Intellia Therapeutics, Inc.

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 Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intelia. Please proceed.

Thank you, Operator, and good morning, everyone. Welcome to Intelia Therapeutics' fourth quarter and full year 2023 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 the call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intelia undertakes no duty to update this information unless required by law. Joining me from Intelia are John Leonard, Chief Executive Officer, David Lebwall, Chief Medical Officer, Laura Sepp-Lorenzino, Chief Scientific Officer, and Glenn Goddard, Chief Financial Officer. John will begin with an overview of recent business highlights. David will provide an update on our clinical pipeline progress. Laurel will review our R&D updates, and Glenn will review our financials before we open up the call for questions. With that, I'll now turn the call over to John, our Chief Executive Officer. Thank you, Ian.

Good morning, everyone, and thank you all for joining us today. 2023 was an outstanding year for Intelia, and that strong momentum has carried into 2024. With our two lead programs either in or approaching Phase III clinical development, We're now closer than ever to the first in vivo CRISPR-based therapies reaching the market. We've made critical advances for the field of genome editing and for patients suffering from ATTR amyloidosis, or HAE. Notably, our one-time treatments offering potentially unmatched clinical profiles would address significant patient unmet need in two large and rapidly growing commercial markets. Having clinically validated our in vivo CRISPR gene editing technology by inactivating genetic targets in the liver, we're now bringing forth the next wave of innovation. This new frontier will come in two dimensions, broadening what we can do and expanding where we can go, all of which will allow us to increase the number of diseases we can pursue. The genome editing revolution is only made possible by the unique properties of CRISPR-Cas2. Intellia's expertise with CRISPR-Cas9 is unsurpassed and serves as a foundation for the diverse set of editing tools that we've developed and continue to advance. Whether using base editing or DNA writing tools, each of these technologies rely on the specificity and versatility of the CRISPR system. With our wide range of editing and delivering capabilities, we can apply the best tool for each therapeutic application. This allows us to address diseases where there is a meaningful opportunity to improve the standard of care. In some cases, we may even be able to pursue diseases that would otherwise be considered untreatable, if not for the power of CRISPR. It is this expansive and modular platform, coupled with our strong balance sheet, that will allow us to achieve the three-year strategic priorities announced earlier this year. Our focus remains on both near-term clinical execution as well as value-creating platform innovation. With this as a backdrop, we expect the following by the end of this year. Two in vivo knockout programs in active phase three studies, two in vivo gene insertion programs in first in human studies, and five different tissues outside the liver with active research programs. And additionally, we expect to have six or more collaborations with at least a dozen potential drug products utilizing our technology and research and development. We're confident in our ability to deliver on these ambitious goals. We have a proven track record of success with regulators in advancing CRISPR-based therapies and clinical trials. We've consistently delivered on our commitments to the scientific, patient, and investment communities. And finally, we have a world-class team of drug developers who have pioneered some of the most innovative and commercially successful medicines in history. In summary, Intellia is the company with the most advanced and expansive in vivo and ex vivo pipeline in the industry. With a potential BLA submission in 2026, we're well positioned to bring forth the first-ever in vivo CRISPR-based therapy. I'll now hand the call over to our Chief Medical Officer, David Levwall, who will provide an update on our clinical programs. David?

Thanks, John, and welcome, everyone. I'll begin with 2001, our in vivo CRISPR candidate for the treatment of ATTR amyloidosis. In December, we initiated the phase three magnitude trial for patients with cardiomyopathy. Since then, we're hitting the aggressive timelines we have set for ourselves, including multiple sites opening and regulatory approvals in geographies with large patient numbers. Notably, we have our first U.S. site actively enrolling patients and on track to dose the first patient in the first quarter. We are making great progress and expect many additional sites to ramp up throughout the year. At the same time, we are actively preparing for global pivotal phase three study of 2001 for the treatment of patients with polyneuropathy. We expect to provide additional information on our phase three plans later this year. Finally, we plan to present new data from the ongoing phase one study this year. I'll now turn to 2002, our in vivo CRISPR candidate for the treatment of hereditary angioedema or HAE. A few weeks ago, the New England Journal of Medicine published our landmark phase one data. This marks the second consecutive INTELLiA in vivo program to have initial clinical data published in this prestigious medical journal. We are continuing to follow the phase one patients and plan to present additional data this year. As previously announced, high interest in 2002 allowed us to identify all patients for the phase two study in only six months. We have since completed enrollment and dosing. We look forward to presenting the initial results for the first time later this year. Importantly, these data will determine the dose selected for the pivotal phase three study. We expect to initiate the Phase III study in the second half of this year. Of course, this is subject to regulatory feedback, but we think we're in an excellent position. With five special regulatory designations granted to 2002, we've taken advantage of the opportunities for additional interactions with the FDA and other agencies to gain early alignment on our Phase III plans. In summary, We believe both programs could reset the standard of care for people living with ATTR amyloidosis or HAE. I'll now hand over the call to Laura, our Chief Scientific Officer, who will provide updates on our R&D efforts.

Thank you, David. Good morning, everyone. We're continuing to advance novel gene editing and delivery technologies for both in vivo and ex vivo therapeutic applications. Building on the success of our in vivo gene inactivation programs, we're leading the development of CRISPR-based targeted gene insertion. Here we're leveraging the same NMP platform using our gene knockout programs to deliver the CRISPR machinery, along with an AAV to deliver a functional gene. Unlike traditional gene therapy, we expect our approach will permanently restore a missing or defective protein without a waning of effect over time. Earlier this month, our collaborator on GENERON announced that the Factor IX gene insertion program for hemophilia B has achieved IND clearance. This milestone puts Intelia at 343 in vivo IND clearances within 30 days of submission, a testament to our high standard for drug development. We also expect to begin this year the phase one study of our wholly-owned program, NTLA-30-01 for alpha-1 antitrypsin deficiency. Based on our preclinical data, NTLA-30-01 could potentially achieve normal human levels of the alpha-1 protein after a single dose. Further, the potential human proof of concept of our modular gene insertion platform would open a whole new category of diseases that require restoring a missing or defective protein. This may include diseases that are not addressable by either base editing or DNA writing. Beyond our liver-directed program, our goal is to harness the full potential of gene editing by extending the reach of our industry-leading platform to other tissues. Recently, we announced a collaboration with Ricoh Therapeutics to accelerate the development of CRISPR-based treatments targeting genes in the lung for cystic fibrosis. This collaboration provides yet another example of our partnering strategy to enable pipeline optionality outside our core areas of focus while retaining attractive commercialization rights. With this new collaboration, alongside our own and other partner programs, we're actively pursuing gene editing programs across five different issues. Finally, in the ex vivo setting, we're continuing to advance multiple programs, both wholly owned and with collaborators. For example, Adencel is now dosing patients in their first in-human study of an allogeneic candidate. Kiberna is utilizing our allogeneic platform to advance a next-gen CAR-T program for autoimmune disease. Both collaborators are using Intelia's proprietary Allo solution, which is designed for both T-cell and NK-cell mediated rejection, a previously unsolved challenge for the field of cell therapy. I'll now hand over the call to Glenn, our Chief Financial Officer, who will provide an update on our financial results as of fourth quarter 2023.

Thank you, Laura. Good morning, everyone. Intelia continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform. Our cash, cash equivalents and marketable securities were approximately $1 billion as of December 31, 2023, compared to $1.3 billion as of December 31, 2022. The decrease was driven by cash used to fund operations of approximately $448.8 million. The decrease was offset in part by $119.8 million of net equity proceeds from the Companies at the Market program, $49.8 million of interest income, $18.7 million of collaborator reimbursements, and $10.5 million in proceeds from employee-based stock plans. Our collaboration revenue decreased by 15%. to negative $1.9 billion during the fourth quarter of 2023, compared to $13.6 million during the fourth quarter of 2022. This decrease was mainly driven by a $10.3 million one-time revenue recognition adjustment related to Regeneron extending the technology collaboration to April of 2026. Intelia will receive a $30 million payment due in April as part of the Regeneron extension. R&D expenses increased by $9 million to $109 million during the fourth quarter of 2023, compared to $100 million during the fourth quarter of 2022. The increase was mainly driven by the advancement of our lead programs and personnel growth to support these programs. Stock-based compensation included in R&D expenses was $21.7 million for the fourth quarter of 2023. G&A expenses increased by $5.4 million to $29 million during the fourth quarter of 2023, compared to $23.6 million during the fourth quarter of 2022. This increase was primarily related to an increase in stock-based compensation of $4.3 million. Stock-based compensation included in G&A expenses was approximately $13.3 million for the fourth quarter of 2023. Finally, we expect our cash balance to fund our operating plans into mid-2026. 2024 will be another productive and catalyst-rich year for Intelia, and we look forward to updating you on our continued progress. With that, we will now open the call for your questions. 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 1 on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then 2. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Mari Raycroft with Jefferies. Please go ahead.

Hi, good morning. Congrats on the progress and thanks for taking my question. As you accumulate data from the phase one 2001 cardiomyopathy study, are you getting a sense of how TTR levels are tied to CV events in individual patients and how this compares to silencers potentially as it relates to Apollo B and Helios B? And how much data and follow-up do you aim to collect before providing your update? And maybe talk more about what you'll report in the update later this year.

Thanks, Maury. It's John. Appreciate your question. Remember, the phase one study is limited in size, so the amount of information it'll provide from a clinical point of view and the ability to tie TTR levels to clinical progression is going to be inherently limited. We look to what we see other competitors doing in the space and use that as a complement to what we see with our own work. I don't think that anything that we've seen thus far that's been put out there is really changing fundamentally how we're thinking about prosecuting the Phase III program, but I'm sure we'll be talking a little bit more about that as the call progresses. I don't know, David, if you wanted to add anything to what might be presented later this year.

Yeah, I think you've given the most important points. People should just recall that the dose expansion just completed towards the end of 22, so the patients have had just a little bit over a year, and we've seen in other studies that even The difference between placebo and treated patients in the phase threes of other compounds starts to diverge at about one year. So we do need significant follow-up to see trends. Of course, we don't. This is a single-arm trial, so we don't have quite the right controls to compare any of our results to. But we do have the results, of course, from the other studies to look at.

Got it. Thanks for doing my question.

The next question comes from Luca Isi with RBC. Please go ahead.

Oh, great. Thanks for taking our question. This is Lisa for Luca. Just a question again on TTR cardiomyopathy. We know an island celiac disease study is going to read out this summer. So just wondering, should this read out positively? Could this result in and early termination of your TTR cardiomyopathy study with NTLA-2001. Any color there would be helpful. Thanks.

I don't see how the Helios results are going to affect, you know, the early termination of our own work. I mean, just to remind you what David went through in the earlier comments, we're actively enrolling the 21 phase three trial, which we call Magnitude. We're aggressively opening up sites. We've got multiple sites open and enrolling now, and we'll communicate some more about the progress later this year. Obviously, we look to information as it's presented, whether, you know, the Helios study or other studies to think about how we conduct our own program, but based on everything we've seen thus far, based on our own data, the data that's accumulated by others, we're very confident and satisfied with the trial design that we have. I'll remind you it's an endpoint study, so whatever happens from a time point of view at Helios really doesn't relate to the work that we're doing. This is an events-driven study. We size the study appropriately, and we're going to have patients that we expect to present clinical endpoints just based on the stage of their disease, which is somewhat more advanced in our study. So, All things considered, we think we're in a really good position. Of course, we'll watch Helios as it comes out, but it doesn't really fundamentally change anything that we're doing.

The next question comes from Greg Harrison with Bank of America. Please go ahead.

Hey, good morning, and thanks for taking the question. Could you give some color on your latest thinking on 2002's potential place in the treatment landscape given recent competitor data updates?

Yeah, it's an important question because we acknowledge there's other drugs out there that have some activity in HAE. And certainly over the last few years, progress has been made in the pharmacopoeia for the HAE patients, which is great news. The fundamental problem, the challenge for patients that we hear from doctors and from patients themselves is to make attacks go away, make them be in a position where they never have to worry about an attack and don't have to carry on-demand therapy. So as new forms of on-demand therapy come out that fundamentally we don't think addresses what patients are looking for, And from a prophylactic point of view, as long as those drugs need to be readministered, that is going to be a continuing burden for those patients. So as we look at where we are with the data that we've seen thus far and look forward to continuing to expand, We believe that we're going right to the heart of the matter, which is preventing attacks once and for all, which we anticipate, assuming the success we've seen thus far continues, that patients will be able to dispense with their therapy once and for all. And I think that's the solution patients are looking for.

Makes sense. That's helpful. Thanks again.

The next question comes from Gina Wand with Barclays. Please go ahead.

Hi, good morning. This is Hershita on for Gina. Thank you for taking our question. I just had one on the magnitude ATTR-CM trial. For clinicaltrucks.gov, your secondary outcomes included change in baseline to month 18 in serum TTR and also KCCQ. So first, I wanted to confirm that these were the only secondary endpoints being measured, and if so, I wanted to get your thoughts on why these were selected as the sole secondary endpoints versus, you know, some other common ones, such as six-minute walk, invite your class, NT ProBNP, echo parameters. So, any color you could provide there would be really helpful. Thank you.

David, do you want to speak to how we think about secondary endpoints and why we included the ones we chose?

Yeah, those were chosen as being the most important secondary endpoints, of course, in consultation as well with regulatory agencies. The important things for patients we think are, first of all, what we see in the primary endpoints, reduction in cardiovascular events and mortality. Of course, that's the most important thing. This will be associated, we think, with an improvement in quality of life, and, of course, quality of life is, therefore, an important endpoint for these patients. The other measures, like six-minute walk, have had inconsistent results in recent studies, as you've seen, and we don't think is a really important measure part of what's happening for patients, especially because they may have other things other than their heart disease that's really affecting their six-minute walk, as these are older patients. Same for ProBNP. It's a biomarker that indicates something about heart function, but not really getting to the heart of what's important to patients.

The next question comes from Troy Lankford with TD Cowan. Please go ahead.

Hi, congrats on all the progress this quarter, and thanks for taking our question. For 2002, do you all expect that you could file a regulatory application in Europe at around the same time as in the US? And do you see European regulators, or do you think that European regulators seem mostly aligned with what the FDA wants at this point, or do you see any divergences there?

David, do you want to address the filing of the 2002? So this is, you know, for 2002,

The design of phase 3s is fairly well set for this indication. We've seen a number of drugs going forward, both with approvals or with new phase 3 studies, and they all have really similar design. And that includes a feature that they tend to be very small studies. They could be well under 100 patients. And really looking to, in our case, the idea that we may be able to prevent any events in these patients. This is in coordination with the FDA filing, which would be sort of an end of phase two meeting. In Europe, they don't have that kind of meeting, but we have other types of discussions that indicate that the design that we have moving forward will be acceptable in Europe as well.

The next question comes from Costas Belluri with BMO Capital. Please go ahead.

Good morning, everyone. Congrats on the progress, and thanks for taking our question. Maybe one question on your recent collaboration with Recode. Can you provide any additional color on approximately when we can see the first early data there, and how are you thinking about the competitive landscape, especially other gene editing approaches that are being developed for this disease? Thank you.

Thanks for the question. We're really excited about the work that we're embarking on with Recode. I think it's a little early at this time to project exactly what we're going to have and when we're going to have it, but we're convinced that the work that they've done with LMP delivery to the lung puts us into a really interesting position where we can take the gene writing approach that we've developed and go and address a variety of different genetic lesions that are currently unsatisfied for patients with CF. Obviously, that's a landing pad from which one can expand and can think more broadly about what might be possible in that space. In terms of other competitive approaches, I think there's obviously a race to get to solving once and for all the problem that these patients suffer from. And we think we've chosen the best partner to be in a position to be highly competitive and ultimately prevail.

Thank you. Very helpful.

The next question comes from Dagon Ha with Stifel. Please go ahead.

Hello, this is Benazir. I'm on for Dagon. Maybe a couple questions on NTLA-3001. You know, given the rapid, like, crowding of the gene therapy, gene editing approaches in AATD, what is the ideal product profile for NTLA-3001? And can you remind us again that the Serapina-1 gene insertion Is it directional, and what are some supportive pieces of evidence or tools that are available to detect the correct insertion of the gene? Thank you.

So, we'll turn to Laura to speak to what the insert is and if there's any sort of directionality to it. We think we've addressed it nicely. Just with respect to the product profile, our objective is to get to essentially normal human levels of wild-type proteins. Once one does that, which we've accomplished preclinically in non-human primates, those patients should be essentially the same as patients without the mutation in the first place, at least with respect to their lung disease. So whether or not we'll get to that in humans is the basis of the phase one trial that we're embarking on now as we speak. And of course, we're really excited about getting that information which we think will address not only what we're doing with 3001, but a whole plethora of other sorts of insertion programs that will be associated with that. Laura, you want to say a word about the insert and how that works?

Sure. And this is, we're using our insertion platform where we're inserting into the Intran1 of the albumin locus. So the expression is driven by albumin, which is a really strong promoter. And, of course, the gene, right, is wild type. So, this is, you know, fully functional wild type. So, there is no issues with, you know, any errors in sequencing or bystander edits, for example, that you introduce with other editing modalities.

Okay. Thank you very much.

The next question comes from June Lee with Truist Securities. Please go ahead.

Hi, good morning. This is Mehdi on for June, and thanks for taking that question. This one also may be for Laura on NTLA-30-01. So could you please talk about a potential risk of exacerbation in the liver manifestation of a patient treated with 30-01 based on the heteropolymerization capacity of the normal form with the mutant form? Thank you.

You want to address?

Yeah, we haven't seen any in our preclinical models using, you know, cell lines where there is expression of the mutant form that, you know, would lead us to a concern with regards to exacerbation of aggregation after 31 treatment.

Thank you. The next question comes from Brian Chang with JPMorgan. Please go ahead.

Good morning. Thanks for taking my questions. What's the latest thought around the 3001 phase 1 trial design? Specifically, how do you sequentially space out the AAB and the LMP administrations? And can you touch on also the bar of the CMAAT that you're aiming to present? Thanks.

David, can you summarize the essence of the phase one design? I think that it was a little hard to hear, but I think part of the question was how much time elapses between AAV and LNP administration within a particular patient.

Yeah, we haven't told the exact clinical study, but they are both going to be, they're not given exactly at the same time because, you know, we do want to separate them a bit, but they are given sequentially. And both the CRISPR mechanism and the AAV will be present in the cells at the same time once they are administered. And that's the key feature to be successful to get the gene insertion. Otherwise, it really is a standard phase one study with a dose escalation based on the preclinical findings that we have. And again, we'll be giving more details of that once the trial is fully approved.

The next question comes from Salveen Richter with Goldman Sachs. Please go ahead. Excuse me. Salveen, at Goldman Sachs, your line is open. Is it muted accidentally on your side?

Can you hear me?

Go ahead. Thank you.

Hi. Sorry. This is Lydia. I'm for Salveen. Thanks so much for taking our question. Just another on 2001. Could you just speak to your comfortability around the powering for the magnitude trial and when you expect to complete enrollment? Thanks so much.

David, do you want to address that?

Sure. So we're very confident in the design. I recall that we've used an event-based study rather than having the follow-up on patients. So the advantage of this, of course, is that you would not need to extend the time of the study based on perhaps slower event rates than you predict. But given that, we did make a very conservative estimate, both on our powering and predicted event rate. So again, we're confident in what we have with the design, with a larger study than Helios B at 750 patients. The completion of enrollment, you said, is going to be in the, yeah, it would be looking at some of the other studies to get a sense. And you've seen that these studies enroll very quickly. And so that would give you a good idea when we do expect to complete enrollment.

Thanks so much.

The next question comes from Debjit Chattopadhyay with Guggenheim. Please go ahead.

Good morning. This is Rai. I'm for Debjit. Do you see opportunity for 2001 differentiation by potentially enriching the magnitude trial with NYHA Class III subjects or other patient demographics that capture a sicker population relative to contemporary ATTR-CM trials?

David, do you want to speak to the mix of patients we've allowed in, patients who have more advanced disease? What does that do for us?

We do allow, of course, Class III patients. An important feature of what we looked for is patients who are somewhat sicker than the other studies. And the way we did this is to have the baseline pro-BMP be greater than 1,000 and to not have an upper limit on the pro-BMP. This could differentiate us in a few ways. First, we did this because by the events occurring more rapidly, the trial will be completed more rapidly. In addition, we do think these sicker patients are the ones most likely to benefit from TTR reduction. If you have a very healthy patient, they won't have events in either arm of the trial, and they really won't contribute to what we learn about the trial. So we do think that by choosing these patients, we will be able to differentiate our treatment of getting to lower TTRs than the other treatments in this study.

Got it. Thank you. The next question comes from William Pickering with Bernstein. Please go ahead.

Hi. Thanks for taking my question. In AATD, what dose level of AAV was used in your NHP studies, and how would the human dose equivalent compare to what we see from traditional AAV gene therapies that aren't integrating into the genome? And how much margin for error do you have on not lowering albumin in terms of the insertion efficiency that you're expecting versus the levels that would be required to make a meaningful dent in albumin levels? Thank you.

but we're not speaking to the precise dose of AAV, but it's lower than what's used for standard gene therapy. Laura, maybe you could say a word about the strength of the albumin promoter and why just a few integrins are necessary to get to the levels we need.

Yeah, so, you know, albumin promoter is, you know, the strongest promoter in the liver, so you just need, you know, a few percentage of cells to have, you know, productive insertion to achieve normal levels. You know, and here we're looking at 22 micromolar, you know, as an average, right? So, you know, the preclinical data, of course, we did matrices of LMPs and AAVs, keeping the goal, as John just said, to ensure that the AAV dose is low. We, you know, don't need to hit all the cells in the liver, just a few. And that gives us safety. You know, we feel very good about the margin. Oh, and with regards to albumin, we do not see significant decreases in albumin, right? Because you're only editing in a few cells. So albumin expression remains constant and that we've seen in preclinical models and that was further evaluated in our GLP TOC studies.

Thank you.

The next question comes from Rick Benkowski with Cancer Fitzgerald. Please go ahead.

Great. Good morning, everyone. Thanks for taking the questions. For the pivotal study in HAE, given the timelines for the potential 2026 BOA filing, I wanted to ask about the degree of confidence in being able to use a six-month primary endpoint in the pivotal study, just given the gene editing mechanism is so different from the competitors here. And also, in the phase one data, there was the initial 16-week period after dosing where some patients experienced breakthrough attacks. I was wondering if this phenomenon could be accounted for in the pivotal trial design in any way.

David, do you want to speak to six-month endpoints? I mean, obviously, you've been on the front line talking to regulators around the world. Do you think that there'll be the need to extend beyond these standard sorts of approaches?

Yeah, what we believe is that the six-month endpoint, which has been standard in these studies, will be the same standard that we apply to this study. In terms of longer follow-up, of course, we will have Phase 1 and Phase 2 patients with longer follow-up when we file the DLA, and as well as a very extensive safety database from our other gene knockout program with TTR. So we do feel very confident that the safety database we're bringing will satisfy what the regulators want. Of course, for all gene therapies, we will continue to follow the patients for the standard 15-year period. In terms of the breakthrough attacks, we are looking at how to account for this in the pivotal study. We're not talking about the exact design. You have to recall those patients were only the patients who had very unusual number of attacks, up to 15 attacks a month, as you recall. So that's an unusual patient, kind of patient who is waiting for the phase one study. Most of the patients in the study would be more like the other patients where the attacks were pretty much gone after the infusion.

Rick, I appreciate your noting the BLA in 2026. It is one of our key strategic objectives for the company in the next two to three years. And we're very excited about being in a position to take what we think will be the very first in vivo CRISPR-based approach to approval and go into what we think is a marketplace that we can be extremely successful in.

All right, I appreciate the caller. Thank you.

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

Great. Thanks for taking our questions. So just wondering, a very quick one on magnitude. What is the percentage of ontofamilis patient you target in the trial? And also wondering if you could talk a little bit about your DNA writing technology. I think this is the first time we hear about a program since you acquired the technology in 2022. So wondering, for example, is there a correction template and whether it is RNA or DNA format? Thank you.

Maybe I can say a word about the DNA writing approach. And David will address how we think about tefamidase in the magnitude study. The way we think about gene editing in general is capabilities. By that I mean introducing the particular type of change that one is interested in introducing into the genome for whatever therapeutic purpose. There's different ways to introduce those changes. When we think about gene writing to us, that's a category that brings with it a variety of approaches to introduce a string of nucleotides. As you commented, we acquired work that was complementary to the work that we're doing a couple of years ago, and we're excited with what that brings to us to add to the work that we're already doing. And at the right time and the right place, we'll talk about exactly what we're doing and how it fits into our pipeline. But I think it's just important to note at this point that we're making excellent progress and doing everything that we want the technology to do. David, do you want to say a word about defamitis?

Yeah, for defamitis, we expect about half the patients to be treated with defamitis. And this is similar to what's been seen in the pivotal studies that have been reported so far as well.

Great.

Thanks for the answers. The next question comes from Steve Seathouse with Raymond James. Please go ahead.

Hi, good morning. This is Timur Ivankov on for Steve Seathouse. So we have a question in AATD. Historically, it's been difficult to show improvement in lung function with augmentation therapies and other therapies on endpoints such as FEV1 or pulmonary exacerbations. And even more advanced augmentation therapies haven't attempted to show this improvement. So how do you think about improvement in lung function? Do you expect regulators to require you to show an improvement?

David, you want to speak to that?

Yeah, you know, the regulatory standard hasn't been set here. There have been some reports publicly that the FDA may accept having normal levels of alpha-1 antitrypsin could be a way to move forward. Of course, with some associated clinical findings, but not necessarily a definitive improvement. And we do think because our program can get to normal levels, really the only gene editing program that's shown this so far, that this may be something that the regulators will work with us on and give us a way forward to an approval, mostly based on the high levels that we'll be achieving.

Thank you.

The next question comes from Jay Olson with Oppenheimer. Please go ahead.

Well, hey, thanks for providing the update. And congrats on the recent collaboration with Recode and Cystic Fibrosis. Can you just talk about some of the features of the LNP platform that you found attractive? And what is the route of administration? And is the collaboration only focused on Cystic Fibrosis? Could you potentially leverage the collaboration to study additional targets and diseases? Thank you.

Laura, you want to take that?

Yeah, sure. So, RECODE has been pioneering a new class of lipid nanoparticles that are targeted to different organs. These are the sort lipids. They have, we were quite interested in what they were doing in the lungs. And as you may know, they're already in the clinic with two inhale LMP mRNAs for PCD and cystic fibrosis. Actually, I think they dose the first patient with an mRNA yesterday. So with this LMP that goes to lung for which they already have preclinical and clinical data and, you know, the manufacturing and the route of administration of inhalation, they have demonstrated that they can get to not only the mature cells, but also the target cells that you would need to edit to have long-lasting benefit if you're looking after a CFTR correction. So when we're looking at partnerships, we're looking to marry technologies. We have a strong gene editing technology that allows us to target specific mutations, and they bring in validated delivery modalities. So I think it's a great partnership, and we're looking forward to make quick progress.

The next question comes from Sylvain Turcan with JMP Securities. Please go ahead.

Yeah, good morning. Congrats on the quarter and congrats on the progress and thanks for taking my question. Just a quick one on the HAE program. What are some of the considerations that you're thinking about, you know, selecting the dose for the Phase 3 and what can we see in the Phase 2 data later this year to, you know, give us confidence in that dose selection? And then regarding the Phase 3 design overall, is there any impact or any information that get from the Phase III OASIS HAE study from IONIS that will be presented mid-year. That will help us also in the design or think about the design of the Phase III trial here. Thank you.

David, how are you going to choose your dose for Phase III?

Yeah. So recall that we've completed the enrollment to a Phase II in which the patient, there are 10 patients on 25 milligrams, 10 patients on 50 milligrams, and five patients on placebo. So we have a very good setting in which to evaluate those two doses. We chose those two doses because in the dose escalation phase, as you recall, all patients basically achieved no events after the infusion except a single event in one patient a year after treatment, which was related to a sports injury. So with the phase two, we'll have a very extensive database of these two doses. The things we'll be looking at, of course, is the clinical findings, the event rate, but also the consistency of the pharmacodynamic effect we'll be looking at as part of this. There was more variability at the lower dose. So on first principles, we would tend to think that the 50 doses can be better, but we want to look at all the data and make a decision about the phase three, and it will be a very robust decision based on this phase two study.

The next question comes from David Lebowitz with Citi. Please go ahead.

Thank you for taking my question. A competitor has a switch study for its HAE trial, and I'm just curious as to whether there is a similar type of study that would be needed or what that would look like for a gene editing product.

I'll speak to that.

Yeah, we haven't talked about doing a switch study. In the pivotal studies, what usually happens is that you withdraw from any kind of prophylactic therapy. We have seen, in our study, patients withdrawing from lanodilumab as well as other prophylactic therapies, and we do think that will be of interest to patients when this is an approved therapy to get off the therapies that they have to take repeatedly and go on to a one-time therapy. We haven't yet guided to there being a switch therapy, but this is something obviously that would be considered a switch study.

Thanks for taking my question.

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

Great. Thanks for taking my question, and congratulations on the progress. I wanted to ask if you could comment a bit more about your plans to enroll slightly more advanced patients in magnitude as compared to Helios B. And how do you expect positive results from Helios B could affect enrollment in Magnitude, being Magnitude will be a placebo-controlled study?

David?

Yeah, the idea of enrolling more advanced patients is that these are the patients who can really benefit from the therapy. If you imagine some of the studies we've seen, some patients who can be quite healthy despite having some early heart failure, And those patients have very few events and therefore contribute very little to the findings in the study. So that's the idea of doing that. And we do think a positive Helios B study is a positive for us as well. It would show that TTR reduction is a value to patients with cardiomyopathy, the hypothesis that really all the experts really believe in. So we do think as well that it's very likely that Helios will be positive. The physicians are already very excited about our therapy so that, first of all, they've seen that we have a very consistent and deeper reduction in TTR. It could be the best-in-class agent. So we expect the enrollment to be brisk in any case. Of course, having a positive study demonstrating that TTR reduction is important may be a further value in driving our enrollment as well.

Great. Thanks so much, Dr. Colley.

This concludes our question and answer session. I would like to turn the conference back over to Ian Karp for the closing remarks.

Great. Thanks so much, Drew, and thank you, everyone, for joining us this morning. It's certainly been an eventful and successful start to the year, and we look forward to updating you throughout the year with additional progress. So thanks again, and look forward to talking with everyone soon.

Thank you. The conference has come to a close. You may disconnect your line.

Thank you.