Earnings Call: Q4 2020

Feb 25, 2021

And welcome to the Intellia Therapeutics 4th Quarter 2020 Earnings Conference Call. At this time, all participants are in a listen only mode. Following the formal remarks, we will open the call up for your questions. Please be advised that this call is being recorded at the company's request. At this time, I would like to turn it over to Josh Rappaport, Managing Director at Stern Investor Relations. Please go ahead. Thank you, operator. Good morning, everyone, and welcome to Intellia's Q4 and full year 2020 earnings call. Earlier today, Intellia issued a release outlining the company's progress this quarter and the 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 also be archived on the company's website. Before we get started, I'd like to remind you that during this call, Intellia Management may make certain forward looking statements and ask that you refer to SEC filings available at sec No duty to update this information unless required by law. Joining me on today's call from Intellia are Doctor. John Leonard, Chief Executive Officer Doctor. David Levall, Chief Medical Officer Doctor. Laura Sep Moranzino, Chief Scientific Officer and Glenn Goddard, Chief Financial Officer. For today's call, John will begin by discussing the company's highlights, David will provide an update on clinical efforts with NTLA-two thousand and one. Lara will recap the company's R and D progress and Glenn will review financial results from the Q4 and full year Following their prepared remarks, we will open the call up for Q and A. With that, let me turn the call over to John. Thank you, Josh, and thank you all for joining us this morning. This is an exciting time to be in the genomics field. There's never been greater appreciation for the revolutionary applications of gene editing technologies in medicine and beyond. We at Intellia We are proud to be at the forefront of this movement, developing curative genome editing treatments to transform the lives of people with severe disease. Our leading CRISPRCas9 based platform supports a full spectrum strategy, which deploys differentiated modular solutions across in vivo and ex vivo therapeutic applications. For genetic disease, we utilize our in vivo approach, which leverages a lipid nanoparticle based delivery system to selectively knockout disease causing genes or precisely insert genes to produce normal proteins. Rx Vivo T cell receptor or TCR based approach is designed to produce a homogeneous Robust cell product that epitomizes a patient's own natural immune system to eliminate cancer cells. Across these efforts, We've generated a broad pipeline, including emerging clinical candidates and an expansive research stage portfolio. 2020 was a landmark year for our team. We submitted our first clinical trial application and shortly thereafter Dose the first patient in our global Phase 1 study for NTLA-two thousand and one. It's the 1st systemically delivered CRISPR based therapy to enter clinical development. This was a tremendous milestone for Intellia, the gene editing field and for patients with genetic disease. In addition, we advanced IND enabling activities for our next two development candidates, NTLA-five thousand and one, our first engineered TCR T cell therapy and NTLA-two thousand and two, our 2nd in vivo knockout candidate, which nicely demonstrate the modularity of our platform. We built on our Nobel Prize winning scientific foundation, broadened our platform capabilities and further differentiate Intellia's solutions for gene editing, delivery and cell engineering. And we strengthened our corporate position with the expansion of our Regeneron collaboration and significant support from both new and existing investors. Today's call is an opportunity not only to reflect on these achievements, but also to review our key priorities and anticipated milestones for this year. Our top three priorities are demonstrating clinical validation of our approach with MTLA-two thousand and one, advancing and expanding our pipeline and continuing to build our platform capabilities. This year, we will continue the evaluation of the clinical profile of TLA-two thousand and one that we began last year, both as a potentially curative treatment option for ATTR patients and as validation of our non viral approach to in vivo delivery. In addition, we will continue to advance and expand our pipeline with 1st in human regulatory submissions planned for NTLA-five thousand and one in NTLA-two thousand and two, and we also expect to nominate at least one new development candidate. Finally, We will continue building a complete gene editing toolbox to enable the next wave of pipeline candidates. At our founding, we set out to develop modular platform components that could serve as the engine powering an expansive portfolio of curative therapeutics. Our progress since has paved a rapid and reproducible development path, both in vivo and ex vivo that should play out in additional programs moving forward. In anticipation of first in human data this year and as our investment in R and D matures into a broad pipeline of With that, let me turn the call over to our Chief Medical Officer, David Lebwold, who will provide an update on our progress in the clinic with NTLA-two thousand and one. David? Thank you, John, and good morning, everyone. I'll start with a bit of background. Framtarmetin amyloidosis or ATTR is a progressive and fatal disease, caused by the buildup of TTR protein in multiple organs. People living with the disease can have either the hereditary or wild type form of ATTR, which results in diverse disease manifestations, most frequently Polyneuropathy and cardiomyopathy. Globally, there are an estimated 50,000 people with hereditary ATTR and between $200,000 $500,000 with wild type ATTR. NTLA-two 20 and 1, our investigational therapy for the treatment of all manifestations of ATTR, applies our in vivo approach to knockout the TTR gene in the liver, which is the source of circulating wild type and mutant TTR protein. Although there are approved chronic therapies for this condition, there remains significant unmet medical need in this population As patients are at best stabilized and not cured of the underlying condition, Leading investigators in the field are enthusiastic to bring a potentially curative treatment to their patients, and they tell us 2,001 would deliver meaningful value to both patients and our healthcare system. Our robust preclinical data showing deep and long lasting TTR reduction support 2,001's potential as a one and done treatment to halt and possibly reverse disease progression. Following authorization to initiate our Phase 1 trial with the U. K. Clearance of our CTA in October, We dosed the 1st patient in this study in November, marking our transition into a clinical stage company. We continue to enroll patients across sites in the United Kingdom and New Zealand and are submitting additional clinical As a reminder, this is a 2 part open label multicenter Phase 1 trial that is designed to evaluate the safety, Tolerability, pharmacokinetics and pharmacodynamics of 2,001 in adult patients with hereditary ATTR with polyneuropathy. We will enroll up to 38 patients who each receive a single dose of 2,001 to an intravenous infusion. Part 1 is a single ascending dose study with up to 4 cohorts following a traditional 3 plus 3 design and aimed at identifying the optimal biologically active dose. Then we plan to quickly move into the second part, which will be a single dose expansion cohort of 8 additional patients To characterize further the activity of 2,001, including an initial assessment on clinical measures of neuropathy and neurologic function and obtain additional safety data at the optimal biologically active dose. This trial design includes the measurement of We expect to share interim results from Part 1 of this study at a scientific or medical meeting this year. The results from the initial doses in the trial will give us a preliminary view of the safety and activity profile of the drug as the study progresses. Importantly, We believe our interim results will establish clinical proof of concept for our modular LNP delivery platform. In addition, we expect this data to represent an important milestone towards identifying the optimal biological dose for 2,001. Once we have evaluated safety and identified the optimal biologically active dose, We plan to run studies assessing 2,001 in ATTR patients with polyneuropathy and with cardiomyopathy. In the cardiomyopathy patient population, we expect to be able to start at the optimal dose identified in our Phase 1 study in polyneuropathy patient. As we anticipate, the editing activity will be the same across these different disease manifestations. Before passing the call off, I want to acknowledge the momentous achievement in dosing our first patient with 2,001. We look forward to sharing our first glimpse into clinical data later this year. Now I'll turn this over to our Chief Scientific Officer, Lara Sep Florenzino, for updates on our 2 additional development candidates, 2,002 and 5,001 and across our R and D efforts. Thanks, David. I'll begin with our 2nd in vivo knockout candidate, MDLA-two thousand and two, in development for the treatment of Hereditary androedema or HAE. HAE patients experience recurrent, unpredictable and painful swelling in multiple tissues. While there are acute and prophylactic therapies for HAE, the treatment burden on patients remains significant. We believe there is additional opportunity for a therapy that not only further reduces frequency and intensity of attacks, but which can prevent and eliminate them altogether. MDLA-two thousand and two is designed to knockout the KLKV1 gene in the liver, leveraging the same LNP delivery system used for MDLA-two thousand and one. We will be sharing new preclinical results from this program this week at the American Academy of Allergy, Asthma and Immunology Annual Meeting confirming greater reductions In serum kalikron protein levels and activity in non human primates versus the current standard of care for HAE. In addition, the data will capture durability of this effect sustained so far through 15 months following a single dose in an ongoing non human primate study. We also confirm the therapeutic hypothesis in a humanized KLKV1 mouse model of bradykinin mediated vascular permeability, where a single administration of NTLA-two thousand and two resulted in robust scale KV1 editing subsequent reductions in total plasma catacrine and prevention of cabochryl induced vascular leakage. If translatable to patients, we expect LTLA-two thousand and two could effectively free patients from a lifetime of disease and its debilitating symptoms by permanently reducing allicline levels after a single course of treatment. We commence GMP manufacturing activities and remain on track to submit a regulatory application to begin clinical trials for MTLA-two thousand and two in the second half of this year. To my earlier point, we're leveraging insights from NTLA-two thousand and one and therefore anticipate being able to start NTLA-two thousand and two at the higher dose for our 1st in human study, which we expect will evaluate safety, tolerability and measures of activity, including levels of calicare and nogla. Turning now to our ex vivo efforts. Here we're using CRISPRCas9 as a tool to create engineered Similar to our efforts in vivo, our proprietary approach to cell engineering underpins a modular platform with Regardless of solutions, we can achieve highly efficient sequential editing, high yields, optimal cell performance and scalable manufacturing. Our lead program, MPLA-fifty 1, employs a TCR based approach. We have shared a great deal of data differentiating our process to precisely edit and replace the patient's T cell receptors with a tumor targeting TCR. This process reduces safety risk and should translate to improved potency and function versus other technologies for multiplex editing. MTLA-fifty 1 is targeting WT-one and will be initially developed to treat ANL. Despite recent therapeutic advances delivering improved response rates in subsets of ANL, long term outcomes And if you recall, WT1 is overexpressed in over 90% of AML patients regardless of subtype. So our hope is that pairing advantages of our proprietary cell engineering process with these Broadly prevalent target. MDLA-fifty 1 will be a well tolerated solution capable of improving long term outcomes for patients across all mutational subtypes and forms of AML. Core to this approach is to ensure patients receive a high quality, Robustal product that mimics natural T cells and enhances their natural immune response. At the American Society of Hematology Annual Meeting in December, we share additional preclinical data showing MPLA-five thousand and one produce High anti tumor activity means proof of concept mouse models of acute leukemias. The data also showed Faster expansion and superior function compared to T cells engineered with a standard genome editing process. We continue to make steady progress with IND enabling activities and we're on track to submit an IND or equivalent for MPLA-five thousand and one mid year. Our first in human trial is expected to evaluate the safety and activity of MPLA-five thousand and one in patients with persistent or recurrent AML who have previously received first line therapies. Moving on to our research programs and platform advances. Across our wholly owned and partner efforts, We're developing new therapeutic candidates for genetic diseases and next generation engineered cell therapies for cancer. The versatility of our platform enabled full spectrum approach allows us to move quickly with pipeline expansion. And as John noted, We plan to nominate at least 1 new development candidate this year. Further, we have broadened applications of our technology Leveraging this modular toolbox. Within our in vivo works, we're pursuing research efforts across multiple liver targets, including for targeted transgene insertion. In December, we presented a second non human primate proof of concept study Building off our work with Factor IX for hemophilia B, insertion of the SERPINA1 gene into the albumin locus Produce normal levels of circulating human alpha-one antitrypsin or AAT after a single administration. This is an important demonstration further differentiating our approach to insertion, which we are advancing against both wholly owned and partner targets. Additionally, in November, we received a grant from the Bill and Melinda Gates Foundation to Importantly, this sets the stage for our next wave of in vivo genome editing, enabling us to treat diseases across multiple tissue types. Ex vivo were evaluating potential use of the same construct to treat WT1 positive solid tumors in preclinical studies and we're working towards an allogeneic solution for the development of off the shelf T cell therapies. In developing our cellular therapies, we believe it is important to optimize for cell health and function, both to boost the body's own immune response with targeted reinforcements against resistant cancers and to ensure the engineered cells are not rejected. Enhanced T cell products with desired characteristics should yield additional benefits for patients, improved safety and efficacy. Finally, we continue to expand the genome editing tools at our We look forward to sharing more details in the coming year as we plan to present at scientific conferences across all these efforts. And with that, I would like now to hand over the call to Glenn, who will provide an overview of our Q4 and full year 2020 financial results. Thank you, Laura, and good morning. Intellia is well positioned for our upcoming milestones. Our cash, cash equivalents and marketable securities were $597,400,000 as of December 31, 2020 compared to $284,500,000 as of December 31, 2019. The increase was mainly driven by net proceeds of $346,100,000 from external financing activities, $100,000,000 from the expanded Regeneron collaboration and $31,400,000 from our Regeneron and Novartis collaborations, offset in part by cash used to fund operations of $164,600,000 Our collaboration revenue decreased by $4,300,000 to $6,600,000 during the Q4 of 2020 compared to $10,900,000 during the Q4 of 2019. The decrease was mainly driven by a decrease in Novartis revenue as the resource Portion of the collaboration ended in December of 2019. Our R and D expenses increased by $6,500,000 to $38,200,000 during the Q4 of 2020 compared to $31,700,000 during the Q4 of 2019. This increase was mainly driven by the advancement of our lead programs, Research personnel growth to support these programs and the expansion of the development organization. Our G and A expenses increased by $1,800,000 to $10,800,000 during the Q4 of 2020 compared to $9,000,000 during the Q4 of 2019. This increase was mainly due to employee related expenses, including stock based compensation of $1,300,000 Finally, we expect our current cash balance to fund our operating plans through at least the next 24 months. And now I will turn the call back over to John to briefly summarize our upcoming milestones. Thanks, Glenn, And to David and Laura as well for your updates. As you can see, there's a lot going on here at Intellia. Coming off for productive 2020, in which we dosed the first patient with a systemically delivered CRISPR therapy and advanced our portfolio, We're poised to carry this momentum forward in 2021. We're progressing our Phase 1 study of MPLA 2,001 and look forward to sharing interim results later this year for clinical validation of our platform. Across wholly owned and partnered efforts, we continue to progress our pipeline. This includes 1st in human regulatory submissions anticipated mid year for NTLA-five thousand and one and in the second half of this year for NTLA-two thousand and two as we advance our research stage portfolio towards the clinic. And we will further differentiate our capabilities with new platform innovations across Multiple in vivo targets in the liver, in vivo editing of other tissues and an allogeneic approach enabling next generation engineered cell therapies as we continue to expand our genome editing toolkit for search and therapeutic development. As we keep focused on these Core priorities for 2021, we're committed to making genome editing's promise a reality for patients. We'll now open the line to any questions. Operator? We will now begin the question and answer The first question comes from Salveen Richter with Goldman Sachs. Please go ahead. Hi. Thank you so much for taking our question. This is Sonia on for Salveen. Could you talk a little bit about the AAT asset in And what the benchmark will be, will you have to match the RNAi knockdowns or would you need to show And then also when can we expect additional data through the year? Are there particular conferences that you're targeting? Thank you. Sonia, thanks and good morning. It's John. We've always paid very, very careful attention And as we do our initial Phase 1 study here, which is progressing as we've said, We have in mind 80% or thereabouts as a benchmark, which we think is competitive, But the aspiration is to exceed that. So the way we think about that particular program and amyloidosis in general is that Certainly advances have been made and we think that's really wonderful for amyloidosis patients, but There's more to get and it's really in the form of additional improved outcomes. There's we think unmet medical need in the form of Effigy, that's yet to get. So if we can not just delay the progression of disease, but actually reverse it, which we think Comes with reductions beyond 80%. That's very much what we're going to look for. With respect to data this year, The study is underway. And as we accumulate that, we'll look for medical conferences that will be appropriate venues I'll share that, but at this point, we can't guide to any particular one. Thank you. I think I was asking more about the alpha-one antitrypsin asset In terms of, I guess the other ROE and T assets, etcetera? I'm sorry, I misheard your question. The data we presented thus far has been not a knockdown data, which maybe is The basis of the confusion here, we presented insertion data that shows production of the normal human protein. And that work has So demonstrate that not only can we get a production of that normal human protein, but we get it at normal human levels. And so as we look at the benchmarks that are out there, we're already well beyond anything that's therapeutically available to patients including replacement therapy. So from that standpoint of replacement therapy, we think we're in a wonderful position. The approach we're taking does not directly address production of the abnormal protein and that's separate from the work that we're currently doing. Thanks. And will we see any additional data through the year from that program? There's a good possibility we'll have more to share as the year goes on, but we're not guiding to any particular release at this point. Okay. Thank you so much. The next question comes from Maury Raycroft of Jefferies. Please go ahead. Hi, good morning and congrats on the progress and thanks for taking my questions. First question is on ATTR. Just wondering if you can provide any more specifics on where you're at with enrollment and dosing? I guess, are you still at the first dose level? And are there specific reasons why you now have clarity and confidence into providing data in 2021? Great. Thank you for the question. We appreciate it. As you know, we started enrolling in November of last And things have progressed pretty much as per plan. We're not sharing Progression by patient or by cohort group, but we've taken the position that as we get A body of clinical data that we think is meaningful and representative that that's what we would choose to disclose. I think what you should take is that we're moving forward and we've laid out that study plan And we look forward to sharing it when we have a more complete story to tell. Got it. That makes sense. And John, you mentioned 80% or greater knockdown for ATTR. I guess, should we expect that degree of knockdown in the initial emerging data? Or I guess how many cohorts of data will we see in the initial data? And the right way to think about that is that that should provide a line of sight into getting to that 80% or greater optimal knockdown? Yes. Thanks again. I'm not going to be in a good position to give you clarity with respect to outcomes per cohort, which is somewhat implicit in your question, Maury. The way we set the program up in the first place is that each of these different cohorts has some reasonable likelihood of having a therapeutic effect. And as you know, this is the first time we've moved from preclinical work into humans. So some of this is a good time to validate the Thinking and the modeling that we've done, but each of the different doses that was chosen was done with the intention of seeing an effect And that effect will the optimal biological effect is something that we'll determine as we escalate across the different cohorts. So Well, we have something that we think is meaningful and that is readily interpretable. That's what we'll share and we would expect that that will be while the study is still taking place. Got it. And so the initial update should give us A level or a line of sight into the trajectory of the knockdown that you're getting with each dose. Is that fair? The Sort of data that we would anticipate sharing with you would be a dose and a TTR effect and of course the safety that goes with that. With respect to extrapolating what subsequent doses will be, I think we can speculate together on that, But you would certainly be in a position to see what we've achieved at a given particular dose. Got it. Okay. And Maybe last quick question just on the regulatory applications being submitted. So just wondering if you can say if you submitted a U. S. IND and will you provide an update 1Q or 2Q on whether some of the additional regulatory applications are accepted or should we just keep an eye on clinicaltrials dotgov? So we haven't shared yet exactly which regulatory filings we will have for the programs or subsequent to the TTR program. As those are cleared, we'll definitely share that information with you. Got it. Okay. Thank you for taking my questions. Of course. The next question comes from Marni Tuhoohar from SVB Leerink, please go ahead. Hey, good morning. This is Rick on the line for Mani. For my first question, there was an earlier comment about submitting clinical trial applications for the TTR program in additional countries As a part of a global development strategy, I was hoping maybe you could just expand on the strategy a bit. We are wondering how many countries this study might eventually expand into And how many clinical sites you anticipate you might need in order to complete the Phase 1 study? Yes. So currently, we're conducting the study in both the UK and New Zealand. We have a Couple other applications that were progressing, whether or not we will actually activate them to finish the Phase 1 study is something that's It's a matter of discussion and as the study unfolds, we'll share that with you. But we believe that as currently structured, we're in a position to conduct the Phase 1 study and get the information that we need. We're always interested in expanding the regulatory network, because the program ultimately, I A program broadly Phase 1 and beyond certainly will be broad based and global. We've had a multiplicity of regulatory Interactions as we played the basis for the advance for the program. I got it. Thanks. My second question was just focused more on forward looking financials. How would you think about R and D spend in 2021? I understand that 2021 is currently in the clinic and 2 additional INDs are expected by year end. So I guess we're wondering if we should expect a steady increase in R and D spend throughout the year or if Changes in R and D spend might be more lumpy as the company hits specific milestones quarter to quarter. Yes. So let's turn to our CFO, Glen. Do you want to take that please? Sure. Yes. We're as you noted as we noted in the call, we have a very strong cash position as of the end of the year. We've guided that that will get us through at least the next 24 months. We're not giving specific kind of year by year OpEx guidance out, but I think it is fair to assume that The R and D operating expenses will drift up over time. We don't expect it to be lumpy. I think it will be Similar to the trend you saw going from 2019 into 2020, you could expect a similar trend going into next year. Great. That's really helpful. Just want to congratulate you guys on all the progress and thank you for taking our The next question comes from Gena Wang with Barclays. Please go ahead. Hi. Good morning. This is Swapnil on for Gena. So one clarification question for the cardiomyopathy patients that you plan to enroll in the TTR trial, would that be included in the Part 2 in the 8 patients or is that the plan of the last year of pivotal study? Yes, I'll take that. It's So the way you should think about this is we have a Phase 1 study that is patients with predominantly polyneuropathy. There are patients, As you know, it's a mixed phenotype that had some degree of cardiomyopathy, although that's not the predominant manifestation in this first in human study. We will not be mixing patients with predominantly cardiomyopathy into the 1st in human study. But as David said in his comments, we believe that the optimal biological dose that we're finding will be readily applicable to cardiomyopathy Patients which we would address in a subsequent study. Okay. And then just a follow-up To that, can you tell us like what is your definition of optimal dose? So you have these 4 dose escalation in the Part 1. So what exactly would you be looking for and what constitutes an optimal dose to move into the part 2 of the trial. David, do you want to address how you're thinking about optimal biological dose? Yes. Thanks, John. The idea for Optimum Biotic dose has really 2 pieces. 1, of course, it has to be a safe dose. So this is a Phase 1 study. We're characterizing the safety carefully and that will be important at whatever dose we choose for this. But even the big piece of this is what The potential activity and ultimately efficacy of the dose. As we've talked about, we do want to get a deep reduction in TTR as we go forward because we think this can make a bigger difference for patients. And what you saw on the non human primate studies is that 95 We think getting towards that range would be valuable to patients and that's We're looking for something between, of course, the 80% that's now being attained with current therapies, but Potentially getting to higher degrees of reduction. Okay, got it. Thanks for taking our questions. The next question comes from Steve Seedhouse of Raymond James. Please go ahead. Yes. Hi, good morning. This is Timur Ivanyakov on for Steve Seedhouse. And so we have a question about Phase 1 ATR study slightly different Ask slightly differently. But in terms of your procedure for reviewing data and assessing knockdown and other metrics, could you talk about at what Time points you take those measurements, NHP study that it looks like weekly, is that sort of similar timeline that you have for the human study? Thank you. Yes. Broadly, the assessments are laid out on clinicaltrials dot gov where you can get a lot of these details. But maybe, David, you could To summarize some of the particulars of the studies so people can relate that to the preclinical work. I think an important measure in this is really TTR, which is measured by the gold standard of ELISA. And I said it's measured intermittently through the study as you mentioned. But as you what we see from preclinical models and what we expect in people as well is that you reached the lowest point at around 28 days. So you really have a good idea by 28 days what the Ultimate reduction will be. We will continue to follow it. And as you know, this is expected to be permanent based on all the work that we've done previously. But we will have a good idea of how the patients are doing in terms of TTR reduction at that early point. Okay. Thank you for that. And then a follow-up question in terms of the mixed polyneuropathy, cardiomyopathy, sinusitis. Are you doing anything differently for those patients in terms of monitoring? And maybe in the future for cardiomyopathy patients, will you be doing any different monitoring versus polyneuropathy? Thank you. David, do you want to kick on with that? I'm back to that. Yes. So these patients we are doing So the standard monitoring that's done for patients with cardiomyopathy. It turns out that almost all patients do have involvement to the heart, even though it may not have A functional effect in these patients. So we will learn something about that in the early study. And going forward So this next study dedicated to pay for patients with cardiomyopathy, we haven't fully designed that, but we will Bring you more details as that design is being prepared. Okay, great. Thank you very much for taking our questions. The next question comes from Joon Lee with Truist Securities. Please go ahead. Hi, thanks for taking our questions. In light of the recent update from Bluebird Bio, remind us Again, what gives you comfort that you won't see any cancer signal 5 to 6 years down the road regarding off target effects of CRISPR cat? And with regards to your partnership with Gates Foundation to develop in vivo approaches for sickle cell, is So thanks. It's a really important question. But I don't think the Bluebird Bio results Really even relate to the work that we're doing. Certainly, on the in vivo side, I would contrast Two really important different approaches. Number 1 is the nature of a precise editing as opposed to A lengthy virus sort of random insertion, which is somewhat difficult to control with respect to where the gene lands and what happens thereafter. I think we're seeing possibly some of the outcomes that may come with that, but the field is trying to sort that out. And then secondly, the in vivo approach We're taking with our TTR and related other programs, doesn't utilize a conditioning regimen at all. So whatever other Safety questions that are provoked by taking that type of chemotherapeutic approach doesn't even apply to the in vivo So when you turn to the ex vivo side of the equation for us, again, everything that we've done and Laura's team has done, I think, a really wonderful job Controlling the process, demonstrating that genetic architecture is preserved, that the insertion goes exactly where we want it to go. So we feel really good about that. And when you think about preparing those patients for receiving, NTLA-five thousand and one, The conditioning regimen is just very different from what you see with a bone marrow transplant. So we feel really good about our approach. Now with respect to the Gates Foundation, I think and increasingly people looked at, I think the wonderful opportunities there are To apply gene editing to diseases like sickle cell disease and thalassemia, and we've demonstrated as I feel that from an editing point of view, you can address the problem. The challenge is exactly what we're talking about here, which is All those patients with current therapies required a bone marrow transplant. And that brings with it whatever consequences of If you're using an imprecise approach, the safety issues that come with that, but across all of the bone marrow transplant approaches, The conditioning regimen that is inherently morbid and sometimes brings with it mortality. So We as a company and from the standpoint of editing and delivery believe that we can Leapfrog the current approaches to bone marrow, capture the highly desirable outcomes that would come with gene editing Potentially avoid the bone marrow transplant altogether. And with that, we think, you can bring genome editing to many, many thousands of patients with sickle cell disease, which we again believe current therapies are not going to be able to do. Great. Thanks for that clarification. And on the follow-up question, Is the new development candidates A1AT program or hemophilia or something different altogether? We saw Lara's presentation at ES It's very impressive. I'm just curious, what we can look forward to on that front? Thank you. Thanks. Well, we have a lot to choose from and I think that's the point that you're making. We ask Laura to make sure that both sides of the company are advancing both On the in vivo side and the ex vivo side, and we have very active programs there. And as you point out, we have A very exciting relationship with Regeneron that's moving forward as well. So the particular development candidate, we're not going to point to just yet, But there is at least one in that list and we're very, very excited about it and some of the others that we're sorting through as we go. So that's one I would just stay tuned for. We'll give you a little bit more clarity as we get further into the year. Thank you. The next question comes from Jay Olson of Oppenheimer. Please go ahead. Hi, this is Chung on the line for Jay. And congrats on the progress. Just one more question on 2,001. Wondering is there any key safety signal you'll be monitoring for the clinical trial. And if like side effect arise, how would you tease out if that's a consequence of on target or off target gene editing or you could do something else like the VACTO or RNA? Thank you. David, do you want to address that? What particular things are you monitoring for and this Off target even figure into the realm of the discussion at this point. Right. Thank you, John. In terms of off target, we feel we've addressed this really with the program that we've done pre clinically. And we could you'll hear more about that as we move forward how we do. But this is Comprehensive both in vitro and in vivo studies to establish that we're precisely editing the right target and Knocking it out, but not affecting other genes. So in the study itself, the main safety thing that we're looking at is the immediate effects of lipid nanoparticles. Now lipid nanoparticles are really pretty well characterized. Ours is somewhat different and So we do want to understand its safety. But based on the non human primate studies, we do Feel that we can get to the deep reductions with the 95% range reductions that we're seeing in non human primates with doses that would be tolerated in people because they were tolerated in the non new candidates as well. And was there a follow-up? Okay. Continuing, the next question comes from Yanan Zhu with Wells Fargo. Please go ahead. Hi. Thanks for taking my questions. So first, maybe a couple of quick one on the TTR program. Does the cadence of enrollment so far meet your internal expectations? And could you remind us whether repeat dosing is allowed by protocol? And if it is, then at what time point Can repeat dosing be considered? Thanks. Yes. I can take that. Thanks. Yes, the study has been going well. We've been really quite satisfied and excited with So that's just been a really gratifying sort of thing to be involved with. With With respect to, I forgot the second question, if you could just repeat it. I want to make sure I said it. Repeat dosing. Yes, thank you. Yes. Repeat doses are not formally a part of this particular study across the program where we're working on provisions so that If patients who came early into a study did not receive an optimal biological dose, there will be other means for those Got it. On the WT1 TCR program, Could you talk about any consideration for whether filing the IND in the U. S. Or an equivalent outside the U. S. Just curious about what the thought process for determining where to file? Yes. So we're not guiding yet to precisely where and what we're filing, although we want to have a broad based Ultimately global program there. We're confident that we're going to be able to do that and we're confident that we're going to be in a position to Meet the requirements to get into the clinic this year. So that's going very, very well. There are complexities to the program and we're making sure that we have the most robust regulatory package Possible and we've had extensive regulatory interactions to prepare for that. And so we're really in the final stages of completing those submissions and filed in the packages. So stay tuned and as those filings clear, we'll share that information more broadly. Got it. And lastly, maybe a question on the in vivo sickle cell approach Collaborated with Gates Foundation. Just curious what would be the delivery vehicle For that approach, is it going to be non viral? And if it is, then what kind of visibility do you have on The feasibility of a non viral delivery approach to the bone marrow hematopoietic stem cells. Do you have any initial data, preclinical data there? Thanks. Yes, thanks. Yes, we believe that The in vivo approach in the end is the winning approach for patients with sickle cell. And as you know, from the origins of the company, we've emphasized non viral delivery approaches. That may not address every single tissue in the body, but it can certainly address many of them, including the bone marrow. So the emphasis of this program and the basis of the collaboration with the Gates Foundation is in fact nonvial delivery because they see the merits of that approach as do we. We've shared some preclinical information with them, which I think was the basis for their enthusiasm. And as we make more progress, we'll be in a position to share that more broadly with a more general audience. Great. Thank you. And the last questioner today will be Tony Butler with ROTH Capital Partners. Please go ahead. Good morning. This is Tash on for Tony. Just a Follow-up question, well, a question about follow-up about the TTR program. Can you tell us about the duration of, That's a safety follow-up a patient must undergo before your dosing the subsequent patients begin and also any word on the long term follow-up, please? Can I just make sure we understand the question? Are you talking about The safety evaluation before dose escalating and then the ongoing Safety characterization of a patient once dosed, I think that's what you asked. Is that correct? So first, And the dose escalation in the 3 plus 3U dose 1 patient. And then I'm assuming here That first patient in that in a specific dose cohort, they're going to be followed for a set amount of time. Could be something like 8 weeks, but I was hoping if you would be able to give us any details about that. That's the first part. Yes. So David, do you want to give some general guidance with respect to how the protocol runs? I think you're on mute. All right. Yes. Thanks, John. I said the main safety event Looking forward due to the lipid nanoparticles. So these are events that are again well characterized in the past and they occur in a short period of time. So our follow-up is relatively short, Most of it within a few weeks that you could see. So this does allow us to, for the first There's different intervals for the different dose levels, but basically it's a typical 3 plus 3 design with a short look between each patient to make sure that that dose And then after the first patient in a specific dose cohort, What about the following 2 patients? Are you able to dose them simultaneously? Or do you have to wait for a sequential In the initial cohort, we did wait, but in the subsequent cohorts, they can be dosed together. Thank you. And lastly, what about long term follow-up? Do we have a window here? For example, well, For certain therapies, the FDA requires patients to follow-up for approximately 15 years, give or take. Is there any such requirement? Yes, really around the world that regulatory agencies are looking for, let's say, a 15 year period. It's not completely defined, but it's in that range. So we will be having planning a long term follow-up for And what about well, actually, yes, what about any possible shortening of this initial safety follow-up Based on data generated from lower dose cohorts, do you envision Having a shorter follow-up period in the subsequent higher dose cohorts? The period is short enough that it wouldn't Thank you very much and grateful for your time. This concludes our Question and Answer Session. I would like to turn the conference back over to John Leonard for any closing remarks. I'd like to thank all of our listeners today for their questions and for following us. We appreciate it. I wish you all a good day and we can certainly follow-up offline as necessary. Thank you. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.