Let's get going. Thanks for joining this session with Intellia Therapeutics. My name is Alec Stranahan. I cover SMID biotech here at Bank of America, and I'm pleased to be joined by Edward Dulac, Chief Financial Officer of Intellia. Thanks for being here, Ed.
Thanks for having us. Great conference again.
Yeah.
It's a really productive day. Look forward to the discussion.
Great. Yeah, another year, in Vegas. Maybe just to start, you've had some recent updates. Maybe if you just wanna kinda level set, and step through, you know, the most important ones, whether that's, lonvo-z or, you know, the next few, studies we started.
A lot has happened.
Yeah
At the company over the last few months. I think most notably what you're referencing is we presented top-line results from our phase III HAELO study in HAE. We couldn't be more excited.
Yeah.
We've been thinking about commercialization, what that would mean for the product, but also for the company. Have been thinking about this for quite some time. To have top-line data, and just to provide a high-level overview, we showed essentially, you know, all patients get a meaningful clinical benefit. 62% of these patients at the end of the 28-week primary observation period are already attack free and therapy free. Super important outcome. Those are as good or better than anything that's ever been reported. From an attack rate reduction, we're at the very high upper 80%, which again, is as good or better than anything that's been reported.
We think there are limitations with the phase III placebo-controlled study in HAE we can talk about. We're encouraged by the crossover data that we shared. Once patients know that they're on therapy, they think about their disease differently. I think that bodes well for longer term follow-up, which is what we also showed in our phase I/II study. Really like the profile. Team's highly motivated. There's a tangible energy at the company right now.
We're preparing for the rest of the process to hopefully have a commercial launch in the first half of next year. From a nex-z perspective, that's our TTR program, it's been a very interesting six-month period. We were on clinical hold for a period of time. We cleared that in roughly three months for the polyneuropathy indication, we call that study MAGNITUDE-2. We did that at the end of January, then about four weeks, five weeks later in early March, we announced that we were off clinical hold for the larger opportunity, which is MAGNITUDE is the study name, but that's in cardiomyopathy. We are going through all the approval process with various, you know, multinational regulators, but also from IRBs and the clinical study sites that are participating.
We're now screening patients, and what we've indicated on PN, which is the smaller of the two opportunities, we'll complete enrollment in the second half of this year. For CM, we've made substantial progress. Before we were on hold, we got up to 650+ patients.
Yeah.
We continue to follow them. There are accruing events, but we're now back to screening and enrolling patients, and we'll provide an operational update towards the end of the year.
Okay. Great. Well, maybe we can step through each of these, first starting with lonvo-z and HAE. You alluded to the phase III top-line that we showed, 87% attack rate reduction, and I think placebo was closer to 62%, so a pretty meaningful improvement. And patients were entirely attack free on a single dose of therapy. I guess, can you speak to where those figures come in versus your expectations, and sort of how this stacks up versus competitor data?
Yeah, I'll spend a minute on this 'cause I alluded to it.
This is not unique to what we're doing in HAE, but if you run a placebo-controlled randomized study like we did, these patients are required to wash off their therapy. If they're on LTP therapy, they have to come off that therapy, they have to have a specific number of attacks, actually go onto attacks, to be able to eligible to go onto a study.
Yeah.
Once they're enrolled, they run the risk of being randomized to placebo. That is not a comfortable position for an HAE patient to be in.
What happens is that in that 28-week period, these patients are blinded. They don't know if they're on active drug or not, and their whole ever since being diagnosed, their whole existence is around surveilling their body at the first sign of an attack using an on-demand therapy.
If that happens in a study, regardless if it's actually an HAE attack, it counts as an attack. There's going to be limitations. It's very hard to see data that's going to be numerically greater than what we had. This is the behavioral, the human component of things, but we're very, very happy with the data. Going into this data set, we were just mindful the market leader has mid, upper 80% attack rate reductions. We've matched or exceeded that. From an attack-free status, we have not seen anything more than 44% from that market leader, and the best ever produced is 60%-62%. We're right where we wanted to be, as good or better than all the existing therapies, but we also like to think what we're doing, we're playing an entirely different game, right?
It's important to get patients attack free, but in our case, we do that after a single outpatient four hour infusion, and they may never have attacks and never require chronic drug therapy again.
That is a profound statement. There is many benefits for patients. We also see a very strong value proposition with physicians, and ultimately with payers that we've been doing work with since last year.
Great. Right. It was 87% attack rate reduction, 62% entirely attack free, which that latter number was even above what you would expect with the competitor.
Yeah, it's a really good outcome.
Yeah.
I think could potentially get better once patients know they're on therapy and in longer-term follow-up.
Right
A position to share that from our phase I/II study later this year. These will be patients out to four years at this point.
Then we will be excited to share likely next year, I mean, more mature data from the phase III study.
Okay. Yeah. I think in that 38% of patients that were not fully attack free, they still achieved meaningful attack rate reduction, and it actually improved in the crossover period, right? The data later this year that you alluded to, is that the EAACI presentation? What else should we sort of learn about this group that we didn't get in the top line, and, you know, how does that maybe inform real world expectations?
Yeah. We're still working through exactly what we'll present, but the EAACI meeting will be held in Europe, I think in Turkey this year. It's June 12 through the 15.
Yeah.
We'll get much more granular in terms of patient specific, you know, swim lane type information. We'll also be, you know, more articulate around how patients were doing on their prior therapy. This is a bit unique in our study design. Not only do we have attack rate reductions from baseline, we actually understand how these patients were performing on their prior therapy. These are data that we have not yet shown. I think what you'll end up seeing is that even if they have not yet gotten to attack-free status, they have received substantial clinical benefit with the potential that that improves over time.
Super exciting information that we'll have at EAACI. I think to double down on your point, the crossover data. Once patients get to that primary observation period at week 28, they have an optional opportunity to cross over. At the time of our February data cut, there were 20 patients in that placebo group, all of whom opted to get a crossover. They are still technically blinded, but they actually know that they've gotten therapy, right? They either got it initially or they got it at crossover, and now they are completely confident they have active therapy. That changes how they think about their disease.
It changes how they act on their disease. What you see already in the first few weeks of follow-up, small patient numbers, but you see a very significant reduction once they know that they're on therapy, and we think that speaks to the real world experience, which again, to go back to our phase I/II data, we presented 32 patients that now know they've gotten therapy. 31 out of 32, as of that data cut off last August, has gotten to an attack free status and therapy free status of various durations. We're really excited to play that movie out, share longer term follow-up. The thinking is that the vast majority of these patients will be both attack free and chronic therapy free, which is a very unique value proposition in this, in this market.
Great. I guess as you're packaging up the data and, you know, having initial payer conversations, one question we've been asked is like, how do you justify, you know, the price vis-a-vis the value proposition if you're reimbursing for this medicine versus what's currently available? I guess, how do you, how have those initial conversations gone and, you know, how are you sort of framing the lifetime value of a one-time therapy here?
This is, I love talking about this 'cause the value proposition is so clear. You have patients with HAE. First of all, there's a trend towards LTP use in the U.S. At least 60%-70% of patients are using LTP therapy.
Patients do have options. They are accustomed to switching. They will switch, either convenience or greater clinical benefit. We think we're gonna bring both to that conversation. We really like the market research and what we're seeing from a patient's perspective.
We can talk more about physicians, but your question's more on payers. They see the value prop, right? Today, the average annual cost of treating patients is not inexpensive. If you think about premium LTP therapies that are $650, $700,000 or more, that's an annual cost to them. They still have to carry and often use on-demand therapy.
There's still doctor's visits, there may be ER visits. The average annual cost for these payers today to treat HAE is every bit of $750,000 per year. When you show up with a therapy that has the promise of one infusion, a very simple to administer infusion, doesn't require hospitalization, all these patients go home, and you couple that with majority of patients getting a profound and durable clinical benefit, they see the possibilities.
What that can mean from, you know, their payer perspective. The conversations we've had have been, what's the right price for an average, you know, for a one-time treatment? They will typically think of a multiple, 2, 3, 4, 5x the average annual treatment cost. I'm not gonna set price here today. That gives you a range of what we talk about, and I think our value proposition is very strong. We definitely don't wanna leave value on the table. We've got a company to run, we've got shareholders to reward, and we think we've got a really strong position. That said, if you wanna get very aggressive on price and getting into the $4 million, $5 million range, sort of precedented, but high end of the range, you're gonna face resistance.
Right? Step edits, other administrative burdens. We wanna reduce the friction and make this as easy as possible for patients to have interest, prescribers to write that prescription, and then payers to pay for this.
We've done a lot of work here. We're doing it all again now that we have the definitive phase III data that'll be part of our label. So far it's been a very constructive conversation. They see a very short payback period and potentially the transformational nature of what lonvo-z will bring.
Great. You know, when you talk about the patients, is there a particular profile that you saw more apt to enroll on the study or is there maybe a patient population that you think would choose a commercial one-time treatment?
Yeah, there's lots of to unpack in that. We've got lots of market research that says really good things. I think the best indicator of demand is how patients actually behave.
If we just take a step back, we ran initially a 60-patient study in HAE, right? Placebo controlled everything that we talked about earlier. We had more than 40 patients show up in a single month to enroll in that study.
Right? What you now have seen, which is what we've known for quite some time, is 70% of our phase III population, not surprisingly, are on existing LTPs. Half of those patients come off lanadelumab. That's the market leader, right?
There's clearly unmet need, including on some of the leading therapies. We think that's very encouraging. I don't wanna ignore the 30% of patients that are on on-demand therapy only, right?
We look at this total addressable market as very broad, both existing LTP and at least a portion of on-demand therapy patients who really resonate with our profile. As we think about post-approval, who's likely to show up, I think it could come from certainly existing LTP therapy use.
I wouldn't ignore the on-demand side of the equation. What we've seen is we've got young patients, we've got older patients, but all seem to really resonate with this potential to not have attacks and not have therapy. Clearly, the patients who are on good LTPs, but are still having breakthrough attacks, both the number of those attacks and the severity. If they're moderate-severe, they're obvious candidates. They're going to be super motivated to engage with the physician, have the conversation. We look at about 25% of this market being switchable, sort of early adopters, if you will. We think that helps the initial adoption.
You're gonna have a much bigger camp, roughly half of the patient population, that understands what's available to them, the new options included, but is more of a watch and wait, right? They see it, they hear it, they may know someone who's had the experience, but they wanna make sure it's super safe.
They wanna make sure that this is now demonstrated in more of that HAE community. They're very likely to consider a switch.
we see roughly, you know, 75%-80% of market switchable, and we think we see a nice adoption curve over that first few years as a result.
When you think of the drivers of the demand kinetic, if lonvo-z is approved, is it a highly motivated patient population where you might see kind of a pull-through demand from the patient level? Or is it more of the prescriber assuming that it, you know, access is not a barrier, kind of making that ultimate decision?
HAE patients are pretty well educated. They're well-informed. There is a clear advocacy group where everyone knows everyone. It's a very tight-knit community, so there's lots of good communication. That's exactly what you would want when you're introducing a therapy. High degree of awareness, still high degree of unmet need, and a sophisticated purchaser, if you will, that understands what's possible. That conversation is clearly had with the physician. They are still very heavy-handed in the prescribing, but it is much more of a partnership dynamic in that conversation. What are we solving for? What are we trying to achieve? When we speak to patients, they love the profile. Physicians, interestingly, also respond to the profile. Today's therapies are either orally administered or self-injected at home. There isn't a financial incentive that we're sort of working against with physicians.
In many respects, they not only have to get prior authorization for these expensive therapies, they have to reauthorize at least annually and increasingly every six months because payers wanna make sure that these patients are getting the benefit from these therapies. If not, they want them redirected.
I think there's a lot of tailwinds that we see that when we enter into that conversation, we want to make sure a physician's educated. We've had medical field force in the field for quite some time, talking about gene editing, talking about the clinical data. We want to make sure they're highly educated. Patients have an advantage here just based on the advocacy group. Collectively, they'll make that treatment choice, and we want to make sure we're very much a part of that conversation.
Great. Maybe just thinking towards approval, I believe you've initiated the rolling BLA. What are sort of the two or three most critical operational items between now and the BLA, you know, completion? When do you start scaling the commercial infrastructure?
Yeah. The BLA is a known thing. We know exactly what we have to do. We've had RMAT designation for a while. We've participated in the CDRP program. It's a special pilot program for manufacturing CMC considerations. We've taken full advantage of that, hence our kind of speedy initiation into a rolling BLA submission. What is ahead is completing that submission.
What we've indicated, that will definitely be done before the end of this year. Hopefully, we can accelerate that, then we'll know PDUFA date and those sorts of things.
Alongside that, we've already built the foundational leadership team last year in 2025 related to commercial brand leads, pricing and market access, expertise, all those things that you'd want to see. Now it's a question of how do we build and in what time and in what quantity the field force related to the actual sales force, but also the reimbursement field team. That's on the horizon as well. We've already started to do some of that. That'll be more back-end weighted.
We clearly need to ultimately talk about our pricing and contracting strategy. I'm thinking a lot about this. At some point, we're gonna have to declare our intentions and what our final price is. Those are some of the big milestones leading up to what we expect will be approval in the first half of next year.
Okay. Okay. You know, obviously, U.S. is the first stop. It sounds like this is something that you're going to be equipped to handle on your own. When you think about the ex-U.S. opportunity, I guess how large is that opportunity, and is that sort of a geography that you'd want to partner, and just kind of keep the U.S. piece for yourselves?
Yeah. In many ways, we're following what I would say is probably the playbook for a U.S.-domiciled company. There's a lot of value in the U.S. market, as we all know. Honestly, we're a small company doing this for the first time. HAE is almost a perfect indication for us. It's not gonna be a huge field force requirement.
Other companies have talked about the size of their footprint. We're not gonna be any really any different there. We really like to set up in the U.S., but the company has a philosophy, and we feel very strongly about gaining access outside the U.S. Treatment practices are different. Price point is different. We are not able to operationalize that ourselves at this point in time, so partnership is our preferred, right?
We think about large, medium-sized companies that have the existing call point and the infrastructure to help accelerate that, and we're looking now with our phase III data to find that ideal partner. There are also distributors that are capable of doing cell and gene therapy that's been demonstrated, and it may be a combination of those things. We have run multinational studies. It is very important for us for many reasons to go outside the U.S. Right now, our preferred path is partnership, and we'll think about, you know, what comes next after that.
Okay. One more question on lonvo-z, and I do wanna talk about ATTR. I guess, when you speak to physicians, or payers even, I guess maybe potentially, and you can let me know if this has popped up in your conversations, are there any questions around kind of the longer term durability or the benefit sort of beyond the trial period? I guess what is sort of the longest followed patient showing in your study, and, like, how are you, I guess communicating the durability piece.
Yep.
Yeah.
In HAE, I'm gonna probably bring in TTR, it might be a good segue, for HAE, if you go back to the data we most recently presented, that was not phase III. This is the pooled analysis of the 32 patients from phase I, phase II. I believe that was an end of August 2025 data cut. The longest patient is out three years, right? We're sitting here now getting to that point in 2026. We will be in a position later this year to fast-forward that movie another 12 months.
We will have patients on the phase III dose or greater for at least four years by the time we're at the time of approval, and probably then some. There are similarities to how that program is in terms of LNP, the CRISPR machinery to TTR. We have even longer follow-up. We're already at four years. We're now going to get to that five year point, and by the time we're launching, we'll be at 5+ years. We look at this in totality in terms of the safety database that we have, in terms of the durability of a response, and I think it's safe to say everything we publish indicates that you get rapid reductions in the desired protein, depending on HAE or TTR. Every patient gets that benefit. They get it very quickly, and they do not go backwards.
We have no waning of effect, which is super important for a one-time therapy that I think has to have a strong value proposition.
That durability of effect is important. The short answer is we're already at three years in HAE, we're already at four years in TTR. We are gonna build on that, and then obviously we're gonna follow phase III patients into a much more mature state as well, and we expect to see a similar result.
Yeah. I think you've committed to at least a decade, if not more, of follow-up, right?
It's 15 years for cell gene therapies, but even our own studies in HAE, like this is a two-year study, so we'll formally follow them. We'll put them in a more of an extension, and we'll continue to monitor them, but yes.
Okay, great. Maybe shifting gears here to ATTR amyloidosis. For MAGNITUDE-2, this is your PN study. It's off clinical hold. Full enrollment I think is expected by the end of this year. I guess what sort of protocol modifications were accepted for PN, and how do you expect this to maybe extend to the CM study as well?
Yeah, we're off hold on both. I will say what's common across both studies is the following. There are two potential paths here, right? When you're on clinical hold, ideally you find the root cause. What's the smoking gun? Like, what's causing the problem? We have hypotheses. We're still doing work on that. We haven't really pinpointed the exact cause. The other path, which is the one we're on and where we have alignment with the agency, is more monitoring. To take a step back, we saw liver abnormalities in a very small, less than 1% of the population in the CM study, right?
That led to a temporary pause, a clinical hold that we've subsequently, we got off of. Those, if they do occur, they occur usually between weeks three and five. Very consistent with immunological reaction, almost without exception, that's exactly how these patients perform, the ones that do have this.
They usually self-resolve without intervention. What we've agreed to with the agency is to monitor more frequently. Now we have bi-weekly, you know, every three or four days, blood draws during that window of like 3- 5 weeks, and then for patients that get to grade two or greater transaminase elevations, they will be administered a short course of steroids. That's sort of what we primarily agreed to across both studies for PN and CM. In addition, there's exclusion criteria, and what we wanted to make sure is that regardless of it's the PN or CM patient, if they have a preexisting condition, think about viral hepatitis or MASH, anything that might predispose them to liver injury, we wanna probably exclude those patients. We don't think in practice that's gonna really increase our screen fail rate.
It's gonna probably have a very modest impact.
Yeah
abundance of caution, focused on patient safety, we've agreed to do those things. What's unique to MAGNITUDE, which is CM, this is a much older patient population, right? Things like cardiac stability, are they stable on their meds before they come into the study? Do they have symptomatic bradycardia that we need to sort out?
Those are the types of things that we're now screening for. Again, we don't think it's gonna have a big impact. For patients that have an ejection fraction less than 25%, they are now excluded. That's not gonna really change our screen fail rate, and we still see a very large addressable patient population. We need to now operationalize that. We are re-screening patients and then enrolling patients. We need to make sure those mitigation strategies are successful. As I mentioned earlier, we'll be in a position later this year to give an update on how things are progressing, what's our best sense of timelines for CM.
Okay. I guess in terms of benchmarks and for TTR reduction in PN, I think tafamidis has established a pretty strong benchmark here. It's obviously established in CM. I guess what does nex-z phase III need to demonstrate on TTR reduction depth, the durability, any other clinical endpoints to justify sort of usurping the market leader here?
I appreciate the question. We focus so much on safety, we forget about the clinical benefits side of things. At the end of the day, it is the combination of those things which determines is there a product and what is the ultimate potential of that opportunity. What I would say is you gotta look at our phase I/II data, and I know there's a lot of focus on TTR reductions, 80%, 90%. That's a little abstract.
Yeah.
I would think the closer connection here is almost to LDL cholesterol. Most people appreciate lower is better. When you look at our phase I/II patients, which half had New York Heart Association Class 3 and a third had hereditary forms, those are more difficult to treat patients, we had a really profound benefit on TTR.
From baseline, within 30 days post-infusion, almost every single patient, and there's a very narrow range around this, are at 19 or 20 µg/mL , okay.
Remember that number, 19 or 20. When you compare that to a drug like vutrisiran, which is approved in this space, 50 or more. We have almost a third less TTR. This is a disease of a toxic protein. You don't wanna have it, you don't wanna have it for very long. Our ability to lower TTR quickly, substantially less than what is available today, and very consistently over a long period of time, that results in a differentiated clinical profile.
What we've shown in phase I is not just the ability to slow disease progression. Tafamidis works, slows disease progression. Acoramidis works, slows disease progression. siRNA work, slow disease progression. What they don't really do is halt disease progression, and in our case, in a subset of patients, reverse that.
We've seen that in PN and CM. We do think that is possible. We're mindful of the safety now with the TTR post-clinical hold, but when we talk to our investigators, they understand that risk. They also see the very strong possibility of having a highly differentiated clinical benefit, and that combination they're very excited about. We're curious to see how this plays out once we're fully up and operating, but there's a lot to play for here, particularly when we're talking about TTR levels as low, as quickly and as consistently. That is not a profile that exists today.
Okay. When we think about the read-throughs between PN and CM, PN seems like the one that's gonna get over the finish line first. Are these the same physicians that are treating these two patient populations? Does a hit in PN actually increase physician comfort in CM, either on safety or efficacy or the balance?
Yeah, it's a good question. We, you know, in a model, in a conversation, we talk about like they're two different flavors.
There's a lot of mixed phenotype. It's not that clean and simple. There are a lot of patients that have a PN diagnosis that are seen by a cardiologist, so there's a degree of overlap, so this experience really matters.
The patient populations are pretty different. I mean, one of the things we didn't touch on, PN tends to be a younger patient population. They're probably more resilient to some of the side effects that we've seen and considerations on the safety side with CM, and you see that almost in our collaboration with the FDA. They were much more comfortable coming off more quickly with fewer considerations on PN than CM. I still think there's a lot to learn, right? It is the same product. It's the same dose. We won't have nearly the patient experience. We've increased the study size from 50- 60, we'll have that body of evidence in PN. When physicians have that experience and they know how the drug operates, it is valuable, in part because there's overlap between the CM and PN patients that they treat.
Ultimately, we're gonna have to enroll a good number of patients. We still have roughly 550 patients on CM to get to our target of 1,200, and I think that allows us to demonstrate that the mitigation strategy that we've agreed to with the agency is in fact working as intended. Ultimately, that's gonna be required, but it'll be an early positive sign if we have success in PN.
Okay. Maybe last question just around the safety profile, and sort of the read across for the pipeline. Appreciate we're still sort of figuring out what were the drivers. I think this is uncharted territory in terms of the average age in ATTR, which could be like 70, 75 years old, which is, yeah, really uncharted ground for gene editing. Is there anything like the LNP that would be shared across, you know, your clinical programs or any sort of read across to, say, HAE from what we're seeing in ATTR?
I think a couple things. I mean, the LNP are essentially the same, right? Even the mRNA, which is the CRISPR machinery, is the same. The only thing that's really different is the guide RNA.
There's a lot of, you know, optionality there, and maybe we can go into different diseases as a result of that. I do think we touched upon a few of these things. We've seen consistent knockdown of proteins, right? We're essentially knocking out these genes that are causing the problem, and you're seeing the desired effect. That's been true in HAE. It's true in TTR. Where I thought you were going is there still the same value proposition in an elderly patient population?
Mm. Mm
right, who may not have 20, 30, 40 years.
Right
Of therapy? What I think is very interesting is that look at the studies. Every time you wait another year to run a phase III study, patients are better served. More diuretic use, more SGLT2 inhibitor use. The standards of care are just improving. That's a great thing. What it results in, though, are patients who are 75, 80 years old that are no longer just living two or three years.
In fact, you've got 80%+ of patients making it to three years and maybe dying from something else. The value proposition I still think is there, and while there's less dosing frequency with available therapies and maybe that improves, I still think a one-time intervention is a very familiar paradigm for a cardiologist. When it comes with a benefit that can be 4, 5+ years, I still think if you've got this right risk-benefit profile that we talked about earlier, there's still plenty of opportunity. This is already a big market. There's more coming. Better diagnosis rates. I still think this doesn't have to be a zero-sum game. There could be multiple modalities, but we really like what we're seeing with nex-z, and we need to complete the phase III study to prove that out.
Okay. Maybe last question in the last minute, just around the cash balance vis-à-vis pushing, you know, through the next steps of de-risking. How are you feeling as the Chief Financial Officer around the cash position and, you know, what sort of how does that carry you through, you know, lonvo-z approval, et cetera?
I'm just happy to get a finance question. Thank you for that. We just raised a little bit of money on the back of the top-line data, which was part of the plan. Sitting here today, we've got about $700 million. The conservative guidance, if we forget about lonvo-z, we're gonna build all this infrastructure. If we never see a dime from lonvo-z, we still have enough cash to get us into 2028. That's a good place to be. What is much more fun is how will lonvo-z transform our P&L and our capital needs. It's possible that we require far less.
And/or from different institutions, maybe not just the good old equity that we do in biotech. I think it can transform our P&L. A little bit with a premium price product with a high margin can really change how we think about our capital needs. We require probably far less or potentially none-
For the foreseeable future, which is exciting possibility. It's up to us to make that happen. A lot of work to do, but we're super enthusiastic about what's ahead.
Yeah, good position to be in for sure. Well, I think with that we'll have to end it there since we're out of time. Ed, thank you so much for the great conversation, and thanks everyone for your interest in Intellia. Thank you.
Thank you.