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. [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, 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 for 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.

Importantly, our full spectrum strategy is generate 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 knockout disease causing genes or precisely insert genes to produce normal proteins.

For cancers, we utilize our ex vivo approach to create engineered self therapies. Our T cell receptor or TCR based approach is designed to produce a homogeneous robust cell product that epitomizes the patient's own natural immune system to eliminate cancer cells.

In October, we received approval from the United Kingdom'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 are 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. Both programs continue to progress through IND enabling studies and 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 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 Therapeutic Society.

Finally, we celebrated the achievement of our scientific cofounder, 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 launch 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 is my pleasure to provide an update on our IND 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 a source of circulating wild-type and [indiscernible] TTR protein. Our robust preclinical data showing deep and long lasting TTR eviction support NTLA-2001's potential to be a one on that treatment to halt and reverse disease progression.

As John noted, we are now authorized to initiate our Phase 1 study with UK's clearance of our CDA [ph] 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 a most efficient path to defining the optimal dose. 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 1 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 1 will be a single ascending dose study with up to 4 cohorts following a traditional 3+3 design aimed at identifying the optimal biologically active dose.

Then we plan to quickly move into Part 2, which will be a single dose expression cohort of 8 additional patients to further [indiscernible] PDP of NTLA-2001, including an initial assessment on clinical measures of neuropathy and neurologic functions 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 knockout. Of note, we are not disclosing dose levels at this point. We anticipate biological activity at all dose levels including the starting dose.

We are 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 are 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 [indiscernible] patients is significant and there is opportunity for additional clinical efficacy.

Today we are 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.

This translates our patients these reductions for up to approximately 90% and 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 are using CRISPR/Cas9 as a tool to create engineers of therapies.

We employ a TCR based approach enabled by our groundbreaking self editing and engineering process to harness the whole strategic [ph] potential of arming T cells toward that 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 improve potency and function. Our technology enables multiplicity of edits with high efficiency, cell view viability and the desired memory phenotype.

Importantly, the favorable cell product profile is achieved without introduction of translocations and in a shorter window of time as compared with the standard T cell engineering process.

Essentially, we are unlocking the potential to develop next generation T cell products with characteristics that should translate in traditional benefit for patients such as reduced [indiscernible] times and improved safety and efficacy.

With our lead TCR T cell therapy development candidate, NTLA-5001 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 form 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-5001 in the first half of 2021.

Moving on to our research efforts and platform, our team has made great strides broadening the in vivo and ex vivo applications of genome editing, utilizing our modular approach and 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 a murine model to evaluate the ability of the genome edits under conditions of rapid hepatocyte proliferation.

After resection of two-thirds of the liver, and subsequent full liver regeneration, the genome edits and close bonding 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 further approach to assessing durability built on the deep and permanent protein reduction that we have seen in our year long NHP in support of NTLA-2001 and NTLA-2002. 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 progress in 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 and good morning. In short, Intellia is well positioned for our upcoming milestones. Our cash, cash equivalents, and marketable securities were $407.9 million as of September 30, 2020, compared to $284.5 million as of December 31, 2019.

The increase was mainly driven by net proceeds of $122.4 million from external financing activities and $100 million from the expanded Regeneron Corporation, 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.

And now, 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 1 study of NTLA-2001 and 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 have rapidly progressed NTLA-5001 and NTLA-2002 toward the clinic and we remain on track to submit an IND or equivalent regulatory application for each program next year.

Further, 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 are focused on retaining the strong momentum across our pipeline and platform as we head into the final months of 2020 and beyond. We will now open the line to any questions.

Operator?.

[Operator Instructions] The first question comes from Salveen Richter of Goldman Sachs. Please go ahead..

Good morning. I'm 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 kind of 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? And on the latter, just curious about progress in other geographies in addition to starting a U.S. trial? Thank you..

Good 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, very clean background to get to some clean, some very clear insights with dose and safety.

And 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. But 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 who are somewhat more complicated.

So with that in hand, which I hope will follow very, very quickly, on the heels of this Phase I study or potentially even overlapping, we're thinking through the best way to begin, the idea would then be to go ideally globally, focused very much on cardiomyopathy, which we think is where the greatest unmet need is, and then of course, bring polyneuropathy along with it.

So 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. Now, 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. So we will be in other geographies.

And of course, that is the foundation to go into subsequent work as well. So like going on and fingers crossed, we'll be able to progress this very, very quickly..

Thank you. And, John, if I could followup, 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 the cell gene editing?.

I wouldn't characterize it as so much difference as perhaps depending on how one is proceeding and the particular disease indication, the rate at which you can progress.

And 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 environment in different geographies around the world and then make a decision in terms of how we can get the best information the most efficiently. So we'll definitely be back in the US.

I mean, it is - that is an objective to come here very, very quickly. But for the purposes of getting up and running and collecting this critical information quickly, we made the judgment that the UK and related geographies would be more efficient..

Thank you..

Okay..

The next question comes from Maury Raycroft of Jefferies. Please go ahead..

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Maury, I don't know if you could hear me, I can't hear you. It’s - you might want to try another connection..

[Indiscernible].

No, I want to hear you, but I can't..

[Indiscernible].

I'm sorry, it's not….

The next question comes from Madhu Kumar of Baird. Please go ahead..

Yes, thanks for taking our questions. So I think our first one is kind of really just something that Salveen asked.

How do you think about assessment of cardiomyopathy kind of clinical parameters in the Phase 1/2 considering that patients in the, you said just now, John, you will allow patients who have a mixed polyneuropathy, cardiomyopathy phenotype into the dose escalation?.

Yes, I think it's important. First of all, thank you, Madhu and it's nice to get a question from you this morning. Remember, in our Phase 1 study, there's limited opportunity to get many detailed physical and physiological assessments of these patients.

It's a 3+3 design 4 cohorts, and then we expand only get to what we think is the optimal biological dose. So what we would get would be descriptive sorts of assessments. The primary readout is safety in TTR. What we're looking for is the effect on circling 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 getting enrollment, you get a lot of mixed phenotype patients, could you amend the protocol to include say blood test for NT-proBNP is 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.

But 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, so called part two of the study and remember that the patients with cardiomyopathy will be not severe patients at all, very, very, out [indiscernible] the patients coming into the study are primarily suffering from the symptomatology of polyneuropathy.

And as you know, I mean, these phenotypes overlap to a large degree. So 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 and again, TTR level reductions is the primary read out..

Okay, and then one last question about kind of the ex vivo programs, both the internal ones and your partnered program and in sickle cell with Novartis? How are you guys thinking about CMC considerations? When we look at the travails that it appears, one of your competitors is having regarding CMC, in sickle cell disease? And like, how do you plan for that and how are you kind of like envisioning both how are you different from say, non-gene editing more kind of like viral approaches, and how you need to kind of plan ahead for setting up a good CMC test for your either cancer cell therapies or kind of 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 responsibility that they've taken on and they can speak for their own progress. And I think that they're very, 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 and at ASH we talked a little bit about that in in vivo settings, and we're well on our way to transferring that to a third party manufacturer who is highly experienced in this space and that is all proceeding very, very well.

So currently, we think we're in excellent shape to meet our guidance and to begin, move this into the clinic next year. So I think the entire process has been going quite well..

Awesome. 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, very carefully at the benchmarks that have been set by people who've been in this space, who have validated levels of TTR reduction with clinical outcomes. And certainly [indiscernible] done a nice job of paving the way for that. So our goal is to at least match that and ideally surpass that.

We go and look at our preclinical data, and we see very, very extensive reductions that we think are very, very promising, assuming that they're translatable in the clinic. And that's what this work that we're beginning now has started to show. With respect to their ability and knowing that it is, in fact, won and done.

There's two lines of evidence, obviously, the single best line of evidence just to watch a patient over time. And, that means you've got to have time, but there are the ways to approach that, which we've done pre-clinically with - on our model systems.

And 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 of which cells divide. So 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.

And what grows back is what was there in the first place. So as far as we can tell, with every single line of evidence that we've explored, passive waiting and animals of different species accelerated turnover studies as well. There's no loss of effect. So to be frank, I'll be quite surprised if the effect is lost in here..

All right, excellent. Thanks 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, and we saw at the ASH abstract looking very impressive top line data, just wondering is that the program or that data was that the clinical assets that NTLA-5001 that you are going, moving to clinic, and then also will you try to file for IND or CTA.

And my second question is regarding the ATTR program, wondering if you can remind us, how the dose escalation work, what will make you determined to reach like, say, complete all the full cohorts or are there any stopping rules, say if you reach ATTR knock down already 80% will you stop at the third dose or second dose?.

Hey Gena, this is Glenn. John is having a little bit of audio problem with his headphone. I'm going to ask, so thank you for your questions. I think I'm going to have Laura, our CSO jump in and address some of those. So I apologize. We're just having a little bit of audio function, but Laura can address I think those questions. Thank you..

Yes. So, 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 rate I will be presenting at ASH. So, that is in fact with the WT1 TCR and the process that we're interested in, that's NTLA-5001 that we had put into the clinic.

So, there were 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 blasts from - primary blasts from AML patients, as well as a very aggressive AML model.

And important there another piece of data is that, there we demonstrated that there is no signs of graph versus OCCs in this model reflecting the nature of the WT1, TCR that was sourced from normal people.

Sorry, what were the other questions?.

Oh so, the question, will you file IND or CTA for this program? And then, the other question is the ATTR program, how do you the, dose escalation works? You know, do you have a bar for like, hitting? I'm just making up numbers, like say 80% knocked down when you stop further dose escalation or is that irrelevant to team knocked down more? Is it to test the efficacy or the test and the safety?.

Yes. Okay, so with 5001 as we're going for ATTR, we're pursuing a global clinical development strategy. So we have engaged with multiple regulatory agencies in U.S. and in Europe. And, we're incorporating that regulatory guidance, as we design our clinical, firstly, human clinical trial.

With regards to TTR our intention is to move quickly through the four cohorts in the NTLA-2001 Phase 1 trial. We have used the data from our preclinical work in consultation with regulatory agencies to select the starting doses. Right? And try to move fairly quickly through the dose escalation.

As John was saying before, the goal is to meet and surpass the benchmarks that had been established by others who, maybe TTR with the RNA silencer compounds, and I believe that John is back..

Yes, thank you. I didn't want to interrupt you, he has reconnected..

I am back. I'm sorry. My connection died for some reason. Sorry..

So, Gena do you like have all your questions?.

Yes, 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 as a different attitudes across different countries in terms of willingness to approve something like this that is systemically delivered, genome editing program and what key piece of evidence do you think as soon as any concerns about off history targeting, particularly of the germ [ph] cells, which I think could be important? And then following up on the ATTR program? Are you -- your initial patients that you're hoping to enroll will they have failed antisense oligos? And if so, what gives you the confidence that this approach could work in those patients? Thank you..

I hope I've got all that, but thanks for the question. First, to the last part, for patients coming into the first part of the study, they will not have preached -- receive prior treatment with other therapies, that are gene silencers route and nucleotide.

So, this notion of if they hadn't responded in that setting, would that somehow affect this trial or not? We're excluding those patients. So you have to have never received treatment in the first place.

With respect to attitudes, if I understood the question, what are many requirements?.

Yes..

Yes, no, no. In fact, we're saying that patients cannot have been, cannot have received prior treatment with gene silencers. So there is no -- we are not asking that patients come into the study based on , which means silencers.

So there's no, we're not asking that patients come into the study based on a failure with a prior therapy, so just to be clear..

Yep..

Yes, so 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 from a standpoint of unmet need. And, well, 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 has been written here. Curative therapy or improved levels of reduction that truly halt progression and perhaps lead to reversal of the progression of the disease is what doctors and patients are looking for.

And so, 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 any would be the case for any drug. And that's the information that we bring to them as we plan this program.

So we think we're in great shape to go and study this and patients and doctors are quite enthusiastic about it. In terms of tissue off target, I think that's the question, that's all part of a preclinical assessment, where we'd look at, where the LNPs go in the first place.

And 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..

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. So 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 or manufacturing process or characterizing the cell products that need to get completed before the IND submission?.

I would characterize it this way. We are very much on track to meet the guidances we've offered. The work is 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 is a lot in it.

It's an engineered cell and there is insertions and knockouts and so on and so forth. And 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.

And 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 and we think we're in excellent shape to go and meet those requirements..

All right, great, and I do have a follow up. So I know that 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 validated clinical data from RNA knocked down 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.

But 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 Murine models.

And 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. So, 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 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 with tafamidis switchers and then also knockdown switchers potentially in the dose expansion part.

And relatedly, just curious what percent of the sort of diagnosed addressable market by the time you launch would you anticipate already being on treatment with tafamidis or knock down therapy?.

Yes, so for the first part of your question, tafamidis as you know, has a different mechanism of action that's a stabilizer as opposed to an agent that lowers TTR levels. So, 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.

And so 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 1 study.

So it's a different kind of situation from the Gene silencers, as you see. It's -- the reason we include them is not necessarily to get experience in tafamidis switchers, although I guess you could say that that will be maybe a happy outcome of this particular study.

It really just makes it available, 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.

So I think that's 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. So first, on the TTR program, thanks for the clarity you provided for the long term development path beyond the Phase 1 study. Just curious, the ongoing pivotal trials of RNA therapeutics in ATTR cardiomyopathy have the 600 to 700 patients in the treatment arms.

So what trial size do you think would be required for a genome editing trial? I guess 600 to 700 patients would be unprecedented for any gene therapy or genome editing trial.

So I would like to hear your thoughts there? And then on the Phase 1 study, as you begin to dose patients, is there a requirement for a waiting period between patients and also between cohorts? And lastly, in the Phase 2 portion, I'm sorry, in the dose expansion portion of the Phase 1 trial, do you plan to look at liver biopsy for editing efficiency or tissue biopsy to look at TTR amyloid adherence 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 and 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.

So the most important direct measure is levels of circulating TTR and that is a really good surrogate for the extensive editing. And 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. And 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 will be determined by the endpoints that we're measuring of 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 extensive and effect that's measured physically or clinically and related to a particular TTR reduction and that's what will be taken into consideration as we size the study to measure a particular outcome.

And 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. And finally, in this 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.

But I think you should think of this as a pretty standard 3+3 design where patients get fill cohorts, there's an assessment and then you watch the next cohort and we've 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 W1 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 thing in patients with a certain level of Leukemia blasts, but perhaps not too much, too high leukemia blast burden.

And 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.

So David, do you want to talk about our initial patient population and how that relates to some of the prior work?.

Yes, thanks, John. So the patients in this study will be patients who generally had prior therapy. So they have had their disease come back after prior therapy, so very similar to other studies in AML.

But as you mentioned, we are looking for patients who might have a lower to or last burden or as 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 this we're targeting an antigen, which is not highly present on normal tissue.

So we don't expect to see the type of severe toxicity that's been seen in the AML studies with a one CD123 or 33..

Got it? Just maybe one more curious question, in terms of the WTI TCR product, because it's a TCR, and you've also mentioned the antigen is not highly abundant in the antibody. Does that have implications in persistence and TCR memory after that, also, because it's a TCR T-cell, which looks much like a T cell as opposed to a CAR T.

So, maybe perhaps some implication on the memory formation, yes. Thanks..

David, if you want to keep comment from going through….

Yes, so these patients, as you know, will have blast. So obviously, the initial antigen is due to the tumor itself. Of course, if you completely eradicate tumor, which is the goal of our studies, there will be left antigen present, but the thinking is that often these cells do persist T cells can have a long life.

And the advantage of that is if the, if the blast 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 [indiscernible] for Jay. Thanks for taking our question. And maybe just a quick one on 2002, so we are wondering if you are planning to maybe follow us, did not have 2001 that's not in the trial in euro, and then move back to us or maybe you can start the trial directly in the U.S.? Thank you..

Jay, thanks for the question. We learn a lot from what we do with TTR. And that certainly influences our subsequent in vivo programs. We're still laying out exactly what our regulatory strategy is that we've. And we've looked very, very carefully around the world and U.S. as well as Europe. And we've seen the advantages of the different geographies.

So as we have more details on that final selection, we'll share them with you. But I will say this, we've certainly 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..

The next question comes from Roger [indiscernible] of Credit Suisse. Please go ahead..

Hi, everyone, and good morning as Roger on for Marty, thanks for your time. So I've 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? And then 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. But 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.

But 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 de escalate. Anything, you'll start somewhere where you think you can have efficacy, and then escalate to something that is a preferred house or call it the optimal biological, though.

So that's the logic that applies in this program. And as, when the comments that we made, this is the first of its kind in, 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.

So 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 four 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. I mean, that's first time it's been done.

And editing of any kind, I think will be a very, very important insight that suggests that this is a viable approach for patients in many different domains. And then there's the optimal biological dose, which when we'll get to that in the of course the study is obviously the primary objective.

So 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, but when and where that remains to be seen. But again, I think this is a small study that should enroll quite quickly.

So we look forward to getting answers as soon as possible..

Great, thank you so much..

And the next question is from Maury Raycroft from Jefferies. Please go ahead with your question..

Hi, thanks for taking the question. [Indiscernible].

May be we 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 Lena 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..

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