Perfect. Thank you. Welcome back to the next session of this year's Global Healthcare Conference here in Miami. Once again, Mani Foroohar, senior analyst at Leerink Partners. I'm hosting John Leonard and Ed Dulac from Intellia Therapeutics. Welcome to Miami, guys.
Good to be here.
Thanks.
I feel like I should sing that at some point. No one needs to be punished with my karaoke voice. Before we dive into nuances and data analysis, et cetera, give us a sense of where we are in terms of timing to the next key data event for you guys, which will be the pivotal HAE data from the HAELO study.
I mean, we're really looking forward to the completion of our Phase III program for Halo, which, you know, assuming things work out the way that we anticipate they will be the first launch of an in vivo gene editing product next year. We'll have top-line data mid this year, and you should expect to see, you know, attack rate reductions, attack-free intervals, and headlines on safety.
Before we sat down to chat about this, we talked about how that data matures, and it's something that's been talked about on calls, et cetera. How should we think about the data we're going to see at that first press release and presumptively conference call, and how it's going to mature towards what it's going to look like upon filing approval, et cetera, and how that data evolves over time on each of those metrics?
Yeah. I mean, when we look forward this year to the data, I would expect that we're going to be very, very competitive with what is already out there in terms of attack rate reductions, attack-free intervals, which is something that we think we really excel at. We would expect to be comparable or better than the best. The market leaders, you know, is about 45% attack-free rate reductions. There's a just inherent sort of limitation to these Phase III studies. Patients come off the therapy, they wash out the randomized placebo or active drug. The way patients are managed, and this is proper medical care, is that, if they have a visible attack, they report it as such, and they take appropriate measures.
If they also believe that they're about to have an attack, there may be some subtle, call it a twitch or whatever, without visible swelling, they'll act on that with on-demand therapy, and that counts as an attack. What we've learned in our work, but this is seen in other programs as well, is that if you have patients who know they received drug and are willing to wait a little longer before an attack fully develops, many of those so-called twinges turn out to be something that's not in fact an attack. We've seen that in our data, that once patients are unblinded or they've actually you know, on an open label basis, gotten the drug, as time goes on, their data really improves.
Let's talk a little bit about how attacks are defined in this pivotal study, and how to think about attacks as determined by the patient, attacks as determined and defined by a clinician, and then what that looks like in the real world once this thing becomes a commercial drug presumptively.
Well, patients have a diary, and they record what they do and what they experience, and that's reviewed by a physician. A physician says, "Yes, I believe that this actually represents an attack." By definition, if you're using on-demand therapy, regardless, that's considered an attack. That's, you know, that's the point behind the comments I was just making. What did you want to know about?
In the perspective of physicians, when I talk about patients-
Uh-uh
...when I talk about this is what you should expect about attack rate, attack-free reduction, et cetera, they have to be aware of this nuance because they've been treating these patients for many years.
They are, but it's an inherent limitation of the study. These are study designs that apply to all, you know, people who are active in that space. It's because these swelling attacks can be very, very dangerous, in fact, in some cases, even lethal, if your larynx is involved. For example, patients are trained, this is standard medical practice, to as soon as they believe an attack is beginning, to try to prevent it from actually taking place. Because there's no biomarker that says we can confirm that, in fact, this was an attack, you know, it's we're not able to do anything other than score it as such because, you know, the on-demand therapy was used or there was actually a visible swelling.
I think one of the conversations that we have with a lot of investors is, there's so many improved therapies, and they're a lot better than they were in the Cinryze era. I'm dating myself by referencing Cinryze there. It's a couple generations ago. Talk to us about how, and maybe this is a question for Ed, about the commercial opportunity, unmet need, how switch prone is this market?
Yeah, it's a good question, and we're actually pretty excited about it. The way we look at the HAE market, particularly in the US, it's large and growing. It's already filled with premium products. With therapies that are already available, what you've seen is a few tailwinds as we look into approval potentially early next year. One is a trend towards LTP use, right? There's a lot of those approved. Patients are willing to try those. Two is there are switches with options. People are looking for better treatment, and we feel like we have a very winning product in there. When we ask patients what they're looking for. Keep in mind, I think, I don't think we spend as much time talking about this as we should. HAE is not a trivial disease, right?
Your ability to go on vacation, switch jobs, do things that most people consider to be normal or routine is very challenging. There's some social considerations, emotional, financial considerations, prior authorizations. It is not easy to be an HAE patient. When you put that in the context of someone who's diagnosed in their 20s, this is multiple decades that you have to be this patient. When you ask a patient who has HAE, "What are you looking for?" They don't want to have HAE, which means no attacks and no therapy. That's our profile. If you look at amongst the different options that are available, there is only one that you can have, in our case, a single simple up to a four-hour infusion, where you have the prospect of getting extremely better.
Every patient gets better in our studies, most of those patients also go on to have no attacks and no long-term chronic therapy. We like how we are positioned in that space, and we think there's a lot of tailwinds. We've done a lot of work with payers. We're not just looking at just physicians, the feedback has been universally, very positive, we're encouraged. We have a lot of work to do, we're really well positioned to enter the market next year.
Let's talk about the first initial patients who are appropriate for uptake. This is a debate that we have invested as well, obviously coming to you from your future competitors, et cetera, which is just the nature of this business. Talk to us about who is the right patient to be the initial early adopter for this product.
We don't have any inherent limitations. If you look at our study design, Type one, Type two, there isn't anything about our inclusion or exclusion criteria that are unique. It is very much an all-comer population that we're excited about. Your question is about the early adopters. I think like any technology, there are certain people who just show up early, and we expect probably stating the obvious here, patients that are very well underserved today, right? Patients that continue to have breakthrough attacks that are really going to be looking for the next therapeutic option that might make a big difference. Again, that's what we believe our profile is. If we look at our market research, it sort of suggests 75%, 80% of patients are in the market looking for alternatives.
They may not be the first people to show up, but we look at this being a switch market, and there's going to be a tail like any technology where they're super comfortable with their existing therapy, but that's a pretty small minority of patients. We see about 20%-25% being fairly early adopters after approval. There's this big bolus of almost one in two patients that we think is up for grabs sometime after. They just want to make sure the data looks as good, not just in the trial but in the real world practice. I'll say what gets us really excited about this is the HAE community is very tight-knit. They're highly educated. They're very, very informed. There's great advocacy groups. There's one in the U.S., one outside the U.S. that we've been engaged with.
When they have a good experience, that they become almost like an evangelist. They can talk to other patients about that. It gets and builds excitement. We think we're going to stand very well, but we see, you know, one in four being early adopters, two out of four being up for grabs over a period of time. There's probably a stickier group that likes their existing therapy. They're probably not going to switch regardless of the opportunity in front of them.
I had this conversation with one of your competitors earlier today. How do you guys think about the opportunity set globally where LTP adoption is lower than in the U.S.? How do you think about that? I know you guys have talked about the U.S. opportunity and haven't talked about commercial U.S. Just how do you think about accessing that opportunity? That's something you do yourselves, something that requires a partner, TBD.
Small company, you're looking to do this for the very first time, not just the in vivo gene editing aspect of this, but building the operational capabilities. Perhaps not surprisingly, nearly 65%, 70% of the market value is in the U.S. We're happy to be domiciled in the U.S., we're going to build the infrastructure, and we have been doing that for quite some time. That said, we've been running our studies as multinational, from a philosophical perspective, we absolutely want to make sure that we can get our therapy to patients outside the U.S. The question, to your question, becomes how best to do that. We haven't ruled out potentially building it more practically, and what would accelerate that further would be some sort of a collaboration, licensing arrangement, or even a distribution arrangement in certain markets outside the U.S.
We have been doing that work. That would be a win-win situation for us as a company and for a prospective partner. I do think the pending top-line data is an unlock for us, right? Because we've seen really encouraging early data, but de-risking the pivotal phase III study is a great set of information to be having those discussions. We're active in that regard, and we'll see if we have an opportunity ahead. There have been deals outside the US in this space, so I think there may be an appetite, and there's not that many phase III assets that are as de-risked as we think ours will be in the next few months here.
Okay. Let's talk a little bit about the product profile. I think I've probably brought this up on every single earnings call for two years. I think there's a perception around the margin profile of gene editing products as being sort of CAR-T-like and challenging, which in some cases has been true. Talk to us about what we should think about Since we don't have a price yet because we don't have a label or pivotal data, talk to us how we should think about the cost of manufacturing a dose of this construct per patient?
Why don't you keep going, Ed?
It's pretty straightforward. I guess I'll start. Just from a manufacturing perspective, CMC is super important. The FDA has pilot programs we've participated in, so we're actually very well positioned on the CMC side, and we've got CDMOs primarily in Europe for lonvo-z, where we make the various drug substances and the drug product. We're really well positioned there. From a margin perspective, I mean, this is pretty simple chemistry, and this is a wholly owned asset.
We haven't talked about exact cost of goods. When you start thinking about what a potential price point could be for a highly effective, durable, one-time therapy, which is what we believe we have with Lonvo-Z, a payer will typically think about of a multiple, right, approach to setting a price. That multiple is applied to the existing standard of care or existing standards of care. In the HAE space today, you have therapies that are commonly $650,000-$700,000 annually. That serves as the basis. Whether you're talking about two, three, four, or five time multiple, there are different considerations there. At any of those price points, we are going to have a highly profitable, in excess of 95% gross margin product that we're really excited about.
Since I'm CFO, I'll just put in the plug, that can transform how we think about the capital needs of the company. When we're talking about a launch in our first half of 2027, what that could mean to Intellia, we've got very high aspirations in terms of what we will ultimately achieve in the market. If that is not correct, and we have just a modest mid-single digit share percentage in the U.S., that will cover the entire operating cost of the company. We're really excited about it from that perspective as well.
Let's talk a little bit about the TTR side of the house, which I think has gotten a little less tension in this conversation, but perhaps not in the market. Let's talk about where we are now as we reenter TTR land, study restart timing, implications for cash spend. Obviously, we can't just flip a... Well, there's no video, so people can't see me snap my fingers. You can't just snap your fingers. Talk to us about the timing to restart, how to think about where that study is, and when we might expect data.
Well, you'll remember that there's two studies, right?
That's right.
The polyneuropathy and the cardiomyopathy studies for TTR, both of which were enrolling extremely well last year, then we had this safety event at the end of October in the cardiomyopathy program. We voluntarily put both programs in pause mode and then subsequently a clinical hold. We're now off clinical hold, first for polyneuropathy and then most recently for cardiomyopathy. The word is out, we're working with the investigators in both studies. I do want to remind everybody, the studies have been ongoing. You know, we had over 650 patients enrolled at the end of October in the cardiomyopathy program. They've continued to contribute endpoints. They've been seen in all of their clinical visits, et cetera. Same thing is true for the 47 patients of the 50 targeted for polyneuropathy.
The investigators are engaged. The patients enrolled are actively participating. The only thing we haven't been doing is accruing additional patients. With the lifting of the hold, there's some operational things that we need to do. Making sure people understand the protocol, some minor modifications, which I'm sure we'll talk about. There's local IRBs in operationalizing the sorts of things that they need to do to take care of the patients in the study. Outside the US, this is a multinational program. There may be, in certain countries, some additional regulatory steps. We've had seen already some of these steps already being accelerated. We're really quite pleased with, you know, the field side, if you will, of the study.
In terms of actual patients coming in, it's going to take a while before we get everybody up and running. I would say later this summer, early fall, we'll have a good sense of where we are vis-à-vis where we were. At that point, I think we'll have more or a better line of sight to where this thing's going to wind up from an overall enrollment point of view.
That makes sense to me. Let's talk a little bit about those protocol modifications, what they mean in terms of trial conduct and patient mix, and how they could influence what the ultimate data set looks like, because now you're going to have patients enrolled under two slightly different but materially different protocols in the same study.
Yeah, I'd say there's going to be a de minimis effect overall on the patient population. Remember that when we put the studies on hold, we ourselves introduced some additional blood draws in this window where if the LFT rise is going to take place, and it only happens to a small percentage of patients, that we would be aware of that. What we've done in both cases is added a trigger that if patients have, in that window, a Grade 2 or above increase in transaminases, that they get a course of steroids. Looking back retrospectively, we would expect in almost all cases that to be just a few days, well less than a week. In terms of the patient population, it's largely unchanged. In fact, I would say polyneuropathy, it's essentially identical.
In the case of cardiomyopathy, what we've done is put in place some inclusion/exclusion criteria where if a patient had what we would call some cardiac instability, we want that stabilized before they come in. For example, if somebody's had a recent change in medications, we want to make sure that that change is stable and there's no moving target, so to speak, before the patient's randomized. In the case of patients with symptomatic bradycardia, get your pacemaker installed before you come into the study, that kind of thing. If you look back and say, "Who's going to be affected by this?" It really... It's barely at the margins in terms of the patient population being studied. I would say that we've also looked very carefully for patients who may be at risk for LFTs.
We can't put our finger on exactly who that's going to be. We've added some provisions if patients actually have active autoimmune hepatitis or, you know, significant liver disease. Again, that's at the margin in terms of who we were already seeing.
I think one of the questions that comes out of this, which is one that's, you know, Express more by more bearish investors, more concerned ones saying, hey, how do I not obviously, there's been +600 patients dosed in the cardiomyopathy study, some number of close to 50, 47 dosed so far in the polyneuropathy study. That is a different number of patients that have been dosed for HAE. That is a very different patient population, age, disease, et cetera, constantly somewhat different. Obviously, because the gene is different.
How do I know, quote-unquote, or what gives you assurance that there isn't some read across there where we may need to make these changes for HAE as well down the road, and that's something that's going to, you know, throw a hiccup into a commercial launch down the road as that number of patients dosed expands?
I don't think it's strictly a numbers game. You know what I mean? That's what some are asking for, which is, you know, after we have lots and lots of patients, will that finally resolve that question? I mean, we'll have more numbers as time goes on. If you step back and ask the other question, which I think is inherent to what you're asking here, is it the platform itself? We just don't see data that indicates that's the case. The LNP is the same in terms of the lipid structure, the mRNA is the same, the guide itself is different, the gene is different, the edit is different, the degree of expression of the gene is different, the polypharmacy is different, the patient population is different.
When we look across from TTR to PN, we see a bit of a difference, but when we look across TTR all the way to HAE, we see no indication of Grade 3 or Grade 4 LFT elevations. If there's any elevation that's been observed, which we've reported on already, that's usually associated with other things that are readily identifiable. At this point, as far as we can tell, we think they're quite distinct in our actions with the FDA. They treat them as absolutely distinct. You know, I think when we're talking about data a little later this year, people can judge for themselves, but we're very, very excited about the safety profile that we have in the HAE patient population.
I think the flip side of that being the efficacy profile and how that translates to pricing and commercial. Obviously, these are patients that are horrifically expensive for the systems in which they live because of the premium pricing of the drug, for an LTP plus on-demand, hospitalizations, et cetera. It's obviously very severe and expensive disease to take care of over many years. How do you think about positioning yourself to capture the appropriate amount of value for all the savings you're providing to these healthcare systems based on your data? Is there, is that a place where you need novel pricing and reimbursement mechanisms? Is it just a question of showing up with long-term durability data? Like, how do you approach that?
I'll let Ed address the actual, you know, how we arrive at need. Alright, spoke a little bit to that. I will say this, as innovators in the field and as bringing forward probably the first, and we hope also the second, products for in vivo gene editing, we will be responsible in how we do this. We want to make it very easy for patients. We want to make it easy for payers and physicians to get the benefit of these drugs. As I've said in other venues, we're not going to be setting any new land speed records when it comes to prices, but the thesis is correct, particularly if you think of HAE, where, you know, as Ed has already pointed out, a lot of these patients are diagnosed in their adolescence, and you're talking about 50-plus years of extremely expensive care.
There is no way that we do not save a fantastic amount of resource utilization for the healthcare space. I think that's also going to be true in the TTR space, where this is also a very, very highly prized market. I don't know if you want to talk a little bit about how we think about getting the numbers, et cetera, but be my guest.
I'll just try to add in color into a couple of things. One, we've been engaged with payers for a while. We're not taking this for granted. Your question's a good one in that, you know, one-time therapies can be broadly defined. I look at this very simplistically. We have a one-time therapy that is both easy to use and has a long-term durable treatment effect. Both of those things I think are very important as you think about quote-unquote one-time therapy. The value proposition when we're across the table from payers and having those conversations, they look at very much like our pooled analysis that we presented last November, this sort of Phase 1, Phase 2, we had 37 patients. The vast majority get to an attack-free state, and they don't require additional drug therapy.
That has benefits in terms of the ongoing annual cost of prophylactic treatment, which we already talked about in this conversation, is extremely high. It is also accompanied by on-demand therapy for these patients, which adds to cost. Now we're getting into the healthcare resource utilization component of things, right? These patients may have hospital visits for very extreme attacks. There is a lot of cost in the system. In the context for a payer, where this is a relatively small percentage of their portfolio, right? We're only talking about 7,000 or so patients treated in the U.S. This isn't some other therapeutic area where this is a major budget consideration for them. When they look at what the profile of lonvo-z is, to the extent we have that durable effect, you don't see a lot of resistance, right?
You don't really see them wanting to go into a more complicated arrangement, value-based agreement, for example. They have those experiences, but to the extent you have a winning profile and the vast majority of patients are doing extremely well, that really isn't much part of the conversation. Yes, we haven't set price. We do want to make sure we capture value. We think that's important for our employees, but shareholders and a lot of the entire healthcare system. We feel like we're in a really good spot there, and we're continuing to do work with payers to make sure.
By the way, I'll just remind everyone, it is in the U.S. a largely a commercial market, so about 70% of all the payers will be in the commercial space, so we'll get, relatively speaking, quicker reimbursement upon approval, and those are the types of companies that we've been talking with in advance of our prospective launch.
It's probably worthwhile adding that in that commercial space, patients tend to stay longer. You know, as said earlier, you know, how patients think about their jobs and access to insurance, they tend to be very, very sticky with respect to their jobs. When commercial payers look at this, they'll also see a patient population that tends to linger longer in their pool.
That makes sense to me. From the patient perspective, assume you have a data set that reflects the long-term data we've seen thus far for this product construct. Fairly robust, very arguably best-in-class attack rate reduction. Definitively, in my view, best-in-class attack-free reduction. It's probably the only attack-free asset that you can just take once. Functional cure if you want to use the C word.
The F word.
F word, C word, both of them. I'm like, "Oh, whoops." What are physicians going to tell these patients? The day after they get their up to four-hour infusion, they shouldn't be throwing their Orladeyo or whatever away, their Kalbitor away, because it's theoretically possible they can have another attack. At what point do you start talking about cure?
It's a really great question, which is when do we know we're there, right? It's hard to know for sure, right? What we've seen, and we present this pooled open label data in November, that back to some of the comments I said earlier, the longer you go, the more clear how, you know, patients behave and what their experience. They learn how to deal with their disease. What we see is that once patients seem to get past a six-month interval of no attacks and no additional therapy, they seem to be on their way. I don't know if that's going to be true for everybody, but thus far, we have no exceptions to that. I think that there's going to be a lot of learning that takes place.
My minimal estimation is that the overall use of long-term prophylaxis that this patient population's going to need is going to diminish rapidly. You can imagine, if you think of this as a spectrum, patients who are taking LTP, patients who take these drugs in almost every single case stop their LTP. If some of them, while they're getting to whatever their equilibrium point is, as you pointed out, have a dose of on-demand therapy, that's fine. We'll see where they settle out. If you add it all up across the board, the overall utilization is day and night compared to what it was before, at least looking at the patients that we've seen thus far.
It's my expectation that as we get out there and have the drug used widely in an approved setting, that real world evidence will start to see that, and it'll become apparent to the doctors and the physicians, as time goes on, that this is a really winning profile.
I'll just add to that briefly. I mean, we've got a medical field team that's out there educating, talking to physicians and investigators. The PD markers we talk a lot about in TTR, and we're happy to talk about it more, but it's very similar on plasma kallikrein levels as well, right? You've got the benefit of knowing that the drug has the intended effect that should speak to physicians and get them comfortable. In fact, when you look at the pooled analysis, there's this one patient who actually has attack rate reductions but has not gotten to that attack-free state. It's, like, the only one in the swim lane that hasn't done that, and we can't say too much now, but there's probably more going on there than HAE. They're actually received the benefit in kallikrein reduction.
There's other comorbid conditions allowing that patient to continue to experience some sort of an attack. I think there's a lot of data pointing in the right direction here. The maturation of that and the long-term durable effect, I think that's also part of the education materials. What we have been talking about, what we'll continue to talk about as we have longer-term follow-up.
Is that a teaser for future data? Is that what that is?
Yes.
Yeah. That's helpful. I think one of the questions that people have, and we're coming to the end of the time here, is presuming all these things play out, how durable is the HAE market if you are giving one-time therapy to 100, 200 patients a quarter at some point? There are only 78,000 patients. This is not a subtle phenotype where there's 20,000 U.S. patients to be discovered. Like, how do you, how do you think about the durability of that market and the out-year tail?
Yeah, look, if we're doing our job well here, the number of eligible patients should shrink, right? What I would say is that That's one of the reasons I came to Intellia, but the total addressable market, if you just look at it, and again, we haven't named the price, but we talked about the multiple of existing annual therapy. It's a $14 billion-$15 billion-plus market, depending on what price point makes sense here. It's not insignificant. You're right, it's a prevalent pool of patients. We don't have a lot of new patients coming in, you know, our goal is to get these patients to attack-free status. That should mean that there are patients coming out of the pool because they are completely satisfied.
I mean, that is, in many ways, their target product profile and why we think, while it's competitive, we feel like we're the only game in town. If you really want to have an opportunity of the functional cure, there's nothing in the market today, and we don't see anything in the market coming that's going to match that profile. We'll have improvements in frequency of dosing, but for the most part, if you want a one-time infusion, no attacks, no therapy, it's going to be Lonbo Z.
I can't think of a better topic to close out on that, and we're out of time.