Good morning, and welcome to Intellia Therapeutics First Quarter 2024 Financial Results Conference Call. My name is Drew, and I will be your conference operator today. Following formal remarks, we will open the call up for a question-and-answer session. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics First Quarter 2024 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 & 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'd like to take a minute to remind listeners that during this call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. Joining me from Intellia are John Leonard, Chief Executive Officer; David Lebwohl, Chief Medical Officer; 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. Laura will review our R&D updates and Glenn will review our financials before we open up the call for your 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. We've made outstanding progress in the first quarter of 2024 with one ongoing and two soon-to-be initiated pivotal Phase III trials. Intellia is undoubtedly leading the gene editing revolution. And with well over 100 patients already dosed across our two lead programs, we have already amassed the largest set of safety and clinical activity data for any in vivo CRISPR-based therapies. Notably, we believe our one-time treatments for ATTR and HAE offering potentially unmatched clinical profiles could overcome key hurdles faced by patients in two large and rapidly growing commercial markets. Moreover, our first two investigational gene editing therapies are designed to be especially patient-friendly and convenient for physicians and caregivers. There's no extensive preconditioning regimen, no long-term steroid requirement and no hospital stay, all of which can be very challenging for patients and limit commercial uptake associated with other gene therapies. And of course, with a one-time treatment, there's no annual insurance reverification needed, which is typically required for chronic specialty therapies and can be a tremendous burden. But this is just the beginning for our industry-leading CRISPR-based technology. We're now entering the next stage of growth, pushing the boundaries of what we can do and expanding where we can go with CRISPR from gene knockdown, to gene insertion, from liver targets, to a broader set of tissues. Our first wholly owned CRISPR-based gene insertion program, NTLA-3001, is expected to enter human clinical development this year. NTLA-3001 holds the potential to provide normal alpha-1 levels after a single-dose treatment for people with alpha-1 antitrypsin deficiency. We will also have a second clinical program utilizing our modular gene insertion platform run by Regeneron for hemophilia B expected to start patient dosing later this year. Building on our clinical success, we are now pursuing gene editing in five new tissue types outside the liver. As part of this expansion strategy, we have and will continue to establish collaborations with external innovators. These R&D efforts have already yielded at least a dozen potential drug candidates utilizing our technology. Further, we are advancing our modular platform by developing a diverse set of editing and delivery tools for in vivo and ex vivo applications. Whether it's our proprietary LNP formulations, novel gene editing tools or differentiated allogeneic cell therapy approaches, we emphasize safety and therapeutic activity at each step of development. Through our commitment to these principles, we are well on the path towards transforming cutting-edge scientific tools into real-world medical treatments. With this as a backdrop, we expect to end this year with five enrolling clinical studies, three of which are in Phase III. This includes a newly planned Phase III for NTLA-2001 in patients with ATTR polyneuropathy. Additionally, we plan to submit a BLA submission in 2026 for NTLA-2002, which we anticipate will lead to the first-ever approval for an in vivo CRISPR-based therapy. By that time, our expectation is we'll have accumulated safety, efficacy and durability data for over seven years and have treated as many as 1,000 patients in our clinical studies. In summary, we will continue transforming medicine with gene editing therapies with at least three important clinical data readouts expected this year.

Thanks, John and welcome, everyone. I'll begin with 2001, our in vivo CRISPR candidate for the treatment of ATTR amyloidosis. This multisystem disease primarily manifests as either cardiomyopathy due to amyloid deposits in the heart or polyneuropathy due to progressive accumulation of protein deposits in the nervous system. As demonstrated in our Phase I study, a one-time treatment of 2001 led to greater than 90% TTR reduction. Importantly, we demonstrated best-in-class reduction of absolute TTR levels among TTR silencing agents, which we believe will be a key differentiator for treating patients with CM and/or PN. In ATTR-CM, despite the introduction of TTR stabilizers, patients continue to experience worsening heart failure, hospitalization, strokes and heart attacks. Ultimately, it remains a fatal disease. Today, I am pleased to report that patient enrollment in the Phase III magnitude trial for patients with cardiomyopathy is off to a great start. In March, we announced the first patients in both the U.S. and globally have been dosed. With over 30 patients already dosed and another 40-plus in screening, we are tracking well ahead of our initial projections. Further, we expect many additional sites to open in the weeks and months ahead, which will further accelerate enrollment in the trial. While we will not be providing patient-by-patient enrollment updates moving forward, we will look for opportunities to keep you abreast of our progress. The rapid rate of enrollment reflects the enthusiasm we hear from physicians and patients who believe 2001 holds the potential to revolutionize the ATTR treatment landscape. In parallel, we are also excited to announce today that we now expect to initiate a new Phase III trial for patients with ATTR polyneuropathy by year-end. Importantly, ATTR-PN patients are typically diagnosed earlier in adulthood, and their disease often progresses more rapidly than ATTR-CM. Published data from chronically dosed TTR silencing therapies demonstrate that deeper reductions of TTR are highly correlated with improvements on standard measures of neuropathy. To date, no other agent approved or in clinical development has demonstrated the depth and consistency of TTR reduction regardless of baseline levels like 2001, which gives us tremendous confidence in our ability to positively impact patients. Based on productive discussions with the FDA, we have aligned on a trial design to support a BLA filing for 2001, subject to review of the IND application. We plan to initiate the Phase III by year-end. The study is expected to be a small placebo-controlled trial of approximately 50 patients conducted in ex U.S. regions with limited or no access to silencers. We are making significant strides in advancing 2001 and look forward to presenting data from the ongoing Phase I trial in the second half of the year. We expect to be presenting safety and TTR reduction data on all 72 patients from both the CM and PN arms. Additionally, we plan to include for the first time, data beyond TTR levels, such as NT-proBNP, 6-minute walk test and mNIS+7. In summary, we continue to believe 2001 may halt and potentially reverse the disease as well as dramatically reset the ATTR treatment landscape. I'll now turn to 2002, our in vivo CRISPR program for the treatment of hereditary angioedema or HAE. In January, landmark findings from the Phase I were published in the New England Journal of Medicine highlighting a single dose of 2002 led to a 95% attack rate reduction. On June 2, we will be presenting updated data from the study at the European Academy of Allergy and Clinical Immunology Annual Congress. These long-term data will speak to the safety and durability of effect on both kallikrein and attack rate reduction. Importantly, we will also present on the number of patients who remain completely attack-free with extended follow-up now reaching beyond 18 months for all patients and longer than 2 years in some. Additionally, we plan to report top line results from the randomized, placebo-controlled Phase II study shortly thereafter. Full results evaluating the 25-milligram and 50-milligram doses are expected to be presented at an upcoming medical meeting. These data updates will provide clarity on which dose to move forward into the Phase III trial. Assuming 2002 continues to show a strong safety and efficacy profile, we believe that 2002 will become the preferred prophylaxis treatment in a growing commercial market. In the U.S. market, for example, currently about 70% of HAE patients use chronic prophylaxis treatment, and that number is increasing. Many patients continue to seek better efficacy and more convenience, expressing a strong willingness to switch to new treatments that can deliver on both fronts. As previously discussed, we plan to initiate the pivotal Phase III trial in the second half of 2024. At this point, we are mainly waiting for the Phase II data before submitting regulatory amendments to begin our global Phase III. Notably, we have now also completed the additional preclinical mouse study requested by the FDA to support inclusion of women of childbearing age in the U.S. As expected, these data did not show an impact to female reproductive health in the animals treated with 2002. This is consistent with the extensive preclinical work completed and reviewed by regulators prior to our initial IND clearance, and we plan on submitting these data to the FDA prior to Phase III. Let me now turn to exciting developments with our modular gene insertion platform. Here, we are leveraging the same LNP platform used in our gene knockout program 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. We expect to begin this year a first in-human study of 3001, our wholly owned gene insertion program for alpha-1 antitrypsin deficiency. As a reminder, the main hurdle with treating this disease is getting patients to consistently normal levels of alpha 1. Current standards of care, which involve weekly infusion of augmentation therapy, do not achieve this. Other approaches in development have also been unable to yield normal levels of alpha 1 and in some cases, have only been able to produce a modified version of the protein with unknown consequences. 3001 is the only drug candidate to show AAT levels restored to normal levels after a single dose in nonhuman primates. It is designed to precisely insert the wild-type SERPINA1 gene and permanently restore production and secretion of fully functional alpha-1 protein. Assuming success, 3001 could be life-changing for alpha-1 patients and unlock a whole new category of diseases we can pursue with in vivo gene insertion. Separately, our collaborator Regeneron has achieved clearance from both U.S. and EU authorities for the Factor IX program using our modular gene insertion platform and plan to enroll the first patient later this year. Our clinical development of the in vivo pipeline is rapidly accelerating, and Intellia is well positioned as the leader in this new era of medicine. I'll now hand over the call to Laura, our Chief Scientific Officer, who will provide updates on our R&D efforts and what's coming next.

Thank you, David. Good morning, everyone. At Intellia, we're advancing novel gene editing and delivery technologies for in vivo and ex vivo therapeutic applications. As John mentioned, core to our strategy is the emphasis on safety and performance at each step of development. Our success to date is not by chance, and it's a common misconception that gene editing and delivery tools have become commoditized. By leveraging the experience of a world-class team and making dramatic improvements in adaptations to our platform technologies, we have been able to lead the entire industry forward. But don't just take my word for it. Let me give you some real-world examples. Intellia is now 5 for 5 in INDs approved by the FDA for our investigational therapy. Groundbreaking clinical data sets for both NTLA-2001 and NTLA-2002 have been published in the New England Journal of Medicine. We have already gained regulatory clearance for multiple clinical trials in 8 different countries. Together with Regeneron, we're conducting the largest global Phase III study of a genetic medicine. Intellia has become the reference gene-editing company, which has helped us foster important relationships with the world's leading scientific and medical experts as well as advocacy organizations. And now building on the success of our work in cases that originate in the liver, we're expanding the range of tissues that can be targeted with our CRISPR-based technology. We now have active research programs in 5 different tissues outside the liver, either independently or in collaboration with partners. This includes the bone marrow, brain, eye, lung and muscle. We're particularly excited about pursuing diseases, such as sickle cell disease, muscular dystrophy, cystic fibrosis, ALS and many other delineated genetic conditions. We're also advancing a pipeline of new ex vivo programs, both wholly owned and in collaboration with partners for the treatment of immuno-oncology and autoimmune diseases. In fact, two of our partners are leveraging our allogeneic platform, one of which is already in the clinic. Our differentiated allogeneic solutions, including HLA matching is uniquely positioned to avoid both T-cell and NK cell-mediated rejection and results in more favorable processes and disease control. Further, therapies engineered with our allogeneic platform combined with edits to enhance cell function, offering a new approach to target solid tumors. We look forward to updating you on our progress across our R&D platforms more broadly this year. I'll now hand over the call to Glenn, our Chief Financial Officer, who will provide an update on our financial results as of first quarter 2024.

Thank you, Laura. Good morning, everyone. Intellia 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 $953.4 million as of March 31, 2024, compared to $1 billion as of December 31, 2023. The decrease was driven by cash used to fund operations of approximately $137.2 million. The decrease was offset in part by $58 million of net equity proceeds from the company's at-the-market program, $12.6 million of interest income, $5.9 million of collaborator reimbursements and $2 million in proceeds from employee-based stock plans. Our collaboration revenue was $28.9 million during the first quarter of 2024 compared to $12.6 million during the first quarter of 2023. The $16.3 million increase was mainly driven by a $21 million noncash revenue recognition adjustment related to the AvenCell collaboration. R&D expenses were $111.8 million during the first quarter of 2024 compared to $97.1 million during the first quarter of 2023. The $14.7 million increase was mainly driven by the advancement of our lead programs. Stock-based compensation included in R&D expenses was $20.2 million for the first quarter of 2024. G&A expenses were $31.1 million during the first quarter of 2024 compared to $27.4 million during the first quarter of 2023. The $3.7 million increase was primarily related to stock-based compensation. Stock-based compensation included in G&A expenses was $14 million for the first quarter of 2024. Finally, we expect our cash balance to fund our operating plans until late 2026. Notably, our strong balance sheet gives us the financial power to execute on the three-year strategic priorities laid out at the beginning of this year. First, to execute pivotal trials for our first two in vivo CRISPR-based therapies; second to launch the next wave of in vivo and ex vivo clinical programs; and third, to deploy the new editing and delivery modalities. We're well on our way to realizing the promise of gene editing. This will be a catalyst-rich year for Intellia, and we look forward to updating you on our continuing progress.

With that, we will now open the call for your questions. Operator, you may now open the call for Q&A.

It's great to see the progress made this quarter. Congratulations on that. I have a question regarding your comments about the enrollment speed in the ATTR Phase III trial, which is exceeding internal expectations. How many sites have been opened, and what is the breakdown between U.S. and non-U.S. sites? Additionally, what is the patient enrollment rate per site per month that you are currently seeing? Do you have any updates on the timeline for completing enrollment?

Yanan, thank you for the many questions you just asked. And on that one question, we're not going to be giving updates on patients per site, numbers of sites, et cetera. As we said before, this is a balanced study around the world, where it’s still actively initiating study sites. We've said we expect about one-third of all of the ultimate sites will be in the United States and the remainder will be spread around the world. I think the takeaway that I would encourage you to see here is that we're early in this process and things are going very well. I mean, we're very excited about the enthusiasm that we see with investigators. We've been clearing the regulatory submissions expeditiously. We've been able to initiate sites and patients have been waiting to come into the study. We think it's a testimony to what patients and physicians see with the current state of therapy, which as you know, with current approved drugs, patients continue to suffer from the morbidity and the mortality of disease with ongoing progression. So we will not be giving updates patient by patient as we go. But I would encourage you to see that we're off to a very, very strong start. We're enthusiastic about the progress we're making.

If I may make a quick follow-up on that. From your interaction with, in particular, the U.S. sites, what do you hear from GIs and patients in terms of how you think about the potential upcoming approval of silencers? How does that impact their thinking of going on the gene therapy treatment?

In our interactions thus far, it hasn't influenced how they're thinking about the trial or putting patients on it. Again, I think people have been very impressed with the data that we presented and are encouraged to put their patients on the study. I'll remind you that we created a study that's very favorable to patients. We've put in the study the ability for patients with Stage III heart failure, a higher proBNP level, etc., a 2:1 randomization that favors drug over placebo. There's lots of reasons for patients and physicians to want to participate in the trial, and we're seeing that in these early results. Thanks. I look forward to the next question.

Sorry about the technical issue. Congrats on the progress. For the ATTR-PN study, just looking at precedented studies in the space, so Ionis their study was 168 patients. APOLLO-A was 225 and then HELIOS-A was 164. And so just wondering if you can talk about how the conversation went with FDA to align on your Phase III with 50 patients. Maybe talk about what expectations are for clinical endpoints and results on those endpoints? And what does this imply about the size of what your HAE Phase III study could be?

Well, let me take the last point first, and then I'm going to hand it over to David to address the specifics on polyneuropathy. HAE endpoints and polyneuropathy endpoints are two totally different animals. And I wouldn't read how one study is designed into how we think about the other. As we get more specificity with respect to both of these trials, we'll certainly speak to that so you can see. But I would just emphasize, before David speaks to some of the specifics, we've developed a very close working relationship with the Food and Drug Administration and other regulatory agencies around the world. I think they have a very good understanding of the expected effects of these drugs and have a very good understanding of how to show them in a meaningful way for their own purposes as well as for physicians and ultimately for other regulatory agencies around the world. David, maybe you can say a few things about how we're approaching that study and why we think it will be successful.

The overall situation is that both we and the FDA acknowledge that patients continue to progress despite the current medications. We discussed our clinical data with them, emphasizing that we are achieving significant and consistent reductions in TTR, which has positively influenced our conversations with the FDA. They have reviewed several studies demonstrating that TTR reduction benefits patients, establishing this as a recognized fact. The FDA is particularly interested in how biomarkers might not only indicate disease progression but also facilitate future approvals. Therefore, the scale of our trial is tied to their confidence in our approach, and in addition to the 50 patients in this trial, we also have extensive data from Phase I and the ongoing cardiomyopathy Phase III trial.

So for NTLA-3001, how quickly do you think you can move through development with this asset? So do you think you would try to take this asset into a pivotal study shortly after the Phase I dose work like with NTLA-2001, or do you think we'll have a more traditional placebo-controlled Phase II to further refine the dose for a pivotal study like with NTLA-2002?

Thanks for the question, Troy. I'd just start by saying, as was emphasized in our comments earlier today, we emphasize understanding these drugs, especially from a safety as well as from an efficacy point of view. And so those will be our guiding principles as we carry out the study of 3001. We're excited about what we think the drug can do. I'll remind you that in the preclinical data, we've established that we're able in nonhuman primates to reach normal levels as seen in human beings. We think that's fundamental to the regulatory strategy. Our hope is that we'll show that in Phase I studies, and assuming that we see that, we will progress as quickly as we can, working with the Food and Drug Administration and other related agencies to establish what is the shortest, most efficient way to regulatory approval. So that lies ahead, and we'll give you updates as we proceed.

Congrats on all the progress. Maybe David, on TTR cardiomyopathy, given the recent changes from your competitor, are you rethinking any aspects of your trial design? In a scenario where HELIOS-B hits all the monotherapy and shows no benefit as add-on to tafamidis, do you have any optionality to split the primary endpoint between the overall population and the monotherapy arm similar to what they did? And then maybe quickly on TTR polyneuropathy, can you just expand on why not enrolling patients in the U.S. for the pivotal?

So we'll let David speak to some of the specifics of the trial, but I'd just start by pointing out that there's some fundamental differences in how we've approached the pivotal trial. In the case of TTR, we've certainly been mindful of understanding the rates of progression. We've been able to learn from other drugs as they presented data as they have gone before us, and we've been really thoughtful about an endpoints-driven study, which is driven by the rate at which things happen, not by some prespecified moment in time when we surmise that all the events may be in. I think the standard approach to these trials is, in fact, an endpoints-driven approach. And that's what we've embraced from the beginning. I think, David, maybe you can just say a few words about how HELIOS does or it does not affect our thinking at this current time.

We are confident in the design of the magnitude study, as we've been conservative in our assumptions. It's a larger study than HELIOS, which is significant. We also included patients with more advanced disease, and their proBNP levels are higher without an upper limit. There is no restriction on how long we follow these patients in this event-driven trial. We believe that our deep and durable TTR reductions position us to be best in class, outperforming drugs in other studies. We will closely monitor the data from HELIOS-B and expect it to yield positive results. However, we cannot predict how much it will add to tafamidis at this stage. Regardless of the results, we have the flexibility to modify our trial based on findings related to other drugs.

I think you also wanted some insight into the polyneuropathy site for Phase III, where we're conducting it and why?

So our discussions with the FDA, it’s clear that it was important to have a control on a placebo-controlled arm. So these are patients in the world who do not have access to silencers. In the U.S., there is very good access to silencers. So the main reason we have not began having patients in the U.S. is because of the satisfied need for those patients. John?

And it's important to note that we're aligned with that approach. They understand how we would be doing a study and where we'll do it, and because the treatment practices are so similar we think that this information should be readily applicable to the United States.

Just a quick question about NTLA-2002. Now that you have completed the preclinical embryological development study, can you provide more detail on when you plan to submit this data? Is the submission imminent? Also, how long do you anticipate the agency will take to review this data?

Thanks for the question, Harshita. We don't go through report-by-report and submission processes and procedures for each of those things, and I'd remind you that this is not even gating for the Phase III program. The first point I think to make is that we've seen the data, it's as expected. There's no issues and we're in a really good position to proceed. What's really going to drive the Phase III start is getting the data in with respect to our Phase II program. And as was referred to by David during the comments earlier, when we have those, we'll be sharing those later this year, and that's something we're very enthusiastic about.

Congrats on the great progress. One question on 2001 from us. You have previously seen data from other types of amyloidosis that suggest that the lower the residual TTR levels post treatment, the higher the survival may be. Given that you are presenting more data from NTLA-2001 this year, I'm wondering whether the data you have collected so far across different doses can be sufficient to ultimately show trends that allow you to test the relation between TTR levels and survival.

David, you want to speak to what we can extract so far from TTR decreases and endpoints? I know it's early, but any additional comments you might want to provide?

Yes. So you're right when you say that what's been found with other diseases is lowering the protein is extremely important. In fact, when you achieve a complete response, for example, with light chain disease, the patients essentially have a normal survival. So we do see this as an important goal and one we're very excited about the deep level of reductions we're getting. To do that because our results are so consistent in our own data, we won't be able to see a relationship between TTR reduction and survival because all the patients are getting very deep reductions. But you can look back, for example, to the data from polyneuropathy with silencers that as you do go to deeper reduction, you see, for example, a greater improvement in the neuropathy. There is a really important finding already.

This is Benazir on for Dae Gon. We just noticed that recently there was a Stanford Group that published on a concatenated insertion when CAS and a remediator repair templates are introduced. Can you comment on what methods you're employing to detect such incidents with NTLA-2001 and in your interaction with the FDA, have they discussed this phenomenon at all?

Maybe Laura, the question was about an academic group that has discovered concatemers for insertion. Are there techniques that can be used to understand the extent of this occurrence in a cell?

Yes, of course. That's part of the clinical development, you could use different types of next-generation sequencing including long-range sequencing to understand whether you have a single insertion or concatemers.

Excellent. Has the FDA brought up anything about wanting that kind of information?

The FDA hasn't asked about that.

I recall from our prior conversation, the goal is to always have about 2 years of cash on the balance sheet. Can you give us a sense of how you're thinking about your cash burn and runway overall as you are set to tee off the 2 pivotal studies later this year? How are you prioritizing and allocating resources when you're moving forward with focus like TTR, HAE and AATD?

Yes, Brian, this is Glenn. Thanks for the question. So basically, what we talked about this morning is we're having runway now to late 2026. That's about 2.5 years' worth of cash. And that contemplates the three-year strategic priorities all being funded that we've been laying out for investors. So we feel like we're in pretty good shape there. The other thing I would say is just the operating expenses are going to stay pretty consistent as we go forward here from what you've seen in the last couple of quarters.

This is Robert on for Debjit. Two from us this morning, what is Intellia's view on potential synergistic effects of 2001 knockdown and tafamidis stabilization? And on gene insertion, how does Intellia and Regeneron plan to maintain expression within a therapeutic window, particularly in a disease like Heme B?

David, do you want to say a word or two about how we're thinking about the interaction between 2001 and tafamidis? And then maybe, Laura, you can follow up as how we aim for the therapeutic levels that we're pursuing with a reminder that hemophilia B is being pursued primarily by Regeneron at this point?

As we have already mentioned, we believe that the lower the levels of the precursor protein or the abnormal protein, the more positive the impact on the disease will be. If the protein levels decrease sufficiently, we expect that not only will the kidneys stop accumulating amyloid, but there may also be a reduction in amyloid as the body eliminates it from the organs. Our objective is to achieve the lowest possible TTR levels, which we have discussed in some of our recent research. At some point, people may inquire about our TTR number, which will be crucial going forward. Regarding tafamidis, if we can lower the protein levels adequately, tafamidis could still play a role since any remaining abnormal protein might be stabilized. This would enhance the already low amount achieved with our drug, potentially leading to an even better outcome with tafamidis. Therefore, there may be a beneficial or synergistic effect as we reach these very low levels.

So with regards to the question on the gene insertion and how do you maintain therapeutic levels. Part of the preclinical development package involves doing a matrix of dose, of how much insertion template, right? And you clearly and deeply characterize what's the range of insertion that results in therapeutic protein production. And that data is then taken into account allometric scaling for humans, right, as part of your clinical development plan. In the clinic, there is going to be a very purposeful and safe way of dose escalating to understand what's the level of expression and how does that translate across multiple patients in a cohort. So, remind me that Regeneron is being driven by Regeneron. So they're already approved to move into the clinic, and we're expecting we're going to be seeing data, clinical data in due time, which not only is important for that program but it's a validation of the insertion platform that will translate to 3001 and a number of other diseases for which insertion is the most appropriate gene therapy modality.

Part of the question was how to maintain levels? Maybe you could say a word about the stability that we expect.

Well, yes, for maintenance, right, we have shown for alpha 1 and other inserts that when such thing inserted into the genome, you see very, very stable insertion. This is a key difference from traditional gene therapy where you have an episome where over time, that episome could be silenced or can be lost just by the proliferation of the liver cells over time. So we expect that once you achieve those stable levels, those are going to be persistent and well controlled.

I guess looking at your earlier stage pipeline with your recent collaboration with ReCode, could you talk about the opportunity and potential market with gene editing medicine and cystic fibrosis and maybe also the opportunity of utilizing your DNA writing technology to address this indication?

I'll start why we're excited about cystic fibrosis and maybe Laura can talk about some of the technical things that we believe we can address successfully with our approach. As I think is well known, there are many people who suffer from cystic fibrosis in the United States and around the world, and therapies that currently address it are chronically administered. There's no doubt that's represented an advance for patients relative to where they were some years ago. But the fact remains, this is chronic therapy and many of these patients continue to progress. There's a set of patients for whom no therapy is available and as exciting as some of the advances are that they're just irrelevant to a large subset of these patients. This is a very large market as we've seen with other companies, and it's something that we think we can make some very, very significant contributions to. Maybe Laura can say a word about how we can address that and our work with ReCode.

Yes. As John mentioned, we believe there is still a significant unmet medical need in cystic fibrosis, especially for individuals who do not respond to existing therapies or cannot tolerate them. A key group within this population is Class 1 patients, who do not produce CFTR protein. We see a strong opportunity to initiate our efforts by combining our DNA writing technology with ReCode's LNP. We were pleased to observe ReCode's progress in LNP development, particularly as they are currently in the clinic with cell LNP aimed at two indications, one of which is CFTR. Their preclinical data shows robust evidence that they can effectively deliver the necessary edits to cells for long-term CFTR correction. We are very excited about this collaboration and are committed to advancing experiments as quickly as possible, with a great team from both sides working together.

I think the ReCode work is a good example of our approach to partnerships in general. We look for leaders in the space. People that share our values and approaches to patients. And those are the partnerships that we think are going to yield important new drugs, and we look forward to the five areas that we've talked about in our comments as we progress outside the liver.

Congrats on all the progress. So for 2001 in TTR, I had a follow-up from Luca's earlier question on magnitude. I was hoping to hear your thoughts on how important it is for 2001 to show a strong treatment benefit on top of tafamidis and what the potential commercial implications would be for showing different treatment effects in the patients on baseline tafamidis versus those not on treatment?

David, do you want to address the benefit and importance thereof?

We believe that drug 2001 has the potential to outperform tafamidis as a standalone treatment. Additionally, we think there could be added benefits when used alongside tafamidis, although this still needs to be confirmed. Feedback from investigators and physicians suggests there is a demand for improved treatments for this condition, as many patients continue to experience progression while on tafamidis. Therefore, we see a need for a superior single agent compared to tafamidis, particularly evident among patients not receiving tafamidis in the study. This will be a key focus in our analysis moving forward.

I think it's important to state that nobody is satisfied with tafamidis. I mean patients all progress on that drug. The disease remains a mortal illness, and investigators and patients know that. And what we think will prevail in the marketplace is drugs that offer the very best outcomes to patients. And that's the approach we've taken from the beginning of the development program. We're excited with the data we've seen thus far, which we've been sharing, and we expect to show that at the end of our Phase III trial that we represent a significant advance over what is currently the state of treatment, whether used in combination or alone, and that's going to be a real advance for the field.

And a quick follow-up. I just had a quick follow-up on Alpha 1. Since there's two moving parts here, the LNP and the AAV, I was hoping if you could just comment on how you're thinking about the dose escalation. Would you be able to escalate those components in tandem? Or would you have to maybe do an extended dose escalation to control for those two different delivery vehicles?

I'll turn to David, but just to set the table, we do a lot of preclinical work to try to address as many of the variables as possible before ever entering into the clinic. So I don't want anybody to think that we go in with a complete unknown. Just as our work with 2001 and 202, where we shared earlier, our modeling was essentially dead on in terms of what we saw in the clinic, we expect that many of the insights we've learned from the preclinical work will apply very, very directly to the 3001 as well. So David, maybe you could just say a word or two about some of the contraction of what would be a standard sort of checkerboard study of 3001.

Right? So with these two parts, the LNP and the AAV, we've learned a lot already about LNP, the ability to go to a particular site and target that site. And what we've learned from both the 2002 and 2001 programs is that we can achieve essentially every allele being targeted with this so that we can open that up for the contribution that the AAV will make. So we think more as we have a good idea of the LNP dose and the variation will be more in terms of how much AAV is needed to optimally get expression of alpha-1 antitrypsin. Again, our goal is to get normal levels; that's what we've achieved preclinically, and that's our goal clinically as well.

This is Mahdi on for June. Staying on ATTR. So assuming a positive update from HELIOS-B possibly late June and July. How does a third-generation RNAi candidate with potential once-a-year dosing could change the treatment landscape in your view?

Well, I would point out that things that follow us will be by definition after us. And we expect to be in a position where we will demonstrate the effect of our drug, which we think is going to be defining for the space. And our belief is that people will be comparing themselves to us as opposed to the agents that are out there. Regardless, I have not seen data that surpasses anything that we presented thus far. Patients will still be receiving the drug chronically, which brings with it all of the issues that apply to that. And we think that the one-and-done approach is ideal for this patient set, and we are unique in that space. So it's important for patients to have different options. But nonetheless, we think that we will be setting the standard.

Mine is more strategically. Maybe you can give us like a 10,000-foot view on your strategy in the new tissues. I know you touched before on bone marrow and today, a little bit on cystic fibrosis. But within all of these tissues that you've mentioned, which ones are closer to IND-enabling studies, which ones are further along? And how should we think about those programs coming to fruition over the next couple of years towards moving towards an IND?

Thanks for the question. It's an important one. But I don't want you to think it's a horse race, and we give updates on the individual laps that these relay races run. All of these tissues are very, very important. It really goes back to the philosophy and the strategic intent that has been the basis of the company since we first set out. It's a very deliberate approach that thinks about delivery and editing technologies. So as is apparent, we started out with knockouts in the liver, which you see with the 3001 program as a gene insertion into the liver. We have technology to add to that in the form of gene writing in the liver. And the goal has been to take these various editing technologies and apply them to diseases that reside outside the liver. And as Laura has mentioned earlier, we do that with collaborators, where people have technologies that can supplement our own and take us to places that we may not be able to get there by ourselves. We're excited about the work with ReCode. We're doing work with SparingVision. We have collaboration, as you know, with Regeneron. Each of these tissues, five of them that were delineated earlier have very important diseases with large populations with unmet medical need. Some of those opportunities surpass what we see in the liver at the current time. And so all of them benefit from the common approach from an editing point of view, and all of them are being resourced very, very aggressively to get to those preclinical development candidates.

This is Timur for Steve Seedhouse. So congrats on the rapid enrollment in Phase II MAGNITUDE study. One thing we would like to clarify is what type of patients are expressing more interest in this study? Is it patients who have no access to any treatment, patients who couldn't enroll in other trials or patients on tafamidis or some other category? And one other thing I'd like to clarify is what is the screen failure rates out of the 40 patients that are screened, what proportion do you think will be dosed?

Thanks for the question. We're not going to go into the details of screening failures. And as I said earlier, the number of sites and patients per sites and all that, that's our work to do, and we'll share as appropriate as we go forward. But David, is there any general insight you can provide in terms of the type of patients that's coming or not coming into the study at this point?

We were actually just meeting with investigators earlier this week, and there's excitement from these investigators for all of their patients that this can affect the disease at all stages. As you can imagine, patients with early disease, they want to prevent progression of disease if they're doing well. For the sicker patients, they want to at least stabilize or even reverse their disease. So they are really coming forward from what we are hearing from the investigators with all their patients. What we expect is about half of them have access to tafamidis, about half don't around the world, and that's the proportions we expect in the trial. The screen failure rate is low, but we will continue. That's obviously a piece of any trial with some patients who might be too sick or too healthy in some cases. But it's going very well, as you've heard, with more than 30 patients already randomized and more than 40 right behind them.

Congrats on all the progress this quarter. I believe you said that you filed the AATD CTA application in December. Could you share if you have received any response or feedback to that application? And once the trial is underway, what duration of follow-up would you want to include in any initial data presentation?

David, do you want to speak to the CTA status of the alpha-1 program?

Yes. We have received some straightforward questions regarding the CTA, which we have addressed. We anticipate hearing back any day now about its status. As for follow-up, we will adhere to our established principle of reporting significant data when available. It's worth noting that Regeneron has obtained approvals in both Europe and has cleared the IND. We are confident in the platform's ability to move forward globally.

Great. Thanks so much, Drew, and thanks, everyone, for joining us today for your great questions and for your continued interest in Intellia. We look forward to updating you as we continue to progress. Have a great day, everyone.

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