Good morning. My name is Drew, and I will be your conference operator today, and welcome to the Intellia Therapeutics third quarter 2020 earnings conference call. At this time, all participants are in a listen-only mode. Following the formal remarks, we will open the call up for your questions. Please be advised that this call is being recorded at the company's request. If you require operator assistance, please press star then zero on your telephone keypad. 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, everyone, and welcome to Intellia's third quarter 2020 earnings call. Earlier today, 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 and Media section of our website at 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 presented on this call 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, Dr. David Lebwohl, our Chief Medical Officer, and Glenn Goddard, our Chief Financial Officer. 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 third quarter of 2020. Following their prepared remarks, we will be open for Q&A. With that, let me turn the call over to our CEO. John?
Thank you, Lina, and thank you all for joining us this morning. Since our last quarterly call, we've made excellent progress to move us closer towards providing curative treatments to patients with life-threatening diseases. Our full spectrum strategy has generated a robust pipeline that includes both in vivo and ex vivo therapeutic applications. For genetic diseases, we utilize our in vivo approach that leverages a lipid nanoparticle-based delivery system to selectively knock out disease-causing genes or precisely insert genes to produce normal proteins. For cancers, we utilize our ex vivo approach to create engineered cell therapies. Our 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.
In October, we received approval from the U.K.'s Medicines and Healthcare Products Regulatory Agency to begin the clinical evaluation of NTLA-2001, our investigational therapy for the treatment of transthyretin amyloidosis, or ATTR. This is momentous news on multiple fronts. First, as an advancement in the field of genome editing, NTLA-2001 will be the first systemically delivered CRISPR-Cas9 therapy to reach human clinical studies. Second, for Intellia, this clinical trial will provide us the opportunity to validate our proprietary non-viral delivery technology and is a significant step forward in our mission. Third, and most importantly for patients, our therapy is a first-in-class product that potentially halts and reverses ATTR after a single course of treatment. We're pleased to reconfirm today that we are on track to dose the first patient by the end of this year.
Laura will go into more detail shortly as she reviews the design of our trial. In parallel to NTLA-2001, we've also advanced our wholly owned programs, NTLA-5001 and NTLA-2002 for acute myeloid leukemia and hereditary angioedema, respectively. Each is on track for an IND or equivalent regulatory submission in 2021. We are equally excited by the progress we continue to make across our platform, where the potential of genome editing is being realized in the broadest manner possible. Our modular approach is fueling our pipeline engine of therapeutic candidates that should have lifelong effect for a variety of rare genetic diseases. One recent update that reflects the power of our platform was our presentation of compelling preclinical data for both in vivo knockout and insertion technologies at the 16th Annual Meeting of the Oligonucleotide Therapeutics Society.
We celebrated the achievement of our scientific co-founder, Jennifer Doudna, and her research collaborator, Emmanuelle Charpentier, who were jointly awarded the 2020 Nobel Prize in Chemistry for the discovery of CRISPR-Cas9 genome editing technology. Their breakthrough 2012 science paper opened the door to new ways to modify DNA and thereby launched the revolution in biology that we are proud to be a part of at Intellia. We believe this work fundamentally improves therapeutic options for many categories of disease and creates prospects for patients suffering from conditions that are poorly treated today. We are honored to bring the promise of this genome editing technology to patients as Intellia embarks on our next chapter evaluating CRISPR-Cas9 based therapies in the clinic. I'll now pass the call over to Laura, who will provide more details on our programs. Laura?
Thank you, John, and good morning, everyone. It's my pleasure to provide an update on our R&D progress, starting with our lead candidate, NTLA-2001, in development for the treatment of all clinical manifestations of ATTR. ATTR is a progressive and fatal disease caused by the buildup of TTR protein in multiple organs. People living with the disease can have either the hereditary or wild-type form of ATTR, which results in diverse disease manifestations, most frequently polyneuropathy and cardiomyopathy.
There are an estimated 50,000 hereditary ATTR patients worldwide, and between 200,000 and 500,000 patients with wild-type ATTR. NTLA-2001 applies our in vivo approach to knock out the TTR gene in the liver, which is the source of circulating wild type and mutant TTR proteins. Our robust preclinical data showing deep and long-lasting TTR reduction supports NTLA-2001's potential to be a one-and-done treatment to halt and reverse disease progression. As John noted, we're now authorized to initiate our phase I study with a U.K. clearance of our CTA for NTLA-2001, which is the first systemically delivered CRISPR-Cas9 therapy to enter clinical trials. For this first-in-human study of a novel modality, we selected hereditary ATTR with polyneuropathy as the initial study population. This approach provides the most efficient path to defining the optimal dose, since it is validated that reduction in TTR protein correlates with clinical efficacy.
Additionally, it provides us with the best opportunity to obtain a clean read on NTLA-2001's safety and tolerability, since polyneuropathy patients are less likely to have comorbid conditions than ATTR cardiomyopathy patients. Once we have established safety and the optimal biologically active dose, we plan to expand evaluating NTLA-2001 in ATTR patients with polyneuropathy and cardiomyopathy. Our global phase I study is a two-part open-label multicenter trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of NTLA-2001 in patients with hereditary transthyretin amyloidosis with polyneuropathy. Up to 38 patients will enroll and receive a single dose of NTLA-2001 through IV infusion. Part one will be a single ascending dose study with up to four cohorts following a traditional three plus three design aimed at identifying the optimal biologically active dose.
We plan to quickly move into part two, which will be a single dose expansion cohort of eight additional patients to further characterize the activity of NTLA-2001, including an initial assessment on clinical measures of neuropathy and neurologic function, and to obtain additional safety data at the optimal biologically active dose. This trial design includes the measurement of serum TTR levels as a direct biomarker of liver gene knockouts. Of note, while we're not disclosing those levels at this point, we anticipate biological activity at all those levels, including the starting dose. We're delighted to be working with experts in the field who have expressed great enthusiasm for NTLA-2001 and who are actively screening patients. We remain on track to dose the first patient by year-end, and we're submitting additional regulatory applications in other countries as part of our ongoing global development strategy for this program.
We look forward to updating you once we dose our first patient, an exciting milestone for patients, for the field of genome editing, and for Intellia. Now moving on to updates on our two wholly owned programs, NTLA-2002 and NTLA-5001. NTLA-2002, our second in vivo therapy, is in development for the treatment of hereditary angioedema, or HAE. HAE patients experience recurrent, unpredictable, and painful swelling in multiple tissues. While there are acute and prophylactic therapies for HAE, the treatment burden on patients is significant and there is opportunity for additional clinical efficacy. Today, we're pleased to share completed data from a year-long durability study in non-human primates. NTLA-2002 is designed to knock out the KLKB1 gene in the liver, leveraging the same LNP delivery system used for NTLA-2001. Following a single dose, we achieved sustained reduction of serum kallikrein protein levels and activity.
If translatable to patients, these reductions of up to approximately 90%, are expected to be highly efficacious and durable in preventing HAE attacks. Based on the consistency of effect, we're optimistic that NTLA-2002 could effectively free patients from a lifetime of disease and its debilitating symptoms. We initiated GLP toxicology studies this quarter as we continue to advance NTLA-2002 towards the clinic, and remain on track to submit a regulatory application for a first-in-human study in the second half of 2021. Turning now to our ex vivo efforts. Here we're using CRISPR-Cas9 as a tool to create engineered cell therapies. We employ a TCR-based approach enabled by our groundbreaking cell editing and engineering process to harness the full therapeutic potential of arming T-cells to attack a variety of cancers.
Our objective, simply put, is to ensure patients receive a high-quality, robust cell product that mimics and enhances their own natural defense system against their tumor. We use our proprietary T-cell engineering process to precisely edit and replace the patient's T-cell receptors with a tumor-targeting TCR. This approach reduces safety risks and should translate to improved potency and function. Our technology enables a multiplicity of edits with high efficiency, cell yield, viability, and the desired memory phenotype. Importantly, this favorable cell product profile is achieved without introduction of translocations and in a shorter window of time as compared with a standard T-cell engineering process. Essentially, we're unlocking the potential to develop next generation T-cell products with desired characteristics that should translate into additional benefit for patients, such as reduced vein to vein times and improved safety and efficacy.
For our lead TCR T-cell therapy development candidate, NTLA-501, for the treatment of all forms of AML, we continue to make steady progress with IND-enabling activities. We recently received regulatory guidance and feedback from leaders in the field that will inform our early development strategy. We look forward to presenting additional data from preclinical studies of our program at the upcoming American Society of Hematology annual meeting in December and remain on track to submit an IND or equivalent regulatory submission for NTLA-501 in the first half of 2021. Moving on to our research efforts on platform, our team has made great strides broadening the in vivo and ex vivo applications of genome editing. Utilizing our modular approach, we're generating leading solutions for targeted transgene insertion and consecutive editing in vivo.
At the recent OTS annual meeting, we presented striking evidence that further validated the expected lifelong therapeutic impact of our technology. For both knockout and insertion approaches, we employed a partial hepatectomy in murine model to evaluate the durability of the genome edits under conditions of rapid hepatocyte proliferation. After a resection of two-thirds of the liver and subsequent full liver regeneration, the genome edits and corresponding effects were unchanged in magnitude despite cell proliferation. The persistence of these edits supports the permanent nature of our technology to durably reduce a disease-causing protein or restore a functional protein after a single course of treatment. For knockout, this orthogonal approach to assessing durability builds on the deep and permanent protein reduction that we have seen in our year-long NHP studies in support of NTLA-201 and NTLA-202.
For insertion, the promising data further demonstrated the potential of our platform to be best in class when compared to traditional AAV gene therapy. In the in vivo partial hepatectomy study, we observed a 95% loss in transgene expression with AAV-based gene therapy, whereas our targeted gene insertion approach yielded no significant loss in expression. We believe these results highlight our ability to durably restore a functional protein, including the opportunity to intervene early in a patient's life. We look forward to working with Regeneron on our joint hemophilia programs, as well as progressing our wholly-owned insertion and consecutive editing programs. With that, I would like to now hand over the call to Glenn, who will provide an overview of our third quarter 2020 financial results.
Thank you, Laura, good morning. In short, Intellia is well positioned for our upcoming milestones. Our cash equivalents, and marketable securities were $407.9 million as of September 30th, 2020, compared to $284.5 million as of December 31st, 2019. The increase was mainly driven by net proceeds of $122.4 million from external financing activities and $100 million from the expanded Regeneron collaboration, offset in part by cash used to fund our operations of approximately $119.8 million. Our collaboration revenue increased by $11.6 million to $22.2 million during the third quarter of 2020, compared to $10.6 million during the third quarter of 2019. The increase in collaboration revenue was mainly driven by our recognition of $15.3 million of deferred revenue related to completing the transfer of the hemophilia A program rights to Regeneron.
Our R&D expenses increased by approximately $12.2 million to $39.8 million during the third quarter of 2020, compared to $27.5 million during the third quarter of 2019. This increase was mainly driven by the advancement of our lead programs, research personnel growth to support these programs, as well as the expansion of the development organization. Our G&A expenses increased by $2.1 million to $10.6 million during the third quarter of 2020, compared to $8.4 million during the third quarter of 2019. This increase was mainly driven by employee-related expenses, including stock-based compensation. Finally, we expect our cash balance to fund our operating plans for at least the next 24 months. I will turn the call back over to John to briefly summarize our upcoming milestones.
Thanks, Glenn and Laura, for the updates. In summary, we've had a very productive year at Intellia while tackling unprecedented challenges. We've received regulatory authorization to initiate our phase I study of NTLA-2001. We're looking forward to announcing that we have treated a patient with the first systemically delivered CRISPR therapy before the end of the year. We've rapidly progressed NTLA-5001 and NTLA-2002 toward the clinic. We remain on track to submit an IND or equivalent regulatory application for each program next year. We've advanced innovative platform technologies that will enable us to continue building a broad and deep pipeline to address a variety of cancers and rare genetic diseases. I want to extend my gratitude to the entire team at Intellia for their unwavering commitment to realizing the power of CRISPR and delivering treatments that could cure patients.
I'm also offering my sincerest thanks to patients, their families, and those of you who have been following our progress. Thank you for entrusting us to bring forward the promise of genome editing. We're focused on retaining the strong momentum across our pipeline and platform as we head into the final months of 2020 and beyond. We'll now open the line to any questions. Operator?
We will now begin the question and answer session. To ask a question, you may press star, then one on your touchtone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster. The first question comes from Salveen Richter of Goldman Sachs. Please go ahead.
Good morning. I was wondering if you could provide us with more details as to how you will take the TTR program and progress beyond polyneuropathy into cardiomyopathy, whether these will be one large trial or separate trials, or you're thinking about various geographies and how you would incorporate a U.S. study in another indication. On the latter, just curious about progress in other geographies in addition to starting a U.S. trial. Thank you.
Morning, Salveen. Thanks for the question. The study that we're beginning with is in polyneuropathy patients for the reasons that Laura went through, which gives us a very clean background to get to some very clear insights with dose and safety. Although it's primarily polyneuropathy patients with some degree of cardiomyopathy are permitted into the study, so we'll get a peek at that point. We want to move very quickly from this study to get a more detailed look at how the drug will perform in cardiomyopathy patients. Now, we fully expect that the degree of editing should be the same. The approach that we're taking should be indistinguishable in either patient population. It's just that we want to have some experience with background that's clean as we move into patients that are somewhat more complicated.
With that in hand, which I hope will follow very quickly on the heels of this phase I study or potentially even overlap it, we're thinking through the best way to begin. The idea would then be to go ideally globally, focus very much on cardiomyopathy, which we think is where the greatest unmet need is, of course, bring polyneuropathy along with it. You shouldn't think of this as primarily a polyneuropathy program by any stretch of the imagination. It's just the point of departure here. With respect to this particular trial, as we mentioned in our comments, the goal is to have other sites up and running, and we've made great progress there. We will be in other geographies, and of course, that is the foundation to go and do subsequent work as well.
A lot going on and fingers crossed we'll be able to progress this very quickly.
Thank you. John, if I could follow up, is there a difference between the U.S. and Europe in terms of what they might want to see in order to start trials in in vivo gene editing?
I wouldn't characterize it as so much a difference as perhaps depending on how one is proceeding in the particular disease indication, the rate at which you can progress. What we've tried to do is, with all of our programs, take a very good look at what the opportunities are for patients, the regulatory environments in different geographies around the world, and then make a decision in terms of how we can get the best information the most efficiently. We'll definitely be back in the U.S. That is an objective to come here very quickly, but for the purposes of getting up and running and collecting this critical information quickly, we made the judgment that the U.K. and related geographies would be more efficient.
Thank you.
Sure.
The next question comes from Maury Raycroft of Jefferies. Please go ahead.
Maury, I don't know if you can hear me. I can't hear you. You might want to try another connection.
Can you hear me now? Okay.
No. I want to hear you, but I can't. I'm sorry.
The next question comes from Madhu Kumar of Baird. Please go ahead.
Yeah, thanks for taking our question. I think our first one kind of related to something that Salveen asked. How do you think about assessment of cardiomyopathy, kind of clinical parameters in the phase I-II, considering that based on something you said just now, John, you will allow patients who have a mixed polyneuropathy cardiomyopathy phenotype into the dose escalation?
I think it's important. Well, first of all, thank you, Madhu, and it's nice to get a question from you this morning. Remember, in a phase I study, there's limited opportunity to get many detailed physical and physiological assessments of these patients. It's a three plus three design, four cohorts, and then we expand when we get to what we think is the optimal biological dose. What we would get would be descriptive sorts of assessments. The primary readout is safety and TTR. What we're looking for is the effect on circulating TTR levels, and that's the point of departure to go get those more detailed assessments that I think you're asking about, which would be done in a subsequent study.
I guess more practically, like if you find that in the enrollment you get a lot of mixed phenotype patients, could you amend the protocol to include, say, blood tests for NT-proBNP as a kind of surrogate biomarker for cardiac effects?
I don't think it would be our intention to go and amend the protocol. Looking backwards, we've got all kinds of exploratory assessments that we will collect, and many of the particular lab tests that you're requesting or asking about, we will have the opportunity to measure. Again, the ability to derive real insights, I think, is going to be limited, particularly given that we're trying to get to an optimal biological dose. There may be opportunities to get a little bit more information on that expansion cohort of so-called part 2 of the study. Remember that the patients with cardiomyopathy will be not severe patients at all. They'll be very low. The patients coming into the study are primarily suffering from the symptomatology of polyneuropathy. As you know, these phenotypes overlap to a large degree.
I just don't think that we're going to be able to draw many detailed conclusions in terms of the physical consequences of TTR reduction, but we should be able to get some description of it. Again, TTR level reductions is the primary readout.
Okay. One last question about the ex vivo programs, both the internal ones and your partnered program in sickle cell with Novartis. How are you guys thinking about CMC considerations when you look at the travails that it appears one of your competitors is having regarding CMC and sickle cell disease? How do you plan for that, and how are you envisioning both how you different from, say, non-gene editing or viral approaches and how you need to plan ahead for setting up a good CMC path for your either cancer cell therapies or blood progenitor cell therapies?
That's a big question, Madhu. There's a lot in there. With respect to our partner, which is Novartis, in the case of the HSC work, that's a responsibility that they've taken on and they can speak for their own progress. I think that they're very adept at this kind of work, given that they've been in the space for some substantial period of time. In our own work with the 5001 program, again, which is TCR directed against WT1, we've developed our approach to making the cells. We've shared some of the information in terms of how those cells perform in in vitro settings. At ASH, we'll talk a little bit about that in in vivo settings. We're well on our way to transferring that to a third-party manufacturer who's highly experienced in the space, and that is all proceeding very well.
Currently, we think we're in excellent shape to meet our guidance and to begin move this into the clinic next year. I think the entire process has been going quite well.
Plus one last one. I apologize. I'm just going to lay it out there. What level of TTR knockdown do you think is a winner, and what level of durability convinces you you've got really durable TTR silencing?
Well as we've talked previously, we look very carefully at the benchmarks that have been set by people who've been in the space, who have validated levels of TTR reduction with clinical outcomes. Certainly Ionis and Alnylam have done a nice job of paving the way for that. Our goal is to at least match that and ideally surpass that. We go and look at our preclinical data and we see very extensive reductions that we think are very promising, assuming that they're translatable in the clinic. That's what this work that we're beginning now is set to show. With respect to durability and knowing that it is in fact one and done, there's two lines of evidence.
Obviously, the single best line of evidence is to watch a patient over time. That means you've got to have time, but there are other ways to approach that, which we've done pre-clinically with model systems. As Laura went through in her comments, one of the ways to explore this, which we think is a very, very high bar to overcome, is to take the liver and accelerate the rate at which cells divide. This is the partial hepatectomy study that she referred to, where you can take a liver, reduce it by two-thirds, and look at what grows back. What grows back is what was there in the first place. As far as we can tell, with every single line of evidence that we've explored, passive waiting in animals of different species, accelerated turnover studies as well, there's no loss of effect.
To be frank, I'll be quite surprised if the effect is lost in here.
All right. Excellent. Thank you so much.
The next question comes from Gena Wang of Barclays. Please go ahead.
Thank you for taking my questions. I have two. The first one is regarding the WT1 program. We saw at the ASH abstract, looked very impressive top-line data. Just wondering, is that the program or that data, was that the clinical asset, that NTLA-5001 that you are moving to clinic? Also, will you try to file for IND or CTA? My second question is regarding the ATTR program. Wondering if you can remind us how the dose escalation work, what will make you determine to reach, let's say, complete all the full cohorts? Are there any stopping rules, say, if you reach ATTR knockdown already 80%, will you stop at the third dose or second dose?
Hey, Gena, this is Glenn. John's having a little bit of audio problem with his headphone. Thank you for your questions. I think I'm going to have Laura, our CSO, jump in and address some of those. Apologize, we're just having a little bit of audio function, but Laura can address, I think, those questions. Thank you.
Yeah. Good morning, Gena, and thank you for the question. I'll wait for John to cover some of that, but I'll start with NTLA-5001 and the data we'll be presenting at ASH. That is in fact with the WT1 TCR and the process that we're intending, that NTLA-5001 that we're taking to the clinic. There we're going to be sharing more data on the performance of those modified cells, on the activity of the TCR in vitro as well as in vivo in using primary blasts from AML patients as well as a very aggressive ALL model. Important there, another piece of data is that we demonstrated that there is no signs of graft versus host disease in this model, reflecting the nature of the WT1 TCR that was sourced from normal people. Sorry, what were the other questions?
The question, will you file IND or CTA for this program? The other question is the ATTR program, how do the dose escalation work? Do you have a bar for hitting, I'm just making up numbers, like say 80% knockdown, will you stop further dose escalation or is that irrelevant to the knockdown? More is that to test the efficacy or the?
Right
Sorry, more to test the safety?
Yes. Okay. With 5001, as we're doing for ATTR, we're pursuing a global clinical development strategy. We have engaged with multiple regulatory agencies in the U.S. and in Europe. We're incorporating that regulatory guidance as we design our first-in-human clinical trial. With regards to TTR, our intention is to move quickly through the four cohorts in the NTLA-2001 phase I trial. We have used the data from our preclinical work in consultation with regulatory agencies to select the starting doses, right? Try to move really quickly through the dose escalation. As John was saying before, the goal is to meet and surpass the benchmarks that have been established by others who led in TTR with the RNA silencer compounds. I believe that John is back.
Yes. Thank you. I didn't want to interrupt you. He's reconnected.
I am back. I'm sorry. My connection died for some reason, so sorry.
Gena, did I cover all your questions?
Yeah. I think that's very good. Thank you.
I appreciate it. Thank you.
The next question comes from Joon Lee of Truist. Please go ahead.
Hi. Thanks for taking our questions, and congrats on the progress and all the accolades. Regarding your ATTR program, it's a global study. Are you seeing any different attitudes across different countries in terms of a willingness to approve something like this, a systemically delivered genome editing program? What key piece of evidence do you think assuage any concerns about off-tissue targeting, particularly of the germ cells, which I think could be important? Following up on the ATTR program, your initial patients that you're hoping to enroll, will they have failed antisense oligos? If so, what gives you confidence that this approach could work in those patients? Thank you.
I hope I got all that in. Thanks for the question. First, for the last part, for patients coming into the first part of the study, they will not have received prior treatment with other therapies that are gene silencers or oligonucleotides. This notion of if they hadn't responded in that setting, would that somehow affect this trial? We're excluding those patients. You have to have never received treatment in the first place. With respect to ATTR, if I understood the question what-
Maybe requirements. Yeah.
Yeah. No. In fact, we're saying that patients cannot have received prior treatment with gene silencers. We're not asking that patients come into the study based on a failure with a prior therapy. Just to be clear.
Yep.
With respect to attitudes with systemic therapy, in our interactions with patients, regulators, and KOLs pretty much around the world, I think they all look at it from the standpoint of unmet need. While there's no doubt that progress has been made in the space in terms of bringing therapies to patients with amyloidosis, I don't think anybody believes that the final chapter's been written here. Curative therapy or improved levels of reduction that truly halt progression and perhaps lead to a reversal of the progression of the disease is what doctors and patients are looking for. I think when they look at this particular modality, it's with that outcome in mind, and obviously they're interested in the preclinical assessment as would be the case for any drug. That's the information that we bring to them as we plan these programs.
We think we're in great shape to go and study this, and patients and doctors are quite enthusiastic about it. In terms of off tissue, off target, I think was the question.
Yep.
That's all part of a preclinical assessment, where we look at where the LNPs go in the first place. We think that the bulk of the LNPs go exactly where we want them to, or to tissues where it really doesn't matter with respect to TTR expression.
Okay. Thank you.
Sure.
Next question comes from Mani Foroohar of SVB Leerink. Please go ahead.
Hey, good morning. This is Rick dialing in for Mani. Congrats on all the progress. First, I was hoping to get some more detail on some of the work that's going on in the background as you prepare for the IND for the AML cell therapy program. Are there any major gating steps in either developing the manufacturing process or characterizing the cell product that need to be completed before the IND submission?
I would characterize it this way. We are very much on track to meet the guidance as we've offered. The work pretty much is characterized by Laura and her comments, which is transfer of the manufacturing approach to a third party. I think when you step back and look at what the product is, there's a lot in it. It's an engineered cell and there's insertions and knockouts and so on and so forth. Regulatory agencies are very interested in making sure that all of those components are appropriately assessed and characterized and that the right specifications are put in place to release those products. That's the nature of the regulatory interaction so that we have that information in hand and can incorporate that into all of the documentation as we open up the regulatory filings for these things.
We think we're in excellent shape to go and meet those requirements.
All right, great. I do have a follow-up. I know the Alpha-1 Antitrypsin Deficiency Program hasn't been in the forefront for a bit, but I was just hoping to get your most recent thoughts on this as a target in gene editing now that we have some validating clinical data from RNAi knockdown for this disease.
Yes. Thanks for the question. As Laura said in some of her comments, there's a lot going on in the background at the company. We certainly spend a lot of our time talking about what we call the big three programs that are moving into the clinic, and that's certainly an area of focus for these kinds of discussions. We're very excited about the work that we've done with our gene insertion work. Some of that data has been presented previously for the hemophilia space. We've presented some data with respect to Alpha-1 in mirroring models. It's an area of active investigation for us, thinking about how well we can express human proteins of interest in other targets, including Alpha-1 antitrypsin. This is an area that I would encourage you to stay tuned with.
All right, great. Thanks for taking our questions.
The next question comes from Steve Seedhouse of Raymond James. Please go ahead.
Good morning. Thank you. The dose escalation part of the TTR study looks like it's enrolling treatment-naive patients with respect to knockdown therapies, but patients can, I think, stop tafamidis, for example, and join the study a couple of weeks later. Can you just talk about whether that's an important population to ensure you enroll to get some data on in phase I, the tafamidis switchers, and then also knockdown switchers, potentially, in the dose expansion part? Relatedly, just curious what % of the sort of diagnosed addressable market by the time you launch would you anticipate already being on treatment with tafamidis or a knockdown therapy?
Yeah. For the first part of your question, tafamidis, as you know, has a different mechanism of action. It's a stabilizer as opposed to an agent that lowers TTR levels. It was our judgment, and interactions with KOLs and other experts concurred, that that really would have little influence in terms of actually measuring TTR levels. What we do is ask that patients who have received tafamidis or are receiving tafamidis as they come for screening, wash that out and the effects at that point are not present in the body, doesn't affect TTR levels, so that we're then able to carry out the assessments that we need in our phase I study. It's a different kind of situation from the gene silencers, as you say.
The reason we include them is not necessarily to get experience in tafamidis switchers, although I guess you could say that that'll be maybe a happy outcome of this particular study. It really just makes the study available to a larger patient population and permits us to enroll it more quickly and get the data that we need. With respect to the proportion of the market that will have been on tafamidis and that will be patients that we are thinking about down the road, that's a little hard for me to speculate on at this point in time. We're talking about a few years from now. I think that's best that we come back to that at a future date and think about how that may impact our study or not at that time.
Great. Thank you.
Sure.
The next question comes from Yanan Zhu of Wells Fargo. Please go ahead.
Hi. Thanks for taking my questions, and congrats on the progress. First, on the TTR program, thanks for the clarity you provided for the long-term development path beyond the phase I study. Just curious, the ongoing pivotal trials of RNA therapeutics in ATTR cardiomyopathy have 600-700 patients in the treatment arms. I guess 600-700 patients would be unprecedented for any gene therapy or genome editing trial. Would like to hear your thoughts there. On the phase I study, as you begin to dose patients, is there a requirement for a waiting period between patients, and also between cohorts?
Lastly, sorry, in the dose expansion portion of the phase I trial, do you plan to look at liver biopsy for editing efficiency or tissue biopsy to look at TTR amyloid clearance in the tissue? Thank you.
Okay, well, let's do the last one first. That's very straightforward. We're not going to be doing tissue biopsies of any kind. We don't need to. We think the information that that would provide would be of really limited value. Remember what we're trying to achieve here, and that is the reduction of a protein that is the pathologic agent. The most important direct measure is levels of circulating TTR, and that is a really good surrogate for the extent of editing. Frankly, that's what's going to determine our optimal biological effect, the degree to which TTR is reduced. With respect to size of the trial, you can think about modalities and what have been tested previously, and you can think about the therapeutic objective and the type of information you're getting.
My best guess at this point would be that just because we're a gene-editing technology doesn't mean you necessarily do a small study. This is going to be a study size that'll be determined by the endpoints that we're measuring. They almost certainly will be clinical in nature, which is certainly the case for cardiomyopathy. We will learn, I think, a lot of information from those that are going before us in terms of the extent of an effect that's measured physically or clinically, and related to a particular TCR reduction. That's what will be taken into consideration as we size the study to measure a particular outcome. Then, related to some earlier questions we had here in terms of what's the background population and other drugs, et cetera, all of that, I think, is going to have to figure in the work that we do.
Finally, in the phase I study, there are rules in terms of the cohorts and how they advance. It's not the place to go through that here. I think you should think of this as a pretty standard three plus three design, where patients fill a cohort, there's an assessment, and then you launch the next cohort, and we set this thing up so that we can get those assessments done quite quickly and move at a brisk pace.
Got it. Thank you. If I may, just one more question on the WT1 TCR program. In terms of the population of patients in your first human trial, I think you've indicated that you're looking to study the drug first, study the product first in patients with a certain level of leukemia blast, but perhaps not too high a leukemia blast burden. I'm just wondering, is that target population similar or different from the ongoing CAR T trials targeting various surface antigens in AML?
Maybe I'll call on our CMO, David Lebwohl. David has very direct experience in prior CAR T trials and is responsible for the work that we're doing with our TCR program as well. David, do you want to talk about our initial patient population and how that relates to some of the prior work?
Yes, thanks, John. The patients in this study will be patients who generally had prior therapy, so they have had their disease come back after prior therapy. Very similar to other studies in AML. As we mentioned, we are looking for patients who might have a lower blast burden or some patients who may have a higher blast burden and look at them separately. I think what's important and different from other CAR T therapies is that we're targeting an antigen which is not highly present on normal tissue. We don't expect to see the type of severe toxicity that's been seen in the AML studies with CD123 or CD33.
Got it. Just maybe one more curious question in terms of the WT1 TCR product. Because it's a TCR and you've also mentioned the antigen is not highly abundant in the body, does that have implications in persistence and TCR memory? I ask that also because it's a TCR, T cell, which looks pretty much like a T cell as opposed to a CAR T. It may perhaps have some implication on the memory formation. Yeah. Thanks.
David, if you want to keep commenting, go ahead.
Sure. Yeah. These patients, as you know, will have blasts. Obviously their initial antigen is due to the tumor itself. Of course, if you completely eradicate tumor, which is the goal of our study, there will be less antigen present. The thinking is that often these cells do persist. T cells can have a long life, and the advantage of that is if the blasts do return at some point, again, the T cells will be present there to eradicate the tumor.
Got it. That's very helpful. Thank you.
The next question comes from Jay Olson of Oppenheimer. Please go ahead.
Hi, this is Chen on the line for Jay. Thanks for taking our question. Maybe just a quick one on NTLA-2002. We're wondering if you are planning to maybe follow us in the path as NTLA-2001 that's starting the trial in Europe and then move back to U.S., or maybe you can start the trial directly in the U.S. Thank you.
Chen, thanks for the question. We learn a lot from what we do with TTR. That certainly influences our subsequent in vivo programs. We're still laying out exactly what our regulatory strategy is. We've looked very carefully around the world, in U.S. as well as Europe. We've seen the advantages of the different geographies. As we have more details on that final selection, we'll share them with you. I will say this, we've clearly benefited from the many interactions that we've had with TTR and all those advantages and synergies will find their way into this program.
Okay, thank you.
Sure.
The next question comes from Roger Xu of Credit Suisse. Please go ahead.
Hi, everyone, good morning. This is Roger on for Marty. Thanks for your time. I have just two quick questions regarding the design of the 2001 dose escalation study. One, do you expect the low dose to be within therapeutic range, or are you intentionally under-dosing in this low-dose cohort? Secondly, how are you thinking about initial disclosure plans? How much data are you looking to have before there's an update, and should we expect an update next year? Thanks.
Let me take a crack at that, and if necessary, we can involve David here. The idea of this first-in-human single ascending dose study is to start as much as possible in the zip code, I would say, of where we think there will be efficacy as measured by TTR reduction. As we start to bias that to the lower side as opposed to the higher side, and that's, I think, for obvious safety reasons. There's no reason to overdose and deescalate. If anything, you'll start somewhere where you think you can have efficacy, and then escalate to something that is a preferred dose or call it the optimal biological dose. That's the logic that applies in this program, and as you know, the comments that we made.
This is the first of its kind, and we're extrapolating from prior preclinical work, and this is where we're going to really get, I think, a good notion as to how predictive those models actually are. Our thinking is that there should be biological activity, the extent of which remains to be seen, and that's something we will assess. There's only 4 cohorts in this study, so it's something that we think we'll get to pretty quickly as we enroll it. With respect to data disclosures, we're not going to guide to any particular time or date. I do think that there's two elements of information to bear in mind. One is, this is a first-of-its-kind assessment where we're doing systemic dosing of CRISPR-Cas9 systemically. That's first time it's been done.
Editing of any kind, I think, will be a very important insight that suggests that this is a viable approach for patients in many different domains. Then there's the optimal biological dose, which, when we get to that in the course of the study, is obviously the primary objective. As we accumulate information and we look at what it is, and as we make determinations about how interpretable and meaningful it is, we'll make the appropriate disclosures in the appropriate venues. When and where, that remains to be seen. Again, I think this is a small study that should enroll quite quickly. We look forward to getting answers as soon as possible.
Great. Thank you so much.
The next question is from Maury Raycroft from Jefferies. Please go ahead with your question.
Hi. Thanks for taking my question again. Sorry about the technical issues earlier. I had a follow-up question on WT1. Laura, you mentioned you got some feedback from-
Sorry. We'll have to follow up. Maybe they can check back with you, sir. At this time, this concludes our question and answer session. I would like to turn the conference back over to Lina for any closing remarks.
Thanks, operator, and thank you all for joining today's call and for your continued interest and support. We look forward to updating you on our progress. I hope everyone has a nice day.
Conference has now concluded. Thank you for attending today's presentation. You may now disconnect.