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spk09: Good morning and welcome to IntelliA Therapeutics' first quarter 2024 Financial Results Conference call. My name is Drew and I will be your conference operator today. Following formal remarks, we will open the call up for a question and answer session. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. As a reminder, all participants are currently in listen-only mode. If anyone requires operator assistance during the conference, please press star zero on your telephone keypad. I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at IntelliA. Please proceed.
spk03: Thank you, operator, and good morning, everyone. Welcome to IntelliA Therapeutics' first quarter 2024 earnings call. Earlier this morning, IntelliA issued a press release outlining the company's progress this quarter as well as topics for discussion on today's call. This release can be found on the Investors 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'd like to take a minute to remind listeners that during this call, IntelliA management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for 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 Lebowall, Chief Medical Officer, Laura Lorenzino, Chief Scientific Officer, and Glenn Godden, Chief Financial Officer. John will begin with an overview of recent business highlights. David will provide an update on our clinical pipeline progress. Laura will review our R&D updates, and Glenn will review our financials before we open up the call for your questions. With that, I'll now turn the call over to John, our Chief Executive Officer.
spk05: Thank you, Ian. Good morning, everyone, and thank you all for joining us today. We've made outstanding progress in the first quarter of 2024 with one ongoing and two -be-initiated pivotal Phase III trials, and IntelliA is undoubtedly leading the gene-editing revolution. And with well over 100 patients already dosed across our two lead programs, we have already amassed the largest set of safety and clinical activity data for any in vivo CRISPR-based therapies. Notably, we believe our one-time treatments for ATTR and HAE, offering potentially unmatched clinical profiles, could overcome key hurdles faced by patients in too large and rapidly growing commercial markets. Moreover, our first two investigational gene-editing therapies are designed to be especially patient-friendly and convenient for physicians and caregivers. There's no extensive preconditioning regimen, no long-term steroid requirement, and no hospital stay, all of which can be very challenging for patients and limit commercial uptake associated with other gene therapies. And of course, with a one-time treatment, there's no annual insurance re-verification needed, which is typically required for chronic specialty therapies and can be a tremendous burden. But this is just the beginning for industry-leading CRISPR-based technology. We're now entering the next stage of growth, pushing the boundaries of what we can do and expanding where we can go with CRISPR, from gene knockdown, to gene insertion, from liver targets, to a broader set of tissues. Our first wholly-owned CRISPR-based gene insertion program, NTLA-3001, is expected to enter human clinical development this year. NTLA-3001 holds the potential to provide normal alpha-1 levels after single-dose treatment for people with alpha-1 antitrypsin deficiency. We will also have a second clinical program utilizing our modular gene insertion platform run by Regeneron for hemophilia B, expected to start patient dosing later this year. Building on our clinical success, we are now pursuing gene editing in five new tissue types outside the liver. As part of this expansion strategy, we have and will continue to establish collaborations with external innovators. These R&D efforts have already yielded at least a dozen potential drug candidates utilizing our technology. Further, we are advancing our modular platform by developing a diverse set of editing and delivery tools for in vivo and ex vivo applications. Whether it's our proprietary L&P formulations, novel gene editing tools, or differentiated allogeneic cell therapy approach, we emphasize safety and therapeutic activity at each step of development. Through our commitment to these principles, we are well on the path towards transforming cutting-edge scientific tools into real-world medical treatments. With this as a backdrop, we expect to end this year with five enrolling clinical studies, three of which are in phase three. This includes a newly planned phase three for NTLA-2001 in patients with ATTR polyneuropathy. Additionally, we plan to submit a BLA submission in 2026 for NTLA-2002, which we anticipate will lead to the first ever approval for an in vivo CRISPR-based therapy. By that time, our expectation is we'll have accumulated safety, efficacy, and durability data for over seven years and have treated as many as 1,000 patients in our clinical studies. In summary, we will continue transforming medicine with gene editing therapies with at least three important clinical readouts expected this year. I'll now hand the call over to our Chief Medical Officer, David Lebowall, who will provide an update on our clinical programs. David?
spk07: Thanks, John, and welcome, everyone. I'll begin with 2001, our in vivo CRISPR candidate for the treatment of ATTR amyloidosis. This multi-system disease primarily manifests as either cardiomyopathy due to amyloid deposits in the heart or polyneuropathy due to the progressive accumulation of protein deposits in the nervous system. As demonstrated in our SAVE-1 study, a one-time treatment of 2001 led to greater than 90% TTR reduction. Importantly, we demonstrated -in-class reduction of absolute TTR levels among TTR silencing agents, which we believe will be a key differentiator for treating patients with CM and or PN. In ATTR-CM, despite the introduction of TTR stabilizers, patients continue to experience worsening heart failure, hospitalizations, strokes, and heart attacks. Ultimately, it remains a fatal disease. Today, I am pleased to report that patient enrollment in the Phase III magnitude trial for patients with cardiomyopathy is off to a great start. In March, we announced the first patients in both the U.S. and globally had been dosed. With over 30 patients already dosed and another 40-plus in screening, we are tracking well ahead of our initial projections. Further, we expect many additional sites to open in the weeks and months ahead, which will further accelerate enrollment in the trial. While we will not be providing -by-patient enrollment updates moving forward, we will look for opportunities to keep you abreast of our progress. The rapid rate of enrollment reflects the enthusiasm we hear from physicians and patients who believe 2001 holds the potential to revolutionize the ATTR treatment landscape. In parallel, we are also excited to announce today that we now expect to initiate a new Phase III trial for patients with ATTR polyneuropathy by year end. Importantly, ATTR PN patients are typically diagnosed earlier in adulthood, and their disease often progresses more rapidly than ATTR-CM. Published data from chronically dosed TTR silencing therapies demonstrate that deeper reductions of TTR are highly correlated with improvements on standard measures of neuropathy. To date, no other agent approved or in clinical development has demonstrated the depth and consistency of TTR reduction regardless of baseline levels like 2001, which gives us tremendous confidence in our ability to positively impact patients. Based on productive discussions with the FDA, we have aligned on a trial designed to support a VLA filing for 2001 subject to review of the IMD application. We plan to initiate the Phase III by year end. The study is expected to be a small placebo-controlled trial of approximately 50 patients conducted in ex-US regions with limited or no access to silencers. We are making significant strides in advancing 2001 and look forward to presenting data from the ongoing Phase I trial in the second half of the year. We expect to be presenting safety and TTR reduction data on all 72 patients from both the CM and PM arms. Additionally, we plan to include for the first time data beyond TTR levels such as NT-ProBMP, 6-minute walk test, and MNIST plus 7. In summary, we continue to believe 2001 may halt and potentially reverse the disease as well as dramatically reset the ATTR treatment landscape. I'll now turn to 2002, our in vivo CRISPR program for the treatment of hereditary angioedema or HAE. In January, landmark findings from the Phase I were published in the New England Journal of Medicine highlighting a single dose of 2002 that to a 95% ATTR reduction. On June 2nd, we will be presenting updated data from the study at the European Academy of Allergy and Clinical Immunology Annual Congress. These long-term data will speak to the safety and durability of effect on both calicrine and ATTR reduction. Importantly, we will also present on the number of patients who remain completely attack-free, with extended follow-up now reaching beyond 18 months for all patients and longer than two years in sum. Additionally, we plan to report top-line results from the randomized placebo-controlled Phase II study shortly thereafter. Full results evaluating the 25-milligram and 50-milligram doses are expected to be presented at an upcoming medical meeting. These data updates will provide clarity on which dose to move forward into the Phase III trial. Assuming 2002 continues to show a strong safety and efficacy profile, we believe that 2002 will become the preferred prophylaxis treatment in a growing commercial market. In the U.S. market, for example, currently about 70% of HAE patients use chronic prophylaxis treatments, and that number is increasing. Many patients continue to seek better efficacy and more convenience, expressing a strong willingness to switch to new treatments that can deliver on both fronts. As previously discussed, we plan to initiate the pivotal Phase III trial in the second half of 2024. At this point, we are mainly waiting for the Phase II data before submitting regulatory amendments to begin our global Phase III. Notably, we have now also completed the additional preclinical mouse study requested by the FDA to support inclusion of women of childbearing age in the U.S. As expected, these data did not show an impact to female reproductive health in the animals treated with 2002. This is consistent with the extensive preclinical work completed and reviewed by regulators prior to our initial IND clearance, and we plan on submitting these data to the FDA prior to Phase III. Let me now turn to exciting developments with our modular gene insertion platform. Here, we are leveraging the same LNP platform used in our gene knockout programs to deliver the CRISPR machinery, along with an AAD to deliver a functional gene. Unlike traditional gene therapy, we expect our approach will permanently restore a missing or defective protein without a waning of effect over time. We expect to begin this year a first in human study of 3001, our wholly owned gene insertion program for alpha 1 antitrypsin deficiency. As a reminder, the main hurdle with treating this disease is getting patients to consistently normal levels of alpha 1. Current standards of care, which involve weekly infusion of augmentation therapy, does not cheese this. Other approaches in development have also been unable to yield normal levels of alpha 1, and in some cases have only been able to produce a modified version of the protein with unknown consequences. 3001 is the only drug candidate to show AAT levels restored to normal levels after a single dose in non-human primates. It is designed to precisely insert the wild type Serpin A1 gene and permanently restore production and secretion of fully functional alpha 1 protein. Assuming success, 3001 could be life changing for alpha 1 patients and unlock a whole new category of diseases we can pursue with in vivo gene insertion. Separately, our collaborative regeneron has achieved clearance from both US and EU authorities for the Factor IX program using our modular gene insertion platform and plan to enroll the first patient later this year. Our clinical development of the in vivo pipeline is rapidly accelerating, and Intelia is well positioned as a leader in this new era of medicine. I'll now hand over the call to Lara, our Chief Scientific Officer, who will provide updates on our R&D efforts and what's coming next.
spk16: Thank you, David. Good morning, everyone. At Intelia, we're advancing novel gene editing and delivery technologies for in vivo and ex vivo therapeutic applications. As John mentioned, core to our strategy is the emphasis on safety and performance at each step of development. Our success to date is not by chance, and it's a common misconception that gene editing and delivering tools have become commoditized. By leveraging experience of a world-class team and making dramatic improvements and adaptations to our platform technologies, we have been able to lead the entire industry forward. But don't just take my word for it. Let me give you some real world examples. Intelia is now 545 in IMD approved by the FDA for our investigational therapy. Groundbreaking clinical data sets for both NTLA-21 and NTLA-22 have been published in the New England Journal of Medicine. We have already gained regulatory clearance for multiple clinical trials in eight different countries. Together, we regenerate and we're conducting the largest global phase three study of genetic medicine. Intelia has become the reference gene editing company which has to help us foster important relationships with the world's leading scientific and medical experts as well as advocacy organizations. And now, given on the success of our work with diseases that originate in the liver, we're expanding the tissue types that can be targeted with our CRISPR-based technologies. We now have active research programs in five different tissues outside the liver, either independently or in collaboration with partners. This includes the bone marrow, brain, eye, lung, and muscle. We're particularly excited about pursuing diseases such as sickle cell disease, muscular dystrophy, cystic fibrosis, ALS, and many other delimited genetic conditions. We're also advancing a pipeline of ex vivo programs, both wholly owned and in collaboration with partners for the treatment of immunology and autoimmune diseases. In fact, two of our partners are leveraging our allogeneic platform, one of which is already in the clinic. Our differentiated allogeneic solution, including HLA matching, is uniquely positioned to avoid both T-cell and NK cell mediated rejection and results in cell persistence and disease control. Further, therapies engineered with our allogeneic platform, combined with edits to enhance cell function, offer a new approach to target solid tumors. We look forward to updating you on our progress across our R&D platforms more broadly this year. And now hand over the call to Glenn, our chief financial officer, who will provide an update on our financial results as of first quarter 2024.
spk04: Thank you, Laura. Good morning, everyone. Intelia continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform. Our cash equivalents and marketable securities were approximately $953.4 million as of March 31, 2024, compared to $1 billion as of December 31, 2023. The decrease was driven by cash used to fund operations of approximately $137.2 million. The decrease was offset in part by $58 million of net equity proceeds from the companies at the market program, $12.6 million of interest income, $5.9 million of collaborator reimbursements, and $2 million in proceeds from employee-based stock plans. Our collaboration revenue was $28.9 million during the first quarter of 2024, compared to $12.6 million during the first quarter of 2023. The $16.3 million increase was mainly driven by a $21 million non-cash revenue recognition adjustment related to the Avoncel collaboration. R&D expenses were $111.8 million during the first quarter of 2024, compared to $97.1 million during the first quarter of 2023. The $14.7 million increase was mainly driven by the advancement of our lead programs. Stock-based compensation included in R&D expenses was $20.2 million for the first quarter of 2024. G&A expenses were $31.1 million during the first quarter of 2024, compared to $27.4 million during the first quarter of 2023. The $3.7 million increase was primarily related to stock-based compensation. Stock-based compensation included in G&A expenses was $14 million for the first quarter of 2024. Finally, we expect our cash balance to fund our operating plans until late 2026. Notably, our strong balance sheet gives us the financial power to execute on the three-year strategic priorities laid out at the beginning of this year. First, to execute pivotal trials for our first two in vivo CRISPR-based therapies. Second, to launch the next wave of in vivo and clinical programs. And third, to deploy new editing delivery modalities. We're well on our way to realizing the promise of gene editing. This will be a catalyst-rich year for Intellia, and we look forward to updating you on our continued progress. With that, we will now open the call for your questions. Operator, you may now open the call for Q&A.
spk09: We will now begin the question and answer session. To ask a question, may press star then one on your touchtone phone. If you're using a speaker phone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Mari Raycroft with Jeffreys. Please go ahead. We will go to the next questioner, Yanan Zhu with Wells Fargo Securities. Please go ahead.
spk14: Great. Thanks for taking our questions, and a lot of progress this quarter, so congrats on those progress. I have a question about your comment about the speed of enrollment in an ATTR phase 3 trial tracking ahead of the internal expectation. Wondering how many sites have you opened? What's the number of US versus ex-US sites, and what is the per site per month patient number that you are currently tracking? Any updated thinking on the enrollment completion timeline? The faminist use in terms of the currently enrolled patients? I think, yeah, thank you. A lot of questions. Sorry about that.
spk05: Yanan, thank you for the many questions you just asked in that one question. We're not going to be giving updates on patients per site, numbers of sites, etc. As we said before, this is a balanced study around the world. We're still actively initiating study sites. We've said that we expect about a third of all of the ultimate sites will be in the United States, the remainder will be spread around the world. I think the takeaway that I would encourage you to see here is that we're early in this process, and things are going very well. We're very excited about the enthusiasm that we see with investigators. We've been clearing the regulatory submissions expeditiously. We've been able to initiate sites, and patients have been waiting to come into the study. We think it's a testimony to what patients and physicians see with the current state of therapy, which as you know, with current approved drugs, patients continue to suffer from the morbidity and the mortality of disease with ongoing progression. We will not be giving updates patient by patient as we go, but I would encourage you to see that we're off to a very, very strong start. We're enthusiastic about the progress we're
spk14: making. Thanks for those colors. If I may make a quick follow-up on that, from your interaction with in particular the US sites, what do you hear from PIs and patients in terms of how they think about potential upcoming approval of silencers? How does that impact their thinking of going on the gene therapy treatment? Thank you.
spk05: In our interactions thus far, it hasn't influenced how they're thinking about the trial or putting patients on it. Again, I think people have been very impressed with the data that we presented and are encouraged to put their patients on the study. I'll remind you that we created a study that's very favorable to patients. We've put into study the ability for patients with stage III heart failure, a higher pro-BMP level, etc., a -to-one randomization that favors drug over placebo. There's lots of reasons for patients and physicians to want to participate in the trial, and we're seeing that in these early results. Thanks. I look forward to the next question.
spk09: The next question comes from Maury Raycroft with Jeffreys. Please go ahead.
spk11: Hi. Sorry about the technical issue, and thanks for taking my question, and congrats on the progress. For the ATTRPN study, just looking at precedent studies in the so IONIS, their study was 168 patients. Apollo A was 225, and then Helios A was 164. Just wondering if you can talk about how the conversation went with FDA to align on your Phase III with 50 patients, maybe talk about what expectations are for clinical endpoints and results on those endpoints, and what does this imply about the size of what your HAE Phase III study could be?
spk05: Well, let me take the last point first, and then I'm going to hand it over to David to address the specifics of polyneuropathy. HAE endpoints and polyneuropathy endpoints are two totally different animals, and I wouldn't read how one study is designed into how we think about the other. As we get more specificity with respect to both of these trials, we'll certainly speak to that so we can see. But I would just emphasize before David speaks to some of the specifics, we've developed a very close working relationship with the Food and Drug Administration and other regulatory agencies around the world. I think they have a very good understanding of the expected effects of these drugs and have a very good understanding of how to show them in a meaningful way for their own purposes, as well as for physicians and ultimately for other regulatory agencies around the world. David, maybe you can say a few things about how we're approaching that study and why we think it'll be successful.
spk07: First, the big picture is that we and the FDA recognize that patients are still progressing despite the existing drugs, and we talked about this design, but they have seen our clinical data. An important part of that is that we're getting very deep and consistent reductions in TTR, and we do think that's been a positive effect on our discussions with them. In terms of the number of patients, the FDA also has seen a number of studies that show TTR reduction leads to a better fit in patients. So that's becoming a well-established fact. Of course, the FDA is more interested in how biomarkers may be a way to not only reflect what happens with disease but actually go forward to approvals in the future. So I do think that the size of the trial has to do with their confidence in how we're working. And of course, we also have not only the 50 patients at this trial but a much larger database from the Phase I as well as the ongoing cardiomyopathy Phase III.
spk11: Got it. Thanks for taking my question. I'll hop back into the queue.
spk09: The next question comes from Troy Langford with TD Cowan. Please go ahead.
spk08: Hi. Congratulations on the progress this quarter, and thanks for taking our question. So for NTLA 3001, how quickly do you think you can move through development with this asset? So do you think you would try to take this asset into a pivotal study shortly after the Phase I dose work like with NTLA 2001? Or do you think we'll have more traditional placebo-controlled Phase II to further refine the dose before a pivotal study like with NTLA 2002?
spk05: Thanks for the question, Troy. I just started by saying, as was emphasized in our comments earlier today, we emphasize understanding these drugs, especially from a safety as well as from an efficacy point of view. And so those will be our guiding principles as we carry out the study of 3001. We're excited with what we think the drug can do. I'll remind you that in the preclinical data, we've established that we're able, in beings, we think that's fundamental to the regulatory strategy. Our hope is that we'll show that in Phase I studies. And assuming that we see that, we will progress as quickly as we can, working with the Food and Drug Administration and other related agencies to establish what is the shortest, most efficient way to regulatory approval. So that lies ahead, and we'll give you updates as we proceed.
spk08: Great. Thanks
spk09: for the color. Coordinator The next question comes from Luca Isi with RBC Capital. Please go ahead.
spk19: Luca Isi Oh, great. Thanks so much for taking my question. Congrats on all the progress. Maybe, David, on TTR Cardiomyopathy, given the recent changes from your competitor, are you rethinking any aspects of your trial design? In a scenario where Helios B hits only monotherapy and shows no benefit as add-ons to FAMDIS, do you have any functionality to split the primary endpoint between the overall population and the monotherapy arm, similar to what they did? And then maybe quickly on TTR Polyneuropathy, can you just expand on why not enrolling patients in the U.S. for the pivotal?
spk05: David So, I'm, well, David speaks to some of the specifics of the trial, but I just started by pointing out that, you know, there's some fundamental differences in how we've approached the pivotal trial. In the case of TTR, we've certainly been mindful of understanding the rates of progression. We've been able to learn from other drugs as they presented data as we've gone, that have gone before us. And we've been really thoughtful about an endpoints-driven study, which is driven by the rate at which things happen, not by some pre-specified moment in time when we surmise that all the events may be in. I think the standard approach to these trials is, in fact, an endpoints-driven approach, and that's what we've embraced from the beginning. I think, David, maybe you can just say a few words about how Helios does or does not affect our thinking at this current time.
spk07: David So, you know, the first point is that we are confident, as John is saying, in the design of the magnitude study, because in all those points you made, we've been conservative in the assumptions we've made as we designed it. Of course, it is a larger study than Helios, who thinks that's very important. And we also took on some more advanced disease in these patients. The pro-BMP is higher, and we don't have an upper limit at that. We don't limit the amount of time that we follow these patients in this event-driven trial. Of course, we, as we've stated before, because we get consistently deep and durable TTR reductions, we do think we can be the best in class and can be better than drugs and other studies. So, we will be paying very, obviously, very close attention to the data that comes out from Helios-D. We do expect it to be a positive trial. Would you point out how much it will add to defamidus? We don't know at this point, but whatever comes out from those results, we have the potential to modify our trial in order to address whatever is found with the other drugs.
spk05: I think you look also looking for some insight into the polyneuropathy study for phase three and where we're conducting it and why.
spk07: So, our discussions with the FDA is clear that it was important to have a control arm, a placebo control arm. So, these are patients in the world who do not have access to silencers. In the U.S., there is very good access to silencers. So, the main reason we would not be having patients in the U.S. is because of the satisfied need for that, for those patients.
spk05: And it's important to note that we're aligned with that approach. They understand how we would be doing a study and where we'll do it. And because the treatment practices are so similar, we think that this information should be readily applicable to the United States.
spk19: Got it. Thanks so much.
spk09: The next question comes from Gina Wang with Barclays. Please go ahead.
spk12: Hi. Good morning. This is Harsheeda on for Gina. Thanks for taking our question. Just a quick one on us, from us on NTLA-2002. Now that you've completed the pre-clinical embryological development study, are you able to provide more granular color on when you plan to meet these data? Is the submission imminent and any color you can provide on how long it'll take the agency to review this data? And I understand that you can't speak for the agency and each situation is unique, but if you're able to provide at least a range on timelines, that would be helpful. Thank you.
spk05: Thanks for the question, Harsheeda. We don't go through report by report and submission processes and procedures for each of those things. And I remind you that this is not even gating for Phase 3 program. The first point I think to make is that we've seen the data. It's as expected. There's no issues and we're in a really good position to proceed. What's really going to drive the Phase 3 start is getting the data in with respect to our Phase 2 program. And as was referred to by David during the comments earlier, when we have those, we'll be sharing those later this year, and that's something we're very enthusiastic about. And because we have some regulatory designations that allow us to interact more readily with the FDA, we think we're going to be in a really strong position, actually poised, to take that data and very, very quickly submit it to the FDA to begin Phase 3, which as a reminder, we said we expect to start this year and hopefully be in a position to enroll patients before the end of the year.
spk09: The next question comes from Costas Belouris with BMO. Please go ahead.
spk15: Good morning, everyone. Thanks for taking our questions and congrats on the great progress. One question or two zero zero one from us, you have previously showed data from other types of amyloidosis that suggest that the lower the residual TTR levels post-treatment, the higher the survival may be. Given that you are presenting more data from NTLA 2001 this year, I'm wondering whether the data you have collected so far across different doses can be sufficient to ultimately show trends that allow you to test the relationship between TTR levels and survival. Thank you.
spk05: David, do you want to speak to what we can extract so far from TTR decreases and endpoints? I know it's early, but any additional comments you might want to provide?
spk07: You're right when you say that what's been found with other diseases is lowering the protein is extremely important. In fact, when you achieve a complete response, for example, with light chain disease, the patients essentially have a normal survival. We do see this as an important goal and why we're very excited about the deep level of reductions we're getting. To do that, because our actual results are so consistent in our own data, we won't be able to see a relationship between TTR reduction and survival because all the patients are getting very deep reductions. But you can look back, for example, to the data from polyneuropathy with silencers that, as you do go to deeper reductions, you see, for example, a greater improvement in the neuropathy. This is one really important finding already. It goes along with the findings in other types of cardiomyopathy and just gives us the confidence that this trial will be successful in what it's going to do.
spk15: Thank you. Very helpful.
spk09: The next question comes from Dagon Ha with Stiefel. Please go ahead.
spk17: Hi, this is Benaziran for Dagon. We just noticed that recently there was a Stanford group that published on a concatamized insertion when cath and AAV immediate repair templates are introduced. Can you comment on what methods you're employing to detect such incidents with NTAEA 2001? And in your interaction with the FDA, have they kind of discussed this phenomenon at all?
spk05: Maybe, Laura, if you... The question was, an academic group has found concatamers for insertion. And are there techniques that one can employ to understand the extent to which that might occur in a cell? Oh,
spk16: yeah, of course. That's part of the preclinical development. By then you could use different types of next generation sequencing, including long range sequencing to understand whether you have a single insertion or concatamers.
spk17: Okay, excellent. Thank you. Has the FDA brought up anything about wanting that kind of information?
spk07: The FDA hasn't asked about that at all. No.
spk17: Thank you very much.
spk09: The next question comes from Brian Cheng with JP Morgan. Please go ahead.
spk13: Hey, guys. Thanks for taking our question this morning. I recall from our prior conversation, the goal is to always have about two years cash on the balance sheet. Can you give us a sense of how you're thinking about your cash burn and runway overall as you're set to tee off the two-pivotal study later this year? How are you prioritizing and allocating resources when you're moving forward with focuses like TTR, HEE, and AATD? Thank you.
spk04: Yeah, Brian. Hey, this is Glenn. Thanks for the question. So basically what we talked about this morning is we're having runway now to late 2026. That's about two and a half years worth of cash. That contemplates the three-year strategic priorities all being funded that we've been out for investors. So we feel like we're in pretty good shape there. The other thing I would say is just the operating expenses are going to stay pretty consistent as we go forward here from what you've seen in the last couple quarters.
spk09: The next question comes from Debjit Charapadhyay with Guggenheim Securities. Please go ahead.
spk02: Hey, good morning, team. This is Robert. Thanks for taking our questions. Two from us this morning. What is Intellia's view on potential synergistic effects of 2001 knockdown and to fabulous stabilization? And on gene insertion, how does Intellia and Regeneron plan to maintain expression within a therapeutic window, particularly in a disease like Heem B? Thank you.
spk05: David, do you want to say a word or two about how thinking about the interaction between 2001 and Tephamidus? And then maybe Laura, you can follow up as how we aim for the therapeutic levels that we're pursuing with a reminder that hemophilia B is being pursued primarily by Regeneron at this point. David?
spk07: So, what I discussed already, the way we think about it is that the lower the amount of this precursor protein, of the abnormal protein, the better the effect on the disease. And in fact, if the protein gets low enough, then what we expect not only that you don't start accumulating amyloid, but you actually might see the reduction of amyloid, that the body will remove the amyloid from organs. So, our goal is to get the lowest absolute TTR levels. We've talked about that in some of our recent work. In fact, at some point, people may ask, what is your TTR number? That's going to be the important thing moving forward. So, what happens with Tephamidus? If you do get the levels low enough, then Tephamidus could be valuable still because the bit of remaining abnormal protein could be stabilized. So, you go from what is a very low amount already with our drug to make it even better perhaps with the Tephamidus. So, it may be a valuable interaction. It might be a synergistic interaction as you get to these very low levels.
spk16: So, with regards to the question on the gene insertion and how do you maintain therapeutic levels, part of the preclinical development package involves doing a matrix of those, how much LNP and how much insertion template, right? And you clearly and deeply characterize what's the range of insertion that results in therapeutic protein production. And that data is then taken into account, you know, allometric scaling for humans, right? That's part of your preclinical development plan. In the clinic, there is going to be a very purposeful and safe way of those escalating to understand what's the level of expression and how does that translate across multiple patients on the cohort. So, you know, reminding that, you know, Fentermine is being driven by Regenon. So, you know, they're already approved to move into the clinic and we're expecting we're going to be seeing, you know, data, clinical data in due time, which not only is important for that program, but it's a validation of the insertion platform that, you know, will translate to 31 and a number of other diseases for which insertion is the most appropriate gene editing modality.
spk05: Part of the question was how to maintain levels. Maybe you could say a word about the stability that we expect.
spk16: Oh, yeah, and for maintenance, right, we have shown now for Factor 9, for Alpha 1 and other inserts that, you know, once it's inserted into the genome, you see very, very stable insertion. This is a key difference from, you know, traditional gene therapy where you have an epithome or over time, you know, that epithome could be silenced or can be lost just by the proliferation of the liver cells over time. So, we expect that once you achieve those stable levels, those are going to be persistent and well controlled.
spk09: The next question comes from Mary Kate Davis with Bank of America. Please go ahead.
spk01: Good morning. Thank you for taking my question. I guess looking at your earlier stage pipeline with your recent collaboration with Recode, could you talk about the opportunity and potential market with gene editing medicine and cystic fibrosis and maybe also the opportunity of utilizing your DNA writing technology to address this indication? Thank you.
spk05: I'll start. Why we're excited about cystic fibrosis and maybe Laura can talk about some of the technical things that we believe we can address successfully with our approach. As I think is well known, there's many people who suffer from cystic fibrosis in the United States and around the world and therapies that currently addressed are chronically administered. There's no doubt that that's represented in advance for patients relative to where they were some years ago. But the fact remains, this is chronic therapy and many of these patients continue to progress. There's a set of patients for whom no therapy is available. And as exciting as some of the advances are, they're just irrelevant to a large subset of these patients. This is a very large market as we've seen with other companies and it's something that we think we can make some very, very significant contributions to. Maybe Laura, you can say a word about how we can address that and our work with Recode.
spk16: Yeah, so as John was saying, we believe that cystic fibrosis is still significant in medical need, not only the people who don't respond to current therapies, but there are patients who don't tolerate them. Important among those patients is what's called the class one, that they don't make CFTR proteins. So we believe that that's the perfect place for us to start by combining our DNA writing efforts with Recode's LMP. We were encouraged to see the LMP development by Recode and particularly they're in the clinic, right? We inhale LMP for two indications, one being CFTR. They have really robust preclinical data demonstrating that they can get to the cells that we need to edit to have persistent long-term CFTR correction. So we're very enthusiastic about the collaboration and really pushing experiments to move as fast as we can. A great team on both sides working together. I
spk05: think the Recode work is a good example of our approach to partnerships in general. We look for leaders in the space, people that share our values and approaches to patients, and those are the partnerships that we think are going to yield important new drugs and we look forward to the five areas that we've talked about in our comments as we progress outside the liver.
spk09: Coordinator The next question comes from Rick Binkowski with Cancer. Please go ahead.
spk06: Rick Binkowski Hey, good morning, everyone. Congrats on all the progress and thanks for taking the questions. So for 2001 and TTR, I had a follow-up from Luca's earlier question on magnitude. I was hoping to hear your thoughts on how important it is for 2001 to show a strong treatment benefit on top of TIFAMIDUS and what the potential commercial implications would be for showing different treatment effects in the patients on baseline TIFAMIDUS versus those not on treatment.
spk05: Dr. Michael Binkowski David, do you want to address the benefit and importance thereof?
spk07: Dr. Michael Binkowski So I think what we believe is that the drug can be, 2001 could be better than TIFAMIDUS as a single agent. We also believe that there will be a benefit on top of TIFAMIDUS. Of course, that's still to be proven. What we are hearing from investigators and physicians is that they're looking for better drugs for this disease. Patients continue to progress on TIFAMIDUS. Virtually all the patients as best we can understand from investigators and from the literature. So we do think there is a for a single agent that is better than what TIFAMIDUS is doing. This could be seen in the patients who are obviously not receiving TIFAMIDUS in the study. So this will be an important analysis as part of our work.
spk05: Dr. Michael Binkowski I think it's important to state that nobody is satisfied with TIFAMIDUS. I mean, patients all progress on that drug. The disease remains a mortal illness and investigators and patients know that. What we think will prevail in the marketplace is drugs that offer the very best outcomes to patients. That's the approach we've taken from the beginning of the development program. We're excited with the data we've seen this far, which we've been sharing. We expect to show that at the end of our phase three trial that we represent a significant advance over what is currently the state of treatment, whether used in combination or alone. That's going to be a real advance for the field.
spk06: Dr. Michael Binkowski Very great. Thank you. And a quick follow up. I just had a quick follow up on Alpha 1. Since there's two moving parts here, the LMP and the AAV, I was hoping you could just comment on how you're thinking about the dose escalation. Would you be able to escalate both components in tandem or would you have to maybe do an extended dose escalation to control for those two different delivery vehicles?
spk05: Dr. Michael Binkowski We do a lot of free clinical work to try to address as many of the variables as possible before ever entering into the clinic. So I don't want anybody to think that we go in with a complete unknown. Just as our work with 2001 and 2002, where we shared earlier our modeling was essentially dead on in terms of what we saw in the clinic, we expect that many of the insights we've learned from the preclinical work will apply very, very directly to 2001 as well. So, David, maybe you could just say a word or two about some of the contraction of what would be a standard sort of checkerboard study to 2001.
spk07: Dr. Michael Binkowski Right. So with these two parts, the LMP and the AAV, we've learned a lot already about LMP, the ability to go to a particular site and target that site. And what we've learned from both the 2002 and 2001 program is that we can achieve essentially every allele being targeted with this so that we can open that up for the contribution that then AAV will make. So we think it's more as we have a good idea of the LMP dose and the variation will be more in terms of how much AAV is needed to optimally get expression of alpha-1 antitrypsin. Again, our goal is to get normal levels. That's what we've achieved preclinically and that's our goal clinically as well.
spk09: David Lambert Are you ready for your next question? The next question comes from June Lee with Truis Securities. Please go ahead.
spk18: June Lee Hi. Good morning and thanks for the update and taking our question. This is May on for June. Staying on ADTR, assuming a positive update from HDSB possibly late June or July, so how does a third generation RNAi candidate with potential once a year dosing could change the treatment landscape in your view? Thank you.
spk05: David Lambert Well, I would point out that things that follow us will be by definition after us. We expect to be in a position where we will demonstrate the effect of our drug, which we think is going to be defining for the space. Our belief is that people will be comparing themselves to us as opposed to the agents that are out there. And regardless, I have not seen data that surpasses anything that we've presented thus far. Patients will still be receiving the drug chronically, which brings with it all of the issues that apply to that. And we think that the one and done approach is ideal for this patient set and we are unique in that space. So, you know, it's important for patients to have different options. But nonetheless, we think that we will be setting the standard.
spk09: David Lambert Thank you. Coordinator The next question comes from Sylvan Turcon with JMP Securities. Please go ahead.
spk10: Sylvan Turcon Thank you for taking my question. Mine is more strategically. Maybe you can give us like a 10,000 foot view on your strategy in the new tissues. I know you touched before on marrow and today a little bit on cystic fibrosis. But within all of these tissues that you've mentioned, which ones are closer to IND enabling studies? Which ones are further along? And how should we think about, you know, those programs coming to fruition over the next couple of years towards, you know, moving towards IND? Thank you.
spk05: David Lambert Thanks for the question. It's an important one, but I don't want you to think it's perhaps that these relay races run. All of these tissues are very, very important. It really goes back to the philosophy and the strategic intent that, you know, has been the basis of the company since we first set out. It's a very deliberate approach that thinks about delivery and editing technology. So, as is apparent, we started out with knockouts in the liver, which you see with the -in-1 program is a gene insertion into the liver. We have technology to add to that in a form of gene writing in the liver. And the goal has been to take these various editing technologies, imply them to diseases that reside outside the liver. And as Laura has mentioned earlier, we do that with collaborators where people have technologies that can supplement our own and take us to places that we may not be able to get there by ourselves. We're excited about the work with Recode. We're doing work with Sparing Vision. We have collaboration, as you know, with Regeneron. Each of these tissues, five of them that were delineated earlier, have very important diseases with large populations with unmet medical need. Some of those opportunities surpass what we see in the liver at the current time. And so, all of them benefit from the common approach from an editing point of view. And all of them are being resourced very, very aggressively to get to those preclinical development candidates.
spk09: Thank you. The next question comes from Steve Seathouse with Raymond James Financial. Please go ahead.
spk21: Hi. Good morning. This is Timur Vanikopal for Steve Seathouse. So, congrats on the rapid enrollment in the Phase II Magnitude Study. One thing we would like to clarify is what type of patients are expressing more interest in the study. Is it patients who have no access to any treatment, patients who couldn't enroll under the trials, or patients on the thamidus, or some other category? And one other thing we'd like to clarify is what is the screen failure rate? So, out of the 40 patients that are screened, what proportion do you think will be dosed? Thank you.
spk05: Thanks for the question. We're not going to go into the details of screening failures. And as I said earlier, number of sites and patient-first sites and all that, that's our work to do, and we'll share as appropriate as we go forward. But David, is there any general insight you can provide in terms of the type of patient that's coming or not coming into the study at this point?
spk07: Yeah, we were actually just meeting with investigators earlier this week, and there's excitement from these investigators for all of their patients that this can affect the disease at all stages. Now, you can imagine patients with early disease, they want to prevent aggression of disease if they're doing well. For the sicker patients, they want to at least stabilize or even reverse their disease. So, they are really coming forward from what we are hearing from the investigators with all their patients. What we expect is about half of them have access to thamidus, about half don't around the world. That's the proportions we expect in the trial. The screening failure rate is low, but we will continue. That's obviously a piece of any trial. Some patients might be too sick or too healthy in some cases. But it's going very well, as you've heard. There's more than 30 patients already randomized and more than 40 right behind them. Thank you very much.
spk09: And our last question comes from William Pickering with Bernstein. Please go ahead.
spk20: Hi, good morning. Congrats on all the progress this quarter, and thank you for taking my question. I believe you said that you filed the AATD CTA application in December. Could you share if you have received any response or feedback to that application? And once the trial is underway, what duration of follow-up would you want to include in any initial data presentation? Thank you.
spk05: David, do you want to speak to CTA's status of the Alpha-1 program?
spk07: Yes. So with the CTA, we've gotten some straightforward questions that we've addressed. We're expecting to hear any feedback about the status of that. In terms of follow-up, we'll follow the principle we always have that when we have a significant body of data to report on, that we will be bringing the data forward. As a reminder, Regeneron has gained approval to Europe and the IMD cleared so that in terms of the application itself, the platform, we have high confidence in its ability to go forward around the world.
spk20: Thank you very much.
spk09: At this time, I would like to turn the conference back over to Ian Karp as this concludes our question and answer session. For any closing remarks.
spk03: Great. Thanks so much, Drew. And thanks everyone for joining us today for your great questions and for your continued interest in Intellia. And we look forward to updating you as we continue to progress. Have a great day,
spk09: everyone. The conference has now concluded. Thank you for your participation. You may now disconnect.
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