Earnings Call: Q4 2019

Feb 27, 2020

Good morning. My name is Andrew, and I will be your conference operator today. And welcome to the Intellia Therapeutics 4th Quarter and Full Year 2019 Financial Results 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 Lena Lee, Associate Director of Investor Relations at Intellia. Please proceed. Thank you, operator. Good morning, and thank you all for joining us today to discuss Intellia's 4th quarter and full year 2019 operational highlights and financial results. Earlier this morning, we issued a press release outlining our progress this quarter and the topics we plan to discuss on today's call. This release can be found on the Investors section of our website atwww.intelliats.com. This call is being broadcast live and a replay will also be archived on our website. Before we get started, I would like to remind you that during this call, we 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 in this presentation is current as of today, and Intellia undertakes no duty to update this information unless required by law. Joining me on today's call from Intellia are Doctor. John Leonard, our Chief Executive Officer Doctor. Laura Seth Lorenzino, our Chief Scientific Officer and Glenn Goddard, our Chief Financial Officer. Following our prepared remarks, we will be open for Q and A for which Andrew Schirmeyer, our Chief Operating Officer and Nishla Kaiser, our Deputy General Counsel will also be joining. For today's call, John will begin by discussing the company's highlights, Laura will provide an update on our R and D progress and Glenn will review our financial results from the Q4 full year of 2019. With that, let me turn the call over to our CEO. John? Thanks, Lena. Good morning, everyone, and thank you for joining us today. Here at Intellia, we're advancing our full spectrum genome editing strategy to develop a diverse pipeline of in vivo and ex vivo programs to address life threatening diseases. Our in vivo approach delivers CRISPRCas9 components as the therapy and our ex vivo approach uses CRISPRCas9 as a tool to create engineered cell based therapies. With strong progress across our pipeline, we believe that our modular approach and innovative science position us well to translate genome editing into new medicines that address critical areas of unmet medical need. We have generated a robust set of preclinical data supporting our potential to cure genetic diseases with a single administration. And we're especially excited about the progress of our ex vivo approach, which we believe can capture the full promise of novel engineered cell therapies for the treatment of cancer and autoimmune diseases. On the in vivo side, with our systemic lipid nanoparticle based delivery system, we believe we have unlocked treatment of genetic diseases that have their origin in the liver. We've demonstrated we can selectively knock out disease causing genes and also precisely insert genes to produce normal human proteins for therapeutic purposes. On the ex vivo side, we focus on engineering lithocytes that retain normal cell physiology, while targeting various liquid and solid tissue cancers. Our approach to engineering both sites is designed to overcome the limitations of currently available cell based therapies. When we look back on 2019, we made substantial progress across our pipeline and platform. We nominated our 1st development candidate, which is designed for the treatment of transtyrene amyloidosis and worked expeditiously towards an IND submission for NTLA thousand and one. We advanced our engineered cell therapy efforts to the selection of our 2nd development candidate, NTLA-five thousand and one for the treatment of acute myeloid leukemia. And we demonstrate our continued leadership in progressing differentiated genome editing strategies, including targeted insertion and consecutive editing. Both are important capabilities, which enable us to either remove and or restore function of a gene across our in vivo and ex vivo efforts. These accomplishments place us in a strong position for 2020, which will be a significant year for our company as we advance our 1st CRISPR based therapy into the clinic with a steady stream of programs poised to follow. In early January, we made several pipeline announcements. First, we remain on track to submit an IND for NTLA-two thousand and one in the middle of this year and we expect to dose our first patients in the second half of the year. 2nd, we've begun IND enabling activities for NTLA-five thousand and one and anticipate submitting an IND in the first half of next year. And third, we disclosed a new development program, which is designed to treat hereditary angioedema or HAE. This program will utilize an in vivo knockout approach and we plan to nominate a development candidate in the first half of this year. We look forward to an exciting year ahead with several important milestones, in particular, as patients begin to receive our potentially curative CRISPR based therapies. I'll now pass to Caldolor, who will provide additional details on our lead programs and highlight the new data presented at the Keystone Symposium earlier this month. Laura? Thanks, John, and good morning, everyone. Starting with our in vivo program, we're moving our lead candidate, MTLA-two thousand and one, for transdermaline amyloidosis, or ATTR, through the clinic. ATTR is a progressive and fatal disease where the reposition of misfolded TTR protein can build that in multiple organs causing diverse disease manifestations, most commonly, polyneuropathy and cardiomyopathy. The disease can be either hereditary or non hereditary, which is also known as wild type ATTR. With MTLA-two thousand and one, our goal is to treat patients with ATTR, both the hereditary and wilder forms of a disease, by notching out the TTR gene in the liver that is the source of circulating TTR protein. We believe the potential to hold disease progression following a single course of treatment gives MDLA-two thousand and one a differentiated profile as compared to chronic therapies. As we have seen with other rare diseases with options we can available for patients, there is an increase in disease awareness and diagnosis. Specific to ATTR, we believe it is a highly under diagnosed condition and there remains a substantial unmet medical need. Throughout the past year, we have been assembling a robust package of preclinical data to support our IND and other regulatory submissions outside of the U. S. In December 2019, we completed a year long durability study of our lead LNP formulation, maintaining an average reduction of over 95% serum TTR protein after a single dose in non human primates. We're very encouraged by these results as they demonstrate that we can achieve therapeutically relevant levels of serum PTR protein reduction. Our TTR number 1 approach is validated by other ATTR therapies, which demonstrate a strong correlation between knockdown of serum TTR protein levels and patient outcomes. We're now nearing completion of Phase 1 material manufacturing and finalizing our regulatory package for submission. When appropriate, we will share the finalized Phase 1 study signed. We expect the Phase I trial will be a single ascending dose study intended to assess the safety of NTLA-two thousand and one. Given the readily observable serum biomarker, we will be able to evaluate efficacy by monitoring the decrease in circulating TTR levels in patients. We remain on track to submit our IND application in the middle of the year and to those first patients in the second half of the year. We're incredibly excited about moving forward with NTLA-twenty one and have received similarly enthusiastic feedback from key opinion leaders about our potentially curative single administration treatment for ATTR patients. As a reminder, this program is being developed as part of our collaboration with Regeneron with Intellia as a lead party. Now moving on to our next in vivo program. In January, we announced our plans to utilize a novel approach in the liver for the treatment of hereditary angioedema, also known as HAE. For this program, we were able to rapidly achieve NHP proof of concept, leveraging the same MLP used for ATTR only with a different guide RNA. This is a clear demonstration of the benefits of our modular approach as the program builds on the insights and infrastructure developed for the ATTR program. Is a rare genetic disease characterized by recurring, painful and unpredictable edema in various parts of the body. People with HAE lead with a constant uncertainty of when the next swelling attack will occur, which can be triggered by everyday events such as typing or prolonged seating. It can be significantly debilitating and fatal in certain cases. Most patients with had a C1 esterase inhibitor deficiency, allowing the unregulated release and buildup of bradykinin, which in turn mediates vascular permeability and swelling. The disease is estimated to affect 1 in 50,000 people. While their existing acute and prophylactic therapies to treat HAE, it is still a disease with significant treatment burden as people with HAE require regular injections and many continue to experience unexpected attacks. In this program, we aim to note out the KLKV1 gene to reduce the spontaneous activation of kinine, radicynine system and ameliorate the frequency and intensity of attacks in HAE patients. We believe KLKV1 knockout to be safe as humans with precalicryne deficiency appear to have no known health effects. In addition, inhibition of clicranin activity is a clinically validated approach towards treating AJE. At the recent Eastern Symposium, we showed our first preclinical data set in support of our HAE program. Following a single dose in noncimabrhymej, we demonstrated liver knockout of KLKV1, resulting in dose calytrane protein levels and activity up to approximately 90%. So far, we have observed that these levels are sustained through 5 months in our ongoing studies. All the dose levels that we tested resulted in activity reductions expected to be therapeutically relevant in reducing attack rates. Data from these and other ongoing studies will inform our selection of a development candidate for HAE, which we expect to achieve in the first half of this year. Similar to the ATTR program, our KLKV1 HAE program is subject to an option by Regeneron to enter into a co development and co commercialization agreement prior to the initiation of IND and IND studies with Intellia as the lead party. We look forward to sharing additional updates on the HAE program as we believe our approach could provide a compelling treatment option for patients. Additionally, we believe that these programs demonstrate how our platform's modularity supports a rapid path to nominating a development candidate. Switching now to our ex vivo efforts in immuno oncology. At Intellia, we're pursuing a T cell receptor or TCR based approach for adoptive T cell therapy, we have chosen to pursue TCRs as it enables us to direct our engineered T cells to a broad universe of targets. Unlike CAR Ts, T cells recognize epitopes derived from both surface and intracellular antigens, expanding the opportunity to address small heme and solid tumors. Furthermore, we believe that our CRISPR platform and know how allows us to engineer TCR T cells that closely mimic the natural biology of T cells. In January, we announced the nomination of MDLA-five thousand and one, our wholly owned engineered T cell therapy development candidate for the treatment of acute myeloid leukemia or AML. MDLA-fifty 1 utilizes a naturally occurring TCR directed approach to target the Wilms Tumor 1 or WT1 antigen, which is over expressed in 90% of ANL regardless of driver mutation and disease subtypes. I'm pleased to walk through the key data presented recently at the Keystone Symposium, highlighting our path to the identification and characterization of NTLA-five thousand and one. 1st, in collaboration with Chiara Bonini and her team at Hospital de Santrassaile, we screened for naturally occurring TCRs that bind to a WT1 epitope efficiently processed and presented by tumor cells. These TCRs were restricted to an HLA subtype, which accounts for an estimated 40% to 45% of the population in the U. S. And Europe. By sourcing TCRs from healthy donors, we may minimize the risk for immune toxicity against normal tissues associated with Affinity enhanced TCRs. The late TCR was unselected based on further characterization for specificity and potency. 2nd and a key differentiator for us is our proprietary and highly efficient CRISPR based engineering to uniformly note out over 98% of the endogenous TCRs alpha and beta chains and insert the therapeutic TCRs in locus with high efficiency. Our presentation at Keystone show that our approach resulted in improved T cell product homogeneity with enhanced expression of an inserted therapeutic TCR and reduce the risk of unwanted reactivity against normal tissues. Using our approach, we have heard transfer of therapeutic TCR into more than 70% of T cells. Of those, greater than 95% of ADT cells carried exclusively the therapeutic TCR. This is a significant improvement over alternative approaches that do not remove or only partially remove the endogenous TCR. For example, we observed that these alternative approaches yield T cells with a mix of TCRs, where the alpha chains of the therapeutic receptor meets pair with a beta chains of the native receptors and vice versa. The result, only a small fraction of the TCR's niche cell recognized WT1. The NIST pair TCRs not only failed to recognize a target epitope, but also have the potential to lead to unwanted toxicity. As a result of selecting a natural high affinity TCR and applying our expertise in CRISPR engineering, the engineered T cells heal primary AML blast with high specificity and potency. There was also no detectable off target reactivity in small marrow cells that express no physiological levels of WT1. These results are quite exciting to us as they not only continue to demonstrate the strategic potential of our CRISPR mediated approach to T cell engineering, but they're also supportive of our development candidate, MTLA-five thousand and one. We have begun IND enabling activities and remain on track to submit an IND for MDLA-five thousand and one in the first half of next year. While treatments developed for AML over the past several years have led to improved response rates, long term outcomes continue to be poor with overall 5 year survival below 30%. With our approach, we believe our engineered T cell therapy for AML represents an opportunity to improve these long term outcomes. And importantly, we also believe NTLA-fifty 1 will be broadly applicable to ANO patients regardless of the mutational background of their underlying leukemia. Additionally, as we've noted in the past, WT1 is overexpressed across many tumor types. As such, we're actively evaluating the potential to use the same TCR construct targeting WT1 in multiple solid tumors. Outside of our wholly owned ex vivo effort, our partner Novartis has completed IND enabling studies for CRISPRCas9 based therapy for the treatment of sickle cell disease. At the conclusion of our research collaboration this past December, Novartis selected certain CAR T, hematopoietic stem cell ocular central targets for development. Rights to all non selected targets have reverted back to Intellia. Finally, in addition to our development programs, we have a strong research engine that continues to advance our modular platform and is focused on delivering the next wave of clinical candidates. These research programs leverage our various genome editing and delivery capabilities across a variety of diseases, including hemophilia B, alpha-one antitrypsin deficiency and others. We look forward to keeping you updated as we approach several important milestones in the months ahead. With that, I would like to hand over the call to Glenn to provide an overview of Q4 and full year financial results. Thank you, Laura, and hello, everyone. Intellia continues to remain in a strong financial position as we advance multiple programs forward into development. Our cash, cash equivalents and marketable securities as of December 31, 2019 were $284,500,000 compared to $314,100,000 as of December 31, 2019. The decrease was mainly due to cash used to fund operations of approximately $125,000,000 which was offset in part by $72,300,000 of net equity proceeds raised from the company's at the market offerings, dollars 9,000,000 of funding received under the Novartis collaboration, dollars 9,900,000 of ATTR cost reimbursements made by Regeneron and $4,200,000 in proceeds from employee based stock plans. Our collaboration revenue was $10,900,000 for the Q4 of 2019 compared to $7,900,000 for the same period in 2018. The increase in collaboration revenue in 2019 was mainly driven by amounts recognized under the company's ATTR COCO agreement with Regeneron. As previously disclosed, Regeneron funded approximately 50% of development costs for the ATTR program. Starting in June, Regeneron will share approximately 25% of the worldwide development costs future commercial profits for the ATTR program. Our R and D expenses were $31,700,000 for the Q4 of 2019 compared to $19,900,000 for the same period 2018. This increase was mainly due to IND enabling activities for NTLA-two thousand and one, research efforts supporting the selection of NTLA-five thousand and one and the expansion of our research and development team. Our G and A expenses were $9,000,000 for the Q4 compared to $8,700,000 for the same period in 2018. This increase was driven primarily by employee related expenses. Finally, today, we are reaffirming that we expect our current cash balance to fund our operating plan through at least the end of 2021. And now, I'll turn the call back over to John briefly summarize our upcoming milestones and corporate updates. Thanks, Glenn and Laurel for the updates. In closing, we're extremely pleased with our recent progress. We advanced our full spectrum strategy in 2019, guiding our lead programs towards the clinic and further genome editing and delivery capabilities to enable a rapid succession of clinical candidates. Looking ahead, it is indeed an exciting time for the company as we advance our diverse pipeline for severe genetic diseases and cancer. Before we open this call for Q and A, I'd like to summarize our upcoming milestones. We remain on track to submit an IND application for NTLA-two thousand and one in the middle of the year and plan to dose the first ATTR patients in the second half of the year. We've begun IND enabling activities for NTLA-five thousand and one in AML and we plan to submit an IND application in the first half of next year. And we expect to nominate a development candidate for our HAE program in the first half of this year. With these anticipated milestones alongside continued investment across our emerging pipeline, we continue to advance our mission to make genome editing based therapies a reality. Again, I'd like to thank you all for tuning into the call today. We'll now open the line to any questions. Operator? We will now begin the question and answer The first question comes from Martin Auster of Credit Suisse. Please go ahead. Hey, this is Patrick on for Marty. Thanks for taking my question. Just briefly wondering if you could elaborate more on the consecutive editing and then highlight any potential safety concerns around that? Thanks so much. Thanks, Patrick. We use the term consecutive editing, meaning example that we provided recently at the end of last year was with alpha-one antitrypsin, where it could knock out the causative gene pathology, the aberrant ELK1, and then substitute at a different locus, in that case, albumin with replacement wild type gene and have that expressed and yield therapeutic proteins. It doesn't have to be that way. You could have 2 knockouts in 2 different places. You could have 2 different insertions. I think we use the term generally, and I think it's important to think about it that way. From a safety point of view, we think about it in ways similar to a single administration. So we characterize the gene that we intend to knock out and we do the standard sorts of assessments for that. And if we're going to insert, we would do a similar kind of analysis. I think one point that may be implicit in your question is risk for that may come from doing the administrations simultaneously. But in these cases, in all of the cases, consecutive editing that we're doing, the applications are spread through time separated by days. Got it. Thanks so much. That's very helpful. The next question comes from Maury Raycroft of Jefferies. Please go ahead. Hi, everyone. Good morning and congrats on the progress. First question is on 2,001 and ATTR. Just wondering if what some of the feedback is that you're getting from KOLs and potentially even from patients regarding use of a one time permanent editing method to treat disease versus chronic therapy options? And then separately, I was wondering if the first in human studies, if you can say whether those are going to be conducted in the U. S. Or the EU? Good morning. Thank you, Maury. With respect to key opinion leaders and patients, as you might imagine, we interact routinely and regularly with them because that's an important source of information to think about how these drugs will be used, the patient populations that they'll serve and how doctors intend to administer it. And what we've seen is a very broad based and genuine enthusiasm for the potential here. Single dose is certainly part of the appeal when you think of the alternative, which is lifelong administration of other agents. But with it, the ability to potentially have a curative approach, I think everyone has expressed broad excitement about that. So we're looking forward to seeing if we can live up to those high expectations in our clinical program and hope that we'll learn a lot more about that as we begin dosing in the second half of this year. With respect to the first in human study, could you repeat the question? I just want to make sure that I guess, will it be in the U. S. Or Europe, I'm sorry. The expectation is that we'll be in a position to have sites outside the United States in addition to the U. S. How those open and where they are is something that we'll provide an update as we go forward. But we want to be in a position to advance the study briskly and get clinical data as quickly as possible. Got it. Okay. And then for HAE, I'm wondering if you nominate a development candidate in the first half of 'twenty based on what you've learned with ATTR, is it possible to file that HAE IND by the end of 2020? When I nominate the DC, I will come with that information, so we can all update our models and think about the way forward. I would point out that an appeal of the modular system and this has been inherent in our thinking from the very, very beginning is that one learns from prior experience. And it's our expectation that we'll be able to move very, very quickly once we have the appropriate target in hand and are moving forward. Got it. Okay. And then last question, just generally for the insertion and consecutive editing techniques that you guys have been developing, those programs are currently wholly owned, right? And so I'm just wondering, I guess, what are plans do you have plans to keep those technologies in house or potentially out licensed? Yes. Thanks. Some are wholly owned, others are not. For example, we presented data on Factor IX that was done in collaboration with Regeneron, and they would certainly have rights to that. And I would stay tuned to see how that unfolds as we go forward. Alpha-one antitrypsin is an example of a wholly owned program. There are others that we have, but alpha-one is that we presented data most recently on. So we'll think about how we progress that as we continue to develop it. Got it. Okay. Thank you for taking my questions. Sure. The next question comes from Gena Wang of Barclays. Please go ahead. This is Dave on for Gena. Congratulations on the progress. I have two questions. The first one is for the ATTR program, I understand that you're not disclosing the Phase III dose levels. But should we be expecting the starting dose to be within the therapeutic range based on your nonhuman primate studies? And then can you just share with us your thoughts on the modeling the dose translation from the non human primates to human for this study? Thanks. All right. David, thank you for your question. As we've shared previously, the alpha-one antithesis, the ATTR Phase 1 study will be a single ascending dose study done in patients. The objective is to choose a dose that will be well on its way to being therapeutic, but drawing that line from non human primates into humans is something that we're going to learn with this first experience. So it's very much a considered calculation to be as close as possible, but do it in a way that permits us to live well within the therapeutic index and escalate as we go forward. So I would say in terms of modeling, what we've learned broadly from LNPs and how they're used in non human primates is that the non human primates tend to be a pretty good predictor and we're basing our assumptions on that. Got it. Very helpful. And then second question is, so again for the Phase III program for ATTR, just wondering what are your thoughts on the target TTR knockdown levels and also the target biomarker levels readout to moving to a cohort expansion? Yes. I mean those who have gone before us and validated TTR knockdown is having therapeutic value guidance. And we're very mindful of the work that Elm Ilim and Ionis have done. We look at that and believe that knockdowns in excess of 60% are likely to be therapeutic, but our objective is to improve upon that. And we believe that levels that lead to lower levels of back down will translate to therapeutic benefit for patients. So that's what we're mindful of and we'll see what we learn in the clinic. The specifics of cohort expansion imply a certain Phase 1 design. We haven't revealed that Phase 1 design and this is something that is subject to the IND preparation that we're doing. When we're in a position to talk more exclusively about that, we'll be happy to share that information. The next question comes from Mani Foroohar of SVB Leerink. Please go ahead, sir. Thanks for taking the question. A couple of quick ones. I want to you John, you touched on A118 briefly and for filling up your comments, can you give us an update on the status of that program and how you're thinking about that target going forward? And secondly, the structure of your partnership with Regeneron has been tinker with just a little bit. How should we think about changing how we project OpEx tempo over the course of the next few years going forward? Thanks, Manny for the question. With respect to alpha-1 antitrypsin, it's something that we're acutely interested in for, I think, all the obvious reasons. We believe the therapeutic approach that CRISPR based gene editing brings to it as an ideal way to address the problem. The data we presented earlier as a first example of consecutive editing was done in mice. That was something that we shared at the end of last year in ESGCT. As we've done with our other targets, the goal is to move that into models that are more relevant to humans. And so work in non human primates and ways to optimize that are very much underway. As we have information that's appropriate, we'll be happy to share that at upcoming scientific meetings. I think with respect to the OpEx questions, I'll turn it to Glenn and maybe you can address that for me. Sure. Good morning, Manny. So I think if you look at our Q4 OpEx, I think that's a good benchmark to use for modeling going forward for the remainder of this year and even into early 2021. I will say the financial impact of Regeneron's cocoa modification does not materially affect the runway or the OpEx. Great. Thanks for the answers, guys. The next question comes from Madhu Kumar of R. W. Baird. Please go ahead. Hey, everyone. Thanks for taking our questions. So thinking about TTR amyloidosis, how long do you think you would have to monitor serum TTR levels and any declines that emerge do you feel comfortable that you've gotten to a potentially one time administration leading to a permanent suppression of TTR? Yes. Thanks for the question, Madhu. It's an important one. We believe based on work that we've done in animals and understanding how the protein behaves in humans that we should be in a pretty good position with respect to knowing where we are from an editing point of view and hitting those kinds of equilibrating levels that you would get with any particular dose after about 4 weeks of observation. Now whether that level is the particular level that we want at a particular dose is something that we'll learn as we carry out our Phase 1 study. But as you can imagine, the ability to see an effect and understand that editing is active is something that we believe we'll be able to learn very, very quickly. And that is one of the appeals of the entire PTR approach here, where you have a readily measurable serum biomarker that we do in patients. And I think we'll be in a position where we can turn that into an expectation of what that would mean for patients looking forward. Okay. My question is a little bit different. So yes, certainly before we get you to trough based on the RNAi and antigen studies, my question is how long after administration do you think you'd have to see durable TTR suppression to feel confident that that is a one time kind of permanent TTR suppression as compared to something that goes down and comes back up? Like how long is enough to feel that this could be really a one time drug? Yes, I understand. We're starting with the premise that it's going to be a one time drug. And the reason is we extrapolate more we've done in mice and non human primates where we know that the LNP is delivered not only to hepatocytes, which is the source of the TTR, but also precursor cells that turn into hepatocytes. And with extended observation in those animals, what we've seen is over the course of a lifetime in mice and over very extended observation non human primates, what one achieves is an invariant after that one dose. So it's clear that in humans, more time brings more confidence with that. And certainly, I think the 1st few months of observation will be key. But again, we're starting with the expectation just based on knowing how the material is dosed from the cells that receive it, that this is likely to be single dose therapy. Okay. And then one last one about the Novartis sickle cell program. So as you said, they discussed completing IND enabling studies and they secured some candidates. Is it reasonable to assume that the sickle cell program is part of that secured candidate list? And if they were to start a clinical trial in sickle cell disease, would that be something that you all would announce? So I can't speak to the specifics of the Novartis program. We're very excited about the work we've done. And certainly, as you know, at their R and D, they talk about it having completed IND enabling studies. It's our expectation that if they're in a position to begin clinical work that we would certainly remind people about that, but it's not our call to make at this point. The next question comes from Steve Seedhouse of Raymond James. Please go ahead. Hi, couple of questions on HAE, interesting new program. This looks like a case where the gene editing approach would impact bradykinin, which is also impacted by standard of care of the coenestrase inhibitors. So the mechanism is converging on standard of care. So as you think about planning clinical development for something like that and establishing the rationale for gene editing, is it an add on to standard of care or replacement or given the C1S3 inhibitors are effective? I don't think in patients with normal C1 inhibitor levels, would you target a focus subpopulation like that? Yes. Those are important questions for the clinical program and we haven't addressed all of them yet. When we begin is looking at the final common pathway to radicaine activation, which is calacrine. And we look at those that have gone before us with calicrine inhibitors, usually antibodies, and they set the standard in terms of what one needs to achieve. So our expectation is that that's the benchmark. We would certainly hope to meet and improve upon that. How those specific clinical trials are done is work that we're beginning with our KOLs, as you might imagine. When one thinks about potentially life threatening diseases, as is the case with HAE, how one does that in setting of existing therapy is a very careful calculation and certainly patient safety is foremost for us. But we think we'll be able to readily determine the effect despite existing therapy and that will be the basis for deciding how to go forward. So early days, but we believe this is a very, very powerful way to address essentially all patients who have underlying HAE. Okay. And in the preclinical models you've used or you will be using delivery, potentially C1 inhibitor deficient disease or C1 inhibitor impact disease? This is done in the setting of in cat C1 esterase. But again, we're looking for a knockdown of the calacrine gene or pre calacrine gene, which is that protein that ultimately activates bradykinin. So in the absence of calacrine, one does not get bradykinin just a question on the pre just a question on the preclinical knockdown data, same programs that are in your corporate presentation. You had 3 dose levels and looks like all 3 achieved 90% above that or higher knockdown in the case of the 2 highest doses. I'm just curious how wide of a range those 3 doses cover and if you think you just overshot with a minimally effective dose or is there actually a limit to the dynamic range you can achieve with in vivo dosing with this particular gene? This is work that we typically do, which is dose ranging work to build on the database that we've built with other programs, again, working on this modular system that we have. What we showed here is a range of doses that are readily physiologically relevant to human beings. And we showed that those that we're very familiar with and even less than others that we've worked with in the past are highly effective. So we feel really good about moving these kinds of levels into humans and what would be a Phase 1 study when we're ready to do that. In terms of overshooting, I would just call attention to the fact that once one edits all of the hepatocytes, you're essentially done. You've eliminated Calatrade. And this is where we can turn to nature where we know that there are human adults who do not have the coaching at all. They have no clinically relevant conditions and that gives us guide and I think it's guided the field in terms of the other inhibitors that are available to feel quite confident about inhibiting this protein. Okay. Appreciate that. Thank you. And then last question quick, just regarding the selection of sickle cell disease target by Novartis. Can you clarify what gene target that is? Is it BCL11A or something else? Thank you. Yes. I'd love to talk about it, but that's their story to tell. Fair enough. Thank you. The next question comes from Amanda Murphy of BTIG. Please go ahead. Hi, everyone. This is Max on for Amanda. Just a few high level questions from me around strategy on oncology. First, given W21 is over expressed in a variety of solid tumors, just seeing if you can give some additional detail around where you are in terms of narrowing down the next potential indication and what factors specifically you're evaluating as you make that decision? And then I believe last quarter you said that there would not be any edits to INTELLIO-five zero one across indications in just making sure that this is still the case or seeing if you're looking to make any changes to the product candidate as you expand potentially into solid tumors moving forward? Yes. So I'd start by saying NLA-five thousand and one is what it is as a product. This is an autologous lymphocyte in which the alpha and beta endogenous chains of the T cell receptor have been removed. And as Laura exemplified in her comments, essentially completely so. And that enables the insertion of the TCR that we've selected, which comes again from healthy doubters. What we try to do here is isolate the variable, which in this case is the TCR in that edited cell. And the basis of the program is to take that first into liquid tumors, AML as we discussed, because we think that, that is a place where we can readily evaluate the effect of that. And then from there, move into a possible range of other solid tumors. We've shared elsewhere, you can see in our corporate deck that WT1 is over expressed across a wide range of different solid tumors. We're exploring now as we advance the clinical program for WT1, those other solid tumors and how they might behave. So we have more information to share about that. Believe me, we'll be happy to talk about it because we're very excited about what the potential brings. I'd just add, the story will not stop at 5,001 for engineered cells. There's all Okay, great. Thank you. And then just as a follow-up to that, Okay, great. And then just as a follow-up to that, you're talking about doing work in different cells. I think one of the things that we've been interested in is editing maybe NK cells and Tregs. I just wanted to see if that was something that you're evaluating as well or if you're kind of focusing more on T cells specifically right now? Yes. It's implicit in your question is the wide range of things that one can do with gene editing. And we're certainly mindful of those things, and we think about the options that we have. Currently, our focus is on the T cell receptor in lymphocytes. And the reasons for that are that we believe we've learned a lot from engineered cell therapies that have gone before us, primarily in the form of CAR Ts. We note there are many limitations. And that range of approaches tends to be applicable to just a small set of tumors. It's very well investigated by many, many different companies. We think the broader opportunities to step out of that very crowded space and rely on the potential that PCR is bringing across all kinds of other tumors. We'll think about some of those other cell types as we go forward and we certainly have discussions about that. But right now, you should view us as primarily a TCR story. Okay, great. Thank you very much. Sure. Next question comes from Silvan Kerkven of Oppenheimer. Please go ahead. Hi, good morning and congrats on the quarter and thanks for taking my question. I just wanted to know about some maybe threats or gating factors that you are looking at towards that could delay or dose the first dosing in the ATTR program in the second half of twenty twenty? Like just things that are different than your tafamidis or patisiran trial. Do you need to select different kind of patients or special kind of patients? And what have you thought about could these patients have taken any of the other agents before? Or do they have to be naive? So thanks for the questions. There's several in there. When it comes to the specifics of the Phase I study, we'll be happy to share that after we've completed that work with the Food and Drug Administration, which all relates to this IND filing that we're working towards. We're mindful of all of those things. And the nature of gene editing necessitates, and I think this is one of the desirable things, treating patients. And that's why we talked earlier about working with KOLs and patient groups, etcetera. We're mindful that there are other agents out there and we think about how to administer our drug with that as a background, which is why, again, we look to guidance from the physicians. And again, what we see is a lot of enthusiasm to do that for any number of reasons, starting with the fact that there's a set of patients that don't respond very well to the existing therapies. I think that's an easy place to begin, but we're far from limited from that patient population. And the goal of the program is to get some clinical data quickly, understand that the editing is effective. And then as broadly and quickly thereafter move into the full set of patients that are cardiomyopathic or neuropathic. And I think one of the exciting things about TTR that we're learning is that there's a lot more patients than anybody ever expected. And our guess is that we will recapitulate the experience that has happened in many other cases, which is when there's therapeutic modalities or diagnostic modalities, patients that weren't known about become identified and the set of patients acceptable and suitable for therapy grows substantially. I think we're already seeing that. So we're not worried about finding patients. Great. And then on the same trial, how can we use the early biomarker data that you will eventually get to triangulate kind of efficacy on either symptoms of neuropathy or cardiomyopathy to kind of think about what the profile of this drug could look like? Yes. So symptoms are symptoms and that comes from interacting with patients and measuring and speaking with them. But the biomarker is a very direct measure of what is the positive pathogenic agent, which is the TTR protein itself. And I think we've learned in spades now that if one can lower TTR levels, that affects septomatology and the physiology and clinical outcomes of patients. So it's not a surrogate marker for the Food and Drug Administration, but it's a very powerful indicator of the utility of the agent and it lets one set up a study design to go and measure those ultimate clinical benefits. So we think it's the ideal marker and frankly a direct measure of the effect of the drug. Great. And maybe one last question on the WT1 program. You put in really great data on how you can replace the chains of the TCR. Could you already quantify the potential benefits, maybe in broad strokes that in terms of GvHD benefit or lower risk versus other CD19 CAR T cell therapies? Or is it kind of early too early to say? Are there any data sets that kind of could hinder that? Yes. So it's an important question. And I guess there's two levels to that answer. 1 is the esartoligous cells. So from the first perspective, one would expect no problem. The other issue here is PCRs and their specificity. You'll recall from Laura's presentation, some numbers that were shared and if you turn to our corporate website, there's a lot more information in terms of the specifics. But we believe, and I think it's just a matter of normal physiology that if you have a TCR that is normal coming from a normal human being that has undergone thymic selection in the setting of a matched HLA type and you have nearly perfect removal of the endogenous T cell receptor and insertion of the chosen TCR with essentially a homogeneous population of those cells, the likelihood of a safety issue is very low. I mean, of course, that remains to be demonstrated in the clinic. But we've done testing even in vitro where we've taken other cells that express low levels of WT1 and shown that the thinking is right. The specificity of the TCR is high and the cells react only against tumor cells. So obviously, the clinical setting is the way to get the best read here, but we think the thinking in the period is very, very sound. Great. Yes, thanks for taking my questions. This concludes our question and answer session. I would like to turn the conference back over to Lena for any closing remarks. Thanks. And thank you all for joining today's call and for your continued interest in support. We look forward to updating you on our progress. Have a great day. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.