Get started. Hello, everyone. Thanks for joining the session with Intellia Therapeutics on day one of the 2025 Bank of America Healthcare Conference. My name is Alex Stranahan. I'm a Senior Biotech Analyst covering Intellia here at BofA, and I have the pleasure of being joined by Ed Dulac, the Chief Financial Officer of Intellia. Ed, thanks for being here.
Really excited. We've got a lot going on. Happy to talk about it.
Yeah, yeah. Maybe we can just dive right in if you want to tee up the conversation with sort of the main assets and any sort of upcoming events that you're excited for, and then we can get into the specific programs from there.
Yeah, of course. We're basically a gene editing company focused on in vivo applications, and we've got a broad toolkit that we're working on and research, but really the focus for the company has been squarely on the late-stage programs. We have two assets, three phase III studies, and a couple of different very interesting indications. We've made really good progress on the operational side, and we sort of restructured the company early in the year to map the financial plan to that. Things are working really well, judging from the first quarter. We've got a number of catalysts over the next 12 to 18 months, and we're going to continue to do more of the same, but we're really excited about the prospects ahead.
Okay. Maybe we can jump into the ATTR program. Maybe just we can talk about how the space is evolving overall. How do you see the recent approvals from Attruby, Amvuttra? How does that sort of change the commercial makeup as you're thinking about going to launch?
Yeah. We have two phase III studies in our TTR program, one focused on PN and one focused on CM. We can talk about both. As relates to CM, you're referencing a more recent approval in the competitive space. I think, look, they ran a good phase III study. They have a label that reflects that phase III study, and we'll see how that commercial opportunity unfolds. I think, generally speaking, most of us look at cardiomyopathy as an already large and increasingly larger market opportunity, more diagnosis in this space. We're continuing to see that although there's options for patients, there's still a high level of unmet need. Our hypothesis and our approach has always been one of lower TTR really matters, right? A pathogenic protein causes these manifestations.
To the extent that you can quickly reduce TTR levels, do that very deeply, very consistently, and very durably, that will benefit patients. I think we have seen our phase I data that we presented in November of last year. It is a very encouraging profile that we are hoping to replicate in our phase III magnitude study. Overall, we like the trajectory of the CM opportunity, and I think we are well positioned to execute our clinical studies. We have guided that we will complete enrollment by the end of 2026 for that 765-patient study, and we are excited about the investigator enthusiasm we have seen. The patients have shown up, and the momentum has been very strong. We continue to execute ahead of our estimates, and we have not seen a deviation since we started that study in March of last year.
Okay. Okay. So no real impact at all, it sounds like, from the pace of enrollment from the recent approvals.
No. I think we can look at the data in more detail, but the attributes that I mentioned for our next C program, that deep, fast reduction, we just do not see that profile on the market today. In a world where there may be combination therapies, right, increasingly patients are on tafamidis as a background therapy. There has not been a lot of incremental effect with the addition of some of these more recent therapies in development. We suspect that might change with our next C program. A lot of the patients will be on background tafamidis. We think that combination could really be a game changer. We think there is still significant unmet need, and we are running a really good study. We have been comfortable with the design, but we have seen no inflection.
If anything, we've seen momentum kind of increase after our November disclosure that says AHA. So we're very excited about that.
Yeah. It is a pretty differentiated drug profile, right? being a potential one-time treatment, pretty differentiated from what's currently out there. Do you think durability of response is maybe a key focal point for the study and sort of the profile?
Most definitely.
Yeah.
I think that the therapy we're providing will give benefit to the patient, but also to the healthcare system. We are mindful of all the stakeholders, and we think gene editing is uniquely positioned to deliver on all those.
Yeah. Is there a particular durability threshold that would be sort of a value unlocking event for the program in terms of just physician buy-in to the one-time nature? Is it two years, three years?
I don't know the exact number. It's depending on who you talk to. I do think as you think about in the case of CM, for example, it's an elderly patient population. I think all of us would acknowledge that background therapy has improved, right? Diuretics, SGLT2 use, new novel therapies that are available. I think patients are living longer. For us as a one-time intervention, I do think the ability to give patients a significant benefit over time in a matter of years is the goal. As I mentioned before, if we're able to knock out these genes that does reduce the pathogenic toxic protein, that should give these patients a long-term durable benefit. This year, we'll present two years' worth of data.
As you think about where the company will be in two or three years' time, as we're thinking about launching our first program, which will be directed at HAE, we'll have patients that are on our earliest programs from six, seven years out. It will be a substantial safety database, but a lot of information around the durability of effect. We continue to accumulate data as we add more patients. So far, we really like the profile.
Okay. Yeah. Definitely want to ask about HAE. Maybe we can split the last part on that program. Maybe just another one on ATTR. I think you've said in the past that an interim analysis could maybe be possible depending on the magnitude of the TTR knockdown. I guess what's sort of the gating around this and any reason to expect different knockdown from what you saw in the phase I?
Yeah. As it relates to TTR, I think we're running the gold standard, randomized placebo-controlled study, multinational. It's a very well-considered study. I don't see any differences. The patient population, if anything, will be the more contemporary population. Just reminding folks that our phase I study was almost enriched for the variant type. Although cardiomyopathy is a disease of aging, it's really a wild-type patient population. 90% are wild-type patients. About a third, almost about 31% of our phase I data were in variant, more difficult to treat patient populations. Still, we saw a great effect, very consistent TTR knockdown. We get to nadir in 28 days. The error bars around that are extremely narrow. It's very impressive. That's a very long-lasting, durable effect. We've showed in the 12-month data, but again, we'll have two years.
That is the goal for the phase III data. If we're successful there, I think that positions us really well in a competitive marketplace.
Okay. It's probably the right way to be thinking of CM and PN as separate markets here. Maybe starting with CM, any functional endpoints that either clinicians or patients you think could be focusing on, like what's most meaningful for these groups?
We have a lot of endpoints. We're running a traditional study in the sense that we're looking at cardiovascular outcomes, right? Mortality and hospitalization. We are looking at TTR levels if those matter. There's a clear correlation between your ability to knock down TTR and the ultimate clinical effects. We do think that's important. We're doing things like the Kansas City Cardiomyopathy Questionnaire. Then we've got functional endpoints, some of the more traditional, like six-minute walk test. We do New York Heart Association classification. Maybe things that I was less familiar with, but there's SPPB, which is a sort of a short physical performance assessment, a battery test that sort of mimics the everyday daily activities for patients.
There is a number of things that we are tracking that we hope, in addition to the hard clinical outpoints, we will demonstrate very important improvements on some of these functional considerations as well.
Okay. I imagine even just directional benefit, just given how the breadth of the metrics that you could potentially show a benefit on, it does not necessarily, and the study would not be powered to show statistic on many of those, right?
Yeah. We'll see where it goes. We showed early trends. The treatment effect on the phase I population was not insubstantial. For the first time, we thought about the possibility of can we actually halt progression of the disease, right? Patients are well served today, but they invariably progress. The thought of more deeply and maybe early intervention that could lead to disease stabilization or even regression in certain patients, that's a very exciting prospect. In a dynamic disease like this one, we can't rule out that possibility. We'll be looking to all these metrics to see, is there a clear signal, and do we have some very interesting data that we can share more holistically?
Okay. Okay. For PN, I guess why pursue two endpoints here? Do you need to hit on both the TTR for filing, or how is this study designed?
Yeah. It's a co-primary endpoint. We talked to our internal colleagues that are experts in this space. We talked to physicians, our KOLs, talked to regulators. They see the value in TTR reduction. I think the data is pretty clear. When you intervene and TTR comes down meaningfully, you get the neurological benefits to follow. In our case, the TTR reduction, we hit at day 28 already, sort of that low level, that nadir of serum TTR. It's easy for us to capture. In addition, we'll be following the MNIST endpoints that are traditional for a study in PN, but that combination will serve to support the filing.
Okay. Maybe you could touch on sort of the choice to screen silencers and wash out for stabilizers in the study. Could there be a compounding, or could there be influence from that that you're trying to minimize in terms of how clear the efficacy signal is?
Yeah. This is quite a bit different than the CM population. I think it's important to talk through this. There isn't a lot of use of stabilizers. tafamidis, for example, isn't really approved. There's not a lot of use of a product like tafamidis in PN. There are other products that are in this space that honestly would be unethical to wash them out of an effective therapy. We are running a randomized, blinded, placebo-controlled study. The prospect of them going on placebo and coming off a therapy that patients still can progress on but does have a good treatment effect would be a really almost impossible study to run by definition. We're looking at geographies where those therapies aren't available. We're outside of the United States for this particular program.
It is the rationale for why we are not running it on top of a silencer.
Okay. Okay. Maybe last question on ATTR before we flip to HAE. As you think about pursuing in tandem both of these markets, is the go-to-market strategy maybe different the way that you would approach? It would be a great problem to have approvals in both, but maybe walk us through sort of the commercial approach that you would take and anything that's being done proactively along those lines.
I'll take a big step back for this one. We're a pretty small company, and we have three phase III programs, which is an embarrassment of riches in some sense, but it's a real operational challenge that we want to make sure that we don't fumble on and misstep. We're going to start to build the company through a launch of HAE. It's important to recognize that's a relatively small opportunity. It doesn't require a lot of infrastructure as I think about what's needed commercially to be successful. We have some already in-house expertise here, and we've got a really clear plan we've already begun to implement at the end of last year. That general framework applies to PN, where it's still a relatively small patient population for a company our size. To operationalize that financially and otherwise, I think is still very doable.
The goal, quite frankly, is to build the company on the back of those types of indications. These are going to be highly profitable businesses for us, and that allows us to think about the company differently and how we invest behind the company. The bigger nut to crack is going to be CM. There's just that much more patients. It's going to require a larger footprint. We have a clear plan that we've been working against, and we would like to be able to sequence these in a way that allows us to capture as many patients as we can, but also make sure that we successfully build the company. That's the plan. We'll see how things go, but so far, it seems to be working out as we expected.
Okay. Obviously, you'd want to retain as much of the economics as you possibly can from both of these programs.
Without question. I mean, it's been a tough biotech market. I will say the company, I've only been with the company 10 months, but the company has worked really hard. We've had dedicated people for a long time working on these programs. I love the setup of the data, the whole setup for the next 12 to 18 months. We are going to try to find a way to make sure that we can capture the value for the company, but also for patients, payers, the whole ecosystem. It's going to be a lot of firsts that we've done at Intellia. We've got a lot of New England Journal of Medicine publications. We would love to add to the list the ability to launch these products successfully.
That is the task, and we want to make sure that whether it's a financing strategy or a partnership strategy, that we're doing so in a way that reflects the fair value of the programs that we have.
Okay. That's very well said. Maybe flipping to HAE, sort of walk us through the stage of development for this asset, and then we can get into the data.
We just gave a pretty good update as the first quarter results that we reported last week. We've been saying for quite some time that there's been a lot of engagement from investigators and patients. We've been saying it. The better judge is to see how people are actually acting in the marketplace. We've been enrolling very aggressively. The update that we provide is we previously said we will enroll the study by the end of this year. We've brought that into the third quarter, and we feel really comfortable about that. We threw in a little one-liner that I'm not sure many people picked up, but from first patient enrolled to last patient will be less than nine months. It's a very fast enrollment for an HAE study. That's a pivotal phase III program.
We see a lot of U.S. interest, a lot of ex-U.S. interest, a lot of enthusiasm for investigators, and a lot of enthusiasm for patients, more so when they gain the experience of the program itself. We will be in a position to give updates on the clinical side, both mid-year and probably later in the year on HAE. You will begin to see us lean more forward into the market research that we have done. We have got a commercial team that is now in place on the leadership side. We have done a lot of work on the patient perspective. This is a switch market, a patient-driven market. That patient perspective is super important. We will begin to share that more clearly. We obviously talk to physicians. That perspective is important as well. We have done some interesting market research there.
Payers are going to be super important, as they always are. We have a lot of expertise, and we are doing a lot of work. There will be a steady stream of clinical updates and some more of the commercial side of what we are doing. We are not that far from the top-line phase III data. We are roughly a year away. There is a lot going on here in just HAE alone, but we will be talking about that very soon.
Okay. I guess from your market research or what you've seen in the literature, what kind of attack rate reduction do you think you'll need to show to be competitive versus other options?
I love this question. We fundamentally think about HAE very differently. Attack rate reductions is what a lot of our peers are looking at, and we obviously have that data. When we're working with a gene-editing technology, and again, we can get at the root cause of the disease, and you see the calprotectin reduction and sort of the implications for patients, we have the opportunity to change a narrative substantially. The goal for this program is no attacks and no therapy. We're not talking about attack rate reductions. We're talking about getting to no attacks, zero, and no requirement, right? Today, you have an option to choose long-term prophylaxis, which could be oral or injectable. These patients are young at diagnosis. On average, about 20 years. That could be decades long of chronic therapy. It's a chronic disease.
is on-demand therapy for some patients, but we see this market really transitioning into potentially a one-and-done paradigm. For an otherwise healthy 20-something-year-old patient, the prospect of having a single four-hour infusion, this is a very simple administration for a gene editing. It is not like anything else that investors and others maybe have experience with. It is a very simple profile. It has a very profound effect. To the extent that we replicate the early data, the vast majority of patients could be in a position to have no attacks and have no therapy.
Yeah. Maybe talk to the reductions you've seen in the phase I and phase II. Were there any differences between these patient groups that maybe led to at least percent differences? They're both pretty impressive, but maybe just talk us through the attack rate data that we've seen so far.
Yeah. The data are very good. They're at the very high end of the range. There are some important differences to the point of your question. The phase I study was not blinded. So unblinded study, there was no placebo control, and patients were not required to wash off their existing therapy. So a very different paradigm. They can come on study with their existing therapy, get the addition of NTLA-2002, and that's where we saw the 90-plus, 98% attack rate reduction. Very, very good outcome. The phase II study is very different. It was randomized. It is placebo-controlled, and patients were required to wash off their long-term prophylaxis or any other therapy that they were on. So it's a very different test than the phase I, but it happens to represent the phase III study very well. It'll be a very similar set of circumstances.
Patients require the wash-off. They're readily willing to do so, including on some of the leading therapies today. It does change the primary observation period. For a patient that has HAE, their entire life is to make sure that they're surveilling their body. They're looking for attacks, and they want to prevent what could be a life-threatening attack. They use on-demand therapy readily. To ask them to wash off therapy, potentially going to a placebo arm, is not comforting. They're hypervigilant. If they feel like they're having an attack, particularly if it's not external swelling and it's obvious, they will use on-demand therapy. Where it gets very interesting, though, is after the primary observation period, where the study is unblinded, the patient now has the comfort of knowing that they've received therapy. When they know that, they can think about their disease differently.
The data we shared in October was from the primary observation period. Eight out of 11 patients had no attacks and no therapy, but there were three that responded. They had attack rate reductions, but they did not have complete elimination of their attacks. The data that we will present later in the year will be longer-term follow-up, and we will see how those patients now behave knowing that they have received active therapy. These patients can continue to evolve in a favorable way. Some very interesting data is coming up in the second half of this year, and I think that will be a very good lead into the phase III program that is going to follow shortly thereafter.
Okay. Do you think that washout period is something that would be required in the commercial setting, or is that just exclusively a clinical trial aspect where you want to really see what the drug effect is?
It's a clinical trial aspect. I think this market, for the benefit and good of patients, there have been a lot more treatment options. So a lot of physicians are comfortable with switching. There are quite a few switches. I think in the real world, I think physicians will contemplate half-life, and they'll think about the overlap. There isn't anything inherently concerning from a safety perspective as you would think about transitioning from one or the other. A degree of overlap is probably not problematic, but it's sort of required to have a true test of an investigational agent in a phase II or phase III study in our case. That doesn't necessarily reflect. Clearly, there won't be a blinding of experience. Patients will know that they've received therapy, and they can immediately start thinking about their disease differently as a result.
Okay. Okay. It seems like speaking with physicians that 28 weeks is kind of the common HAE treatment durability that folks would want to see. Does this sort of resonate with what you've heard, or do you think maybe longer durability could maybe be additive to the profile?
It's definitely additive, right? To go back to what we talked about before, the promise of gene editing is really fixing the root cause and having a prolonged therapeutic effect. We see that in our early data. We're very likely to see that in our phase II or the two-year data follow-up that we present across our programs this year. I do think that's important for us to have that durable effect. People ask, have we redosed? And we have on certain occasions, but we don't see that being required. Those are for patients that have had a lower dose or, in some cases, placebo that have gotten a higher dose. We've had very consistent reductions in desired biomarkers. Those have not waned in the follow-up that we have seen to date.
I do think longer follow-up will further support the profile, and I think that will only give confidence to physicians and patients that this is a very good and appropriate therapeutic intervention for them.
Yeah. I mean, maybe just on that last point about the redosing, I was curious if there's been any patients that maybe didn't have as robust response as others that maybe deepened over time or if this would even be anticipated given the MOA.
We're going to have data at the end, towards the end of this year in HAE. The phase II portion of the study, there were six patients on placebo, so never had active therapy, and there were about 10 or 11 that were on the 25 mg lower dose. We selected the 50 mg phase III dose. There was a clear dose effect in kallikrein reduction, and we've seen clinical benefit as a result. For the first time, 15 of those patients that had placebo or lower dose that have opted for the 50 mg will be presented later this year. It'll give you a sense of how patients that have received the higher dose, what does that look like over time. That body of evidence is not trivial. Combine all the patients on our phase I and two portions of the study at 50 mgs.
It totals more than 30 patients. Our entire phase III exposure is 40 patients. You are going to have a really good read into the clinical profile at the end of the year, and then we are six months or less from top-line data. It is going to be a really important update for the company at year-end.
Okay. Yeah, very good cadence of updates coming over the next 12 months. Maybe we could just touch on sort of the cash balance. I think over $700 million. What does that sort of carry you through in terms of launch prep? Obviously, this is well beyond sort of the upcoming redos.
Yeah. We took a very hard look at the business at the end of last year. What resulted was the restructuring that we announced in January. As painful as it was, it was very deliberate. At the highest level, we essentially continue to do research, but we have dialed that down. We are much more focused on research. What we wanted to make sure is that the existing balance sheet allows us to fully execute all the phase III programs that we have touched upon today, build the commercial infrastructure in the U.S. to make sure we can capture the value starting with HAE, and in the process, allow the company to click through a lot of milestones. We just talked through a few of them. We have data coming this week on PN and CM.
There's a lot of data second half of this year into 2026, and then it gets even more exciting as we file a BLA and think about approval in the first half of 2027. My hope is that markets improve. There's better appreciation for the data that we've produced. These are pretty de-risked. The pathology is very clear. We feel like we have very winning products. We're well on our way, but we're going to click through a number of milestones. We'll look to finance the company as we need to, but we don't need to today, which is a good thing in today's market. We're really pleased with the operational performance. We're pleased with the plan, and it's very clear where we're going through the first half of 2027.
Okay. Okay. Looking forward to the updates. I mean, maybe just in the last minute, and I appreciate there's potentially not much you can say here, but we have seen gene-editing companies catch a little bit of a bid following McKerry's comments that are constructive on the space and rare diseases overall. Any changes with your FDA interactions or if you could maybe talk about how your studies reflect today in the current and evolving dynamic there?
I'll say two things just for the sake of time. One, we are running gold standard studies, right? I mean, the fact that we're running randomized placebo-controlled studies, I think bodes really well. I think it may be more challenging if you're trying to run a single-arm study on a surrogate endpoint, but we're using hard clinical endpoints. We're not doing anything fancy. We're doing exactly what they would expect us to do. The second thing is there's been a change at the top, but Nicole Verdon is the Super Director of OTP that we've been working with, her and her team. We've interacted with them very recently. There's been no changes. There's been a good relationship. We expect that to continue, and we'll leverage the RMAT designations that we have across all of it.
We're buckled in and paying attention, but we're cautiously optimistic that we're running the right programs and we'll get the right result.
Okay. Okay. Very well said. With that, I think we'll have to leave it there for the sake of time. Please join me in thanking Ed for the really great discussion, and thanks for attending the conference, Ed.
My pleasure. Thank you.