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Okay, good. Good afternoon, everyone. My name is Gena Wang. I'm a 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. We're now in our 11th year, one of the three 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 we have three different programs in phase three for two different targets. I'm sure we'll be talking about that. We 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. Maybe I will start with your ATTR program. I know this is already moving very fast to phase three. Regarding the phase three trial design, I'm pretty sure this is one of the key questions, given we have so many other phase three trials ongoing and we have a readout. Maybe regarding the phase three trial design and the ATTR cardiomyopathy, what are the latest thoughts regarding the trial design? I will ask a specific question.
Sure. I mean, just the basic design is a placebo-controlled randomized study. Patients are randomized two-to-one drug to placebo on top of standard of care, which increasingly means more tafamidis patients, both in the U.S. and ex-U.S. The endpoints we're looking for are a composite of cardiovascular exacerbations, heart failure, arrhythmias, that sort of thing, along with cardiovascular deaths.
Okay. There are many details regarding the trial design within the trial design. Maybe one question is the baseline stabilizer. Is there a cap that you allow percentage-wise?
Yeah. As I said, we view it as a standard of care program. Tafamidis is increasingly used around the world. As we began the study, there were some countries where it was not available, with the U.K. being an example. That has now changed, where it is made available in the U.K. We are not capping it. As we did our initial design work, we anticipated it would be 50%-60% or so patients coming into tafamidis. That may actually rise over the course of the study. That is not a problem for us. I mean, the basic design is to show an effect overall for patients receiving the drug on top of whatever they are getting or not. We are 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. Having additional observations for patients on tafamidis is actually quite helpful for that.
Okay. And then because it's a stabilizer, now we have Attruby just recently received approval. And would you allow both Attruby and tafamidis on the baseline?
Yeah. I mean, we view them essentially as interchangeable. The effects we've seen clinically don't really differentiate the two that much. That is something that we will allow into the study, whether it's a drop-in after a year or coming in after a minimum of two months on the drug at the get-go.
Okay. Regarding the drop-in, are you allowing silencers to drop in?
We probably will as that becomes more relevant. Again, that would be minimally after a year of therapy. Again, when we look at the clinical data that we've seen presented thus far, the effect that we see looks a lot like tafamidis with Amvuttra. It is almost, you call it a tafamidis surrogate.
Okay. You just said minimum after one year. Does that mean patients will not allow silencer drop-in after one year? They're on study?
For patients that don't come in on a stabilizer, we ask them to wait a year before they would add a stabilizer, whatever it is, or a silencer. That just gives us a cleaner data set to actually analyze the drug and its effects. Yeah.
Okay. 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. To the extent that it comes up, I'd be surprised if we'll have many examples of people moving from tafamidis to acoramidis. To the extent that it comes up, I'm sure we'll have a plan.
Okay. Because our feedback with the doctors regarding ATTR cardiomyopathy, after Amvuttra approval, likely March 23, if it's on-time approval, then they are planning to switch quite some of the patients to Amvuttra.
Yeah. I mean, those patients will—we won't be doing that in the study unless they follow within that broader framework that I laid out.
When you enroll these patients on the baseline tafamidis, were they more or less stabilized, or they were on their way to progress?
Can you say that again?
To progress?
I'm not sure I heard the question.
Oh, the stabilizer, say, patient on tafamidis, when they enroll, do you assess certain baseline? Are they relatively stabilized, or are they on the trajectory of progressing?
We collect all the baseline labs and measurements, et cetera. Over the course of the study, look for those endpoints that I mentioned, which is progression, et cetera. We are not stratifying for things beyond that sort of thing and level of heart failure.
Okay. What is your assumption for, say, drop-in rate and also the baseline stabilizer? It seems like increasing.
As I mentioned.
Yeah. Then the drop-in rate, what is your assumption there?
We've factored it in statistically. It could be 10%-20%. Again, I don't think that that's going to be something that really fundamentally alters how we think about the study or analyze it.
If the drop-in rate becomes a little bit higher, in the end, this is event-driven. Does that mean the study likely, say, the events somehow happen a little bit less, then the study will be longer?
I mean, it is an event-driven study, as we mentioned. 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 three trials tend to be better than they were some years ago. We think that what we've seen with the recently published acoramidis data, along with the HELIOS-B study, et cetera, we have a pretty good notion of the rate at which things should progress. As 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 TTR 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 NTLA-2001 actually brings down much lower compared to, say, another drug. Maybe if you can elaborate a little bit, what could that translate to the clinical outcome?
I think the right way to think about the disease, and this is increasingly widely held in the field, is that TTR is this homotetramer. As it breaks down into the monomeric components, that's what's doing the damage. To the extent that you have a higher concentration of those monomers, you will have progression of the disease. It's not just the laying down of those proteins, but probably the actual concentration of it in the blood. When you look at TTR levels, as everybody's doing in the space, what we've seen is 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 a third or so of what you see in the Amvuttra data.
Flip it upside down and think of it as an area under the curve problem. Essentially, with Amvuttra versus nexiguran ziclumeran, you're seeing about a 3x exposure, three times higher exposure of these toxic monomers to cardiomyocytes. If you look at the rate of decline for NTLA-2001 nexiguran ziclumeran versus what we've seen reported now from the Amvuttra phase three studies, the time to nadir is offset by six-plus months in Amvuttra versus what we've observed in our own data. The extent of that reduction is never equal. 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 as you can possibly make it. That's what drives the difference.
Okay. How's the enrollment so far? Aligned with your initial expectation? I know you have a very bullish.
I am bullish. I mean, 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 see the Amvuttra label. The sites are performing exceptionally well. Patient excitement is high, and we are ahead of our projections. I am very excited about where we're going and the path to get there. I would point out that along the way, I think there'll be an opportunity for an interim analysis.
If we replicate the kind of clinical results that we've been seeing in the phase one study that we reported, you could even see the study stopping early.
That's a lot of new information. Maybe.
I said I was bullish.
Right. It could be more than 500 patients, and that total patient number could be more than 765 patients. You just say it depends on the event rates and Amvuttra labels. Maybe starting with Amvuttra label, how Amvuttra label will impact.
We're looking for any surprises 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 the study. We think we have a good idea of what it's likely to be, but until we actually see it, we'll hold off making any adjustments. Getting more events under our belt, I think, will give us additional confidence over what we expect the event rate to be in the study. 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. I have several questions here. One is the event rates. First, do you track blinded event rates?
Do we?
Do you track blinded event rates on your end?
The events that take place are known to us. Yes.
Okay. How do the event rates align 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. Right now, we're very excited by what we're seeing.
Regarding, say, the patient baseline characteristics and also the drop-in, is that also still aligned with your assumption?
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. You did mention the trial size. Alnylam did disclose their TTR sc04. Now, name is nucresiran, the phase three trial design. It's a 1,200 patient. Right? Ionis also has a huge study. 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?
The Ionis data and then the 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 timeframe that has some relevance for an interim analysis. We'll see. That could potentially affect how we think about that. 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're going directly from healthy volunteers into a phase three study. My guess is, and I emphasize that this is a guess. You should ask them exactly how they came up with the study.
My guess is that they're being very conservative based on not hitting the tafamidis 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 vutrisiran, 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. It is a conservative design, not one that we need because of the size and the consistency of the TTR knockdown, as well as the profound effect on clinical events already observed.
Okay. Very helpful. Regarding the MAGNITUDE, the TTR polyneuropathy study, you do have two endpoints, like day 29 serum TTR level and also the NIS+7 data at 18 months. Right? Will you share the TTR level first, and then until 18 months, you share with us the functional data?
We wouldn't unblind the study, obviously. I mean, if 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 compromised 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. Maybe some also very technical questions because it is quadruple masking. Do you think that the placebo patient could tell due to the side effect?
No. I mean, we've already done one double-blinded study in phase two where we had, if you'll remember, two 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. Regarding the screening period, you do have a wide range there. You have, I think, 4-18 weeks.
Four to eight. Four to eight.
Oh, I see. Not 18. Okay. Our doctor feedback did suggest like 8 weeks will be better because 4 weeks, it could be some variability that for whatever no reason, the patient may have a less attack. Any thoughts there?
Yeah. I mean, obviously, we work with leaders in the space, experts. There is a standard approach that has been tried and true with the FDA, and that is exactly what we are doing. I mean, we are following the standard sort of approach. If you think of patients who have severe disease and have a high propensity to attack, to deny them any drug being in the trial and what that affords them would be something that I think many investigators would not be supportive of. It is the standard study design that is routinely done for this class of drugs.
Okay. Maybe remind us the enrollment criteria for baseline attack rate, and then what is your powering phase three stats assumption there?
Yeah. 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 two different doses versus placebo, discern effects. This is a bigger study. Sixty total patients, forty on drug, twenty on placebo. The effect size will overwhelm any sort of statistical consideration. That is not an issue. In terms of coming into the study, we ask that patients have three attacks within the first four weeks, and if not, three attacks by eight weeks. If they do not have that degree of attacks, then they do not qualify for the study.
Okay. Very good. Your primary endpoint is like week 28 and still very short, right? We do see this could be cured in the patient population. How long, I think a total extended period is week 104. Maybe at what point do you think you can claim those patients are attack-free?
Yeah. A couple of points. First of all, 28 weeks is the standard observation period for all of the drugs that are studied for HAE. So that's standard. Whether it's 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 measure that, and it'll be primarily determined five weeks after initiating therapy and then by the end of 28 weeks. But the category that we're most interested in, and then the one that physicians and patients are looking for, are the so-called functional cures.
Where 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 attack for a couple of months, the likelihood is that they'll never have an attack again as far as our measurements go. Obviously, we're accumulating more experience in that regard, but we're very excited about what we've seen. We think that the overwhelming majority of these patients are likely to become functional cures.
Right. One last question. I know both programs, you show impressive data, both biomarker and functional data. Yet, when we look at the stock price, it's a huge, big disconnect there. The main pushback from investors is those at the disease with good standard of care, there's no unmet medical need, and it'll be challenging for commercial use for the genomic medicine. Maybe your thoughts based on your doctor feedback and what you think investors around.
Yeah. I actually think investors talk to each other a lot. It is not what we see. It is not what we hear from the patients and physicians. I think it is easy to trivialize the disease as just swelling. Once you have met a patient who has a tracheostomy as a result of being intubated multiple times because of laryngeal swelling, you realize it is far from trivial. What patients want is not to be good enough. They want to be cured if they can be cured. This is the brave new world that we are coming into where this is possible. I think that people's understanding will catch up to what the reality is. What that does to the stock price, we will see.
We are quite confident that this represents a major advance for patients and sets the stage for cardiomyopathy where there is an abundance of patients who, because it is a disease of aging, will benefit from the drugs that we are making.
Great. Thank you very much. We look forward to the data update later this year.
Thank you.
Okay. Thank you.