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

Okay. Good afternoon, everyone. My name is Gena Wang. I'm a SMid-Cap Biotech analyst at Barclays. It is my great pleasure to introduce our next presenting company, Intellia Therapeutics. On the stage with me is John Leonard, the President and also Chief Executive Officer. John, maybe before we dive into the questions, could you maybe give a quick overview of Intellia?

Sure. Intellia is a CRISPR-based gene editing company, where -- now in our 11th year, one of the 3 original pioneers in the space. We've focused primarily on in vivo-based therapies where we've pioneered some of the work with lipid nanoparticles, now have 3 different programs in Phase III for 2 different targets. I'm sure we'll be talking about that and then continue to build the technology base to pursue other targets within the liver and outside the liver as well as a circumscribed ex-vivo program.

Okay. Great. So maybe I will start with your ATTR program. I know this is already moving very fast to Phase III. So regarding the Phase III trial design. I'm pretty sure this is one of the key questions given we have so many other Phase III trials ongoing and the readout. So maybe regarding the Phase III trial design in the ADT cardiomyopathy. Now what is the latest thoughts regarding the trial design? And I will ask a specific question?

Sure. I mean just the basic design is a placebo-controlled randomized study patients are randomized 2:1 drug to placebo on top of standard of care, which increasingly means more tafamidis patients, both in the United States and ex U.S. The endpoints we're looking for is a composite of cardiovascular exacerbations, heart failure, arrhythmias that sort of thing, along with cardiovascular deaths.

Okay. So there are many like details regarding the trial design -- within the trial design. So maybe one question is the baseline stabilizer. Is there a cap that will allow percentage-wise?

Yes. As I said, we view it as a standard of care program. So tafamidis is increasingly used around the world. As we began the study, there were some countries where it wasn't available with the U.K. being a sample that's now changed where it's made available in the U.K. So we're not capping it as we did our initial design work. We anticipated it would be 50% to 60% or so of patients coming on tafamidis. That may actually rise over the course of the study. That's not a problem for us. I mean we're -- the basic design is to show an effect overall for patients with receiving the drug on top of whatever they're getting or not. But we're also looking for an effect on top of tafamidis. We want to show that, in fact, it's a clear addition to the effects of tafamidis, which has been missing so far in the knockdown space. So having additional observations for patients on tafamidis is actually quite helpful for that.

Okay. And then because as a stabilizer. Now we have [ ATTRv ] just recently received approval. And will you allow both [ ATTRv ] and tafamidis on the base plan?

Yes. I mean we view them essentially as interchangeable. The effects we've seen in the -- clinically don't really differentiate the 2 that much. So that's something that we will allow into the study, whether it's a drop in after a year or coming in after a minimum of 2 years -- I'm sorry, 2 months on the drug at the get-go.

Okay. And then regarding the dropping, are you allow financers to dropping?

We probably will as that becomes more relevant. Again, that would be minimally after a year of therapy. And again, it's -- when we look at the clinical data that we've seen presented thus far, the effect that we see looks like tafamidis with AMVUTTRA. So it's almost call it a tafamidis surrogate.

Okay. And you did say minimum after 1 year, doesn't mean that patients will not allow silencer dropping after 1 year, their own study?

For patients that don't come in on a stabilizer, we ask them to wait a year before they would add a stabilize or whatever it is or a silencer. And that just gives us a cleaner data set to actually analyze the drug and its effects. Yes.

Okay. And then for the patient on baseline stabilizers, can they switch less than a year to say, silencer?

I don't know the answer to that just yet. We'll see as that plays out. We have a steering committee that will go through all those questions. And to the extent that it comes up I'd be surprised if we'll have many examples of people moving from taf to acoramidis, but to the extent that it comes up, I'm sure we'll have a plan.

Okay. Because our feedback with doctors regarding ATTR cardiomyopathy after AMVUTTRA approval likely March 23, if it's on-time approval, then they are planning to switch quite some patients to AMVUTTRA.

Yes. I mean those patients will -- we won't be doing that in the study unless they follow within that broader framework I laid out.

When you enroll these patients on the baseline types, were they more or less stabilize or they were on their way to progress.

Can you say that again?

To progress.

I'm not sure I heard the question.

The stabilizer, say, like a patient want tafamidis, when they enroll, do you assess certain baseline like that they are relatively stabilized? Or are they on the trajectory of progression?

We collect all the baseline labs and measurements, et cetera. And then over the course of the study, look for those endpoints I mentioned, which is progression, et cetera. But we're not stratifying for things beyond that sort of thing and level of heart failure.

Okay. And then what is the assumption for, say, dropping rate and also the baseline stabilizing, it seems like increasing, and then the dropping rate, what is your assumption there?

It's -- we've factored it in statistically, it could be 10% to 20%. And again, I don't think that that's going to be something that really fundamentally alters how we think about the study or analyzing.

So If the dropping rate becomes a little bit higher, well, [ and then ] this is event-driven, does that mean the study likely see the event somehow happen a little bit less, then the study will be longer?

Well, to the -- I mean it is an event-driven study, as we mentioned. And we already know that our drug based on data that we presented at the American Heart Association back in November is likely to have a very profound effect in terms of events. I mean, we put those numbers out and presented that data. We know that, generally speaking, patients coming into these Phase III trials tend to be better than they were some years ago. But we think that what we've seen with the recently published acoramidis data along with the HELIOS-B study, et cetera, but we have a pretty good notion of the rate at which things should progress. So long as the general framework is the way I've described it, I think we're going to be fine. We're quite confident that with the profound effect that starts with the lowering of TTR and then the concomitant effect as we observed at AHA on the clinical outcomes that whether it's all comers or it's the [ tafs ] a patient set, whether it's acoramidis or tafamidis, we're quite confident that we will have a significant benefit on top of that.

Maybe give us a little bit more color? I know the absolute serum TTR level with nex-z actually bring down much lower compared to, say, Alnylam's drug. So maybe if you can elaborate a little bit what could that translate to the clinical outcome.

Well, I think the right way to think about the disease, and this is increasingly widely held in the field is at, TTR is -- this homotetramer, and as it breaks down into the monomeric components, that's what's the damage. And to the extent that you have a higher concentration of those monomers, you will have progression of the disease. It's not just laying down of those proteins but probably the actual concentration of it in the blood. And so when you look at TTR levels as everybody is doing in the space, what we've seen as we get to -- as far as we can tell, the lowest reported levels of TTR that have been found in patients with these diseases. It's about 1/3 or so of what you see in the data. So flip it upside down and think of it as an area under the curve problem, essentially with AMVUTTRA versus nex-z. You're seeing about a 3x exposure -- 3x higher exposure of these toxic monomers to cardiomyocytes. And if you look at the rate of decline for 2001, nex-z versus what we've seen reported now from the AMVUTTRA Phase III studies. The time to nadir is offset by 6-plus months in AMVUTTRA versus what we've observed in our own data and the extent of that reduction is never equal. And so that duration of time and the overall concentration of the protein is very consequential for clinical results as we've seen in the data that we've already presented. You want to go down as fast as you can and stay as low as you can for as long you can possibly make it. That's what drives the difference.

Okay. And then how the enrollment so far aligned with your initial expectation right? I know you have a very bullish...

I'm bullish. I mean it's -- I think doctors and patients are responding to the data we put out. We've said that by the end of this year, we'll cumulatively have at least 550 patients I actually think that we can do better than that based on what I'm seeing already. You'll know that we're looking for current 765 patients that may go up a little bit depending on some adjustments we may make as we look at event rates and the AMVUTTRA label. But the sites are performing extremely well, patient excitement is high, and we are ahead of our projections. So I'm very excited about where we're going and the path to get there. I would point out that along the way, I think there will be an opportunity for an interim analysis. And if we replicate the kind of clinical results that we've been seeing in the first Phase I study that we reported, you could even see the study stopping early.

That's a lot of new information. So maybe...

I said I'm bullish.

Right. And then it could be more than 500 patients and then the total patient number could be more than 765 patients. So you just see it depends on the event rates and AMVUTTRA labels, maybe like starting with AMVUTTRA label, how AMVUTTRA label will impact?

Well, we're looking for any surprises and just in terms of how the FDA labels and what appears ultimately in the label, we want to be very careful about where we're going with study. We think we have a good idea of what it's likely to be, but until we actually see it will hold off making any adjustment, getting more events under our belt, I think will give us confidence -- additional confidence over what we expect the event rate to be in the study. And that will lead us to decide how we tweak the site. We've always said from the beginning that we had an opportunity to adjust the study size. It's unlikely to be anything like what you've seen with Ionis and AstraZeneca, there's no way the study will ever have to be that large because of the size of the effect of TTR reduction.

Okay. Then I have several questions here. One is the event rate, how -- first, do you track a blend of event rates?

Do we...

Do you track a blend event rates on your end? Do you see that?

At the events that take place is known to us. Yes.

And then how the event rate aligned with your assumption so far?

It's early yet. Ask me that question later on in the year, and I'll give you a sense of that. But right now, we're very excited by what we're seeing.

And regarding the patient baseline characteristics and also the dropping, is that also still aligned with your assumptions?

It is. I would say that the patient population that you've seen in the acoramidis study as well as HELIOS-B is pretty representative of what we're seeing and what we expect to see.

Okay. And then you did mention the trial size and then Alnylam did disclose there TTRsc04, now, name is Nucresiran, the Phase III trial design, it's a 1,200 patients, right?

Yes.

And then Ionis also has a huge study. So maybe your thoughts on their study and then how would that maybe also Ionis data will read out 2026. How would that inform you regarding the update and then also decision on the interim analysis?

Well, the Ionis data and then the Alnylam study design. I mean I think that we have a pretty good notion of what the Ionis data is likely to yield just based on knowing what the TTR knockdowns are that they've already reported. Obviously, we'll look at that, that may be in a time frame that has some relevance for an interim analysis, we'll see. And I think potentially affect how we think about that. But with respect to the Alnylam follow-on product. I think the basic design is what you would expect. I would point out that as far as I can tell, there's no patient experience yet. I mean they are going directly from healthy volunteers into a Phase III study. So my guess is -- and I emphasize that this is a guess, you should ask them exactly how they came up with the study. But my guess is that they're being very conservative based on not hitting the taf effect previously, not knowing what they're going to get in patients, I would compensate for that if I were in their shoes. I don't know what the fundamental variability of the drug levels are if it's at all like AMVUTTRA, which is quite variable. There's patients with only 50% knockdown and very good knockdowns with an average of 80-ish, they're probably trying to compensate for that as well. So it's a conservative design not one that we need to because of the size of -- and the consistency of the TTR knockdown as well as the profound effect on clinical events already observed.

Okay. Very helpful. And then regarding the MAGNITUDE-2, the TTR polyneuropathy study. So you do have a 2 endpoint like Day 29 serum TTR level, and also the mNIS+7 data, the 18 months, right? So will you share the TTR level first? And then into 18 months, you shared with us the function of data.

We wouldn't unblind the study, Obviously. I mean there's an observation early and then patients are measured versus their baseline 18 months later, both of those endpoints are important they may have relevance for how we pursue the drug from a regulatory point of view. There are opportunities to accelerate it, but we would never do that in a way that unblinded the study and compromise the clinical observations.

Okay, okay. Good. Now quickly on the HAE program, which progressed much faster. The study already started enrollment on January 15 per clinicaltrials.gov. So maybe like -- also very technical questions. It is [indiscernible] masking, but do you think that the placebo patient could tell due to the side effect?

No. I mean it's -- we've already done 1 double-blinded study in Phase II where we had, you'll remember, 2 different doses versus placebo. There were no issues with the blind. I mean if I'm going to try to speculate if somebody -- if they had a profound infusion reaction, which we have not observed I mean. But otherwise, just in terms of the standard conduct of it, that has not been an issue.

Okay. And then regarding the screening period, you do have a wide range there. We have, I think, 4 to 18 weeks.

4 to 8.

I see. Not 18?

No.

Our doctor feedback did suggest like 8 weeks will be better because 4 weeks could be some variability that for whatever no reason the patient may have a less attack. So any thoughts there?

Yes. I mean, obviously, we work with leaders in the space, experts. There's a standard approach that has been tried and true with the FDA. And that's exactly what we're doing. I mean, we're following a standard sort of approach. If you think of patients who have severe disease and have a high propensity to attack deny than any drug being in the trial, and what that affords them, would be something that I think many investigators would not be supportive of. So again, it's just -- it's the standard study design that's routinely done for this class of drugs.

Okay. And maybe remind us the enrollment criteria for baseline attack rate and where is your powering Phase III steps assumption there?

Yes. I mean it's -- I mean, first of all, the effect size of the drug is massive, right? And we were able to do in a 25-patient study testing 2 different doses versus placebo discerned effects. This is a bigger study, 60 total patients, 40 on drug, 20 on placebo, the effect size will overwhelm any sort of statistical consideration. So that's not an issue. In terms of coming into the study, we ask that patients have 3 attacks within the first 4 weeks. And if not, 3 attacks by 8 weeks and if they don't have that degree of attacks, then they don't qualify for the study.

Okay. Very good. And your primary endpoint is like week 28 and still very short right? And I do -- we do see like this could be cured in the patient population. And how long, I think a total extended period is week 104. So maybe at what point do you think you can claim those patients are attack free?

Yes. A couple of points. First of all, 28 weeks is the standard observation for period for all of the drugs that are a study for HAE. So that's standard whether short or not I guess, it's sufficiently long for regulatory agencies to say make a recommendation to approve the products, we will continue studying the patients, as you said, for 104 weeks. The interesting challenge is the creation of a new category of response. I mean this class of drugs has been looked at for attack rate reductions while taking therapy. And of course, we'll make sure that and it will be primarily determined 5 weeks after initiating therapy and then by the end of 28 weeks. But the category that we're most interested in, then the one that physicians and patients are looking for the so-called functional cares. We're after a single dose, patients at some point, cease to have attacks, discard whatever therapy they may be taking. whether it's prophylactic or on-demand therapy and go as if they were without the disease. What -- that will be defined as in a regulatory framework is a work in progress. What we've seen thus far is generally speaking, once you see a patient who hasn't had attacked for a couple of months. The likelihood is that they'll never have an attack again as far as our measurements go. So obviously, we're accumulating more experience in that regard, but we're very excited about what we've seen, and we think that the overwhelming majority of these patients are likely to become functional cures.

Right. One last question. I know like both programs you show impressive data in both mall marker and the functional data. And yet, when we look at the stock price, it's a huge big disconnect there. And the main pushback from investors is those of the disease with good step care. There's no unmet medical need, and it will be challenging for commercial news for the genomic medicine. Maybe your thoughts based on your doctor feedback? And what you think of investors.

Yes. I actually think investors talk to each other a lot. And it's not what we see. It's not what we hear from the patients and physicians. What -- I think it's easy to trivialize the disease as just swelling. But once you've met a patient who has a tracheostomy as a result of being intubated multiple times because of laryngeal swelling, you realize it's far from trivial. And so what patients want is not to be good enough, they want to be cured if they can be cured. And this is the brave new world that we're coming into where this is possible. And I think that people's understanding will catch up to what the reality is and what that does to the stock price, we'll see, but it's -- we're quite confident that this represents a major advance for patients and sets the stage for cardiomyopathy where there's an abundance of patients who -- because it's a disease of aging will benefit from the drugs that we're making.

Great. Well, thank you very much, and we look forward to the data update later this year.

Thank you.

Thank you.