Thanks, everyone, for coming. My name is Yanan Zhu, and I'm one of the Biotech analysts here at Wells Fargo. It's our privilege to have a Fireside Chat with Intellia Therapeutics, and with me today is John Leonard, CEO of the company. John, thank you for being with us.
My pleasure. Good to see you.
Thanks. And, so I think if we can start with ATTR cardiomyopathy and its development strategy. And could you remind us of the value proposition for NTLA-2001 in ATTR cardiomyopathy? Is superior efficacy to standard of care critical to the value of the drug and future success?
Well, with all the programs we work on, and this one in particular, we start with a theory that we're going to advance the efficacy, and we certainly set that out as a key objective. I think that's a fundamental part of the story here. The idea is that by reducing TTR levels to very, very low levels in a very consistent way across a patient population, that should drive superior outcomes to what we're seeing with the various drugs that are out there. I think what we've learned as a field is that knocking down TTR gets you somewhere, but it's our belief that a lot of efficacy has been left on the table, which we intend to get with and demonstrate in our phase III program.
Got it. In terms of demonstrating the benefit in phase III study, I was wondering, do you have a sense of the size, study size, and duration necessary to demonstrate incremental benefit over the current standard of care?
Well, what we expect to measure will be the so-called hard outcomes, looking for hospitalizations, mortality events, and so on and so forth. And we would expect that to be an event-driven sort of approach where, you know, the drug, as it plays out, will show us what it's got. We're not interested in doing a 12-month, six-minute walk sort of thing. I don't think that regulators are particularly interested in that, and certainly payers and physicians are not so moved by that kind of an approach. In terms of what it takes to see a really meaningful benefit, I would look to more the HELIOS-B-type size trial as opposed to some of the larger designs that others have addressed. And that relates to the depth of the TTR levels that we're able to achieve.
We've shown that and, equally importantly, the consistency of that effect. So if you look across the patient population that we've treated, virtually every single patient at the chosen dose in the cardiomyopathy arm is achieving levels of 90% or so reduction from where they started, and I think that can lead to a more economical, and efficient study design, which is what we'll do.
Got it. When do you expect to discuss the phase III design with FDA? And is the... You know, presumably, it's going to be a global study, but would the discussion with FDA be a gating factor to initiating a study outside the U.S.?
Well, we've made clear for a long time that, you know, the U.S. is a very important part of our program. As we've guided with our last earnings release not so long ago, we expect to have an IND filed here this month. And getting an agreement with the FDA in terms of that final protocol is something that's very important to have because we would expect to have many American patients in that study. So what we'll see as we work through that IND with the FDA, which is essentially an end-of-phase II meeting. I think that's probably a more productive way of thinking about it. We would expect to get final agreement on that protocol, which is then the protocol that we will use on a worldwide basis. You said global study. That, that's absolutely the case.
There will be many countries in Europe, and South America, North America, et cetera. We think we'll have a very, very good availability of patients as we conduct the trial.
Got it. So essentially, the IND filing would also be the same meeting to discuss the phase III design. Is that correct?
I think that's the right way to think about it. That's why I say it's tantamount to an end-of-phase II meeting. We've had interactions with the FDA several along the way, so they know where we're coming from. We've talked about principles, you know, for the clinical program. We've talked about, you know, the CMC material, which is essentially going to be the commercial material, et cetera. So this is very, very advanced. You know, when people hear IND, sometimes it's, you know, people think about it as first in humans. This is really just bringing the finality of the program to the U.S..
Right. Right. So obviously, I believe there will be a lot of attention on the clearance of this IND filing. You have cleared the HAE filing before, so this is not the first in vivo gene editing targeting the liver. But as you said, this is a bigger undertaking because it's for a phase III study. What's your sense of your understanding of what FDA want to see, and your-- what's your confidence that you could achieve clearance with this filing?
Well, I fully expect to clear the filing. Whether it's on day 30 or a day after that, I think it's gonna be a function of FDA's capacity and the material that, you know, to go through the material that we reviewed. We have a very good line of sight to what they want, based on the interactions that we've had with them for this program and the precedent with HAE. I think it's important to remember that with the approach that we've taken with our in vivo programs, and even on the ex vivo side, there's great similarity with the material that we use. And so, the experience that we get clinically tends to apply from one program to the other. The experience that we get from a CMC and a toxicological point of view tends to apply broadly, et cetera.
So many of the things that we've worked through with HAE that the FDA has already seen applies very much to the 2001 program as well.
Got it. Very helpful, and it's, as you said, it's IND filing at the end of September. So, will you provide an update, like, I think, does it take 60 days for FDA to respond?
Well, for an IND filing, the FDA is mandated to give you a response at the end of 30 days. And the approach we'll take, which is what we've done with all of our programs, is not when we send it in, but when we get feedback, approved or otherwise, and we will share that information. And what we learn, you know, we will make publicly available.
Got it. Got it. And then, you know, in thinking about the phase III design, you know, a key component is about background, stabilizer or silencer use, and maybe it could be as important as a discussion of whether you need a control arm of those active treatments. How... What's your thinking on that, or any feedback from the regulators on that so far?
Well, we've already had interactions with the FDA with those topics, so I, I think we're fairly well-versed in terms of what the FDA is looking for. Like others in, in the space, tafamidis is a drug that's, you know, pretty widely used. It's appropriate for patients with, you know, cardiomyopathy tied to TTR. That will be available to patients in the trial, and what we expect to have is enough patients with tafamidis and without tafamidis, that we'll be able to draw real insights into how NTLA-2001 behaves in those various populations. So, the FDA knows that, and, you know, a- again, I think with respect to particular ratios of types of patients, et cetera, that'll be finalized as we, you know, have these, upcoming discussions with the FDA.
Got it. And then, obviously, there might be a stabilizer approved, we don't know yet, on Onpattro, based on a six-minute walk test, is going to have an AdCom meeting, September 13th. If it's approved, would that impact the design or the future relevance of the, your phase III study?
I think you meant to say a silencer as opposed to stabilizer.
Oh, silencer.
Our perspective is it'll have little to no effect. I don't think it's really going to compete to any great extent for patients. That's what we hear from KOLs. That's, you know, and as we look around the world at the rate that these drugs roll out, if it becomes available, I don't think it's gonna be a major competitor for patients.
Got it. Got it. And then, in, on the stabilizer front, Bridge, BridgeBio, does have its recent, data, presented at the ESC meeting. How does that data affected your thinking about your phase III design?
Well, it continues to add weight to the TTR reduction hypothesis, in cardiomyopathy. You know, obviously, a stabilizer is a different mechanism of action, but by stabilizing the tetrameric form of TTR, you get less deposition of the monomers. Everything we've seen goes in the direction of supporting those kinds of approaches to having an effect on cardiomyopathy. But what we see is a drug that works, but that leaves a lot of efficacy on the table. You know, I was struck by the absence of a meaningful effect in patients with Class III heart failure, for example. Fewer than a half of the patients really improved their proBNP levels.
Our early clinical work suggests that we're able to get very low levels of TTR in all of the patients tested, and so it's our expectation that we'll be able to have superior outcomes to what we've seen thus far. Obviously, that remains to be seen in the clinical program, but that's the premise behind it, and that's the sort of study that we're designing to that we expect will show that outcome.
... Got it. Got it. If I think about what you have said about phase III study design, feels like it's a placebo-controlled study, but allowing-
Standard of care.
Standard of care, right?
Yeah.
Yeah. So that's not a, definitely not a head-to-head with, for example, silencers. Maybe you can dissect the patient population and have a sense of what it—how it performs with, with, tafamidis, by looking at patient subset. But in terms of comparing with silencers, which might have data later, from their, hard endpoint, trials, do you think that it will be possible to look at your study's result and those results and see an incremental difference, in, in supporting your value proposition for, for the treatment?
Well, I think it's going to be possible, but obviously, that awaits the actual data and looking at it. You know, I think what we're trying to get to, Yanan, is this idea that, there's a very direct relationship between TTR levels and what happens to patients over time. And it may be a function of, you know, how long you've had the disease, you know, where you are in the natural history, how much deposition has taken place, et cetera. But, we think where this will go is you want to have the lowest TTR levels possible, and people will start to look for those kinds of numbers. It's our expectation that as these patients are followed for longer periods of time and as we get more data, that relationship will be even more clear than it is today.
We're going to make it really easy for people to see what their TTR numbers are. You know, we anticipate showing that if you take the drug, there's a very, very high, high likelihood that you'll have a very, very low TTR level.
Great. That's very helpful. If we can then maybe switching gears a little bit and talk about upcoming data readout for the TTR programs. First, in cardiomyopathy, I think you will be presenting data later this year. How many patients of data and how long the follow-up, what the endpoint might be, and, you know, will we see KCCQ six-minute, six-minute walk, NT-proBNP, cardiac amyloid, those endpoints, and essentially, what to look out for?
Will we see the kitchen sink, in other words? We're collecting all those things, right? And the principle that we've applied since we first began presenting clinical data a couple of years ago is that we'll tell a story that is complete and consistent when we have the information. So rather than telling you exactly what we're going to say and when we're going to say it, we'll, you know, as that information becomes available, we'll telegraph when and where, but at this point, it's a little too early to commit to exactly what that's going to be. There will be additional information this year, however.
Got it. Got it. And would that, this data release be at a medical meeting or a company event?
Our preference is always a medical meeting, and that's where the bulk of our releases have been. But again, it really comes down to when we have the information in hand, and we'll make the judgment at that time.
Got it. And then on ATTR polyneuropathy, you I think you also committed to a data update. Again, how many patients of data here, and how long would be the follow-up, and will we see mNIS+7 data in this, in the expansion cohort?
Yeah, we're collecting all of that information. It's the same sort of approach. We expect to present information that we have before the end of the year. When and where, again, is a function of, you know, how that data matures, but we'll talk about that as, as appropriate.
Got it. And also, is the preference also a medical meeting or?
Yes. That's, that's always the preference. Again, it's a function of when we get the information and, and where we are in the calendar of those events.
Got it. Great. Yeah, looking forward to those updates. Then maybe let's talk about the HAE program, to NTLA-2002. I was wondering, what is the FDA's main focus in their recent request for supplemental preclinical data related to inclusion of patients with child-bearing potential? Is the focus related to how gene editing might affect the ability to conceive and carry a pregnancy rather than germline transmission? And if it is the former, then is the focus more on the genetic change you're making or about the components of the therapy, the mRNA, the LNP?
Yeah, I think the way to think about this is there's a set of studies to do that addresses a range of things that are related to reproduction. We've answered the question of whether or not there's germline transmission, and the answer is there is none. I mean, that's been tested at supra pharmacologic exposures in many, many animals with hundreds of pups that are then looked at for any evidence of editing. There is none. You can then go and look at distribution as to whether or not the material in any form arrives in reproductive tissue and, you know, gametes. There is none, and the FDA has seen that information.
The remaining category is, I think what you're asking, which is, okay, knowing that, might there be any possible effect on the development of a fetus unrelated to germline editing or, you know, access to, you know, germline cells that may be related to the chemicals in an LNP or, you know, any other sort of untoward effect? And that's a developmental study. So that's what they've asked us for, which is essentially an abbreviated standard sort of study that's typically asked for a little later in the program, but not unusual. And so we're doing that work. It's not gating for a phase III program in any way. And in some respects, we already know the answer because we already have 100s of animals that we've looked at that have developed normally.
So in some respects, I don't want to call it box checking, but I think it falls sort of you know close to that category, to have the complete set of these studies in hand before a phase III program.
Got it. Got it. Very, very helpful. Would this type of study, do you think, will be brought up with the IND for ATTR as well?
It may be. I mean, we'll find out. Our hope is that the work that we're doing now, which is essentially with the same LNP... I mean, remember that, the lipid format is identical, the mRNA that's contained in the lipids is identical between programs. The guide RNA, the 100 nucleotides, 80 of them are identical except for the last 20, which defines specificity. So it would be our preference that this be viewed as a class, you know, sort of a platform, study, but that remains to be seen if FDA will accept that.
Got it.
I guess I would point out that if it's not, it really has little bearing on 2001. The patient population there tends to be elderly. If you go and if you were, you know, you flip it and say, "Well, let's look for women of childbearing potential," it would be hard to identify many that have cardiomyopathy tied to TTR.
Right. Right. Got it. Then, would there be an update for NTLA-2002 later this year? If not, then what, when could we expect the next data from that ongoing phase I study?
Yeah, I mean, we try to characterize information as it accumulates, and the idea is, you know, all of the phase I patients have been dosed. We've been collecting outcome data on those patients. You've seen data that we presented, which show essentially a 95% reduction in attack rates. Much, any attack happens typically very, very early after administration, and so as appropriate, as we extend that observation period, we would always be enthusiastic about sharing that. Really, what- where the action now is in our phase II program, and, you know, as we said in our last earnings call, all of the patients have been identified.
That's essentially on target to complete as fast as we had hoped for optimistically, and as we said, we could be at a point where we're actually beginning phase III for the 2002 program as early as the third quarter of next year if all the green lights align, as so far seems to be the case.
Got it. Got it. Maybe we can touch on, on that, phase III, potential phase, the design of that study. Do you think that study would need an active comparator? And if so, would the study needs to be a superiority trial, or would a, a non-inferiority trial be sufficient?
You know, there's a pretty well-established paradigm for HAE pivotal trials, and we would expect to follow that precedent. In most cases, these are placebo-controlled trials. Patients wash off any drugs that they may be taking for prophylaxis. You make rescue therapy available to patients so that if they have an attack, whether on active drug or placebo, they're able to treat that. And over a specified period of time, 26 weeks or so, you count the number of attacks after, you know, during this study period. That's the sort of design that I anticipate we'll do. I mean, obviously, this relates to, you know, ongoing regulatory feedback, but the precedent, I think, is the best guide to keep in mind at this point.
Got it. Got it. As you alluded to, in Europe, you have had a very strong interest in participating in a trial. But do you anticipate a similar level of interest when you start the phase III study in the U.S.? I was wondering whether there's any standard of care differences between these geographies that could lead to a difference in interest.
There's minimal standard of care differences. I mean, for example, we have patients who, in our ongoing phase I trial, have had what we think is the benchmark drug, lanadelumab, which they've stopped to come onto the trial. And we think that that is indicative of how American patients will also think about this. We don't see a big difference when we talk to, you know, opinion leaders in the U.S. or any of these, you know, European or, you know, New Zealand, Australia, et cetera, countries. It's a very close-knit group. HAE, you know, it's not millions of patients. It's a smaller group, and the investigators tend to be a very closely knit group.
We talk to them as, you know, a single group, and what we've seen thus far is essentially indistinguishable enthusiasm based on, you know, where a particular patient or a physician resides.
That's really nice to hear, and bodes well for uptake for once-and-done genetic treatment for this indication.
Yeah, I mean, we're very enthusiastic about having American patients. That will be the centerpiece of the next study that we do, and you know, I think people look at the data and that's what's really driving the decision making. It's if you think about HAE patients in general, and the physicians that care for them, they're looking for a couple of different things. Certainly, efficacy is important. Although, you know, we've seen people trade off efficacy to get to some of the oral drugs because of the burden that comes with infusions and things like that. So if we can address efficacy, which we think we'll do, the burden of care, essentially potentially curative therapy, one hopes. I mean, early indications are that, you know, this, you know, will be a very, very profoundly effective drug, probably lifelong.
And if patients can get to the point where they may be able to dispense with even carrying their other prophylactic agent or rescue therapies with them, that will address a huge hole in current therapies.
Got it. That, that's very helpful. Then perhaps let's pivot to the earlier stage pipeline. You have this AATD, a two-prong approach for AATD. On 3001, you are... Are you still on track to file a CTA by year-end this year? And what is, in general, the AAT level that you hope to achieve?
Yeah. So as you pointed out, we have two approaches that are independent of each other but can be combined, if necessary, within a single patient. One is 2003, which is to knock out the gene that produces a defective protein that's particularly important for patients who have the liver manifestations. Tends to be a younger patient population, generally speaking, and the bulk of patients who suffer from Alpha-1 Antitrypsin Deficiency of the pulmonary disease, which comes from the absence of the protein getting to where it needs to go, which is the lung, and slowing down the degradation of lung tissue. So in the case of 3001, as we've shared at our last earnings call, it's our expectation to have a CTA by the end of this year.
We tend to keep our promises at our company, so I'd bear that in mind. But the objective there is to normalize the levels of protein. What's available to patients today are infusions that, even with very large amounts of material delivered, typically only get up to levels that are even half or so of what would be a normal level, and there's debate amongst KOLs, how much efficacy that really brings. The approach is to normalize it, and with the preclinical data that we presented in non-human primates, we do that. And so that's the premise. That's what we will be looking for as we carry out our phase one study, and if we see that kind of an effect in humans, I think we'll be on our way.
Yeah, it's certainly very exciting that you could achieve normalization with in the animal studies. I was wondering, because this is a approach that hijack the Albumin locus for expression, what % of the Albumin, Albumin loci do you need to edit to achieve this level of expression?
I guess I would use a word different from hijack. We, we borrow, or utilize a very small percentage. I mean, typically it's single digits, is what we've seen in preclinical models. And what you're able to do is use what is a very, very potent promoter to drive high levels of the Alpha-1 and see essentially no discernible effect on albumin levels. So that's the work we've done in non-human primates. It works very, very well, and we expect to, or certainly hope to replicate those findings in humans in the phase I program.
Got it. And then, another maybe technical detail here is that, the ideal outcome is a insertion of the AAT gene, but there could also potentially be an indel instead of an insertion. Would the indel affect Albumin expression, and is that even a large proportion of your outcome?
Well, just to kind of go through the steps, remember, we start with the same LNP. We're delivering the hepatocytes, right? Which is the area where the defective gene resides. So we're using the same lipid, the same mRNA, again, the same guide, - 20 nucleotides. That takes us now to the Albumin locus, as opposed to HAE or TTR. You're correct in that that opens up the locus to drop in the wild type coding sequence, but that's done in a non-coding region so that if nothing is introduced, no, you know, no transgene, it has no effect on the normal coding sequence of the exonic activity of that particular gene. So, it's, again, the only thing that will matter is if there's an insertion that will drive the production of the protein.
If there is an indel in the intron, it has no perceptible effect.
Got it. Got it. Could you touch on the differentiation of your approach vs a base editing strategy?
Yeah. I think the premise of a base editing approach is to try to correct something locally as opposed to provide a normal coding sequence. It remains to be seen how effective that approach is. Our view at Intellia, you know, we have our own proprietary base editors. We don't think that that's the ideal approach, primarily for the reason that I think it's very hard to properly characterize off-target effects with base editors in the in vivo setting. It's a function of how those proteins behave and some of the, you know, non-Cas activities and their activity. I think base editors in our hands are ideally suited in the ex vivo setting. So I just, you know.... Again, our view is that that's not the best application to get to the intended effect.
Got it. Thanks for the color. I have a last question here on early pipeline about in vivo HSC editing. There has been some development in the area, you know, reported at ASGCT, and we begin to see some development. Like, Sanofi had a collaboration that's focused on this, in this area. I think your company was the first, actually, to talk about this, via your collaboration with the Bill & Melinda Gates Foundation for in vivo sickle cell approach. Could you give us an update on where you are in this pretty exciting area?
Well, we set out from the beginning to have an in vivo approach because we think that that's the definitive solution to sickle cell. I think what we see as a field is that you can cure sickle cell, which is an incredibly exciting development, but to have a bone marrow transplant or the equivalent of that, with its associated morbidity and mortality, our belief is that if you can avoid that by going directly to the HSC, using some of the same technology that we've been using going to the liver, that will very quickly supplant the bone marrow transplant. And that's the work we're going for. I mean, we've presented data on humanized mice and shown that you can accomplish that.
The model that becomes particularly relevant is non-human primates, and that's work that's ongoing, and as we make headway, which we fully expect to do, we'll share that at the appropriate time. But it is an area that we are very, very interested in.
Got it. Got it. With that, I think we are out of time. Thank you so much, John, for all these updates.
My pleasure. Thank you.
Thank you.
All right.