to ask what internal sign-off needs to be met before you consider redosing? Is that a safety review completion, the patient's recovery, some type of protocol amendment are you thinking weeks or something like months for a time line? And then separately, has the FDA indicated -- I think you had maybe touched upon this, but just to confirm, has the FDA indicated whether or not a formal hold is under consideration or is not under consideration?

With respect to your last point, we are actively engaging with the agency. We do not -- have not heard that a hold is in the works. We'll see how that plays out as we give them time to consider the information that we shared with them. Again, I would emphasize that they will know that we've paused the trial, which is effectively a self-induced hold. And the first order of business is working out with them exactly what is the appropriate set of changes and to what extent before we go back. Again, we have RMAT designation, which allows a very active and efficient engagement with the agency. We look forward to talking with them as soon as we can have an extended conversation with them.

In terms of sign-off, obviously, we're going to think very carefully about this with all the expertise we have in the company. We have a set of consultants that we speak with. We have a steering committee and the DSMB. We will involve all of them. And we're not going to begin redosing until we have good alignment with regulatory agencies. I can only speculate on how long that will take, certainly some weeks. Nonetheless, we are absolutely in the belief that the drug has a very favorable benefit risk. And I look forward to sharing the data that we will have at AHA, where you'll see the reasons we're so enthusiastic about the agent.

So as the story unfolds, we'll share more information. And obviously, we have an earnings call coming up here at some point in time, so there may be some more information then.

And ladies and gentlemen, with that, we've reached the end of the allotted time for today's question-and-answer session. I'd like to turn the conference call back over to Intellia's CEO, Dr. John Leonard, for closing remarks.

So thank you, everyone. We look forward to speaking with you soon in conjunction with our Q3 results and our upcoming presentation of lonvo-z data at the upcoming ACAAI Scientific Meeting and our presentation of next-z data at AHA 2025.

That concludes our call, operator. Thank you.

And ladies and gentlemen, with that, we'll conclude today's conference. We do thank you for attending today's presentation. You may now disconnect.

Good morning, and welcome to Intellia Therapeutics Second Quarter 2025 Financial Results Conference Call. My name is Drew, and I will be your conference operator today. Following formal remarks, we will open the call up for a question-and-answer session. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. [Operator Instructions]

I will now turn the conference over to Brittany Chavez, Senior Manager of Investor Relations at Intellia. Please proceed.

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics Second Quarter 2025 Earnings Call. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter as well as topics for discussion on today's call. This release can be found on the Investors & Media section of Intellia's website at intelliatx.com. This call is being broadcast live and a replay 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 you to refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. Joining me from Intellia are John Leonard, Chief Executive Officer; David Lebwohl, Chief Medical Officer; Ed Dulac, Chief Financial Officer; and Birgit Schultz, our Chief Scientific Officer, who will join for Q&A. John will begin with recent business highlights. David will then provide updates on our clinical pipeline progress and Ed will review our financials before we open the call for questions.

With that, I will now turn the call over to John, our Chief Executive Officer.

Thanks, Brittany. Good morning, everyone, and thank you all for joining us today. 2025 is proving to be a year of excellent execution and exciting clinical updates. Thus far, we're meeting or exceeding all the objectives we set for ourselves, which sets us up well for the second half of the year. Financially, our restructuring is delivering the benefits that we expected, which support a runway through several major milestones and into the first half of 2027 when we expect to be launching Longos for HAE. Clinically, presentations of a longer-term follow-up data presented from our ongoing trials suggest our lead programs have the potential to set new standards for the treatment of HAE and for both the polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis.

Also, from an operational perspective, all 3 Phase III studies across LONVOZI and NEXI are enrolling faster than we expected. We're benefiting from strong interest from both patients and physicians. That interest, coupled with our team's excellent execution, positions us to accelerate guidance we set at the beginning of the year. We now anticipate completing enrollment earlier in our HAE and ATTR polyneuropathy programs than previously thought, and we expect that we will enroll more patients this year in our cardiomyopathy program than originally planned. Among the many favorable updates we provided across our programs today is our decision to increase enrollment to approximately 1,200 patients in magnitude our Phase III study evaluating Nex-z in ATTR cariomyopathy subject to health authority review.

Expanding the patient number in the study will provide a more robust data set particularly in the stabilizer stratum, which we know will be very important to patients, clinicians and payers. We believe Nex-z in combination with the stabilizer will provide meaningful clinical benefits beyond treating with only a stabilizer, which will be a key differentiator in the commercial setting. It's also important to note that the improvements gained from a larger study size do not impact either our previously projected enrollment or our cash runway. When we initially designed our study, we recognized that the TTR treatment landscape could change as new agents became available during their Phase III program. We also knew that we were well positioned to adapt to changes in TTR treatments because of the timing of our program.

Now with the benefit of recent clinical readouts -- we know how to best capitalize on the rapid, deep and consistent TTR reduction achieved with Nex-z to make it into a formidable and differentiated competitor in this large and growing market. Based on the strong enrollment in magnitude, we also said this morning that we are now targeting at least 650 patients cumulatively by year-end. Again, we believe this increase relative to our prior guidance for more than 550 patients is made possible by the operational excellence of our team. But importantly, it also reflects the enthusiasm from investigators and significant demand from patients to participate in the trial.

Let's turn to magnitude 2 for the treatment of poetry ATTR polyneuropathy. We've seen the same high-level engagement from patients and physicians in response to the promising data and potential of Nex-z. Enrollment continues to track ahead of our initial projections and we've refined our guidance now expecting the complete enrollment of the trial in the first half of 2026. We are also equally excited about our Phase III HALO study of Lompoc formerly known NTLA-2002. Today, we announced we have ended recruitment and expect to complete randomization during the third quarter. This milestone consistent with our market research, reflects the high unmet need in the HAE community despite existing treatment options. We believe LomvosI's maturing data a profile as a onetime therapy administered in an outpatient setting resonates with patients and physicians.

Building further on our strong momentum, we shared positive interim data throughout the quarter that continues to support the growing body of evidence for both LONvozIand Nex-z. David will expand on that in a moment. We also look forward to sharing more clinical and operational milestones from our lead programs later this year. The positive developments within our studies have been matched by the progress we have made in building our commercial and medical teams required for a successful launch.

Senior leadership positions hired within the commercial and medical affairs organizations during the first half of the year include Head of U.S. Sales and Head of Commercial Operations; as well as several additional senior leaders with responsibilities for commercial data and field operations marketing, pricing, patient services, market access, forecasting and medical communications. We've now largely completed our build-out of the commercial and medical affairs leadership teams. We're well underway to becoming a strong commercially ready company. We're confident in our plans, diligent in our execution and excited by the value-creating opportunities that lie in the not-so-distant future.

Lastly, I want to take this time to announce the future retirement of David Lebwohl, our Chief Medical Officer, that will go into effect a year from now in August. David will continue to serve as CMO until a successor is appointed and will remain on as a medical advice to work closely with Intellia and his successor during the transition period to ensure a seamless handover. As this is part of our routine succession planning, we've already begun the search for his successor. We are committed to finding a highly qualified candidate who will continue to build on a strong foundation David established. In the meantime, David will continue to lead Intellia through the important clinical milestones ahead. David's leadership has been instrumental in advancing our pipeline and positioning Intellia for future success.

I'll now hand the call over to David, who will provide a more detailed update on our clinical programs. David?

Thanks, John. I'll begin with in development for HAE. As John mentioned, we are very pleased about the enrollment in our Phase III study in HAE. Patient and investigator interest has been strong in study initiation and enrollment has exceeded our expectations. When you consider that the HALO study requires 60 patients to complete enrollment, it is notable that we screened 41 patients in April alone. This degree of demand in our study is remarkable. And has enabled us to stop recruiting during the second quarter a mere 4 months after dosing the first patient. A majority of these patients are coming off of leading therapies, including lanadelumab, which we believe supports the underappreciated degree of unmet need.

The rapid enrollment in the HALO study echoes what we see clearly in our market research. Patients and physicians value a therapy like lomboZ. We find they are looking for a therapy that has the potential to give freedom from attacks and freedom from ongoing therapies. The percentage reduction in attacks is 1 measure of therapy for HAE, but our goal is to go beyond that standard. We aspire to reset expectations and the standard of care for patients living with this debilitating disease to achieve 0 attacks in most of the patients without the need for any HAE medication. We look forward to sharing additional data from our ongoing Phase I/II trial later this year.

In June, we presented positive 3-year follow-up data from our ongoing Phase I trial of limbo at the European Academy of Allergy and Clinical Immunology Congress, after just a single dose, patients remain attack-free and treatment-free for a median of 23 months. This underscores the unique value proposition of Longos, the potential to offer freedom from attacks and freedom from chronic treatment. Londax was well tolerated and showed a safety profile consistent with earlier data presented at ACI in 2024. The most frequent adverse events during the study period were infusion-related reactions that were mostly grade 1 and resolved with all patients receiving the full dose.

With up to 3 years of follow-up no treatment-related adverse events were observed after the first 28 days and no serious adverse events reported in any patient. Later this year, we plan to present longer-term data from patients in the Phase II portion of the study, including those who initially received a 25-milligram dose or placebo were subsequently given the 50-milligram dose of Lombo selected for the Phase III study. This Phase II update will more than double the total number of patients who have received a 50-milligram dose to more than 30 patients. Intellia is committed to transforming the treatment landscape for HAE. We believe that the value proposition for LonboZ is compelling and centered on 3 pillars: First, freedom for people living with HAE, free them from both HAE attacks and the need for chronic prophylaxis.

Second, relief for physicians the administrative complexity of managing insurance coverage for chronic HAE therapy is vastly underappreciated. And third, meaningful pharmacoeconomic advantages for payers. Lon is well positioned to become the first ever onetime treatment for people living with HAE and the first approved therapy to take advantage of in vivo CRISPR gene editing.

We'll now turn to Nex-z in development for the treatment of ATTR amyloidosis. I'll begin with ATTR cardiomyopathy. As John mentioned, due to strong demand and magnitude we're now targeting at least 650 patients cumulatively by year-end, and we plan to expand the study from 765 patients to 1,200 patients, subject to health authority review. This decision is driven by our desire to increase the likelihood of achieving statistically significant outcomes that are clinically relevant for patients, clinicians and payers. This is made possible by the strong demand to participate in our study. Increasing the sample size to 1,200 patients offers a critical advantage, enhanced statistical power within the stabilizer stratum. This will strengthen our ability to generate robust data for Nex-z alone as well as Nex-z in combination with a stabilizer. We anticipate both approaches will be compelling based on promising Phase I results observed to date.

The expansion and sample size will also accelerate the accrual of clinical events. As John mentioned, our guidance remains unchanged. We will complete magnitude enrollment by early 2027.

In May, we presented wild-type and hereditary ATTR cardiomyopathy data from our ongoing Phase I study at the World Congress on acute heart failure. Participants who receive Nex-z have reduced TTR production and improved outcomes for both wild-type and variant ATTR cardiomyopathy patients. Absolute TTR levels dropped from 225 to 17 micrograms per ML in the wild-type group and 132 to 17 micrograms per ml in the inherited disease group. Functional capacity and clinical biomarkers were favorably impacted in both patient groups and evidence of stability or improvement in disease progression markers was observed across both populations at similar rates. The most commonly reported treatment-related adverse events were infusion-related reactions, which were mild or moderate and did not result in any discontinuations.

Later this year, we will present longer-term data from patients with ATTR cardiomyopathy in the Phase I study, which will include updated measures of clinical efficacy and safety extending our promising data presented last year at AHA.

Turning to ATTR polyneuropathy. We made great progress in the first few months with our global Phase III magnitude 2 study after randomizing the first patient in the first quarter. This pivotal study is a placebo-controlled study with planned enrollment of approximately 50 patients. Patients are randomized to either a single 55-milligram infusion of Nex-z or placebo. We will measure MLIS+7 at 18 months and serum TTR levels as key endpoints in the study. Enrollment is expected to be completed in the first half of 2026 to enable our second BLA filing in or before 2028. We also presented positive 2-year follow-up data from the ongoing Phase I study of Nex-z in hereditary ATTR polyneuropathy at the Peripheral Nerve Society Annual Meeting in May. This data showed ongoing persistent declines in TTR at 24 months following a onetime dose of Nex-z. Among the patients in whom MNIS+7 assessment was completed at 24 months, -- as of the data cutoff, 13 of the 18 had an improvement from baseline greater than the 4-point threshold, which is considered clinically meaningful.

Most of the patients in the cohort who had progressed on patisiran improved and only a single patient among the 18 had a deterioration of greater than 4 points. Nex-z has been generally well tolerated across all patients and at all dose levels tested. Treatment-related adverse events were consistent with those described for the cardiomyopathy population. This supports our growing body of evidence as single dose of Nex-z may lead to disease stability and clinically meaningful improvements in neuropathic incurment measures. They tuned for a symposium in September where we plan to present extended interim Phase I polyneuropathy data at the international ATTR Amyloidosis Meeting for patients and doctors.

We are poised to complete enrollment across all of our studies by early 2027 and achieved several important clinical and regulatory milestones before the end of 2026.

I'll now hand over the call to Ed, our Chief Financial Officer, who'll provide an update on our financial results as of second quarter 2025.

Thank you, David. Good morning, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our clinical pipeline and build important capabilities required for future success. Our cash, cash equivalents and marketable securities were approximately $630.5 million as of June 30, 2025 compared to $861.7 million, as of December 31, 2024. Our collaboration revenue was $14.2 million during the second quarter of 2025 compared to $6.9 million during the prior year quarter. The $7.3 million increase was mainly driven by cost reimbursements related to our collaboration with Regeneron Pharmaceuticals.

R&D expenses were $97 million during the second quarter of 2025 compared to $114.2 million during the prior year quarter. The $17.2 million decrease was primarily driven by employee-related expenses, stock-based compensation, research materials and contracted services, offset by an increase in the advancement of our lead programs. Stock-based compensation expense included in R&D expenses was $14.1 million for the second quarter of 2025. G&A expenses were $27.2 million during the second quarter of 2025 compared to $31.8 million during the prior year quarter. The $4.6 million decrease was primarily related to lower stock-based compensation, offset in part by increased expenses related to the ongoing build-out of our commercial infrastructure.

Stock-based compensation expense included in G&A expenses was $8 million for the second quarter of 2025. We continue to expect a year-over-year decline in GAAP operating expenses and are now guiding to an approximately 10% decline this year. and that our cash balance is sufficient to fund our operating plans into the first half of 2027.

Thanks, Ed. Our continued progress is fueled by the core values of the company. One team, exploring possibilities, delivering results and disrupting the status quo. We're committed to changing the treatment paradigm for patients suffering from HAE and ATTR amyloidosis. We look forward to meeting and exceeding our goals from these programs before the end of the year.

With that, we'll now open the call for your questions. To do our best to address as many questions as possible, we will only be able to take 1 question per caller. Operator, you may now open the call for Q&A.

[Operator Instructions] The first question comes from Mani Foruhar with Leerink.

This is ironSongo on for Mani. So I wanted to ask, so now that you've increased the target number for the PDCM study. Do you have a target proportion of patients you would like to be on stabilizers to be able to see the work to be powered to see the benefit in combination?

So thanks for the question. As we started the study, we estimated that we would have 50% to 60% of the patients on stabilizers. It's become apparent over the course of the study that these stabilizers has become more and more the standard of care. We estimate that we may have 70-ish percent of patients who are on stabilizers. That's not a target number that we set. This is a study that looks at the addition of Nex-z on top of standard of care. And that's essentially what's the rate of use out there around the world that we're seeing.

So as we made clear with the adaptation of the study, we want to have a highly statistically significant finding, not only for the overall group in the study, but also for the combination of Nex-z with stabilizers, which we think is an important clinical differentiator in the market as we see it today and expect it to evolve.

The next question comes from Gena Wang with Barclays.

This is Han from Barclays on behalf of Gena. I want to follow up with this. So could you walk us through how cash runway won't have a major change after this trial expansion?

So we'll turn to Ed. But I would just start by saying as I hope has become apparent over the years. We're very thoughtful about how we peer into the future and take a very conservative view to the guidance we give and to our financial planning. But maybe, Ed, you can give a little bit more detail to that.

Yes. Thanks, John. Thanks for the question. Generally, we do take a conservative approach to our long-range planning and for significant investments like clinical studies so that we can run the business with confidence. For our late-stage clinical programs, which may last years from planning to execution and completion. We always assess different scenarios, different potential time lines different potential investment needs at a pretty standard practice for us here at Intellia. For magnitude specifically, we consider the possibility of increasing enrollment within our scenario planning. Based on the emerging data from our peers in the TTR space, our own maturing Phase I data from our TTR program.

And then we have increasingly more market research that we are getting from physicians and payers to inform our thinking here. And so we've only recently made the decision to increase the 1,200 patients, which relative to our 3-year plan represented a modest uptick, immaterial uptick in costs that we can absorb without impacting our cash runway or our net cash burn guidance that we provided through 2025 and 2026.

The next question comes from Maury Raycroft with Jefferies.

This is Farzin on for Maury. -- for Nex-z, while you're accruing longer-term Phase I/II data, what is the latest regarding your assumptions on Phase III events accrual rate? And if that also prompted you to expand the study to 1,200 patients.

Thanks for the question. We're not talking about specific event rates. But obviously, we look at information that's become available from a variety of sources -- as we said in our comments to open the call, we've seen information has come from competitors in the space, which we think provides useful information in terms of the current standard of care and how patients are treated and the weight of their disease progression. We supplement that with databases that comes from other sources that, again, we think, gives us contemporaneous information in terms of how patients with the disease progress.

But also of significant importance is the information we're collecting from our own Phase I patients, which we've reported on previously, and we will extend the reports later this year. And what we've seen in work that was published in New England Journal and presented elsewhere that the very deep rapid and sustained levels of TTR reduction translate into what we long expected to be a lower EBIT rate. And so as we continue to monitor those patients, that also figures into our calculation. So when you step back and look at the changes in toto, -- we expect that we will have an even more robust outcome than we expected before, not only for the overall, but for patients on stabilizer. We'll be able to have enrollment fall within the original guidance, which we're very excited about. -- and be in a position to march towards what we think will be prospective launches by 2030.

So all in all, we think we're increasing the overall likelihood of success for the program in a way that fits within the guidance that we've long put out.

The next question comes from Luca Issi with RBC Capital.

Great. Maybe, David, can you just talk about enrollment pace between your trial for TTR cardiomyopathy versus the leaders? It looks that AstraZeneca started their pilot trial around the same time as your trial, and they have now enrolled 1,200 patients versus you're obviously guiding for 650 patients by the end of the year. Does that reflect the higher appetite for patients and physicians to choose the leader versus gene adding? Or are there any other factors like differences in inclusion exclusion criteria that we should keep in mind here?

And then maybe bigger picture, has the availability of 3 commercial action in TTR cardiomyopathy slowed down the pace of enrollment in any capacity?

David, do you want to take that?

Yes. What we've seen in the pace of our trial, we think, is pretty astounding to get to more than 650 patients at the end of this year and 1,200 patients by the first quarter of 20 is really unprecedented and very exciting. The -- there are differences from the depleter study. They took basically all patients, including some very sick patients, patients on any type of therapy, including TTR reducers. So it is a very different trial. When you look at our trial in a period in which vutrisiran is coming out, acoramadis is coming out -- our enrollment has actually increased during the period that the new drugs are available. What we see is a strong interest from both patients and physicians to get on to our trials, and we feel very good about that.

The next question comes from Joon Lee with Truist Securities.

This is Ned on for June. Given almost binary response to lonvo-z, how would you maintain the study blindness -- and for the patients that still might show some breakthrough attack, wouldn't have or food those retails in be able to ensure complete responders?

David, do you want to speak to how we protect the blind. I mean we're taking standard procedures, and there's nothing inherent about the design that should lead to unblinding. But if you want to expand on that, be my guest.

Yes. Our trial is very similar in design to other pivotal trials in this disease. Patients will get an infusion that is -- it's actually the -- it's unknown to them what that infusion is. The physician doesn't know what the infusion is. So it really is a very well blinded study. Of course, the patients may experience different things whether they have a response with the drug they're receiving or not. But that is not considered unblinding because I really don't know if they've received the drug or not. As you know, there is also a strong placebo effect that can take place in every trial.

So -- we are confident that the trial has a great deal with integrity in terms of finding, and it's really in good shape moving forward.

I would just add to that, that the -- 1 of the very valuable aspects of this particular trial is that we're actually measuring clinically Vince -- there's not much subjectivity involved. Patients either have an attack or believe they're having attack and act on that with on-demand therapy. So we measure discrete outcomes -- and that is why these studies are so effective at finding the effects of the drugs. It's true that based on our earlier data, patients respond very well who get the drug. And we're looking forward to hopefully replicating those results in our Phase III study as that becomes available.

The next question comes from Alec Stranahan with Bank of America.

This is Matthew on for Alex. Maybe double-clicking on a previous one. I guess, can you speak to whether changes to your enrollment expectations in magnitude or stabilizer percentage have changed your thoughts around the likelihood or timing of a potential interim readout?

I would say that as we've made the adjustments, we are increasing the overall power of the study not only for the primary outcome, which is the addition of drug on top of standard of care, but presumably also for the TAP subgroup, which was a lot of the thinking that went into this -- our expectation is that at some point, we will do an interim analysis, and we would expect that these changes would favorably affect the ability to find an effect at the point that we do that.

The next question comes from Andy Chen with Wolfe Research.

This is Brendan on for Andy. In regard to the expansion of magnitude, you mentioned increasing the likelihood of seeing stat SIG. What were the specific data that you're trying to generate for you to show compelling information to payers.

And physicians to cars on -- without getting into specific statistics, -- maybe David, if you could just talk about the importance of showing profound clinical benefit in ways that are unambiguous, feel free to enlarge on that.

Yes. So what we're very interested in as we -- as the trial went forward is that tafamidis is becoming a standard of care around the world. We're seeing increasing percentage of patients who are receiving tafamidis in our trial. And of course, we hear it in the commercial world as well. This seems like it will be a baseline going forward. And we thought it was very important to show a major benefit over that, a significant benefit and a clinically meaningful benefit. This has not been shown with any other drug, the ability to add to stabilizers.

But looking at our Phase I data, it looks that we do have that possibility. We have very strong data related. As John mentioned, we get deeper and more rapid reductions than other drugs. And that seems to translate based on our AHA data we showed last year into better clinical results. So we're very excited about what we're seeing, and we do think that our goal will be to show a benefit over tafamidis, and that's why we wanted to enlarge the trial and actually get to the endpoints more quickly because we have more patients. Of course, events will accumulate more rapidly by having more patients.

I think it's important to add that all in at the end of the study, we want the data to be absolutely unambiguous across the spectrum of treatment of the disease, whether it's Nexi added to standard of care, whether it's Nex-z alone. -- or Nex-z in any way that may be used. And this study has increased with the number of patients gives us the power to demonstrate those outcomes, which will be very, very important to differentiate the product and have it be successful in the marketplace.

The next question comes from Troy Langford with TD. Cowen.

All the progress this quarter. With respect to the Phase 1 ATTR-CM update later this year, can you just give us a little bit more color around what level of progression you all would normally expect to see on the various functional measures in patients just given the patient population enrolled in that study and the amount of follow-up.

Are you asking about within within the Phase I study, I guess. So David, do you want to speak about the clinical results that we reported thus far and what would otherwise have been expected.

Yes. Let's talk about that. As mentioned, the first thing is to look at the effect on TTR. So the levels come down within a month, and they come down to levels of about 90% reduction in all patients, very consistently. No patient is left behind with that. With that, what we showed at AHA last year was that there is -- when you have the measures of progression such as proBNP, such as 6-minute walk, unlike placebo patients and unlike patients from other agents, they do not show the worsening that those -- in those trends that we've seen historically.

And there's now a lot of data available for multiple Phase III trials. What we do see is stabilization and in some cases, improvement in the patients in those measures. So this is unprecedented really with any drug. Based on that, we've also looked, as John mentioned, at event rates and the event rates in this group of patients who are actually at high risk of worsening because they're 50% Class III patients, a high percentage of variant patients. Despite all that, the event rate is very low relative to what we see historically in other settings. So all that comes together to say that in this data update, we look forward to seeing it. We have more extended data in this group of patients. And as we said, we're excited about what we're seeing in those Phase I patients.

The next question comes from Costa Bill is with BMO Capital Markets..

This is Yuri on for Costa. -- have 1 on S ATTR cardiomyopathy. And so what are your latest thoughts around potential drivers grade 4 LFT changes following NCtreatment given these signals occurred roughly 3 to 4 weeks post dosing.

Yes. You're referring to a patient that we reported on back in May, where a patient had a transaminase elevation. I would point out that with respect to drug-induced delivery scores this was a grade 1, which is mild. The patient was asymptomatic or no therapy has returned to baseline, continues in the study and is otherwise doing well. We're unaware of other instances of that in the study. And at this point, our belief is that this is unlikely to be directly related to LNPs. And as we consider other alternative explanations at this point, -- that's under investigation, and we're not in a position to attribute any particular mechanism to the funding.

The next question comes from Brian Cheng with JPMorgan.

Questions this morning. Just maybe I want to confirm 1 thing. With the expansion in magnitude, -- is the study now powered to show statistical significant difference in the subset or on stabilizer background?

The answer is yes.

The next question comes from Mitchell Kapoor with H.C. Wainright.

Can you speak to the qualities of patients who are coming on to your gene editing studies who are comfortable with a permanent treatment? What are you learning about these patients in particular that could help with commercial launch positioning for gene editing options in both HAE and ATTR. And based on these learnings, what proportion of these patients from the total addressable market standpoint might be open to a permanent option versus the proportion who would likely not opt for a permit option. What are your findings on that?

There's several levels to the question you're posing the quality of our patients, if I understand the question is high. These are patients who meet the inclusion/exclusion criteria that are set for these studies, which is representative of all studies typically done in these different conditions. Patients, if I understand your question, do not have their back against the wall or anything like that, they consider the treatment options that are available to them otherwise. And we encourage them to discuss that with our physician and you see the results.

I mean the clinical trials are all enrolling robustly. And as we've said several times today, all are ahead of what we thought were already very aggressive enrollment criteria and plans. So we've been very, very enthusiastic about that. As David said in his comments earlier, it's interesting to look at how patients act when in the case of lonvo-z receiving standard of care that is widely used in, for example, the United States, nab -- many of the patients have chosen to come off that therapy and enter into our study. What that means is they wash out of the drug, they expose themselves to the opportunity of getting drug or placebo and subject themselves to what happens during that observation period that suggests to us that they're strongly motivated to find the outcomes possible with what we think may be a permanent improvement in their disease.

Same thing is true with cardiomyopathy. These are patients who are not denied any of the therapy that is otherwise available to them up to this point and patients have come into the study in a very robust fashion, independent of where they're located. The United States or elsewhere around the world. So we've been very enthusiastic about the response to the patients to the study and to how they think about options for care. So I think the notion of a permanent fix, if you will, for their disease is something that we find patients and physicians embracing when they consider the alternatives for the particular diseases that we're studying.

The next question comes from Jay Olson with Oppenheimer.

This is Chai for Jay. Congrats on the quarter. Just back to the MERIT study, I'm wondering why the 1,200 number is the right one? And is this the final number? Were you seeing you may further adjust target enrollment down the road, if any assumptions may change over time?

We're not planning on adjusting the numbers going forward. But David, maybe you can give a little more information just in terms of what 1,200 does for the study and why it's -- what we think is an optimal approach.

Yes. When we looked at here are several things. One, game, as I talked about, are the Phase I results -- we saw there based on the outstanding results we reported that there's an opportunity to show a benefit in the stabilizer population. This is not an opportunity that we think the drugs have had seen that there have been -- there has not been a significant difference, for example, in some of the leading drugs going forward. But we see in our data that possibility. Based on that, we thought -- we felt it was very important to show that statistically significant as well as clinically meaningful benefit in that subpopulation.

With a very brisk enrollment to the trial, we also saw that we could enroll 1,200 patients in the time frame in which we've guided to complete enrollment. And that number really looked optimal in terms of the timing of both the final analysis and an interim analysis that will be taking place. But this is -- gets us there to analysis faster because you have more patients, more even securing, but also it's not so many patients that you're you're waiting a long time for the enrollment period. So that's where we got to. And we think this will be -- and as you've also heard it maintains our runway. So putting that all together, this is a number we chose to actually see this size is similar to other studies that are out there.

So it's not that unusual. The difference is that we do believe that based on our efficacy, we can show benefit specific benefit in the TAS group. It doesn't seem like that would be possible with a lesser effect on TTR.

The next question comes from Yanan Zhu with Wells Fargo Securities.

I was wondering in your statistical planning you allow any -- did you consider any difference between the first-generation stabilizer and the newly approved stabilizer and perhaps also any updated thinking on the percentage of patients on silencers in the study. And what do you expect to learn from those patients?

Yes. I can start us off, and David can deal with the silencers. I mean as we look at the clinical data for the second-generation stabilizer. We don't really see much of a difference between that and tafamidis, and that's how we're approaching that with respect to the study. David, if you want to talk about silencers or any other comments on stabilizers be my guest.

Yes. We did anticipate that sciences would become available during the period of the trial. -- based on the Phase III trial and based on what Anylam is saying, the main usage of that would be upfront or a switch from a stabilizer to TTR reducing drug? We do not allow the patients who come on to the drug as a first-line agent on to silencer as a first-line agent. And the physicians around the world are obviously very aware of that, that the patient we need to choose between 1 or the other.

What we're hearing from physicians are excited about the possibility of getting both the stabilizer and a TTR reducing agent in combination as they can on our trial so that -- as you see, we still have very good enrollment of patients joining the trial despite the availability of silencers at this point. We also anticipated that some patients might switch from tafamidis to vutrisiran during the trial that is figured out in our statistical analysis, and we find the predictions that we're able to get a positive result despite that despite these crossovers, seems quite clear based on our analysis.

The difference between Trub and tafamidis in your statistical consideration?

No, they're considered to be the same based on the data that we have available.

The next question comes from Jonathan Miller with Evercore ISI.

Congrats -- since you've had so many on magnitude, maybe I wanted to switch over to the Atomic commercial commercial side of things. I know you've been building a commercial team and market access, et cetera. I'd love to get updated feedback from those folks on how you think payers are going to react to gene editing, obviously, especially in the HAE setting, -- is there a "cure rate" that the bar for payers at particular price points? I just want to get a sense of how you're viewing commercial setup.

Thanks for that question. As we've said, elsewhere in previous calls, we expect to be working within precedented numbers with respect to prices. So some individuals have very imaginative approaches to what they think the pricing will be. I don't think that's going to apply -- we take a very thoughtful approach to the pharmacoeconomics, and we're trying to come up with products that will be win-win for the clinical setting and for the payer side as well. We've been interacting with payers as our commercial team has come into being here and by and large have corroborated our early thinking.

It really comes down to the nature of the outcome, which has been commented on here in several instances, whether it's lonvo-z the treatment effects that we're seeing with TTR, both in PN in cardiomyopathy, those effects with the studies that we're designing should make the clinical benefit very apparent to the payers. Onetime therapies are easily confused. There are precedents out there that don't directly apply to us. And the ease of use of the outpatient infusion approach that we have coupled with the excellent outcomes, we think are going to offer a real positive opportunity for the payers. And as that story becomes clear, we'll share more results perhaps even later this year.

Next question comes from Salveen Richter with Goldman Sachs.

This is Mark on for Salveen. Congrats on -- so our question is on the competitive landscape for Nex-z -- so I'm sure you saw that competing RNAi therapy post really strong results this quarter. And I wanted to get your thoughts here on how this impacts the overall market, patient physician awareness, those payer dynamics and your views on Nex-z's commercial positioning in the space?

Yes. As we said at the -- of the call, we expect to have a product that will be a very formidable competitor for buta or any of the other agents that are in the space. And we're taking actions in the study to give us a label that we expect will position us very, very favorably. But overall, with respect to the performance of these other drugs, it confirms our long-held belief which has been corroborated by market research, talking to physicians and leaders in the space that this is a large, growing significantly underdiagnosed marketplace that is frequently misunderstood.

While it's true that patients with peripheral neuropathy typically have a heritable form of the disease, -- in the case of cardiomyopathy, the vast majority of these patients on the order of 90% or so have wild-type disease. That means these patients have the result of their TTR cardiomyopathy caused by aging, not by an underlying genic disease. There is a large supply of these patients that we will compete for very aggressively when the product becomes available, and we're excited about our prospects.

The next question comes from David Lebowitz with Citi.

Curious, given that there's another therapy that does Kallikrein knock down potentially entering the market soon. Obviously, a different overall modality. But is there anything that you would be looking for in their launch to help inform how you think about a potential launch for yourselves with lonvo-z?

Well, we pay close attention to how all of the other products and new entrants are doing -- we believe that the profile that we're bringing forward is unique in the space, while there are ways to knock down calacrine we're aware of only a single agent Lobos which knocks it down on what we believe will be a permanent basis that yields outcomes that are truly unique. -- excellent clinical performance that is absence of attacks for the vast majority of patients and no further need to take therapy.

No other drug accomplishes that. And if you ask patients what they're looking for primarily is read them from their disease to the greatest extent possible so that they can change jobs, they can avoid stressors, -- they don't have to carry agents with them to the greatest extent possible, lonvo-z uniquely offers that. from a physician point of view, taking care of these patients is very challenging because of the ongoing and recurring insurance reauthorizations -- and for those physicians, we believe lonvo-z will offer a very significant advantage in the care of their patients by making it easier. So across the board, we expect to be, again, a very formidable competitor.

This concludes our question-and-answer session and Intellia Therapeutics Second Quarter 2025 Financial Results Conference Call. Thank you for attending today's conference. You may now disconnect your line.