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

Good afternoon. Welcome to Barclays' Global Healthcare Conference. My name is Gena Wang. I'm a SMID-cap biotech analyst. It is my great pleasure to introduce our next presenting company, Intellia. With us today, we have David Lebwohl, Chief Medical Officer. We also have Glenn Goddard, Chief Financial Officer. And Glenn will give us a brief overview with a few slides.

Great. Thank you, Gena. And I'll just start. We picked 3 slides from our corporate deck to start us off; help level set, especially for people that may be newer to Intellia. So this first slide, I think, is an important one. It's really how we've built the company and really focuses the company strategy in one picture here. So one thing to know about the company is, at its core, [indiscernible] platform. And that's based on a set of novel editing tools that we've pulled together and some delivery tools. And from this foundation, we're building an emerging pipeline. And the way to think of that pipeline really is in 2 areas of focus, 1 being in vivo applications of CRISPR and CRISPR-related tools. And the way to think about that is really using CRISPR as the therapy, so to think about it at a higher level is we're trying to fix broken genes and applying this in the genetic disease space. On the flip side of this slide, we talk about ex vivo and using CRISPR to create the therapy. So what we think about here is really using cells and rewiring them to give them different functionality to -- and we can use them in the oncology and autoimmune space. So as I click ahead to this next slide. Really this summarizes the last 2 years, some of the key important milestones that the company has achieved. So I think one of the things we're really proud about is we're really the first and only company to demonstrate successful systemic CRISPR-based genome edit in humans. To date, we have dosed over 50 patients. And now we've shown clinical data from 3 programs successfully, and we're well positioned to start the first-ever CRISPR-based pivotal trial. And if you look to the pipeline: We have over 10 programs that are moving forward. We've done 6 collaborations to date, and again the underpinning of this is our deep platform based on CRISPR. So if I click ahead. And now if you think about where the company is focused for the next 2 years [indiscernible]. So first and foremost is we're going to be laser focused on starting global pivotal trials for both our TTR and ATD programs. So that's priority 1. Second is really bringing new programs forward that leverage our gene insertion capabilities [ and our allogeneic ] technology, so we're very excited to be moving these programs forward as well. And then behind this, we're going to continue to bring forward some of these new gene editing capabilities we've been talking about, and delivery modalities, into our pipeline, so stay tuned for that, but that's a -- really a good snapshot of where the company is focused as we look forward for the next 2 years. So that's our overview, Gena, so I'll turn it back over to you to start the chat.

Sure. Sounds good. So I think you recently achieved a very important milestone in cleared IND in the U.S. Actually that's the first-ever IND that cleared, so can you share [ some feedback ] on the safety profile the FDA is looking for? And what is the difference between CTA and IND?

Okay, [ why don't I do that ]? The -- so the -- what the Europeans want in a CTA and, with the U.S., they want -- the FDA wants an IND actually is not very different. They're pretty close, but each authority has [ the majority list. We have ] [indiscernible] questions [ they ask about things ], and we obviously prepare to be able to answer those. So the achievement in the IND is based, most importantly -- INDs usually go in for first-in-human studies. We're coming in for Phase II. What's important there is that you're going to look very carefully, as [ they ] do for Phase I, at how you manufacture the drugs. That's very key for them. In the case of in vivo gene editing, a big question is about, as you've seen, if they're off targeted. How do you test for off-target editing? And we think, we do think we've set the standard there. We've talked -- we've given talks to the FDA [ to say how we do that ]. And of course, the clearing of the IND is [indiscernible] at that point. They also asked for early nonclinical studies, how you -- if you're interested in potential for germline editing, those type of things. And then in our case, what was great is we did have that safety data. And the drug looks quite good in terms of tolerability at the 3 doses we've tested. And they also had to agree to the Phase II design. So part of this is saying you're studying 2 doses, 25 and 50, which looked very good in the first part of the study; or the placebo arm. And that was again supported going forward in the IND.

That's very helpful. So the kind of thinking -- because now you have initial experience with the IND clearance. And how would that be -- now you have [indiscernible] and also very important in IND clearance [ for the global Phase III ] study. So how much more do you have -- or how much extra confidence you gained by clearing this IND.

Yes. There are a number of things which helps us with the TTR IND. One of those fundamental things we've talked about: How do you manufacture the drug? How do you test for off-target editing? How do you do the safety studies, preclinical studies? And of course, the safety that we saw in HAE with the LNP is really a very similar safety that we did see in TTR and have expected to see in TTR, so they support each other in terms of clinical safety. Now there are differences in these INDs. In the case of the TTR IND, we are asking to be a Phase III study. That's a bigger ask of the FDA. They really -- this is a study that will lead us to the BLA, so [ they ] would be very careful in terms of the design of that study. You also have to do more controls for your drug manufacturing as you go into Phase III, so that's important. On the positive side -- those are the increased hurdles. On the positive side, we have more than 40 patients treated. We'll be bringing them data on that set of patients so they have, again, very good confidence in knowing what our drug does in these patients.

So David, you mentioned that you will need more control for manufacturing, so maybe could you elaborate a little bit on what kind of more control compared to, say, a HAE [ active goals ]? Yes.

Yes. So the main thing, as you go into Phase III, your drug has to basically be the same drug that you expect to see in the commercial setting. It really should be the process that gets you there. The [ flows of ] that are a bit complicated, but in this case it's been a fairly straightforward scaling up to get there. And we do think we've addressed the questions they've asked about in the pre-IND meeting.

Okay, very good. And then the timing for [ such. Are you ] still on track for mid-'23?

That's right. For mid-'23 is the time line.

Okay, okay. What is your definition of mid-'23? Because every company has different definition...

[ Definitely ]...

Yes. It's a good -- so mid this year could be anytime in Q2...

Okay, so 2Q, okay, yes. And then you announce. Or will you -- will it be similar, you announce submission? Or will you announce when it's FDA gave you a feedback?

Yes. The plan will be to announce once we get feedback from the FDA, yes.

Yes. So basically [indiscernible]...

We're not sure here, but...

Yes. So [indiscernible].

Yes. [indiscernible], which we hope [indiscernible].

Yes. That's right, yes, okay, very helpful. So now we'll switch gear to, let's see, [indiscernible] regarding [indiscernible] later this year. So maybe, first, like, would that be at a medical conference? And...

Yes. So yes, the plan would be at a medical conference. I think you know with the first data that showed the events come away completely. [ They, we're ] very happy with that, patients treated. We haven't shown yet data on events [indiscernible] actually bridged by the 25 and the 75. So we know what we anticipate there, but the other thing is we'll have longer follow-up on the patients as well. This will be a good view of -- give you a pretty good idea of what's going to happen in Phase II because we'll have the whole spectrum [indiscernible].

So given you already showed 25 milligram and the 75 milligram managed to -- actually, if we look at attack rate reduction, starting from week 5, it actually leads to a very comfortable 89% reduction. And would that be the -- kind of reasonable to think in the [ typical branch ] it could be similar range?

Yes. We would think it's going to be similar to the others. The main difference even the 25 -- the 50 and 75 were very similar in terms of reducing prekallikrein. So the reason we chose the 50 for Phase II is a lower dose gets basically the same effect as 75. 25 actually had a more uneven reduction of prekallikrein. And so again we wanted to test a lower dose and have these 2 doses to compare. [ If ] attacks went away [indiscernible] it's hard to say one is really better than the other at this point.

So what additional data could help you understand which dose will be the best dose and with a longer follow-up? [ Like are we ] expecting -- so because the -- [ post ] first 2 doses, you do see patient -- and most of them already -- the last follow-up is already [ attack free ]. So like what would be the best data points to help you understand this is the right dose?

Yes. There are a couple of things. One, of course, is always safety [ because safety first ]. Like those [indiscernible], so far. [ And they're explaining all these safety ] [indiscernible]. The only thing that seems to be related to the [ IND ] are infusion-related reactions. Next big point is how consistent is the effect on the pharmacodynamic end point, which is both prekallikrein protein and prekallikrein activity. It was more consistent at the -- in the initial part of the study, but we do need more patients to really confirm that. And then of course, the attacks: Over time, are there any breakthrough attacks at one or the other dose? What can we say about that? Yes.

Okay, good. And then the other part is your IND cleared, U.S. IND cleared. And then this is ex U.S. You already start [indiscernible] maybe a little bit more color on the U.S. sites. How many active sites? And then we -- and given we have pretty good standard of care, give us a little bit of color on [ how you're seeing demand there ], the enrollment speed [indiscernible].

Yes. So in terms of starting up in the U.S., we did just get the IND. You really need that at most sites in order to activate sites, so the activations are in process. And we can't -- I'm not saying exactly when that will happen, but it -- also we are screening outside the U.S. So the trial will -- what we're hearing from the investigators, will enroll quite efficiently. And the second question is -- I'm trying to remember. What was the second question again...

I think the speed of enrollment...

Yes...

Yes. So as -- yes. What we think is, based on what investigators are telling us, it should be quite brisk...

Okay. I mean, if we look at the Phase II study design, we only have 10 patients [ at 50 milligram. With ] 25 milligram, there were also 10 patients; placebo, 5 patients, so it's a relatively small number of patient. Like how quick do you think you can complete enrollment? And now you have the U.S. onboard, yes.

Yes. We want to go as quickly as possible. I guess the one thing we did show is we want to be in pivotal stage by next year. So I guess that's -- during the next year -- in like the next few years. So that gives you an idea. [ We want to get that resolved ] and launch [ a Phase III ] program in that period, yes.

Okay. So which means we should see the data sometime this year, for you to start next year.

Not -- well, I would not say [indiscernible] exactly, but one thing to say about -- saying if it's a small trial. Pivotal trials in this area can be 80 patients. With 25 patients may even be a significant difference in the arms because the effect size is so large. Patients who aren't treated will continue to have attacks. As you see, if we go to 0 attacks in the active arms, you can see it's quite a -- good results then.

Okay. Any restriction regarding what percentage of patient has to be from U.S. for the study?

No. It -- we want to enroll it efficiently to get to the pivotal study. Of course, when we get to pivotal, we want to enroll. I know you did ask about patients from the U.S. There's a lot of interest. If you think about it: Patients in the U.S. might be taking, [ in fact, 0]. They have to go [indiscernible]. They have to go in periodically to the doctor. They can have breakthrough attacks, with -- the levels basically can change if you miss a dose [ particularly ]. So that, the idea that a single dose may treat them for life, that they may need no more -- they have no more breakthroughs if it goes very well -- so that is definitely driving a lot of interest not only overseas but also in the U.S.

Good. And another question is a naive patient versus a patient already [ on prophy ]. Like any thoughts like what kind of patient population you will be selecting?

Yes. The patients -- like all these pivotal trials are done with patients who -- not on prophylaxis. Some patients [ maybe join ] because they [indiscernible] the observation [indiscernible] it's not threatening to them, [ so they'll be able to take often prophylaxis ] in that period. And then as soon as possible, we would get them randomized in the trial.

Okay. So basically prophy patients wash out and then take in...

Exactly, yes.

Okay, good. And the baseline attack rate, any thoughts to like [indiscernible]?

Again it's pretty much a standard that patients have -- at least one attack a month is most standard. We haven't set exactly a pivotal design. We'll have to discuss it with health authorities, but something like [ the existing metrics ] will be there.

Okay, good, very good. So I think -- we'll switch gear to TTR programs, some of the kind of additional steps we've kind of discussed, but for you to submit -- we only have maybe a few more months [ to submit ]. Like what are the remaining steps you need to complete?

Yes. So this program is along with the Regeneron hemophilia program, or our first 2 insertion programs. So here, instead of knocking out the gene, we're putting in a new gene into the targeted locus, so it is a little more complex. The LNP, we feel very confident about, of course, because of what we've done with the other programs, that this will be able to target the albumin site in this case. We're using albumin because of the very high level...

Sorry. I'm just -- maybe I misquote -- ATTR, yes...

Yes -- ATTR. Sorry. I was thinking of AATD...

Yes.

Okay. We will also [indiscernible] that's not...

All right. On the [ next steps ]...

Yes, yes.

In this case, then we've treated [ a lot of ] patients. We treated [ a bunch of them ] by the end of the year. We've talked about that with cardiomyopathy. We are -- the other steps we've talked about are putting -- talking about putting together the documents about the drug manufacturing. It's certainly very important, summarizing the safety from the new patients as well. Putting in a Phase III trial, we're working with the -- pretty much every leading investigator in this area around the world to help inform how we're designing the trial. And so that's all coming together. It takes a while to assemble that. And then [ complete in the middle of the year ].

So mainly it's assembling existing data. And you do not need to [indiscernible] some assay or anything.

Yes. So yes, at this point, we are putting it together.

Okay, that's very good. So now, the Phase I additional data in 2023, maybe again similar, like timing of data update and also what's -- venue or format of the data update...

Yes. So we'd like to be at a medical meeting. We haven't said exactly what meeting that would be, but we always do announce it before we get there. Of course, we'll have more follow-up on the existing patients. [ We've got ] patients who we're treating [ at ] 55 milligram, which we predict will be the Phase III dose. The other thing, because it's been at about a year, we've started information on some of the cardiac functional things. One thing we're very interested in is cardiac MRI. It's a very good way of [ gauging what's ] happening to the actual amyloids in the heart. So that -- what we would -- that will be a very good measure beyond the TTR levels as well.

Okay. And then the [ NIS ] score, will you also be able to show that?

The...

The [ NIS ]...

[ NIS ] score.

Yes.

Yes. I'm not sure. We -- that, of course, you have to have enough data to put together. And we'll see [ what we'll get ] at the time. The main focus, most important focus, for most people [ is ] cardiomyopathy. It's -- now the -- for polyneuropathy, we are, again, planning -- it's designing a pivotal study now, but our priority has been cardiomyopathy. And then polyneuropathy will come after.

Okay. I think that makes sense. It's the much larger bucket.

Yes, yes.

Yes, yes. And then [ the cardiomyopathy ]. I think I remember, in the past, we also -- will we also see additional safety? Because we did, I think, complete [ the cohort on fast track ], cohort 2. Or like...

Yes, part 2, yes.

Yes, part 2, yes.

So that's -- yes. So that's the patients [ with 55 ]. And that will be -- there will be full data on...

Okay. So safety and then the efficacy and the cardio measurements.

Yes, yes, yes.

Okay. That makes sense.

Most patients [ will be ready ] for the cardio measurements [ than ] patients at the end of the year, but some of the earlier patients will have some information.

Okay, yes. So now going back to [ clinical ] study design. Actually it's not that long distance. That would be like end of this year we'll be updating the thoughts there. So maybe your updated thoughts on what will be the best trial design that maximize the -- your [indiscernible] but minimize the development [ and ] trajectory [indiscernible]...

Yes. We think there are a couple of important features. It's going to have to be a larger trial like HELIOS-B. We think...

Well, even -- maybe I wanted to ask because Ionis has [indiscernible] or the Ionis...

Well, we think, if you have a good treatment effect, you'll need a smaller trial, so we do anticipate that we wouldn't need that large a trial to show the treatment effect. First, the huge thing we have in the design is we [indiscernible] the results from those other trials before we [ unwind ] our trial. So as you know, AstraZeneca has larger trials, for the reasons [ they have wanted ] -- completely explained, but we would also have the opportunity [ to become a ] large trial and make other modifications to the analysis based on what we see. In terms of other design features, we think a lot of the patients [ will be on ] tafamidis, that being very widely used in the world, but there are still places where the patients would not be treated with tafamidis...

So [indiscernible] like you can still allow patients [ tafamidis ]...

For sure, yes.

Yes. [ Wasn't that causing some heavy dynamic ] of the patient population? Why not just allow everyone to [ be on tafamidis ]...

Well, they could be allowed, but it's not available to some people. So that's probably [indiscernible] on why they can't get access to this tafamidis. And we do think a majority of patients will be on it given [ the use in kind of the world ] now.

Okay. And the control arm, you would be thinking [indiscernible] before. Like which [ flow like you need to do ]...

Like HELIOS-B. It will be a placebo, like HELIOS-B. And because there's no TTR-lowering agent that's approved, that's the appropriate [ arm ].

Okay, good, okay. So this is very helpful. Now we switch to AATD. I know you've started.

[ Now I'm ready ].

So let me go back, yes, yes.

Yes. So again. So AATD is our first insertion program, along with the hemophilia program at Regeneron. What we've seen preclinically [indiscernible] alpha-1 antitrypsin [indiscernible] nonhuman primates, which is something that has not been achieved with any other therapy to get to normal wild-type alpha-1 antitrypsin. The difference from this -- from the other studies is the likelihood of success is much higher, because we have been successful with the TTR program and the HAE program, because we know, with the LNP that we use, that it's almost identical. It's modular, but if you get some [indiscernible] TTRs or prekallikrein, now we're hitting the albumin locus. The idea is -- there is that's the best place [indiscernible] because you get very high levels of expression. In this case, [ gene is contributed ] by, more or less, AAV. It should be relatively safe compared to other types of AAV and relatively low doses. And that AAV contributes to the alpha-1 antitrypsin [indiscernible] that goes into the albumin locus.

So basically very similar to the heme A and heme B, right, insertion to the albumin and, I'll assume, the -- after the [ first human trial ], right?

Yes, yes, that's right.

Yes, yes. Okay, good. And then -- and by the way, what is the status of the heme A program, the -- I know it's a partner [ focus ], yes.

Yes, we've partnered, yes. So we actually let Regeneron [ talk of ] that basically.

Yes. [indiscernible] so Regeneron is the lead party. So they're the ones who will speak to it, but they have their -- that program is lining up well with 3001. [ So its programs are going well, yes ].

Yes, hemophilia B lining up. And then hemophilia A is coming after that, will be coming after that.

Yes, okay. So going back to AATD, the IND: Now slightly different, but we do have insertions slightly different holistically, so what do you think about the IND package and additional data pack you need to include so that you can have also [ one shot for you ]?

Yes. So the biggest new piece is the AATD itself and, of course, the requirements with that. Now that's been pretty well worked out [ because that's in a lot of ] gene therapy companies, so we want to know what we need for that, [ based on ] -- I said it's somewhat safer than a traditional gene therapy AAV. Of course, they will be interested in all of the same questions. How have you manufactured this? What do your preclinical studies show in terms of safety? Of course, the expression is very good, as I say, so I don't think there'd be any questions about the possibility of benefiting patients, because you're getting alpha-1 expressed in those patients. So -- and of course, the trial design itself, they're interested in. A big part of that is dose selection. Now you have 2 drugs. They're -- or not 2 drugs but 2 elements. You have the LNP and the AAV, so it's a little more complex. And we're doing a lot of modeling work to pick the right doses to go to.

So will you -- the 2 will definitely -- I assume both will be IV infusion. And will you do the same time? Or you have like spacing now 1 day part. Or any thoughts there?

Presumably there'll be some spacing that we will be justifying again in the IND of why we do that spacing. So just on the basic idea: You probably want the AAV to be there when the gene is targeted so that's ready to contribute, yes.

Yes, [indiscernible], yes, okay. Okay, I see. And since you are inserting to albumin locus, the promoter -- you'll probably leverage albumin promoter, right? So any extra safety packs you need to present to the FDA?

I think it's important that you don't want to lower albumin. If you -- let's say you insert it into every gene. That would be a problem but hasn't -- in general, we don't think you're getting to a high percentage, but you don't need a high percentage because the albumin promoters are strong and you just need a small proportion. So our findings would be what is the albumin in the patients -- in the animals preclinically. They'll be interested in that, for sure.

Okay. Actually, is there any like up threshold the FDA did not want you to go above?

I think people feel, the higher alpha-1 antitrypsin, the better. No one thinks -- but I haven't heard anyone having problems going to higher levels [indiscernible].

[ Like the -- what is preferred insertion? What if you had ] -- like albumin insertion, yes.

Yes. I think they'll be very interested in what happens to albumin [ in patients ], and that will be an important feature; and the animals first, and then the patients...

Yes, okay. [ I kind of ] [indiscernible] less than 1%, okay.

Yes, very different.

Yes, yes. Well, I think we are running out of time. And thank you very much, a lot of update. And then we are looking forward to important additional milestone later this year. [ Well, guys ], Thank you.

Yes. Thanks for that...

[ Thanks too ].