Intellia Therapeutics Inc (NTLA) 2018 Q3 法說會逐字稿

Good morning. My name is Mary, and I will be your conference operator today. At this time, I would like to welcome everyone to the Intellia Therapeutics Third Quarter 2018 Earnings and Corporate Developments Conference Call. Today's conference is being recorded. (Operator Instructions) Thank you. Miss Lindsey Trickett, you may begin your conference.

Good morning, and thank you for joining us today for Intellia's conference call to discuss our third quarter 2018 earnings and corporate developments. I'm Lindsey Trickett, Intellia's Head of Investor Relations.

For those of you on the phone, there's a presentation available for download at intelliatx.com under the Events and Presentations section so that you can follow along with us today.

Before we get started, on Slide 2, you'll find our forward-looking statements disclaimer. I'd like to remind everyone that during our presentation and Q&A, we may make certain forward-looking statements and ask that you refer to our SEC filings available at SEC.gov for a discussion of potential risks and uncertainties. All information in this presentation is current as of today, and Intellia undertakes no duty to update this information unless required by law.

Moving to Slide 3. Joining me on today's call from Intellia are John Leonard, President and Chief Executive Officer; Andrew Schiermeier, Executive Vice President of Corporate Strategy and Development and Interim Head of Research; Glenn Goddard, our newly announced Executive Vice President and CFO; and John Hayes, our Controller.

Our primary speakers for today will be John Leonard and John Hayes, but we will all be available for questions during the Q&A.

Moving to Slide 4. We'll start the call with an update on our leadership team, an update on the in vivo and ex vivo progress we're making in R&D and a review of our financials.

On Slide 5, I'd like to introduce you to 2 new members of the leadership team at Intellia. Glenn Goddard recently joined us as our Chief Financial Officer, and Dr. Jesse Goodman recently joined our Board of Directors. We'd like to extend a warm welcome to Glenn and Jesse from the entire Intellia team.

Now I'll turn it over to John Leonard for an R&D update.

Thanks, Lindsey, and thank you all for joining us today. I'm John Leonard, Intellia's CEO. I'll start today with Slide 7, serving as a reminder of our long-term strategy. We are building a full-spectrum genome editing company with balanced efforts across both our in vivo and ex vivo pipelines. We're building modular platforms to create long-term value and that will achieve our mission to develop curative genome editing treatments that can positively transform the lives of patients living with severe and life-threatening diseases.

Note that with our in vivo approach, we first emphasize lipid nanoparticle or LNP-based delivery to the liver with the most basic edit, a knockout. That work also serves as the basis for more complex edits such as gene insertion required to address other conditions and diseases of the liver.

While the liver is the first tissue that we're pursuing with our LNP platform, our scientists are additionally working in parallel to apply LNP delivery to other tissue types. The right side of this slide depicts how we are taking a similar stepwise approach to ex vivo engineered cell therapy. We've chosen a T cell receptor based approach and targeted an important epitope of the Wilms' Tumor 1 or WT1 antigen that plays a significant role in the blood-based cancer, acute myeloid leukemia.

Moving beyond the limitations that come with autologous cell therapy is the key to success, and fundamental to our approach is building an allogeneic T cell platform that goes beyond major histocompatibility complex 1 and 2 knockouts. This work promises to address the manufacturing limitations that typify autologous approaches and can serve as the basis for a broad T cell platform for Intellia.

Another aspect of our approach is enhancing T cell's ability to enter solid tumors, which may rely on additional edits aimed at overcoming a solid tumor's suppressive microenvironment. Because WT1 also happens to play an important role in many solid tumors, we believe this TCR target has broad applicability and is an attractive way to move beyond blood-based malignancies such as AML.

Turning to Slide 8. I want to share with you nonhuman primate data that we are very excited about that we have not previously presented. In the yellow column, you can see the results of our initial nonhuman primate study that we shared exactly 1 year ago today. And in the middle column in teal, you will see the data that we shared recently at the European Society for Gene & Cell Therapy (sic) [European Society of Gene & Cell Therapy] meeting where we showed that on average with our first generation of formulation, we achieved 34% liver editing with a corresponding TTR protein knockdown of about 60% from baseline following a single IV dose. A 60% decrease from baseline is the level that other treatment approaches have shown to be therapeutically relevant. These data we're generating in collaboration with our partner, Regeneron.

We've worked hard to understand how to enhance the performance of our proprietary LNP delivery system and specifically to identify improvements in each of the components of our first generation formulation. We've learned much from our efforts as illustrated in the graph on the right side of this slide. The red column depicts new levels of in vivo hepatocyte editing in nonhuman primates that we achieved with various recent modifications to the components of our LNP system and shows a substantial performance improvement beyond that of our first generation formulation.

We believe that we have set a new bar for in vivo editing in nonhuman primates. With a single dose of CRISPR/Cas9 delivered by our proprietary modular LNP platform, we've now seen liver editing rates up to 78% with a corresponding TTR protein knockdown of up to 96%. It is important to note that this graph shows editing results with the same range of doses tested in earlier results shown in the first 2 bars.

Modifications to the components of our in vivo delivery formulations yielded a performance improvement. But of particular interest to us are the highest data points. These were achieved with a change to a single component of the LNP cargo and followed administration of the lower of the 2 tested doses which was well tolerated. We believe this experiment shows potential for a product profile that is significantly improved in both liver editing rates and TTR knockdown relative to our first generation development candidate.

On Slide 9, you can see the high correlation between liver editing and TTR protein knockdown that we have seen with nonhuman primates. One important relationship that guides our thinking is captured in the beige-colored box in the lower right. Here, we show that an editing level of about 35% to 40% is sufficient to yield TTR protein level reductions associated with therapeutic success in patients. The points illustrated here reflect previously reported data from our lead candidate as well as from our recent in vivo delivery improvements always administered as a single dose. But it is important to note, the levels of editing with the new delivery improvements we made, shown as red dots, in most cases fell into the beige-colored box also after a single dose. This indicates to us that this enhanced approach performs at a higher level than our previous formulation.

In light of these data, Intellia will pursue confirmatory studies with the goal of integrating enhanced cargo components into our lead development candidate. As a result of these confirmatory activities to investigate delivery improvements that could potentially result in a materially improved product profile, we're now targeting an IND submission for 2020, rather than by the end of 2019 as previously communicated.

We understand that delaying an IND submission isn't the fastest way to clinic. But I'm convinced it's the right decision. We believe that LNP delivery of CRISPR/Cas9 has significant advantages over other approaches, and it is our objective to develop the most effective formulation that we can. We are developing medicines that are meant to be significant advances for patients, and we're building a modular delivery platform with broad applicability in many diseases. Having well-designed high-performing LNPs with optimized cargo is the way to accomplish that.

The potential significant impact of these enhancements extends beyond the TTR program. The modifications here apply to LNPs in general and should have immediate applicability to our follow-on in vivo programs, which we believe should result in improved product profiles in these programs as well.

Moving on to Slide 10. Intellia also continues to make major strides consistent with our strategy in moving beyond gene knockouts to complex edits. Complex edits are edits that introduce new genes or genetic material at the CRISPR cut site. This is an important next step in our in vivo work as we continue our focus on the liver, but our learnings here are also applicable to our ex vivo strategy, where complex editing capabilities will commit a wide range of engineered cell therapies.

Let's turn to Slide 11 for our most -- for our first demonstration of CRISPR-mediated insertion that we presented at ESGCT just a couple of weeks ago. Here, we illustrate how we carry out a gene insertion using a hybrid system that we've developed. This system uses LNPs to deliver CRISPR/Cas9 with guide RNA in our standard format and combines that with adeno-associated virus or AAV as a delivery approach for our proprietary bidirectional donor DNA template. This hybrid approach maintains the benefits of transient delivery of CRISPR/Cas9 and combines it with a very effective way to deliver a DNA copy of a gene intended for insertion. Note that in this case, the template carries FIX, the gene that encodes Factor IX, which is the clotting factor defective in patients with hemophilia B. The Factor IX work is done with our partner, Regeneron.

On Slide 12, we show some of the recently presented in vivo Factor IX data from the Regeneron collaboration. This work targets insertion of the FIX gene into the albumen locus in mouse hepatocytes. The albumin locus is an attractive target for gene insertion because it is a very actively expressed gene in the liver. The image on the left depicts individual hepatocytes expressing Factor IX RNA. Note on the left that when template-containing AAV is provided without the addition of the LNP, hepatocytes do not express Factor IX. On the right side of the panel, we see the result when an LNP carrying CRISPR/Cas9 that enables gene insertion is combined with AAV delivering the FIX DNA template.

Note the contrast. Over 50% of the cells are expressing Factor IX RNA after treatment with a hybrid LNP-AAV approach.

On the right side of the slide, we show there is a direct correlation between the number of expressing cells and the level of Factor IX present in the blood of these mice. It's important to note that the levels of Factor IX produced in these experiments are levels that would be expected to have a therapeutic effect achieved if achieved in a human with hemophilia B.

So together with Regeneron, we have shown that in mice, we can insert the FIX gene into the liver. We can insert it into a precise location. We can identify sites that modulate expression of the gene, and we can produce protein at levels that are therapeutic if translated to humans. Furthermore, we observed that varying either the LNP or AAV dose modulate levels of Factor IX expression.

Let's turn Slide 13. We're applying the learnings from the FIX insertion work to other programs. On this slide, you see data we recently presented in our wholly-owned in vivo program for alpha-1 antitrypsin deficiency. In this condition, patients harbor a mutation that leads to low circulating levels of the protein alpha-1 antitrypsin. In the work shown here, we insert the SERPINA1 gene, the gene that encodes the deficient protein. We target the albumin locus of mice with the same hybrid LNP-AAV approach that we just discussed. The results are similar to what we saw with Factor IX. The graph on the right shows that AAV carrying the alpha-1 gene alone does not produce protein. But when both LNP and AAV are dosed together, expression of corrected alpha-1 antitrypsin protein is achieved in mice in the range of 2,000 to 3,000 micrograms per milliliter.

Note that therapeutic levels in humans are shown by the gray shading and range from 1,000 to well over 3,000 micrograms per milliliter of blood. The hybrid LNP-AAV system produce levels that in humans should be sufficient to protect against the loss of pulmonary capacity, the most frequent consequence of this disease. These protein levels remain stable throughout the 5 weeks of the study duration. Once again, this program is wholly-owned by Intellia.

Moving to Slide 14. We show data that speaks to the generalizability of the hybrid approach for gene insertion. We studied expression levels of the 2 different transgenes when inserted at the same site. The alpha-1 protein levels are on the x-axis and for the Factor IX transgene, protein levels are found on the y-axis. Because there is a good correlation between Factor IX expression and alpha-1 antitrypsin expression for any given insertion site, this suggests that our proprietary hybrid LNP-AAV delivery platform may work independently of the transgene being inserted. And most importantly, the particular guide site is an important determinant of expression levels.

Transitioning now to the ex vivo pipeline on Slide 15. I want to remind you that we think about cell therapies as an engineering problem, where the next generation of advancements will almost certainly require a strong command and application of multiplex gene editing in order to arrive at dramatically improved efficacy and functionality. Our strategy is to start with transgenic T cell receptors and build an engineered cell therapy platform that will be efficacious not only in hematological cancers but also on solid tumors. While we intend to produce multiple development candidates along the way, our ultimate goal is very ambitious: to create truly allogeneic cells that can be derived from a renewable cell bank, pre-edited and then customized on a patient by patient basis.

Slide 16 highlights one of the key challenges associated with conventional approach to the knock-in of transgenic TCRs. This is typically done with lentivirus constructs that lead to integration of the transgenic TCR at random sites in transduced T cells. That approach has limitations. In particular, if the endogenous TCR has not already been fully eliminated, the new transgenic TCR may combine with the endogenous TCR to produce hybrid molecules and may then lead to graft-versus-host reactions.

Our approach on the right demonstrates that we not only knock out the expression of the endogenous TCR locus, but we are then able, by virtue of the specificity of CRISPR/Cas9, to knock-in the transgenic TCR into the same locus and utilize the existing physiological promoters and cell circuitry.

Introducing the transgenic TCR into the original TCR locus provides both a modular approach as well as reduces the risk inherent to the nonspecific, lentivirus approach.

Slide 17 simply highlights that when it comes to knocking out these existing TCR genes, we're able to do so at rates near 100%. Our preliminary work, conducted in collaboration with our academic partner, Ospedale San Raffaele, also shows that insertion of a WT1-specific transgenic TCR in cells having undergone a double knockout of both the alpha and beta chains achieved around 98% efficiency in the CD8-positive T cells. We presented elsewhere that these T cells are functional and have high activity against the WT1 epitope. This work serves as the basis for our AML program. And as we said, it will have broad applicability to solid tumors as well. We continue to progress in vitro and in vivo studies in the WT1 program and look forward to sharing additional updates as they're available.

To wrap up the R&D update on Slide 18, I'd like to highlight the accomplishments we've achieved in 2018 today. We've continued to progress our ATTR program, including today's exciting new levels of editing and protein knockdown based on enhancements to the LNP cargo.

We also presented data on delivery as well as editing in the central nervous system. We showed data in more complex types of edits, most recently with FIX in collaboration with Regeneron, and also with SERPINA1, our wholly-owned alpha-1 antitrypsin deficiency program.

On the ex vivo pipeline, we identified our first target, WT1 for AML, and showed early data on our engineered T cells. We continue to build our platform, including next-generation sequencing and bioinformatics capabilities as well as protein engineering. We also strengthened our intellectual property position through the granting of additional patents. And as we mentioned at the beginning of the call, we welcome Dr. Jesse Goodman, a new board member, and Glenn Goddard, our new CFO.

And with that, I'll turn it over to John Hayes to provide you with an overview of our third quarter financials.

Thank you, John, and hello, everyone. I'm John Hayes, Intellia's Controller.

As you can see on Slide 20, Intellia is in a very strong financial position today. Our cash and cash equivalents as of September 30, 2018, were $293.2 million compared to $340.7 million as of December 31, 2017. The decrease was primarily driven by cash expenditures from operating expenses of $78.1 million, which was offset in part by $16.6 million we received in funding from our collaborators, $10.1 million related to employee equity issuances and $3.8 million of investment income.

Our collaboration revenue is $7.4 million for the third quarter of 2018 compared to $7.3 million during the same quarter of 2017. As a reminder, our collaboration revenue is related to our partnership agreements with Novartis and Regeneron.

Our R&D expenses increased to $23.2 million for the quarter as we continued to expand both our in vivo and ex vivo platform development and progress our pipeline programs. Our G&A expenses increased $8.3 million for the quarter, which was largely related to increased personnel-related expenses and other administrative expenses to support our growing research and development operations.

Today, we are also reiterating our previous guidance that we expect our current cash balance to fund our current operating plan through mid-2020.

With that, I will turn the call back over to Lindsey.

Thanks, John, and thanks, everyone, for your participation today. We look forward to continuing to share our progress in the upcoming months. With that, I'll turn it over to the operator to manage the call lines for questions.

(Operator Instructions) We will take our first question from Maury Raycroft from Jefferies.

Welcome to Glenn and Jesse. The first question is for the hybrid LNP-AAV approach. I'm just wondering how you envisioned incorporating that into the development plans? And would you bridge the technology into your initial ATTR program? Or is it designed for specific applications or disease indications?

Thanks for the question, Maury. It's John. The hybrid approach is focused on repairs and insertion. And our expectation is that the TTR program is best addressed by a knockout. So I don't see that hybrid approach really having applicability for that. But as you can imagine, there is a long list of potential insertion targets to pursue. So we're very excited about what we've shown with the 2 targets that we discussed today. And we think that there's lots of places where we can take it in vivo, and I want to make sure that you recognize that the approach of insertion in general, whether it's with the hybrid approach or not, has applicability to the ex vivo side as well. So we think this is a very significant move forward along our strategic plan.

Got it. Okay. And for the bar graph figure on Slide 8. Just to clarify, so that's the same dose for each of the time points. And I'm wondering if you could specify whether the change that you've made over time is more heavily weighted toward the LNP, the guide or the Cas9. And I guess, what requires the most optimization there?

Yes, I wouldn't know how to score it more heavily one way or the other. We've been coming down a systematic path of looking at the various components, whether it's the lipid aspects of the LNP, and that's the constituents and how you put them together, or the individual cargo elements contained within the LNP. So each of those have been tested and are the result of many, many experiments. So shown on the red are elements that address each of those individual aspects. The doses are the same doses, I emphasize plural, a low and a high that we did way back in October, and those same doses are shown in the red graph here. Clearly, we're getting a lot more out of those than we did a year ago.

Okay. And last question is just on the IND time line and if you can provide more granularity on whether you're thinking first half of 2020 or second half.

My approach is always to under promise and over deliver, Maury. And there are very quick ways to get to an IND, and there are longer ways. And what our objective right now is to have the best-performing LNP, and with that guidance we're putting out, I'm very comfortable that we will get the work done on time.

We will now take our next question from Gena Wang from Barclays.

I wanted to -- first, congratulations on the launch of the progress in R&D part. I know, actually for the investors, I think one pushback is always when the company can enter.

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I know that quite some other competitors, already in clinic -- or ready to go into clinical development this year. So just wondering, I'd follow Maury's question regarding the R&D filing. So can you just walk us through the steps you need to do before R&D filing for the ATTR program?

Yes, thanks, Gena. It's John again. It's interesting when you say competitors. I'm not sure I know how you think about it. I'll tell you how I think about it. We take the view that we want to have a format that is the best possible agent that we can bring forward for any particular condition that we're going after. And I don't measure progress by first IND date. I measure progress by the best medicine that we can bring to the patients. And that's the approach here. So I don't want it to escape people's attention that the progress we've made here is broadly applicable across our pipeline and I think enhances the product profile of probably virtually everything that we are working on and secondly, I think deals with optimizations that we might have had to play out for some of those individual targets. But to the heart of your question, in terms of what we need to do, as I said in my remarks, we want to extend the data here, and that's done in very short order. We know exactly what we need to do in terms of building out the data set. And some of the approach is deciding on what we choose to do here given that there's a variety of ways to bring this all together. Some of the steps can be done very, very quickly. It's really just a matter of swapping in versus swapping out and then going back to -- directly to tox studies. That's why I'm comfortable saying that in 2020, I fully expect to have an IND, and I just don't want to tell you which month. But it's my objective to make that happen as quickly as possible.

Okay, that's very helpful. And I do want to comment, in vivo approach is certainly much, much, much challenging than ex vivo approaches. And I certainly acknowledge the data you've provided at the ESGCT certainly, a lot of the progress. My next question is regarding the insertion approach. We know that similar concept with other technologies already in Phase I clinical trials. Of course, I do see this is a much improved version. Just wondering if you have any thoughts. What will be the next steps that you need to do before you will be able to enter clinical development?

Yes. Well, one of the programs we're doing in collaboration with Regeneron, so that's a discussion to -- perhaps have with them. But I think both parties, when they look at that data, are very enthusiastic. So we will progress that as quickly as we can. I think the first order of business is to make sure that the work that we're showing here, that we portrayed on Slide 8, is absolutely applicable to the insertion program as well. And we will do that. That's part of this confirmatory work. And with that, then it becomes a matter of capacity to a certain extent. I mean, we want to move very quickly. We're a small organization. But believe me, we will put pedal to the metal as quickly as we can when we believe we have a product that's going to be absolutely compelling in the marketplace. It goes back to the question you asked. It's about competition, which I view as irrespective of platform, irrespective of modality. In the end, doctors and patients don't care about the particular treatment. They care about the results. And we are trying to design a platform here in our approach that will be better than the choices that doctors and patients have. That's the objective.

Thank you. Just one last technical question regarding the hybrid insertion approach. Just wondering if you have thoroughly detected in terms of other forms of insertions in addition to transgene, like for example AAV or other components that's inserted into the genome?

Yes. Gena, I had to get back to you on that in terms of the extent to which that testing has been done. We -- I can tell you this, the transgene is, as I said in my remarks, introduced at the cut sites. It's -- we've demonstrated insertion with the specificity that we think is highly desirable with the program. AAV insertion as at least detected by the presence of protein in the first place doesn't occur. The extent of the sequencing results, which I think is what you're asking me, we can get back to you separately on it.

We will now take our next question from Martin Auster from Credit Suisse.

I had a follow-up on Slide 9 where you're showing the range of effect, the percent -- I think the percent of TTR knockdown in the -- with the new construct. It looks like you've got about between kind of a 20% and 88% gene editing rate with, I believe, that's all from a single dose. Was curious, are you satisfied with that degree of variability? Are you -- are there methods you can employ to kind of work to further narrow that and ensure kind of a higher portion of subjects achieving a therapeutically relevant range here?

Thanks, Martin. It's -- the red dots here correspond to changes in different components, so not every single red dot is identical. So that's one way of approaching the variability. I'm showing data from only a single change. But this is portrayed here, that demonstrate that there's multiple levers for us to pull to get to what in our hands is substantially different from the effects that we've been talking about up until now. Variability, I think, is inherent to populations in general. But it is something in the next few months that we'd like to attempt to reduce. I don't think we're ever going to get to the point, which is true for any drug, where every dot is superimposable on the others. But it's always preferable to have less variability than more.

Okay. And then just one follow-up. I think since the markets have gone a little choppier in October, we've been getting increasing calls from investors kind of really focusing on balance sheets. You guys are actually in a very strong position now with a good capital position. But I'm curious how you're thinking long term because it is going to be a period of time before you have approved products and kind of sustainable revenue from product sales. How you're thinking about forming new strategic partnerships and kind of what areas you kind of consider to be most attractive to license or to kind of work with a partner on.

Yes, thanks for the question. I'd first point out that the situation hasn't changed for us. I mean, in terms of the resources that we have and where we think they'll take us, that's really unaffected by this. And we feel very confident we'll be able to complete the work and make the headway that we need to. Always fundamental to our work has been having it broad-based. This is this full-spectrum notion that we had. That as you see here today, we think there's any number of projects that we have that have attraction to a potential partner should we choose to go that route. So rather than doing one thing, some people would like us to do that, I think having a choice of things that we can do very well and differentiate ourselves on is the way to proceed. So whether it's the insertion, whether it's via knockout, whether it's via the modular approach on the ex vivo side, if we need partners, I'm confident we will have many to choose from.

We will now take our next question from Joseph Schwartz from Leerink Partners.

This is Dae Gon dialing in for Joe. So a couple from me. I guess I'll just dive right in since a lot of the questions have been answered. So if we look at just the TTR program specifically, I was just referring back to Dr. Yong Chang's presentation at ESGCT, where in one of the slides, he was highlighting what you've referred to as the previous version, where you knock -- where gene editing was about 34%. But right next to that, he was also showing the TTR protein knockdown of roughly 70% by mean, and that was on day 30. So if we look at the updated enhanced version today, you say protein knockdown mean of 78% but up to 96%. So I'm just wondering what exactly changed here or if I'm missing anything. And just as a follow-on to that, how much of a TTR knockdown is really best for, I guess, patient outcomes since you highlight that greater than 60% knockdown is therapeutic? And I've got a couple of follow-ups.

Yes, so I don't have his presentation in front of me. I'd point out a couple of things. First of all, we're showing day 21 effects here with the most recent data, and this is a system that equilibrates over an even longer period of time. So I would expect to have additional data that we'll be able to talk about as time goes on. The -- how much is the right amount? Well, we are of the belief that more is better. And if -- implicit in your question is, is there a point where it's too much? I have not seen that data. I've not seen anything that makes that case convincingly. I think that when we look at the other agents that are out there, and this is why we've chosen the 60% decrease as our target, when TTR levels fall into that range, patients get better. It's just they do. They don't progress, and that's a very good thing. The extent to which products may differentiate themselves within that box is something I think we're going to learn more about. But our thesis is pretty straightforward, which is this is a protein that's doing bad things. And having less of it is probably desirable. And the likelihood of not making it, I think, is not something that we have to worry about at this point with any of the approaches that are here.

Great. Just 2 more. One with regards to the TTR program. So with the new enhanced version, you can now use low dose with, I guess, a much higher efficacy than what you saw with the previous versions of your components. But any way you can disclose what kind of safety profile or AEs you're seeing with the previous version when you're using the high dose? And that, I'm assuming you've overcome that with the new enhanced version. And my last question is on your LNP-AAV hybrid approach. Just wondering if you could provide some context or some more granularity on the AAV and LNP doses that you used. You've mentioned that you can modulate based on the doses of each component. And what kind of effects you see in terms of antibody emergence or T cell responses to the Factor IX?

Yes. I don't think I'm going to be able to address your antibody question today here. In terms of the doses for the hybrid approach, these are doses within the range of what we've already been working at. And the comment I made about being able to modulate, there's a relationship between varying one or the other element of it, and that can set the degree to which the insertion actually takes place. So it's possible with Factor IX to achieve super therapeutic levels. And one of the things that I think we want to really understand is how to set that so it's just right for the patients who need it. And again, I would emphasize that, that's work that we're doing in collaboration with Regeneron so they will clearly have a lot to say about that. So the point I think you should take away is that we're not stretching to make it work. We have a range of different approaches that at least in these animal models, where it works handily. So we're very excited about that. In terms of safety, we've presented data in the past that shows that when LNPs are provided, you can have a brief response with some cytokines and low level of LNP elevations and that profile hasn't really changed with any of the new material that we're working on here.

We will now take our final question from Steven Seedhouse from Raymond James.

John, I just had a theoretical question, just thinking about the relative editing efficiency and variability of those NHP data sets that you're showing on Slide 8. So for indications that you can use just LNPs without the AAV component like ATTR, do you think it's more desirable once you get into the clinic to start at a low dose and enable redosing to titrate to very precise editing levels? Or would it be preferable to try and get to maybe therapeutic editing levels at the first dose, avoiding having to redose and maybe accepting more of that variability or higher editing than you might even need for a full effect?

Thanks for the question. I don't think that's a theoretical question. Well, I think it's a very practical question, which is when it actually comes to dosing a patient, how should one proceed. I think about it this way. You want to have choices, right? You want to have the capacity to do whatever is right for the patient. So ideally, we would like to have the ability to get to where we need to be in a single dose. And this data, I think, is consistent with that kind of a trajectory. So we're very, very excited about it. But there's a lot of learnings that take place through the course of this clinical program, which is true for all modalities, and the ability to come back and dose again if one starts from a very low dose is another desirable aspect to have. One of the beauties of TTR and one of the primary reasons we chose it is that the effect is readily measured. There's a circulating protein that can be detected. And just as we've shown with our animal data here, you get a pretty good idea of where you are. So instead of flying blindly, one can measure the TTR effect. And in theory, back to your word, set this target exactly to a particular TTR level. So that will emerge, I think, as the program proceeds and as we enter the clinic. Bottom line for patients, if all this plays out the way we think it's headed right now, is that whether it's one or a very brief treatment course, patients will have the ability to be treated and presumably, for a very, very long time, perhaps even the rest of their lives, have the offending agent of their disease reduced to the point where it's not an issue. So that's what we're working on.

Okay, appreciate that. Maybe just a follow-up. Last question. So since you can measure TTR, again, thinking ahead to initial clinical trials, are you expecting that you would want to or need to collect liver biopsies and assess gene editing at the B and A level in your initial clinical studies? And also are you anticipating needing or wanting to immunosuppress patients at least initially in the first ATTR trial?

Thank you. Yes. I don't know why the biopsy would be necessary. It's not fundamental to understanding the therapeutic effect because as I said before, the offending agent is the protein, and there's a correlation between the extent of the edit and the level of protein that's achieved. So not to make light of it, but doing a liver biopsy is almost just spectator sport. It's to know as opposed to judge what is the right regimen for the patient, because again, it's about getting to the TTR protein levels. And again, that's one of the reasons why we chose this particular target. In terms of immunosuppressing patients, that's not been part of our program so far. And if we see reasons to include that, that's fine. We would do that. It's -- one of the appeals of this is that given the short treatment course that we would anticipate, that shouldn't be an issue for a patient as opposed to having an immunosuppression applied every 2 to 3 weeks when a regimen has taken lifelong for patients. So if it is necessary, and right now we don't see indications that it is, we would certainly explore that. But again, I don't think that that's a major issue for us.

The Intellia Therapeutics Third Quarter 2018 Earnings Conference Call is now concluded. Thank you for attending today's meeting and presentation.