Intellia (NTLA) Q4 2025 Earnings Call Transcript

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DATE

Thursday, Feb. 26, 2026 at 8 a.m. ET

CALL PARTICIPANTS

• President and Chief Executive Officer — John Leonard
• Chief Financial Officer — Ed Dulac
• Head of Investor Relations — Jason Fredette

TAKEAWAYS

• Cash Position -- $605.1 million in cash, cash equivalents, and marketable securities at year-end, down from $861.7 million the previous year, which management expects will fund operations into the second half of 2027 and past key milestones.
• Collaboration Revenue -- $23 million in the quarter, up from $12.9 million in the same period last year, mainly due to SparingVision agreement termination and higher Regeneron cost reimbursement.
• R&D Expense -- $88.7 million, a decline from $116.9 million in the prior year quarter, attributable to lower personnel, stock compensation, materials, and contracted services, partially offset by increased lonvo-z clinical expenses.
• G&A Expense -- $33.1 million, essentially flat versus $32.4 million last year; stock-based compensation for G&A was $6.2 million.
• Net Loss -- $95.8 million for the quarter, a substantial reduction from $128.9 million in the same quarter last year.
• MAGNITUDE-2 Clinical Hold Lifted -- The FDA lifted the clinical hold on the MAGNITUDE-2 polyneuropathy trial, accepting protocol amendments such as expanded liver monitoring, conditional steroid use after transaminase rises, and stricter patient screening to mitigate liver injury risk.
• Patient Enrollment -- MAGNITUDE-2 enrolled 47 of a now-planned 60 patients, with full enrollment targeted for the second half of 2026; MAGNITUDE cardiomyopathy trial remains on FDA hold, with 650+ patients already enrolled.
• Lonvo-z HAELO Phase 3 Enrollment -- Completed with 80 patients in nine months, beating internal targets, reflecting strong patient and physician demand.
• Patient Survey Insights -- 99% of surveyed U.S. HAE patients were at least somewhat likely to use a gene-editing therapy matching lonvo-z's profile, with nearly two-thirds "extremely or very likely"; 92% of surveyed U.S. healthcare providers indicated willingness to prescribe it.
• Clinical Outcomes: HAE -- Only 20% of surveyed patients on current prophylaxis therapies reported being attack-free in the past year, compared to 76% attack-free rate among lonvo-z-treated patients one year after a 50 mg dose in pooled clinical analysis.
• Phase 3 Data Readouts -- Top-line results for HAELO's placebo-controlled phase 3 trial expected by mid-year 2026, with BLA submission planned in the second half of the year.
• Manufacturing and CMC Readiness -- Phase 3 lonvo-z trial utilized commercial-scale material with validated processes; no manufacturing changes required for approval, per management’s statements.
• Operating Expense Outlook -- Management expects future cash needs to be covered by achieving mid-single-digit U.S. HAE market share for lonvo-z, citing a treatment population of approximately 7,000 HAE patients and high orphan pricing in this segment.
• MAGNITUDE-2 Protocol Amendment -- Target enrollment increased from 50 to approximately 60; supplementary liver lab tests and steroid regimen instituted for at-risk patients, excluding those with high enzyme levels or prior liver conditions.
• Liver Safety Events -- Grade 4 liver enzyme elevations noted in less than 1% of MAGNITUDE patients; one patient death attributed to a ruptured duodenal ulcer, with uncertain relation to treatment; management described such cases as outliers.

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RISKS

• FDA clinical hold remains in place for the MAGNITUDE cardiomyopathy trial, with required protocol modifications and uncertainties around timing for lifting the hold.
• Liver enzyme elevations, including one patient death, triggered regulatory holds and necessitated stricter screening and monitoring, highlighting continuing risks for TTR gene-editing programs.
• Cash balance fell by $256.6 million over the year due to ongoing R&D and commercialization investments, with management planning additional spend to prepare for potential lonvo-z launch.

SUMMARY

Intellia Therapeutics (NASDAQ:NTLA) reported a sharply reduced quarterly net loss and decreased operating expenses following company-wide restructuring, while maintaining a robust cash runway through planned clinical milestones. The FDA’s lifting of the MAGNITUDE-2 clinical hold, subject to extensive liver-related safety protocol amendments, allows patient accrual to resume for the ATTR polyneuropathy indication, with full enrollment expected later this year. Physician and patient survey data reported unprecedented demand for lonvo-z as a potential one-time therapy for hereditary angioedema, driving rapid phase 3 enrollment and reinforcing management’s anticipations for near-term pivotal data and regulatory submissions.

• Chief Financial Officer Ed Dulac emphasized that if lonvo-z captures a mid-single-digit U.S. market share, “the resulting cash flows would likely enable us to fully fund our entire operations.”
• Manufacturing controls for lonvo-z are considered complete, with Commercial Manufacturing and Controls (CMC) work “in a very, very robust fashion,” and the same material used in both phase 3 trials and anticipated commercial supply.
• CEO John Leonard stated, “the incidence of Grade 4 elevations was less than 1% in the entire patient population of MAGNITUDE,” directly addressing risk discussions with regulators.
• Supplementary patient monitoring and steroid use are new protocol requirements in MAGNITUDE-2, aiming to minimize future liver safety events that previously mandated study holds.
• Dulac reported, “roughly 70% of the opportunity is commercial payers for lonvo-z,” indicating the company targets a largely private insurance market for future sales.

INDUSTRY GLOSSARY

• MAGNITUDE/MAGNITUDE-2: Phase 3 clinical trials for Intellia’s in vivo genome-editing therapy in patients with transthyretin amyloidosis, stratified by cardiomyopathy (MAGNITUDE) and polyneuropathy (MAGNITUDE-2).
• HAELO: Phase 3 clinical trial for lonvo-z in hereditary angioedema (HAE).
• BLA (Biologics License Application): Regulatory submission to the FDA seeking approval to market a biologic therapeutic.
• LFT (Liver Function Test): Laboratory assays assessing liver enzymes and function, used here to monitor safety in gene-editing trials.
• LTP (Long-Term Prophylaxis): Chronic preventive therapy for HAE patients, contrasted in the transcript with Intellia’s one-time treatment approach.
• CMC (Chemistry, Manufacturing, and Controls): Regulatory framework governing the manufacturing consistency and quality of biopharmaceutical products.

Full Conference Call Transcript

John Leonard: Thank you, Jason. 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 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, Inc. 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 a one-time treatment that is administered in an outpatient setting. We believe our two lead candidates, lonvo-z and nex-z, fit this profile. With up to three 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 1 and 2 trials. Even more encouraging, the observations of improvement in clinical and disease measures that we track in the phase 1 and 2 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 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 two to four hours, and then they go home. A decade plus after our founding, it's for good reason that our excitement is building as we approach the world's first phase 3 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 Therapeutics, Inc. With lonvo-z, we rapidly enrolled HAELO, our phase 3 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 3 clinical trial by year-end, and we had not yet begun enrollment in MAGNITUDE-2, our Phase 3 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-2. 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 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 U.S., we are now working through the relevant local regulatory processes to resume patient screening. 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, we're 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. Given the positive phase 1 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 and HAE.

We completed enrollment in the HAELO phase 3 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 lonvo-z among those with HAE and their 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 1 and 2 trials on a blinded basis, and were told the data was from a gene-editing candidate.

They were 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 US healthcare providers were presented the same target product profile and 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. 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 showed 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 1 to pooled analysis, showing that 76% of patients who were at least a year beyond a 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 AAAAI meeting that is taking place this weekend in Philadelphia. 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 three data for approved LTPs, the best attack reduction rates have been in the eighties, and the very best attack-free rate we have seen from an LTP is approximately 60% of patients. 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 it is a one-time therapy. As was shown in the pooled analysis that was presented at AAAAI, 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 Therapeutics, Inc. 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.

Ed Dulac: 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 plan to 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 $multi-millions.

Given this backdrop, we believe a one-time 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. 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'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-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 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. 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: We will now begin the question-and-answer session. To ask a question, you may press star, then 1 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 2. Please limit yourself to 1 question, 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 Maury Raycroft with Jefferies. Please go ahead.

Maury Raycroft: Hi, good morning. Congrats on the progress, 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?

Ed Dulac: Morning, Maury. Thanks for the question. It's correct that the phase two work and phase one work was done, outside the United States. The phase three trial is done globally.

John Leonard: In some of those same countries, especially in the United States. As we look at the patient populations, in the phase 3 group versus the phase 2 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. We think that's indicative of patient interest, that they're willing to go through all of that, to participate in the trial. From a comparability of data, perspective, or at least from a patient population, point of view, what you're seeing for the phase 2 patients is largely representative of what we expect to see demographically for U.S., for the phase 3 trial.

Maury Raycroft: Got it. Okay, that's helpful. Thanks for taking my question.

Operator: The next question comes from Mani Foroohar and Leerink. Please go ahead.

Lidiya Rizova: Hi. Good morning. This is Lidiya Rizova on for Manny. Maybe just 2 questions from us. 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 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. 2nd question on the PTR program. Thinking back 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.

John Leonard: Thanks, Lydia. I'll start with some comments about the PTR program and then hand it over to Ed, who can speak about your questions with respect to HAE. With the PTR amyloidosis program, NTLA-2001, 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.

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. 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 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. We're never gonna 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. As we have more information, we will obviously update everybody and bring you up to speed. Ed, maybe you want to say a few words about how we're thinking about HAE.

Ed Dulac: 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 a 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.

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. Quite frankly, we're the only therapy that can provide both freedom from attacks and freedom from drug therapy. We like the profile we're playing with, and we also see that, you know, as we think about going to market and the strategy there, we are looking for, you know, how do we make sure that physicians are educated? How do we input the infrastructure required to do that? 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 the treating physicians. We've been engaged with payers for quite some time. We're encouraged by what we see there. We have our overall long strategy plan in place. We're already playing from a position of strength from an operational perspective. This year, the focus is really gonna 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. Overall, we feel really good about the prospects we have in HAE.

Mani Foroohar: Very helpful. Thank you.

Operator: The next question comes from Alec Stranahan in Bank of America. Please go ahead.

Alec Stranahan: Hey, guys. Good morning, thanks for taking our question. Maybe on the PN study, now that's restarting, do you think an interim analysis would be possible here? Curious what you think about the nine-month endpoint on NIS for the new eplontersen study. Thank you.

John Leonard: I'm not gonna 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 1 patients, and we've 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 PTR reductions largely do not progress, and many of them, in fact, there's a cohort of patients in that group that had failed patisiran, i.e., progressed on the drug, who actually improved relative to their baseline. That thinking goes into the design of the study and the patient number of the study. 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, at the stopping criteria negative. 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 within the behavior of the patients. Right now, it's the endpoint is set for 18 months.

Operator: The next question comes from Joseph Thome and TD Cowen. Please go ahead.

Joseph Thome: 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 lonvo-z potential approval and launch, and if there were any manufacturing changes between the phase 2 and the phase 3? 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.

John Leonard: 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'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 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 gonna see in the marketplace. 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 3 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.

Ed Dulac: I'll do that, Joe. I mean, we have a network for lonvo-z CDMO providers that have been long established, primarily in Europe, for the product. 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 equipped for commercial launch.

Operator: The next question comes from Luca Issi with RBC Capital Markets. Please go ahead.

Shelby (for Luca Issi): 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? 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.

John Leonard: 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, 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 PN and the CM programs are, I think, viewed as somewhat distinct because of the patient populations there. That has not been a matter for discussions or submissions that we've made to the FDA. I don't know if you want to say a word about payers and lonvo-z.

Ed Dulac: Yeah, 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 one-time therapy like we're presenting with them in lonvo-z. 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, you know, 60% as the largest number we've seen to date in terms of attack-free rate.

That's kind of the efficacy bar. We expect to be very competitive on those figures. 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.

Operator: The next question comes from Jonathan Miller with Evercore ISI. Please go ahead.

Jonathan Miller: 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? Sort of the same question, if you're excluding patients with liver risk, you know, that might reduce enzyme spikes, that makes sense. It likely doesn't reduce the rate of immune reaction to edited protein. Is that fair to say? If that's true, is it possible to screen patients for reactivity ahead for edited peptides ahead of dosing?

John Leonard: 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, you know, 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, 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, you know, something in, 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 three to five weeks, typically, and we do not see anything that resembles that subsequent. 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. 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.

In most cases, I think there's going to be just not a particularly meaningful concern in that number of cases in which we would actually use steroids, I think is going to be very low, single digits.

Operator: The next question comes from Andy Chen with Wolfe Research. Please go ahead.

Emma (for Andy Chen): 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? Are there specific factors that differentiate the FDA's view across the two indications? Thank you.

John Leonard: 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, you're correct in that they're receiving the same drug and it's the same gene that is being edited, but 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 seventies 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. 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.

Operator: The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.

Mark (for Salveen Richter): Hi, this is Mark on for Salveen. Thank you so much for taking our question, and congrats on the quarter. 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? Also, we just wanna 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.

John Leonard: We've said previously that the incidence of Grade 4 elevations was less than 1% in the entire patient population of MAGNITUDE, I'd work with that number. That's part of the thinking that we're addressing with the FDA, 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, there's many, many points of commonality between the two patient populations and some of the assessments.

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.

Operator: The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.

Yanan Zhu: Hi. Thanks for taking our questions. I think maybe our question is a little similar to the prior one, maybe asked differently. Do you think this Grade 5 AE in a CM study, you know, 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, do you think those two proposals would have changed the course or prevented this Grade 5 AE case? Separately, I was wondering, Argo Biopharma issued a press release for their AAAAI presentation last night. I'm wondering your thoughts about that data, would that, you know, introduce any new considerations in a competitive landscape for ramucirumab? Thank you.

John Leonard: 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 were 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 also disease, if in fact it's active, would be something that we would not want to have come into the study. With respect to the actual LFT rise, what would be different is that it would be detected earlier, and the course of 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 gonna do that. Things would have been handled somewhat differently, and I think that's important.

Operator: The next question comes from Brian Cheng with J.P. Morgan. Please go ahead.

Brian Cheng: Hey, 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? 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.

John Leonard: 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 this sometimes get lost, that 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. 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+ patients that were enrolled in MAGNITUDE. Things are moving, and I just, I don't want that lost.

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. That's already in the protocol. If that changes or not, we'll see, you know, when we finalize that any protocol modifications with the FDA. I, 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. We have a really good bin sampling through the time when patients are most at risk.

Operator: The next question comes from Silvan Tuerkcan with Citizens. Please go ahead.

Silvan Tuerkcan: Hey, good morning. Congrats on the quarter, and thanks for taking my question. I just wanna 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 6, or dosed every 6 months, silencing RNA technologies that may be coming to the market? Do doctors already appreciate the difference here? Thank you.

John Leonard: That's an important question, and I think one part of this that gets lost is what is the so-called burden of care? 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 risk associated with it. There are sometimes delays associated with it.

Then the next year, you do it all over again, and the year after that, you do it again. These doctors are also engaged in this. 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. You know, it's attack rates are important, and attack-free rates are, you know, critical for the actual outcomes of these patients. As we've said, we think we have a very, very attractive profile that you can look at what we've seen from, you know, the pooled analysis.

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.

Ed Dulac: 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 to 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'd prefer not to have HAE, and they'd prefer not to have drug therapy. We are gonna 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 LNP use, and we do see it as a switchable population for the most part.

We're, 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. There's pre-phase 1 or phase 2, that depending on how patients have come on to the study, are they on LNP 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. You know, 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, you know, very different outcomes, you know, very high attack-free rates and very high attack rate reduction. That's not necessarily the case in a phase 3 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. I think we're very careful about how we think about our phase 3 data that we'll report out.

As we said before, we're very encouraged by 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.

Operator: The next question comes from Myles Minter with William Blair. Please go ahead.

Jake (for Myles Minter): Hi, this is Jake on from Myles. 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? Maybe could you sort of dig into the underlying biology that would lead to that hypothesis? Does the evidence of this liver enzyme elevations being immune-mediated sort of influence your analysis of that question? Thank you.

John Leonard: 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 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 threads of evidence that would help us sort that out. On a going-forward basis, we're gonna 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. 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-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.

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. 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. As we've reported elsewhere, whether you look at our phase one work or phase two work or the phase three work across the HAELO 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.

We think that we're dealing with something that's primarily playing out in the CM patient population. 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.

Myles Minter: 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, then how to think about, you know, timing of any Medicaid coverage in the event of approval? Then on the expense side, you know, your comment about if you achieve mid-single-digit market share in a year, that 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.

John Leonard: 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.

Ed Dulac: Yeah. Thanks, John. Thanks, Aaron. 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. We did that to create capacity for the build that we were gonna need to do on a 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. 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. 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, you know, we can definitely do ourselves. You know, we've been very thoughtful about the approach that we're taking. That's behind the commentary this morning. From a commercial split perspective, roughly 70% of the opportunity is commercial payers for lonvo-z.

Operator: The next question comes from Mitchell Kapoor with H.C. Wainwright. Please go ahead.

Mitchell Kapoor: Good morning. Congrats. Mike on for Mitchell. Congrats on the year and the quarter. What are the gating factors to get the ATTR studies back up and running? For ATTR-CM, what have you heard from regulators on the path forward? Thank you.

John Leonard: 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, yeah, 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. 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, outside the U.S., any additional regulatory submissions that may apply to any particular country. Once we're off hold, should we get off hold, we will tell everybody exactly

Operator: The next question comes from Jack Allen with Baird. Please go ahead.

Jack Allen: Great. Thanks so much for taking the questions, and 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 dataset pre- and post- the implementation of those protocol amendments? Is there any risk that the FDA views the protocol amendment as creating a differentiated dataset, you know, given the change in protocol?

John Leonard: 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 3 months. The evolution of the patient population, you know, things like new therapies, et cetera, really doesn't come into play.

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. 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.

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

Jason Fredette: Well, thanks, Drew, and thanks, everyone, for joining us. We'll 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.

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

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