Intellia Therapeutics, Inc. (NTLA) Earnings Call Transcript & Summary

Thank you, everyone. My name is Gena Wang. I'm SMID-cap biotech analyst at Barclays. I first hope that everyone stay healthy, and I would like to thank all the participants, investors and companies, and especially our event team and corporate access team who made this virtual health care conference possible. With that, I would like to introduce our next presenter, John Leonard, President and the Chief Executive Officer from Intellia. Hi, John.

Hi, Gena. How are you?

Good, good. Maybe I will start with more of the big picture question. I know you don't have a slide for investors. Maybe wondering if you could just give us a quick overview of Intellia, so that would be helpful for those investors who are not familiar with the company.

Of course. So Intellia is a genome-editing company based on the CRISPR/Cas9 technology. And we view ourselves as, what we call, a full-spectrum genome editing company. The idea being that we've taken CRISPR/Cas9 and used it both for delivering into patients for in vivo therapies, where CRISPR actually serves as the therapy, but it also can be used outside the body in ex vivo settings, where CRISPR is a very powerful tool for engineered cell therapy, which is basically ex vivo therapy. One of the things that characterizes the in vivo approach that we use, and something that we've certainly put a lot of time and effort into over the last few years, is developing a liponanoparticle delivery approach of taking CRISPR/Cas9 into the body. Basically, what that means is one takes lipids, assembles them with messenger RNA that encodes the Cas9 and then a guide RNA that directs the Cas9 to cut in a particular gene. And once you solve delivery for a particular tissue, we've emphasized the liver, you can use that as a modular system and essentially repeat going from target to target by changing only the guide RNA. We've presented a lot of data, which maybe we can talk about. And on the ex vivo side, we've tried to take a similar modular approach, emphasizing T-cell receptor biology as opposed to CAR-T biology, and use that approach to direct lymphocytes against a long set of malignancies that CAR-Ts are not suited well to address. Maybe I could tell you a little bit about some progress that we're looking forward to making this year as well. Our guidance has been to take our first in vivo product, which is known as NTLA-2001, into the clinic. The expectation is that we will submit an IND to begin clinical testing here mid this year, with the objective of dosing our first patients sometime in the second half of the year. We're also very excited about the in vivo approach for another new target, which is for hereditary angioedema, and that is a program that follows on that modular approach for the in vivo effort that we expect to have a development candidate named here sometime in the first half of this year. And on the ex vivo side of the company, we've nominated NTLA-5001. This is again a TCR T-cell-based approach that's directed against AML, and we expect to be submitting an IND to begin clinical studies sometime in the first half of 2021.

Okay. Great. John, so maybe I will start with more general questions in terms of the gene-editing platform. It seems like there are quite a few new editing tools emerged, such as base editing and prime editing. How would you stay at innovation forefront of gene-editing field? And then how do you see your technology compared to the other technology?

Yes. One of the exciting things about CRISPR/Cas9 is that it's really a very, very powerful technology. And I -- it's interesting to see people try to advance it into other places and stretch the limits of what might be possible. But we think about it in terms of the nature of the problem itself that needs to be solved. And when we think about deploying CRISPR/Cas9, and in our case, it's typically Spy Cas9, and that's the agent that I think we -- all of us in the academic world and the industrial world know the most about, we think it's ideally suited for the programs that we're deploying it against. So any number of different knockout targets in vivo, insertion targets where it's necessary to actually open the DNA to introduce a coding sequence, it's ideally suited for that. And when you think about engineering lymphocytes, especially multiple changes, we think it's very important to be able to knock in, knock out and do that with great specificity and great activity. And one of the things I think that we've learned as we've advanced the technology in our hands and watched it done by others is that there are really very few problems that can't be addressed with Spy Cas9 as it is so long as you work out the delivery techniques and are very thoughtful about how you deploy it. So as we look to say, base editing per se or even now the new prime technology, they clearly have a role, we think, in the laboratory. I believe that the additional complexity that they bring will require a lot of work on the delivery side. It will have many of the same sort of issues of specificity and efficacy except multiplied. And I think in most cases, actually, the number of cases in which they are well suited to the problems that we think about is a short list. So we like what we've got, we like what it can do and we're very excited about bringing it forward to the clinic.

And John, you did mention that delivery, it's very important. Could you maybe give a little bit more color on advantage of in vivo lipid nanoparticle delivery versus AAV delivery?

Right. That's a fundamental question and one that goes back to the beginning of how we thought about putting the company together and our in vivo strategy. It's important to recognize that CRISPR/Cas9 is a bacterial system. And with that as bacterial protein, you want to get the benefits of that, which are the editing, and you want to avoid as much as possible what might be the downsides of it, which would be the continued presence of this bacterial protein. And so we've emphasized from the outset a transient delivery system where, using mRNA contained in a lipid nanoparticle, one can provide the coding sequence of the Cas9. That protein is made. It's gone in hours to a couple of days, permits the editing to take place, and then you have what you want, which is not -- a cell with no persistence of the Cas9 enzyme. And the advantages go beyond that in that there's capacity advantages, the lipid nanoparticle is not inherently immunogenic, therefore, you can redose it. And one of the things that I think is going to be increasingly recognized is that manufacturing a lipid nanoparticle, which is essentially starting with chemical elements as opposed to a biological process, is a significant cost advantage and just ease of manufacturing in general. So we think it's well suited for in vivo delivery, and that's where we've put the bulk of our in vivo efforts.

Great. Beyond the liver delivery, are you exploring other tissues?

We've done some surveying of LNPs as we have them for the liver or lightly modified to other tissues and have some interesting leads. We've certainly presented data on the CNS of mice and monkeys and have done some other work. The major efforts today is directed at the hepatic-based programs themselves. But we see the LNPs as well suited to go off and address any number of these different tissues, although that's not the primary focus today.

Okay. Great. Maybe we'll go to the specific program. For 2201 -- 2001 for ATTR program. Just wondering, are you on track to file the IND in mid-'20? And also, what additional preparation would you need for the IND filing?

We are on track, and we're very excited about that. That will be our first clinical program, so we're on the verge of a lot of work that has gone into this first truly systemic CRISPR/Cas9 approach. And the work is very, very advanced, what's taken place over the last few months, and we're in the final stages of assembling the reports that go with the tox program that's required to do this work as well as the final steps of manufacturing the clinical material that will ultimately go in the patients. So well advanced. Things are moving as expected. And we anticipate that we'll be dosing patients later this year.

Okay. John, I think that there are a few clinical hold on IND filing. We just saw one recently in the gene editing or gene therapy space, more like gene-editing space. Just wondering, any extra or additional caution while you're preparing the IND filing package?

Well, we try to be well prepared and thoughtful as we assemble the information that the FDA has to evaluate. And this is where pre-IND meetings come into play. One hopes to lay out as clearly as possible what we intend to do and listen to the FDA's reaction to that and what they expect will be done, so they have the information that they're looking for so that they can make a considered judgment about whether or not we're ready to move forward dosing patients. And we have been very careful about that. We asked a lot of questions at the FDA, and they were very engaged and forthcoming. And to the best of our ability, we will meet what standards that were set and those requirements that were set. So I'm not at the FDA. They'll look at it with their eyes as reports are assembled, and they'll decide. But we think we're going to give them a robust package that ideally will make it easy for them to, say, proceed.

Okay. And at what stage you will share with the investors? Would that be your IND filing or IND cleared or dose the first patient?

It will be once the IND is accepted. I think that's the better way to proceed here as opposed to once the patient has been dosed or the alternative.

Okay. Okay, that's good. Also, for the initial trial design, could you share a little bit more color in terms of the dose and initial dose and the cohort?

Yes, up to certain limits. Our expectation is that we'll give great clarity with respect to the particular clinical trial once we have clearance from the FDA. But the general principles are the following. Necessarily, this work has to be done in a patient. I mean these are people who will have their hepatocytes edited. It doesn't make sense to do that in healthy volunteers. This will be a single-ascending dose study. And the art of this is to try to extrapolate from work that's been done from the nonhuman primate work extrapolated into what we think will be the behavior in humans, coupled with working within the therapeutic index. And what one hopes to do is be somewhere in the vicinity of what might be efficacious but with a bias to undershooting as opposed to a bias to overshooting. Obviously, the idea of dose finding is get to that dose where you get the right balance of safety and efficacy. And it's typically, you start lower and go up to it as opposed to overdosing and go down. And that will be the basic approach that we take.

Okay. So I think that for gene therapy and because of the existing neutralizing antibody, FDA's strategy seems like they wanted the sponsor started with minimum effective dose. And now we are a slightly different technology, it's a gene-editing approach. So based on your interaction with the FDA, were they more focusing on the safety since we don't have that many CRISPR/Cas9 clinical data yet compared to other gene therapy data? Or you think FDA actually will kind of have the similar view on gene therapy and wanted you to start with minimal effective dose?

I think they're biased to dose finding, with a strong bias to safety, recognizing -- and this goes back to your LNP question, that once one finds the right dose, it's possible to administer that to dose -- that dose to patients who may have received something that was subtherapeutic in the first place. So in contrast with virus, where in addition to avoiding antibodies that already exist, where you're put in a difficult position of creating antibodies once you expose a patient, and therefore, it's very difficult to come back, we have the advantage, I think, of knowing that we can come back and administer a second dose to a patient somewhere at some point, probably not in this particular study, but some parallel effort, so those patients should be able to drive whatever benefit we ultimately find.

Okay. Very helpful. So the -- regarding the safety, what kind of safety should we watch for related to the LNP delivery and also ATTR knockdown?

So I view safety in 2 forms, one is the time of the administration itself and then the other one is over an extended period of time. And extended period of time is one that comes with watchful waiting and being observant. And that's, I think, the same principles that apply to those that have gone before us with gene therapy and any other sort of permanent modifications apply to us. And that's where you assemble your tox package, come up with the best data you can and follow those patients. Acutely, all LNPs at some point, typically at very high doses, will have some LFT elevations, they'll have some low level of complement activation, et cetera, and this gets back to this therapeutic window and moving up within it. So our expectation is to, as I said, start lower, well within a window where there should be little to no response to the LNPs, and move up and find that optimal dose. So no new findings, nothing that's unusual. We feel quite good about the profile that we have determined thus far.

Okay. And what would be your target serum TTR level? Also, the -- any concerns of permanent knockout of ATTR gene?

Well, what we target comes from those who have gone before us. And we know that at least a 60% decline from baseline flips, a clinical trial is positive. So we view that as clear evidence of activity and patients should derive benefit. But our objective is to improve upon what's already been done in addition to just the convenience of avoiding lifetime administration and all the multiple concomitant meds, et cetera, need to be provided to these patients with some of the other modalities, we believe that we can get to levels of TTR reduction in excess of 80%. And we believe, based on work that's been done and the accumulating data in the clinic, that low levels and very low levels of TTR are ultimately beneficial and more beneficial to patients. So I don't think that we're going to eliminate all TTR from the body. We've never done that even in a monkey, especially since TTR is made in the brain as well. But we believe that in excess of 80%, that's going to be good for patients.

Okay. Good. And just switch gear, discuss about WT1 program, the TCR program. I'm wondering, what is your target vein-to-vein time?

Yes. So the first program is autologous. And just to step back and remind your listeners that this is a T-cell receptor-based system, where we're dropping a wild-type normal TCR into cells that have been edited and are essentially devoid of their own endogenous T-cell receptors. We think that that's an ideal test of TCRs in general. The manufacturing process is going to mimic what's done elsewhere with other engineered cell therapies. So I think we're going to be 3 week-ish, is what I would say at this point. But we're early in that work, and we all recognize that shorter is better and we'll do everything we can to make it as short as possible.

Okay. Your recent data actually show 5001 spared hematopoiesis stem cells with normal WT1 expression. Just wondering, what could be the implication of this? Does that mean a safe -- better safety profile? Or could that lead to escape of AML cells with low WT1 expression?

Yes. It's both of those, actually, I guess, would be the -- an interpretation. The reason we did the experiment in the first place is to look at WT1 in healthy people, right? So WT1 is expressed broadly on a long list of tumors, especially AML, which is our lead target here. It's expressed in very vanishing levels in some bone marrow cells and certain kidney cells, very, very low levels. And so we ask the question, if you take a T-cell receptor, dropped it into lymphocytes the way we prepare them and find those cells that kill tumor, will they affect healthy cells? And what we determined, the experiment you cited, is that, in fact, bone marrow cells were not affected. And this is where the threshold of the extent of the epitope and the surface of these cells is really important. So we feel quite good about the safety profile and are very excited about what this will be. I'd point out also that this particular peptide that's expressed on tumors is different from peptides expressed in nontumors, and that's another aspect that we think is an important distinguishing feature. When you think about tumor escape, it's -- obviously, as a T-cell receptor, it's HLA-restricted. If cells can get by without that, then that would be a way for a tumor to escape. But we'll see as we move into the clinic. And we think that, again, AML is just an ideal condition to go and test these TCRs and look for clinical effect that would serve as the basis for further work.

Great. And one last question from me. I mean we saw some chromosome translocation, I think, up to 1% from autologous TCR cell therapy at UPenn. Just wondering, did you see any -- have you seen any translocation from your CRISPR editing in your TCR system?

I'll answer the question this way: The level of editing and the simultaneity of it as done by that first publication is work that doesn't apply to our own. The editing purity that we get is just frankly at a different level. We're talking about 98% editing versus the, I think, 15%, 25% and 40-something percent for the loci. And we've been able to work out techniques where we're able to not completely eliminate translocations, but have levels that are substantially better than what's been reported. So we think we're in a really good place with what we're doing, and that's yet another reason why we think the base editing approach is really something that's not necessary for the ex vivo work that we're doing.

What kind of inflammation you did to avoid chromosome translocation?

That's something that's proprietary that we've done a lot of work on, Gena, but at the appropriate time, we'll share more about it. It's something that we're quite excited about.

Great. Well, thank you very much for giving us this opportunity.

Thank you.

Thank you. Thank you, everyone, for listening. And this concludes our call.