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

Good afternoon. Thanks for joining us for another session at the 42nd JPMorgan Healthcare Conference. I'm Brian Cheng, one of the senior biotech analysts here at the firm. I'm joined by my associate Sang Kim, who's also in the audience. On the stage, we have Intellia's management team. I'll pass the mic to John Leonard for a short presentation followed by a live audience Q&A. John, the stage is yours.

Thank you, Brian. You hear me, okay? I just want to make sure. So it's a real pleasure to be here to tell the story of Intellia. And I've got 2 of my colleagues, Glenn Goddard, our CFO, [ and Ian ] there; and David Lebwohl, who's our Chief Medical Officer, [ answer any of the ] questions. So [ participating ] in some of the things that may come up. I'll be making some forward-looking statements today. You can see the disclaimer that made available. The company is approaching its 10th year. And it was formed shortly after some similar work that was done in the CRISPR field. And what we've been setting off to do in this journey is to find ways of making what has become Nobel prize winning science in medicine and I'll give you the progress report of what we've been doing and where we are and where we think we're going. But at this point, we would say that we're poised to have the first-ever in vivo CRISPR therapy come to the market as we begin our first pivotal Phase III program for TTR amyloidosis. And if we hit the time lines that we're working for, we expect to have later this year, even a second in vivo Phase III program for [ HAE ]. We'll talk a little bit about some of the data that lies behind that. Okay. One of the things to keep in mind is that, we're getting a very clear notion of safety and efficacy of these products. We've now dosed in excess of 100 patients from the --. Okay. So, as I said, we're -- some of the safety and efficacy profiles are coming into focus. We now have over 100 patients that we've dosed across 2 indications. We're building a pipeline that goes beyond these programs in both the in vivo and ex vivo space, and we'll say a word or 2 about the platform that we have, which we think is the most comprehensive theme at a toolbox in the industry. Just by way of introduction for people who may be new to the story, I think it's really important to understand just a fundamental aspect of why people are so excited about CRISPR, in CRISPR and whatever derivative form exists. And it really comes down to [ the points ] depicted on this slide. It's a very simple modular 2-part system. In that complex of 2 parts, CRISPR guide RNA, as depicted here in the cas protein. A simple way of thinking about this is the guide RNA is essentially a GPS system that confers incredible selectivity and brings with potency of how the complex will behave. It guides that cas protein, which in its native form, access and nuclease to cut DNA. But importantly, that protein also serves as a platform for the various derivative forms of genome editing that have come to the fore in the last several years. What you see on the right is, how that protein complex behaves, which goes to the nucleus in a very top of the cascade of genetic information, modifies genes and now we're able to modify genes in any number of different ways. That's captured here. And I think it's a really important notion to understand because there's different names and different capabilities that have been developed all of that. I mean, all of them begin with CRISPR/Cas. It's this notion of the selectivity that comes from guide RNA and that platform of protein cas, either in its nuclease form or as the platform to add other enzymatic activities. So whether you're doing base editing, whether you're doing DNA writing, there's different forms of that or other forms of technologies to bring genetic change into the nucleus. All of them rely on CRISPR/Cas, they're all relied on guide RNAs, and it's impossible to do those well without being proficient and understanding this protein and guide RNA. We have all of those different capabilities, proprietary forms in our toolbox, and we're at a point where we can choose the best tool for a particular dramatic challenge that we're looking to pursue. You can think of the archetype of sorts of edits, which are depicted on the right, whether it's some backing out of a gene, you can search material, you can repair the level of code on and you can combine and mix and match this, especially in the ex vivo setting, where taking cells outside the body, you can make any number of different combinations of that. We've made a lot of progress with that. Again, the idea is that, having all of these tools and the company we're able to choose what we would need for whatever might happen. Anyway, I mean, just to -- this is where we left off, the different tools and the toolbox and the archetype of sorts of edits. You're only as good as the delivery you have. And it's absolutely necessary to have a variety of different delivery tools, which we've also been working to collect with the company. First and foremost, we use chemical approaches in the form of lipid nanoparticles, some of which can be functionalized to go to places beyond the liver, in particular, the bone marrow, et cetera. We also have biological approaches in the form of AAV, and this can be modified with other technologies as well. Together, what we've done is, put ourselves in a position on the in vivo side of things, where now accessible to us are the liver, bone marrow and collaborators working through central nervous system, i.e., in muscle and all of these things figure our priorities for the next several years. As we look back over the last year in terms of the progress that we've made as we've been building our company and moving towards these pivotal trials, it's been a very, very successful year with -- especially moving our lead programs forward. NTLA-2001 is targeted at TTR amyloidosis, and NTLA-2002 hereditary angioedema. And what we were able to do in the last year was clear, the first in vivo CRISPR IND and, in fact, the second CRISPR IND for both 2001 and 2002. We've advanced the 2001 program for an amyloidosis to Phase III, and we'll talk a little bit about the MAGNITUDE trial, which is the pivotal program for TTR cardiomyopathy. In addition, last year, we began and completed enrollment for the Phase II program for the HAE study from 2002. And along the year, we presented interim data for both of those programs that has been remarkably consistent and remains highly positive. We've also moved beyond knockouts to the liver to knock-ins of the liver. This is the idea of reconstituting genes and then submitted a CTA for NTLA-3001 for alpha-1 antitrypsin deficiency associated with lung disease. And as part of that platform of different approaches, we continue to make progress with the various tools that we have, especially with DNA writing technology. We begin the year with over -- with approximately $1 billion in cash, which we expect that to carry us well into the middle of 2026, and that will take these clinical programs, either to completion in the case of 2002 or well beyond enrollment in the case of 2001. The strategic priorities for the company broadly as we think over the next 2 to 3 years really fall into 3 broad categories: executing those pivotal trials; launching the next wave of in vivo and ex vivo clinical programs as we expand beyond knockouts in the liver; and continuing to build out the platform. So, going a little bit more deeply into the pivotal trials. And as I said, we expect to complete patient enrollment in this time period. And we anticipate that we'll be submitting a BLA for hereditary angioedema sometime in 2026. The next wave of in vivo and ex vivo clinical programs are looking for a proof-of-concept for that insertion, as well as initiating clinical development on the ex vivo side for what we think is a breakthrough allogeneic approach that if successful, should enable solid tumor of [ allogeneic cell ] engineering. And then finally, we'll continue to build out the editing and delivery mortalities by moving those different delivery approaches beyond the liver, as I mentioned, in advancing DNA writing technology for a platform. So key milestones for the upcoming year by program fall into dosing our first patients for the Phase III trial for cardiomyopathy, continuing to expand the enrollment of that program as expeditiously as possible and moving the companion indication of polyneuropathy forward as we prepare for a Phase III program. And again, along the way, we'll present data as the cohorts originally treated continue to [ move forward ]. For 2002, the hereditary angioedema program, we anticipate that we'll be initiating Phase III study in the second half of this year, subject to final agreement with the FDA and other regulatory agencies. And we will continue to expand on the Phase I data that we -- I will review very quickly, as well as presenting the Phase II data that will be completed here in this year. And then finally, as I said, we anticipate beginning dosing for the gene insertion program for AATD. So let me hit just a couple of highlights for the clinical pipeline with those 2 programs. And we begin with just a summary of safety statement with the 75 patients that we've reported on for Phase I studies 2001 and 2002, we've been struck by what is a very favorable safety profile. We've now observed patients in the case of 2001 for up to 2 years and for 2002, the HAE program for over a year, and that continues to mature. When adverse events occur, and tend to be very mild in severity and typically consistent infusion-related reactions right around the time of dosing. The effect of editing has been followed by following surrogate markers in the form of the proteins that are encoded by the targeted genes. And here, what you're seeing is the effect of editing the kallikrein gene, which is related to attacks of [indiscernible] which you've seen on the Y axis is the decline in the circling of that protein from baseline, a dose escalation study. So starting at the top, you're seeing the low dose and intermediate dose and the highest dose. What you see is that, growth at dash-line which constitutes benchmark levels of inhibition, typically forming with attack 0 sort of levels of inhibition. All of those levels that especially beyond the initial dose or beyond the benchmark approach. So very enthusiastic and excited about the level of editing that we've been able to achieve. That reduction in kallikrein protein can be assessed by attack rates, of course, line to those same patients. What you're seeing here are those 3 groups, and I'll just call your attention that it's the lowest group and the highest group and then the middle group, and it's a function of the chronology of the study. But what you're looking at is the attack rate during the screening period, the administration of the drug a several-week observation period and then the continued follow-up weeks. So we count in that observation period the number of attacks. But what I think is important to note is that, every single patient achieved a nil attack status in those 2 instances where patients had attacks essentially every other day. It took a little while longer, and we don't really understand why that's the case. But all of those patients achieved an attack-free status. I'll call your attention to that top patient, which is in the lowest dose group, far out on the right, to see an attack is actually a sports injury where the individual had abandoned all prophylaxis, playing soccer had a sports injury, some swelling of his hand, whether it was HAE or getting hit with the soccer ball, we don't know, so it's called an attack. But I think the remarkable finding here is that, all of these patients have reached a point where they can abandon the prophylaxis they had in maintaining an attack-free status. We will update this -- these efficacy data as we go forward. And this is the basis for a lot of the excitement that we have. As we think about 2002, as it goes forward, that was Phase I, where we've chosen 2 doses from that work, the low and the intermediate dose, 25 milligrams and 50 milligrams. And we're completing that Phase II study, which will serve as the basis for a dose selection for the ultimate pivotal trial that we expect to begin second half of this year. And as I said, we will present those data when we have them and continue presenting the follow-up to the patients. As we turn to 2001, which is the program to knock down the pathogenic protein that causes amyloidosis of the TTR type. What you're seeing here are the results of similar sort of design, which is dose escalation for cardiomyopathy indication and the polyneuropathy indication on the right. And what you can see is, with various doses in all cases, if you get to the higher doses, we've been able to knock down TTR levels to extremely lows. As a function of change from baseline, these are in the order of 90% to 95%. And what's I think important to realize is that, we're at the point where we're measuring the absolute levels of the protein. And what we found is that, the residual absolute TTR concentration at day 28 to start 17 micrograms. To our knowledge, this is the lowest that's been reported and seems to be about half or 1/3 what's found with silencers where we've been able to see those kinds of numbers. I do think as this program move forward and as people think about TTR and proper treatment of that disease, these numbers and these [ measurements ] will be very, very important. One thing to keep in mind, just to remind you is that, these patients have been treated at a single time, a time 0. What you're seeing are the results that are remarkably consistent over the observation period where it's 2 years on the right because we [ need ] polyneuropathy and the cardiomyopathy patients. Again, these data will be updated as the year goes on. That information goes into the dose chosen, 55 milligram fixed dose for a Phase III program, which is now called MAGNITUDE. This is a randomized, double blind, placebo-controlled study, which is essentially adding 2001 or not for the standard of care, including tafamidis. You see 765 patients that we expect to randomized 2:1 from the placebo. I think that's attractive to patients that should drive the rapid approval of it. The primary endpoint consists solely of cardiovascular type endpoints, whether cardiovascular mortality or a variety of different cardiovascular-related consequences. Or secondary endpoints as shown here, including TTR and [indiscernible]. And in contrast with some of the other sites done what we're doing is allowing some like sicker patients in with higher levels of NT-proBNP baseline, which we think will add to the rapid completion of the study. It will be stratified by disease severity, wild-type versus mutant of TTR and then again with tafamidis use. We estimate that the average duration of patients on the trial will be about 30 months, all patients will need to be followed for at least 18 months over the course of the trial as we account for the events. So as we see NTLA-2001 going forward, we're imminently to those patients, much of the activity this year will be opening sites, enrolling patients as quickly as we know how to do. And we will progress the companion indication of polyneuropathy as we do that work. And over the course of the year presents some of the data. We do think both of these programs were successful, have tremendous commercial potential. If you look at what is happening from the amyloidosis market, we're now on our way through a projected $11 billion-plus marketplace. There's over 0.5 million patients estimated now diagnostic tools that come to the fore that allow us to find these patients. And when we think of what the current cost of treatment is for the existing therapies, you see in excess of $450,000 a patient. Similarly, for 2002, which is a less prevalent condition, about 20,000 patients worldwide. It's a very, very extensive treatment paradigm. And with that, a global market that is estimated to be on its way in excess of $6 billion. And again, these are very, very expensive patients. And we think that we'll be able to price our product without the health resource of sparing the system and are very, very competitive here. Finally, as we think about going forward, I think some ways of thinking about the progression of the program in the company beyond these pivotal trials are the waves of activity. So look for data with respect to in vivo gene insertion and importantly, how we take ex vivo allogeneic cell therapies into the clinic. And then as we progress the platform of DNA writing and these different delivery modalities outside the liver. A quick look at the pipeline of the company. You see later-stage programs with 2001 and 2002, alpha-1 lung disease here and in a variety of different research programs that we expect to play out here over the next 2 to 3 years, as well as work in the ex vivo side. Finally, just back to where we began, which is the mission of the company coming up with approaches to solve and create curative medicines for gene-based diseases, innovations at the core of the company as we think about having the incredible tools that CRISPR makes available to us. And from our standpoint, CRISPR revolution is here to stay, and it's only going to get bigger and more comprehensive as time goes on. So with that, I'm happy to turn it to Brian and take whatever questions you want to address.

Great. Let's start off with the Q&A. [Operator Instructions] I think last year, when we spoke, we hosted a dinner with you and your team, you haven't started a pivotal study, lots of questions about how the regulatory agency thinks about gene editors as a whole. When you look at your portfolio today, you have taken a pretty big leap across the board, right? You're now in pivotal stage ATTR-CM. Looking back, what have been the biggest challenge to get to the pivotal stage for ATTR-CM? And as you think about your earlier stage programs and even your peers that are focusing on base editing, what is the potential uphill challenges that you think you -- or maybe even other peers may see?

Well, I'm not going to be able to comment on what goes on in other companies than how they do their work. But for us, I think it's important to remember that we started literally from scratch. And what we did was identify delivery modalities that have been developed for a different approach siRNA. And so, we spend a lot of time adapting that to the coding sequences and RNA for CRISPR/Cas, lot of work with basic chemistry, et cetera, for making the LNP delivery be possible to be effective. And that took time because I was working on a lot of basic systems. The other part that was, I think, really essential, but has served as well is coming up with comprehensive ways to understand where the enzyme goes and how it behaves when it gets there. So we spent a tremendous amount of effort thinking about how to characterize off-target profiles of any of these different guides and industrializing that process. So, I think it's a testament to how that's played out. But the 4 INDs that we've submitted, 1 collaboratively with Novartis, every single one of those has used that same off-target methodology. And every single one of those INDs have been cleared in the requisite 30 days. So I think that was probably the biggest hurdle, building up that foundational stuff, but it puts us in a really good position to go and do some of the other things that we want to do now.

Great. Maybe just one more for me before I turn to audience. I want to start off with HAE. Usually, I think we kick off of ATTR. But now that you have planned for BLA in 2026 and potential pivotal start also in the back half potentially this year. What's your latest view on the pivotal design trial? And how confident are you that you can meet that 2026 goal? And beside the pivotal study, what else do you need to kind of line up to get there?

Well, I'm very confident we'll hit the 2026 goal, and David is going to tell us how.

Yes. First, to talk about what we've seen in Phase I. What you saw is, even the attacks going to 0. Of course, having that kind of result makes your design of any future study much easier. You're going to have a very strong treatment effect and you could have a very small trial because of that strong treatment effect. We will have the results of the Phase II, the patients have been enrolled. That'll be followed for 16 weeks. So we'll have those results towards the middle of this year. We'll have -- that will help us to choose a dose. We looked at 2 doses, 25 and 50. I should say, if you look at the data, we think 50 is more likely, there's a more consistent effect and a deeper effect. But, obviously, we want to do the larger group of patients. It involves 25 patients. So now that will be also supportive eventually of our BLA. The trial we're going to do itself is going to be similar to other trials in this disease pivotal trials. They tend to be very small because of the strong treatment effect, as I mentioned, probably less than -- can be significantly less than 100 patients. We saw that the Phase II enrolled very quickly at 9 months at a small number of sites. We do think this trial can enroll very quickly to Phase III. And that hearing the investigator enthusiasm, hearing from enthusiasm through them from the patients themselves, we do think that we can enroll it quickly as a Phase II did and be able to have the BLA in 2026. The other pieces that are important here that are really all set really are: the drug manufacturing is going to be submitted as part of the Phase III study. This will be the commercial drug manufacturing. The 2001, as you know, went through quickly through the IND. Methodology is very, very similar to what we did for 2001. So we also think the manufacturing is in good shape for the pivotal study.

And what about off-target studies and also the preclinical work that you have to do for the productive side as well, how confident that you can finish that before asking for the FDA to see if the Phase III plan is the right one to move forward?

So looking at those 2 pieces, the off-target work has already been presented as part of the submission for the Phase I/II. So they -- we've been able to have discussions with them because we have RMAT designation. This allows a more free communication with the FDA. We feel that the off-target work we have done is satisfying them as it did for 2001 to go into Phase III. For the women in childbearing potential, we had presented data showing -- a breeding study showing that we're not passing this on through the term line, some localization studies showing that it's the editing is not in OVA. So between those 2, they did want us to go one step further. It's a study slightly different from the breeding study. It's a reproductive toxicity study where you look at the developing embryos. Based on the fact in the breeding study, the animals are completely healthy. There are no unexpected deaths in that group. We fully expect that to be straightforward and show good results. And that will be done well before we start the Phase III.

Any questions from the audience? In terms of, I guess, overall data flow. When we think about ATTR-CM, I think part of us also want to see any functional benefits as well. How soon can we see any potential functional measures? And like I think you're tracking the MR, the hard, proBNP levels. Are those mature enough today for us to get a sense this year?

Yes. We think that these things evolve pretty slowly in the MRI, and you see that, for example, the APOLLO-B data, you saw that there's not much functional change over the first year on the drug. So it will take longer to see the maturity. We haven't guided yet to when this will be mature. But as we have in the past, when we have a body of data that we feel was interpretable, we will bring that forward and talk about the data.

Okay. And where are you now in the MAGNITUDE trial? And yes, we'll start with that first.

So we announced, we've initiated the first site. So at this point, we can start to enroll patients. I'm not going to talk about patient by patient, we'll probably announce when the first patient gets treated after they've been screened and actually treated. But -- and then periodically, we'll be giving updates about the enrollment and looking to see that we're keeping that on track.

I think one question about the study is always about the trial size of the study. I guess, one question I always have is, how do you think about the powering of the study? And when you compare to some of your competitors, when you look at Ionis study, it's also much bigger than yours, right? So how do you think about the powering? And how confident are you around the trial design? And lastly is the potential interim analysis, right? What would unlock that piece as well?

Yes. So the trial size, I think you've seen is similar to HELIOS-B. I think our assumptions are close to HELIOS-B, then we could talk about where Ionis is going with a very large trial. It's large enough at 765 patients to see a very important treatment effect for patients in terms of reducing cardiovascular events and cardiovascular mortality. So, we feel confident in terms of the size of the trial. We're going to have a mix of patients, patients who are -- have mutations and don't have mutations, patients who have more advanced disease and less advanced disease, patients are on tafamidis and patients who are into tafamidis, ends up being a similar design to the other studies, we have about 50% of the patients on tafamidis. We expect to have about 50%. We've looked to patients who are a little bit higher stand in terms of having greater medical need. They have a proBNP of greater than 1,000. So this will be a group that we really feel we can demonstrate an important benefit for them in terms of their medical needs. I'm trying to think the other question.