Intellia Therapeutics, Inc.

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 and 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 Intelia 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 NEXE program in ATTR amyloidosis. After that, we'll provide updates on the significant progress we've made with LOMVOSI, which is being developed as a potential one-time 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 one-time treatment that is administered in an outpatient setting. We believe our two lead candidates, Lombosi and Nexi, fit this profile. Now, with up to three years of patient follow-up, we have yet to see any waning of effect in serum calocrine 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 and 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 LOMVOSI and NEXI 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 two to four 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 three 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 Intelia. With Lombosi, we rapidly enrolled Halo, our phase three clinical trial in HAE, and we did this well ahead of schedule. Until the clinical hold in October, we achieved similar enrollment success with Nexi. At the start of the year, we were expecting to have enrolled about 550 patients with ATTR amyloidosis with cardiomyopathy in our magnitude phase three clinical trial by year end. and we had not yet begun enrollment in magnitude two, our phase three trial for patients with polyneuropathy. By October, just 10 months later, we'd enrolled more than 650 patients in magnitude, and we're already approaching full enrollment in magnitude two. 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 two. 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 patient's 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 MASH 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 were 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 one data that's been presented for Nexi, including the encouraging post hoc mortality data derived from a contemporaneous and well-matched cohort of nearly 1800 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 LOMVOSI and HAE. We completed enrollment in the HALO Phase III clinical trial with 80 patients in September, just nine 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 LOMVOSI among those with HAE and the treating physicians. This interest is also reflected in market research we recently conducted and shared at J.P. Morgan 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 one and two 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 two-thirds said that they would be extremely or very likely to take it. The interest also carried over to prescribing physicians. 151 U.S. healthcare 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 Lombosi 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 exist despite today's available HEE 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 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 one to pooled analysis, showing that 76% of patients who were at least a year beyond the 50 milligram dose of Lombosi 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 HALO trial, we believe the LOMVOSI arm will be highly competitive with those numbers, with the added and unique benefit that it is a one-time therapy. And as was shown in the pooled analysis that was presented to ACAAI, LOMVOSI 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 Lambo 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 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 HAA space are well aware that LTPs carry ultra-orphan price tags. Given the average US 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 multi-millions of dollars. Given this backdrop, we believe a one-time treatment like LomboZ 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 Lambo Z could fundamentally change the future capital needs of the company. With about 7,000 patients receiving treatment for HAE in the US, Lambo Z's 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 two this year and the launch of Lambo 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 Sparing Vision, 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 Lambo Z. Stock-based compensation expense included with the 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're ready to begin our question and answer session. Operator, would you please open the line for questions?

We will now begin the question and answer session. To ask a question, you may press star then one on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Please limit yourself to one question And if you have additional questions, you may rejoin the queue. At this time, we will pause momentarily to assemble our roster. The first question comes from Mari Raycroft with Jefferies. Please go ahead.

Hi, good morning. Congrats on the progress and thanks for taking my question. I'm going to focus on HAE. A lot of questions on how the study could read out. The Phase 1-2 data was generated primarily ex-U.S., whereas the Phase 3 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?

Good morning, 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 the Phase III trial.

Got it. Okay. That's helpful. Thanks for taking my question.

The next question comes from Mani Paruhar and Lirink. Please go ahead.

Hi, good morning. This is Lily Nisongo on For Money. Maybe just two questions from us. So one on HEE, 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 G-therapy, meaning the ones that are the youngest or the one 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 should we be thinking about timing and has your understanding of the underlying event that led to the patient death evolved? Thank you.

Thanks, Lydia. 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 next year, 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 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 a cardiomyopathy study, it's a bigger study. There's a lot more data. 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's not lifted until the hold's not lifted. I want to make that point. But I think that, you know, the progress is substantial. That's what 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 four 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.

Yeah, 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 been very simple to administer profile and long-term durable effects. 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. We're already playing from 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. We'll stay tuned for more information, particularly after the top line data, but overall, we feel really good about the prospects we have in each AE.

Very helpful. Thank you.

The next question comes from Alec Strenahan in Bank of America. Please go ahead.

Hey, guys. Good morning, and thanks for taking our question. 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 nine-month endpoint on NIS for the new professor and study. Thank you.

I am not going to be in a position to comment on other people's studies. I would, you know, contrast. the work that we're doing just based on our own extended follow-up from our Phase I patients. 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's a cohort of patients in that group that had failed paticerin, 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 met the stopping criteria 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, the endpoint is set for 18 months.

The next question comes from Joseph Thome and P.D. Cowan. Please go ahead.

Hi there. Good morning. Congrats on the progress, and thank you for taking my question. Can you comment a little bit on your CMC readiness for the Lambo Z potential approval and launch, and if there were any manufacturing changes between the Phase 2 and the Phase 3? And maybe a little relatedly, have you aligned with ex-US regulators that this package would also be sufficient for approval outside the US? Thank you.

Thanks for the question. Let me make a comment overall with respect to BLA preparation and readiness for the LOMBO-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's 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 and have completed the work necessary. I would point out that in our phase three trial for HALO, we're actually using the material that will be the same sort of commercial material. 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've said we'll share those top line data here this year, and the team is ready to write that up and include it into the submission that will be going in the second half of this year.

How did that, Joe? I mean, we have a network for Lungo 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. We are already operating at a very high level and very well for commercial launch.

The next question comes from Luca Isi with RBC Capital Markets. Please go ahead.

Oh, great. Hi, team. This is Shelby on for Luca, and thanks for taking the question. 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. Much appreciated. Thanks.

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 PTR programs as distinct. In fact, largely the PEN 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 and Lombosi.

Yeah, I'll say generally the discussions that we've been engaged with with payers so far have been very encouraging. Payers appear to recognize the unmet need with the current therapies that are available in HAE. high-priced products, as we talked about in our prepared remarks, and they see the value of a one-time therapy like we're presenting with them in Lambo Z. And so we haven't talked price specifically, but we have had really good positive feedback. I mean, 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 a tax-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 Lambo Z. The next question comes from Jonathan Miller with Evercore ISI.

Please go ahead. Hi, guys. Thanks so much for taking my question. 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, you know, that might reduce enzyme spikes. That makes sense. But does that not – 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 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 LFPs, et cetera. That's why we've taken the approach in 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 risings have occurred within this window of three to five weeks typically, and we do not see anything that resembles that subsequent. 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 I've 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 there'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 Wolf Research. Please go ahead.

Hi, this is Emma on for Andy. Thanks for taking our question. Can you elaborate a bit more on why the FDA was comfortable lifting the hold in PN but not CM, just given they're the same product, so we would think safety would be the same? And are there specific factors that differentiate the FDA's view across the two indications? Thank you.

Well, 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. The patient populations have different characteristics. The PN patient population tends to be younger, sometimes several decades younger than those with cardiomyopathy. The typical age of 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. 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. As I said earlier, you know, 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. Please go ahead.

Hi, this is Mark on for solving. Thanks so much for taking our question and 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 two 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 two other instances of liver enzyme elevations, or were there other patients who saw such elevations? Thanks.

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 two 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. Please go ahead.

Hi. Thanks for taking our questions. I think maybe our question is a little similar to the prior one, but maybe asked differently. Do you think this Grade 5 AE in a 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 two proposals would have changed the course or prevented this grade five AE case? And then separately, I was wondering, Argo Biopharma issued a press release for their Quad AI presentation last night. Have you had, I'm wondering your thoughts about that data and with that, you know, introduce any new considerations in a competitive landscape for normalcy. Thank you.

Well, 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 PEN 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 interrogated patients more carefully in terms of other medical issues that they have and somebody with also 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 Chang with JP Morgan. Please go ahead.

Hi, guys. Thanks for taking our question this morning. 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. Thank you.

I would start by saying that we already introduced some additional blood draws into magnitude two when we put the clinical trial on hold. It's important to remember, and I think this sometimes gets lost, that these trials are 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. Things are moving, and I just don't want that lost. And, you know, 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, you know, when we finalize 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 three, four, and five. So we have a really good bin sampling through the time when patients are most at risk.

The next question comes from Sylvain Turcan with Citizens. Please go ahead.

Hey, good morning. Congrats, McCord, and thanks for taking my question. I just want to circle back to the prior question on maybe Argos data and ADARx. You know, 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, you know, potentially six or a dose every six months silencing RNA technologies that may be coming to the market? And do doctors really appreciate the difference here?

Thank you. 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 the burden of care is not just getting an injection, whether it's every two weeks, every four weeks, every six 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 risk 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, you know, attack rates are important, and attack-free rates are, you know, 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'll lose their insurance, is something that gets lost in all of these data, but is top of mind for patients when you go and ask them.

Yeah, 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 HE 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 for LTP 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 one or phase two, that depending on how patients have come on to the study, are they on LTP 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 1-2 study. That's the benefit of patients knowing they're on therapy and you see very different outcomes, very high attack 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 Lambo Z will look like in the markets.

The next question comes from Miles Minter with William Blair. Please go ahead.

Hi, this is Jake on for Miles. Thanks for taking our question. Is it your current stance that 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 this liver enzyme elevations being immune mediated sort of influence your analysis of that question? Thank you.

Thanks for the question. It's not something that I'm going to be able to speculate on at this point. You know, 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 added 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 shreds 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 two, 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 magnitude sorts out. the use of steroids, which is time-tested, 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. 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've reported elsewhere, whether you look at our phase one work or phase two work or the phase three work across the HALO study, we just don't see this phenomenon. There's been no grade threes or grade fours 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. Please go ahead.

Hi. Thanks for taking the question. 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. Thank you so much.

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.

Yeah, thanks, John. Thanks, Terrence. So from a cost perspective, and we're not giving long-term cost guidance, but if you look at where the business is, and 2025 is 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 in a commercialization phase. 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 or 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 Lambo 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 Lambo Z. The next question comes from Mitchell Kapoor.

with H.C. Wainwright. Please go ahead.

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

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 receiving a letter from the FDA that says you're awful. 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. Please go ahead.

Great. Thanks so much for doing the questions and congrats on the progress over the quarter. I wanted to ask on the magnitude two 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 of 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, by that I mean the shorter timeframe to get off clinical hold. In the case of PN, it was three 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 you know, 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'll look forward to seeing many of you at the upcoming TD Cowan and Lee Rankin Barclays events. that are taking place in Boston and Miami.

That concludes the call.