Intellia Therapeutics (ticker: NASDAQ:NTLA) has reported a productive fourth quarter and full year for 2023, emphasizing their strong financial position and promising advancements in their clinical pipeline. The biotechnology company, which specializes in CRISPR-based therapies, is poised to start Phase 3 trials for two of its leading programs. Despite a decrease in collaboration revenue due to an adjustment with Regeneron (NASDAQ:REGN), Intellia's financials remain solid, with a cash reserve that can support operations into mid-2026. The company also discussed their gene therapy safety database, regulatory filings, and ongoing collaborations, signaling a dynamic year ahead.
Key Takeaways
- Intellia is advancing two lead programs into or approaching Phase 3 clinical development, targeting ATTR amyloidosis and hereditary angioedema.
- The company holds a robust balance sheet with approximately $1 billion in cash reserves, extending their operational runway into mid-2026.
- Collaboration revenue decreased by $15.5 million in Q4 2023 due to an adjustment with Regeneron, while R&D and G&A expenses saw an uptick.
- Intellia is progressing with gene editing technologies and has established collaborations for cystic fibrosis and autoimmune diseases.
- Regulatory plans include filing a Biologics License Application (BLA) by 2026 and following patients for 15 years to ensure long-term safety.
Company Outlook
- Intellia expects a year of continued progress and catalysts in their clinical pipeline.
- The company plans to expand its capabilities and explore new disease areas.
Bearish Highlights
- There was a significant decrease in collaboration revenue in the fourth quarter of 2023, primarily due to a one-time revenue recognition adjustment with Regeneron.
Bullish Highlights
- Intellia is confident in the safety database of its gene therapy for regulatory approval.
- The company is making strides in gene editing technology and is optimistic about collaborations, particularly with ReCode for cystic fibrosis.
Misses
- Interest income, collaborator reimbursements, and proceeds from employee-based stock plans totaled $79 million, which could not offset the decrease in collaboration revenue.
Q&A Highlights
- The company is targeting about 30% of tafamidis patients in the MAGNITUDE trial to ensure a diverse patient population.
- Intellia acquired complementary technology for DNA writing and is excited about its potential, promising to share more details in the future.
- There are no plans for a switch study, but positive results from HELIOS-B could influence enrollment in the MAGNITUDE trial.
- The Phase 2 study for HAE will inform the dosing for Phase 3, and there's anticipation for brisk enrollment in upcoming trials.
Intellia Therapeutics continues to forge ahead with its mission to bring the first In Vivo CRISPR-based therapies to the market. With a solid financial foundation and a series of strategic collaborations, Intellia is not only expanding its therapeutic horizons but also ensuring that it remains at the forefront of innovation in gene editing technologies. The company's confidence in its gene therapy safety database and the planned regulatory filings in the U.S. and Europe underscore its commitment to meeting stringent safety standards. As Intellia prepares for a productive year with anticipated updates, the biotech industry and investors alike will be watching closely as the company moves its clinical programs forward.
InvestingPro Insights
Intellia Therapeutics (NTLA) has shown resilience in its financial standing and clinical advancements, as highlighted in the recent report. To provide additional insight, let's delve into some InvestingPro metrics and tips that could be pertinent for investors considering NTLA's stock.
InvestingPro Data:
- Market Cap: 2.35B USD
- Revenue (last twelve months as of Q3 2023): 51.77M USD
- Price, Previous Close: 26.88 USD
InvestingPro Tips:
1. Intellia holds more cash than debt on its balance sheet, which supports the company's assertion of a strong financial position to fund its operations well into 2026.
2. The company's stock price movements have been quite volatile, which is a factor investors may wish to consider, especially in light of the company's advances in clinical trials and the biotech sector's inherent risks.
For those looking to delve deeper into Intellia Therapeutics' financial health and future prospects, there are more InvestingPro Tips available. In fact, there are an additional 7 tips listed on InvestingPro. These could offer valuable insights into the company's cash burn rate, gross profit margins, and revenue valuation multiples.
Interested investors can take advantage of these insights and more by using the coupon code PRONEWS24 to get an additional 10% off a yearly or biyearly Pro and Pro+ subscription. These tips and metrics could be crucial in making an informed investment decision in the dynamic field of biotechnology.
Full transcript - Intellia Therapeutics Inc (NTLA) Q4 2023:
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. As a reminder, all participants are currently in a listen-only mode. [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: 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 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 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 Lebwohl, Chief Medical Officer; and 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 questions. With that, I'll now turn the call over to John, our Chief Executive Officer.
John Leonard: Thank you, Ian. Good morning everyone and thank you all for joining us today. 2023 was an outstanding year for Intellia and its strong momentum has carried into 2024 with our two lead programs either in or approaching Phase 3 clinical development, we are now closer than ever to the first In Vivo CRISPR based therapies reaching the market. We have 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 two large and rapidly growing commercial markets. Having clinically validated our In Vivo CRISPR gene editing technology by inactivating genetic targets in the liver, we're now bringing forth the next wave of innovation. This new frontier will come in two dimensions, broadening what we can do and expanding where we can go, all of which will allow us to increase the number of diseases we can pursue. The genome editing revolution is only made possible by the unique properties of CRISPR/Cas. Intellia’s expertise with CRISPR/Cas9 is unsurpassed and serves as a foundation for the diverse set of editing tools that we've developed and continue to advance. Whether using base editing or DNA writing tools, each of these technologies rely on the specificity and versatility of the CRISPR system. With our wide range of editing and delivering capabilities, we can apply the best tool for each therapeutic application. This allows us to address diseases where there is a meaningful opportunity to improve the standard of care. In some cases, we may even be able to pursue diseases that would otherwise be considered untreatable, if not for the power of CRISPR. It is this expansive and modular platform coupled with our strong balance sheet that will allow us to achieve the three-year strategic priorities announced earlier this year. Our focus remains on both near-term clinical execution as well as value-creating platform innovation. With this as a backdrop, we expect the following by the end of this year. Two In Vivo knockout programs in active Phase 3 studies, two In Vivo gene insertion programs in first in human studies, and five different tissues outside the liver with active research programs. And additionally, we expect to have six or more collaborations with at least a dozen potential drug products utilizing our technology 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 expansive In Vivo and Ex Vivo pipeline in the industry. With a potential BLA submission in 2026, we're well positioned to bring forth the first ever In Vivo CRISPR-based therapy. I'll now hand the call over to our Chief Medical Officer, David Lebwohl, who will provide an update on our clinical programs. David?
David Lebwohl: 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 3 MAGNITUDE trial for patients with cardiomyopathy. Since then we're hitting the aggressive timelines we have set for ourselves, including multiple sites opening and regulatory approvals in geographies with large patient numbers. Notably, we have our first U.S. site actively enrolling patients and on track to dose the first patient in the first quarter. We are making great progress and expect many additional sites to ramp up throughout the year. At the same time, we are actively preparing for a global, pivotal Phase 3 study of 2001 for the treatment of patients with polyneuropathy. We expect to provide additional information on our Phase 3 plans later this year. Finally, we plan to present new data from the ongoing Phase 1 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 1 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 1 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 2 study in only six months. We have since completed enrollment and dosing. We look forward to presenting the initial results for the first time later this year. Importantly, these data will determine the dose selected for the pivotal Phase 3 study. We expect to initiate the Phase 3 study in the second half of this year. Of course, this is subject to regulatory feedback, but we think we're in an excellent position. With five special regulatory designations granted to 2002, we've taken advantage of the opportunities for additional interactions with the FDA and other agencies to gain early alignment on our Phase 3 plan. 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: Thank you, David. Good morning, everyone. We're continuing to advance novel gene editing and delivery technologies for both In Vivo and Ex Vivo therapeutic applications. Building on the success of our In Vivo gene inactivation programs, we're leading the development of CRISPR-based targeted gene insertion. Here, we're leveraging the same R&D platform using our gene knockout programs to deliver the CRISPR machinery along with an AAB to deliver a functional gene. Unlike traditional gene therapy, we expect our approach will permanently restore a missing or defective protein without a waning effect over time. Earlier this month, our collaborator Regeneron announced that the Factor-9 gene insertion program for hemophilia B has achieved IND clearance. This milestone puts Intellia at three for three In Vivo IND clearances within 30 days of submission, a testament to our high standard for drug development. In parallel, we also expect to begin this year the Phase 1 study of our wholly owned program, NTLA-3001, for alpha-1 antitrypsin deficiency. Based on our preclinical data, NTLA-3001 could potentially achieve normal human levels of the alpha-1 protein after a single dose. Further, the potential human proof of concept of our modular gene insertion platform would open a whole new category of diseases that require restoring a missing or defective protein. This may include diseases that are not addressable by either base editing or DNA writing. Beyond our liver-directed program, our goal is to harness the full potential of gene editing by extending the reach of our industry-leading platform to other tissues. Recently, we announced a collaboration with 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 bites. With this new collaboration, alongside our own and other partner programs, we're actively pursuing gene editing programs across five different tissues. Finally, in the Ex Vivo setting, we're continuing to advance multiple programs, both wholly owned and with collaborators. For example, AvenCell is now dosing patients in their first in human study of an allogeneic candidate. Kyverna is utilizing our allogeneic platform to advance a next-gen CAR-T program for autoimmune disease. Both collaborators are using Intellia’s proprietary Allo Solution, which is designed to both T-cell and NK-cell-mediated rejection, a previously unsolved challenge for the field of cell therapy. I'll now hand over the call to Glenn, our Chief Financial Officer, who will provide an update on our financial results as of fourth quarter 2023.
Glenn Goddard: 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 market program, $49.8 million of interest income, $18.7 million of collaborator reimbursements, and $10.5 million in proceeds from employee-based stock plans. Our collaboration revenue decreased by $15.5 million to negative $1.9 million during the fourth quarter of 2023, compared to $13.6 million during the fourth quarter of 2022. This decrease was mainly driven by a $10.3 million one-time revenue recognition adjustment related to Regeneron extending the technology collaboration to April 2026. Intellia will receive a $30 million payment due in April as part of the Regeneron extension. R&D expenses increased by $9 million to $109 million during the fourth quarter of 2023, compared to $100 million during the fourth quarter of 2022. The increase was mainly driven by the advancement of our lead programs and personnel growth to support these programs. Stock-based compensation included in R&D expenses was $21.7 million for the fourth quarter of 2023. G&A expenses increased by $5.4 million to $29 million during the fourth quarter of 2023, compared to $23.6 million during the fourth quarter of 2022. This increase was primarily related to an increase in stock-based compensation of $4.3 million. Stock-based compensation included in G&A expenses was approximately $13.3 million for the fourth quarter of 2023. Finally, we expect our cash balance to fund our operating plans into mid-2026. 2024 will be another productive and catalyst-rich year for 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: [Operator Instructions]. The first question comes from Maury Raycroft with Jefferies. Please go ahead.
Maury Raycroft: Hi, good morning. Congrats on the progress and thanks for taking my question. 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: Thanks, Maury it's John. Appreciate your question. Remember that the Phase I study is limited in size, so the amount of information you'll provide from a clinical point of view and the ability to tie TTR levels to clinical progression is going to be inherently limited. We look to what we see other competitors doing in the space and use that as a complement to what we see with our own work. I don't think that anything that we've seen thus far that's been put out there is really changing fundamentally how we're thinking about prosecuting the Phase 3 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: Yeah, I think you've given the most important points. People should just recall that the dose expansion just completed towards the end of 2022, 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 3s of other compounds starts to diverge at about one year, so we do need significant follow-up to see trends. Of course, we don’t, this is a single-arm trial, so we don't have quite the right controls to compare any of our results to, but we do have the results, of course, from the other studies to look at.
Maury Raycroft: Got it. Thanks for taking my question.
Operator: The next question comes from Luca Issi with RBC. Please go ahead.
Unidentified Analyst: Oh, great. Thanks for taking our question. This is Lisa on for Luca. Just a question again on TTR cardiomyopathy. We know an HELIOS-B study is going to read out this summer, so just wondering should this read out positively, could this result in an early termination of your TTR cardiomyopathy study with NTLA 2001, any color there would be helpful? Thanks.
John Leonard: 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 2021 Phase 3 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 with Helios really doesn't relate to the work that we're doing. This is an events-driven study. We size the study appropriately, and we're going to have patients that we expect to present clinical endpoints just based on the stage of their disease, which is somewhat more advanced in our study. So all things considered, we think we're in a really good position. Of course, we'll watch Helios as it comes out, but it doesn't really fundamentally change anything that we're doing.
Operator: The next question comes from Greg Harrison with Bank of America (NYSE:BAC). Please go ahead.
Greg Harrison: Hey, good morning and thanks for taking the question. Could you give some color on your latest thinking on 2002's potential place in the treatment landscape given recent competitor data updates?
John Leonard: Yeah, it's an important question because we acknowledge there's other drugs out there that have some activity in HAE. Certainly over the last few years, progress has been made in the pharmacopoeia 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 don't have to carry on-demand therapy. So as new forms of on-demand therapy come out that fundamentally we don't think addresses what patients are looking for, and from a prophylactic point of view, as long as those drugs need to be readministered, that is going to be a continuing burden for those patients. So as we look at where we are with the data that we've seen thus far and look forward to continuing to expand, we believe that we're going right to the heart of the matter, which is preventing attacks once and for all, which we anticipate, assuming the success we've seen thus far continues, 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.
Greg Harrison: Makes sense, that's helpful. Thanks again.
Operator: The next question comes from Gena Wang with Barclays (LON:BARC). Please go ahead.
Unidentified Analyst: Hi, good morning. This is Harshita on for Gena. Thank you for taking our questions. I just had one on the MAGNITUDE ATTR-CM trial. For [indiscernible] 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 six-minute walk and write your class, NT-proBNP, echo parameters. So any color you could provide there would be really helpful? Thank you.
John Leonard: David, do you want to speak to how we think about secondary endpoints and why we included the ones we chose?
David Lebwohl: Yeah, those were chosen as being the most important secondary endpoints, of course, in consultation as well with regulatory agencies. The important things for patients we think are, first of all, we see in the primary endpoints reduction in cardiovascular events and mortality. Of course, that's the most important thing. This will be associated, we think with an improvement in quality of life and of course quality of life is therefore an important endpoint for these patients. The other measures like six-minute walk have had inconsistent results in recent studies, as you've seen, and we don't think is a really important part of what's happening for patients, especially because they may have other things other than their heart disease that's really affecting their six-minute walk, as these are older patients. Same for proBNP, it's a biomarker that indicates something about heart function but not really getting to the heart of what's important to patients.
Operator: The next question comes from Troy Langford with TD Cowen. Please go ahead.
Troy Langford: Hi, congrats on your progress this quarter, and thanks for taking our question. For 2002 do you all expect that you could file regulatory application in Europe at around the same time as in the U.S.? And do you see European regulators, do you think that European regulators seem mostly aligned with what the FDA wants at this point or do you see any divergences there?
John Leonard: David, do you want to address the conjugate filing of the 2002.
David Lebwohl: So this is, for 2002, the design of Phase 3s is fairly well set for this indication. You've seen a number of drugs going forward both with approvals or with new Phase 3 studies, and they all are really similar design. And that includes a feature that they tend to be very small studies, they could be well under 100 patients, and really looking to, in our case, the idea that we may be able to prevent any events in these patients. This is in coordination with the FDA filing, which would be sort of an end of Phase 2 meeting. In Europe they don't have that kind of meeting, but we have other types of discussions that indicate that the designs that we have moving forward will be acceptable in Europe as well.
Operator: The next question comes from Kostas Biliouris with BMO Capital. Please go ahead.
Kostas Biliouris: Good morning, everyone. Congrats on the progress. And thanks for taking our question. Maybe one question on your recent collaboration with ReCode. Can you provide any additional color on approximately when we can see the first early data there and how are you thinking about the competitive landscape, especially other gene editing approaches that are being developed for this disease? Thank you.
John Leonard: 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 pad from which one can expand it and 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.
Kostas Biliouris: Thank you very helpful.
Operator: The next question comes from Dae Gon Ha with Stifel. Please go ahead.
Unidentified Analyst: Hello, this is Benazir. I'm on for Dae Gon. Maybe a couple of questions on NTLA-3001. Given the rapid like crowding of the gene therapy, gene editing approaches, and ATD, what is the ideal product profile for NTLA-3001? And can you remind us again, that the SERPINA1 gene insertion is it directional and what are some supportive pieces of evidence or tools that are available to detect the correct insertion of the gene? Thank you.
John Leonard: 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 pre-clinically and non-human primates, those patients should be essentially the same as patients without the mutation in the first place, at least with respect to their lung disease. So whether or not we'll get to bat in humans is the basis of the Phase 1 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…
Laura Sepp-Lorenzino: Yeah sure. And this is -- we are using our insertion platform where we are inserting into the Insert [ph] 1 of the albumin loggers. So the expression is driven by albumin, which is a really strong promoter. And of course, the gene is wild-type. So, this is fully functional wild-type. So, there is no issues with any errors on sequencing or bystander edits, for example, that you introduce with other editing modalities.
Unidentified Analyst: Okay, thank you very much.
Operator: The next question comes from Joon Lee with Truist Securities. Please go ahead.
Unidentified Analyst: Hi, good morning. This is Maddy on for Joon and thanks for taking our question. This one also may be for Laura on NTLA-3001. So could you please talk about the potential risk of exacerbation in the liver manifestation of patients treated with 3001 based on the hetero polymerization capacity of the normal form with the mutant [ph]? Thank you.
John Leonard: You want to address them?
Laura Sepp-Lorenzino: Yeah, we haven't seen any in our preclinical models. We have seen cell lines where the expression of the mutant form that will lead us to a concern with regards to exacerbation of aggregation after 3001 treatment.
Unidentified Analyst: Thank you.
Operator: The next question comes from Brian Cheng with J.P. Morgan. Please go ahead.
Brian Cheng: Good morning. Thanks for taking my question. What's the latest thought around the 3001 Phase 1 trial design specifically, how do you sequentially space out the AAV and LNP administrations? And can you touch on also the part of CMA that you're aiming to present? Thanks.
John Leonard: David, can you summarize the essence of the Phase 1 design? I think the 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: We haven't told the exact time of clinical study, but they are both going to be -- they're not given exactly at the same time because we didn't want to separate them a bit, but they are given sequentially. And both the CRISPR mechanism and the AAV will be present in the cells at the same time once they are administered. And that's the key feature to be successful to get the gene insertion. Otherwise, it really is a standard Phase 1 study with a dose escalation based on the preclinical findings that we have and again, we'll be giving more details to that once the trial is fully approved.
Operator: And the next question comes from Salveen Richter with Goldman Sachs (NYSE:GS). Please go ahead. Excuse me, Salveen at Goldman Sachs, your line is open. Is it muted accidentally on your side?
Unidentified Analyst: Can you hear me?
Operator: Go ahead. Thank you.
Unidentified Analyst: Hi. Sorry, this is Olivia on for Salveen. Thanks so much for taking our question. Just another on 2001. Could you just speak to your comfortability around the powering for the MAGNITUDE trial and when you expect to complete enrollment? Thanks so much.
John Leonard: David, you want to address that.
David Lebwohl: Sure, so we are very confident in the design. Recall that we've used an events based study rather than harping the follow-up on patients. So the advantage of this, of course, is that you would not need to extend the time of the study based on perhaps slower event rates as you predict. But given that we did make a very conservative estimate both on our powering and predicted event rate. So again, we're confident in what we have with the design with a larger study than HELIOS-B at 750 patients. The completion of enrollment we have said is going to be in the -- yeah, it would be looking at some of the other studies to get a sense and you've seen that these studies enrolled very quickly. And so that would give you a good idea when we do expect to complete enrollment.
Unidentified Analyst: Thanks so much.
Operator: The next question comes from Debjit Chattopadhyay with Guggenheim. Please go ahead.
Unidentified Analyst: Good morning. This is Rai on for Debjit. Do you see opportunity for 2001 differentiation by potentially enriching the MAGNITUDE trial with NYHA Class 3 subjects, or other patient demographics that capture sicker population relative to contemporary ATTR-CM trials?
John Leonard: 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: We do allow, of course, Class 3 patients. An important feature of what we looked for is patients who are somewhat sicker than the other studies. And the way we did this is to have the baseline proBNP be greater than 1000 and to not have an upper limit on the proBNP. This could differentiate us in a few ways. First, we did this because the -- 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 learned about the trial. So we do -- we 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.
Unidentified Analyst: Got it, thank you.
Operator: The next question comes from William Pickering with Bernstein. Please go ahead.
William Pickering: Hi, thanks for taking my question. In AATD, what dose level of AAV was used in your NHP studies and how were 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 dent in albumin levels? Thank you.
John Leonard: 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 integrants are necessary to get to the levels we need.
Laura Sepp-Lorenzino: Yes. So, albumin promoter is the strongest promoter for liver, so you just need few percentage of cells to have been a productive insertion to achieve normal levels. Here we're looking at 22 micromolar as an average rate. So, the preclinical data of course we did metrics of LNPs and AAV keeping the goal as John just said, to ensure that the AAV dose is slow with the need to hit all the cells in the liver. And that gives us safety. We feel very good about the margin. Oh, and with regards to albumin, we do not see significant decreases in albumin, right, because you're only editing in a few cells. So albumin expression remains constant and that we've seen in preclinical models, and that was further evaluated in our GLP tox studies.
William Pickering: Thank you.
Operator: The next question comes from Rick Bienkowski with Cantor Fitzgerald. Please go ahead.
Rick Bienkowski: Hey, good morning, everyone. Thanks for taking the questions. The pivotal study in HAE, given the timelines for the potential 2026 BLA filings, I wanted to ask about the degree of confidence and being able to use a six-month primary endpoint in the pivotal study just given gene editing mechanism is so different from the competitors here? And also in the Phase 1 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: David do you want to speak to six months endpoint, I mean, obviously, you've been on the front line talking to regulators around the world. Do you think that there'll be the need to extend beyond these two standard sorts of approaches?
David Lebwohl: Yeah, what we believe is that the six month endpoint which has been standard in these studies will be the same standard that we apply to this study. In terms of longer follow-up, of course we will have Phase 1 and Phase 2 patients with longer follow-up when we filed the DLA and as well as a very extensive safety database from our other knock out program with TTR. So we do feel very confident that the safety database we're bringing will be satisfying what the regulators want. Of course for all gene therapies we will continue to follow the patients for the standard 15-year period. In terms of the breakthrough attacks, we are looking at how to account for this in the pivotal study. We're not talking about the exact design. You have to recall those patients were only the patients who had very unusual number of attacks, up to 15 attacks a month, as you recall. So that this -- we don't expect -- that's an unusual patient kind of patient who was waiting for the Phase 1 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: Rick, I appreciate your noting the BLA in 2026. It is one of our key strategic objectives for the company in the next two to three years. And we're very excited about being in a position to take what we think will be the very first In Vivo CRISPR based approach to approval and go into what we think is a marketplace that we can be extremely successful in.
Rick Bienkowski: Alright, appreciate the color. Thank you.
Operator: The next question comes from Yanan Zhu with Wells Fargo (NYSE:WFC) Securities. Please go ahead.
Yanan Zhu: Great. Thanks for taking our questions. So just wondering, a very quick one on MAGNITUDE, what is the percentage of tafamidis patient you target in a 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 if, for example, is there a correction template and whether it is RNA or DNA format? Thank you.
John Leonard: 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 for whatever therapeutic purpose. There's different ways to introduce those changes. When we think about gene writing tests, 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 a complimentary to the work that we're doing a couple of years ago. And we're excited with what that brings to us to add to the work that we're already doing. And at the right time and the right place we will talk about exactly what we're doing and how it fits into our pipelines. But I think that 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 you want to say a word about the tafamidis.
David Lebwohl: 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.
Yanan Zhu: Great, thanks for the answers.
Operator: The next question comes from Steve Seedhouse with Raymond James. Please go ahead.
Unidentified Analyst: Hi, good morning. This is Timor on for Steve Seedhouse. So we have a question on AATD. Historically, it's been difficult to show improvement in lung function with augmentation therapies and other therapies on endpoints such as FTD1 [ph] or pulmonary exacerbations. And even more advanced augmentation therapies haven't attempted to show this improvement. So how do you think about improvement in lung function, do you expect regulators to require you to show an improvement?
John Leonard: David, do you want to take that.
David Lebwohl: Yeah, the regulatory standard hasn't been set here. There have been some reports publicly that the FDA may accept having normal levels of Alpha 1 antitrypsin could be a way to move forward, of course with some associated clinical findings, but not that square -- certainly a definitive improvement. And we do think because our program can get to normal levels, really the only gene editing program that's shown us so far, that this may be something that the regulators will work with us on and have given us a way forward to an approval mostly based on the high levels that we'll be achieving.
Unidentified Analyst: Thank you.
Operator: The next question comes from Jay Olson with Oppenheimer. Please go ahead.
Jay Olson: Well, hey, 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 root of the administration and did the collaboration only focused on cystic fibrosis or could you potentially leverage the collaboration to study additional targets and diseases? Thank you.
John Leonard: Laura, you want to take that.
Laura Sepp-Lorenzino: Yeah, sure. So ReCode has been pioneering a new class of lipid nanoparticles that are targeted to different organs. These are the short levels. They have, we were quite interested in what they were doing in the lungs. And as you may know, they're already in the clinic to inhale, LNP mRNA for PCD and cystic fibrosis. Actually, I think they dosed the first patient with an mRNA yesterday. So with these LNP 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 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 Tuerkcan with JMP Securities. Please go ahead.
Silvan Tuerkcan: Yeah, good morning. Congrats on the quarter and congrats on the progress. And thanks for taking my question. Just a quick one on the HAE program. What are some of the considerations that you're thinking about selecting the dose for the Phase 3 and what can we see in the Phase 2 data bit later this year to give us confidence in that dose selection? And then regarding the Phase 3 design overall, is there any impact or any information that we'll get from the Phase 3 Oasis HAE study from -- presented, you know, mid-year that will help us also like in the design, I think about the design of the Phase 3 trials? Yeah, thank you.
John Leonard: David, how do you choose your dose for Phase 3.
David Lebwohl: So recall that we've completed the enrollment to a Phase 2, in which the patients, there are 10 patients on 25 milligrams, 10 patients on 50 milligrams, and five patients on placebo. So we have a very good setting in which to evaluate those two doses. We chose those two doses because of the dose escalation phase. As you recall, all patients basically achieved no events after the infusion except a single event in one patient a year after treatment, which was related to a sports injury. So with the Phase 2 we will have a very extensive database of these two doses. The things we'll be looking at, of course, is the clinical findings, the event rate, but also the consistency of the pharmacodynamic effect we'll be looking at as part of this. There was more variability at the lower dose. So on first principles, we would tend to think that the 50 dose is going to be better, but we want to look at all the data and make a decision about the Phase 3, and it will be a very robust decision based on this Phase 2 study.
Operator: The next question comes from David Lebowitz with Citi. Please go ahead.
David Lebowitz: Thank you for taking my question. A competitor has a switch study for its HAE trial and I'm just curious as to whether there is a similar type of study that would be needed or what that would look like for a gene editing product?
John Leonard: You want to speak to that.
David Lebwohl: We haven't talked about doing a switch study. In the pivotal studies what usually happens is that you withdraw from any kind of prophylactic therapy. We have seen in our study patients withdrawing from Lenzilumab [ph] as well as other prophylactic therapies. And we do think that will be of interest to patients when this is an approved drug 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.
David Lebowitz: Thanks for taking my question.
Operator: The next question comes from Jack Allen with Baird. Please go ahead.
Jack Allen: Great, thanks for taking my question. And congratulations on the progress. I wanted to ask if you could comment a bit more about your plans to enroll slightly more advanced patients in MAGNITUDE as compared to HELIOS-B and how do you expect positive results from HELIOS-B could affect enrollment in MAGNITUDE, meaning MAGNITUDE will be a placebo controlled study?
John Leonard: David?
David Lebwohl: Yeah, the idea of enrolling more advanced patients is that these are the patients who can really benefit from the therapy. If you imagine some of the studies we've seen, some patients who 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 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, but 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 have seen that we have a very consistent and deeper reduction in TPR. 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 the TTR reduction is important, maybe for -- maybe a further value in driving our enrollment as well.
Jack Allen: Great, thanks so much for the color.
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: 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.
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