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

Good morning, everyone. My name is Gena Wang. I'm biotech analyst at the Barclays. Welcome to our fifth Gene Editing Gene Therapy Summit. It is my great pleasure to introduce our next speaker, John Leonard, President and Chief Executive Officer from Intellia. John, maybe I will hand over to you to give a brief overview, and we will dive into the Q&A.

Good morning, Gena. It's great to be here again. So that was fun to take your questions. By way of introduction, Intellia Therapeutics, I think the best way to think about us is what we call a full spectrum genome editing company. And by that, we mean a CRISPR/Cas9 and all of its various forms platform that is applied to both the in vivo and the ex vivo setting. And we try to do that in a modular way from both sides, emphasizing systemic delivery on the in vivo. And as you know from work we've done before, we're very, very enthusiastic about our liponanoparticle platform. and have been putting that to great effect. Earlier this year, we were excited to present some landmark clinical data, which is the first example of in vivo genome editing in TTR amyloidosis patients. And that, as you know, received a lot of attention with that work published in New England Journal. And most recently, we've announced the progression of our pipeline with a follow-on in vivo program for hereditary angioedema moving towards the clinic with the expectation to be dosing or treating patients in that study by the end of this year as well as advancing a product from our ex vivo setting, NTLA-5001 for AML, where we expect to be screening patients here by the end of this year as well. And at our last earnings call, just recently, we announced the disclosure of two development candidates moving into the insertion side of our in vivo work first with a jointly progressed program from Regeneron with hemophilia B. And then secondly, our own wholly-owned alpha-1 antitrypsin. So that gives you a broad backdrop of where we are and where we're going and love to take your questions.

And indeed, the ATTR data certainly is transformational for the space and open up a new chapter of drug development for the next phase. So with that, I wanted to start with the gene editing question, the overall big picture. Now you have validated in vivo editing platform. And there are many well-vetted targets. So what will be your criteria to select targets beyond ATTR and HAE?

Well, we believe we've unlocked the liver, certainly from the standpoint of genome editing, and we've done that, we think, in a really very, very compelling way with knockout target. So there's a series of other targets, some of which are well known, of course, hereditary angioedema is the second one. There's a series of other targets that we're considering. But the way we look at them is we want to make sure that the disease and the pharmacology is largely tied to gene activity in the liver. So in terms of where we are currently, we can access it. We're particularly interested in those diseases that have a well-validated biomarker. So very, very early. We can see where we are. We like it when there's a regulatory pathway that's been determined so that as we embark on these programs so we can see our way to the end in a way that's going to be meaningful, not just to regulators, but obviously the patients as well. But we're also particularly interested in extending the platform beyond the knockout approach to the knock-in side of things. We think that, that is a whole broader category to extend to, hence, the interest in the two development candidates that I referred to. So as we think about where we're going as a company, we like to think about it in terms of edit type, knock in, knock out and tissue type as well, particularly on the in vivo side. And our work is meant to extend in all of those different directions.

Okay. So if we focus in on, say, knockout because this is the most validated so far, the other insertion for very exciting that will be also certainly look forward to that as well. But near term, seeing as knockout is much better. We have a clinical validation of these. So like if you're giving all those criteria, you think of PCSK9 is another target you will be thinking about it?

Well, we think about them all, Gena, and we certainly think about PCSK9. I'll tell you how I think about that one versus some of the rare diseases. We're mindful of -- I was keeping foremost in our consideration, benefit/risk accumulating a safety data as we go. So as you expand in the patient populations, you want to do that with the soundest of foundation as possible. So PCSK9 is certainly on our list of knockout targets. And there's a variety of ways we can think about addressing that. I think that when we consider treating risk factors, which is clearly what PCSK9 is for a broad-based cardiovascular disease in a larger patient population, our view is that there's probably some other things that make more sense to pursue approximately before we go directly to PCSK9.

Okay. That's very interesting. So would that be the market opportunity? Would that be also important, like we see, larger disease? Would that be part of the reason for the other targets that you choose over PCSK9?

We always keep in mind benefit risk. And I think that whether you're doing genome editing, small molecule drug development, antibodies, et cetera, you want to start there with what is the benefit you can actually bring to those patients versus the risk known or otherwise, that the particular modality would have. And in the case of PCSK9, you're treating primarily what is a risk factor as opposed to ongoing disease states. So I'm not saying there's not a place for genome editing. We certainly think there is. But as we think about targets to pursue, I would not put that next on our list.

Okay. And when will you share those other candidates with investors?

We like to talk about where we're going when it's very much in focus, and we have data in hand that we're comfortable with so that we can always do what we've tried to do now, which is under promise and over deliver, Gena. And I think that's the way that our investors like to be. So as we accumulate the information, we'll share it when we think the time is appropriate.

Okay. So means by the time you will share that like you already have animal data, very promising, maybe molecule data.

We would -- well, I didn't say that, but we would always -- the right information for us to make a judgment that we think it's the right target to pursue and that we think it's a program that can be successful.

Okay. Fair. So another question also regarding the technology platform. The off-target editing is already a focus for FDA and that way back, years back. So what is the FDA feedback now on the translocation risk? And then is there any CMC release assay data package will be needed for the R&D or pivotal trial, the additional scrutiny that FDA will be asking regarding the translocation of chromosome optimality.

We've been very, very diligent with respect to how we characterize any genomic aberration, as close watchers of the space and our own data we'll see. I mean we start with even the gene transduction approach, which is in the ex vivo setting, electroporation, which is something that's not much talked about by many in the space, but that by itself, irrespective of the gene editing technique, whether you're using a [ Indiscernible ] editor or any other modality introduces significant genetic damage and translocations. And we found ways to eliminate that where we show that even transducing whatever approach, leads to -- with our technique and avoid all translocations. And we've shared that night. I think the regulators are very enthusiastic about that approach. And we think it will address some of the questions that may have emerged with some of the other data that's been shared more recently. But beyond that, what we do is take a sequential approach when we use the standard CRISPR/Cas9. And again, when we compare that to unedited cells, we see essentially no translocations and that's been very comforting to the regulators. So, I would contrast that technique with just about anybody else's work that's been done, and that's something that we feel quite confident we'll be successful in the clinic.

So now move to your lead candidate, ATTR. So since your data, and we saw quite a lot of other companies have started to focusing on liponanoparticle deliver -- liver targeted and some claims based on the monkey data, our data looks better. So any update? We did see, in your case, the monkey translates actually better in human. And any updated thoughts on why your non-human primate data transferred much better in human and compared to the others?

Yes. I think anyone who's going to build a model and certainly draw across species or cross product comparisons should have access to all the information. In our own case, we had information that was really important to the model that we didn't share, which is the performance of the human guide relative to the monkey guide. So I listen to people as they share opinions and speculate and all that. But in my mind, it's merely that, a speculation. And unless you have the information to make the projection, someone certainly going to be flawed. So as we do our work, we take into consideration all of the data that we generate, and we were very, very pleased to see the performance pretty much following along the lines what we had anticipated. But obviously, until you do the experiment in the clinic, you're not sure, but we were quite pleased with the performance of our model.

Okay. Very good. And then regarding the dose level of the fourth cohort, and you announced that at the earnings call that you selected 0.7 milligram per kg. So just wondering why select that? Wouldn't milligram 2 mg per kg to give you more information regarding safety efficacy for the platform? And also, you could have a readthrough to the other candidates. You can dose high or you can check the safety whether you can dose that high. So why choosing 0.7 mg over 2 mg?

Yes. I think it's really important to step back and remember what the purpose of a dose finding exercise is as we made clear from the get-go on this, that fourth cohort was always designed to be kind of a swing factor, if you will, where we could go up or go down based on where we want to focus and get a little bit more information. So we think of it primarily as understanding in the best possible way the dose-response relationship. And so when you think of the shape of those curves, they're not strictly linear, oftentimes they're signal, and you can get on flat parts of the curve that will have less information. And where you really want to understand is those parts of the curve where information is the richest, right? So when we work through our calculations from the first 3 doses and thought about where we wanted to go, we want to interpolate just to get a little bit more information as we close in on what we think is going to be the dose that we're more likely to carry forward. So you'll see once we share data, as we go forward, the importance of that particular cohort and why we're enthusiastic about where we are.

Okay. And John, first half, you will share the data with us. Can you just lay out what kind of data sets you'll be sharing with us from how many cohorts or how many months follow-up from early cohorts, later cohorts? So if you can just lay out what kind of data set you will be sharing with us.

Well, on our last earnings call, we said that we would share information in the first quarter, you said first half, I just want to make sure people understand what we had shared back on the earnings call. But the expectation is that we will have completed all four cohorts. We'll have, obviously, efficacy information along the lines that we've presented before. That first 28 days is key, the safety profile that goes with that. And we'll have extended observations on all four cohorts. We haven't shared exactly how many weeks on every single cohort, but we'll have enough information for us to apply the principles that we've used thus far, which is enough information that's meaningful, interpretable so that we can make decisions going forward. You'll remember also in the earnings call, we shared that we are in the process of amending the protocol to bring cardiomyopathy patients in, which really accelerates the program so we can get information from that important patient population earlier and we would expect to be in a position to have that second stage of the study up and rolling and be well on our way to collecting information that we need to go to the next phase.

John, is it fair to say at the data update, we will see the, say, longer follow-up data from the twelve cohorts -- the first cohort?

Yes. It's obviously, those patients that began first are going to have more information than the ones that came in most recently, and we'll be in a position to share more information on those patients and that would be the plan.

Okay. And then what will be the criteria to determine the dose for expansion cohort as well as for the cardiomyopathy approach?

Well, we follow standard guidance for drug development, which is trying to determine that dose that gives you the most efficacy with the best safety profile at the lowest possible dose. And that's the thinking that we're using as we look at the information we've collected, the modeling that we do. We'll test that in Stage 2. The cardiomyopathy patients will be subjected to that dose as well. So our expectation that because the biology is essentially identical in the liver that it will be the same dose, but we need to confirm that and that's what we'll do as we advance in the Stage 2 going forward.

Okay. And John, if the -- there is one data showing -- one cohort showing 80% to 85% knocking down. The other cohort showing over 90% and they issue almost identical safety. And I heard you mentioned like a lower effective dose, will you select cohort with the over 90% knocking down or you will select the cohort with 80% something?

Yes. Well, I don't want to get into numbers here. What I was trying to convey and again, this is the standard guidance is achieving the maximal effect at the lowest possible dose. So we don't want to compromise on efficacy, and you should not interpret my comments that way. But if one can achieve the same efficacy at different doses, you would choose the lower of those two doses. I mean that's the way the FDA guides us, and that's certainly the way that I think responsible drug development is done.

Okay. Sorry, maybe I should rephrase differently. What will be the bar for you to consider the knocking down threshold that would deliver the best clinical benefit?

Well, our premise has always been that the lower the TTR that you get to, the greater the knockdown, that, that is going to translate into the most efficacy. That's generally true across amyloidosis, irrespective of type, and I'm not talking about just TTR, all forms of amyloidosis. It's also true with the knockdown data that we see from the hands of others. And so the premise here has always been that we should get to very, very low levels of TTR, which should translate presuming it surpasses the standard of care that currently exists. And we've already seen data that looks like that, that, that should translate into greater efficacy. And we would design our clinical programs to capture that information and that would be core to the program.

Okay. Great. And I assume the same dose will also be used for the cardiomyopathy program right?

That's the intention. And again, we haven't tested these patients yet, just to be very clear about that, but the expectation is that the same dose will behave the same way from a TTR knockdown point of view in cardiomyopathy patients. There's little reason, if any, to believe that they're going to perform differently. But we're doing this in a very stepwise diligent fashion to collect information first in the polyneuropathy patients and then the cardiomyopathy patients. The ideal format would be irrespective of manifestation of the disease to wind up with the same dose.

And then what is your plan for the R&D in the U.S. with filing all the data collecting? And what is the next step there?

Well, we'll assemble the information from this early stage study, and that will be the core of an IND filing for TTR program. Remember, as we move into pivotal programs, this will absolutely be a global program. The U.S. will be very much a centerpiece of that. As I said, in the near term, we can get more information faster by amending the protocol that we're currently doing, and we think that puts us in even stronger position when it comes to filing the IND.

Okay, good. Switching gears quickly to HAE. This is another indication that has a very big potential there. Another question I got is usually because HAE, it's a different from polyneuropathy, it takes a long time to see clinical benefit. HAE do see the attack rate improvement very rapidly based on all the existing drugs -- approved drugs. So any thoughts on initial data sets that beyond the biomarker, will you be able to also share with us some kind of clinical data? For example, capture baseline attack rate and then after a certain time point, also sharing with us the attack rate improvement.

Yes. I mean we'll certainly collect that information. It's not the primary purpose of the first step of the study. The HAE program will, in many respects, parallel, the work that we're doing with TTR. In both instances, you have a very, very predictive biomarker. In the case of HAE, it's kallikrein levels, which we know from the work of others correlates with attack rates. So while we'll certainly collect attack rate information to the extent that we can in these smaller data sets, the level of knockdown kallikrein activity is going to be the primary target of interest for us, and that will be what we base decisions on how to progress the program, correlating that dose with the knockdown effect.

And John, I think the last time you mentioned that you will have the higher starting dose compared to ATTR program. So now with the more data you have in hand, like what is the thoughts that will be your initial starting dose for the HAE program?

Well, we haven't shared the precise dose, but we've obviously learned a lot in the course of the TTR program. And when I was making some of my introductory remarks, I commented on the modular approach, which is really helpful when you're bringing essentially the same delivery vehicle, in this case, the same LNP with the same mRNA essentially the same guide with the exception of 20 nucleotides. You can take that preclinical research information and clinical information from other programs and apply it here and we have. So as we go forward and share more data on the trial, not today, we'll be in a position to see how we've benefited from that prior work.

Okay. How soon realistically we could see the initial data for HAE?

Well, it's hard to promise a date. We like to work from principles that we've laid out and really adhere to essentially from the very beginning of our clinical work here, which is when we get information that we think is meaningful, consistent and interpretable. In other words, we'll tell us something about the next step or something about the drug that we think is important. That's when we'll share it. Obviously, we're interested in moving as briskly as we can, and we've tried to design a program that will collect information in a very, very efficient way. So as patients come in and we get that information, when we hit those thresholds, we will share the information ideally in a scientific or a medical meeting.

Okay. Lastly, we have only a few minutes left, I wanted to ask your insertion program. That's also another very exciting field. So what is the reason choosing AATD as your first wholly owned program?

In many respects, that's an ideal program for our approach. It's obviously has its origin in the liver. We've unlocked the liver with respect to our systemic delivery approach. So when you go and think about the TTR work, it's essentially using the same LNP, again, the same mRNA, which is targeting a different gene. And we've shown in humans and in animal work that we can do that quite effectively. We've also shown that you can get to very high levels of the structural protein being produced in animal models, essentially getting to normal human levels of the protein. And given this disease, what it needs, the relative lack of success that we've seen with other modalities, we think that this is an excellent disease state to pursue the work that we've done, and we think that the opportunity is essentially wide open.

Okay. Great. And I know we are running out of time. I do have -- I just remembered like one more question on HAE that given the time line with ATTR starting and to the timing to share the data, like basically June. So is it fair to think the HAE initial data now actually had -- could be a shorter time frame because now you identify sooner the potential optimal dose, but is it fair to say that mid-next year 2022 -- by mid-next year 2022, we should be able to see HAE data?

Well, we're all enthusiastic to see the data, and I'll go back to the principles that we shared before. As quickly as we can meet those principles, we'll be in a position to share that information and would be very, very enthusiastic about doing that. So as I like to say, stay tuned, and we'll watch as we go.

Great. Thank you very much, John.

My pleasure.

Thank you for the insightful discussion. Thank you. Thank you, everyone. Bye-bye.

Bye now.