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

Good afternoon. Welcome to Barclays Global Healthcare Conference. My name is Gena Wang. I'm SMID-cap biotech analyst at the Barclays. It is my great pleasure to introduce our next presenting company, Intellia Therapeutics. With us today, we have John Leonard, our 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, 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 III. So I'm sure we'll be talking about the TTR program, which is enrolling as we speak in Phase III. And later this year, we expect to be in Phase III 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. And I do agree, you guys are pioneering the in vivo programs and now the 2 Phase III ready -- Phase III assets. Yes. So regarding ATTR, 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 gene editing approach? And that -- it's very difficult to disapprove because it will be the commercial opportunity. But another important easy way to show is the enrollment speed. So maybe tell us about enrollment even for your early Phase I/II clinical trials and now the Phase III study, you already -- the IND already cleared and how's the enrollment going?

Yes. I mean so as you said, we've begun the Phase III work. We had a very successful Phase I and II program for alpha-1 -- or I'm sorry, for ATTR amyloidosis, where we learned that one can successfully knock out this gene, which serves as a 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 augurs very well for Phase III work. If you ask where we are in the Phase III effort, we're starting with cardiomyopathy. We've cleared the IND last year in the United States. We're activating sites in the United States at 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, and I emphasize plural, treated here in the next few days before the end of the first quarter. 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. And I think the whole field is like waiting for HELIOS-B data. And I know you got scrutinized by the clinical trial design. And so maybe lay out -- and I do have investor feedback regarding what is the optimal clinical trial design. And when we look back, HELIOS-B, APOLLO-B attribute or even 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 and initially did not allow tafamidis and then realized, oh, we have to allow patients to be on baseline tafamidis and end up 4 arms or 4 cohorts, even though it's a 2-arm study. So now fast forward, and I think by the time maybe or thinking when you start -- you already started your Phase III study. And by the time your study finished, the dynamic also changed again. So with current clinical trial design like maybe give us the rationale why you design this way? Is there a better way? I know you already started, is there a way to modify to make even optimize inefficient...

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 duck, anticipating how the field will evolve as we do our work. I think the trials as done by others have suffered from assumptions that have been made probably with incomplete data, and we've learned as a result of some of those studies that have read out better ways to save these patients, flaws in the form of especially having a time-bound study. You're looking for endpoints, but when should one look. And we've seen that with some of the stabilizers. We've seen that with the knockdown approaches as well, where people anticipated that by a certain point in time, there will be sufficient endpoints to determine the outcome, and that was wrong. And again, there's just a dearth of data to go into design the APOLLO. The approach we've taken is a very traditional one, looking for endpoints that are consequential, hard endpoints, hospitalization, cardiovascular mortality, arrhythmias, et cetera. And not predetermine when to look, but to let the study play out and collect the endpoints looking for the effect that we're looking for. I think what you've seen with the recent Alnylam work, they're kind of trying to compensate for a judgment that was made by having more endpoints to collect for whatever subgroup that is not clear to me exactly which ones. But that's -- we factored all that in. So I just don't see the outcome of some of the recent actions they've taken is really affecting any of our assumptions or challenging them in any way. So we're quite happy where we are. We look forward to the HELIOS data, which we think will be quite informative. We're early enough from our study where if we need to tweak it somehow, we'd be able to do that and of course, we would.

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...

And even the measurements. I mean, like 6-minute walk, while interesting, is not a very discerning endpoint. Why looking at 12 months? I think we know far better, how to do it now.

And then -- but another question I have is like you still allow maybe aiming for 50%, right, the base line tafamidis?

That's why we anticipate about 50%...

Then I was thinking, why not just have either 2-arm study or 3-arm study. And you have a very clean study so that you do not -- because 50% in placebo tafamidis and your drug and then you have a 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 there's -- it sounds attractive. I think that the approach we've chosen is a simpler one, which is to ask all comers, drug versus no drug on top of standard of care, whether it's tafamidis or not what's the effect? And then to look inside of those stratified layers, what is the nature of the effect, but not try to guesstimate what the effect size has to be to find an effect. So we'll have descriptive information that addresses all that, but we're asking a -- in my judgment, a far simpler and more readily addressable question, which is what do we bring the drug on top of whatever it is that the patients take.

So then I was thinking about what 3-arm will be like your drug plus tafamidis versus tafamidis and...

We do have openings in our statistics group and I'd encourage you to apply for it.

Okay. So maybe the similar -- like similar line of question is Alnylam recently after their own internal assessment, they're adding additional -- the update...

They added a duration, right?

They add the like -- yes, extended duration, but they also add the monotherapy part. So like would that have any impact to your...

I don't think so. I mean we see what they did primarily as adding runway to the study, so they can get more endpoints. And again, starting from where we're starting, which is asking the particular question that I just went through, nothing that we've seen that they've done challenges, the assumptions that we've made. We look at that very carefully. 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.

Do you have any flexibility, I think, look at Ionis, Alnylam and they all modified clinical trials as the data evolving and also the competitor data as well. So do you have the flexibility to adjust your clinical trial?

We do. And 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 event rates, design issues, et cetera. And we certainly factored that into our thinking. We have a data management committee that oversees the trial. And obviously, we work with them to give ourselves the greatest chance of success. We have the ability to have interim -- an interim analysis and when and how we do that will be a function of how the data flows and working with that committee. 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 by the time this drug launch likely we may have generic tafamidis already on the market. So what kind of benefit you see will be -- what kind of clinical profile we will be looking for that will be commercially competitive, moving forward?

No. I mean we know what tafamidis, which is a good drug, the patients progress. They progress at a slower rate, but relative to not taking the drug, it's hugely advantageous to take it, and that's good. We believe that we will add on top of that, 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 we find in our study that there's incremental benefit to take that generic drug in addition to what we currently call NTLA-2001.

Yes. Yes. And I think that this is a slightly different story versus the other challenges because they still need to repeat the dosing here is a once and done, if you progress and then you have another chance to...

Well, I think the challenge for the stabilizers because those patients progress, deciding what you're going to wait for. If in fact, we see that one can get to very low levels of progression with the drug combined with our own or our drug alone. And 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. And it's not going to be 90% reduction. It's going to be how many micrograms of TTR to have floating round in my blood. And we're down with levels that have not been achieved elsewhere. And it's -- that's how this field is going to evolve, which I think will be really very helpful in decision-making for physicians.

Okay. That makes sense. And regarding the data update later this year, will the program...

Yes. I mean 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, that'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 -- there was a beginning and an end of those 72 patients. We wanted 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.

So some of the functional data?

Absolutely.

From both cardiomyopathy and polyneuropathy?

Yes.

Okay. Good. And so regarding the Phase III trial design for polyneuropathy, any updated thoughts there?

Yes. We've said that this year we will lay out our plans that is progressing very well. We will comply with our promises as we usually do. And I think we'll have some really interesting news that we'll tell you exactly how we're going to progress that work. And the goal is to make good investments that compliment the core program with TTR knockdown, and those are the 2 primary indications. So you'll hear our plans soon.

And I assume the functional end point will be the NIS.

That's the typical...

Some from modification plus 7...

Yes. I would have make that assumption, yes.

Okay. Okay. Good. So that study should be much faster actually to read out, right, for Phase III?

It can be faster, and it would be our objective to make it as fast as it can be. So when we get to the final point here, which as I said, will I think be fairly soon here, you'll get a sense of exactly what we're going to do.

Okay. Good. So now the second very important program, which also in my view show outstanding data as well for the Phase I/II data. And we do have quite a few evolving competitive landscape and new data that will be coming or already maybe show some data with not a gene-editing approach, but say subcu or oral drug. Yes. So maybe from your -- the longer follow-up data and what is the one feedback the doctors, what they're looking for is like basically attack rate. So far, when we look at all the repeat dosing, whether subcu or oral drug, you still see attack rate, they did not eliminate all the attacks. So it might level be a huge differentiating point and that would be...

That's the goal.

So then like how long do you think you need to show a follow-up to prove this is like convincing data? Clinical trials usually very short, right, like a few months, 3, 4 months. But for -- to claim attack-free, how long do you think they need to show?

That's going to be a subjective 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. And later this year, when we share information on the patients we've already presented, some of this was just in the New England Journal recently. You'll see patients who are now out 18 to 2 -- 18 months to 2 years, and you'll start to get a sense of that picture. But the point you're making is the key one. There's 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 to the extent that, that word applies, which means a attack free and not carrying around syringes, et cetera, 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 health care system. And so our target profile is exactly that. Have patients get to a point where they're truly attack free. They can live their lives normal as if HAE were only history from them and do it in a way that's very, very attractive to the treating community and the paying community as well.

So several questions here. And the first, remind me, have you decided a Phase III dose yet?

What we're doing in our Phase II study, as you know, in testing in a placebo-controlled trial, 25 and 50 milligrams. And we will share data from that later this year that will determine the Phase III dose. And I think importantly, we're already laying the groundwork for that Phase III program. The objective would be makes that decision and very rapidly roll into Phase III. We think that there's excellent prospects that will be running a Phase III program in the third quarter of this year. And as you know, those studies tend to be small in size, some of it has a patient population, but some of it has to do with the massive effect size of those drugs. And 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.

So what would be the sweet spots regarding, say, baseline attack rate for the Phase III study?

We want a very broad label. 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 II study, by the way. The regulators have been quite accommodating for that approach. And when we finalize the Phase III 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 essentially any patient who's old enough who has HAE.

I see. Will you have an experienced patient or the...

Experienced. Well, we're not working for naive. Sort of the patients who have had the disease primarily as opposed to a newly diagnosed patients.

Okay. Good. That will be very exciting. Yes.

I'm excited.

Okay. So the data update, would that be the EACI?

Well, we haven't said where you know that we gave some advanced notice when the data is ready, et cetera. And we try to target a medical or scientific meeting. And I would think that, that will apply this year as well.

Okay. Good. This is very helpful. Now switch to insertion program. That's another -- the pioneer you guys started, and I'm showing very impressive data initially. So maybe the hemophilia B status, you've partnered with Regeneron, maybe a little bit update there and then also your ATT program...

Well, it's -- our hemophilia B is a shared program. It's led by Regeneron, and they cleared an IND earlier this year. It's -- I'm proud to say it's the fifth of 5 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 for the program. They have said that they expect the trial to be up and running middle of the year and be in 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 it's a CTA process as distinct from an IND process. And we expect to be dosing patients this year as well.

Okay. I think that with the in vivo now you have 2 moving to clinic and how similar was your liver targeted? How -- what could be the easy translation to the new indication?

Well, it's interesting. If you think about what we've done with TTR, we've taken a very demanding task, which is can you almost completely knock out a gene? Alpha-1 is the opposite, which is can you replace a protein at a very, very high levels? And so in between those 2 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, 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 a long list of inborn errors in metabolism, lysosomal storage disorders, et cetera, all of which would be best addressed by an insertion approach as opposed to, say, a gene writing approach.

That makes sense. Okay. Well, we're on time. Thank you very much, John. Thank you, everyone.

Thank you. Great.