Good morning and welcome to the Intellia First Quarter 2025 Financial Results Conference Call. My name is Drew, and I will be your conference operator today. Following formal remarks, we will open the call up for a question-and-answer session. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. As a reminder, all participants are currently in listen-only mode. If anyone requires operator assistance during the conference, please press star zero on your telephone keypad. I will now turn the conference over to Brittany Chaves, Senior Manager of Investor Relations at Intellia. Please proceed. Thank you, Operator, and good morning, everyone. Welcome to Intellia Therapeutics First Quarter 2025 Earnings Call. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter, as well as topics for discussion on today's call. This release can be found on the Investors and Media section of Intellia's website at intelliatx.com. This call is being broadcast live, and a replay will be archived on the company's website. At this time, I would like to take a minute to remind listeners that during this call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. Joining me from Intellia are John Leonard, Chief Executive Officer, David Lebwohl, Chief Medical Officer, Ed Dulac, Chief Financial Officer, and Birgit Schultes, our Chief Scientific Officer, who will join for Q&A. John will begin with recent business highlights. David will then provide updates on our clinical pipeline progress, and Ed will review our financials before we open the call for questions. With that, I will now turn the call over to John, our Chief Executive Officer. Thank you, Brittany. Good morning, everyone, and thank you all for joining us today. We entered the year with clear priorities and a plan for operational excellence, and we've already made tremendous progress in the first quarter. We're on a mission to offer life-changing benefits with one-time therapies for people living with severe diseases. Our progress is fueled by the core values of the company: one team, exploring possibilities, delivering results, and disrupting the status quo. We are committed to changing the treatment paradigm for patients suffering from Hereditary Angioedema and ATTR Amyloidosis. Of the six milestones we outlined for 2025, we've accomplished two critical ones in the first three months of the year: dosing the first patient in our phase three study for HAE and dosing the first patient in our phase three study for Hereditary ATTR with Polyneuropathy. We continue to see significant interest from both investigators and patients across our programs. Enrollment in our global phase three HALO study for HAE is progressing rapidly and reinforces our market research that the unmet need remains high despite existing treatment options. Patients are eager to pursue more convenient and more effective therapies. The transformational potential from a single infusion of NTLA-2002 resonates strongly with patients and physicians. Our global phase III MAGNITUDE study for ATTR with cardiomyopathy continues to be ahead of schedule. We now have over 90 sites actively enrolling, and we continue to benefit from interest in our emerging profile for Nexiguran Ziclumeran, which we also refer to as Nex-Z, from our phase I data presented last November. In the first quarter, the FDA granted Intellia the RMAT designation for Nexiguran Ziclumeran for the treatment of ATTR with cardiomyopathy, which follows prior RMAT designations received for Nexiguran ziclumeran for ATTR with polyneuropathy and for NTLA-2002 in hereditary angioedema. In parallel to the great execution of our phase three studies, we've been building critical commercial foundations in order to bring our promising therapies to patients as quickly as possible. During the past few months, our commercial team has broadened its leadership capabilities and includes extensive experience with one-time therapies and in disease areas of interest. We're increasingly confident in our ability to evolve into a strong, commercially ready company. We're excited to share multiple clinical updates throughout the year. We expect longer follow-up to further solidify the emerging and highly differentiated safety and efficacy profiles of our lead programs. In the case of HAE, we'll present new data from patients who have crossed over in our phase two portion of our phase one two study later this year. This expansion of patients receiving the 50 mg dose will provide a more robust perspective with more than 30 patients in total on the unique and valuable profile afforded by a one-time therapy like NTLA-2002. More immediately, in June, we'll have two-year follow-up data from our ongoing phase one study of NTLA-2002 at the European Academy of Allergy and Clinical Immunology Congress. For ATTR with polyneuropathy, we'll extend the durability window out to at least three years, further extending our leadership position in in vivo gene editing. We're confident in our plans, diligent in our execution, and excited by the value-creating opportunities that lie ahead. Before I hand the call over to David Lebwohl, our CMO, I want to take a moment to address how we're thinking about the regulatory environment given leadership changes and developments at the FDA. Like everyone else, we will monitor the situation closely. At this point, we've experienced no tangible changes to our interactions with the agency or timelines associated with our programs. We remain on track to meet or exceed our stated regulatory timeline and objectives. We remain in close communication with our review teams and continue to move our programs toward approval as per our original plan. We have a strong, active relationship with the FDA, as exemplified by the two prior RMAT designations and our most recent in ATTR-CM. We remain on course to file our first BLA in 2026. Similarly, we continue to monitor potential implications of pending pharmaceutical tariffs. We have well-established manufacturing and distribution capabilities and are confident in our ability to manufacture and deliver supply for our clinical trials and eventually commercial product upon approval. Beyond that, we're convinced our products will yield significant value for patients and the healthcare system. We're continuing to monitor the environment, but amidst all the changes, there's one thing that remains the same, and that's our dedication to bringing highly differentiated therapies that have the ability to reset the treatment standards for patients with HAE and ATTR. I'll now hand the call over to David Lebwohl, who will provide an update on our clinical programs. David. Thanks, John. I'll begin with 2002 in development for HAE. As John noted, we dosed the first patient with 2002 in our HALO Phase III S tudy in the first quarter. HALO is a 60-patient global randomized double-blind placebo-controlled study. Patients are randomized two to one to either a single 50 mg infusion of 2002 or placebo after washing out their long-term prophylaxis therapy. They are then followed for a 28-week primary observation period and for a total of 104 weeks in the study. Enrollment is going very well and progressing ahead of our projections. We are motivated by the early progress and excited by this patient and investigator interest. The team is executing well, and we are in a position to go from the first patient to last patient dosed in less than nine months. This speed of enrollment confirms our market research and speaks to the high unmet need and demand in the HAE community, as well as the significant room for improvement. We expect to complete enrollment by the end of the third quarter of this year. We are pleased to share that new NTLA-2002 data were accepted for an oral presentation at the European Academy of Allergy and Clinical Immunology Congress on Sunday, June 15th, in Glasgow. This update will include at least two years of follow-up in patients in the phase I portion of the phase I/II study. Later this year, we plan to present longer-term data from patients in the phase II portion of the study, including those who initially received a 25 milligram dose or placebo and were subsequently given the 50 milligram dose of NTLA-2002 selected for the phase III study. As John mentioned, this phase two update will more than double the total patients who have received the 50 milligram phase III dose to more than 30 patients. Intellia is committed to ending the burden of HAE attacks and chronic treatment for HAE. The emerging profile of 2002 from our phase I two study suggests that many HAE patients can be free from attacks and free from the medications that are currently used to treat this disease. We believe, and our market research shows, that 2002 will bring significant value to patients, physicians, and payers. The value proposition for 2002 is comprehensive and compelling, offering patients freedom from HAE attacks and chronic treatment, physicians freedom from persistent administrative burdens in managing chronic HAE therapies, and material pharmacoeconomic benefits for payers. NTLA-2002 is poised to be the first-ever one-time treatment for people living with HAE and the first approved therapy using in vivo CRISPR gene editing. Let's move on to Nexiguran Ziclumeran in development for the treatment of ATTR Amyloidosis. In March, the first patient was dosed in the global phase three MAGNITUDE-2 study for the treatment of hereditary ATTR Amyloidosis with Polyneuropathy. This pivotal study is a placebo-controlled study with expected enrollment of 50 patients. Patients are randomized to either a single 55 mg infusion of Nexiguran Ziclumeran or placebo. We plan to measure mNIS+7 at 18 months and serum TTR levels as key endpoints in the study. Full study enrollment is expected to be completed in 2026 to enable our second BLA filing by early 2028. Also, in March, we announced the FDA-granted RMAT designation to Nexiguran Ziclumeran for the treatment of ATTR Amyloidosis with Cardiomyopathy. As John mentioned, with the granting of a third RMAT designation, all of our lead programs and indications will benefit from earlier and more frequent engagement with the FDA. This is a testament to the potential of our therapies to reset the standard of care and the impact they can have on patients. We continue to be very pleased by the enrollment in the global Phase III MAGNITUDE Study in ATTR Amyloidosis with Cardiomyopathy, which is ahead of our projections. We expect cumulative enrollment to exceed 550 patients by year-end. Later this year, we will present longer-term data from patients with either ATTR Polyneuropathy or Cardiomyopathy in the phase I study, which will include updated measures of clinical efficacy and safety. We will have a median follow-up of two years in Cardiomyopathy and three years in Polyneuropathy. We look forward to sharing these updates in the second half of 2025. I'll now hand over the call to Ed Dulac, our Chief Financial Officer, who will provide an update on our financial results as of first quarter 2025. Thank you, David. Good morning, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our pipeline and platform. Our cash equivalents in marketable securities were approximately $707.1 million as of March 31, 2025, compared to $861.7 million as of December 31, 2024. Our balance sheet evolution reflects normal expenses from operations during the first quarter and non-recurring costs associated with decisions we took to prioritize our portfolio and reduce our real estate footprint and workforce, all of which diminished the medium and long-term capital needs for the company. These outcomes represent positive developments and allow our current balance sheet to bridge to our expected launch for NTLA-2002 in HAE during the first half of 2027. During this time, Intellia will achieve several important value-creating clinical development and regulatory milestones, which we expect will help us further capitalize the company and aggressively pursue our plans for Nexiguran Ziclumeran in ATTR with Polyneuropathy and Cardiomyopathy. Our collaboration revenue was $16.6 million during the first quarter of 2025, compared to $28.9 million during the first quarter of 2024. The $12.3 million decrease was mainly driven by a decrease in collaboration revenue under the AvenCell License and Collaboration Agreement. Recall that during the first quarter of 2024, there was a transition to equity method accounting for AvenCell, which resulted in a one-time recognition of revenue of approximately $21 million. R&D expenses were $108.4 million during the first quarter of 2025, compared to $111.8 million during the first quarter of 2024. The $3.4 million decrease was primarily driven by employee-related expenses, stock-based compensation, research materials, and contract services, offset by an increase in the advancement of our lead programs. Stock-based compensation included in R&D expenses was $12.6 million for the first quarter. G&A expenses were $29 million during the first quarter of 2025, compared to $31.1 million during the first quarter of 2024. The $2.1 million decrease was primarily related to lower employee-related expenses due to a workforce reduction in January 2025 and lower stock-based compensation, partially offset by increases related to severance expenses recorded in the first quarter. Stock-based compensation included in G&A expense was $9.2 million for the first quarter. As guided previously, we continue to expect a year-over-year decline in GAAP operating expenses of between 5% and 10% this year and that our cash balance is sufficient to fund our operating plans into the first half of 2027. Thanks, Ed. In conclusion, Intellia continues to meet and even exceed our goals in all programs, and we're excited to report on our progress in the months ahead. With that, we'll now open the call for your questions. To do our best to address as many questions as possible, we will only be able to take one question per caller. Operator, you may now open the call for Q&A. We will now begin the question and answer session. To ask a question, you may press star then one on your touch-tone 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. At this time, we will pause momentarily to assemble our roster. The first question comes from Gena Wang with Barclays. Please go ahead. Thank you. You have so many updates on different programs, but I will limit my questions to one. Since that's the most pressing question, I'll ask about the MAGNITUDE Phase III T rial enrollment. It seems like ongoing very well. If you can give your updated metrics regarding the patient baseline characteristics, which includes percentage of patients who are on baseline stabilizer and also the silencer dropping rate, what are these rates? Are these rates in line with your internal expectation? David, do you want to speak to the evolving characteristics at baseline of patients? Yeah, and thank you for that, Gena. Yeah, the exciting thing is the rate at which this is enrolling. In terms of the patients around the world, Tafamidis is becoming more commonly used, including the U.K. recently. As we've said really from the beginning, we do expect more than 50% of the patients to be on Tafamidis in the study, and we're monitoring that. We do think it's important to show a benefit over Tafamidis that hasn't been shown yet with the silencers. This is also valuable then to have a large group of Tafamidis patients on the study. In terms of silencer, of course, this has just been approved in the U.S. recently. We don't expect many patients to cross over, though at this point, there are no patients. Over time, we do anticipate in our statistics that a percentage of the patients will be going over to silencer. We are ready for that in terms of the results. Thank you. The next question comes from Mani Foroohar with Leerink Partners. Please go ahead. Hi, this is Lilian Nsongo on for Mani. Thank you for taking our question. I just had a question regarding cash burn and OpEx. You just mentioned that you were expecting a 5%-10% year-over-year decrease in OpEx. Could you maybe give us a little more in terms of what we should expect in terms of cash burn in the next 12 to 24 months, especially as the restructuring progresses? Are there any notable non-recurring costs or events that we should be taking into consideration? Thanks for the question. Ed, if you want to walk through, there's a lot of details, but I think it's really important to understand what's going to be the baseline running rate going forward. Ed can take you through that. Ed? Yeah, thank you. Thanks for the question. This is an important focus for the company. I think the key point I want to make for investors is that we estimate that our average cash use over 2025 and 2026 will be about $95 million per quarter. This is consistent with the guidance that we reiterated today, this morning, that our current cash will fund our operating plans into the first half of 2027. As I indicated during the fourth quarter call a few months ago, we expected the first quarter results today to be pretty noisy, just given the broader structuring decisions that we made at the company earlier in the year. I wanted to just unpack a little bit the cash, what drove our cash use during the quarter. The first key driver was our normal company operations. We spent $86 million to run the business, which again is very consistent with sort of that $95 million per average cash use per quarter that I mentioned previously. Normal operations, we spent $86 million in the quarter. Employee bonuses, of course, this is something we routinely do, but that was $18 million. We did use that to pay bonuses to existing employees, but also those that were impacted by the restructuring that we announced in January. The last driver of cash use for the quarter was sort of these non-recurring costs. That was about $51 million in the quarter. We used some of this to pay employee severance and related costs. Primarily, we used this cash to enter into payments associated with real estate transactions that we disclosed in February as part of our 10-K filing. I'll talk maybe a little bit about our real estate transactions that I just referenced. We're actually very excited about the development and the evolution of our real estate portfolio. Just to remind folks, in February, we entered into a cash-neutral transaction to reduce our portfolio, simplify our operations, and identify additional and significant savings. The cash neutrality to that transaction is really important for us. We essentially took cash that we had budgeted for the company's real estate portfolio through 2026, and we used that to pay agreed-upon lease modification payments. If I say that a little bit differently, the near-term cash outlays associated with the real estate transaction will be fully recouped from the absence of cash payments that we had formerly expected to pay for the real estate portfolio. The bottom line, our real estate portfolio really better aligns with the focus and the needs of the company. It does bring us a few important benefits. The first one is we'll simply have a new corporate headquarters that the company is excited about. By the end of 2026, we'll have a new headquarters located in Cambridge where we plan to consolidate most, if not the entire company. We expect this will support the growth and the support and grow our collaboration and innovation and culture at the company. We're very excited about those prospects. From an operational perspective, we're just going to have to run a very smaller, simpler portfolio. We'll have about a 30% reduction in the real estate capacity over the next couple of years, including the release of all the obligations from a long-term lease that we had in Waltham, Massachusetts, for more than 140,000 sq ft. The last thing I'll say on the real estate portfolio, according to our estimates, we'll expect nearly $50 million in cash savings from operating our smaller footprint. There'll be other synergies and cost savings associated with the management of our portfolio. There's potential sublease income from the smaller buildings that will remain in the portfolio. I covered a lot of ground there, but I think it's such an important topic. I wanted to spend a little bit of time on it. Just to reiterate, we will use an average of $95 million of cash per quarter through this year in 2025 and in 2026. This importantly will allow us to do three very critical things. The first one, fully invest in our three phase three studies that we provided an update this morning. It has, and we will continue to build the commercial infrastructure in the U.S. to capture the significant value that we see across both of our lead programs. Importantly, we created a financial bridge to our first anticipated launch in the first half of 2027 for NTLA-2002 and HAE. The next question comes from Andy Chen with Wolfe Research. Please go ahead. This is Hannah Tran calling. Thanks for taking our question and coming in on a question previously asked. We see that you guide to a cash runway into the first half of 2027. After 2027, have you considered non-dilutive financing? If so, what options and how feasible would they be to obtain? Ed, do you want to keep on going from the prior question? Just talk about how we look further down the road and some of the options that we're actively thinking through. Yeah, I appreciate the question. I'll just start with what we kind of indicated this morning. In January, we made some difficult decisions on the restructuring. We've already seen, I think, early and encouraging signs in the first quarter. Our operating expenses were down 4% versus the year-ago quarter and down 7% already from the fourth quarter of last year. For the things that are immediately in our control, we're definitely focused on making sure that we are operating very efficiently and that will continue over the next few years. As it relates to capital raising going forward, I think we have clearly built an opportunity for the company to click through a number of important milestones. We think they will be value-creating for shareholders. We would think about how do we raise additional capital on the back of some of those catalysts that the company has over the next 12 to 24 months. We are big believers in building the company. We are going to continue the evolution to a commercial-stage company. We also do not talk much about our research pipeline, but we do have one, and we continue to invest there. We are looking to build a company over the long term. I think a number of different levers are on the table for us. One would be collaborations. We currently have a collaboration with Regeneron on our TTR asset. There are opportunities to think about that collaboration potentially differently. We do have wholly owned assets like 2002 that we can consider partnership. We have pipeline assets that are also open to potential collaboration. I would say another option that becomes increasingly more available to a company like Intellia, as we approach commercialization, funding options like royalty transactions could make sense. The other option that you mentioned would be sort of a term debt or venture debt sort of a structure that also could make sense as we think about commercialization, the revenue generation, and the profitability that this company could have on a three-year view. In reality, we may consider one or more of those over the next two to three years. We have been talking about this, just given the current macroeconomic situation and geopolitical situation for quite some time. I think we have some clear plans in place. Stay tuned. We feel really good about the balance sheet, where we're heading. I think we have multiple levers to capitalize the company over the next couple of years. The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead. Good morning, everyone. Congrats on the progress. Thanks for taking our question. A question from us on AJ, given that you plan to file in 2026, and this will potentially be the first-ever commercial in vivo gene editing therapy. Can you help us understand how should we be thinking about the launch dynamics there in terms of activating sites for patients, securing coverage, and potentially time required from patient decision to receive the therapy to infusion time? Should we expect similar timeline dynamics to in vivo gene therapies that we have today in the market? Thank you. Kostas, thank you for the question. It's, I think, really a very important one. As you pointed out, HAE will be not only our first in vivo gene editing launch, but the world's first CRISPR in vivo gene editing launch, and something that we're paying great attention to. In our phase three program, which, as David commented earlier, things have been progressing extremely well. We're ahead of our timeline and learning much about how to deal with sites, how to make the drug available, etc. In parallel, we've been building our commercial organization and have staffed it with people with deep insights into prior one-time therapies from which we can certainly learn a lot. Many of those one-time therapies, however, are not good analogs to what we're doing. The reason for that is ours is a very straightforward outpatient infusion where patients receive a dose of dexamethasone the day before therapy, come sit in the clinic for two to four hours with another repeat dose of dexamethasone and some antihistamines, and they go home. How to provide that versus some of the prior examples that have been made available is day and night. With respect to switching from therapies that patients may already be taking, as you might imagine, as we carry out our phase three trial, we're learning a lot about that. In many instances, this is a simple matter of looking at the pharmacokinetics of the drugs that patients are currently taking and compensating for how those will wash out over time while the effect of the gene edit takes place. We think we're in really excellent position from a drug profile point of view. We presented some of that data. You'll see more this year. We're very excited about how patients do and how the profile evolves over time. We're really looking forward to sharing that soon. From the standpoint of getting into the marketplace, once the drug is approved, we think that we can progress extremely efficiently and bring the drug to many, many patients, which has been what we've been learning from our market research. I think we're in a very, very good position at this point. The next question comes from Luca Issi with RBC. Please go ahead. Oh, great. Thanks so much for taking my question and congrats on all the progress. Maybe a quick one on pricing. What was your reaction when you saw Vutrisiran actually not lowering their price and they got the label expanded from TTR Polyneuropathy to TTR Cardiomyopathy? Were you surprised by it? Just maybe bigger picture, how are you thinking about pricing for your molecules more broadly, given the one-and-done nature of them? Thanks so much. Thank you. Obviously, we're paying attention to the TTR market broadly. It's not just Alnylam. There's, as you know, other oral participants, including a recent entrant. We watch the uptake and the performance of those different drugs. What we see is an increasingly large and rapidly growing marketplace. Diagnostic procedures are improving. The disease is more widely recognized. Across the board, this translates into an opportunity for all entrants. We think with the profile that we've seen thus far from our drug, this is going to be a very exciting market for us to participate in. With respect to Alnylam's price, obviously, they're responding to what they see in the marketplace, the dynamics that they've observed already, Polyneuropathy and the prior experience with Onpattro. We think that translates into a very significant opportunity for us. As we get down the road, we'll further hone how we think about that. In the meanwhile, it's all about getting clinical trials enrolled, which we're doing very, very aggressively. As David has said, especially with the progress of those programs, we're well ahead of schedule. If anything, we see enrollment accelerating. We're looking forward to participating in that marketplace. We're quite confident that we will do very, very well. Got it. Thanks so much. The next question comes from Maury Raycroft with Jefferies. Please go ahead. Hi, good morning. Congrats on the progress. Thanks for taking my question. Going back to enrollment for the Halo phase three, in late March, you changed the minimum age from 18 years old to 16 years old on ct.gov. Just wondering if that's driven by patient interest or demand, or was it to accelerate enrollment or for other reasons? Based on Cardiomyopathy enrollment continuing to track better than expected, can you say more on where you expect enrollment to land by the end of the year? Could it be greater than 100 patients on study or 600 patients on study? I guarantee you it would be more than 100 patients by the end of the year. Thank you for the question. Yeah, let's start with the HALO Study first. Basically, our interest is in having the broadest possible label, whether it's from age or disease severity. We have designed a program that should permit that. Patients coming into the phase three study resemble to a great extent those that have come into the phase II and phase I studies. We see a range of disease severity. We think that is very, very helpful in terms of assessing how the drug performs and should augur well for the label that we expect to get. With respect to enrollment of that study, we have been extremely gratified by interest across the board, United States, outside the United States, where we have had patients essentially lined up. That is not an exaggeration at all sites. We are well ahead of what we projected. We will have some opportunity to further refine exactly what that looks like. As we look down the road into how we think uptake will go in the marketplace, many of the comments that we have seen others offer where this is a well-satisfied space, we see that is not correct. Patients and physicians tell us that there is significant remaining need, desire to get to a state of no attacks and no further therapy, which we have seen in the majority of patients thus far, is very, very compelling to patients. We actively see people very, very actively seeking that out. With respect to the cardiomyopathy enrollment, similarly, we have been very gratified by the very rapid enrollment there. As we have guided, we expect to have cumulative enrollment beyond 550 patients. Typically, we underpromise and overdeliver. That may be a further instance of that. As we get down through the year, we'll give some additional details there. We like where we are. As we look at comparators from prior experience, we've been very pleased because we're well ahead of those projections. Got it. Thank you. The next question comes from Alec Stranahan with Bank of America. Please go ahead. Hey, guys. This is Matthew on for Alec. Thanks for taking our question. Maybe just one looking forward from us. I know that you said you're still developing other in vivo and ex vivo candidates. Maybe just some color on the timeline of these, whether they're likely to come after the potential approval in HAE/ATTR. You're referring to our pipeline? Is that? Yes. Okay. We've talked about some things in the past that we've been working on. What we've been focusing on since the end of last year and throughout this year is very much the clinical programs. That will be what we spend most of our time talking about because that's what's going to be the near-term driver of significant value. I think to separate us from other companies in the space, we're well beyond the proof of concept phase where we've demonstrated clinical activity with these drugs. What we're doing now is building a label with pivotal trials and gaining approval. That's where the focus is going. We do have very significant efforts underway for additional in vivo candidates. We're not talking about most of those at this point. In the past, we've spoken some about Alpha-1. You may hear about that as time goes on. We're very excited about the progress we're making with our gene writer. We can imagine areas where that can bring real utility. From an ex vivo point, we think we have some insights that can significantly open up that space. As time goes on, we'll be talking more about that. These are competitive areas. We'll focus on the clinical work. The next question comes from Mitchell Kapoor with H. C. Wainwright. Please go ahead. Hey, everyone. Thanks for taking the question. Can you just talk a bit about the payer perception of potentially having to cover both Tafamidis and Nex-Z and how that changes the way we should interpret data from ATTR studies? David, do you, in the clinical trials, have you seen any information that bears on how payers are looking at Tafamidis in the—actually, you asked about Nex-Z. I'm sorry. I was misinterpreting. I'll say this. We're building a database with respect to payers where we have increasing insight. Much of the early insight we're getting is for HAE, which has been the bulk of our work. We expect that at the time of launch for Nex-Z, that Tafamidis will be a generic drug. Most estimates suggest that that will be the case. If that is, in fact, the situation, I would expect from a payer point of view that that will not be a significant point of discussion. I think we'll get some early insights in terms of how payers behave in the most stringent circumstances with the Inotersen option. Look for examples where Tafamidis may or may not be used together. Again, the clinical circumstances are a little different in that case where the clinical benefit was not shown in a statistically meaningful way in the HELIOS Study. As David said, we are designing our trial in such a way and have sufficient patients coming in on Tafamidis to, in fact, demonstrate an expected benefit when the two drugs are used on top of Tafamidis alone. Regardless of payers, we'll have the clinical evidence, and we would certainly intend to have it in the label. That is where the situation stands as we speak today. The next question comes from Jay Olson with Oppenheimer. Please go ahead. Oh, hey. Thanks for taking the question. Maybe just to follow up on the previous question about the patient baseline characteristics enrolling in MAGNITUDE, can you talk about how these characteristics will impact your estimate for the time to reach the required number of events for the primary endpoint and whether that would happen before or after the first half of 2027? Thank you. Yeah. I don't know if we're going to be talking about timelines, but you want to talk about baseline characteristics and how you're thinking about that, David, with respect to the study progression. Yeah. The patients in this study are looking very similar to the other phase three studies, other than what I mentioned, that there's more and more use of Tafamidis. If you look at the number of patients with variant disease, which is a more aggressive disease, the proportion is in the same range, 10-15%, as it is in the other studies. Class three patients who also progress at a more rapid rate are also in the same range, in the 10-15% range. We do think the events do evolve fairly similar to the recent studies based on patients who—obviously, more patients on Tafamidis. Again, the timing, as we obviously get closer to analyses, we'll be able to tell you more about the timing of that. The next question comes from Rick Bienkowski with Cantor Fitzgerald. Please go ahead. Hey, good morning. Thanks for taking the question. For NTLA-2002, I was hoping you could expand on the value proposition in HAE and thoughts on the degree of flexibility you'll have for pricing. Just given the competitive landscape here, I'd like to know your thoughts on how a one-time treatment should be valued against chronic treatments and what potential cost offsets could be realized by payers over time. Yeah. It's a very important question. I think it's important to start with the clinical profile that we've seen thus far, where, in addition to attack rate reduction, which we see across the board in patients, the vast majority of patients reach a point of no attacks off therapy. I repeat, no attacks without any other therapy. That is a very important distinction. It is a category of outcomes that's unique to 2002. That clearly brings value to patients. If they can behave in a way where they don't have to think about their disease, that's what they want. They don't want faster on-demand therapy or longer-term prophylaxis. They want to get rid of their disease if they can. That's what's driving interest. That is true for the physicians as well, who, in many cases, struggle with the time demands to reauthorize patients for their very expensive therapy year in and year out. Remember that many of these patients are diagnosed in adolescence. The value that the drug brings, when you look at it from a purely pharmaco-economic point of view and a payer's perspective, is substantial and very, very significant. These patients in the U.S. start at over $250,000 a year, with many of them costing over $1,000,000 a year in drug therapy alone. That provides a substantial window for us to price the drug in a way that can be very competitive with any other existing therapies. That can be very, very resource-sparing for the healthcare system generally and perform very well for the shareholders of our company. We're refining that work today, where prior precedents are taken into consideration and relationships between annual costs and the price of one-time therapy give us some guideposts. We will not be setting any new records for high-priced drugs here at Intellia. What we're trying to do is address all of our stakeholders in the best possible way. As that story unfolds, we'll provide more insights. Great. Thank you. The next question comes from Yanan Zhu with Wells Fargo. Please go ahead. Hi. Thanks for taking our question. Our question is also around Nex-Z in ATTR-CM. We know overall the phase three study enrollment is progressing well. Can you specifically talk about the enrollment in the U.S.? Are you seeing any impact from the approval of Vutrisiran and Inotersen? Are you allowing drop-in of those two drugs? Thank you. David, do you want to speak to have you seen any impact from the new drugs and the MAGNITUDE enrollment in the United States? Sure. Yeah. Just first speaking to the enrollment being risked, what we saw—I think what you saw at AHA last year—is that the drug is doing something different from what's been seen with other drugs for this disease. We've seen that the progression is really stopped and patients even improve. We've seen a very low event rate in this group. This seems to have touched the investigators looking at this and really pushed forward the enrollment. That includes the U.S. and really all over the world. We really have sites pretty much everywhere where there are specialists for this disease. What we've seen in terms of Vutri, you've heard from Alnylam. They don't expect there to be a significant combination of Tafamidis with Vutrisiran. In the U.S., where Vutrisiran is approved, virtually every patient is on Tafamidis right now. Though there is the chance to go on—there is the possibility of patients being able to get Vutrisiran—it's not expected to be a common event based on the data that Alnylam has provided. So far, we have been able to keep up. Obviously, it's early for Vutrisiran, so we don't know a lot. But we so far have been able to maintain the enrollment and even accelerate in recent months, despite the fact that Vutrisiran is coming out. The way we see it is that physicians may choose Vutrisiran for a patient or Tafamidis initially. With our trial, it gives them the chance not only to get Tafamidis if they're on Tafamidis, but also to get a drug that may add substantially to the Tafamidis effect. That's what we're seeing so far. Obviously, we'll be keeping close tabs on that going forward. In terms of being able to cross over the protocol, we're telling physicians if they intend to use Vutrisiran, they should not enroll in the study right now, obviously. That would be their decision and the patient's decision. If they are enrolling in the study, we do not expect them to go over to Vutrisiran during the initial year or two. I think it's also the case that most physicians, in our experience, don't see much of a difference between Tafamidis or Vutrisiran, at least with the data. Yeah. That's what we're hearing from them. We're still getting very brisk enrollment despite the availability of Vutrisiran. Got it. The next question comes from Troy Langford with TD Cowen. Please go ahead. Hi there. Congrats on all the progress this quarter. Thanks for taking our questions. I just want to follow up on one of the comments that you actually just made about recent NTLA-2001 phase one data for functional data from last November. When you all show that data to physicians since you presented it, can you just talk a little bit more about maybe what one data point stands out most to them or seems to resonate most with them? David, you speak to the physicians. What do they like about 2001? Sure. The first point is the profiles we showed on TTR reduction. If you recall, we reach our nadir in one month and reach about a 90% reduction to levels of 19 micrograms per mL. What Vutrisiran has shown in a recent New England Journal is that they take about nine months to get to the nadir. It is a very delayed reduction in TTR, and they reach a level of about 50. It is a very big difference in terms of what is happening with TTR. That is what physicians believe, many of them, that that is what drives efficacy. All the results are consistent with that from last November. We do not see increases in Pro-BNP. We do not see decreases in six-minute walk. All those things are seen in populations of patients receiving either silencer or a stabilizer drug in recent Phase III Studies that are available in a similar group of patients. The other thing they see is we've recently presented the time to first event, and that also looks very different from what we've seen in those Phase III Studies. We think when we do talk to physicians, most of them are quite impressed by the data we're seeing with Nex-Z. As I said, I think this is driving enrollment and also, obviously, will be important in our trial results that this will drive a successful Phase III T rial. Great. Thanks for the color. The next question comes from Miles Minter with William Blair. Please go ahead. Hi. This is Jake Roberge from BMO. Thank you so much for taking our question. We had a question about some changes that have recently happened at Seaborne and whether this is influencing your plans for timing of your BLA submission or plans for hiring on a Salesforce potentially in relation to NTLA-2002. Thank you. Generally speaking, changes at the FDA have been much commented on by others for good reason. We all have to work with the FDA. In our experience thus far, none of those changes have directly affected us. We've established strong working relationships with our review teams. As David mentioned in his comments during the earlier part of the call, just recently, we received our third of three instances of RMAT designation. We know people are working hard on looking at the merits of the drug, etc. Our review team has been engaged. We have meetings with the FDA, and we think we're in good shape. With respect to the most recent change at Seaborne, what we see is a strong interest in actual clinical data as opposed to surrogate markers, which we think affects areas where we're not active, whether it's vaccines or single-arm studies, surrogate markers, in oncology. All of the programs that we're running are randomized comparative trials that are controlled, and they have clinical endpoints that are unambiguous and well-standardized in the field. We think that we're speaking the same language as some of the new participants at the FDA, and we look forward to sharing our data on time or ahead of time, given the enrollment and the RMAT designation with all the indications. Thanks. The next question comes from Brian Cheng with J.P. Morgan. Please go ahead. Hey, guys. Thanks for taking our question this morning. I'm curious if you can elaborate a little bit more about your latest thinking on just a timeline for ATTR cardiomyopathy. Since during the call, you said that the enrollment is progressing ahead of projection. What should be our base case for the time to get to events, to have a first interim look for this phase III? And just given that the recent trials have been taking a little bit longer than expected, yeah, can you elaborate a little bit more on the timeline? Thanks. Just maybe lay the groundwork, and David can deal with the details. You're right. Enrollment, as we've said, is going extremely well. We're very pleased with where we are and the progression of the study around the world, U.S., ex-U.S. It's all progressing very, very quickly. Interim analyses are a function of enrollment and event rates. That's something that we'll be watching here. David, do you want to talk about any enrollment for the study? Regardless, we think we'll be done by when? How are you thinking about interim analyses? Yeah. So what we've said, and we'll keep to, is that the enrollment be finished by the beginning of 2027 and the 2026. We do think that interim analysis, the first timing, would be after enrollment is complete. In 2027, as you say, the idea of an interim analysis is that you have a drug with outstanding efficacy that you can stop a trial early because you see something at that early point. As I just talked about, we do think we have outstanding efficacy with this drug. We will continue to follow closely the long-term results in the phase one. We'll be looking at the event rate, obviously, and MAGNITUDE as well, as well as looking back at other trials. Looking at all that, we do think it's certainly possible that this trial could stop at an interim analysis based on the efficacy we're seeing. The exact timing, as I said, you need to be following these other things, events, to know when that is. We would not rule out 2027 based on what we are seeing. Obviously, as we get closer, we will give you more information on that. I would say, in contrast with prior studies, it's more likely to be early than later. I think we're pretty confident about that. The next question comes from William Pickering with Bernstein. Please go ahead. Hi. Thank you for taking my question. For the MAGNITUDE-2 PN Study, could you talk about your expectations for the enrollment rate? I know you said completion in 2026, which is understandably a pretty wide range, just given it's fairly early in the study. Do you think the Alnylam and Ionis PN studies are reasonable benchmarks? Any color you can share on early interest in the study. Thanks so much. Take that, David. Yeah. This is different from the earlier studies in that, of course, the widespread use of Vutrisiran has required us to go to countries that do not yet have Vutrisiran available. However, because those studies do not have the modern therapies, there is a very large interest from the investigators in this therapy. It will enroll briskly. As said, into 2026, as we get closer, we could give you more details on when that enrollment ends. It does give us the possibility of a submission in 2028 using standard timelines. Again, because of the high level of efficacy we are seeing in PN, and we will be talking more about this just in June at PNS, because of that, this also could stop at an interim analysis or even an accelerated approval type situation. Keep in touch. Look for the data in June, and you'll get more on where this timeline may go. Thank you. The last question today will come from David Lebowitz with Citi. Please go ahead. Thank you very much for taking my question. In terms of the primary endpoint of the MAGNITUDE Trial, given the range and for the events from, I think, 18 weeks to 18 months to 48 months, what are the dynamics relative to, I guess, costs? Number one, if the events were to come in slower, does it change at all your thoughts on what type of cash you have and need? Additionally, when looking at the Alnylam label, because they had shuffled their primary endpoint, one of their endpoints from 30 to 36 weeks to 36 to 42, but in the labeling, it ultimately was pulled to being 30 to 36 weeks for all the endpoints. How do you think the FDA would look at your primary endpoint with such a wide range on timing? Two points. First of all, from a runway point of view, we've taken a conservative view that considers the scenario that you touched on and even adding additional patients should that be the case. We think from a runway point of view, we're in good shape. With respect to the prior work that was done by Alnylam, a contrast in the design of our study with HELIOS V is that from the get-go, our study MAGNITUDE has been an endpoint study. It's not dictated by time. It's dictated by when patients experience any of the various endpoints that are included in the composite list. We don't see ourselves patching it up at the end of the study to get to some sort of average duration to get to endpoints. By its design, it should accomplish that. We think that overall, we're in good shape. We have the funding to complete the enrollment and the trial. As Ed said in his earlier comments, the bridge that we've built takes us into the launch of 2002. In contrast with other companies in the space, we're talking about commercialization and revenues coming into the company, and we're well beyond the proof of concept stage. We're well on our way to being the fully integrated pharmaceutical company that we've always intended to be. Thank you very much. Appreciate it. This concludes the question and answer session and Intellia Therapeutics F irst Quarter 2025 financial results conference call. Thank you for attending today's conference. You may now disconnect your line.