Intellia Therapeutics, Inc. (NTLA) Q4 2019 Earnings Report, Transcript and Summary

Good morning. My name is Andrew, and I will be your conference operator today, and welcome to the Intellia Therapeutics Fourth Quarter and Full Year 2019 Financial Results Conference Call. [Operator Instructions]. At this time, I would like to turn it over to Lina Li, 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 fourth 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 at www.intelliatx.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 Dr. John Leonard, our Chief Executive Officer; Dr. Laura Sepp-Lorenzino, our Chief Scientific Officer; and Glenn Goddard, our Chief Financial Officer. Following our prepared remarks, we will be open for Q&A, for which Andrew Schiermeier, our Chief Operating Officer; and Nishla Keiser, 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&D progress, and Glenn will review our financial results from the fourth quarter and full year of 2019. With that, let me turn the call over to our CEO. John?

Thanks, Lina. 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 diversified line of in vivo and ex vivo programs to address life-threatening diseases. Our in vivo approach delivers CRISPR/Cas9 components as the therapy and our ex vivo approach uses CRISPR/Cas9 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 knockout 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 lymphocytes that retain normal cell physiology while targeting various liquid and solid tissue cancers. Our approach to engineering lymphocytes 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 first development candidate, which is designed for the treatment of transthyretin amyloidosis, and worked expeditiously towards an IND submission for NTLA-2001. We advanced our engineered cell therapy efforts to a selection of our second development candidate NTLA-5001 for the treatment of acute myeloid leukemia, and we demonstrated 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 first 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-2001 in the middle of this year and we expect to dose our first patients in the second half of the year. Second, we've begun IND-enabling activities for NTLA-5001 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 the call to Laura, who will provide additional details on our lead programs and highlight the new data presented at the Keystone Symposium earlier this month. Laura?

Thanks, Johns, and good morning, everyone. Starting with our in vivo programs, we're moving our lead candidate NTLA-2001 for transthyretin amyloidosis, or ATTR, towards the clinic. ATTR is a progressive and fatal disease, where the deposition of misfolded TTR protein can build up in multiple organs causing diverse disease manifestations, mostly commonly polyneuropathy and cardiomyopathy. The disease can be either hereditary or non-hereditary, which is also known as wild-type ATTR. With NTLA-2001, our goal is to treat patients with ATTR, both the hereditary and wild-type forms of the disease, by knocking 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 NTLA-2001 a differentiated profile as compared to chronic therapies. As we have seen with other rare diseases, with options becoming available for patients, there's 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 yearlong durability study of our lead LNP formulation, maintaining an average reduction of over 95% of serum TTR protein after a single dose in nonhuman primates. We are very encouraged by these results as they demonstrate that we can achieve therapeutically relevant levels of serum TTR protein reduction. Our TTR knockdown approach is validated by other ATTR therapies, which demonstrate a strong correlation between knockdown of serum TTR protein levels and patient outcome. We're now nearing completion of Phase I material manufacturing and finalizing our regulatory package for submission. When appropriate, we will share the finalized Phase I study design. We expect the Phase I trial will be a single ascending dose study intended to assess the safety of NTLA-2001. 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 dose first patients in the second half of the year. We're incredibly excited about moving forward with NTLA-2001 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 the lead party. Now moving on to our next in vivo program. In January, we announced our plans to utilize a knockout 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 LNP use for ATTR, only with a different guide RNA. This is a clear demonstration of the benefits of our modular approach as the HAE program builds on the insights and infrastructure developed for the ATTR program. HAE is a rare genetic disease characterized by recurring painful and unpredictable edema in various parts of the body. People with HAE live with a constant uncertainty of when the next swelling attack will occur, which can be triggered by everyday events such as typing or prolonged sitting. It can be significantly debilitating and fatal in certain cases. Most patients with HAE have a C1-esterase inhibitor deficiency, allowing the unregulated release and build of bradykinin, which in turn mediates vascular permeability and swelling. The disease is estimated to affect 1 in 50,000 people. While there are 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 knockout the KLKB1 gene to reduce the spontaneous activation of the kinin bradykinin system and ameliorate the frequency and intensity of attacks in HAE patients. We believe KLKB1 knockout to be safe as humans with prekallikrein deficiency appear to have no known health effects. In addition, the kallikrein activity is a clinical validated approach towards treating HAE. At the recent Keystone Symposium, we showed our first preclinical data set in support of our HAE program. Following a single dose in nonhuman primates, we demonstrated liver knockout of KLKB1, resulting in [indiscernible] reduction in serum kallikrein 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 our ongoing studies will inform our selection of the relevant candidate for HAE, which we expect to achieve in the first half of this year. Similar to the ATTR program, our KLKB1 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-enabling 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 this program demonstrates 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 adopting 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, TCRs recognize epitopes derived from both surface and intracellular antigens, expanding the opportunity to address multi and solid tumors. Furthermore, we believe that our CRISPR platform and knowhow allows us to engineer TCR T cells that closely mimic the natural biology of T cells. In January, we announced the nomination of NTLA-5001, our wholly owned engineered T cell therapy development candidate for the treatment of acute myeloid leukemia, or AML. NTLA-5001 utilizes a naturally occurring TCR-directed approach to target the Wilms' Tumor 1 or WT1 antigen, which is over-expressed in 90% of AML 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-5001. First, in collaboration with Chiara Bonini and her team at Ospedale San Raffaele, 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 in the TCRs. The lead TCR was then selected based on further characterization for specificity and potency. Second and a key differentiator for us, is our proprietary and highly efficient CRISPR-based engineering to uniformly knockout over 98% of the endogenous TCRs' alpha and beta chains and insert the therapeutic TCR in locus with high efficiency. Our presentation at Keystone shows that our approach resulted in improved T cell product homogeneity with an enhanced expression of an inserted therapeutic TCR and reduces risk of unwanted reactivity against normal tissues. Using our approach, we observed transfer of the therapeutic TCR into more than 70% of T cells. Of those, greater than 95% of edited T cells carries 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 mispair with the beta chains of the native receptors and vice versa. The result: only a small fraction of the TCRs in each cell recognize WT1. The mispaired TCRs not only failed to recognize the target epitope, but also have the potential to lead to unwanted toxicities. As a result of selecting a natural high-affinity TCR and apply our expertise in CRISPR engineering, the engineered T cells healed primary AML blasts with high specificity and potency. There was also no detectable off-target or activity against bone marrow cells that expressed low physiological levels of WT1. These results are quite exciting to us as they not only continue to demonstrate the therapeutic potential of our CRISPR-mediated approach to T cell engineering, but they're also supportive of our development candidate NTLA-5001. We have begun IND-enabling activities and remain on track to submit an IND for NTLA-5001 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-5001 will be broadly applicable to AML patients regardless of the mutational background of their underlying leukemia. Additionally, as we've noted in the past, WT1 is over-expressed 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 our wholly owned ex vivo efforts, our partner Novartis has completed IND-enabling studies for a CRISPR/Cas9-based therapy for the treatment of sickle cell disease. At the conclusion of our research collaboration this past December, Novartis selected certain CAR-Ts, hematopoietic stem cells and ocular stem cell targets for development. Rights to all non-selected targets have reverted back to Intellia. Finally, in addition to our development programs, we've had 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-1 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 fourth quarter 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 $284.5 million compared to $314.1 million as of December 31, 2018. The decrease was mainly due to cash used to fund operations of approximately $125 million, which was offset in part by $72.3 million of net equity proceeds raised from the company's at-the-market offerings, $9 million of funding received under the Novartis collaboration, $9.9 million of ATTR cost reimbursements made by Regeneron and $4.2 million in proceeds from the employee-based stock plans. Our collaboration revenue was $10.9 million for the fourth quarter of 2019 compared to $7.9 million for the same period in 2018. The increase in collaboration revenue in 2019 was mainly driven by amounts recognized under the company's ATTR Co/Co agreement with Regeneron. As previously disclosed, Regeneron funded approximately 50% of development cost for the ATTR program. Starting in June, Regeneron will share approximately 25% of the worldwide development cost and future commercial profits for the ATTR program. Our R&D expenses were $31.7 million for the fourth quarter of 2019 compared to $19.9 million for the same period in 2018. This increase was mainly due to IND-enabling activities for NTLA-2001, research efforts supporting the selection of NTLA-5001 and the expansion of our research and development team. Our G&A expenses were $9 million for the fourth quarter compared to $8.7 million 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 will turn the call back over to John to briefly summarize our upcoming milestones and corporate updates.

Thanks, Glenn and Laura, 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 establishing genome editing and delivery capabilities to enable the rapid succession of clinical candidates. Looking ahead, it is indeed an exciting time for the company as we advance our diversified line for severe genetic diseases and cancer. Before we open this call for Q&A, I'd like to summarize our upcoming milestones. We remain on track to submit an IND application for NTLA-2001 in the middle of the year and plan to dose the first ATTR patients in the second half of the year. We've began IND-enabling activities for NTLA-5001 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?

[Operator Instructions]. The first question comes from Martin Auster of Credit Suisse.

This is Patrick on for Marty. Just briefly wondering if you could elaborate more on the consecutive editing and then highlight any potential safety concerns around that.

We use the term consecutive editing meaning one LNP administration followed by another, targeting different genetic targets. An example that we provided recently at the end of last year was with alpha-1 antitrypsin, we could knockout the causes of gene pathology, the aberrant alpha-1, and then substitute at a different locus, in that case albumin, with replacement wild-type gene and have that expressed and yield therapy proteins. It doesn't have to be that way. You could have 2 knockouts in 2 different places. You could have 2 different insertions. So 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 if we characterize the gene that we intend to knockout and we do the standard sorts of assessments for that and if we're going to insert, we would do a similar kind of an 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 of consecutive editing that we're doing, the applications are spread through times separated by days.

The next question comes from Maury Raycroft of Jefferies.

Congrats on the progress. First question is on 2001 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 onetime 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?

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. A single dose is certainly part of the appeal when you think of the alternative, which is lifelong administration of other agents, 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 began 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 - oh, yes, 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 Unites States in addition to the U.S. How those open and where they are is something that we will provide in updates 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 2020 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 will be able to move very, very quickly once we have the appropriate target in hand and are moving forward.

Got it. Okay. And then the 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 license them?

Some are wholly-owned, others are not. For example, we presented data on Factor IX. That was 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-1 antitrypsin is an example of a wholly-owned program. There are others that we have, but alpha-1 is that we presented data most recently on. So we'll think about how we progress it as we continue to develop it.

The next question comes from Gena Wang of Barclays.

This is David Allen 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 I, II dose levels. But should we be expecting the starting dose to be within the therapeutic range based your non-human primate studies? And then can you just share with us your thoughts on the modeling of the dose translations from the non-human primates to human for the study?

All right. As we've shared previously, the alpha-1 - I'm sorry, the ATTR Phase I 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 as 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 I guess for the Phase I, II program for ATTR, just wondering what are your thoughts on the target TTR and knockdown levels and also the target biomarker levels readout to moving to a core expansion.

Yes. I mean, those who have gone before us and validated TTR knockdown as having therapeutic value guide us, and we're very mindful of the work that Alilum and Inois 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 we need to - lower levels of knockdown 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 I design. We haven't revealed that Phase I 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.

A couple of quick ones. One, you - John, you touched upon on a-1 - AATD briefly and CRISPR in a couple of 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 tinkered with just a little bit. How should we think about changing how we project OpEx tempo over the course of next few years going forward?

With respect to the 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 is an ideal way to address the problem. The data we presented earlier as a first example of consecutive editing was done in mice, and that was something that we shared at the end of last year at 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 working on human primates and ways to optimize that are very much underway. And 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 to Glenn and maybe you can address that for Mani.

Sure. So I think if you look at our Q4 OpEx, I think that's a good benchmark to use for modeling going forward and for the remainder of this year and even into early 2021. I will say the financial impact of Regeneron's Co/Co modification does not materially affect the runway or the OpEx.

The next question comes from Madhu Kumar of R.W. Baird.

So thinking about TTR annually doses, how long do you think you would have to monitor here in TTR levels, any declines that emerge to feel comfortable that you've got to a potentially onetime administration leading into a permanent suppression of TTR?

Yes, thanks for the question, Madhu, since 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 or a particular dose is something that we'll learn as we carry out our Phase I study. But as you can imagine, the ability to see in 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 TTR 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. And my question is a little bit different. So yes - certainly before we can get you to talk based on the RNAi and antitrypsin studies, my question is how long after the administration do you think you would have to see durable TTR suppression to feel confident that, that is a onetime kind of permanent TTR suppression as compared to something that goes down and comes back up? But how long is enough to feel that this could be easily a onetime drug?

Yes, I understand. We're starting with the premise that it's going to be a onetime drug, and the reason is we extrapolate from work we've done in mice and nonhuman primates, where we know that the LNPs deliver not only to pericytes, which is the source of the TTR, but also precursor cells that turn into pericytes. And with extended observations in those animals what we've seen is over the course of a lifetime in mice and over very extended observation on nonhuman 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 first few months of observations will be key. But again, we're starting with the expectation just based on knowing how the material is dosed into cells that receive it that this is likely to be a single dose therapy.

Okay. And then one last one about the Novartis sickle cell program. So as you said - you discussed, its 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 they've done. And certainly, as you know, at their R&D Day, they talked about 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

A couple of questions on HAE. I'm interested in your program. This looks like the case where the gene editing approach would impact the rate of timing, which is also impacted by standard of care of the C1 esterase inhibitors. So the mechanism is converging on the 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 the standard of care or a replacement? Or given the C1 esterase inhibitors aren't effective I don't think in patients with normal C1 inhibitor levels, would you target a focused subpopulation like that?

Yes, those are important questions for the clinical program and we haven't addressed all of them yet. Where we begin is looking at the final common pathway to bradykinin activation, which is kallikrein. And we look at those who have gone before us with kallikrein inhibitors, usually antibodies, and they set the standard in terms of what one needs to achieve. So our expectation is that, yes, that's the benchmark. We would certainly help 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 a setting of the 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 the 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, do they recapitulate C1 inhibitor deficient disease or C1 inhibitor impact disease?

This is done in a setting of intact C1 esterase. But again, we're looking for a knockdown of the kallikrein gene or prekallikrein gene, which is that protein that ultimately activates bradykinin. So in the absence of kallikrein, one does not get bradykinin activation, and that is the basis of the work that we're doing here.

Okay. And just a question on the preclinical knockdown data, the same programs that are in your corporate presentation. You had 3 dose levels and it looks like all 3 achieved 90%, about that or higher knockdown in the case of the 2 highest doses. I was just curious how wide of a range those 3 doses cover and if you think you just overshot with the 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 built with other programs, again, working off 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 show that doses that we're familiar with and even less than others that we've worked in the past are high effectively. So we feel really good about moving these kinds of levels into humans in what would be a Phase I study when we're ready to do that. In terms of overshooting, I'll just call attention to the fact that once edits all the pericytes, you're essentially done. You've eliminated kallikrein. And this is where we can turn to nature, where we know that there are human nulls who do not have the protein 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. I appreciate that. Thank you. And then last question quick just regarding the selection of the sickle cell disease target by Novartis. Can you clarify what gene target that is? Is it BCL11A or something else?

Yes. I'd love to talk about it, but that's their story to tell.

The next question comes from Amanda Murphy of BTIG.

This is Max on for Amanda. Just a few high level questions from me around the strategy on oncology. First, given WT1 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 are evaluating as you make that decision. And then I believe last quarter you said that there would not be any edits to NTLA-5001 across the indications. And 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. I'd start by saying NTLA-5001 is what it is as a product. This is an autologous lymphocytes in which the alpha and beta endogenous chains of the T cell receptor have been removed, and has 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 donors. What we've tried to do here is isolate the variable, which in this case is the TCR, in that edit it so. 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 from there, move into a possible range of other solid tumors. We shared elsewhere - and you can see in our corporate deck - that WT1 is over-expressed across a wide range of different solid tumors. And we're exploring now, as we advance the clinical program for WT1, those other solid tumors and how they might behave. So when we have more information to share about that, believe me we'll be happy to talk about it because we're very excited about the potential it brings. And I'll just add, the story will not stop at 5001 for engineered cells. There's all kinds of work that we're doing still in the research group, but that would come forward in different forums, and we'll talk more about that as those products appear.

Okay. Great. Thank you. And then just a little 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 single 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 cell specifically right now.

Yes, 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. But we note there are many limitations in - yes, that range of approaches tends to be applicable to just a small set of tumors and it's very well investigated by many, many different companies. We think the broader opportunity is to step out of that very crowded space and rely on the potential that TCRs bring across all kinds of other tumors. We'll think about some of those other cell types as we go forward, and we certainly had discussions about that. But right now, you should view us as primarily a TCR story.

The next question comes from Silvan Tuerkcan of Oppenheimer.

Congrats on the quarter. I just want to know about some maybe threats or leading factors that you are looking at towards that could delay the first dosing in the ATTR program in the second half of 2020. Like just things that are different than your [indiscernible] 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 remain naive?

So thanks for the questions. There are 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 & Drug Administration, which all relates to this IND filing that we're working towards. We're mindful of all of those things. And yes, 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, et cetera. 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 for 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 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, whether it's therapeutic modalities or diagnostic modalities, patients that we've already known about become identified, and the set of patients acceptable - suitable for therapy grows substantially. And 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 two triangular 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 causative 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 symptomatology and the physiology and clinical outcomes of patients. So it's not a surrogate marker for the Food & 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. Thank you. And maybe one last question on the WT1 program. You put on a really great data on how you can replace the chains of the TCR. Could you already quantify the potential benefits maybe in broad strokes of 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 datasets that kind of could hit that?

Yes. So it's an important question, and I guess there's two levels to that answer. One is, these are target cells. So from the first perceptive, one would expect no problem. The other issue here is TCRs 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 timing selection in the setting of a matched HLA type, and you have nearly perfect removal of the endogenous TCR receptor and insertion of the chosen TCR with essentially a homogenous population of those cells, the likelihood of a safety issue is very low. I mean, of course, that remains to be demonstrated in a clinic. But we've done testing even in vitro where we've taken other cells that have expressed 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 inventory is very, very sound.

This concludes our question-and-answer session. I would like to turn the conference back over to Lina for any closing remarks.

Thanks, and thank you all for joining today's call and for your continued interest and support. We look forward to updating you on our products. Have a great day.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.