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

Okay. Great. My name is Gena Wang. I'm speaking of biotech analyst at the Barclays. Thank you for coming to our first in-person Global Healthcare Conference post pandemic. It is really nice to see everyone in person. I wanted to thank everyone, investors, companies, especially [indiscernible] team who made this event possible. With that, it's my great pleasure to introduce our next presenting company, Intellia. With us today, we have John Leonard, President and Chief Executive Officer. John, do you want to give a very brief introduction before we dive into the questions?

Sure. Sure. Thank you. I can -- real quickly I can kind of lay out what Intellia is. We call ourselves a full spectrum [indiscernible] company, which means we have really 3 legs to the stool, a very, very active in vivo effort where we emphasize systemically administered CRISPR/Cas9. I'm sure we'll be talking about that. We also have a very active ex vivo program, where we emphasize primarily immuno-oncology and some autoimmune disease through collaborations. And then really importantly is the third leg of that stool, which is our platform. We view CRISPR/Cas as is very, very dynamic space with continual evolution of the science and technology, and we very, very actively invest in canonical Cas 9 and what that can do in the various other particular applications of that. So whether it be our own proprietary base editor as appropriate, gene writing where we have a capability as well. So big story, lots of things going on.

Okay. So I think after your recent data update, I got quite a lot of investor feedback and a question mainly focusing on 2 topics. So the first one will be the scientific explanation, why durability of low-dose cohort will be different from high dose, since both will be permanent knockdown. And so maybe I will start with that question.

Well, I think, the answer of the question is wrong in that somehow a difference in durability. What we presented was data achieved at the [indiscernible] which is 28 days after dose, and then we took the farthest out data that we had, and you'll remember, it's a single ascending dose studies that we have, obviously, the most data on the lowest doses and the least amount of durability on the highest doses. And what we showed at the test dose, which was the starting dose of NTLA-2001 was at day 28, there's about a 50% or so knockdown in TTR. There's about a 40% effect as we looked out at about a year from one patient and there are 2 at 9 months at that point. If you look at the variance in those 2 numbers, they overlap. So from a statistical point of view, they're essentially the same number. We know from our preclinical data where you look at animals that are, I would say, lightly edited as you go and look for maximal effect. There's a fair amount of variability, just bounce. Some of that's just assay related. We also know that when you look at baseline data before a patient ever is treated, there's a bounce day-to-day. Some of that's assay-related, some of that's TTR. But as you look at saturating doses where you get -- you remove the ability to have a lot of that variability is hard to go over 100%, obviously. And there's not that much TTR being produced. You see that variability collapse. So we're -- we think, this entirely recapitulate what we expected to see and what we telegraphed that people would probably see in these lower doses. And as we get additional data, we'll share where those numbers sort out, but I would expect them to be continuing along the 40% to 50% range.

So I think that for the low-dose cohort, there are 2 patients at the 2 months was at 54% knockdown. And then after the longer fall off a dropped quite a lot. So it seems like one patient maybe bounced back.

Okay. That's -- thank you for that. Yes, what we showed in our data was day 28 and then we showed everybody out at 2 months. The point was that you reach your nadir at day 28. So you could see that. One of the 3 patients you're referring to was affected by COVID was not actually able to show up to the clinic that day, but that patient contributes to the -- all the data points thereafter.

So then the longer follow-up, when all the 3 patient data together, the percentage show up quite a lot. So is that mainly because that one patient brings the number down or...

All of those patients bounce a little bit. You can see it in the variance, one bounces a little bit more than the other, but sometimes up, sometimes down, and you see that captured in that variance. But again, when you look at day 28 versus a year for 1 and 9 months so that those numbers are largely overlapping in terms of variance. So from a statistical point of view, we would say they're the same number. Biologically, there's no reason why they would actually change. And just I think it's really important to remember that TTR that itself, when you measure it when there's a lot of it, there's a lot of variability assays even at baseline before patients treat it. That goes away as there's much less to measure. So not surprised by any of the information. Again, it's exactly what we saw in our preclinical work.

Okay. Do you think that another layer is low dose, then you have maybe more monolithic editing...

More, I'm sorry?

Monolithic editing versus biolytic editing? Would that cause any variability there?

I don't see how. I mean it's -- I don't know -- well, the way we think about it is there's some number of alleles, it's defined by the number of hepatocytes you have. And when you have incomplete editing, again, in the context of an ascending dose study where you're walking up to find the dose, that's going to work, you will have, by definition, you complete editing. So whether that is some hepatocytes with zero editing, a few with 1 for 2 alleles. We can't sort that out exactly. But generally speaking, all of the preclinical data that we have would suggest that once CRISPR/Cas gets into a cell, we're going to have both alleles [indiscernible].

Okay. So you think alleles is because the assay variability causing the fluctuation?

Exactly. The other thing to remember, just to put this out there, TTR is also an acute phase reactant. People forget that. In just physiological states, infection, fever, things like that will cause it to bounce around a lot as well.

Okay. Good. And another question regarding the fixed dose and the safety. I think that's another topic a lot of investors asking. So maybe before I ask a specific question, what was the weight for the Grade 3 gastroparesis patient?

I don't remember the precise weight, but it was well within the group for the gastroparesis patients. I think it's important to remember that polyneuropathy manifests as both peripheral nerves when we think about motor neurons but also autonomic neuropathy, which is why these patients have trouble standing up. They can't control the blood pressure. That doesn't work right, which is gastroparesis. This particular patient had this manifestation of this disease, gastroparesis, where -- which means that his gut wasn't functioning properly. You've been hospitalized several times before vomiting it in part of the manifestation of that. And while in the study you find, you had an episode of vomiting that caused him to stay over the standard confinement period, which automatically gets defined as the dose-limiting toxicity. But whether or not CRISPR 21 contributed to that at all, nobody really knows, which is why we say it's possibly related. But patients well after there's been no long-standing effects after that. This editing went very, very well. And I think it's just one of those things when you're dealing with sick people in the first place, they will have their underlying conditions become apparent in the course of the study.

Okay. Very good. So maybe can you remind me the onset of gastroparesis after dosing, how quick the gastroparesis?

When does this vomiting begin?

Yes.

It was around the time of dosing. I think after, I don't know, how many minutes, if that's what you're asking.

Okay. Yes.

But remember what the patient is, baseline is a nonfunctioning gut with vomiting, et cetera. Patient to travel from another country had gotten other medications have been changed, et cetera, and he had the material administered to him. So whether it contributed, we don't know how it's possibly. But I don't think it's anything that's going to have any effect with respect to the drug, its administration of the patients that we study as we go forward.

Okay. I think if it's a living minute.

Well, if you want to write a note what the precise number, I'll follow up and we can give you that.

Okay. So another question, I think, the investor was asking about fixed dose versus weight based. So even though we understand it's more convenient, but you do have a patient in the initial phase, you have the patient over 80 kilograms. So would you be worried about underdosing actually?

So we've been doing weight-based administration as we walk up to find the dose that we think is most appropriate to carry forward. And we explore that very carefully from a pharmacokinetic point of view. As patients get bigger in body mass, the liver doesn't typically grow at the same rate as the body mass. So at some point, in very, very large people, you're essentially overdose in the liver. If you want to think about those time. And so from the standpoint of thinking about what you need to actually achieve from an exposure point of view, that's the way we think about it. And what we did very, very carefully was look at the extremes of weight, low and the high and then applied standard sort of bioequivalence standards as if you're getting a generic drug approved, for example. And either extreme of that, the way the drug behaves as almost bioequivalent, the exposure is very relatively little difference at the either end of it. So when you weigh that and consider convenience in the hospital, pharmacy errors, how payers tend to think about weight-based medicines, there's a lot more reasons to put a decision on this side of the equation than to chase something where you're going to have very little differences that as far as we can tell, don't translate into therapeutic benefit.

So why using weight based for cardiomyopathy cohort?

Well, I think, it's really important to bear in mind what we're doing. I mean this is still a Phase I study where the polyneuropathy arm has moved ahead because that's where we began. And then we've begun the cardiomyopathy study offset in time. We've forgone the first 2 of those 4 doses and are applying the 2 higher doses in that single ascending dose arm to the cardiomyopathy patients only to determine whether or not we exactly recapitulate what we've already seen. The assumption is we will, but I think we have to recognize that's an assumption until we actually do it, right? And then the objective would be and the expectation is that, that will collapse to the same common dose in that expansion phase part 2, as we call it, and we'll continue to collect exposure data there. But I think it's just a little premature from a study design point of view to conclude that it's all going to be exactly the same to we actually prove it.

Okay. So I think some pushback is now you need to -- like once you identify dose, you need to -- if you add an additional step to do the fixed dose in order to truly understand the clinical profile for the pivotal data?

I don't understand what the extra step is.

So like you say, weight based and then you need to do another study was fixed dose.

No, no. The idea -- and this is very important, is that in that first Phase I study, there's 2 parts to it. So it's the same study. There's the single ascending dose phase, which is weight based. And then we are able to modify the protocol choosing a dose that's either weight-based or fixed dose. And so we've opted for that fixed dose in that expansion phase of as you set up for that being the basis to move in the pivotal trial. So we're not imagining unless we learn something, which is always the case with drug development, we don't think that there's another step that's necessary in between that and going to the larger studies.

So basically, no more cohort in order to -- yes?

I mean we'll add the cardiomyopathy and the polyneuropathy patients from this expansion phase, and we think that, that should be sufficient to know what we want to do.

And for the next update, have you maybe initiated the dose expansion cohort, I think, we previously guided 1Q? And also can you detail the data -- type of data you will be sharing with investor in the next update?

Well, we -- the expansion cohort is moving. And we're very excited about that. And just as is the case with every study, you got to get the patients and collect the data before you present it. So we're trying to do that as expeditiously as we can. What we have said is we'll share more data this year at a medical or scientific conference, we'll expand on the exposure data to the extent that we have it. I think one thing that's important to remember is that the sampling of the study is less frequent as you go out. We're not collecting every week or every month. It's not all that meaningful. So it goes after 6 months, 9 months, 12 months, et cetera. So you got to wait a little longer to get those additional data points. And as for the expansion parts of this first study, we've been guided to presenting any of that information this year, but we'll see what we have as the year goes on. I think the thing to look for in the upcoming data will be a pretty purple walk through some of the pharmacokinetics, so people can see how we got to that single dose for that -- I'm sorry, fixed dose application.

Okay. Very helpful. When you see medical conferences later this year, can you provide us some of the candidates like that venue that will be good for the presentations?

It's premature to do that. I mean we always promise that when we start closing in on having a story to tell, and we will telegraph well in advance where we're going to do that presentation. But again, it's very much determined by the rate at which we can collect data. So rather than listing off the many conferences that might take place this year once to stay tuned, and we'll save you a lot of work.

Okay, good. So another, I think, a pushback from the investor was the lack of transparency regarding the data presentation, basically complaining about no individual patient data. So for the next update, will you be able to share like [indiscernible] for every patient or...

We'll see what we have. And I think we'll present the data that we think is most informative and that best tells story. Part of the challenge is that when you have patients that only different stages by definition because of dose-escalation story, trying to tell that in a way that's meaningful is something that we focus on really very, very carefully. Our belief is that the most meaningful information on durability is the longest time point. And as time goes on, what we see others doing and what I think is being the fields present averages for groups so that people don't follow an individual bouncing ball through all time. But we'll see if there's something that's particularly informative, we'll look at that and consider talking about that as well.

Okay. But we have 6 minutes left, I wanted to ask about a few other questions. One is the IT part. That was when you presented data the IT announcement. So what is the latest thoughts? I'm pretty sure the CDC will appeal. And what do you see, let's say, fast forward 3 years, where do you settle and do you figure your IT, the foundational IT was to be strong enough for -- to be able to hold and you will be able to have the right to do the clinical development on certainly we're cross-licensing?

I don't think we're really in a very different place from where we've been since 2016 when this began or even before. The one common misconception is that the companies are somehow fighting, traffic companies are fighting. It's 2 institutions, University of California and the abroad. And I would argue primarily for reputational purposes, a personal belief, although I know of many others who hold that view. In some respects, the reputation part of this has already been determined, and the Nobel Prize was awarded. But from the standpoint of what -- where the IP sits, the process is far from over. There's been no statement that University of California will appeal. I think it's a highly likely outcome. We've heard Jennifer [indiscernible] say that publicly. I think we have to remember that the road is still subject to 2 interference proceedings not from the University of California, but from 2 companies that filed the same patent in advance of the broad hardly reported on. So it's easy to misunderstand that. One of the fundamental questions that has been out there is in the public documents, is whether or not some of the legal proceedings by which that patent was filed were correct in equitable contact, which the PTAB doesn't address. That's a legal proceeding. And so whether or not the broad even keeps that patent down the road remains to be same. But even if all of that plays out in a way that leads to the situation as it stands today, the broad is very little outside the United States. And if they're going to be in a position to exercise any commercial rights at all side of the United States, they'll need the University of California. And so the likely outcome here is as it has been since 2016 is some cross-licensing agreement, which if you do the math and you think about what those royalties typically are, if it even occurs, the net present value of that would be a de minimis number. So it's -- I think it's something that is a story, but from the economics of how we think about the business actually runs, it has very, very little effect.

John, would you be able to comment like the royalty way? What will be the industry norm for the situation like that?

Well, it's complicated. I'm not negotiating here. It's not just me, by the way. but it's -- I mean, a typical number would be low single digits. I think it's the sort of thing that you'd expect. And remember that the broad will feed the University of California's IP for a lot of what they do in the United States and almost everything that they do outside the United States.

Okay. Very helpful. We have a few more minutes. I wanted to touch on your second very important program as well. Actually yes, later this year, you will have the data. So the -- is it fair to say the 90% knocking down is your goal?

Well, we haven't put a number out. I think we expect to get very high levels of knockdown. I mean it all stems from the modularity approach where remember that the LNP is identical to the TTR LNP with the exception of 20 nucleotides. So it's our expectation that it will behave very, very similarly. You don't have to get to a 90% effect. It's a little different from TTR. We know that a 60% knockdown just when you look at the antibodies, it leads to a very, very significant clinical benefit, and we would expect to handily surpass numbers like that. But I'm not chasing 90% if that's what you mean by your question.

So based on what we've seen so far with ATTR program is like 0.7 and 1 milligram. That's a good way to think about it?

Well, we'll see. I mean I would expect that we'll wind up with doses that are reminiscent of what we're seeing with TTR, but until we get the data, that's the work we're doing now. And as soon as we know, we'll share that. But I think there's little reason to believe it will be very different from what we're currently seeing with TTR.

Okay. And the data also will be at the scientific meeting, right, later this year?

That's the plan, yes.

Okay. I assume...

To the extent that we have it. I mean we're doing cohort by cohort just as we did the TTR, but assuming we have a group of patients, we can talk about, we absolutely will.

Will you be able to collect the outcome data, like attack rates from patient baseline and the follow-up data?

We'll collect attack rates, but I think it's premature to read much into that from a standpoint that it's descriptive in the sense that we'll collect what there is, but the study is not set up to have that be the primary outcome. What we're primarily looking for is effects on kallikrein levels, and then we can impute what the likely effect is going to be based on what we know from other programs. But these are small patient numbers in the Phase I. It's primarily trying to get the protein knockdown and then set up a start to actually measure those attack rates with the chosen boes.

Last 1 or 2 minutes, your insertion program, ATTD we do have insertion approach. You also have a knockdown approach. So maybe elaborating a little bit how you...

Well, there's a 2 manifestations of Alpha-1, the liver disease where you have a protein you can't get out and then the pulmonary disease, which is the primary cause of the morbidity mortality where the protein that can't out doesn't arrive to this destination. And what we tried to do is break those into 2 problems. So 2003 is the knockdown where you take out that protein, then 301, which you just referenced is the knock in to different low side. And so we treat those programs as independent of each other, but we can certainly bring them together into the same patient that we choose to. So we think we'll have a total solution at the end, but we can do it in a way that's risk mitigated and lets us be sure to take advantage of what we've already learned on knockdowns and then take the next step with genome editing and the insertion separately.

I know we're running out of time. Well, thank you very much, John.

Good to see you. Thank you.

Thank you, everyone.