All right, great. Hello, everybody. Luca Issi, Senior Biotech Analyst here at RBC Capital Markets, today it's our great privilege to have Intellia as part of our 2026 Global Healthcare Conference. Representing the company, we have John Leonard, Chief Executive Officer. John, thanks so much for joining us. How are you doing today?
I'm doing well. It's a pleasure to be here. Good to see you.
Good to see you, too. Yeah, good to see you, too. John, we have a long list of questions here, but maybe before we go into the specifics, and we ask you about all the individual programs, it would be great if you can maybe step back and give us a big picture or overview of what progress has the organization made over the last few months, and maybe what's ahead here for Intellia.
Super. Well, we're very, very proud to say that we've completed the very first phase III program for an in vivo CRISPR product. We've been pioneers since the very early days of the CRISPR era by being the first people to go and do in vivo genome editing. As I'm sure you've seen, others are going into that space as well. Pioneering the use of lipid nanoparticles, reporting the first cases of any human genes being edited in people, and we did that first and second company to do that. What we're seeing is the fruition of that work. Data we released was phase III results for hereditary angioedema.
I suspect we'll probably be talking a little bit about the data, but we were excited that we were able to get results that confirm what we'd seen in some of the earlier studies, where patients who get this outpatient IV therapy, in the vast majority of cases, are essentially devoid of their disease afterwards.
I think that shows the promise of CRISPR. The second program, which is a larger program, is for the treatment of transthyretin, the transthyretin amyloidosis. Two primary indications of that, polyneuropathy and cardiomyopathy, where we've rebooted our phase III programs and are excited about completing that work. We still have, as you might imagine, a lot of work going on on the research side, things that we'll talk about down the road. We try to be pioneering yet again and doing some things that are a little outside the standard approach.
Got you. That's super helpful. Let's maybe double-click here on hereditary angioedema. I know you have started the rolling BLA submissions, and you're obviously hoping to complete that by the second half of the year. Maybe just remind us what are the benefit of doing a rolling BLA submissions versus a standard BLA submissions? How should we think about priority review versus standard review in the context of, obviously now there's a bunch of other therapies available there for HAE?
Yeah. We benefit not only in HAE, but also the TTR program by having RMAT designation. What that affords us is the opportunity to have frequent engagement with the FDA. We've used that to our advantage to get a really good notion of what they're looking for, and we've shared the progress that we've made. Part of that also enables the rolling BLA. We had started that before we released our phase III data. You can imagine the preclinical work, some of the CMC things, which has been largely put to bed, if you will. The overall advantages have to do with an early start, the likelihood of having a priority review, and some opportunities for having this whole thing being foreshortened. We'll know more when the filing is complete, which we've said will be in the second half of the year.
I would say we try to underpromise and overdeliver.
Sure.
Have things moving along at a quite prodigious rate. At that point, we'll know a little bit more about the trajectory of that review and other things that lie ahead.
Got you. That's helpful. Maybe kind of higher level, one of the common conversations we have with investors is data's great, but there's also a lot of other therapeutic alternatives available out there, whether you look at ONPATTRO or TAKHZYRO or some of the CSL drugs or some of the others. Again, the competitive landscape continues to intensify here. Just maybe remind us why you think you're different and why you think that a relatively large proportion of patients will actually pick a one-and-done therapy that comes with the permanent editing of your liver and other kind of considerations there.
Right. There's no doubt that it's better to be a patient with HAE today than it was 10 years ago. The pharmacopeia's moved forward. That's good for patients. That really falls into two broad categories. Patients take long-term prophylaxis. Some patients take on-demand therapy. There's a lot of overlap between those two. Drugs are, as I say, are reasonably effective in this patient population. The challenge that patients have, however, lies in what they experience as they do that. Most patients continue to have attacks when you go out. We've done this work, as you might imagine, just asking free range patients, well over 80% of them will report having had attacks in the last year. From the standpoint of control of the disease, it's better. It's not perfect.
All of these patients take drugs that are typically very expensive, which require ongoing prior authorizations at least annually, sometimes twice a year, depending on the drug and the carrier. That represents, in addition to the disease itself, a burden for these patients. It's the living with the disease and the uncertainty of when you're going to have an attack, but also living with the uncertainty of knowing that you're going to continue to be able to have access to the drug. When they have jobs, and most of these patients do have commercial insurance, they don't change their jobs. They adhere to that because they're afraid that as they move into other places, there'll be real limitations. Whether it's the experience they have with respect to the disease itself, accessing the therapy, taking a therapy, there's a burden that patients have to contend with.
The promise of a one and done approach, or the potential of it, is that much, if not most or all of that can be addressed.
What we've shown in the data that we've presented thus far is that following a single application, this is an outpatient therapy where there's no conditioning, there's no virus, these are all synthetic molecules. Patients get a simple regimen the day before, and on the day of therapy, they're done and they go home. With that, in most cases, over time, these patients get to a state of no attacks and no therapy.
if you look across the program from the time that we started phase I through phase II and now through phase III, essentially all, nearly all of these patients, once they get the drug, are off long-term prophylaxis.
For any patient that has an attack, which is the small minority of these patients, the utilization rate is a fraction of what it was previously. The patient experience improves, the certainty of access goes up. The anxiety that comes with whether or not I have access to my drug or any interruptions goes away. When you look at this, we've said from a financial point of view, we will not be setting any new records in terms of sky-high prices, even though some of the traditional measures would suggest that we should.
We will not. This will be resource sparing across the board. The payers to patients, and to the physicians who take care of them. I think it's a win-win across the board.
Yeah. Obviously, you're not commenting directly on price. I know it's premature and there's still a lot of things that it has to go through it, would it still be fair for us to assume that the price is going to be higher than whatever is the annual price of DAWNZERA or TAKHZYRO or some of the drugs that are available out there? If so, will the payer get it? Meaning, will the payer understand the pharmacoeconomic value of your drug and will think two, three, four years down the line and not, "I'm going to just reimburse whatever is cheaper today." The price tag is probably going to be lower from an annual standpoint. Like, how do you think about all that, I guess? Yeah.
No, it's an important question. When you have a one and done therapy, it is a different model than if you have chronic therapy, which is what applies to a large part of the pharmacopeia. Yes, I think it's a reasonably safe assumption it'll be more than the annual use of, or cost of those typical agents. The way payers usually look at this, and we look at similarly, is there's some multiple of a reference product.
That might range from 2x- 5x , typically. What goes into the thinking of that is the outcomes themselves, the quality of that response. We have essentially all of our patients responding. The durability, we are now on our fourth year. We have not a single patient who's lost the effect thus far. We don't expect that to change, as far as we can tell. When we look across programs to TTR, I include them who are now the earliest treated patients out in their sixth year. We don't have a single example of patients losing effect. From a standpoint of when they look for analogs, they're not good ones. Some of the hemophilia products were valiant attempts but fell short in terms of either the outcomes and/or the durability of the response. That doesn't apply to us.
It's interesting when these patients typically, they're a little different from standard sort of commercially insured patients where our data says that they stay with a carrier for over four years.
As we think about the standard models, these insurers should see a payback. Certainly, as patients move amongst carriers, clearly they will see a payback.
Got you. That's helpful. I'm just kind of reflecting back on the commentary you just made around we don't have patients losing effect. Right? Which I think is an important distinction of your therapy versus others. In that context, are you potentially considering value-based agreement with payers where if a patient does lose that efficacy and will require to go back to a prophylactic regimen to any capacity, they get some sort of discount or price cut or reimbursements? I guess, how should we think about value-based agreement in that context?
As we've had conversations with payers, and we've been doing this for over a year now, so we've been sharing the information we have, which will now be augmented by the phase III data. Generally speaking, the payers are not all that enthusiastic about pay-for-performance or value-based agreements because there's an administrative aspect that comes with that. Assuming what I just shared doesn't change all of a sudden, I don't know why it would, we would expect that in most cases, standard models will apply. At least that's what we're taking away from some of these conversations. One can imagine that in some cases, they'll require step edits and that sort of thing. As you might imagine, as the price goes up, the obstacles become progressively more onerous. Our approach is to make sure the value is clear.
Sure.
Not put this in a zone where we're going to encounter all kinds of resistance. We want it to be a clear win for the patients, the doctors, and the payers. I would point out that when you think of what step edits are, our experience is that the vast majority of these patients will have already been through the necessary steps even to get to the therapies that they would be starting on.
Sure. That's helpful. Appreciate that on a relative basis, the number of patients on a prophylactic therapy for hereditary angioedema in the U.S. is a much larger proportion versus the number of patients that are on prophylactic therapy ex-U.S. How are you thinking about the ex-U.S. opportunity, like pursued by yourself, partner, have a distributor? How are you thinking about the ex-U.S.?
There is an opportunity outside the U.S. It's different from what we see in the United States, who will be launching this product ourselves. This is in some respects, a good one for a company like us.
Yeah.
We have people who've been in the space, who know it well, who've been involved with the leading products. The aspect of finding new patients is really not such a challenge as it might be with other examples. These patients are known. It's a prevalent patient population as opposed to an incident one. With a modest-sized effort, we think we can reach them. It's very much an access game, and that's where we've been putting a lot of our emphasis. As we look outside the United States, yes, we think there's value to be captured, and we're working through what those options are, and it ranges from potential partnership to distributors and that kind of thing. We'll do what we think is right for the company that captures the right balance without extending us beyond where we want to go.
Got you. Super helpful. Pivot to TTR in the interest of time here. Congrats, obviously, on the recent clinical hold being lifted. Can you just recap what happened there and maybe why you're confident that the new mitigation strategy that you have put in place will allow you to spare that tox? Related to it, can you just comment, as a question we get from investors all the time. Can you just comment about expectations for enrollment pace before and after? Obviously, this is now in the news, and people have talked about it. Do you anticipate that the enrollment pace will be a little slower going forward?
Right. What happened, TTR has two indications, polyneuropathy, cardiomyopathy. The manifestations overlap somewhat in patients, but from a regulatory point of view, those are the two manifestations that are primarily measured. We had an incidence of liver injury at the end of October last year in a patient who had a very complicated clinical course, who died of a perforated duodenal ulcer and sepsis related to that. People get confused. The patient did not die of liver failure, but he did have some degree of liver injury. We paused the study, worked with the FDA, and looked for anything that could help identify patients who might be at risk or find ways that we could reduce the risk. We didn't come up with a smoking gun, at least not yet, and we continue to do this work.
We did agree with the FDA that the appearance of the injury followed a pattern that was very representative of what we thought was an immune-mediated sort of event. The way we've addressed that is because these instances, when they occur, are all highly reminiscent of each other. Essentially, a stereotypical pattern where there's a time period where when the events happen, it's essentially always there between weeks three and five, and they resolve by themselves. What you don't want to do is have high excursions like this particular patient who had the unfortunate outcome did. What's in place is the standard approach for immune-mediated events. We'll surveil carefully for any indication that patients are starting to have any kind of evidence of liver injury, even modest, and then we would begin a course of steroids.
When we apply those rules retrospectively to the first 650 patients, there's a handful of patients that will have received any steroids. No one will have received it for over a week, including the one case that we just talked about. Typically, if anyone receives steroids, it'd be days three to five or so. That's kind of a standard sort of thing. With respect to enrollment, we were very close to completing the study for the polyneuropathy program. That will finish its enrollment here, the second half, and it's a time-bound observation period, so 18 months after the last patient comes into the study, we'll do that determination of how he or she is doing. With respect to cardiomyopathy, which is a larger undertaking, we're looking for 1,200 patients.
Yeah.
We had over 650 when we paused. There's more sites spread out in more countries. It's just a bigger thing to get going. That's happening. Informed consents, the protocol amendments, which are modest changes from what we had before, and dealing with IRBs, etc . We're actively screening. I think we'll know later this year where this all plays out in terms of hitting that final enrollment number.
Got you. That's helpful. I do want to go back to something you just mentioned a couple of minutes ago, because I think it's important for the broader field of gene editing, and you guys are pioneers, so it's important the broader field learns from the pioneers as well. No smoking gun but immune-mediated. Who's the person of interest? Who's the primary suspects here? I guess, how should we think about it? Is that because of the bacterial enzyme? Is that because something happened late in the game, right?
Yeah.
Relatively later in the game. What's the primary hypothesis at this point?
It's not the LNP. That's one question we get a lot. We've looked, as you might imagine, very carefully into that. You can measure the presence of the components which are gone within just a few days after a patient's administered the drug. What appears to be happening is that there's a response to something. Something has changed. What that is, we can't rule in or rule out just yet. What we're doing is a very, very extensive effort of looking at essentially all of the patients. We haven't completed every single patient yet, but as many of them as we can across the program and certainly in the MAGNITUDE study, to see if we can find a molecular signal of what correlates with the finding in the study, and is there some mechanistic link between those two things.
That work is ongoing, and it's something that we've prioritized. I believe that if we can find a, quote, "smoking gun," the thing that we can point to, we'd be in a better position than we are now. We're confident that the site can be done safely for patients as it is. I think if we can take out the patients, at least for the meanwhile.
Yeah
who may be at increased risk, then patients will enjoy the benefit of the therapy, which is substantial based on everything we've seen thus far, and presumably we'll be able to ward off some of the other issues that applies to just a tiny percentage of these patients.
Got you. Sounds good. Always super important to keep risk-benefit profile in mind here. Maybe on TTR cardiomyopathy, you just mentioned you enrolled half of the patients, roughly, that you were supposed to enroll, now you have a little pause, now obviously you're enrolling them again. Does that complicate the stats in any capacity? Obviously you're going to have events. This is event-driven. You're going to have wave one of the events and wave two, if you will. That's probably an oversimplification, there's going to be a wave before the pause and after the pause. I appreciate the pause is relatively short here, does that complicate a Kaplan-Meier curves and anything, considerations in the stat?
I'm not sure it complicates it so much. It does change where the majority of events will come from. Exactly as you pointed out, if you have a three and half or so month time gap between that first group of patients and then this enrollment momentum pickup in the second half, a disproportionate share of the endpoints will come from the earlier set of patients. I don't think that's really going to affect how things turn out. It delays it somewhat because the average patient would've been to the left on the Gantt chart, if you will, than will be the case. What you worry more about is, does the patient population change somehow? Is the therapy different, or have you altered the protocol in such a way that who comes in part two doesn't look quite the same as part one? That's not the case.
I think that our approach that we put in place last year applies. As you might imagine, even during the hold, we were having events and monitoring those patients that had come in. If that affects the very last patients, we'll take that into consideration. Right now, we're sticking with the plan that we had.
Got you. I know we're already out of time. Maybe a last question, John, before I let you go. On TTR polyneuropathy, and correct me if I'm wrong, I believe that that trial is being run exclusively ex-U.S.
That's right.
I don't think there's any sites in the U.S. How confident are you that a trial that is exclusively ex-U.S. will ultimately lead to an approval in the U.S.?
We've worked on the FDA with this. This is a placebo-controlled trial. The only way that you can carry out a placebo-controlled trial is essentially outside the United States at this point, where drug may not be available, and this is a source of care for these patients. With that, you can run a very compact study because the effect size is so big-
Sure
with the drugs. The study's done under the IND. It is a protocol we worked on with the FDA. They are fully aware and agree that this is done outside the United States with no American patients. We would only do that if we had good alignment with FDA.
Got you. There was never a consideration at some point to run synthetic placebo type of trials or anything. I see some of your competitors have done that, I appreciate those are different molecules at this point.
if you have access to that data.
Yeah
from your prior programs, as is the case with ONPATTRO, it's harder for us to be able to do that.
Okay. John, I have 3,000 more questions, but no more time. Appreciate you joining us here at RBC.
Thank you.
Thanks everyone for joining.
It's fun.
We'll talk soon. Yeah. Thank you. Appreciate it.