Intellia Therapeutics' (NTLA) CEO John Leonard on Q3 2018 Results - Earnings Call Transcript

About: Intellia Therapeutics (NTLA)
by: SA Transcripts

Intellia Therapeutics, Inc. (NASDAQ:NTLA) Q3 2018 Earnings Conference Call October 31, 2018 8:00 AM ET


Lindsey Trickett – Vice President-Investor Relations

John Hayes – Controller

John Leonard – Chief Executive Officer

Andrew Schiermeier – Executive Vice President, Corporate Strategy


Maury Raycroft – Jefferies, LLC

Gena Wang – Barclays

Martin Auster – Credit Suisse

Steven Seedhouse – Raymond James


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

Ms. Lindsey Trickett, you may begin your conference.

Lindsey Trickett

Good morning and thank you for joining us today for Intellia’s conference call to discuss our third quarter 2018 earnings and corporate development. I’m Lindsey Trickett, Intellia’s Head of Investor Relations. For those of you on the phone, there is a presentation available for download at, in the events and presentation 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 would like to remind every that during our presentation and Q&A we may make certain forward-looking statements. And as you refer to our SEC filing available at 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 and update on the in vivo and ex vivo progress we are making in R&D and a review of our financials.

On Side 5, I’d like to introduce you to two new members of the leadership team, of 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 R&D update.

John Leonard

Thanks Linsy. And thank you all for joining us today. I’m John Leonard, Intellia’s CEO.

I’ll start today with Slide 7, serving as reminder of our long-term strategy. We’re building a full spectrum of 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 life-threatening diseases.

Note that with our in vivo approach, we first emphasize lipid nanoparticle or LNP based delivery to liver with the most basis 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 are 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 limitation, so I 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 one and two knockouts. This work promises to address the manufacturing limitations that typify autologous approaches and can service the basis for broad T-cell platform for Intellia.

Another aspect of our approach is enhancing T-cells’ ability to intra solid tumors, which may rely on additional edits aimed at overcoming a solid tumor suppressive micro environment. 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 Side 8, I want to share with you non-human 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 non-human primate study that we shared exactly one year ago today. And in the middle column in keel you’ll see the data that we shared recently at the European Society for Gene and Cell Therapy Meeting, where we showed that on average with our first generation 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 were generated in collaboration with our partner, Regeneron.

We 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 the slide, the red column depicts new levels of in vivo hepatocytes editing and 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 the 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 early results, shown in the first two bars; modifications to the components of our in vivo delivery formulations, due to the performance improvement but a particular interest to us, or of 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 two sets of the doses which was well-tolerated. We believe this experiment shows potential for a product profile that a 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've 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 editing level about 35% to 40% is sufficient to yield TTR protein level reductions associated with therapeutic success in patients. The points illustrated here reflect previously recorded data from our lead candidate, as well as from our recent in vivo delivery improvements that was administered as a single dose. But it is important to know 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, performance at a higher level than our previous formulations.

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 the 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 is our objective to develop the most effective formulation that we can. We're developing medicines that are meant to be significant advances for patients, 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. A potential significant impact of these enhancements extends beyond the TTR program. 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 introduced 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 permit a wide range of engineered cell therapies.

Let's turn to Slide 11 for 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 guide RNA in our standard format and combines that with adeno-associated virus, or AAV as a delivery approach for our proprietary, bi-directional 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 F9, the gene that encodes factor 9, which is the clotting factor defective with hemophilia B. The factor 9 work is done with our partner Regeneron.

On Slide 12, we show some of the recently presented in vivo factor 9 data from the Regeneron collaboration. This work targets insertion of the F9 gene into the albumin 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 9 RNA. Note, on the left that when template containing AAV is provided without the addition of the LNP, hepatocytes do not express factor 9. On the right side of the panel, we see the result when an LNP caring CRISPR/Cas9 that enables gene insertion is combined with AAV, delivering the F9 DNA template. Note the contrast, over 50% of the cells are expressing factor 9 RNA after treatment with a hybrid LNP-AAV approach.

On the right side of the slide, we show there's a direct correlation between the number of expressing cells and the level of factor 9 present in the blood of these mice. It's important to know that the levels of factor 9 produced in these experiments are levels that would be expected to have a therapeutic effect we have achieved in a human with hemophilia B.

So together with Regeneron, we've shown that in mice we can insert the F9 gene into the liver, we can insert it into a precise location, we can identify sites that modulate the expression of the gene and we can produce protein at levels that are therapeutically translate to humans. Furthermore, we observed that varying need of the LNP or AAV dose modulate levels of factor 9 expression.

Let's turn to Slide 13. We're applying the learnings from the F9 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 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 supplies with the same hybrid LNP-AAV approach that we just discussed. The results are similar to what we saw with factor 9. 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 1000 to well over 3000 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 consequences of this disease. These protein levels remained stable throughout the five weeks of the study duration. Once again, this protein is wholly owned by Intellia.

Moving to Slide 14, we show data that speaks to the generalized ability of the hybrid approach for gene insertion. We studied expression levels of the two different transgenes when inserted at the same site. The alpha-1 protein levels are on the X axis and for the factor 9 transgene, protein levels are found on the Y axis, because there's a good correlation between factor 9 expression and alpha-1 antitrypsin expression for any given insertion side, this suggests that are 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 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 to build an engineered cell therapy platform that will be efficacious not only in hematological cancers, but also in 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 lengthy lentivirus constructs that lead to integration of the transgenic TCR at random sites in transduced T cells. That approach has limitations. In particular, the endogenous TCR has not already been fully eliminated. The new transgenic TCR may combine with the endogenous TCR to produce hybrid molecules that may then lead to graft 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 in self circuitry. Introducing the transgenic TCR in to 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 and 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 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 are available.

To wrap up the R&D update on Slide 18, I'd like to highlight the accomplishments we've achieved in 2018 to-date. 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 show data on more complex types of edits most recently with F9 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.

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

John Hayes

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 equivalence 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 was $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&A expenses increased to $23.2 million for the quarter. As we continue 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'll turn the call back over to Lindsay.

Lindsey Trickett

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 of questions.

Question-and-Answer Session


Thank you. [Operator Instructions] We can take our first question Maury Raycroft from Jefferies. Please go ahead.

Maury Raycroft

Hi. Good morning everyone and welcome to Glenn and Jesse and congrats on the progress. The first question is for the Hybrid LNP-AAV approach. I am just wondering how you envision 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?

John Leonard

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 the knockout, so I don't see that hybrid approach really having applicability for that, but as you can imagine there's a long list of potential insertion targets to pursue. So we're excited about what we've shown with the two 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 the [indiscernible], 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.

Maury Raycroft

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

John Leonard

Yes, I wouldn't know how to score it more heavily one way or the other. We've been coming down a systematic path, 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, [indiscernible] a low and a high that we did way back in October. And those doses are shown in red graph here. Clearly we're getting a lot more out of dose and we did a year ago.

Maury Raycroft

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

John Leonard

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

Maury Raycroft

Got It. Okay. Thanks again and thanks for taking the questions.

John Leonard

Thank you.


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

Gena Wang

Thank you for taking my questions that I wanted to first, congratulations on a lots of the progress on the R&D part, I know actually for the investors I think, one pushback is always when the company can enter – I know that a, quite some other competitors already in clinic or ready to go into clinical development this year. So just wondering, I follow Maury’s question regarding the R&D filing. So can you just walk us through the steps you need to do a before R&D filing for the TTR program?

John Leonard

Yeah, 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 agents 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 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 it enhances a, the product profile of probably virtually everything that we're working on. And secondly, I think deals with optimizations that we might 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 approaches 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 PAC studies. That's why I'm comfortable in saying that in 2020, I fully expect to have an IND, I just don't want to tell you which month, but it's my objective to make that happen as quickly as possible.

Gena Wang

Okay. That's very helpful; and I do want you to comment, if vivo approach is certainly much, much more challenging than the ex vivo approaches and certainly acknowledge the data you've provided at the EDGCT certainly a lots of progress? My next question is regarding the insertion approach. We know that’s similar concept with other technology is already in Phase 1 clinical trials. So of course I do see this as a much improved version, just wondering if you have any thoughts, what will be the next step you need to do a before you will be able to enter clinical development.

John Leonard

Yes Well, one of the programs we're doing in collaboration with Regeneron, so that's a discussion to 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 Gena, 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.

We will do that, that's part of this confirmatory work and with that, when it becomes a matter of capacity to a certain extent, I mean, we want to move very quickly, because 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 market, but it goes back to the question you asked, it's about competition, which I view as irrespective of platform, irrespective of the modality. In the end, doctors and patients don't care about the particular treatment, they care about the results and we're trying to design a platform here and an approach that will be better than the choices that doctors and patients have. That's the objective.

Gena Wang

Thank you. Just one last technical question regarding the hybrid insertion approach, just wondering if you, how thorough you detected it in terms of other forms of insertions in addition to transgenes like for example, AAV or other components that got inserted into the genome.

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

Gena Wang

Okay. Thank you very much.

John Leonard

Thank you.


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

Martin Auster

Hi. Thanks for taking my question. I had a follow-up on Slide 9, where you're showing the range of effect and the percent of the TTR knockdown in the year with the new construct. It looks like you've got about between kind of 20% and 80% genome editing rate with I believe that's you said that's all from a single dose. Just curious, are you satisfied with that degree of variability? Are there methods you can employ to kind of work to further narrow that and ensure kind of a higher portion of subjects or achieving the therapeutically relevant range here? Thanks.

John Leonard

Thanks Martin. The red dots here correspond to changes in different complex. So, not every single red dot is identical. So that's one way of approaching the variability, showing data from only a single change, but this is portrayed here to demonstrate that there's multiple levers for us to flow, to get what, in our hands is a substantially different from the effects that we've been talking about up until now.

Variability, I think it 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 a point which is true for any drug, where every dot is superimposable on the others, but it's always preferable to have less variability to mark.

Martin Auster

Thanks. And then just one follow-up, I think since the – since the markets have gotten a little choppier on October, we've been getting increasing calls from investors in kind of really focusing on balance sheets. You guys are actually in a very strong position now with 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 improved products, in 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 order kind of work with a partner on. Thanks.

John Leonard

Yes, thanks. 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. How its fundamental to our work has been having a broad base, this is this full spectrum notion that we have.

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 be a knockout, whether it' be a modular approach on ex vivo side. If we need partners, I'm confident. We will have many to choose from.

Martin Auster

Great. Thanks for the answer. Appreciate it.


We'll take our next question from Joseph Schwartz from Leerink Partners. Please go ahead.

Unidentified Analyst

Yes, hi good morning. Thanks for taking the questions. This is Dave on diving for Joe. So 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, which you've referred to as the previous version, whereas for genome editing with about 34%.

But right next to that he was also showing the TTR protein knockdown of roughly 70% by meaning and that was on day 30. So if we look at the updated enhanced version today, you'd say TTR 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 of therapeutic? And I've got a couple of follow up, thanks.

Andrew Schiermeier

Yeah, 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 affects here with the most recent data. And this is a system that equilibrates over and 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. How much is the right amount? Well, we are of the belief that more is better. And if implicit in your question is there a point where it's too much. I have not seen that data. I have 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 approach that’s already here.

Unidentified Analyst

Great, thanks for that color. Just two 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've seen with the previous version when you were 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. I'm just wondering if you could provide some context or some more granularities on the AAV and LNP doses that you’d use. 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? Thank you.

Andrew Schiermeier

Yeah, I don't think I can 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 is a relationship between varying one or the other elements of it and that can set the degree to which the insertion actually takes place. So, it's possible with the 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 then again I would emphasize that that's work that we're doing in collaboration with Regeneron. So that will clearly have a lot to say about that. But 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 at least in these animal models where it works [indiscernible]. 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 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. Please go ahead.

Steven Seedhouse

Hi, good morning. Thanks for taking my questions. 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 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 re-dose and maybe accepting more of that variability or higher editing than you might even need for full effect?

Andrew Schiermeier

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 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 excited about, but there's a lot of learnings that take place, so 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 effect is readily measured.

There is a circulating protein that can be detected and just as we've shown with our animal data here, we 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 entered the clinic. Bottom line for patients, you know, if all those 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.

Steven Seedhouse

Okay, I appreciate that. Maybe just to 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 DNA level in your initial clinical studies? And also are you anticipating needing or wanting to immunosuppressed patients at least initially in the first ATTR trial? Thank you.

Andrew Schiermeier

Thank you. Yeah, uh, 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, you know, not to make light of it, but doing a liver biopsy is almost just spectator support. 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 patient as opposed to having potent immune suppression applied every two to three weeks when, you know, regimen is taken lifelong for patients. So if it is necessary and right now we don't see indications that it is. We will certainly explore that. But again, I don't think that that's a major issue for us.

Steven Seedhouse

Thanks very much.

Andrew Schiermeier

Thank you.


The Intellia Therapeutics third quarter 2018 earnings conference call is now concluded. Thank you for attending today's meeting and presentation.