Earnings Call: Q1 2021

May 6, 2021

Quarterly report

Good morning. My name is Izzy, and I'll be your conference operator today. Welcome to the Antilia Therapeutics First Quarter 2021 Financial Results Conference Call. As a brief reminder, all participants are currently in a listen only mode. Following formal remarks, we will open the call up for questions. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. I will now turn the conference over to Helene O'Lee, Director of Investor Relations at Intellia. Please proceed. Thank you, operator, and good morning, everyone. Welcome to Antalya's Q1 2021 earnings call. Earlier today, the company issued a press release outlining the company's progress this quarter as well as topics further 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. At this time, I would like to take a minute to remind listeners that during this call, Antilia management may make certain forward looking statements and ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Antilia undertakes no duty to update this information unless required by law. Joining me on the call today are Doctor. John Leonard, Chief Executive Officer Doctor. David Leadwall, Chief Medical Officer Doctor. Laura Sephoranzino, Chief Scientific Officer and Glenn Goddard, Chief Financial Officer. For today's call, John will start with the company's Q1 and recent business highlights, followed by David, who will provide an update on our NTLA-two 201 clinical efforts. Laura will then recap the company's R and D progress followed by Glenn's review of Antilia's financial results for the quarter. John will then make some closing remarks, and we will open the call for Q and A. With that, let me turn the call over to our CEO. John? Thank you, Lita. Good morning, everyone. We're happy to provide an update on recent progress against our core priorities for this year and a view forward to our key upcoming catalysts. At Antilia, we're committed to developing curative genome editing treatments to transform the lives of individuals with severe diseases, And we're proud to be at the forefront of genomic medicine. Our deep scientific, technical and clinical development expertise and robust intellectual property portfolio position us to transform the broad therapeutic potential of CRISPR Cas9 to new classes of revolutionary medicines. Our leading 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, Leveraging 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 have generated a broad pipeline, including emerging clinical candidates The first quarter was a productive one for Intellia As we continue to make headway across these efforts, we were pleased to receive the European Union's orphan drug designation for NTLA-two thousand and one, Demonstrating regulators appreciation of the potential significant benefit of NTLA-two thousand and one in the treatment of ATTR patients for whom there is no cure. Additionally, we presented key preclinical data expanding our modular capabilities in new directions. In March, we introduced our proprietary base editing for enhanced cell engineering. In a separate presentation, we showed proof of concept for systemic in vivo editing in bone marrow. Platform innovations such as these lay an important foundation for Intellia's continued pipeline growth and the advancement of the next wave of genomic medicines. Finally, we were pleased to welcome Doctor. Georgia Christie, who joins our Board with more than 35 years of pharmaceutical industry experience, including as a scientific and operational leader across stages of clinical development and commercial manufacturing. Our progress on these Q1 and upcoming milestones provides us the opportunity to advance not only our core priorities for 2021, Our long term vision for Intellia. We continued the evaluation of the clinical profile of NTLA-two thousand and one Both as a potentially curative treatment option for ATTR patients and a validation of our non viral in vivo delivery platform. In the middle of this year, we anticipate reporting our first clinical data with an interim look at our Phase 1 study of NTLA-two thousand and one, the first systemically delivered CRISPR based therapy dosed in patients. In addition, we plan to submit 2 first in human regulatory filings to advance our lead engineered TCR T cell therapy, MTLA-five thousand and one for AML and our 2nd in vivo knockout candidate, MTLA-two thousand and two for HAE. And we remain on track to nominate at least 1 new development candidate from our research efforts by the end of the year. With key catalysts coming and a strong financial foundation, we are positioned to invest the resources and energy necessary to advance our pipeline, Expand our platform capabilities and deliver on our mission for patients. With that introduction, I'll hand the call over to our Chief Medical Officer, David Leadwall, who will provide an update on our progress in the clinic with NTLA-two thousand and one. David? Thanks, John, and good morning, everyone. I'll start with a bit of background on ATTR and on MTLA-two thousand and one. Plantyretin amyloidosis or ATTR is a rare 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 a diverse range of disease manifestations, the most frequent being polyneuropathy and cardiomyopathy. Globally, there are an estimated 50,000 people with hereditary ATTR and between 200,000 and 500,000 with wild type ATTR. Intellia's candidate 2,001 Applies our in vivo lipid nanoparticle delivery technology to knock out the TTR gene in the liver, which is the source of circulating wild type and mutant TCR protein, therefore reducing amyloid deposition. Based on our robust preclinical data, which shows long lasting TTR reduction of greater than 95% In non human primates after a single dose, we believe 2,001 offers the possibility of halting and reversing all forms of the disease with potent lifelong reduction of serum TTR following a single dose. In March, the European Commission granted Orkin Drug Designations to 2,001. As a reminder, this designation provides regulatory, Financial and commercial incentives to develop therapies for rare diseases defined as having a prevalence of less than 5,000 in 10,000 people in the European Union. This is meaningful as it not only reflects 21's potential to deliver Significant benefit over existing treatments for ATPR, but also the unmet need that remains in this population. We view this as an important acknowledgment that regulators recognize the benefits of a potential single dose treatment indication like ATTR, even when product therapies exist in the market. Importantly, this is in line with our conviction in this program as well as feedback from leading investigators We're enthusiastic about the value 201 would offer patients and our healthcare system. As you may recall, our first immune trial is an open label, multicenter, 2 part study evaluating 20 to 1 in adults with a hereditary form of ATTR and peripheral nerve damage. The study will enroll up to 38 patients and consists of a single ascending dose phase in Part 1. And following the identification of an optimal dose, a single dose expansion cohort in Part 2. The trial's primary objectives are to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of 2,001, which will include the measurement of serum TTR levels following a single intravenous infusion. The secondary objectives are to evaluate the efficacy of 2,001 on clinical measures of neurologic function in htgtrpn patients. Once we have established the safety and the optimal dose, our goal is to expand the study and rapidly move to pivotal studies in which we aim to enroll both polyneuropathy and cardiomyopathy patients. By way of clinical update, we continue to enroll patients across global sites and expect to share interim results from the ongoing single ascending dose portion of this study at a scientific or medical meeting in mid-twenty 21. These results will offer a preliminary view of the safety and activity profile of 2,001 as we progress towards identifying The optimal biological dose. We believe our interim results will establish clinical proof of concept for a modular LNP delivery platform, an important milestone for Antilia, while demonstrating to the field at large The potential for systemic in vivo genome editing in treating life threatening diseases. We are excited to learn how our ability to edit in vivo translates from our observations preclinically into human and look forward to sharing interim results mid this year. And with that, I'll turn this over to our Chief Scientific Officer, Lara, Cephalar and Vito for updates on our 2 additional developing candidates, 2,002 and 5,001 and across our R and D efforts. Thanks, David. I'll begin with our second in vivo knockup candidate, MTLA-two thousand and two, in development for the treatment of hereditary androedema or HAE. HAE patients experience recurring, unpredictable and painful effects of swelling across multiple tissues, where they are approved acute and prophylactic therapies for HAE, the treatment burden on patients remain significant. We believe there is additional opportunity for a therapy that not only further reduces frequency and intensity of attacks, but which may prevent and eliminate them altogether. To that end, we're applying our modular LNP delivery system to MDLA-two thousand and two to knockout the KLKV1 gene in the liver to permanently reduce plasma calycrant protein and activity. This approach is expected to provide continued suppression of calycrant activity and eliminate the significant treatment burden associated with currently available therapies for HAE patients. In March, we presented the clinical results at the American Academy of Allergy, Asthma and Immunology Annual Meeting demonstrating NTLA-two thousand and two achieved greater reductions in serum glycoprotein levels and activity as compared to published results of the current standard of care for HAE. These reductions of up to approximately 90% where we keep staying for over 17 months following a single dose in an ongoing non human primate study of our sema specific NNP formulation for MPLA-two thousand and two. In addition, we presented data for the humanized KL-twenty one mouse model of bradykinin mediated vascular permeability, establishing that a single administration of NTLA-two thousand and two prevented capital induced vascular leakage and therefore is expected to prevent HIV attacks. We continue to make steady progress with IND enabling activities and we expect to submit an IND or equivalent application for NTLA-twenty 2 in the second half of this year. We're leveraging insights from NTLA-two thousand and one and therefore anticipate being able to start MTRA202 at the higher dose for our 1st Q2 study, which will evaluate safety, tolerability and measures of activity including levels of calicard knockdown. I will now turn to our ex vivo efforts. Here, we're using CRISPRCas9 as a tool to create engineered cell therapies. Similar to our efforts in vivo, our proprietary approach to cell engineering underpins a modular platform with versatility to mix and match cell type targeting modality and ability to introduce the efforts necessary for eliciting the desired pharmacology. Regardless of solutions, we're achieving highly efficient sequential editing with high yield, optimal performance and scalable manufacturing. Our lead program, MDLA-fifty 1, is a potential best in class engineered T cell therapy designed to treat all genetic subtypes of KML. This investigational candidate is an autologous T cell receptor or TCR Intel therapy targeting the Wilms Tumor 1 Antigen. NTLA-fifty 1 utilizes our voluntary cell engineering process, which is able to precisely edit and replace patients' T cell receptors with a tumor targeting ECR. This process reduces safety risks and should translate to improve potency and function versus other technologies for Multiplex Eptinez. Despite recent therapeutic advances bearing improved response rates in subsets of ANL, Long term outcomes continue to be poor with overall 5 year survival below 30%. Revenue B1 is overexpressed in over 90% of AML patients regardless of peptide. And so between our proprietary cell engineering process and the prevalence of this target. We believe MTLA-fifty 1 will be a well tolerated solution capable of improving long term outcomes for patients across all mutational peptides and forms of AML. We remain on track to submit an IND or equivalent regulatory application for MDLA-fifty 1 mid year. Our first in human trial with evidence of the safety and activity of MPLA-fifty 1 in patients with persistent or recurrent AML who had previously received first line tags. Moving on now to our research programs and platform advancements. We continue to make strides in developing new therapeutic candidates for genetic diseases and next generation in the years of therapies for cancer. The versatility of our approach allows us to move quickly with pipeline expansion and we remain on track to nominate at least 1 new development candidate this year. During the Q1, we had oral presentations at 2 different scientific conferences broadening the applications of our modular toolboxes. In March, we presented preclinical data introducing our proprietary cytoplasmidionase based editing technology at the Cold Spring Harbor Laboratory Scientific Meeting on KGaA therapies. The data highlights our expansive cell engineering capabilities that enable us to introduce multiple pilots via CRISPR as required by Next Generation Allogeneic Health Therapies. Additionally, at the recent system genome editing meeting, we presented preclinical data extending the modularity of our in vivo delivery strategy. Through our extensive M and P discovery and development efforts, we identified the class of MMPs that achieved dose dependent therapeutically meaningful editing of bone marrow and hematopoietic stem cells inaprochemical mouse model lasting 1 year following a single dose. For inherited blood disorders such as sickle cell disease. This approach could greatly reduce the barriers to treatment associated with bone marrow transplantation. More broadly, these results demonstrate the ability to deliver to and edit tissues of high delivery. We will continue to expand upon this work with financial support provided by the Bill and Melinda Gates Foundation. Although still in the research stage, the technologies shared in this presentation are important demonstrations of our emerging capabilities, which together reflect our commitment to drive our pipeline forward to continued platform innovation to create potentially curative therapies for patients. Looking ahead, we plan to share preclinical data at the ASGCT Annual Meeting taking place next week. This will include an update on our research in alpha-one antitrypsin deficiency, which is the 2nd disease indication for which we have demonstrated robust proof of concept of our targeted in vivo insertion technology to restore normal levels of proteins in anti inflammatory. Further, we will be sharing data on our industrialized experience platform utilized to derisk and identify guide RNAs that are both potent and highly specific with no detectable off target edits. This foundational work has provided us and regulators with key insights and the confidence to move our program, including NKLA-two thousand and one Forward Into Human Clinical Trials. We look forward to these presentations next week at NSGCT. With that, I would like to hand over the call to our CFO, Glenn Gaudner, who will provide an overview of our Q1 financial results. Thank you, Laura, and good morning, everyone. Intellia remains in a strong financial position as we advance our pipeline. Our cash, cash equivalents and marketable securities were $600,800,000 as of March 31, 2021 compared to $597,400,000 as of December 31, 2020. The increase was mainly driven by $45,300,000 of proceeds from the company's at the market agreement, $13,300,000 in proceeds from employee based stock plans and $2,400,000 from the Regeneron collaboration. These increases were offset in part by cash used to fund operations of approximately $57,600,000 Our collaboration revenue decreased by $6,500,000 to $6,400,000 during the Q1 of 2021 compared to $12,900,000 during the Q1 of 2020. The decrease was driven by The $5,000,000 milestone payment earned from Novartis for the IND submission of OTQ-nine twenty three in 2020. R and D expenses increased by $4,600,000 to $39,300,000 during the Q1 of 2021 compared to $34,700,000 during the Q1 of 2020. This increase was mainly driven by the advancement of our lead programs, Research personnel to support these programs and the expansion of our development organization. G and A expenses increased by $2,300,000 to $13,600,000 during the Q1 of 2021 compared to $11,300,000 during the Q1 of 2020. This increase was related to employee related Including stock based compensation of $900,000 Finally, we expect our current cash balance Fund operating plans for at least the next 24 months. And now I will turn the call back over to John for closing remarks. Thank you, Glenn. As you can see, there are many reasons for excitement for what the remainder of the year holds for our company and the field of genomic medicines. Our Phase 1 study of MTLA-two thousand and one is progressing well, and we look forward to sharing interim results mid this year for clinical validation of our platform. We continue to progress our pipeline and expect to file 1st in human regulatory submission mid year for NTLA-five thousand and one. In addition, we expect to submit an IND or IND equivalent application For Intellia-two thousand and two in the second half of this year. We are advancing our research stage portfolio as we expect to nominate at least 1 new development candidate And we continue to expand our toolbox to enable the next wave of genomic medicines. With all this progress And as we close in on key milestones, we remain focused on our core priorities and wholly committed to making genome editing's promise a reality for patients. We'll now open the line for any questions. Operator? Thank you. We will now begin the question and answer session. The first question today comes from Salveen Visas with Goldman Sachs. Please go ahead. Hi. Thank you so much for taking your questions. This is Sonia on for Salveen. We have a few questions on Antilia-two thousand and one. So the first is what data should we expect from the read in mid-twenty 1? How many cohorts should we expect data from? And then the second question is, what is the status of the IND for Antilia-two zero one in the U. S? Thank you. Sonia, thanks for the question. So just to remind you, 2001 is a study that we're we're currently studying 201 outside the United States. So for this First in human study, there's no plan to have an IND as part of this particular study. The expectation is that for subsequent work, we would come back to the U. S. I have an IND for work that would involve cardiomyopathy in subsequent studies. With respect to The ongoing study and the data we anticipate presenting, we're not talking about the number of cohorts other than to say that we progressed well with the study as Thank you. Thank you. Your next question comes from Maury Raycroft with Jefferies. Please go ahead. Hi, good morning and congrats on the progress. Just had a question on the 2,001 clinical study. Just wondering if there's anything additional you can say on safety so far in the clinical study. I guess one concern in the past is on immunogenicity. And is there anything you could say about that at this point? And will that be part of that in midyear update? Thanks, Maury. With respect to safety, I think it's best to look forward to the information that we point in time. Got it. Okay. And then we've been getting questions too on LNP design and I guess some of the characteristics that go into your LNP's. And I'm wondering if we could learn more about that in the mid year update and how your LMPs, the functionalization translates To an improvement in immunogenicity and also the tunable troponin as well. Thanks. As the year unfolds, I'm sure there's going to be opportunities to talk more about the platform and the work that we're doing. I think with respect to the Clinical data that we're talking about, I would anticipate that most of the discussion at that time would be about the study And the results that we have. But as you know, Maury, as our science progresses, there's points in time where we'd like to share Some of the advantages that we have and there may be opportunities later this year to do that. Makes sense. Okay. Thank you for taking my questions. Sure. Thank you. Your next question comes from Gena Wang with Barclays. Please go ahead. Hi. This is Sheldon on for Gena. Thanks for taking our questions. So I think you mentioned in the past that The target knockdown level is about 80% for the 20 1 trial. So right now, you have Almost set up the timing of the presentation. Does it mean you already reached the target level in the initial dose level? The way we've approached this is we've said from the outset that we would share interim data From the study is progressing. Remember that there's 2 phases to it, the ascending dose phase and then the expansion phase Where we would take what we think would be the optimal biological dose and study that more fully in a larger set of patients. The principle that we've applied for this first phase of the study is that we'll have meaningful results that are readily interpretable. We haven't tied that to a specific targets for this particular data release. It's true that we set us a benchmark 80% and beyond. Our objective is to surpass 80% because we think the further one reduces the circulating TTR levels, more beneficial it's going to be for patients. I think there's places we can look for data that seems to indicate that. So that is our ultimate objective. But The particular data that we share here is not necessarily triggered by any specific number. Thank you so much. Thank you. The next question comes from Mani Gora with SVB Leerink. Please go ahead. Hi, good morning. This is Rick on the line for Mani. Thanks for taking our questions. So I actually have a follow-up on Maury's Question on safety and specifically, there are a few novel components being evaluated here for the first time in the clinic and That's the LNP formulation, the transient expression of Cas9 and guide RNA in the liver and then the actual edits being made to the genome. So I was hoping to just get your thoughts on if there is any sort of safety signal observed in the trial, what the ability is there to Parete out which of those components may be contributing to the signal and potential read throughs for the rest of the in vivo platform? Yes. So we're talking in general how we think about safety. And the way we approach it is there's the LNP itself and its administration and then there's the long term effects of that particular intervention, which we expect to be largely Beneficial based on the expected TTR knockdowns that we've achieved in animals. LMPs as a class, You may remember, Rick, generally have a characteristic pattern of safety findings that when one gives sufficient quantities of material you can trigger. All that we've worked on very, very carefully in our preclinical work to develop a Therapeutic Index. So the clinical exposures that we're doing in the human trial here is designed to balance the Desired and expected PTR effects within the therapeutic index that does not trigger those particular LNP class effects. And the Phase I study is to test exactly that, those preclinical findings. And as we've said, we'll share some yearly results here mid this year. With respect to novel components, I guess the way I think about it is the LNP is Largely precedented. Yes, there is a unique piece to it that is the proprietary lipid or cationic lipid. We think we characterized it very, very well and know very well how it behaves based on preclinical work. And the rest of it is RNA, either guide or mRNA. And Again, we think you spent really good preclinical models for that. With respect to the genomic characterization of the effects, That's been extensively addressed preclinically, I would say, more than probably any other drug as far as I'm aware. And I would encourage you to attend the ASPCP meeting where we're going to go through a lot of how that work is done. So you get A really good sense of the completeness and the extent of that effort. So we can maybe revisit after we go through that data later this month. Got it. Really appreciate all the detail there and thanks again for taking the question. Sure. Your next question comes from Joon Lee with Chilis. Hi. Thanks for taking our questions. You just set your EBAR at 80%. Just what, I guess, sRNAs and antisense all of those, they hover around that knockdown level. But as the genome editing So that is constantly working, do you really need to hit similar knockdown as those And this is all about the Xrda's Chief Clinical Efficacy or could you envision a situation where you could get less knockdown but still get equivalent or better clinical effect? And could we get clinical data midyear as well as some of the knockdown levels? And I have a follow-up question. So it's a very important question you're asking, which is when we talk about these numbers of knockdown, what does it actually mean, Right. And so the numbers are typically presented by some of the other modalities that I'm familiar with at least Are typically portrayed as maximal effects. And what you're asking is essentially an area under the curve question, which is, Well, excuse me, if you have a maximal effect at a particular number, call it 80%, what is the average effect over time? And one of the advantages of the approach that we're taking here is that the maximal effect is the effect Because there's no pharmacokinetic variability that occurs over time. So our approach to this is we look at 80 As the benchmark, the goal is to surpass it, not just from a maximal effect, but from a sustained effect. And if you Go back to some of the preclinical data that we presented, you'll see that when it comes to the animal models, that's exactly what we achieved. So Our thesis is that reducing TTR to the lowest possible levels in the blood is going to lead to more clinical benefit, And that's exactly what we're setting out to achieve here. So that's how we think about it. Okay. So we will get clinical data along with the knockdown for the year? So in the early phase of the study, remember, it's a 3 plus 3 design as 4 cohorts. So the extent of clinical data, I think, is going to be very modest here early on. What I would look to is primarily a safety characterization and primarily a TTR effect. There is descriptive clinical data, but the bulk of that information, I would look to the 2nd phase of the study. Got it. And then one more question. For the in vivo genome editing for hematopoietic stem cells, what is the distribution of bone marrow tropic LNP In the liver versus bone marrow and how does that play into the overall efficacy and durability of this approach for sickle cell disease? And does this come in taking any priority in your overall pro form a strategy given the announcement between CRISPR and Vertex, they seem to be moving aggressively to commercialize it or does this not impact your overall strategy? Or do you have something in agreement with Novartis that kind of limits your ability to develop therapeutics for Sysco? Thank you. That's a big question with many subparts. I'll tell you how we think about it. Without going into all the specifics of distribution between liver and bone marrow and various other compartments of the body. Obviously, the objective is to get the right amount to the cells in the bone marrow. And it's very clear that LMPs as a class have a tendency to be picked up fairly avidly by So part of the delivery challenge is addressing the avidity of that Clearance takes place in the liver, and we've made good headway with respect to that. And there's a variety of ways to do that, and our scientists As time unfolds here, I'm sure there'll be opportunities to talk more about it. Just broadly speaking about sickle cell and related We're very excited by the progress that others have made that show, I think, Pretty clearly that one can edit hematopoietic stem cells and treat sickle cell disease pretty effectively. And that's Great news for that set of patients who we all know have long suffered with very, very Inadequate sorts of therapeutic treatments. The challenge, however, is that to get to those benefits, one needs to Be subjected to a bone marrow transplant, which brings with it significant morbidity and even, in some cases, mortality. And so our view is that the final endgame here is avoiding that bone marrow transplant. We know how to edit. It's just getting rid of the bone marrow transplantation. So our belief is that solving that with an in vivo delivery system, That is what will address the fundamental problem here. So other relationships and other approaches that people take, we admire their work and encourage them to proceed. Our approach is to have something that we think will have the broadest reach and the best solution for the greatest number of patients. And that is What we're working on and that's what the Gates Foundation has been helping us to do. Thank you. I'm looking forward to data. Thank you. Thank you. The next question comes from Steven Seedhouse with Raymond James. Please go ahead. Thank you. Good morning. I'm surprised to see you guiding to submitting an IND or IND equivalent with your follow on products. It just seems to imply that either you haven't decided which geography you plan to proceed or That you don't want to say. And I guess I just don't understand why the ambiguity or intrigue is even necessary unless you really don't know and kind of ex U. S. Trial as a backup plan at this point. It's basically outreach to me. So my question is, I was just hoping you could be clear, do you actually have plans to File a U. S. IND near term for HAE or AML or can you say already right now those will be ex U. S. Trials? And if you aren't certain about U. S. IND still. Can you say have you had any pre IND meetings recently and can you share insights from those interactions? Thank you. Well, we're not going to change what we've said, but I thank you for the question. We'll be in a position to We are very, very engaged in the regulatory interactions, and we've certainly I've been discussing things with the FDA as well as other regulators, and we're putting ourselves in a position where we can have the broadest based program that gets the most Clinical Information Most Efficiently. So I'm sorry I'm not going to be able to address specifically your question, but As time unfolds here, we'll share more information. Appreciate it. Thank you. Thank you. Your next question comes from Yi Min Woo with Wells Fargo Securities. Please go ahead. Hi, thanks for taking my questions. A few questions on 2,001. First, in terms of The place, the venue of the medical of the specific medical meeting, could we Is it reasonable to assume it is a P and S meeting in June? And also, could you characterize a little more what you mean by interpretable data. Does that mean data within a certain The ability that you could make a judgment of the result or could it mean Your ability to project some kind of a dose response to predict what might happen with additional dosing. So Any color around that, I hope you're very hopeful. Thank you. Sure. Thank you. With respect to the particular meeting, we're not sharing that information just yet. However, we won't be surprising people as we get Closer to that point in time, we will share in a press release when and where. So People I think will have plenty of information in advance to be prepared to attend the meeting or interact with it To get the information. With respect to interpretable data, that's a principle that we've applied, which really speaks to exactly what you said, with Small numbers of patients in an ascending dose study. One always pays attention to variability if it's there. And one wants to be able to look at those data, see if there's an effect and help Make some assessment of what it's likely to mean for not only of Intillate 201 And how it will fit into the pharmacopeia, but also our platform generally. And so those are the principles that we Applied, and I think when we're in a position to share the data, you'll see that we've addressed them. Thank you. A quick follow-up. In your EU Orphan Drug Designation application, did the committee asked for Clinical Data. I think because obviously there are chronic therapies, so some precedents when Multiple, when there is a standard of care, the committee might ask for data when determining orphan drug status. Thank you. Yes. I think the committee, as it makes this determination, asks whether or not there's remaining unmet need. And they concur with the broad based source of information we get, which includes KOLs, patients and treating health care personnel. So it's less about clinical information, it's about the status of the current treatment state of the art. Got it. Thank you. Thank you. Your next question comes from Sylvain Perkin with JMP Securities. Please go ahead. Thank you. Congrats on all the progress and thank you for taking my question. First, Also, I wanted to ask about a comment from Laura. Could you just please confirm that you mentioned that you may want to start Antilia-two thousand and two at a higher dose compared to Antilia-two thousand and one. And if that is the case, Can we read across from that information to Antilia-two thousand and one saying that the first lowest dose is probably safe or that it may have been too low? Thank you. And then I have a follow-up. I'll stand in Filora here, I guess, just to keep it efficient. But It all goes back to the fundamental premise of modularity. So whether it's on the research side, Whether it's on the preclinical side or on the clinical side, what we learn for an LNP and its cargo Broadly applies. And so as we collect information from any of those different domains, what we found is that we can apply it to incarnations of the product and various either regulatory interactions or even clinical interactions. So The information that we have is I'm not going to characterize it other than that it's able to give us some bearing on how we And it may have some utility there. Thank you so much. And my follow-up question is, could you have possible redosing in the expansion part Of the trial for patients that don't reach the target knockdown levels for some reason? Or is that something you would explore in a later trial? Yes, broadly based in terms of how to get the trial, it's formally a single Sending dose study in a single application, there are provisions that we're making in the course of the program and perhaps In the study, this is work that we're addressing where suboptimal doses, if they occur, Those patients may have subsequent recourse to a more active dose. But as that gets clarified, we'll be in a position to talk more about it. Thank you. And maybe one quick last question, if I may. Just on big picture. Are there any pitfalls that you can point to if we would Compared to the Antilia-two thousand and one data set to tafamidisoproticiran in terms of time to peak or steady state knockdown level or patient populations. Anything you can point us to for this readout to tell us watch out for this or So I'm not sure I got the gist of your question. You're asking about Thanatos and knockdown effects versus Antilia 21, is that what you asked me? Yes. When we get the Reduction from Antilia-two thousand and one. What are some of the straightforward comparisons we can do to the other agents? And what are some of the Yes. I mean with respect to this particular study, There are exclusions with respect to what other people can take or will have Taken effort before coming into the trial. So in terms of measuring any of that in the course of that study directly, that will be a part of it. With respect to the behavior of TTR and its decline, I think there will be a fair amount of information that We would expect to interpret and one can look at the siRNA material and which is the relevant Knockdown comparator, I think. PTR levels are not knocked down by PTHAMATIS, so it's a different kind of calculus that one might make. But I think one would expect to have a pretty good set of data to make some broad based comparisons based on what we're expecting to share. Thank you. The next question comes from Jay Olson with Oppenheimer. Please go ahead. Hey, thanks for taking the question. For the base editor system that you recently presented, will that base editor be used in both In vivo and ex vivo programs and how do you plan to integrate that tool into your overall platform? Yes. Thanks for the question. We're very excited about what particular sorts of applications base editors may be Slide 2, we see their greatest utility in the ex vivo setting. It's not Currently a part of the programs we've been talking about. If you saw the presentation we gave at Cold Spring Harbor, One of the things that we're very mindful of is the state of the art in terms of looking for stochastic off target effects In the in vivo setting, and that's where we think there's additional work to be done for the field broadly. So in the nearest term, we think That the ex vivo setting is probably the best place to use the base editor, but I'm sure work will continue and that may change over time. Great. Thank you. And then maybe as one follow on question. For your upcoming presentation at ASGCT, What kind of preclinical data should we be looking for? And what are the gating factors to moving that program on to the next steps? Well, the at ASGCT, remember, there's 2 presentations that we're making. One is a very detailed analysis of the off target approach, which speaks Broadly to what we do, so it doesn't relate necessarily to any particular program. The other Presentation will be on extended information on the Alpha-one antitrypsin program. We're not talking yet about its status with respect to the pipeline and its candidacy, etcetera. We will have a 3rd presentation where our CSO will also be Speaking broadly about gene editing and its clinical utility, so there'll be some other insights. But we won't be talking about Any particular development candidates in changing their status there? Great. Thanks for taking the questions. Sure. Your next question comes from Joe Allen with Baird. Please go ahead. Hi, thank you. It's Jack Allen here. Thanks so much for taking the question. We wanted to touch briefly on NTLA-two thousand and two. And We were wondering if you could talk a bit about your expectations for the trial as you move it towards the clinic. It's our understanding that there are a number of therapies already approved For HAE, how do you expect the magnitude of clinical benefit here as you move it into the clinic? And then I know someone touched on this earlier, but you briefly mentioned that you may file an IND or IND equivalent for this program by the end of the year. Could you speak to the factors that Are going to dictate the decision to go with an IND or IND equivalent. Is the NTLA-two thousand and one data one of the factors that you're weighing in that decision? Thank you so much. Yes, just a couple of words about where we think Intellia-two thousand and two can fit in the pharmacopeia. We think that the modality that we have is ideally suited to It's certainly the case that advances have been made with respect to treating that condition. Either patients are treated as an attack occurs, patients don't like that or they're prophylaxed outlook ongoing therapy. Remember, these are patients that are typically identified at the time of puberty or shortly thereafter. So essentially, what you're talking about It is lifelong therapy that is a very, very significant treatment burden and one that in Some cases has become quite effective and others as far less so. So therapeutic opportunity clearly remains. Don't forget also that most effective therapies are extremely expensive, starting at over $500,000 a year with many patients Spending over $1,000,000 a year for those same therapies. So whether it's the leading and exceeding the effect that others have achieved Whether it's dealing with the burden of treatment or dealing with the significant pharmacoeconomic Cost to the health care system to those patients, we think that we have something to offer on every single front. With respect to the clinical trial and where we do it, We certainly look across all the work that we do, wherever it is and whatever the drug is and factors into how we think about quarter. What we're doing, how we're doing it and where we're not going to do it. And we would expect that to be Very central factor in our ultimate decision of where we carry this workout. Thank you so much. Sure. Thank you. There is no time for further questions. I will now hand back to Selena for closing remarks. Great. Thank you all for joining us today and for your continued interest and support. We look forward to updating you on our progress. Have a wonderful day. That does conclude our conference for today. 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