Hi, everyone. My name is Maury Raycroft, and I'm one of the Biotech Analysts at Jefferies. I'm happy to introduce and welcome John Leonard, the CEO of Intellia. We're doing fireside chat format. Thanks for joining us today, John. Maybe for those who are new to the story, if you can give a one-minute intro to Intellia. Sure. We are one of the original CRISPR-based companies, and have been in business now since 2014 when the company was created and have looked to take a broad-based approach to CRISPR-based therapy, but focused primarily on in vivo uses. We've been, I'd say, the pioneers in the in vivo space. We reported the very first editing of a human being in vivo with our TTR program, and then the second gene ever edited with the HAE program, and have played that out now where we've just completed phase III studies for HAE, lonvo-z is the name of the drug, and are midway for the phase III program for the TTR type amyloid for cardiomyopathy and polyneuropathy, and we have a research effort as well. Got it. Yeah, it's a great intro. We were just talking before this about how long I've been covering you guys, and it's a great time to see how the programs have developed from preclinical to clinic and seeing these phase III results. Maybe starting with lonvo-z and HAE, you reported impressive phase III top-line data there. What are some of the key takeaways, and what are some of the new observations related to the data that investors should know since the top line? Yeah, thanks. We'll be adding to the data at the upcoming EAACI meeting in about 10 days or so, where we'll go well beyond top line and talk about patient-level data. As you might imagine, we were very pleased with the results. What we showed was in this 28-week observation period, patients had attack rate reductions that were averaged out at 87% from baseline. I don't think that really conveys actually all the benefit that patients had. When you look at what patients came in on prior therapy, virtually everybody was, before they washed out, what we see is that everybody was better off, or if they were well- controlled already, they lost nothing. We were really excited about keeping people excellent or making them better than what they were, without exception. I think that's a really important point. What's unique about the drug, and this is by virtue of its one and done gene editing approach, is that all of this comes following a single application. The IV infusion done as an outpatient. What we saw was that in the six-month observation period, 62% of patients reached a state of no attacks with no other therapy. For the remaining 38% of patients who may have had an attack somewhere in that six-month period, every single one of them was off long-term prophylaxis and have remained that way. When you step back and look in toto across the entire program, we've essentially eliminated the use of long-term prophylaxis and the overall utilization of any therapy, of whatever ilk, for on-demand, is substantially reduced. It's, we think, a very significant advance for patients, for payers, and ultimately for the physicians that care for them. Got it. Yeah. You announced the start of the rolling BLA submission in April and plan to complete it in the second half of this year, targeting a first half 2027 launch in the United States. Walk us through the pacing of the rolling BLA. What modules have already been submitted, and what remains for clinical data, and how much additional follow-up safety is going to be in the filings? Yeah. I won't be able to give you all the chapter and verse, except that we're well into the process. We typically try to be very conservative about the guidance we give and aim to over-perform. I think the key point is that there's really no technical work that needs to be done. It's complete. What we've been waiting for is just what we discussed, the clinical data, so that that could be added and ultimately submitted. We get questions about the CMC state of the program. That's in excellent shape. There's no last-minute thing that needs to be done. There's no comparability studies, for example, that are necessary. For the phase III work, we used what is essentially commercial material, and we've been building an inventory for the ultimate launch. Things are well in hand, and given that we have RMAT designation and have been participating in pilot program for some of these CMC studies, we think we have a pretty good understanding of what the FDA is looking for. Got it. For the filing, how much additional safety follow-up are you going to have in there? Well, what we presented for top-line data was through week 28, then some we anticipate that that will be extended for a late-stage supplementation to the file. The phase I and II work, we will be updating sometime later this year, and we'll be in a position where that will be added to the file. We're working on our fourth year of follow-up for those patients. I think they'll have a pretty good sense of what the durability is from the get-go, with a really long horizon. Got it. It sounds like with the filing, shouldn't be too many surprises based on how things are going so far. As far as we can tell. There's been little controversy in our interactions with the FDA. They've been pretty clear about what they needed. We've tried to design a program that addressed that and shared a lot of information as we've gone. People ask about some of the atmospherics at the FDA. We haven't seen them affect our review team. We've been fortunate in that that's been consistent really for several years now. Yeah. Okay. In your top-line update, you had one slide that shows the attacks over time during the blinded period and then beyond 28 weeks. There's the clear crossover benefit, and then both curves go to zero. Is this zero signal representative and a predictor of the longer-term effect? I think investors appreciate how your data gets better with longer follow-up. Will you and the FDA be able to capture this differentiation in your label? That's the hope. That remains to be seen. That's going to be part of the review process, just how much of that additional information the FDA will permit us to show. It does capture what we think is an important aspect of HAE, the disease itself, and how patients behave with respect to the therapy that they take. In a double-blind study, as we've done, patients don't know if they've received a drug or not, and they're trained that if they believe that they're in the early stages of attack, to act on that with on-demand therapy. All of those instances count as an attack, right? There's th e obvious objective sorts of attacks where you can look in the mirror and see what's going on, and then there's the far less, the more subtle sorts of things where somebody may have an itchy throat or an abdominal cramp, and they act on that as if it were the same type of attack that's readily observable. Knowing that patients have received therapy, which would be after a crossover, so whatever side you were randomized to, once you go past the crossover, you're certain you've received the drug, gives patients the confidence to know that they've received something. Right? What we find, and it's been observed by investigators in other trials as well, that patients are a little bit more confident waiting a little longer before they do on-demand therapy. If nothing develops, you start to see that flatten out to get the real effect of the drug. I would say the phase III double-blind study really underestimates the total effect. As we have seen now in phase III and we saw it in phase I and phase II, once patients know and give them enough time, virtually everybody is off long-term prophylaxis, and the vast majority of these patients are getting to no attacks, no therapy. Got it. You mentioned the phase I/II data going out to four years now at this point, could go in the filing. Do you think that could end up in the label as well? I don't want to commit to that. We're working on our fourth year for the patients who are farthest out. I think the challenge for the FDA and us will be to give good representative data, and that'll be a discussion. Got it. You've guided to having the additional HAELO data at the EAACI in June. What subgroup analyses, quality of life, and biomarker correlate should investors expect, and how could these data inform label discussions with FDA? We gave top-line data just about three weeks ago now, which was the regulatory measure in terms of attack rate reductions, this no attack, no therapy data, and some top-line information, which was really, I think, pretty much captures the safety profile, which was quite clean. What we'll have at EAACI will be patient-level data along the lines of what we've shown previously, where you have swim lanes, that sort of thing. Yes, there'll be more information on secondary endpoints. I think one of the pieces of data that'll be welcomed by many people is typically in these studies, what you see is patients having a baseline attack rate off all therapy. Then you see what happens once they are randomized to whatever drug that is being studied. We will also have data that shows the attack rate for that patient population before they washed out, and then you can compare where patients wind up after therapy to where the group was before they began. I think that's helpful information because that, in many respects, I think captures the real-world situation that patients experience. Got it. Okay. Your phase III enrolled a diverse mix of patients, including approximately 70% who washed out a longer-term prophy to enroll. Do you have a sense of how patients' baseline disease severity and prior treatment regimens impact their responses? It seems like the answer would be that you see pretty consistent effect across all patients, but any unique subsets in there? We haven't. We've looked, obviously, and the inclusion/exclusion criteria allowed a very broad base of patients, whether long-term prophylaxis, only on-demand, or the overlap. Disease severity control, these were not factors that determined that whether or not a patient came into the study. All they needed to do was have a basic attack rate off therapy that we could then measure. When you go back and look at it every which way, we have not seen a clear indication that one type or another tends to behave differently, which we're, as you might imagine, quite excited about. Right. Okay. For the BLA filing completion, do you think by end of October is a fair assumption, or could it be earlier? You're assuming priority review based on the RMAT designation. Is that still the latest thought there? I like your attempt to nail me down. We've said second half. I will say that we try to underpromise and overdeliver. When you look at how we've done things in the past, typically we're ahead of schedule. I hope that will also be true here. We'll see, but I can't commit to a particular month. Yeah. Okay. Yeah. Priority review. The RMAT designation enables us to have certain advantages, and we'll find out when everything's complete how they're going to handle it. Our expectation is that'll be a fairly expeditious review. Okay. What's the latest on ex-U.S. strategy, and are you considering potential collaboration or distribution partnerships or outright out-licensing? Yes. To part two, and right now the focus is the U.S. We're in this by ourselves by choice, and we've assembled a team that we think can get the job done. This is, in many respects, a market well-suited to a company like us. The patients are captive, if you will. They're identified. We have to go out and find them. We know where they are, and we have several people who have joined our commercial group who have been in the space previously. That knowledge I think is very, very helpful. We want to get the U.S. right. That's where the bulk of the value resides. There is value outside the U.S., and we're going through some work now to determine what's the best way to capture that. Got it. All those options are on the table. It could be full- At this point, yes. Yeah. Okay. All treatment-emergent adverse events in the HAELO study were Grade 1 or 2 with IRRs, headache, and fatigue. There are no serious AEs in the lonvo-z arm. What's been the feedback from KOLs on the outpatient infusion experience? It's been very favorable. The infusion reactions when they occur, and as you pointed out, they're there. If it's going to happen, it's on day one. The most significant intervention has been either to slow the course of the infusion to the full four hours, these infusions are designed to be over two to four hours, or using Tylenol. That's essentially been it. When patients experience something, if they do, it tends to be transient. In essentially all cases, it's gone within a day, and typically gone within the time of the infusion. I don't anticipate that's going to be a impediment that's significant as we go forward. Got it. Okay. Maybe talk about where you're at with HAE commercial readiness. You recently noted that your top priorities include scaling reimbursement teams and finalizing pricing and contracting strategies. What's the status here, and how are conversations with payers progressing, and have you narrowed what the price range is going to land at? We're working on the price. We're not right to share where we are. What we have said publicly is we're not going to set any new records. We believe that the product has the potential to satisfy a lot of parties. I think it's going to simplify the life for doctors. I think payers are going to get a rapid return on what this is, given the expense of caring for these patients. Ultimately, the patient is the one that derives the ultimate benefit, which if past is prologue here, they should be looking at a very encouraging life before them that I think in most cases will be devoid of long-term prophylaxis and a lot of the therapy that's been taking, and presumably very few, if any, attacks. The commercial team leadership's in place. We're down a tier below that, and we have people actively engaged with leading accounts, which has been progressing very well. I think we're in a really good spot with respect to the plan that we've laid out, and we've had, as you might imagine, the medical people in the field for many months now. We're doing a lot of educating. It's been some of the early data, but now with the phase III data that we'll have in hand, we want to make sure that people who need to know about that do know about it. Got it. Okay. Walk us through your CMC strategy as you're part of the FDA CMC pilot program, and what do you expect COGS to look like at scale? It's important to recognize that this is an entirely synthetic formulation. This is not viral based. It's not a biologic in the sense of a cellular-based product. We've nailed down our suppliers and how we assemble all this, and we've been, as I said, with the clinical work, carrying that out. We've had a dress rehearsal, if you will, for the commercial point of view. I would expect that at prices that one might anticipate in this space, the margins will be very substantial, which I think gives us a lot of room to think about how we can use those dollars for the company. Got it. Okay. Your internal blinded market research showed that 64% of patients would be extremely or very likely to take lonvo-z based on its target profile. In the real world, how do you expect the actual switching dynamics to play out among patients who may be well controlled on newer orals or long-acting injectables? Sorry, I have a little- No problem. frog in my throat. We think what we've seen in both phase II and phase III gives us a good read in terms of how to switch. If you think about it. It's essentially thinking about the timeline to get the effect of the infusion versus whatever drug you may have been taking to begin with. If you are on demand therapy, that means you're reacting to attacks as they take place. That's not going to change. If you're on some prophylactic agent, it's a matter of thinking about what the half-life of that is and covering that over the duration before our drug takes place. From a pharmacokinetic point of view, I think it's very straightforward. With respect to payers and physicians, I think it's a matter of planning, and the good thing about this is that there should be adequate time and knowledge that we're going to simplify as much as possible with the commercial work that we're doing to make sure that that process is as frictionless as possible for the doctors and the patients that they treat. Got it. Okay. Makes sense. Wondering if there's an ideal low-hanging fruit HAE population that's out there, potentially based on high attack rate frequency or poor response on a long-term prophy. You mentioned you know where these patients are in the U.S. I guess you have good insight into who initial adopters could be. Yes. We have worked with some of the leading centers already as we carried out the phase III program. We have a good sense of those practices, and they are already interacting with the account personnel. That's going very well. Our research does not identify one group that is going to be, by attributes of their disease, whether it's severity or on some other subgroup of medication, et cetera. What we find is that patients are very highly involved in the decision making in a conversation with their physician. A physician doesn't typically mandate. It's very much a, how do you live your life? What's your activities of daily living? What does that look like, and what are you trying to achieve? We believe, and the market research assures us of, that we should be suitable in the vast majority of those cases. I think what we're going to find is that, contrary to what some people think, that people with the worst disease are going to come forward. If they do, we'll take care of them. We'll make the drug available. I think it's going to be a very patient-driven sort of process, where they think about how the disease affects their life and what they're trying to achieve. Not just control the disease, but as much as possible being rid of the burden of whatever administrative exercises they have to go through to get access to the drug on a recurring basis or even how they administer it to themselves, because we can simplify all that. Got it. Okay. Your market research also indicates that treating physicians would prescribe a product like lonvo-z to approximately 54% of their HAE patients. What's your strategy to educate doctors and boost the doctor adoption rate? Yeah. Education is fundamental. If you step back and say, "What's the bigger picture here?" In my opening comments, I said we were first to do certain things. We were the first with phase III data in a gene editing product that's in vivo, and we're, in this particular disease space, first to do this. That's why I said we've had our medical affairs folks out spending a lot of time helping physicians understand what does it mean to gene edit. What is the process by which that happens? Here's the set of data to look at across all the work that we've done, whether it's basic or in the clinic. What we've tried to do is make sure that the affinity associations have what they need to carry that on for us, and then, as you might imagine, have some people become truly experts in the treating space who can carry on that education for us. We just have to assume that this group is starting from a low basis of understanding because this is a new category entirely. Right. Yeah. How do you think about penetration rate, pricing assumptions, and we talked about pricing, but I guess peak sales estimates? That's a second try for the price. We want to be really cautious as we think about the early months after the drug is approved, and there's reasons for that. If you think about it, chronically administered therapies, o f which every other drug in the space is, permit a patient to be on preexisting therapy, an open label extension, for example. Once it's approved and commercially reimbursed, you can flip those patients to pay. You get sort of a running start. That doesn't apply in this situation, because if somebody's been treated, that's it. That's the good news. You only need to have a single administration of the drug. What that means is I don't have momentum of a whole bunch of patients that are initiated that I can flip over. We essentially start from zero. Which is fine. Most of the work will be in the first months very much about access. That's going to be the single biggest. If you want to think of bottlenecks, that's the one that I think really will open up the flow here. I would expect that as that falls into place. We know the demand is there. It's having the approval process and the physicians with the access to infusion sites. We're laying that foundation now to make sure that they can get the therapy. Got it. You talked about educating doctors. The patients that you treated in the study already, they can't convert over because they've already been treated. It's a pretty small patient community in the U.S. I guess, talk about just how the patient advocacy could play out for this. Yeah. The HAE Association does a wonderful job of making sure patients with this disease are well-informed of what the options are. They're not advocates for a particular therapy, they're advocates for the patient population. They do, I think, a really nice job of making sure that patients can come together on a fairly frequent basis to get a lot of information. News travels fast. If you think about it, there's maybe 7,500 or so patients who are treated for HAE in the United States. That may be a little bit of an underestimate, that's what claims data, depending on where you look, that's what it looks like. What we've found is that as patients are treated and have the outcomes that we've described, they become evangelists. Already we're starting to see some uptick in social media from patients from the start. We're passive entirely in that process. Patients tend to be pretty enthusiastic about what happens to them after. Our guess, and I want to emphasize guess here, is that as that picks up in terms of a larger number of patients who have had the experience, the word will spread quite quickly. Got it. Makes sense. I want to shift gears to talk about ATTR for nex-z. Earlier in first quarter, FDA removed the clinical hold on MAGNITUDE for cardiomyopathy and MAGNITUDE-2 for polyneuropathy. What's the status of IRB approvals to resume patient screening with updated enhanced monitoring protocol in place? Yeah. As you just pointed out, we made some modifications to the protocol. Actually, it is both polyneuropathy and cardiomyopathy, which is some more frequent monitoring in the short interval after patients have been treated with the drug and then put in place an algorithm for using reactive steroids for a very short course, we would anticipate if there is a meaningful rise in transaminases. That means that informed consent, investigator brochure, the amendment of the protocol have to be approved. That is playing out as we speak, and given that there is well over 100 sites in a variety of different countries, some of these things have different points along the way. We are currently screening patients, and dosing is beginning. We will see as the weeks go by here, as we get more data points here, just what the trajectory of that uptick looks like. Got it. You've noted that a retrospective look suggests very few prior patients would have been excluded under the new criteria. What's your latest thinking around potential timing for enrollment cadence this year? I guess, would you anticipate you can get back to that enrollment that you had prior? I'm hoping we can. We had, prior to the event at the end of October, every month was ex-- In fact, we were finding we were accelerating on a weekly basis. Doctors liked it because it was simple, patients liked it because it was literally one and done, and the protocol was not cumbersome to follow through on. We'll see how these additional measures pla y out as time goes on. We put a lot of emphasis to make sure that doctors understand how to do it so it's done properly because we want that to be in place as patients come into the study. As I said before, we'll see as a few weeks go by here what the slope of that line looks like. Patients have remained very enthusiastic. The study's been going on. We just had been accrued for a few months here. We've continued to collect endpoints. The doctors have been enthusiastic, wanting to get up and running again. I don't know if we'll be back at exactly the same rate here in a couple of months or four months like that, but I fully expect that we'll have robust enrollment. Got it. Okay. I think in the last conference call, there was discussion around Alnylam upsizing their vutrisiran phase III from 1,250 patients to 1,750, but you've reiterated study size at about 1,200. What's your latest assumptions for event rates for the MAGNITUDE CM study, and do you have to make any changes? Well, we've been watching, we're starting to see some of these data. We're curious about the Ionis AZ data as it comes out here, and that'll help us. I think the Alnylam upsizing, I'm sure they have their reasons. Some of it's competitive dynamics, some of it's, I think, probably overpowering. It's a way of accelerating the trial. If you have more patients at risk early on for an event, you get more events faster. I think that's what's behind it. I'm not sure it's driven primarily by power assumptions. Yeah. Okay. Makes sense. For the IONIS-AZ CARDIO-TTRansform study, it's expected to read out second half of this year. What are your expectations for combo benefit on top of stabilizers? I know that's what they're looking for. I think it's an important thing to try to accomplish. The question for them is, given the degree of knockdown, which I interpret as vutrisiran-like, and there's a lot of variability with vutrisiran. I don't know of the full degree of variability with the Ionis product. The question will be, having that number, does that overcome that variability problem, I would say, so that you can actually see a benefit on top of tafamidis? We'll see. I fully expect that we'll find a benefit. We have a response rate that borders on 100% of patients having these very deep TTR reductions. I think when we're done, the real question's going to be, do stabilizers add anything the other direction? Yeah. Makes sense. We're pretty much out of time. Maybe in closing, if you want to talk about cash position or runway and key catalysts ahead that investors should be focused on. Yes. We completed a raise recently following the presentation of top-line results that, without accounting for any revenues from lonvo-z, gets us into 2028, a year and a half from now. lonvo-z, and its launch, some of the questions you were asking me about what that's going to look like, is going to really determine where we are from the standpoint of cash needs, if any. Our goal is to have lonvo-z really power the company going forward as we play out the rest of the TTR program and the pipeline. Got it. Thanks so much for joining us today, John. Yeah. Pleasure. Thank you.