Good afternoon. Welcome to Barclays Global Healthcare Conference. My name is Gena Wang. I'm a MD Biotech Analyst at Barclays. It is my great pleasure to introduce our next presenting company, Intellia Therapeutics. With us today we have John Leonard, President and Chief Executive Officer. Maybe, John, before we dive into the questions, can you give a brief overview of the company?
Sure. Great to see you and happy to be here. So Intellia is a genome editing company that uses CRISPR/Cas technology and its many derivative forms to go after a wide variety of conditions both in the in vivo and the ex vivo setting. You may know that we're at a really exciting juncture in the company with the first company now with in vivo programs that are entering phase three. So I'm sure we'll be talking about the TTR program, which is enrolling as we speak, in phase three. And later this year we expect to be in phase three for a second in vivo program, which is for hereditary angioedema. That's something we're quite proud of. But we continue to expand the horizon of where we can take genome editing. And we've begun now gene insertion work, emphasizing alpha-1 antitrypsin.
And then with our collaborator, Regeneron and Factor IX, we expect to open up new categories where we can go. And then, I anticipate we'll talk about taking some of those capabilities outside the liver where we put in place multiple different programs now to take what we've learned in these other settings and apply it to tissues that have been historically difficult to access. But, we've been making a lot of headway.
Great. Thank you, John. And I do agree, you know, you guys pioneering the in vivo programs. And now is that 2 phase 3 ready or phase 3 assets? Yeah. So regarding ATTR, you know, so I kind of sharing with the investor feedback, always a concern about, say, the indication, like, with current standard of care, like, who wanted to take a gene editing approach. And that, you know, it's very difficult to disprove because it would be the commercial opportunity. But another important easy way to show is the enrollment speed. So maybe tell us about your, you know, enrollment even for your early phase 1/2 clinical trials and now the phase 3 study. You've already got the IND cleared. And how's the enrollment look like?
Yeah. I mean, so as, as you said, we've begun.
Mm-hmm.
The phase three work. We had a very successful phase one and two program for alpha-1 or I'm sorry, for ATTR amyloidosis.
Mm-hmm.
Where we learned that one can successfully knock out, you know, this gene, which serves as the source of the pathogenic protein, almost completely. And that's done with excellent safety and durability that now, with a couple of years of observation, really doesn't change. So, we think that's really exciting. What we're doing is taking the reduction to new levels, not achieved by other means. And we think that that augments very well for the phase 3 work. If you asked where we are in the phase 3 effort, we're starting with cardiomyopathy.
Mm-hmm.
We've cleared the IND, you know, last year in the United States. We're activating sites in the United States and multiple different countries. We've got several countries online. We've got sites active and currently enrolling. And as we've guided, we expect to have patients in, I emphasize, plural, treated here in the next few days, before the end of the Q1 . So we're very excited about that. We're making headway for the polyneuropathy indication as well. And we think we'll be in a position to talk about exactly what our plans are later this year.
Okay. So now going back to the cardiomyopathy, ATTR cardiomyopathy. I think the whole field is, like, waiting for HELIOS-B data. I know you got scrutinized by the clinical trial design. So maybe lay out and I do have investor feedback regarding, you know, what is the optimal clinical trial design. You know, when we look back, HELIOS-B, APOLLO-B, ATTRibute, or even, you know, the Ionis clinical trial study, they all started several years ago when tafamidis just launched or about to launch. So they have this very weird study design. Initially they're not allowed tafamidis. Then realize, oh, we have to allow patients to be on baseline tafamidis. They end up four arms or four cohorts, you know, even though it's a two-arm study. So now fast forward.
I think by the time maybe we're thinking when you start, you know, you already start your phase 3 study. By the time you've your study finished, the dynamics also change again. With current clinical trial design, like, maybe give us the rationale why you designed this way.
Mm-hmm.
Is there a better way? I know you already started. Is there a way to modify to make it even optimized, you know, in the phase of?
There's a lot in here. But, I'll tell you what we're doing. I mean, I think we're trying to shoot ahead of the dog.
Mm-hmm.
Anticipating, you know, how the field will evolve as we do our work. You know, I think the trials and, you know, as done by others, have suffered from assumptions that have been made probably with incomplete data.
Mm-hmm.
We've learned as a result of, you know, some of those studies that have read out better ways to study these patients.
Mm-hmm.
You know, flaws in the form of especially having a time-bound study where you're looking for endpoints. But when should one look, right?
Mm-hmm.
We've seen that with some of the stabilizers. We've seen that with, you know, the knockdown approaches as well where people anticipated that by a certain point in time, there would be sufficient endpoints to determine the outcome.
Mm-hmm.
That was wrong. And I again, there's just a dearth of data to go and design the optimal study. The approach we've taken is a very traditional one, looking for endpoints that are consequential, hard endpoints, hospitalization, cardiovascular mortality, you know, arrhythmias, etc., and not predetermine when to look but to let the study play out and collect the endpoints looking for the effect that, you know, we're looking for.
Mm-hmm.
You know, I think what you've seen with, you know, the recent Alnylam work, they're kind of trying to compensate for a judgment that was made by having more endpoints.
Mm-hmm.
Collect for whatever subgroup that.
Mm-hmm.
It's not clear to me exactly which ones. But that's, we factored all that in. So I just don't see, you know, the outcome of, you know, some of the recent actions they've taken as really affecting any of our assumptions or challenging them in any way. So we're quite happy where we are.
Mm-hmm.
We look forward to the HELIOS data, which we think will be quite informative. We're early enough in our study where if we need to tweak it somehow, we'd be able to do that. And of course we would.
Mm-hmm. So, I do agree. I think event-driven is so much better than predicting within a certain time frame how many events will be sufficient, right? So I totally agree with that. And I think that that's a much better approach than.
Even the measurements. I mean.
Yeah.
like, six-minute walk, while interesting.
Mm-hmm.
is not a very discerning endpoint.
That's right.
Why look at 12 months? I think we know far better, you know, how to do it now.
Yeah. But, you know, another question I have is, like, you still, you know, allow maybe aiming for 50%, right, the baseline tafamidis?
That's what we anticipate. About 50% will be on point.
Yeah. But then I'm thinking, why not just have either a two-arm study or a three-arm study? And you have a very clean study so, so that you do not, you know, because 50% in placebo tafamidis and, and your drug. And then you have a very clear, clinical evidence whether your drug is comparable or better than.
Which makes assumptions about event rates and all those subgroups and the effect size. So, it sounds attractive. I think that.
Mm-hmm.
The approach we've chosen is a simpler one, which is to ask all-comers.
Mm-hmm.
Drug versus no drug on top of standard of care, whether it's tafamidis or not.
Mm-hmm.
What's the effect? And then to look inside of those, you know, stratified layers.
Mm-hmm.
What is the nature of the effect, but not try to guesstimate.
Mm-hmm.
You know, what the effect size has to be to find an effect.
Mm-hmm.
We'll have descriptive information that addresses all that.
Mm-hmm.
But we're asking, in my judgment, a far simpler and more readily addressable question, which is, you know, what do we bring the drug on top of whatever it is that the patient's taking?
Mm-hmm. So then I was thinking, like, what three-arm would be, like, your drug plus tafamidis versus tafamidis and, and.
Gena, we do have openings in our statistics group.
Mm-hmm.
I encourage you to apply for a.
Okay. So maybe, you know, the similar, like, similar line of question is, Alnylam recently, after their own internal assessment, they're adding additional, they updated the.
They added a duration.
They added, like, a yep. It extended duration. But they also added monotherapy part, you know. So, like, would that have any impact to your?
I don't think so. I mean.
Mm-hmm.
We see what they did primarily as adding runway to the study so they can get more endpoints.
Mm-hmm. Mm-hmm.
And again, starting from where we're starting, which is asking the particular question that I just, you know, went through, nothing that we've seen that they've done challenges the assumptions that we've made. We look at that very carefully.
Mm-hmm.
We've thought about it a lot. We look at all of the data that's there. We have our own board of consultants who have large patient populations who augment the information. So, we feel quite confident in the study design that it should give us a robust answer.
Mm-hmm. Do you have any flexibility? I think, you know, look at Ionis, Alnylam, they all modify their clinical trials as the data evolving and also the competitor data as well. So do you have a flexibility to adjust your clinical trial?
We do.
Mm-hmm.
We've made the point that, coming after some of this work puts us, we think, in a very advantaged position where we can learn from.
Mm-hmm.
You know, event rates, design issues, etc. We've certainly factored that into our thinking. We have a data management committee that oversees the trial.
Mm-hmm.
Obviously, we work with them to give ourselves the greatest chance of success. We have the ability to have interim and interim analysis.
Mm-hmm.
When and how we do that will be a function of how the data flows and working with that committee.
Mm-hmm.
So we will be very, very carefully looking at the information. But as I see it now, I can't imagine too many scenarios that are going to really fundamentally affect the approach that we have.
Okay. Okay. And if we think about fast forward, you know, by the time this drug launch, likely we'll may have generic Tafamidis already on the market. So what kind of benefit you see will be or what kind of clinical profile you'll be looking for that will be commercially competitive moving forward?
Yeah. I mean, we know with tafamidis, which is a good drug.
Mm-hmm.
That patients progress.
Mm-hmm.
You know, that they progress at a slower rate.
Mm-hmm.
But relative to not taking the drug, it's hugely advantageous to take it. And that's good.
Mm-hmm. Mm-hmm.
We believe that we will add on top of that.
Mm-hmm.
And we believe that it will be a very, very clear benefit relative to not taking that drug. If, in fact, tafamidis is generic, that's only advantageous. And we would encourage doctors if, if we find in our study that there's incremental benefit to take that generic drug in addition to, you know, what we currently call, you know, NTLA-2001.
Mm-hmm.
Yeah.
Yeah. Yeah. And I think that this is a slightly different story versus, say, other say, silencers because they still need the repeated dosing. Here is a once-and-done. If you progress and then you have another chance to.
I will.
Yeah.
I think the challenge for the stabilizers because those patients progress.
Mm-hmm. Yeah.
Deciding what you're going to wait for.
Mm-hmm.
If in fact we see that one can get to very low levels of progression.
Mm-hmm.
With, you know, the drug combined with our own or our drug alone.
Mm-hmm.
What we foresee looking down the road is that this will be more and more a quantitative game where patients and doctors are going to want to know what the TTR level actually is. It's not going to be 90% reduction. It's going to be how many micrograms of TTR do I have floating around in my blood?
Mm-hmm.
We're down with levels that have not been achieved elsewhere. You know, it's that, that's how this field's going to evolve, which I think will be really very helpful in decision-making for physicians.
Okay. Okay. That makes sense. Regarding the data update later this year for the program, maybe a little bit online.
Yeah. I mean, we're, we're looking forward to sharing the 72 patients that come from both the polyneuropathy and cardiomyopathy arms later this year. We've collected a host of laboratory information, which we will share. There's cardiac functionality that we'll share. There's the clinical data that we've collected as well. What we wanted to do is have that cohort, you know, there was a beginning and an end of those 72 patients. We wanted.
Mm-hmm.
You know, the full maturation so we'd be in a position to give a full-sum description of that. But we will absolutely share that later this year.
Mm-hmm. So some of the functional data.
Absolutely.
From both cardiomyopathy and polyneuropathy.
Yep.
Okay. Good. And so regarding the phase 3 trial design for polyneuropathy, you know, any update thoughts there?
Yeah. We've said that this year, we will lay out our plans.
Mm-hmm.
that is progressing very well.
Mm-hmm.
We will comply with our promises as we usually do. I think we'll have some really interesting news that, you know, will tell you exactly how we're going to progress that work. You know, the goal is to, you know, make good investments that, you know, complement the, the core, program with, TTR knockdown. Those are the two primary indications. So.
Mm-hmm.
You'll hear our plans, soon.
Mm-hmm. Okay. And I assume the functional endpoint will be the NIS.
That's the typical.
Some form modification.
Yeah. I mean.
+7 or.
Yeah. I mean, I would have made that assumption. Yeah.
Okay. Okay. Good. So that study should be much faster, actually, to read out, right, for phase 3.
It can be faster.
Mm-hmm.
It would be our objective to make it as fast as it can be. So.
Mm-hmm.
When we get to the final point here, which, you know, as I said, will, I think, be fairly soon here, you'll get a sense of exactly what we're going to do.
Mm-hmm. Okay. Good. So now the second very important program, which also, in my view, showed outstanding data as well, for the phase 1/2 data. And we do have quite a few, you know, evolving competitive landscape, the new data maybe coming or, already maybe show some, data with not the gene editing approach but it's, say, subQ or, oral drug.
Right.
Yeah. So maybe from your, you know, the longer follow-up data.
Mm-hmm.
What is the number one feedback the doctors, what they are looking for is, like, basically, attack-free. So, so far, when we look at all the repeated dosing, whether subQ or, you know, oral drug, you still see attack rate. You know, they did not eliminate all the attacks. So, in my view, that would be a huge differentiating point. And that would be easy.
That's the goal.
So then, like, how long do you think, you know, need to show follow-up to prove this is a, like, convincing data? Because.
Yeah.
Clinical trial is usually very short, right? It's a, like, a few months, 3, 4 months. But for to claim attack-free, how long do you think they need to show?
Yeah. It's that. That's going to be a subjective.
Mm-hmm.
Thing that people will decide for themselves. As you might imagine, we're going to follow all of these patients for a very long time.
Mm-hmm.
Later this year, when we share information on the patients we've already presented, you know, some of this was just in the New England Journal recently, you'll see patients who are now out 18 to 24 months to two years. You'll start to get a sense of that picture. But the point you're making is a key one. You know, there are drugs out there. But it's the profile that you're looking for. And it's our judgment based on talking to lots of patients and lots of doctors that patients want to be cured, you know, to the extent that that word applies, which means attack-free and not carrying around, you know, syringes, etc., for some potential attack that they may have.
and then doing that in a way that's economically attractive to what is a very, very expensive set of patients in the healthcare system. And so our target profile is exactly that, you know, have patients get to a point where they are truly attack-free. They can live their lives normal as if HAE were only history for them.
Mm-hmm.
Do it in a way that's very, very attractive to, you know, the treating community and the pain community as well.
Mm-hmm. Several questions here. You know, first, remind me, have you decided a phase 3 dose yet?
Well, we're doing our phase 2 study.
Mm-hmm.
As you know, testing in a placebo-controlled trial 25 and 50 milligrams.
Mm-hmm.
We will share data from that later this year.
And it will.
That will determine the phase 3 dose.
Mm-hmm.
I think importantly, you know, we're already laying the groundwork for that phase 3 program. The objective would be make that decision and very rapidly roll into phase 3. We think that there's excellent prospects that we'll be running a phase 3 program in the Q3 of this year.
Mm-hmm.
As you know, those studies tend to be small in size. Some of it has to do with the patient population. But some of it has to do with the massive effect size of those drugs.
Mm-hmm.
You know, we've said earlier that we expect to be in a position where we're actually submitting a BLA sometime around the middle of 2026, which, in theory, should be the very first approved in vivo genome editing drug ever.
Mm-hmm. So what, what would be the sweet spots regarding, say, baseline attack rate for the phase 3 studies?
We want a very broad label. You know, we're trying to have the broadest age range. We want to have patients who are severe. We want to have patients who are not severe. And the protocol will be designed that way, as is the phase 2 study, by the way. The regulators have been quite accommodating for that approach.
Mm-hmm.
When we finalize the phase 3 program, which we're very close to doing, by the way, because we have this RMAT designation with the FDA, you'll see that it's going to be quite open to, you know, essentially, any patient who's old enough who has HAE.
Mm-hmm. I see. Will you have an experienced patient or the naive?
Experienced. Well, we're not looking for naive. So it'll be patients who have had the disease primarily.
Okay. Okay.
You know, you know, as opposed to a newly diagnosed patient.
Okay.
Yeah.
Okay. Good. This will be very exciting. Yeah.
I'm excited, so.
Okay. So the data update, would that be the EAACI?
Well, we haven't said where.
Mm-hmm.
You know that we give some advanced notice.
Mm-hmm.
When the data's ready, etc. We try to target a medical or scientific meeting. I would think that that'll, you know, will apply this year as well.
Mm-hmm. Okay. Good. This is very helpful. Now, you know, switch to insertion program. That's another the pioneer you guys started. And I'm showing very impressive data initially. So maybe, you know, the hemophilia B status. You're partnering with Regeneron.
Right.
Maybe a little bit update there. And then also your AATD program.
Well, it's hemophilia B is a shared program. It's led by Regeneron.
Mm-hmm.
They cleared an IND earlier this year. It's. I'm proud to say it's the fifth of five INDs that we've had, either ourselves or with partners, that have cleared in 30 days, whether in the in vivo or the ex vivo setting. I think we have a pretty good sense of what the FDA is looking for. And that's been really, really helpful from the program. They have said that they expect the trial to be up and running middle of the year and begin dosing here sometime in the second half. So, we look forward to that. That complements the work that we're doing in alpha-1 antitrypsin, where.
Mm-hmm.
It's a CTA process, you know, as distinct from an IND process. We expect to be dosing patients, this year as well.
Okay. I think, with the in vivo, you know, now you have NTLA-2002 moving to clinic. And how similar was your liver targeting? You know, how, what could be the easy translation to the new indication?
Well, you know, it's interesting. If you think about what we've done with TTR, we've taken a very demanding test, which is, can you almost completely knock out a gene? You know, alpha-1 is the opposite, which is, can you replace a protein at very, very high levels? And so in between those two bookends, there's a lot of targets and a lot of interesting things to do. So as excited as we are about alpha-1 and what we think we can do, you know, assuming we replicate what was done in non-human primates, which was get to normal human levels, the goal here would be to open the pathway for any number of other insertion disorders.
You can think of, you know, a long list of inborn errors in metabolism, lysosomal storage disorders, etc., all of which would be best addressed by an insertion approach as opposed to, say, you know, a gene writing approach.
Mm-hmm. That makes sense. Yeah. Okay. Well, we're on time. Thank you very much, John. Thank you, everyone.
Thank you.
And.
Great.