Great and welcome back to the next session of the 2025 Leerink Global Healthcare Conference. Pardon me for a moment. This is Mani Foroohar, Senior Analyst from Genetic Medicines. I'm very fortunate to be welcoming John Leonard, CEO of Intellia Therapeutics. Welcome to my adopted hometown, John.
Good to see you.
It's good to see you, too. I want to dive right into some of the competitive questions and dynamics around key pipeline assets. Let's start with TTR, which I recognize is not the next data set for you.
That's right.
But it is where a lot of commercial and competitive focus is right now. Let's talk a little bit about what we know in terms of the depth of TTR reduction and durability that you guys have achieved. And then we'll talk about comparisons of clinical trials between yourself and the chronically dosed silencers, which are kind of the closest competitor mechanistically to what you do.
Right, well, we've presented now phase one and the extension of phase I data for TTR, both in polyneuropathy and cardiomyopathy, and what we've shown is essentially without fail at the phase III dose, literally every single patient responds and responds in a really profound way, and I think there's a couple of things to look at. It's the rate of the decline, the depth that's achieved, and then durability. These patients reach their nadir within 28 days. That's important, and you can tell that when you look across programs, which I guess we'll talk about here in a minute, but what you're seeing is a depth of TTR reduction that I don't think it's helpful to talk about in terms of percentage reduction.
The absolute numbers, the actual concentration of TTR is what becomes meaningful, which is 17-19 micrograms per ml, which is about a third of what we're seeing so far for what's been reported for Amvuttra. That matters because when you think about what the disease is, you have these toxic monomers that are raining down on the respective tissues, especially the heart. And for every day that that's happening, damage is done. So the faster 28 days, the deeper down to these levels, the better it is for those patients.
So let's talk a little bit about what that means in terms of progress for the ongoing clinical trial and expectations for timing. And that has two pieces. One is, as you have a profound depth of reduction, that has some implications about event rate, which is an assumption that you're making that's a very powerful assumption. So we'll talk about that. And then the separate question, which is enrollment. So how should we think about the timeline for the ongoing pivotal trial in TTR cardiomyopathy?
Right. So the trial you're talking about is MAGNITUDE.
That's right.
For cardiomyopathy. The enrollment's going extremely well. We're ahead of our targets. And if anything, it's accelerating as all the other sites come online by virtue of the regulatory process that we've been playing out. What we are looking for in that study is an effect overall for patients on or not with tafamidis, and then specifically for the effect on top of tafamidis. The study currently has a design of being randomized two to one that's drug to placebo and a target patient population of 765. We've said that once we see the Amvuttra label, which is just around the corner here, and as we get a few more events under our belt, we'll make a decision, do we augment that a little bit. But either way, we expect to be done with the study in terms of enrollment by end of 2026.
Event rates. We presented data last year at AHA in a very severely affected patient population. This is 50% of patients with class three heart failure. That contrasts with both the Acoramidis and Amvuttra phase III studies, which was about 10% or less with that degree of heart failure, and a patient population included about 30% or so patients with the heritable form, which is the very, very aggressive form of cardiomyopathy.
Again, contrasts with about a third or less of that with the other phase III trials, so what we showed was with these TTR reductions that I already referenced, you can take that patient population, essentially freeze frame it, or in many of them actually reverse, and so that is something that has not been seen previously, and as we think about that in terms of event rates, that has huge ramifications for how we think about the MAGNITUDE study.
We're quite confident based on those observations as we think about the patient population in the phase III trial, which is less severe than what we've already seen a really significant clinical event. We're quite confident that the overall effect, including on top of TAF, will be positive and may well be positive early.
Let's take that enrollment acceleration that you're seeing. Is that a commentary on US enrollment, OUS? Are you seeing geographic trends in response to new agents launching and awareness? How is that flowing into the clinical trial enrollment setting? What's happening commercially?
Yeah, I'd say the only thing we've seen is a higher tendency to have patients coming on tafamidis. Right? We said at the outset it was likely going to be more than 50%. I think that's going to turn out to be the case as tafamidis use gets more widely spread outside the United States. I don't know if we'll wind up 60%-70% even. That does not hurt us. We're quite confident that the overall effect is going to be positive. And as I said, we want to see the effect on top of tafamidis. So having more tafamidis patients on either side is going to be better for us to actually measure the effect.
Some of the other studies that have been done have tried to find enough patients on tafamidis or have not had sufficient numbers of tafamidis to actually find the effect, but that's not going to be a problem for us.
So when you talk about how you want as many patients on TAF as possible, I interpret that as either we want to have an add-on label because we expect tafamidis to be near universal standard of care, or we want to be ready for a tafamidis generalization world. Is that the right way to interpret that?
Well, I'm not saying I want everybody on tafamidis. I'm just dealing with the reality of what's out there. Not everybody takes tafamidis, but many do. And our expectation is at the time that our drug is commercialized, it's almost certainly going to be a TAF generic world. So having the data to right at the outset use both drugs is advantageous for us. We don't want to be in a position where TAF is given and then patients are asked to fail, which I think would be horrible for the patients, and then move to these drugs. You want to have the best data right out of the get-go, either way.
So when you talk about the depth of reduction that you're achieving, the incremental benefit of TAF, just from a mechanistic perspective, seems like it will be quite modest. So is it reasonable to presume that the difference between doing a head-to-head study versus TAF versus an add-on study where everyone has TAF with placebo versus TAF with gene editing, the statistical differentiation between those two designs should be pretty small?
Yeah. I think the reasonable way to ask the question is, does TAF add anything to our effect?
That's right.
Right? And that's not something that we're likely to pursue because it just takes a lot of time and a lot of patience to answer that. I think, generally speaking, cardiology is an add-on sort of field. And especially if you have generic tafamidis, that's not going to be an issue one way or the other.
Let's pivot over to polyneuropathy, if we can, for a moment. That's a more mature silencer market, obviously, which was dominant in terms of market share. When you were launching, it's a very different profile at home, et cetera. Talk to us a little bit about what you think that market's going to look like as you approach it, and to what extent you see differentiation from an absolute knockdown versus sort of one-time profile. How do you think about commercial positioning?
We think that knockdown, just as in cardiomyopathy, will also in polyneuropathy apply and determine the ultimate clinical profile of the drug. And the lower you go, the better it is. I think that's generally accepted to be the case. And certainly, Alnylam has adopted that approach now with their now fourth attempt in the space. From the standpoint of the succession of launches that we expect to see, I know we haven't talked about HAE yet, but that's 2027, perhaps in the next year or so, you could expect to see a polyneuropathy launch. And then certainly within two years, if not earlier, you'd see the cardiomyopathy launch.
So really, three launches between 2027 and 2030. Polyneuropathy gives us the advantage to get out there and start to talk about our drug, et cetera, and I think serves as a nice gateway into what will ultimately be cardiomyopathy. Many patients are mixed, as you know, in terms of manifestations of polyneuropathy and cardiomyopathy.
Now that we've done some table setting.
HAE?
Oh, HAE. We didn't go to HAE. I was going to table set and then go to what I think is the sort of elephant in the room around sort of balance sheet and capital needs, and we talked about this a little bit on your earnings call.
Yeah.
How should we scope the capital needs between now and first commercial launch?
Yeah. So I think it's important to go back to the beginning of the year when we restructured the company and the actions that we took, which was a net reduction of about 27% of the spend and headcount. We put ourselves in a position where peak spend is behind us. This year, you should expect to see a decline of 10%-15% in terms of the actual cash out the door relative to last year, and probably next year, a reduction on top of what you've already seen for this year. So in terms of the $860-some million that we ended up the year with, we're well into 2027, which is beyond the launch or around the launch of the HAE program.
So as you think about the absolute capital needs, some of the models that we've heard about where people think that we need $1 billion or more is just not correct. Whether it's polyneuropathy, HAE, or the combination of the two of them, we would fully expect that by 2028, the company should be self-sufficient, if not even potentially profitable, setting the stage for cardiomyopathy. So the actual dollar amount that lies between here and there is on the order of $400 million or so.
Now we talk HAE.
I'm ready.
Yeah. So let's talk about what we're going to get in the pivotal data set. You talked about assuming timing for filing and launch. What should we expect in terms of the degree of follow-up? Obviously, it's going to depend on when the patients were enrolled. How should we view degree of follow-up and how that translates to functional cure rate? I'm going to stop there instead of making this a compound seven-part Monty question.
Yes, thank you. So what will we see? I mean, look, when the BLA goes in, again, which is 2026, just next year already, which will be the first company in the gene editing space with an in vivo approach to go all the way to filing and registration, et cetera. The data that you'll see will be a phase III data set combined with the ongoing observation of phase two and phase one. That is the data set that the FDA is looking for. It's the standard sort of follow-up that these patients get in the disease. There are no special additional requests that any regulatory agency has.
But what you'll see is if you kind of cure that in terms of follow-up, you're going to have patients out four plus years, even potentially up to five from the phase one program where we reported that those patients collectively had an attack rate out a year and a half of 98% reduction from where they were. And you'll see that that is a durable sort of effect. You'll see the phase two data will be included, which will also now have the redosing of the suboptimal dose that was not selected for phase III. Phase III dose is 50. We had patients at 25 for the dose ranging study, as well as placebo patients. So they'll all be included. And then the phase III patient population where there's 40 additional patients there.
It'll be a range of duration from the follow-up in that phase III study, which will be minimally six months, and then some all the way up to about four plus years for the patients who were dosed way back at the beginning.
So I think one of the conversations that I've had a lot of investors, and you and I have had a couple of times the last few years, is the sense that the HAE market has a lot of approved products that are quite potent. Talk to me a little bit about what in your company's work, your exposure to physicians, et cetera, et cetera, your trial experience, what have you seen in terms of the churn rate of patients in the commercial market between HAE agents?
Yeah. Well, clearly, the space is not satisfied. It's true there's many drugs. If you ask patients, they're not asking for better on-demand therapy. If they have to take prophylaxis, they'd rather take it less frequently than more. But if you ask them what they really want, they want to be cured. They don't want to have the disease. And the data that we've presented suggests that cure, functional cure, as we're calling it, is likely going to apply to the vast majority of patients who take the drug. And as you see later this year, some of the early estimates that we've presented may be low in terms of the proportion of patients ultimately achieve that.
Okay, when you think about the marketplace, you asked about churn, anywhere from one in four to one in three, depending on what sources you go to, of patients in that space will actually try a different therapy because they're not satisfied. Whether it's the efficacy, the convenience, the mode of administration, et cetera, they're searching. You can just look at the lanadelumab launch that took place. You can look at the Orladeyo launch that took place. I think in the case of lanadelumab, maybe it was something like 1,100 patients in the first year out of a total of 7,400 or so in the United States. 10% of that patient population over 700 Orladeyo tried the drug.
So for us, we're quite confident based on what we're already seeing in the phase III trials in terms of patients lining up in the United States and outside the United States that patients are searching for a functional cure. And for our company, especially post-restructuring, not that much of that marketplace is necessary to flip us to being self-sufficient and potentially even being profitable based on HAE alone.
So I think there is a little bit of a misunderstanding about how margin profiles work. I think people extrapolate from other gene editing products that are approved, which are very different in their construction and margin profile than your LNP-delivered oligo. Walk us through how we should think about the comps for the 47th time. Walk us through how we should think about the cogs for a dose for HAE.
Yeah. People tend to, if they hear CRISPR, they lump it into one category, everything's the same, or worse into the category of gene therapy, thinking it's like a biological product in the sense of a virus. That is not correct. In the case of our products for HAE or for TTR, they're delivered as synthetic molecules. This is LNPs containing mRNA and a guide RNA. All of that is made in the laboratory. It's not growing up cells and all that stuff, which lends to a relative simplicity and a huge cost advantage relative to growing up cells and trying to grow a virus, for example. So when you think about the cost of goods as a fraction of what the likely price is going to be, we're talking about a 95%+ margin is what we would expect.
And it may well be higher than that when we get to that scale. So the models that I've seen some people use referencing CAR-Ts and things like that, that's just totally inappropriate and does not apply.
As we talk about modeling and the nuances of finances, can we hop over to TTR? While HAE is wholly owned, TTR, you do have an existing financial partnership arrangement with Regeneron, which has been tweaked in the past. Can you remind us how that flows through to your income statement currently?
It's a 75-25 deal, we're 75, whoops, we're 75, they're 25. So they're paying 25% of the development costs. They will be partners as we commercialize this. There's an opt-in point where they can choose to co-promote or not. It doesn't change any of the economics at all. We benefit from their experience and expertise in the cardiovascular space. And our team works very, very closely with them. And it's been very, very helpful.
And across what geographies does that partnership apply? And across what geographies do you still have independent rights?
It's global. We have the ability to choose a partner other than them outside the US, which is something that will be a point of discussion as the program continues.
Great. Now that I've dragged you through financial statements, I want to hop over to the operations launch around HAE. Once you have a data set in hand, you will have a data set with some proportion of patients who, post the initial washout period, require no additional therapy. How do we think about a functional cure label versus an attack reduction label? Do both need to be presented to payers? How should we think about the regulatory and reimbursement implications of kind of a very different profile than Takhzyro?
Yeah. It's challenging because it's a completely new category, and complete responder, which is sort of the current nomenclature, really doesn't capture what you're asking, which is it's not just absence of attack, but absence of attack and not needing to take any other therapy, which is what we term as functional cure. That's a point of active conversation with the agency because that paradigm needs to be created.
Do we want to have that kind of a thing in the label? Absolutely, because it's unique to the drug. I think that standard sorts of metrics with respect to attack reduction, because that's how you measure these phase III trials, is definitely going to be part of the label. But we are very, very interested in getting that next sort of set of outcomes into the label because we think that ultimately speaks to what the patients and what the doctors actually want to see, as well as payers, by the way.
So when people talk about functional cure, there's sort of two pieces of that, right? There's functional cure, you're not on prophylaxis anymore. You're not having to stab yourself with Takhzyro. And then there's functional cure, you don't have the disease phenotype anymore. You're not even carrying a rescue pen. In your mind, is there a commercial difference between those two?
Not much. What we're seeing of the patients who achieve functional cure is that they dispense with everything, including on-demand therapy. We have some just truly remarkable stories where patients who resume a life that, well, I shouldn't say resume, they begin a life that they haven't had before, where they can play in sports, subject themselves to what would have been stressors, et cetera, and live their lives normally. So we would expect that upwards of 80%, maybe 90%+ of patients, maybe even more, depending on some things that we're working on, will achieve that state. And that just resets the bar entirely for them and their lives. And we think ultimately for how the drug will perform in the marketplace.
When it comes to getting that on a label, is that dependent on duration? Is that attack? Is it something that's, I think you captured the question.
What's the definition of functional cure?
Yeah, right.
That's what we're working on. I mean, clearly, it's having received the drug, having ceased attacks, and then is there some minimal period of which is necessary to have been observed? And that part is under discussion. But the key points of it that we've been pushing to is no other drug is taken. I mean, for people, the best case of other therapies where patients may not have an attack is taking therapy on an ongoing basis. And I think it's really important to operationalize what that means because these are patients that have to get reauthorized on an annual basis. The insurance procedure that they have to go through and their doctors need to go through is a relative barrier to the use of the product. And this can be solved with a single application.
So for those patients that are not complete responders, I think there's a place where more...
We say functional cure. Everybody responds, and it's important because in every single case, any patient who's received the therapy is better off than he or she was before they came onto the study, even if they have a rare attack.
For those patients that still have rare attacks, whatever proportion of the total, that'll be. There's a place that we're more conservative investors, spend a lot of time trying to understand. How do you address the risk that people argue that you're going to sell people on a label of a functional cure and they will not have their on-demand therapy on them and so they could have a tragic outcome if they do have a rare attack? How do you address the risk profile of negative space, if that makes sense?
Yeah. I mean, we're talking about a hypothetical. It'll be data, and it's going to be what actually happens with the patients that we collect and observe over an extended period of time. Thus far, we've not seen what you're referring to. I'm not saying we never will, but we haven't seen it thus far, and more time and more patients followed, I think, will answer the question, and our expectation is based on what we're seeing is I don't know if anybody's going to need prophylaxis on top of after they receive the drug, whether or not for whatever reason they want to carry on-demand therapy, but it's probably going to be a decision between them and their physician as they gain confidence, but in the patients that we've treated thus far, almost all patients have abandoned literally all forms of therapy and done extremely well.
So, let's talk a little bit about everything else in the last three minutes.
Everything else, okay.
So obviously, the company is very narrowly restructured to tighten its focus on these late-stage programs appropriately. But there remains an accumulated pool of knowledge, patient follow-up, safety, et cetera, a safety database that has not been replicated anywhere else in the United Kingdom and will not be for quite some time. What are the opportunities for the business development, outlicensing, partnering to monetize or find homes for other assets, other programs, or other uses of the technology beyond that which you've sort of put temporarily on the back burner?
Yeah. I mean, without going through specific assets, we welcome potential business development deals that make sense for the company. We're not trying to sell things to finance the company. That's not the approach that we've had. Folks that are companies that can extend our reach, add to the technology base, or can help us get to areas of the world that's going to be very difficult for us to reach ourselves, we welcome those kinds of inquiries. People that have technology that can be added to our editing capabilities in tissues outside the liver, those are things we're very, very interested in. But it's not like we have a long list of assets that we're trying to sell to people. That's not the case. We've kept all the things that we think are really best.
Great. Well, on that note, I think we can wind up. Pleasure always to have you, John.
Thank you.
All right.