Good morning. Thanks for joining us for another session at the 43rd JPMorgan Healthcare Conference. I'm Brian Cheng. I'm one of the senior biotech analysts here at the firm. I'm joined by my associate, Sean Kim, and Marion Wagay, who are also in the audience. On the stage, we have the CEO from Intellia Therapeutics. I will now pass the mic to the CEO, John Leonard, for a short presentation followed by a live audience Q&A. John, the stage is yours.
Thank you, Brian. I appreciate it. It's a pleasure to be here and present the progress that we've been making at Intellia Therapeutics. Good morning to our audience. I will be making some forward-looking statements. So here's our legal disclaimer for your reference. Since the outset of the founding of the company, we've been devoted to leveraging gene editing technology to treat patients with the root cause of their disease. The objective is to have best-in-class therapies that yield best-in-class outcomes. With that, we can have a significant effect of reducing the burden to the healthcare system and do that with a single-dose treatment with potential for lifelong benefit.
We're making substantial progress to that objective. In the last 10 years, the entire duration that Intellia has been a company, we've now accumulated significant clinical experience with nearly 200 patient years in total. We've presented data on over 100 patients. We've seen clinical outcomes tied to the knockdown. And with our first patients, we're now in excess of four years of follow-up. Along the way, we've accumulated a lot of regulatory experience and regulatory support as we've embarked on multinational studies around the world. And we've garnered several regulatory designations that lead to accelerated, highly interactive reviews of the breakthrough products we're bringing forward.
The science has been memorialized now in four New England Journal of Medicine publications, which we're very excited about. And we're at the point on the final lap here before we move to commercialization with three Phase 3 programs that are actively enrolling. What are the assets that we're progressing? There are two late-stage assets, both with breakthrough profiles and we believe blockbuster potential, NTLA-2002 for the treatment of hereditary angioedema and Nex-Z for the treatment of transthyretin amyloidosis.
These are substantial markets, and we believe that both of these products have the wherewithal to address the significant unmet medical need. We expect NTLA-2002 to be the first launch for the company starting in 2027, and that will be followed by two launches through 2030 with the two different indications for Nex-Z. One of the key value adds we believe that the technology brings is depicted on this slide. The treatment regimen is simple. Patients get gene edited on an outpatient basis, and you see the entire process represented here. On the day before treatment, patients come in and are administered a single oral dose of dexamethasone.
On the day of therapy, they repeat that dose along with some antihistamines. They receive an infusion for two to four hours. They go home. It's literally that simple. There's no virus. There's no collection of cells. There's no manipulation of material. There's no prolonged dose of steroids. It's entirely an outpatient procedure that is exactly what we're doing in our phase 3 studies. As we complete 2024 and look back on the year, we're excited with the progress that we've made. We presented important clinical data that suggests that Nex-Z may actually be able to not just halt the progression of the disease, but in fact reverse it, as we've seen in some of the patients that we've reported.
In addition, with NTLA-2002 for HAE, we showed what we believe represents a functional cure for these patients. We'll talk more about that. We've accumulated additional regulatory designations that are important. And of course, initiated the three Phase 3 studies that I've talked about. As we embark on 2025, the core focus for us is operational excellence, getting the clinical work done. NTLA-2002 with the HALO study is progressing. And we expect that study to be fully enrolled before the end of the year. And in the case of Nex-Z, there are two parallel studies, Magnitude for cardiomyopathy and Magnitude-2 for polyneuropathy.
And by the end of this year, we expect to have in excess of 550 cardiomyopathy patients enrolled. The actions that we took last week and announced allow us to focus on the clinical progression here. We still carry out important research at the company. We're still dedicated to bringing forward breakthrough products. And you'll hear more about that in the time to come. But in the meanwhile, the job number one is getting the clinical work done. Just one year from now, in 2026, we'll be readying the company for commercial execution. We will have at that time our Phase 3 HALO results. And we'll be planning our first BLA submission. In addition, we will have completed enrollment for the polyneuropathy study.
And we'll be substantially complete, if not complete, for cardiomyopathy. And we'll be completing our commercial build-out for commercial execution. So as we stand back and look at the year behind us and the two years ahead, you see us in the final lap of approaching what we've wanted from the very beginning, which is to form a fully integrated commercial stage company. As we look ahead to 2027, you see the first of three launches taking place with NTLA-2002 for HAE. We'll be reporting our Magnitude-2 studies for polyneuropathy, and we will have completed the cardiomyopathy study and be collecting endpoints.
These Phase 3 studies serve as the basis for the three launches that we expect to take place between 2027 and 2030. Let's dig a little deeper into the products, beginning with NTLA-2002 for the treatment of HAE. Many of you will know that HAE is a lifelong genetic condition. It's rare. It manifests as unpredictable, recurrent, and potentially life-threatening swelling attacks, particularly when it involves the airway. Despite the presence of a variety of different treatments, significant medical need remains, and we believe that NTLA-2002 goes a long way to addressing what those needs are.
In fact, with the data that we've presented thus far, we think we are encountering a new category of outcome for patients, which is a functional cure. We'll talk a little bit more about what that means here shortly. We believe this represents a significant commercial opportunity for the company. We intend to seize it. If you look at the evolution of HAE over the last few years, we've gone from a point of mere survival for these patients, which essentially consisted of managing the airway when there were meaningful attacks. This would be intubation or placement of a tracheostomy.
In the last several years, we've made progress with on-demand therapy or the development of prophylactic regimens. These deal with the attack already underway or, in some cases, with prophylaxis to attempt to blunt the attack or prevent it to the extent possible. In all of these cases, patients contend with significant trade-offs, whether it's convenience and efficacy or the behavioral changes that patients need to make to deal with the regimens to which they are tethered over the course of their entire lives, particularly when you think that most of these patients are diagnosed during adolescence.
We believe that with NTLA- 2002, we're able to get to the final stage of treatment, which is, in essence, a functional cure in which, after treatment, a single infusion of the drug, patients will be free from attacks on a lifelong basis and have lifelong freedom from chronic therapy. This is a profile that's incredibly interesting to patients as well as to the physicians who treat them. So where are we in the progress of developing the product? We've got phase one and two results that we've reported on in the last year or so.
What we show is that the vast majority of patients who are treated cease to have attacks within a 16-week period and abandon their chronic prophylaxis. They are off all therapy. As we watch those patients mature over time, the profile improves further. This is something that patients are very excited about, as we see in the current Phase 3 study and the expected enrollment. We've now demonstrated durability of the effect for at least two years in our Phase 1 work. As we look to preclinical studies and across other programs, we expect this to be a long-lived effect, if not lifelong.
We believe that we're teaching patients that they can think differently about what are acceptable and desirable outcomes for their HAE treatment. Instead of good enough, which is typically viewed as well-managed in clinics, patients can now imagine a circumstance in which they're not having attacks and they're not taking any other medication, and as we look across the profile of approved drugs and other drugs under investigation, this profile is unique to NTLA-2002. Again, this is what patients want, not to be free only from their attacks, but they want to be untethered from the regimens that they're taking.
In fact, physicians feel exactly the same way. As we complete our phase 3 trial called HALO, you see it depicted here. This is a randomized double-blind placebo-controlled study of 60 patients. It's small and very, very efficient. We expect to have endpoints collected at week 28, and this will be completely enrolled this year. During the course of this year, we'll continue to update on the progress of the patients from our phase one and two studies and look forward to sharing that data and extending the duration of the effect, as we've discussed previously.
As we look at the market for HAE, we think it's very attractive for Intellia. This is a multi-billion-dollar market, and it's one that's growing. As we ask providers how they'll treat their patients, we see that in excess of three of four physicians want to treat their patients with this drug, irrespective of the severity of their disease. That doesn't mean just the worst patients. It means any patient because they're attracted by the efficacy and critically by the freedom from ongoing therapy. We believe this is going to be very successful in the marketplace.
And it represents a meaningful revenue opportunity for the company that should start in 2027. Let's move to Nex-Z. This is formerly known as NTLA-2001 and is used for the treatment of TTR amyloidosis. You may know that TTR amyloidosis is a severe, fatal, progressive disease with significant morbidity and mortality. It results from deposition of the TTR protein in a variety of tissues and typically manifests in two primary fashions, either polyneuropathy, in which patients have significant debility as a result of nerve disease that is usually attributable to the heritable form of the illness, a mutated TTR gene.
The other form of the disease, which is cardiomyopathy, represents the bulk of patients with the disease. And in most cases, these patients do not have a mutated form of the TTR gene, but in fact have wild type. In essence, we should think of cardiomyopathy with TTR as a disease of aging. This has a high-incidence population and will continue to grow in incidence as the population ages. There are therapies available. But again, we think that there's significant unmet medical need not addressed by any of the regimens that have been presented, and we look forward to bringing the product forward to address that.
As we look at the progression of the evolution of the treatment regimens for TTR amyloidosis, it's depicted here for a long time. Very little was available for these patients. In the last few years, a variety of different approaches have become approved, either stabilizing the protein that's deposited or attempting to knock it down with siRNA. In all cases, what we see is with these regimens, the progression of the disease has slowed but not stopped. And patients continue to relentlessly progress as they deal with their significant increasing morbidity and mortality.
We believe that with a substantial and very, very deep knockdown of TTR, you can move to a state of disease stasis, which is the lack of progression of the disease or actually reverse the clinical findings in patients, leading to a lifelong reduction in disease burden. And with that, simplifying the regimen for these patients who deal with very, very complex regimens. Clearly, that's an outcome that patients want as they're facing a future of significant morbidity and mortality. As we look at the data that we've collected thus far, you see here the reason for our optimism and our confidence.
As we look at the knockdown that we achieve with TTRs depicted on the left, you see Nex-Z producing fast, very rapid, significant, durable, and invariant levels of TTR knockdown. In a cross-study comparison, these are not from a head-to-head study. You see the recently reported vutrisiran knockdown levels, a level that is not as deep as what you see with Nex-Z, and it's not achieved at the same rate over time. The consequences of this start to emerge as we look at the clinical findings from patients that we reported in The New England Journal of Medicine just a couple of months ago.
As you look at their underlying heart disease in the form of NYHA class of heart failure, at a year's follow-up, you see that most of the patients either do not progress or actually improve and move to a lower state of heart failure. Only a small proportion of those patients actually worsen. And when you look at the biomarkers that characterize the extent of their underlying heart failure, most of those patients also either improve or don't progress. When we look at the event rates that we've seen with a very, very sick patient population in phase one, what we see is an event rate that is lower than any of the reported findings that we've seen for the trials that have read out at phase 3.
The drug is now being studied in two parallel studies called Magnitude for cardiomyopathy. You see the primary endpoints, which are CV-related mortality and CV-related events, and Magnitude-2, which is a small placebo-controlled trial, which we think will go very, very quickly. Here, the primary endpoint is mNIS+7 and serum TTR. Again, in 2025, we're focusing on the rapid enrollment of these studies. As I said, we expect to have an excess of 550 cardiomyopathy patients enrolled by the end of the year. We will present extended data on our Phase 1 and 2 patient populations, just as we've done in years past.
As we look at the market opportunity, once again, it's substantial. In the case of TTR, you see an already large but rapidly growing market that is multi-billion dollars. It's tied to this, again, being a disease of aging and improved diagnostic modalities that cardiologists are using to great effect as they find even more patients in their practice. When you ask physicians how they want to use this drug, approximately 90% of those physicians are very excited about using this because of the efficacy and the simplicity of the use and the results that we presented thus far.
We think that this represents a very significant revenue opportunity for the company, and it could begin as early as 2029, so as we step back and look at the pipeline of the company, you see that our clinical programs that I just went through are at the heart of the work for the next years ahead of us. We continue to have a variety of collaborations, which we work on. Our research teams remain busy, and you'll hear more about what they're working on as time goes on, but in the meanwhile, 2025 is about getting the clinical work across the finish line and into commercial hands, so our guidance for this year is depicted here. Again, it's all clinical in nature.
You see the ongoing enrollment of the HALO study, which will be completed, and the continual progression of our TTR program with a large number of patients coming into the study. I want to emphasize that last week, with the actions that we took at the company to address spend, we're now at a point where we have sufficient cash to fund operations through the commercialization of 2002. And in fact, we think our peak spend years are actually behind us as we go forward to a point of commercialization. So as we look in the mirror, what do we see? I think it's a company that's very well positioned for near-term value creation.
We have three Phase 3 programs that are actively recruiting, two potential blockbusters, and one singular focus on getting the work done. And we keep our promises at the company. We do deliver. So I hope I've given you a sense of our excitement and the progress that we have made up to now and what lies ahead for the company. And Brian, I'd be happy to take some questions.
Thanks, John. So let's start the Q&A session. For those of you who are in the live audience, if you have any questions, you can raise your hands. We do have a runner on the floor. For those joining us virtually, you can submit the questions on the portal. Do you want to join me?
Happy to sit down. Sure.
So let's start with more of the question of what happened last week. I think last week was very interesting in the sense that you have made some very tough decision to address the strategic vision for 2025 and beyond. And I think maybe just taking a step back is what drove that decision to prioritize ATTR and HAE and also setting AATD aside? And why do you think that this is a good pivoting point to have that message getting across the street?
Well, there's a lot going on at the company. You've been reporting to us for some time now. As we look at the work that lay before us, it was a matter of bandwidth and the ability to accomplish everything. So what we did is prioritize what we thought would be near-term value creating. We wanted to be the first company in our space to commercialize an in vivo form of CRISPR. And we think we have two very exciting programs to do that. And so what we did was set distractions aside and programs that competed for resources so that we could, in a way that was unconstrained, carry out the clinical work that needed to be done, as well as build the commercial organization that will commercialize NTLA-2002, as we said, in 2027.
It's what we've done over the course of the company for a decade now. We choose based on what we see as the opportunities. We want to make sure that we get to commercialization as quickly as possible.
Maybe just focusing on Nex-Z in ATTR CM. Last year, late last year, you have demonstrated for the first time that you can demonstrate signs of disease reversal from the longer-term follow-up data. Can you speak to the confidence levels that you have in terms of showing the same thing in terms of disease reversal in the Magnitude trial? And how important is it ultimately for Nex-Z to show that kind of efficacy for the commercial success in the future?
We know that knocking down TTR leads to clinical benefit. I mean, that's been proven by others in the space. The question has been, how much clinical benefit can you get? And the hypothesis in the field, it's not just our own thinking, is that the lower you go, the better it's going to be for patients. And as we saw in the data that we presented in the New England Journal, the very low levels, we're talking about absolute values of 17 micrograms, which is about a third of what's been reported for the knockdown programs, led to, as I said, stasis in patients with class three heart failure and actual improvement in most of those patients or about half of those patients. I think that speaks to the hypothesis itself.
And as you look at what we've reported for TTR knockdowns, every single patient, and I mean literally, every single patient without exception has had knockdowns in excess of 90% or so. That contrasts with the variability that we see with some of the other modalities. And so from a confidence point of view, given the relationship between TTR and clinical results and the consistency of the effect, I'm very confident that the study we're doing will be positive. And I would expect that we'll replicate many of the same findings that we've already reported on.
So I think one of the questions that we always get about the market opportunity for Nex-Z in ATTR has always been, well, there are stabilizers, there are silencers available. And it gets to the point of how competitive is gene editing and what the real market opportunity is. So how do you think about that? And as we get closer to potential data read from Magnitude and Magnitude-2, how do we kind of think through the ultimate market opportunity? Is it one in five? How should we think through the cut of the ATTR CM, also PN market?
If it's only one in five, I'd be disappointed. I mean, I think there's a lot of confusion out there. And I think people misread the information. And I think they misread the market research. I shared some of the findings in terms of how cardiologists think they want the best drug. And that's going to be based on the clinical outcomes that they get. And as there's a deeper appreciation of what is the pathogenesis of the disease itself, which is the presence of TTR protein, I think they will learn, as they're doing already, that the extent to which TTR is reduced is going to be increasingly beneficial for the patients.
That's what we're seeing. And there's a fair amount of education that will take place over the next couple of years. But that's where the space is going. There's talk, I hear from some, that patients don't want to take gene editing. That's not what we're seeing in our clinical trials. I mean, we're ahead of the work that we're doing, the plan that we laid out for ourselves, and in the HAE studies, where you have a younger patient population with a lifetime ahead of them in their disease, the study's oversubscribed. I mean, I think some of the rhetoric is ill-advised and, frankly, not well-informed.
Another thing that we've heard, which I think is also an error, is that patients may hesitate to take the drug because they're old, or payers may hesitate to prescribe the drug because they're old. 90% of patients today are alive at three years. The return on an approach like this, I think, will be excellent for payers. And I don't think the physicians are going to be at all hesitant to use something if they believe it's best in class. So if you're talking about single-digit numbers in terms of where we are in the marketplace, as I've said, I'd be very disappointed with that.
Any questions from the audience?
Thank you. Thanks for your talk. It's great to see that Intellia is on its track to meet its goals. There's a topic that you didn't mention, which is a very important one to assure successful commercialization, and it has to do with manufacturing. Plenty of good therapies could fall at that stage. I just wonder if you could share with us your current as well as your future manufacturing strategy to assure a successful commercial launch. Thank you.
Yeah, thank you. That's a point where people get confused as well. I think that people conflate other gene therapy approaches or even other gene editing approaches with what we're doing. As I showed in terms of the treatment regimen, I'm not going to say it's trivial, but it's certainly simple, and what is actually being delivered is a lipid nanoparticle. It's not a virus. It's not a living organism. These are not manipulated cells. This is an entirely synthetic process, and so the LNPs are something that we've built on a proprietary basis.
We make them from scratch, if you will, and the nucleotides and the mRNA that we produce is also fairly straightforward, so the manufacturing challenges that other modalities have had do not apply to us. We've made almost all the material necessary for our Phase 3 trials already. We're not taking risks with any late-stage comparability sorts of studies, and we think that if my hopes and expectations are realized, where lots of patients want to have access to the drug, we'll be ready to make the drug available without hesitation.
I think we have a question in the front.
Just wanted to know if you're planning on an update on the HAE phase 2, because that follow-up is important.
Yes, as I said in my comments, all of the patients, whether the cardiomyopathy studies from one and two or the HAE patients that we've presented on just recently, we will provide updates. As we shared in our phase one study, it's very interesting to watch patients as they evolve over time. And what we see is they start off very well, and they tend to get even better over time. And so we look forward to sharing that information as the year goes on.
Maybe just as a follow-up to that question, for the non-responders during the primary observation period.
Let me correct you. They're not non-responders. They didn't have complete absence of attack, and they didn't abandon their prophylactic medicines. They all responded. All of those patients were better off than what they started.
Incomplete responders.
That's better. It's important to be precise.
Incomplete responders. Do you have a sense of how they're doing during the longer follow-up period? Any early color that you can provide?
I'm not going to give the data other than to say they're all doing extremely well. And as we saw in our Phase 1 cohort with additional time, we call it tincture of time at the company, what you see is a maturation of the data where patients all tend to get even better over time. So as we present data during the course of the year, I think you'll see very exciting information in terms of the percent of patients that achieve a state of being completely devoid of attacks and not taking any concomitant medication.
While we're on HAE, I think there's this key question from the investors seems to be on what the ultimate profile should look like in terms of mean attack rate for it to be commercially successful. I think heading into just going back to your last year, Vito, I think the expectation was that we need to see zero attack during the follow-up. And you did see some breakthrough. But just based on your feedback from doctors that you talked to, what is the optimal profile that you think you need to show in the phase 3 to have commercial success? And what do you want to see ultimately?
If we merely repeat what we have, the product will be commercially successful. We know that. I think the investor view, which is probably clouded by some of the information they hear from counter detailing, et cetera, does not align with what patients say or what doctors want. Any patient that has the prospects for essentially being cured, what we call a functional cure of the disease, is what they want. I mean, we hear that uniformly. As we do our market research, the majority of patients want access to that very quickly. When we present the profile to physicians and deal with the physicians who are taking care of these patients, they are also highly motivated to use the drug.
I think one thing that's not well understood is that, and I made these comments in my presentation, what is considered well managed is really something that is viewed as good enough. Patients have a very intrusive treatment regimen that they don't like. They live with it because when you consider the alternative, it's undesirable. But when offered the opportunity to abandon their care totally, that's what they want. And one of the things I think is poorly understood is physicians feel the same way. In many cases, doctors view taking care of HAE patients as very challenging, not just for the medical situation itself, but for the underlying dealings with every year, annual reauthorizations, the paperwork, and all the complexity that comes with it. If they can have patients that do not need that kind of activity and support, they want that too.
Any questions from the audience? Are there any telltale signs that you can kind of extrapolate based on the early data to have the basically to get a better sense of the optimal characteristics of the patients for a gene editor for HAE?
The study we're doing allows all patients with HAE, 18 and above, into the study irrespective of the severity of their disease. We want to have the broadest possible label. And we want to have patients have the option, depending on how they view their disease along with their physician, to take the drug. The last thing we want to do is make it available only for patients who have complete absence of control of the ongoing therapy. There are patients who may not be having many attacks, but what they want to do is not have to take the medicine that they're taking and go through all of the challenges of rerouting their life in terms of avoiding stressors, carrying material with them, being tethered to their regimens. They want to be cured. And when they see that they can be, that's what they want.
As you think about just going back to ATTR, as you think about a new stabilizer entering the space, I know that you previously guided just kind of the background stabilizer used in Magnitude. Does new entrant change your way of thinking about the background percentage in Magnitude? And I guess, does that potentially change your way of thinking about the powering of the study?
No. If patients choose acoramidis, that will make that available so that they can come into the study. It'll be tafamidis or acoramidis. In terms of our assumptions and how we view event rates, et cetera, we don't think it's likely to produce any meaningful difference in outcome.
OK. And I think you talked about the potential of an interim read for Magnitude. Any updates on just how you think about the potential factors that can change the timing and also the powering of the study? How much can we get a sense of the timing and also how much we could get at the interim?
I mean, typically, we wouldn't do an interim analysis until all the patients are enrolled, and you got a sense of where we think we'll be at the end of the year, although I intend to beat those numbers. One of the things that we've said from the outset is we want to know what we're competing against, and as the label becomes available for patisiran, that may affect how we think about what we do and how we tweak the study. But in the meanwhile, the design is sound. We continue to follow our earlier patients and get a good sense of what the event rate is in a patient population that's even sicker than that was in the HELIOS-B study or that will be in our own Phase 3 study.
Some of this we'll be watching the actual event rates as they take place over the course of the study. What I would think as a milestone would be when the study is fully enrolled, that would be we would not do an interim analysis before that.
So what are some of the potential triggers for your team to take a look at it at the interim? It seems like you do need to get the trial enrolled. Are there other triggers? I assume it's events, accrued events. But are there other things that can also come into play that can also change the timing of it?
I think you've identified the primary considerations for us.
OK. Other questions from the audience? All right. Well, thank you so much for your time today. That concludes.