Intellia Therapeutics Inc

NASDAQ:NTLA

Earnings Call Analysis

Intellia's Steady March Towards CRISPR Therapeutics

Intellia had a standout year in 2023, transitioning into 2024 with vigor as its CRISPR-based therapies approach commercial markets. Two leading programs are nearing Phase III, aiming to address ATTR amyloidosis in growing therapeutic areas. The company's CRISPR-Cas9 expertise fuels its broad, modular platform, targeting diseases considered untreatable before. Financially, while the cash reserves dipped from $1.3 billion to $1 billion due to operational costs, a strong balance sheet is expected to sustain operations into mid-2026. Collaborations are growing, with 6+ partnerships and a dozen drug products in development predicted by year-end. As they advance a next-gen CAR-T program and expect to kick off Phase III trials for hereditary angioedema later in the year, Intellia forecasts another productive year ahead.

Financial Summary and Operational Outlook

The company experienced a decrease in cash position from $1.3 billion at the end of 2022 to $1 billion at the end of 2023, with a cash burn of approximately $448.8 million due to operations. This decrease was mitigated in part by equity proceedings, interest income, collaborator reimbursement, and proceeds from employee-based stock plans. Despite the decline, the company's cash reserves are projected to fund operations into mid-2026, signaling a moderate runway for pursuing their strategic objectives without immediate financial pressure.

Revenue and Expense Dynamics

Collaboration revenue saw a downtick by $15.5 million to negative $1.9 million in Q4 of 2023, primarily due to a one-time adjustment with a notable partner. Research and development (R&D) expenses climbed by $9 million to $109 million in Q4 of 2023, as the company invests in advancing lead programs and grows its team to support this expansion. General and administrative (G&A) expenses also rose by $5.4 million to $29 million, with increases in stock-based compensation contributing to this rise.

Clinical Development and Regulatory Prospects

The company's clinical programs, particularly the one designated as '2002', are set for Phase III trials, suggesting imminent potential for regulatory applications in both the US and Europe. Such alignment between these geographies indicates the company is on the cusp of pivotal study submissions, which could substantially move the needle for their portfolio. The expectation of the first in vivo CRISPR-based therapy submission for a BLA in 2026 further underscores an ambitious clinical development trajectory.

Strategic Collaborations and Pipeline Expansion

Collaboration with ReCode in cystic fibrosis embodies a strategic integration of gene editing with specialized delivery technologies, aiming to target specific mutations. Likewise, expansive use of their developed lipid nanoparticle (LNP) tool offers the potential for tackling other targets and diseases, opening up a range of therapeutic opportunities. Thus, these partnerships could enhance the company's capacity to bring innovative treatments into clinical translation.

Anticipated Impact of Upcoming Clinical Data

The company is eagerly awaiting the release of Phase II data, which will inform the dosing decision for Phase III in their HAE program. With regulators potentially accepting alternate endpoints for gene editing therapies, the company might navigate a unique approval pathway that leverages the significant advantages of their gene editing capabilities. The positive ripple effects of concurrent studies in the field, such as HELIOS-B, are also anticipated to be beneficial for patient enrollment and broader acceptance of the company's therapeutic hypothesis.

Earnings Call Transcript 2023-Q4

[Operator]

Good morning, and welcome to the Intellia Therapeutics Fourth Quarter and Full Year 2023 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. [Operator Instructions]. I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.

[Ian Karp, executive]

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics Fourth Quarter and Full Year 2023 Earnings Call. Earlier this morning, Intellia issued a press release outlined in 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 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 Lebel, Chief Medical Officer; Laura Selorenzino, Chief Scientific Officer; and Glenn Godard, 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 questions. With that, I'll now turn the call over to John, our Chief Executive Officer.

[John Leonard, executive]

Thank you, Ian. Good morning, everyone, and thank you all for joining us today. 2023 was an outstanding year for Intellia and that strong momentum has carried into 2024. With our 2 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 offering potentially unmatched clinical profiles would address significant patient unmet need in 2 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 2 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-Cas. Intellia's expertise with CRISPR/Cas9 is unsurpassed and serves as a foundation for the diverse set of editing tools that we have 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 3-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, 2 in vivo knockout programs in active Phase III studies, 2 in vivo gene insertion programs in first-in-human studies and 5 different tissues outside the liver with active research programs. And additionally, we expect to have 6 or more collaborations with at least a dozen potential drug products utilizing our technology in 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 expansion in vivo and ex vivo pipeline in the industry, with the 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 Lebwohl, who will provide an update on our clinical programs. David?

[David Lebwohl, executive]

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 III magnitude trial for patients with cardiomyopathy. Since then, we're hitting the aggressive time lines 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 a global pivotal Phase III study of 2001 for the treatment of patients with polyneuropathy. We expect to provide additional information on our Phase III plans later this year. Finally, we plan to present new data from the ongoing Phase I 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 I 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 I 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 II study in only 6 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 III 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 5 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.

[Laura Sepp-Lorenzino, executive]

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 in activation programs, we're leading the development of CRISPR targeted gene insertion. Here, we're leveraging the same LNP platform using our Gen OCD 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 in leasing or effective protein without a waning of effect over time. Earlier this month, our collaborator, Regeneron, announced that the Factor IX geniuses program for hemophilia B has achieved IND clearance. This milestone puts Intellia at 343 in vivo IND cases within 30 days of submission, a testament to our high standard for drug development. In [Indiscernible], we also expect to begin this year the Phase I study of our wholly owned program, MDLA-31 for alpha-1 antitrypsin efficiency. Based on our preclinical data, MDLA-301 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 in leasing or effective protein. These maintain decisions that are not addressable by either base editing or DNA biting. 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 ReCode Therapeutics to accelerate the development of CRISPR-based treatments targeting genes in the line 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 pipes. With this new collaboration, alongside our own and other partner programs, we're actively pursuing gene editing programs across 5 different tissues. Finally, in the ex-vivo setting, we're continuing to advance multiple programs, both wholly owned and with collaborators. For example, Abanca 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 our immune disease. Both connagurators are using Intellia's proprietary allow solution, which is designed to both T cell and NK cell near rejection, a previously untapped 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.

[Glenn Goddard, executive]

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 $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 company's at-the-market program, $49.8 million of interest income, $18.7 million of collaborator reimbursement and $10.5 million in proceeds from employee-based stock plans. Our collaboration revenue decreased by $15.5 million to negative $1.9 million during the fourth quarter of 2023 compared to $13.6 million during the fourth quarter of 2022. The -- this decrease was mainly driven by a $10.3 million onetime revenue recognition adjustment related to Regeneron extending the technology collaboration to April 2026. Intellia, where we received 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. The 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 Intellia, 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.

[Operator]

We will now begin the question-and-answer session. [Operator Instructions]. At this time, we will pause momentarily to assemble our roster. The first question comes from Maury Raycroft with Jefferies.

[Maurice Raycroft, analyst]

Congrats on the progress. As you accumulate data from the Phase I 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?

[John Leonard, executive]

Thanks, Maury. It's John. Appreciate your question. Remember, the Phase I 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 the space and use that as a complement to what we see in our -- 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.

[David Lebwohl, executive]

Yes. I think you've given the most important point. People 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 IIIs of other compounds start to diverge at about 1 year. So we do need significant follow-up to see trends. And, 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.

[Operator]

The next question comes from Luca Issi with RBC.

[Lisa Walter, analyst]

Great. This is Lisa on for Luca. Just a question again on TTR cardiomyopathy -- an [Indiscernible] study is going to read out this summer. So just wondering, should this read out positively, could this result in early termination of your TTR cardiomyopathy study with NTLA-2001, any color there would be helpful.

[John Leonard, executive]

I don't see how the HELIOS results are going to affect 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 III 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 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 event-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.

[Operator]

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

[Greg Harrison, analyst]

Could you give some color on your latest thinking on 2002 potential place in the treatment landscape given recent competitor data update?

[John Leonard, executive]

Yes. 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 pharmacopeia for 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 they 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 that we've seen thus far continues, the patients will be able to dispense with their therapy once and for all. And I think that's the solution patients are looking for.

[Operator]

The next question comes from Gena Wang with Barclays.

[Harshita Polishetty, analyst]

This is Harshita on for Gena. I just had one on the magnitude ATTR-CM trial. For clinical.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 some other common ones such as 6-minute walk and Micras and TMP echo parameters. So any color you could provide there would be really helpful.

[John Leonard, executive]

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

[David Lebwohl, executive]

Yes. 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 6-minute walk have been -- have had inconsistent results in recent studies as you've seen. And we don't think is a really important part of what's happening to patients, especially because they may have other things other than their heart disease that's really affecting their 6-minute walk as these are older patients. The 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.

[Operator]

The next question comes from Troy Lankford with TD Cowen.

[Troy Lankford, analyst]

For 2002, do you all expect that you could file regulatory application in Europe that are on the same time as in the U.S.? And do you see European regulators -- or do you think that European dealers seem mostly aligned with what the FDA wants at this point? Or do you see any divergence there?

[John Leonard, executive]

David, do you want to address the conjugate [indiscernible] filings of the 2002?

[David Lebwohl, executive]

For 2002 the design of Phase III is fairly well set for this indication. You've seen a number of drugs going forward, both with approvals or with new Phase III studies, and they all really similar design. And that includes the 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 II 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.

[Operator]

The next question comes from Konstantinos Biliouris with BMO Capital.

[Konstantinos Biliouris, analyst]

Congrats on progress. 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.

[John Leonard, executive]

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 LNP 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 path from which one can expand. You 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.

[Operator]

The next question comes from Dae Gon Ha with Stifel.

[Benazir, analyst]

This is Benazir on for Dae Gon. Maybe a couple of questions on NTLA-3001. Given the rapid like clouding of the gene therapy, gene editing approaches in ATD, what is the ideal product profile for MTLA-3001? And can you remind us again that the ceropino-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?

[John Leonard, executive]

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 protein. Once one does that, which we've accomplished preclinically in nonhuman 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 as the basis of the Phase I 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?

[Laura Sepp-Lorenzino, executive]

Yes, sure. And this is -- we're using our insertion platform where we're inserting into the intron 1 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 fully functional wild-type. So there is no issues with any errors on sequencing or by standard edits, for example, that you introduced with other editing modalities.

[Operator]

The next question comes from Joon So Lee with Truist Securities.

[Maddie, analyst]

This is Maddie for Joon. This one also may be for Laura on NTL-3001. So could you please talk about a potential risk of exacerbation in the liver manifestation of patients treated with PV-01 based on the heteropolymerization capacity of the normal form with the mutant form.

[John Leonard, executive]

Do you want to address the.

[Laura Sepp-Lorenzino, executive]

Yes, we haven't seen any -- in our preclinical models, you've seen cell lines where there is expression of the mutant form that would lead us to a concern with regards to exacerbation of aggregation after 3001 treatment.

[Operator]

The next question comes from Brian Cheng with JPMorgan.

[Brian Cheng, analyst]

What's the latest thought around the 3001 Phase I trial in specifically, how do you sequentially space out the AAV and the LNP administrations? And can you touch on also the bar of CMAT that you're aiming to present.

[John Leonard, executive]

David, can you summarize the essence of the Phase I 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.

[David Lebwohl, executive]

We haven't told the exact signoclinical study, but they are both going to be -- they're not given exactly at the same time because we want to separate them a bit, they are given sequentially. And the -- 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 I study with a dose escalation based on the pre-clinical findings that we have. And again, we'll be giving more details of that once this trial is fully approved

[Operator]

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

[Lydia, analyst]

Can you hear me?

[Operator]

Go ahead.

[Lydia, analyst]

This is Lydia on for Salveen. 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

[John Leonard, executive]

David, do you want to address that?

[David Lebwohl, executive]

Sure. So the -- we're very confident in the design. I recall that we've used an event-based study rather than having to 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 lower event rates than they do 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 the larger study than HELIOS-B at 750 patients. The completion of enrollment, we've said, is going to be in the -- yes, we'd be looking at some of the other studies to get a sense. So 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.

[Operator]

The next question comes from Debjit Chattopadhyay with Guggenheim.

[Ray, analyst]

This is Ray on 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.

[John Leonard, executive]

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

[David Lebwohl, executive]

Yes. We do allow, of course, Class III patients. An important feature of what we look for is patients who are somewhat sicker than the other studies. And the way we did this is to have the baseline proBNP be greater than 1,000 and to not have an upper limit on the proBNP 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 one most likely to benefit from TTR reduction. If you're -- 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 -- do think that by choosing these patients, we will be able to differentiate our treatment of getting to lower TTRs and the other treatments in this study.

[Operator]

The next question comes from William Pickering with Bernstein.

[William Pickering, analyst]

In ATD, what dose level of AAV was used in your NHP studies? And how is the human dose equivalent compared 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 then in albumin levels?

[John Leonard, executive]

Well, 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 integrations are necessary to get to the levels we need.

[Laura Sepp-Lorenzino, executive]

Yes. So IBM in promoter is the strongest promoter Unilever. So you just need a few percentage of cells to have productive insertion to achieve normal levels. In care, we're looking at 22 micromolar as an average, right? So the pre-clinical data, of course, with the matrices of LNPs and AAV, keeping the goal, as John just said, to ensure that the AAV dose is low. We don't need to hit all the cells in the liver just a few. And that gives us safety. We feel very good about the margin. And with regards to albumin, we do not see significant decreases in albumin right, because you're only editing a few cells. So albumin expression remains constant, and that we've seen in preclinical models, and that was further evaluated in our GLP talk studies.

[Operator]

The next question comes from Rick Bienkowski with Cantor Fitzgerald.

[Rick Bienkowski, analyst]

Great. Good morning, everyone. For the pivotal study in HAE given the time lines for the potential 2026 BLA filing, I wanted to ask about the degree of confidence in being able to use a 6-month primary endpoint in the pivotal study, just given the gene editing mechanism is different from the competitors here. And also in the Phase I 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.

[John Leonard, executive]

David, do you want to speak to 6-month end points. I mean, obviously, you've been on the front line. I'm talking to regulators around the world. Do you think that there will be the need to extend beyond the standard sorts of approaches.

[David Lebwohl, executive]

Yes. What we believe is that the 6-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 a Phase I and Phase II patients with longer follow-up when we file the BLA and as well as a very extensive safety database from our other gene knockout program with. So we do feel very confident that the safety database we're bringing will be -- 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 are only the patients who had very unusual number of attacks to 15 attacks a month, as you recall. So that this -- we don't expect -- that's an unusual patient kind of patient who is waiting for the Phase I study. Most of the patients in the study will be more like the other patients where the attacks were pretty much gone after the infusion.

[John Leonard, executive]

Rick, I appreciate you noting the BLA in 2026. It is one of our key strategic objectives for the company in the next 2 to 3 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.

[Operator]

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

[Yanan Zhu, analyst]

Great. So just wondering, a very quick one on magnitude. What is the percentage of antafamidas 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, if there are a correction template and whether it is RNA or DNA format?

[John Leonard, executive]

Maybe I can say a word about the writing -- DNA writing approach, and David will address how we think about Tafamidis and 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 or 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, in 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 Tafamidis.

[David Lebwohl, executive]

Yes. For Tafamidis, we expect about half the patients to be treated with Tafamidis and this is similar to what's been seen in the pivotal studies that have been reported so far as well.

[Operator]

The next question comes from Steve Seedhouse with Raymond James.

[Timor Revance, analyst]

This is Timor Revance on for Steve Seedhouse. 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 dougmentation 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?

[John Leonard, executive]

David, do you want to ask.

[David Lebwohl, executive]

Yes. 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 atrypsin, 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.

[Operator]

The next question comes from Jay Olson with Oppenheimer.

[Jay Olson, analyst]

Thanks for providing the update and congrats on the recent collaboration with ReCode in 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 does the collaboration only focus on cystic fibrosis? Or could you potentially leverage the collaboration to study additional targets and diseases.

[John Leonard, executive]

Laura, do you want to take that?

[Laura Sepp-Lorenzino, executive]

Yes, sure. So ReCode has been pioneering a new class of flip 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 lung. And as you may know, they're already in the clinic with 2 inhale LMP mRNAs for PCD and cystic fibrosis, actually, I think they dosed the first patient with an mRNA yesterday. So with this M&P that goes to lung for which they already have preclinical and clinical data and 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.

[Operator]

The next question comes from Silvan Tarkan with JMP Securities.

[Silvan Tuerkcan, analyst]

Congrats on the quarter and on the progress. Just a quick one on the HAE program. What are some of the considerations that you're thinking about selecting the dose for the Phase III? And what can we see in the Phase II data that later this year and give us confidence in that dose selection? And then regarding the Phase III design overall, is there any impact or any information that will get from the Phase II OASIS HAE study from Heonis that will be presented midyear that will help us also like in the design or think about the design of the Phase III trial here?

[John Leonard, executive]

David, how are you going introduce your dose for Phase III.

[David Lebwohl, executive]

Yes. So recall that we've completed the enrollment to a Phase II in which the patients there are 10 patients on 25 milligrams, 10 patients on 50 milligrams and 5 patients on placebo. So we have a very good setting in which to evaluate those 2 doses. We chose those 2 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 the -- with the Phase II, we'll have a very extensive database of these 2 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 dose is going to be better, but we want to look at all the data and make a decision about the Phase III and it will be a very robust decision based on this Phase II study.

[Operator]

The next question comes from David Lebowitz with Citi.

[David Lebowitz, analyst]

A competitor has a Switc 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?

[John Leonard, executive]

I'll speak to that. Yes. 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 a varstudy patients withdrawing from labelumab 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 onetime therapy. So we haven't yet guided to there being a switch therapy, but this is something, obviously, that would be considered a Switch study.

[Operator]

The next question comes from Jack Allen with Baird.

[Jack Allen, analyst]

Congratulations on the progress. I wanted to ask if you could comment a bit more about your plans to enroll slightly more advanced patients and magnitude as compared to HELIOS-B. And how do you expect positive results from HELIOS-B could affect enrollment in magnitude being magnitude of be a placebo-controlled study?

[John Leonard, executive]

David?

[David Lebwohl, executive]

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 are -- 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 the -- 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 maybe a further value in driving our enrollment as well.

[Operator]

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

[Ian Karp, executive]

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.

[Operator]

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