Good morning, everyone, and welcome to Intellia Therapeutics' Conference Call. My name is Jamie, and I will be the conference operator today. Please be advised that this call is being recorded at the company's request. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open the call up to your questions. At this time, I'd like to turn the conference call over to Jason Fredette, Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed. Thank you, Operator, and hello, everyone. This morning, we issued a press release and filed an 8-K regarding a safety event that occurred in our MAGNITUDE phase III clinical trial of Nex-Z. Those documents can be accessed on our website, intellia.com, and the 8-K also can be accessed at sec.gov. Before we get started, please note that during this call, Intellia management may make forward-looking statements. We ask that you refer to our SEC filings, which are available at sec.gov, for a discussion of potential risks and uncertainties that may be related to those statements. All information discussed on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. With that, let me turn the call over to Dr. John Leonard, Intellia's Chief Executive Officer. Thank you, Jason, and thanks to all of you who have joined us on short notice. We will address the safety event and will then open the call to questions. On Friday, we learned that a patient was admitted to the hospital after reporting abdominal pain to his principal investigator. This is a patient with ATTR cardiomyopathy in his early 80s who is enrolled at MAGNITUDE and received a dose of Nex-Z on September 30th. The patient's labs showed that his AST and ALT levels exceeded three times the upper limit of normal and that his bilirubin exceeded two times the upper limit of normal. This patient's labs triggered a protocol-specified pause on patient dosing and screening for MAGNITUDE to ensure patient safety, allow time to assess the situation, and consider potential mitigation strategies. Although it was not required by protocol, we also decided to pause patient dosing and screening in MAGNITUDE-2 for patients with ATTR polyneuropathy. The patient is being closely monitored and is receiving medical intervention. In addition to pausing dosing and screening, we've taken a number of other actions over the last two days. We've been consulting with clinical investigators and external experts to ensure optimal care for the patient and further assess the event itself. We've now mandated clinical sites to collect additional labs from patients in the initial weeks following dosing to detect potential liver elevation sooner. We're working with the trial's independent data safety monitoring committees as we consider other potential monitoring and risk mitigation strategies. And of course, we are engaging with global regulatory authorities and other stakeholders to finalize a plan that allows us to resume enrollment as soon as appropriate. As of today, more than 650 patients with ATTR-CM are enrolled in MAGNITUDE, and 47 patients with ATTR-PN are enrolled in MAGNITUDE-2. Of those patients, more than 450 are estimated to have been dosed with Nex-Z. As for our other investigational product, Lonvo-z, we are not pausing our phase III HAELO study, which is a study of a different drug for a different patient population. We announced the completion of patient enrollment in HAELO in mid-September. We'll be reporting longer-term safety and efficacy data for Lonvo-z from our phase I/II trial in early November at the 2025 American College of Allergy, Asthma, and Immunology Annual Scientific Meeting. To the lesser extent of the situation as it stands today, we're working as diligently as possible to ensure patient safety. Despite this recent event, we continue to believe in Nex-Z's potential to address important unmet needs for patients with ATTR amyloidosis. In fact, we will be sharing longer-term data from our phase I trial at AHA 2025 in early November, which includes what we believe will be a compelling update on various disease measures and on mortality. With that, our Chief Medical Officer, Dr. David Lebwohl, and I can now take some questions. Of course, as you might expect, we will be unable to answer some of your questions today given the recency and the fluidity of the situation, so we ask for some patience on this front. Operator, would you please provide the instructions? Ladies and gentlemen, we will now begin that question and answer session. To ask a question, you may press star and then one using your touchscreen telephones. If you are using a speakerphone, we do ask that you please pick up your handset prior to pressing the keys. To withdraw your questions, you may press star and two. In the interest of time, we do ask that you please limit yourselves to a single question. At this time, we will pause momentarily to assemble the roster. Our first question today comes from Maury Raycroft from Jefferies. Please go ahead with your question. Hi, good morning. Thanks for taking my questions. Maybe just starting off, you mentioned that you are consulting with investigators from the study. Can you provide some perspective on just initial responses from investigators and whether it could be age-related? I don't know if you can talk about other patients in the study who are in their 80s or anything else with potential baseline characteristics that could be contributing to this, that you can comment on? Thanks, Maury. It's early days, in fact, early hours, I would emphasize here, and at this point, it's just premature to comment on any sort of predictors or patient populations at risk. Obviously, we're looking into that, and we're assembling a set of questions to pursue with our DSMB and related parties. Our next question comes from Gena Wang from Barclays. Please go ahead with your question. Thank you for taking my questions. So maybe I wanted to ask, you dosed the patient on September 30th, and October 24, you know, have the events basically one month apart. I recall you also had a previous event, also grade four, I think in the previous 8-K release. So maybe if you can comment on these two events, how similar in terms of the timing and the onset and giving the prior experience, have you thought about what could be the reason? Because we understand both lipid nanoparticle and RNA, they should be gone within a few days. So maybe if you can lay out, you know, what could be the possible reason? And first is a comparison of this case versus the last case, and also what is the initial thought in terms of a scientific rationale behind it? Why would be a delayed response? Yeah, thanks for your question, Gena. You're right in that it's about 24 days between the time that the patient was dosed and when we became aware of the finding. There are similarities between the cases, the one you referenced and this particular one, in that timing is similar, that prior case presented with an increase in transaminases. This patient has increased transaminases as well as a total bilirubin increase. And so I would say, while the pattern is similar, it appears that this patient has a more pronounced manifestation of the particular findings. And that's the key difference. We'll see how the patient's course goes. As we said earlier, the first patient that you referenced did very well. He was asymptomatic, spontaneously resolved, and required no intervention. This patient had symptoms and, as we said, is being observed and has medical intervention. As far as theories here, we can only speculate at this time. You are correct in that LNPs have a class effect where typically early following administration, and I'm talking in the first couple of days, one can see some very modest, small increases in transaminases. This, we think, is different from that, and as for the exact reason why that's occurring, we don't know that answer at this point. We're assembling hypotheses, and we'll do our best to determine what we can actually learn to risk mitigate as we go forward, but at this time, we don't completely understand what's going on. Our next question comes from Mani Foroohar from Leerink. Please go ahead with your question. Hi, good morning. This is Lee for the team, so from what we know so far, granted, these are the early hours, but what we know so far regarding the underlying mechanism, is there any reason to think that this could potentially extend to other programs, including Lonvo-z? Our current view on that is that what we're seeing here in the TTR program does not applied to Lonvo-z. We've presented data from our phase I and II program, which has been presented in various forums, and we'll have an update here, as I said in my prepared remarks. I would emphasize that the L onvo-z program treats different patients at a different gene, and at this point, we think that these findings are isolated to the TTR program. Our next question comes from Joseph Thome from TD Cowen. Please go ahead with your question. Hi there. Good morning, and thank you for taking my question. Maybe on the protocol-defined pausing criteria, I guess what specifically triggered that? Because as Gena mentioned, there was the prior grade four elevation in transaminase, I guess. Was this the bilirubin, or was it that it was symptomatic? And are the protocol-defined pausing criteria the same between the 2001 and 2002 programs? Thank you. Thanks for the question. The trigger for this particular protocol was the combination of exceeding the threshold for transaminases coupled with exceeding the threshold for total bilirubin, and that's what triggered the pause. Stopping criteria, I believe, are the same for the two different protocols. Our next question comes from Alec Stranahan from Bank of America. Please go ahead with your question. Hey, guys. This is Matthew on for Alec. Maybe just double-clicking on a previous question on read-through to the pipeline platform. Can you just maybe speak to the differences in LNP drug product and dose between the two studies and why you think the HAELO study is fine moving forward? Thanks. First, I would emphasize that we have data on HAELO that we presented, and as we said in our remarks, we'll give an update on the patients we've already presented and add additional information on patients that have been following dose, either from the placebo group or the 25 mg dose from the phase II group. You'll see a larger data set. Again, I would emphasize that we do not see at this point that this is an LNP effect. The LNP characteristics, when one looks across programs and across different forms of LNPs, typically have findings that are isolated to the very first couple of days following dosing. What we're seeing here is something that's occurring three to four weeks after the dose. It appears to be a delayed response to something. Our current thinking is that that's most likely to be tied to the specific gene target and not inherent to the LNP, irrespective of the gene target. Again, the patient populations are different. What that may contribute is something that we hope to learn as time goes on. Our next question comes from Brian Cheng from JP Morgan. Please go ahead with your question. Hey, guys. Thanks for taking our questions today. Maybe just one. Has the patient liver enzyme and bilirubin been elevated since it's a one-month apart in the observation? Do you know how long it's been elevated in your observation? The patient came to our attention when he had abdominal pain and contacted his primary investigator, who referred him to the emergency room where he was evaluated and blood was drawn. That corresponds to the 24-day point that I shared with the group here in my prepared remarks. That is the first notice that we have of his having crossed these thresholds, and that was just, as we said, Friday afternoon. We'll collect additional information as the program proceeds, but the patient's just recently come to our attention. Our next question comes from Jay Olson from Oppenheimer. Please go ahead with your question. Oh, hey. Can you tell us if this case meets the criteria for Hy's Law and the current status of this patient? Any signs that the transaminase levels are coming down? And you mentioned age, but were there any other notable baseline characteristics for this patient, like viral infection, etc.? Thank you. We're still collecting information on the patient, and so we'll get a more complete picture as time goes on with respect to serologies and things like that. As you pointed out, the patient was in his 80s. Clinically, the patient is stable. Our last report was last night. He was playing cards with the nurse who's assigned to him. The patient has elevated transaminases and the bilirubin, and they've crossed the threshold, which would meet the traditional definition of Hy's Law. Our next question comes from Terence Flynn from Morgan Stanley. Please go ahead with your question. Hi, thanks so much. Maybe just two for me. I was wondering first if you could talk through what the next steps are, you believe, to get off hold and essentially start redosing and rescreening patients. And then for the HAELO study, I was just wondering. I know you've completed enrollment, but how many patients are yet to be dosed? Like, how many have you dosed and how many are yet to be dosed? Thank you. Yeah, thank you. First, I want to make sure that you and the audience understand that we are not on hold. We have, in the protocol, a specified pause mechanism, which is what we're talking about. This is something that the company has chosen to do. This is not coming from regulatory agencies. Of course, regulatory agencies reviewed our protocol with us before we began the program, so they're aware of the rules we've imposed. But I repeat, we are not on clinical hold from any regulatory agency. With respect to HAELO, we reported in September that we had completed enrollment of the study. All of the patients randomized to the drug and placebo arms have been dosed and were several weeks into the study. Our next question comes from Salveen Richter from Goldman Sachs. Please go ahead with your question. Good morning. Thanks for taking my question. You talked about aggregating hypotheses here and how you do believe it's tied to the specific gene target for TTR. Could you just comment on what other hypotheses might be at this point? Thank you. Thanks. I mean, I can only speak in terms of broad categories because that's the stage that we're currently at. We're looking to see if there's some demographic indicator. There was an earlier question about that. We have a very small data set to look at here, so it's going to be difficult to come up with a clear indication as far as we can tell at this point. But we're looking for any kind of baseline indicator that might suggest that a particular patient is at risk. One can imagine the broad category of an immunological response, and that's something that we hope to learn more about as time goes on. But that is a very, very broad category with lots of potential ways to imagine that that could be potentially involved. I would remind us all that of the cases that we've discussed previously. Patients had an increase in the transaminases that occurred in a very similar timeframe. Those patients were asymptomatic. The event resolved very quickly. Patients returned to baseline. They were well and continued the study essentially unaffected. So we'll see how that plays out here, but that would suggest that there's a self-limited course. Our next question comes from William Pickering from Bernstein. Please go ahead with your question. Hi. Thank you for taking my question. I had two, if I may. One was just across your Lonvo-z trials. Are you able to share the total number of patients that have been dosed with drug at this point? And And if available, the total number of patient years of follow-up? And then second was just plans for engagement with the agency on this, if any. Thank you. Yeah. I'm not going to be able to give you a detailed analysis of the total duration of patients on Lonvo-z and how many have been treated. You will get that as an update at the upcoming Allergy Meeting here in November, where you'll see the full duration of follow-up from patients that were in the phase I and phase II trials with the complete safety profile and the efficacy information that we have. Again, all of the patients in the HAELO study have been dosed. The target patient population was 60. We've overenrolled that somewhat. And I'll remind you that patients are randomized to one drug to placebo, so you can make an estimate with that. As far as the agency goes, this is an international trial, multinational trial. We're going through the steps that you would normally imagine. We've begun that process and are laying out whatever findings we can share as we get them. Our own recommendations, as I said in my prepared comments, something about additional monitoring, and we'll be working with our DSMB to come up with a plan that we would hope to present to the agency. Again, I would remind everybody we are not on hold. This is a self-directed program tied to the protocol itself, and we've had R MAT designation with the agency, so we would expect that we will have rapid and active engagement, and we look forward to that. The goal is to have enrollment begin as soon as appropriate, and we want to make sure that that's done in the best possible way. Our next question comes from Jack Allen from Baird. Please go ahead with your question. Great. Thanks so much for taking the questions and being so forthcoming as it relates to the update. I guess I just wanted to ask briefly on some of the prophylactic measures you have post-dosing in place right now as it relates to the existing ATTR program. What kind of steroid regimen are you giving patients afterwards after they receive treatment, and how might you revise that regimen moving forward? I know it's still early days, but I'd love to hear any context you have here. Yeah. Thank you for acknowledging it's early days. In terms of actions we will take, I think it's premature to discuss that. But with respect to what's currently in place, the regimen for patients is very straightforward. They receive a dose of dexamethasone the day before the treatment and then the day of infusion, which is done as an outpatient. Patients receive another dose of dexamethasone and antihistamines. And that's it. There's no subsequent steroid administration that's in the protocol or designed as necessary or appropriate based on anything we've seen thus far. That might be something that's discussed, but again, I'd say it's early days to imagine that that's going to change until we have a more complete plan. Our next question comes from Yanan Zhu from Wells Fargo. Please go ahead with your question. Great. Thanks for taking our questions. I was wondering, can you talk about your criteria for pausing the trial? And also, what regulators might consider with regard to whether to put a trial on hold in this realm of liver toxicity AE? Thanks. So the criteria for pausing are the ones I shared in the prepared comments. It's exceeding a threefold increase of the upper limits of normal in the transaminases, coupled with greater than a twofold increase in bilirubin. This patient surpassed that. There's no alternative explanation readily available to us to indicate something other than the drug. And so with that in mind, this patient meets those criteria, and we initiated the pause, as we said, both in MAGNITUDE where the event occurred and also applied it to MAGNITUDE-2, where it's the same set of patients, although with a polyneuropathy manifestation as opposed to cardiomyopathy. As far as regulators, I can only speculate what they might think. We have very strong relationships with the regulators. We're very forthcoming with information. We've worked with them as we put the program in place, including this protocol. Again, I'm sure that they will understand that this is a self-imposed pause so that we can take whatever actions we think may be appropriate. Those are yet to be determined. I don't know why they would need to apply a clinical hold because we're effectively not screening or enrolling patients at this point in time until we have the clinical course established for the protocol going forward. Our next question comes from Joon Lee from Truist Securities. Please go ahead with your question. Hey, thanks for taking our questions. And at least it's nice to hear that the patient is stable and hopefully recovers fully. Anything you can share about the underlying medical condition of the patient, such as BMI, MASH, viral infection? And are you screening out patients with pre-existing liver disease in the ATTR program? Thank you. Operator, I think we may have lost John. David. John, can you hear me? Yes. Go ahead, John. Sorry. Yeah. So I don't know what happened with the sound. I'm sorry about that. The patient, as I said, has a high BMI. Whether or not that has any relevance to this is something to be determined. As far as other pre-existing risk factors or concomitant medications, it's not obvious that any of those would be contributory to what we're seeing here. Of course, we'll collect additional information and consider whatever information we learn and see how that may apply to thinking about this case or the case that we discussed previously. And our next question comes from Mitchell Kapoor from H.C. Wainwright. Please go ahead with your question. Hey, everyone. Thanks for taking the questions. Wanted to ask, what internal sign-off needs to be met before you consider redosing? Is that a safety review completion, the patient's recovery, some type of protocol amendment? And are you thinking weeks or something like months for a timeline? And then separately, has the FDA indicated, I think you had maybe touched upon this, but just to confirm, has the FDA indicated whether or not a formal hold is under consideration or is not under consideration? With respect to your last point, we are actively engaging with the agency. We have not heard that a hold is in the works. We'll see how that plays out as we give them time to consider the information that we shared with them. Again, I would emphasize that they will know that we've paused the trial, which is effectively a self-induced hold, and the first order of business is working out with them exactly what is the appropriate set of changes and to what extent before we go back. Again, we have R MAT designation, which allows a very active and efficient engagement with the agency. We look forward to talking with them as soon as we can have an extended conversation with them. In terms of sign-off, obviously, we're going to think very carefully about this with all the expertise we have in the company. We have a set of consultants that we speak with. We have a steering committee and a DSMB. We will involve all of them, and we're not going to begin redosing until we have good alignment with regulatory agencies. I can only speculate on how long that'll take. Certainly, some weeks. Nonetheless, we are absolutely in the belief that the drug has a very favorable benefit-risk, and I look forward to sharing the data that we will have at AHA, where you'll see the reasons we're so enthusiastic about the agent, so as the story unfolds, we'll share more information, and obviously, we have an earnings call coming up here at some point in time, so there may be some more information then. Ladies and gentlemen, with that, we've reached the end of the allotted time for today's question-and-answer session. I'd like to turn the conference call back over to Intellia's CEO, Dr. John Leonard, for closing remarks. So thank you, everyone. We'll look forward to speaking with you soon in conjunction with our Q3 results and our upcoming presentation of lonvo-z data at the upcoming ACAAI Scientific Meeting and our presentation of Nex-Z data at AHA 2025. That concludes our call, Operator. Thank you. And ladies and gentlemen, with that, we'll conclude today's conference. We do thank you for attending today's presentation. You may now disconnect.