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

Okay. Hello, everybody. Welcome. Thanks for joining us. This is -- I'm Marty Auster. I'm the lead smid cap biotech analyst at Crédit Suisse. You are tuning in again to the 29th Annual Virtual Healthcare Conference. Right now, we're being joined by Intellia Therapeutics. I've got John Leonard, CEO with me. John, really happy to have you here. We've got a number of questions. We're hoping to kind of throw at you.

Maybe if you could start with just maybe a quick introduction of Intellia and kind of a little bit about just the vision going forward.

So thanks, Marty. Happy to be here. So Intellia is a CRISPR/Cas9-based gene editing company, and a leader in the space, and we've been active now for a few years. The basic notion that we bring is a full spectrum gene editing company, the idea being that we can have in vivo approaches to go after what we call broken genes. Since we'd be taking CRISPR/Cas9 into the body to go after selected disease states. But also, we pursue an ex vivo strategy where we use CRISPR/Cas9 as a tool, the idea being there to engineer cells so that they have different properties that we can bring them to bear in a variety of different diseases. Typically, in our case, Houston's first wave immuno-oncology. So the platform is moving forward well. We've just announced dosing of our first patient with our lead program on the in vivo side, which is for TTR amyloidosis. Very excited about that. And we've guided that we intend to be starting the clinical process for the ex vivo side in the first half of next year. So a lot going on at the company.

So maybe we'll start kind of bigger picture and then sort of drill down into the specifics of those lead programs. But so you've kind of crossed some important steps, obviously, this year with the first in vivo product going to clinic and first dosing. What is the ability to kind of bringing products forward on a go-forward basis? What is the cadence you expect to be able to kind of file INDs and kind of populate the clinical pipeline? And what would you envision this could look like over the course of 3 to 5 years as you start kind of bringing products through?

Yes. So the platform itself -- lends itself to what we characterize as a modular approach. The idea being, as you solve certain problems, you're able to use that as a stepping-stone for the product. So casing point, on the in vivo side, we talked a little bit about TTR amyloidosis, where we worked out our LNP delivery system to go after delivery to hepatocytes, which is where the TTR gene is expressed. But once you have that in hand, you can immediately go to other targets that reside in those same cells, merely by changing the guide. And that is our second in vivo program, which is hereditary angioedema. Likewise, on the ex vivo side, the idea is to get to a modular approach where once you get some very basics done with respect to your cell editing and the chassis, I like to call it, and it's really a mix and match approach. So we've got 3 programs moving either already in the clinic or on their way there. And we would expect with the continuing investments that we're making in the platform that we would be hitting a development candidate or so, at least one or two per year in the foreseeable future. So that's the modularity playing out, and we see a pipeline broadening and deepening as we go.

Great. And then for the initial in vivo program, we'll get into that one in a minute. But the initial program for TTR is targeting the liver, targeting hepatocytes. What are the challenges? And what is the ability of this technology to kind of go and target other tissues? I know there's been kind of differing degrees of success with other kind of other technological modalities to kind of target, if it's muscle, if it's CNS, et cetera, what do you envision to be kind of commonalities and maybe distinct challenges for CRISPR/Cas9 technology to kind of approach different target tissues?

Yes. So delivery is half the challenge. The other half is the editing and what you want to do once you get there. And certainly, delivery is fundamentally enabling. We've chosen a chemical approach, in our case, lipid nanoparticles, as a way to go after systemic delivery because that opens the door to the largest number of tissues. LNPs have a variety of advantages in terms of transient delivery. They're not inherently immunogenic. There's not pre-existing immunity. So that gives you a lot of capability where, say, a viral approach might be somewhat more limiting. In the case of LNPs, others who have gone before us have done a lot of work showing that you can certainly get them into the liver. So we worked on that foundation, building on insights that already exist. So going beyond the liver is a matter of either actively targeting tissues or tuning down the degree to which the liver that takes up those LNPs. So we're actively doing that. And it's an area of very active interest. You may have seen, for example, just in the last day or so, we've announced a relationship with the Gates Foundation, where they're interested in exploiting LNPs as a way of accessing the bone marrow. And that's a tissue that we've already have some preliminary data indicating that it may be a viable way to proceed.

Great. Okay. And let's talk about the first program in clinic in 2001, the TTR program. Again, there's numerable potential targets you can address. How did -- what's the back story of targeting TTR? And how did that kind of come up as a first -- as a lead program?

Yes. So it's an important question to how we think about targets in general. And again, thinking about the in vivo side here. So again, we wanted to go to an area that we knew we should be able to reach with an LNP, so that takes you to deliver. Any editing is going to start with a cut to the genome. And that's a point of departure. You're either going to inactivate a gene or activate one, which, in our case, would be typically trying to insert DNA. So as a first step to being able to do both of those things, knocking out a gene was, we thought, a really good way to begin. And in the case of TTR, we had the advantage of those who had gone before us who had validated the extent to which a gene needs to be silenced before you'd see a clinical effect. So we look to the siRNA companies that have been out there actively plowing this ground. So from a regulatory point of view, it helps show us what we need to do from a knockdown point of view in terms of correlating that to clinical effects, that gives us a lot of guidance. And as a way of seeing where we are very, very quickly once we're in the clinic, we thought TTR was ideal.

Yes. So I was just kind of...

I would add one thing -- I'm sorry, it's something that we come to appreciate, especially in the years that we've been doing this is that one of the really interesting things about TTR is that what I think many people believed was essentially a rare disease is something we've learned is far more common than what's initially appreciated. It's not always the mutant form. It's the wild-type form that presents as cardiomyopathy. So we see that also as a very, very attractive market to pursue.

Yes. Yes. So let's talk about the specifics in this program. And I think it sounds like you're framing this, this is a good kind of example of what you can do with your technology in a kind of liver-mediated disease. And so there's a lot of read-through from this program and how it behaves, and you'll learn a lot also for future partners from this. So what have you demonstrated preclinically in terms of ability to knock down TTR? And kind of how competitive you think that profile looks from the preclinical models as you kind of look across what could be done with other approaches and et cetera?

Yes. So the preclinical work has been extensive. We've worked in rodent models and then moved to what we think is the most relevant model, which is the nonhuman primate, and done a fairly extensive characterization of our material there and have demonstrated that with a single IV infusion of the material that's going into humans, in the nonhuman primate, we're able to get in excess of a 95% knockdown of TTR. And that's for the duration of observation in those animals. When we look at those levels of knockdown, we think they're highly competitive with anything that's been demonstrated anywhere. And since there seems to be an emerging consensus that the extent of knockdown is predictive of the extent of clinical outcomes. Well, 95%, it doesn't leave much more to go. So we're quite excited about what we think may lie ahead.

Okay. And so you've begun dosing in this study now. Could you maybe walk through what the kind of -- it's a Phase I/II study in patients?

Yes. I'd characterize it really more as Phase I. The -- there's a Phase II aspect to it, I guess, if you want to think more broadly. But yes. I mean, the way the study is done is it's a single ascending dose study done in patients with hereditary polyneuropathy. We start with that patient population because it's very well characterized. It's very stable. It gives us a clean background to go. And interpret any safety signals in contrast with cardiomyopathy patients who tend to have more things going on physiologically. But really, what we're looking for is finding that dose that leads to the knockdown of TTR protein levels along the lines of what we've seen with the preclinical work. And then that -- it's set up as a 4 cohort -- well, up the 4 cohort ascending dose study with an expansion cohort in part 2, and we're hoping that we get the data that we need to move immediately into that set of cardiomyopathy patients where we want to get some additional information.

What do you think is the -- obviously, it sounds like the more the better. But what do you think is that -- what's the range you're targeting? Is it something like 70% to 90 percentage-type range is what you're looking for? Or...

Yes. It's -- we...

Knockdown.

Yes. I mean, we're talking about circulating levels of TTR, the actual measurement of the protein. We look at the benchmarks that have already been established, and we'd like to exceed them. So if we're in the 80s or 90s, we'd be very, very pleased with that.

And in terms of the dosing strategy, I understand the need to kind of be methodical and make sure you're getting a useful experience. Is the initial -- are the initial doses being studied anticipated to kind of achieve the lower end of that bound? Or are they intended to be kind of below where there's likely to be a meaningful therapeutic impact? Or how are you -- how have you thought about kind of the dosing strategy there?

Right. It's a very important question. We're asking people to sign up to have their genes edited, and it needs to be a reasonable sort of offering for the patients that come into this trial. They are patients. What we do is try to approximate what we believe may be the optimal biological dose from the lower side. And some of this is validating the preclinical work that we've done. So I'd like to think of it in terms of -- we think we're going to be in the ZIP code of where there will be activity. I think it's quite likely at the lower doses, there'll be less than what we're ultimately shooting for, but we'll see. And one hopes that in a minimal number of escalations, we'll get to where we think it will be relevant for further study.

And can you provide any additional details in terms of number of patients planned for cohort? Or any sort of kind of what disclosure plans might look like down the road next year?

Yes. It's a standard 3-plus-3 design. There's 4 cohorts, so up to 30 patients in what we call the first phase of the study. The second phase would be an additional 8, which we think we've got the dose that we're looking for. Sharing information about the effect is something we're thinking carefully about. We view that there's 2 very important elements to the story as we embark on this work. First, we haven't said it yet, but it should be said. This is the first example of systemic CRISPR/Cas9 gene editing. So we think that activity by itself is meaningful for saying that this is a viable approach. And we can start thinking about all of the things that can come with that. And then there's the particular attributes that come with NTLA-2001 in terms of its behavior. Those may be the same story, but as we go through our dose escalation, it will be interesting to see what information we have and when. And one thing we want to be absolutely certain about is making sure that whatever we share is meaningful and consistent and speaks to what's actually going on with the therapy.

What are the rules around kind of advancing dose cohort? Are you -- you dose one patient and wait a while then dose the remainder of the cohort? Or is it would you dose the full cohort right away and then kind of wait for some period of time to assess safety before going into the next cohort or...

Yes. Without going into the details of patient-by-patient because it's slightly different across the...

What I'm getting at is the time frame to kind of expand and -- yes.

Understood. There are some rules that are not so unfamiliar to studies like this. We would expect to be able to fill cohorts actually pretty quickly once we get going here. And the move to any subsequent cohort comes after a review of the information we've accumulated with an outside group to determine that it's appropriate to begin that following cohort.

Got it. Okay. So can investors think of it similar to how some of the early gene therapy studies were conducted in the dose progression, something like that?

It's related. It's -- yes, it's related, not identical, but definitely in that direction. Yes.

Got you. Okay. Okay. And then just in terms of kind of management's exposure to date on an ongoing basis, is this something that management is blinded as data starts to become accrued? Or are you kind of -- is this open label?

It's an open-label study.

Okay. And then in terms of kind of as you start getting data, if it's behaving the way you expect it to from the preclinical and everything looks pretty good, how do next steps look? So you're looking to expand the trial once you've selected a dose you think is suitable, and you'll expand that into -- would that go into a kind of a Phase II, like potential registrational trial, would that go into just a preliminary step before designing a registration trial? How are you thinking about that progression?