Good morning and welcome to Intellia Therapeutics' Second Quarter 2025 Financial Results Conference Call. My name is Drew, and I will be your conference operator today. Following formal remarks, we will open the call up for a question- and- answer session. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. 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' Second Quarter 2025 Earnings Call. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter, as well as topics for discussion on today's call. This release can be found on the investors 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 you to 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. Thanks, Brittany. Good morning, everyone, and thank you all for joining us today. 2025 is proving to be a year of excellent execution and exciting clinical updates. Thus far, we're meeting or exceeding all the objectives we set for ourselves, which sets us up well for the second half of the year. Financially, a restructuring is delivering the benefits that we expected, which support a runway through several major milestones and into the first half of 2027, when we expect to be launching lonvo-z for HAE. Clinically, presentations of the longer-term follow-up data presented from our ongoing trials suggest our lead programs have the potential to set new standards for the treatment of HAE and for both the polyneuropathy and cardiomyopathy manifestations of ATTR amyloidosis. Also, from an operational perspective, all three phase III studies across lonvo-z and nex-z are enrolling faster than we expected. We're benefiting from strong interest from both patients and physicians. That interest, coupled with our team's excellent execution, positions us to accelerate guidance we set at the beginning of the year. We now anticipate completing enrollment earlier in our HAE and ATTR polyneuropathy programs than previously thought, and we expect that we will enroll more patients this year in our cardiomyopathy program than originally planned. Among the many favorable updates we provided across our programs today is our decision to increase enrollment to approximately 1,200 patients in magnitude, our phase III study evaluating nex-z in ATTR cardiomyopathy subject to health authority review. Expanding the patient number in the study will provide a more robust data set, particularly in the stabilizer stratum, which we know will be very important to patients, clinicians, and payers. We believe nex-z, in combination with a stabilizer, will provide meaningful clinical benefits beyond treating with only a stabilizer, which will be a key differentiator in the commercial setting. It's also important to note that the improvements gained from a larger study size do not impact either our previously projected enrollment or our cash runway. When we initially designed our study, we recognized that the TTR treatment landscape could change as new agents became available during their phase III program. We also knew that we were well positioned to adapt to changes in TTR treatments because of the timing of our program. Now, with the benefit of recent clinical readouts, we know how to best capitalize on the rapid, deep, and consistent TTR reduction achieved with nex-z to make it into a formidable and differentiated competitor in this large and growing market. Based on the strong enrollment in magnitude, we also said this morning that we are now targeting at least 650 patients cumulatively by year-end. We believe this increase relative to our prior guidance for more than 550 patients is made possible by the operational excellence of our team. Importantly, it also reflects the enthusiasm from investigators and significant demand from patients to participate in the trial. Let's turn to magnitude two for the treatment of hereditary ATTR polyneuropathy. We've seen the same high-level engagement from patients and physicians in response to the promising data and potential of nex-z. Enrollment continues to track ahead of our initial projections, and we've refined our guidance, now expecting to complete enrollment of the trial in the first half of 2026. We are also equally excited about our phase III HAELO study of lonvo-z, formerly known as NTLA-2002. Today, we announced we have ended recruitment and expect to complete randomization during the third quarter. This milestone, consistent with our market research, reflects the high unmet need in the HAE community despite existing treatment options. We believe lonvo-z's maturing data and unique profile as a one-time therapy administered in an outpatient setting resonates with patients and physicians. Building further on our strong momentum, we shared positive interim data throughout the quarter that continues to support the growing body of evidence for both lonvo-z and nex-z. David will expand on that in a moment. We also look forward to sharing more clinical and operational milestones from our lead programs later this year. The positive developments within our studies have been matched by the progress we have made in building our commercial and medical teams required for a successful launch. Senior leadership positions hired within the commercial and medical affairs organizations during the first half of the year include Head of U.S. Sales and Head of Commercial Operations, as well as several additional senior leaders with responsibilities for commercial data and field operations, marketing, pricing, patient services, market access, forecasting, and medical communications. We've now largely completed our build-out of the commercial and medical affairs leadership teams. We're well underway to becoming a strong, commercially ready company. We're confident in our plans, diligent in our execution, and excited by the value-creating opportunities that lie in the not-so-distant future. Lastly, I want to take this time to announce the future retirement of David Lebwohl, our Chief Medical Officer, that will go into effect a year from now in August. David will continue to serve as CMO until a successor is appointed and will remain on as a medical advisor to work closely with Intellia and his successor during the transition period to ensure a seamless handover. As this is part of our routine succession planning, we've already begun the search for his successor. We are committed to finding a highly qualified candidate who will continue to build on the strong foundation David established. In the meantime, David will continue to lead Intellia t hrough the important clinical milestones ahead. David's leadership has been instrumental in advancing our pipeline and positioning Intellia for future success. I'll now hand the call over to David, who will provide a more detailed update on our clinical programs. David? Thanks, John. I'll begin with lonvo-z and development for HAE. As John mentioned, we are very pleased about the enrollment in our phase III study in HAE. Patient and investigator interest has been strong in study initiation, and enrollment has exceeded our expectations. When you consider that the HAELO study requires 60 patients to complete enrollment, it is notable that we screened 41 patients in April alone. This degree of demand in our study is remarkable and has enabled us to stop recruiting during the second quarter, a mere four months after dosing the first patient. A majority of these patients are coming off of leading therapies, including lanadelumab, which we believe supports the underappreciated degree of unmet need. The rapid enrollment in the HAELO study echoes what we see clearly in our market research. Patients and physicians value a therapy like lonvo-z. We find they are looking for a therapy that has the potential to give freedom from attacks and freedom from ongoing therapies. The percentage reduction in attacks is one measure of therapies for HAE, but our goal is to go beyond that standard. We aspire to reset expectations and the standard of care for patients living with this debilitating disease to achieve zero attacks in most of the patients without the need for any HAE medication. We look forward to sharing additional data from our ongoing phase I/II trial later this year. In June, we presented positive three-year follow-up data from our ongoing phase I trial of lonvo-z at the European Academy of Allergy and Clinical Immunology Congress. After just a single dose, patients remain attack-free and treatment-free for a median of 23 months. This underscores the unique value proposition of lonvo-z, the potential to offer freedom from attacks and freedom from chronic treatment. lonvo-z was well tolerated and showed a safety profile consistent with earlier data presented at EAACI in 2024. The most frequent adverse events during the study period were infusion-related reactions that were mostly grade 1 and resolved with all patients receiving the full dose. With up to three years of follow-up, no treatment-related adverse events were observed after the first 28 days, and no serious adverse events were reported in any patient. Later this year, we plan to present longer-term data from patients in the phase II portion of the study, including those who initially received a 25 mg dose or placebo and were subsequently given the 50 mg dose of lonvo-z selected for the phase III study. This phase II update will more than double the total number of patients who have received the 50 mg dose to more than 30 patients. Intellia is committed to transforming the treatment landscape for HAE. We believe that the value proposition for lonvo-z is compelling and centered on three pillars. First, freedom for people living with HAE, freedom from both HAE attacks and the need for chronic prophylaxis. Second, relief for physicians. The administrative complexity of managing insurance coverage for chronic HAE therapies is vastly underappreciated. Third, meaningful pharmacoeconomic advantages for payers. lonvo-z is well positioned to become the first ever one-time treatment for people living with HAE and the first approved therapy to take advantage of in vivo CRISPR gene editing. We'll now turn to nex-z in development for the treatment of ATTR amyloidosis. I'll begin with ATTR cardiomyopathy. As John mentioned, due to strong demand and magnitude, we're now targeting at least 650 patients cumulatively by year-end, and we plan to expand the study from 765 patients to 1,200 patients subject to health authority review. This decision is driven by our desire to increase the likelihood of achieving statistically significant outcomes that are clinically relevant for patients, clinicians, and payers. This is made possible by the strong demand to participate in our study. Increasing the sample size to 1,200 patients offers a critical advantage, enhanced statistical power within the stabilizer stratum. This will strengthen our ability to generate robust data for nex-z alone, as well as nex-z in combination with a stabilizer. We anticipate both approaches will be compelling based on promising phase one results observed to date. The expansion in sample size will also accelerate the accrual of clinical events. As John mentioned, our guidance remains unchanged. We will complete magnitude enrollment by early 2027. In May, we presented wild type and hereditary ATTR cardiomyopathy data from our ongoing phase one study at the World Congress on Acute Heart Failure. Participants who received nex-z had reduced TTR production and improved outcomes for both wild- type and variant ATTR cardiomyopathy patients. Absolute TTR levels dropped from 225 mcg per mL to 17 mcg per mL in the wild type group and 132 mcg per mL to 17 mcg per mL in the inherited disease group. Functional capacity and clinical biomarkers were favorably impacted in both patient groups, and evidence of stability or improvement in disease progression markers was observed across both populations at similar rates. The most commonly reported treatment-related adverse events were infusion-related reactions, which were mild or moderate and did not result in any discontinuations. Later this year, we will present longer-term data from patients with ATTR cardiomyopathy in the phase one study, which will include updated measures of clinical efficacy and safety, extending our promising data presented last year at AHA. Turning to ATTR polyneuropathy, we made great progress in the first few months with our global phase three magnitude two study after randomizing the first patients in the first quarter. This pivotal study is a placebo-controlled study with planned enrollment of approximately 50 patients. Patients are randomized to either a single 55 mg infusion of nex-z or placebo. We will measure mNIS+7 at 18 months and serum TTR levels as key endpoints in the study. Enrollment is expected to be completed in the first half of 2026 to enable our second VLA filing in or before 2028. We also presented positive two-year follow-up data from the ongoing phase I study of nex-z in hereditary ATTR polyneuropathy at the Peripheral Nerve Society annual meeting in May. This data showed ongoing persistent declines in TTR at 24 months following a one-time dose of nex-z. Among the patients in whom mNIS+7 assessment was completed at 24 months, as of the data cutoff, 13 months of the 18 months had an improvement from baseline greater than the four-point threshold, which is considered clinically meaningful. Most of the patients in the cohort who had progressed on patisiran improved, and only a single patient among the 18 months had a deterioration of greater than four points. nex-z has been generally well tolerated across all patients and at all dose levels tested. Treatment-related adverse events were consistent with those described for the cardiomyopathy population. This supports our growing body of evidence that a single dose of nex-z may lead to disease stability and clinically meaningful improvements in neuropathic impairment measures. Stay tuned for our symposium in September, where we plan to present extended interim phase I polyneuropathy data at the International ATTR Amyloidosis Meeting for patients and doctors. We're poised to complete enrollment across all of our studies by early 2027 and achieve several important clinical and regulatory milestones before the end of 2026. I'll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results as of second quarter 2025. Thank you, David. Good morning, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our clinical pipeline and build important capabilities required for future success. Our cash, cash equivalents, and marketable securities were approximately $630.5 million as of June 30, 2025, compared to $861.7 million as of December 31, 2024. Our collaboration revenue was $14.2 million during the second quarter of 2025, compared to $6.9 million during the prior year quarter. The $7.3 million increase was mainly driven by cost reimbursements related to our collaboration with Regeneron Pharmaceuticals. R&D expenses were $97 million during the second quarter of 2025, compared to $114.2 million during the prior year quarter. The $17.2 million decrease was primarily driven by employee-related expenses, stock-based compensation, research materials, and contracted services, offset by an increase in the advancement of our lead programs. Stock-based compensation expense included in R&D expenses was $14.1 million for the second quarter of 2025. G&A expenses were $27.2 million during the second quarter of 2025, compared to $31.8 million during the prior year quarter. The $4.6 million decrease was primarily related to lower stock-based compensation, offset in part by increased expenses related to the ongoing build-out of our commercial infrastructure. Stock-based compensation expense included in G&A expenses was $8 million for the second quarter of 2025. We continue to expect a year-over-year decline in GAAP operating expenses and are now guiding to an approximately 10% decline this year, and that our cash balance is sufficient to fund our operating plans into the first half of 2027. Thanks, Ed. Our continued progress is fueled by the core values of the company: one team, exploring possibilities, delivering results, and disrupting the status quo. We're committed to changing the treatment paradigm for patients suffering from HAE and ATTR amyloidosis. We look forward to meeting and exceeding our goals from these programs before the end of the year. With that, we'll now open the call for your questions. To do our best to address as many questions as possible, we will only be able to take 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'll pause momentarily to assemble our roster. The first question comes from Mani Foroohar with Leerink. Please go ahead. Hi, good morning. This is Lili Nsongo on for Mani. Thanks for taking our question. Now that you've increased the target number for the ATTR CM study, do you have a target proportion of patients you would like to be on stabilizers to be able to see the, or to be powered to see the benefit in combination? Thank you. Thank you for the question. As we started the study, we estimated that we would have 50%- 60% of the patients on stabilizers. It has become apparent over the course of the study that these stabilizers have become more and more the standard of care. We estimate that we may have 70% of patients who are on stabilizers. That's not a target number that we set. This is a study that looks at the addition of nex-z on top of standard of care, and that's essentially what's the rate of use out there around the world that we're seeing. As we made clear with the adaptation of the study, we want to have a highly statistically significant finding not only for the overall group in the study, but also for the combination of nex-z with stabilizers, which we think is an important clinical differentiator in the market as we see it today and expect it to evolve. The next question comes from Gena Wang with Barclays. Please go ahead. Hi, this is Hag H u from Barclays on behalf of Gena Wang. Thanks for taking our questions. Could you walk us through how cash runway won't have a major change after this trial expansion? I will turn to Ed, but I would just start by saying, as I hope has become apparent over the years, we're very thoughtful about how we peer into the future and take a very conservative view to the guidance we give and to our financial planning. Maybe, Ed, you can give a little bit more detail to that. Yep, thanks, John. Thanks for the question. Yeah, generally, we do take a conservative approach to our long-range planning and for significant investments like clinical studies so that we can run the business with confidence. For our late-stage clinical programs, which may last years from planning to execution and completion, we always assess different scenarios, different potential timelines, different potential investment needs. That is pretty standard practice for us here at Intellia. For magnitude, specifically, we consider the possibility of increasing enrollment within our scenario planning based on the emerging data from our peers in the TTR space, our own maturing phase I data from our TTR program, and then we have increasingly more market research that we are getting from physicians and payers to inform our thinking here. We have only recently made the decision to increase to 1,200 patients, which relative to our three-year plan represented a modest uptick, immaterial uptick in costs that we can absorb without impacting our cash runway or our net cash burden guidance that we provided through 2025 and 2026. The next question comes from Maury Raycroft with Jefferies. Please go ahead. Hi, good morning. This is Farzin on for Maury. Thank you for taking our question. For nex-z, while you're accruing longer-term phase I/II data, what is the latest regarding your assumptions on phase III events accrual rate? If that also prompted you to expand the study to 1,200 patients? Thanks for the question. We're not talking about specific event rates, but obviously, we look at information that's become available from a variety of sources. As we said in our comments to open the call, we've seen information that's come from competitors in the space, which we think provides useful information in terms of the current standard of care and how patients are treated and the rate of their disease progression. We supplement that with databases that come from other sources that, again, we think gives us contemporaneous information in terms of how patients with the disease progress. Also of significant importance is the information we're collecting from our own phase I patients, which we've reported on previously, and we will extend the reports later this year. What we've seen in work that was published in the New England Journal and presented elsewhere is that the very deep, rapid, and sustained levels in TTR reduction translate into what we've long expected to be a lower event rate. As we continue to monitor those patients, that also figures into our calculations. When you step back and look at the changes in toto, we expect that we will have an even more robust outcome than we expected before, not only for the overall, but for patients on stabilizer. We'll be able to have enrollment fall within the original guidance, which we're very excited about, and be in a position to march towards what we think will be three prospective launches by 2030. All in all, we think we're increasing the overall likelihood of success for the program in a way that fits within the guidance that we've long put out. Thank you. The next question comes from Luca Issi with RBC Capital. Please go ahead. Oh, great. Thanks so much for taking my question. Maybe, David, can you just talk about enrollment pace between your trial for ATTR cardiomyopathy versus the leaders? It looks that AstraZeneca started their Pillar trial around the same time as your trial, and they have now enrolled 1,200 patients versus you're obviously guiding for 650 patients by the end of the year. Does that reflect a higher appetite for patients and physicians to choose the leader versus gene editing, or are there any other factors like differences in inclusion and exclusion criteria that we should keep in mind here? Maybe a bigger picture, has the availability of three commercial options in ATTR cardiomyopathy slowed down the pace of enrollment in any capacity? Thanks so much. David, do you want to take that? Yeah. What we've seen in the pace of our trial is, we think, pretty astounding. To get to more than 650 patients at the end of this year and 1,200 patients by the first quarter of 2027 is really unprecedented and very exciting. There are differences from the depletor study. They took basically all patients, including some very sick patients, patients on any type of therapy, including TTR reducers. It is a very different trial. When you look at our trial in a period in which [flutamide] is coming out, acoramidis is coming out, our enrollment has actually increased during the period that the new drugs were available. What we see is a strong interest from both patients and physicians to get onto our trials, and we feel very good about that. So much. The next question comes from oon Lee with Truist Securities. Please go ahead. Hi, good morning. Thanks for taking the question. This is Mehdi on for Joon. Given almost binary response to lonvo-z, how would you maintain the study blindness? For the patients that still might show some breakthrough attack, would a half or full dose re-dosing be able to ensure complete responders? Thank you. David, do you want to speak to how we protect the blind? We're taking standard procedures, and there's nothing inherent about the design that should lead to unblinding. If you want to expand on that, David, be my guest. Yeah, our trial is very similar in design to other pivotal trials in this disease. Patients will get an infusion that is actually unknown to them what that infusion is. The physician doesn't know what the infusion is, so it really is a very well-blinded study. Of course, the patients may experience different things, whether they have a response to the drug they're receiving or not. That is not considered unblinding because they really don't know if they've received the drug or not. As you know, there is also a strong placebo effect that can take place in every trial. We are confident that the trial has a great deal of integrity in terms of blinding, and you know it's really in good shape moving forward. I would just add to that that one of the very valuable aspects of this particular trial is that we're actually measuring clinical events. There's not much subjectivity involved. Patients either have an attack or believe they're having an attack and act on that with on-demand therapy. We measure discrete outcomes, and that is why these studies are so effective at finding the effects of the drugs. It's true that based on our earlier data, patients respond very well who get the drug, and we're looking forward to hopefully replicating those results in our phase III study as that becomes available. The next question comes from Alec Stranahan with Bank of America. Please go ahead. Hey, guys, this is Matthew on for AleC. Appreciate you taking our question. Maybe double-clicking on the previous one. I guess, can you speak to whether changes to your enrollment expectations in magnitude or stabilizer percentage have changed your thoughts around the likelihood or timing of a potential interim readout? I would say that as we've made the adjustments, we are increasing the overall power of the study, not only for the primary outcome, which is the addition of drug on top of standard of care, but presumably also for the TAP subgroup, which was a lot of the thinking that went into this. Our expectation is that at some point we will do an interim analysis, and we would expect that these changes would favorably affect the ability to find an effect at the point that we do that. The next question comes from Andy Chen with Wolfe Research. Please go ahead. Hey, this is Brandon in for Andy. In regard to the expansion of magnitude, you mentioned increasing the likelihood of seeing that SIG. What were the specific data that you were trying to generate for you to show compelling information to payers and physicians? That's what we're curious on. Thank you. Without getting into specific statistics, maybe David, you could just talk about the importance of showing profound clinical benefit in ways that are unambiguous. Feel free to enlarge on that. Yeah. What we're very interested in as the trial went forward is that tafamidis is becoming a standard of care around the world. We're seeing an increasing percentage of patients who are receiving tafamidis in our trial, and of course, we hear it in the commercial world as well. This seems like it will be a baseline going forward, and we thought it was very important to show a major benefit over that, a significant benefit and a clinically meaningful benefit. This has not been shown with any other drug, the ability to add to stabilizers, but looking at our phase I data, it looks that we do have that possibility. We have very strong data related, as John mentioned, we get deeper and more rapid reductions than other drugs, and that seems to translate based on our AHA data we showed last year into better clinical results. We're very excited about what we're seeing, and we do think that our goal will be to show a benefit over tafamidis, and that's why we wanted to enlarge the trial and actually get to the endpoints more quickly because we have more patients. Of course, events will accumulate more rapidly by having more patients. I think it's important to add that all in at the end of the study, we want the data to be absolutely unambiguous across the spectrum of treatment of the disease, whether it's nex-z added to standard-of-care, whether it's nex-z alone, or nex-z in any way that may be used. This study has increased with the number of patients, gives us the power to demonstrate those outcomes, which will be very, very important to differentiate the product and have it be successful in the marketplace. The next question comes from Troy Langford with TD Cowen. Please go ahead. Hi, congrats on all the progress in this quarter, and thanks for taking our question. With respect to the phase I ATTR cardiomyopathy update later this year, can you all just give us a little bit more color around what level of progression you all would normally expect to see on the various functional measures in patients, just given the patient population enrolled in that study and the amount of follow-up? Are you asking about within the phase I study, I guess? David, do you want to speak about the clinical results that we've reported thus far and what would otherwise have been expected? Yeah, let's talk about that. As mentioned, the first thing is to look at the effect on TTR. The levels come down within a month, and they come down to levels of about 90% reduction in all patients very consistently. No patient is left behind with that. What we showed at AHA last year was that when you have the measures of progression, such as proBNP, such as six-minute walk, unlike placebo patients and unlike patients on some other agents, they do not show the worsening in those trends that we've seen historically. There is now a lot of data available for multiple phase III trials. What we do see is stabilization and, in some cases, improvement in the patients in those measures. This is unprecedented, really, with any drug. Based on that, we've also looked, as John mentioned, at event rates. The event rates in this group of patients who are actually at high risk of worsening because they're 50% Class III patients, a high percentage of variant patients. Despite all that, the event rate is very low relative to what we see historically in other settings. All that comes together to say that in this data update, we look forward to you seeing it. We have more extended data in this group of patients, and as we said, we're excited about what we're seeing in those phase I patients. The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead. Hi, this is Yuriy on for Kostas. Congrats on the progress and thanks for taking our question. We have one on nex-z, ATTR cardiomyopathy. What are your latest thoughts around potential drivers of grade 4 LFT changes following nex-z treatment, given the signals occurred roughly three to four weeks post-dosing? Thank you. Yeah, you're referring to a patient that we reported on back in May where a patient had a transaminase elevation. I would point out that with respect to drug-induced liver scores, this was a grade one, which is mild. The patient was asymptomatic, required no therapy, has returned to baseline, continues in the study, and is otherwise doing well. We are unaware of other instances of that in the study. At this point, our belief is that this is unlikely to be directly related to LNPs. As we consider other alternative explanations at this point, that's under investigation, and we're not in a position to attribute any particular mechanism to the finding. The next question comes from Brian Cheng with JPMorgan. Please go ahead. Hey guys, thanks for taking our questions this morning. Just maybe I want to confirm one thing. With the expansion in magnitude, is the study now powered to show statistical significant difference in the subset who are on stabilizer background? Thank you. The answer is yes. The next question comes from Mitchell Kapoor with H. C. Wainwright. Please go ahead. Hey everyone, thanks for taking the question. Can you speak to the qualities of patients who are coming on to your gene editing studies who are comfortable with a permanent treatment? What are you learning about these patients in particular that could help with commercial launch positioning for gene editing options in both HAE and ATTR? Based on these learnings, what proportion of these patients from the total addressable market standpoint might be open to a permanent option versus the proportion who would likely not opt for a permanent option? What are your findings on that? are several levels to the question you're posing. The quality of our patients, if I understand the question, is high. These are patients who meet the inclusion exclusion criteria that are set for these studies, which is representative of all studies typically done in these different conditions. Patients, if I understand your question, do not have their back against the wall or anything like that. They consider the treatment options that are available to them otherwise, and we encourage them to discuss that with their physician, and you see the results. The clinical trials are all enrolling robustly, and as we've said several times today, all are ahead of what we thought were already very aggressive enrollment criteria and plans. We have been very, very enthusiastic about that. As David said in his comments earlier, it's interesting to look at how patients act when, in the case of lonvo-z, they're receiving a standard of care that is widely used in, for example, the United States, lanadelumab. Many of the patients have chosen to come off that therapy and enter into our study. What that means is they wash out of the drug, they expose themselves to the opportunity of getting drug or placebo and subject themselves to what happens during that observation period. That suggests to us that they're strongly motivated to find the outcomes possible with what we think may be a permanent improvement in their disease. The same thing is true with cardiomyopathy. These are patients who are not denied any other therapy that is otherwise available to them up to this point, and patients have come into the study in a very robust fashion, independent of where they're located, in the United States or elsewhere around the world. We have been very enthusiastic about the response of the patients to the study and to how they think about options for care. I think the notion of a permanent fix, if you will, for their disease is something that we find patients and physicians embracing when they consider the alternatives for the particular diseases that we're studying. The next question comes from Jay Olson with Oppenheimer. Please go ahead. Oh, hey, this is Cheng on the line for Jay. Thanks for taking the question and congrats on the quarter. Just back to the MAGNITUDE study, I'm wondering why the 1,200 number is the right one, and is this a final number where you think we may further adjust the target enrollment down the road if any assumptions may change over time? Thank you. We're not planning on adjusting the numbers going forward. David, maybe you can give a little more information just in terms of what 1,200 does for the study and why it's what we think is an optimal approach. What we looked at here are several things. One, again, as I talked about, are the phase I results. We saw there, based on the outstanding results we reported, that there's an opportunity to show a benefit in the stabilizer population. This is not an opportunity that we think other drugs have had. We've seen that there have not been a significant difference, for example, in some of the leading drugs going forward, but we see in our data that possibility. Based on that, we thought it was very important to show that statistically significant, as well as clinically meaningful benefit in that subpopulation. With the very brisk enrollment to the trial, we also saw that we could enroll 1,200 patients in the timeframe in which we've guided complete enrollment. That number really looked optimal in terms of the timing of both a final analysis and an interim analysis that will be taking place, that this gets us there to analysis faster because you have more patients, more events occurring, but also it's not so many patients that you're waiting a long time for the enrollment period. That's where we got to, and we think this will be, and as you've also heard, it maintains our runway. Putting that all together, this is the number we chose. You actually see this size is similar to other studies that are out there, so it's not that unusual. The difference is that we do believe that based on our efficacy, we can show a benefit, a specific benefit in the TAP group. It doesn't seem like that would be possible with a lesser effect on TTR. Thank you. The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead. Great, thanks for taking the question. I was wondering, in your statistical planning, did you allow any, did you consider any difference between the first-generation stabilizer and the newly approved stabilizer? Perhaps also any updated thinking on the percentage of patients on silencers in the study, and what do you expect to learn from those patients? Thank you. Yeah, I can start us off, and David can deal with the silencers. I mean, as we look at the clinical data for the second-generation stabilizer, we don't really see much of a difference between that and tafamidis, and that's how we're approaching that with respect to the study. David, if you want to talk about silencers or any other comments on stabilizers, be my guest. Yeah, we did anticipate that silencers would become available during the period of the trial. Based on the phase III trial and based on what Alnylam is saying, the main usage of that would be upfront or a switch from a stabilizer to a TTR reducing drug. We do not allow the patients who come on to the drug as a first-line agent onto a silencer as a first-line agent, and the physicians around the world are obviously very aware of that, that the patient would need to choose between one or the other. What we're hearing from physicians, they're excited about the possibility of getting both a stabilizer and a TTR reducing agent in combination as they can on our trial. As you see, we still have very good enrollment of patients joining the trial despite the availability of silencers at this point. We also anticipated that some patients might switch from diflunisal to tafamidis during the trial. That is figured out in our statistical analysis, and we find the predictions that we're able to get a positive result despite that, despite these crossovers, seems quite clear based on our analysis. The difference between [ATTR] and tafamidis in your statistical consideration? No, they're considered to be the same based on the data that we have available. Great. Thanks. The next question comes from Jonathan Miller with Evercore ISI. Please go ahead. Hi guys, congrats on the progress, and thanks so much for taking my question. Since we've had so many on magnitude, maybe I wanted to switch over to the upcoming commercial side of things. I know you've been building a commercial team and market access, et cetera. I'd love to get updated feedback from those folks on how you think payers are going to react to gene editing, obviously, especially in the HAE setting. Is there a "cure rate" that is a bar for payers at particular price points? I'd just love to get a sense of how you're viewing commercial setup. Thanks for that question. As we've said elsewhere and in previous calls, we expect to be working within precedented numbers with respect to prices. Some individuals have very imaginative approaches to what they think the pricing will be. I don't think that's going to apply. We take a very thoughtful approach to the pharmacoeconomics, and we're trying to come up with products that will be win-win for the clinical setting and for the payer side as well. We've been interacting with payers as our commercial teams come into being here and, by and large, have corroborated our early thinking. It really comes down to the nature of the outcome, which, as has been commented on here in several instances, whether it's lonvo-z or the treatment effects that we're seeing with TTR, both in PN and cardiomyopathy, those effects with the studies that we're designing should make the clinical benefit very apparent to the payers. One-time therapies are easily confused. There are precedents out there that don't directly apply to us, and the ease of use of the outpatient infusion approach that we have, coupled with the excellent outcomes we think are going to offer a real positive opportunity for the payers. As that story becomes clear, we'll share more results perhaps even later this year. The next question comes from Salveen Richter with Goldman Sachs. Please go ahead. Hi, this is Mark on for Salveen. Congrats on the progress, and thanks for taking our question. Our question's on the competitive landscape for nex-z. I'm sure you saw that the competing RNAi therapy posted really strong results this quarter, and I wanted to get your thoughts here on how this impacts the overall market patient-physician awareness, also payer dynamics, and your views on nex-z's commercial positioning in the space. Thanks. Yeah, as we said at the call, we expect to have a product that will be a very formidable competitor for Imbutryl or any of the other agents that are in the space. We are taking actions in the study to give us a label that we expect will position us very, very favorably. Overall, with respect to the performance of these other drugs, it confirms our long-held belief, which has been corroborated by market research, cognitive physicians, and leaders in the space, that this is a large, growing, significantly underdiagnosed marketplace that is frequently misunderstood. While it's true that patients with peripheral neuropathy typically have a heritable form of the disease, in the case of cardiomyopathy, the vast majority of these patients, on the order of 90% or so, have wild-type disease. That means these patients have the result of their TTR cardiomyopathy caused by aging, not by an underlying genetic disease. There is a large supply of these patients that we will compete for very aggressively when the product becomes available, and we're excited about our prospects. The next question comes from David Lebowitz with Citi. Please go ahead. Thank you for taking my question. Curious, given that there's another therapy that does kallikrein knockdown, potentially entering the market soon, obviously a different overall modality, but is there anything that you would be looking for in their launch to help inform how you think about a potential launch for yourselves with lonvo-z? We pay close attention to how all of the other products and new entrants are doing. We believe that the profile that we're bringing forward is unique in the space. While there are ways to knock down kallikrein, we're aware of only a single agent, lonvo-z, which knocks it down on what we believe will be a permanent basis that yields outcomes that are truly unique. Excellent clinical performance, that is, absence of attacks for the vast majority of patients, and no further need to take therapy. No other drug accomplishes that. If you ask patients, what they're looking for primarily is freedom from their disease to the greatest extent possible so that they can change jobs, they can avoid stressors, they don't have to carry agents with them to the greatest extent possible. lonvo-z uniquely offers that. From a physician point of view, taking care of these patients is very challenging because of the ongoing and recurring insurance reauthorizations. For those physicians, we believe lonvo-z will offer a very significant advantage in the care of their patients by making it easier. Across the board, we expect to be, again, a very formidable competitor. This concludes our question and answer session and Intellia Therapeutics' second quarter 2025 financial results conference call. Thank you for attending today's conference. 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