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John Leonard

Thank you, Brittany. Good morning, everyone, and thank you all for joining us today. We're off to a strong start in 2025 with renewed focus on our operational execution. With growing support and interest from investigators and patients, we're making remarkable headway with enrollment across our latest studies. We see significant promise with NLA 2002 for the treatment of hereditary angioedema, where we expect a complete enrollment in our Phase 3 study HAELO in the second half of 2025.
We are similarly encouraged by the pace of enrollment with our Phase 3 studies for transthyretin amyloidosis. And expect enrollment in MAGNITUDE, our cardiomyopathy study to exceed 550 total patients by year end. Both HAE and TTR represent substantial market opportunities, and we have doubled down on our efforts to ready the company for the rapidly approaching commercial phase.
In November, we presented positive extended follow-up data from patients in the ongoing Phase 1 trial of Nex-z, previously known as NTLA-2001, in patients with transthyretin or ATTR amyloidosis. The Phase 1 data offered compelling evidence that deep and persistently low levels of TTR reduction achieved with Nex-z may favorably impact disease progression for people living with ATTR amyloidosis. David will review these results in greater detail.
We are actively screening patients with ATTR amyloidosis with polyneuropathy in our Phase 3 MAGNITUDE-2 study and are on track to dose the first patient in the coming weeks. As you may recall, this pivotal trial is an efficient study with expected enrollment of 50 patients. We plan to measure mNIS + 7 at 18 months and serum TTR levels as key endpoints in the study. We expect enrollment to be completed in 2026, enabling their second BLA filing by 2028.
Last month, we announced the first patient had been dosed with NTLA-2002 in HAELO, our Phase 3 study in HAE. Enthusiasm for NTLA-2002 from patients and our investigators is high. And we believe this Phase 3 study will enroll rapidly, enabling us to submit a BLA filing in 2026.
At the beginning of this year, we conducted a pipeline prioritization to focus our resources and efforts on these late stage and high value programs NTLA-2002 and Nex-z. We discontinued our work on NTLA-3001 in favor of a second-generation approach, and we'll now look to see human proof of concept for our insertion technology by Regeneron in their hemophilia A program.
As we look ahead to the rest of the year, we are well positioned for near-term value creation. We have three Phase 3 programs actively recruiting and one singular focus, getting the work done to enable three launches between 2027 and 2030. We're excited by our progress and by our prospects, so we look forward to sharing data from both of our programs later this year.
Lastly, I would like to take this time to welcome Birgit Schultes, our newly appointed Chief Scientific Officer. She's an outstanding scientist with over 20 years of experience in drug development and biotechnology, including the clinical development of cell therapies and complex biologic products. She has experienced with our entire suite of gene editing technologies and is leading our more concentrated in vivo and ex vivo research efforts.
I'll now hand the call over to our Chief Medical Officer, David Lebwohl, who will provide an update on our clinical programs. David.

David Lebwohl

Thanks, John. I'll begin with 2002 in development for HAE. As John noted, we dosed the first patient with 2002 in our HAELO Phase 3 study last month. As a reminder, the HAELO study is a 60-patient global randomized double-blind placebo controlled study. This is an exciting milestone for Intellia and the HAE community. We see high interest for 2002, which we believe will drive rapid enrollment of our Phase 3 study and commercial uptake once approved.
Based on the promising data we've presented thus far, we believe patients could achieve a functional cure. In other words, freedom from HAE attacks and independence from chronically administered prophylactic medications that are commonly used to treat this disease.
We plan to prevent longer term data from the Phase 1/2 study later this year, including patients in the Phase 2 portion who initially received a 25 mg dose or placebo and were subsequently given the 50 mg dose of 2002 selected for the Phase 3 study. With HAELO well underway, we believe 2002 is well positioned to be the first ever one-time treatment for people living with HAE.
The therapy is administered with a simple infusion and no need for extended steroids or other preparative drugs. This transformative therapy would also be the first approved using in vivo CRISPR gene editing.
Let's move on to the Nex-z in development for the treatment of ATTR amyloidosis. Starting with ATTR amyloidosis with cardiomyopathy, enrollment in the pivotal phase through MAGNITUDE study is progressing ahead of our target enrollment projections, and we expect cumulative enrollment to exceed 550 total patients by year end.
In November, we presented data from the Phase 1 study at the 2024 American Heart Association Scientific Sessions and published the findings in the New England Journal of Medicine. Across all 36 patients, a single dose of Nex-z led to rapid, deep, and sustained serum TTR reduction, regardless of baseline levels through the latest follow-up.
At month 12, the mean serum TTR reduction was 90% from baseline, and the mean absolute residual serum TTR concentration was 17 mcg per ML. All patients achieve deep and durable TTR reduction after a one-time infusion. Notably, the TPR reduction occurred rapidly with the [nadir] reached at 28 days. When every day matters, achieving PTR reduction as quickly as possible is crucial in this life-threatening illness.
With TPR silencers, the reported mean reduction was approximately 80%, which is not reached until six months after starting chronic treatment. Now we have observed that the very low levels of circulating TTR seen with Nex are associated with disease stabilization or improvement across several markers of cardiac progression at month 12 compared to baseline.
These favorable results were observed even though half of the patients met criteria for Class 3 heart failure, and about 30% had a mutated TTR gene. Both characteristics of patients with more rapidly worsening disease. This is a significant insight because when patients are untreated, disease progression as measured by these markers is typically evident within 12 months.
In addition to the favorable results across markers of cardiac disease progression, we have also observed a low rate of cardiac hospitalizations in our Phase 1 study despite the advanced patient population treated with Nex-z. This event rate, if reproduced in our pivotal trial, will be associated with a compelling clinical benefit for patients suffering from ATTR cardiomyopathy.
Now on to ATTR amyloidosis with polyneuropathy. Patients are actively screening in the Phase 3 magnitude tube study, and we're on track to dose the first patient in the coming weeks. At last November's investor event, we presented data from the Phase 1 study. Across all 33 patients who received the dose of 0.3 mg per kilogram or higher, the mean serum TTR reduction was 91%. And the mean absolute residual serum TTR concentration was 20 micrograms per ML at month 12.
Consistent with the observations of ATTR CM, the rapid, deep, and durable reduction in serum TTR observed in all patients was accompanied by evidence of disease stabilization or improvement across multiple clinical measures of neuropathy. Across [nis] mNIS + 7, and MDMI, there were favorable trends of clinical benefit at month 12 compared to baseline levels with further improvements noted in nis and MDMI in the part 1 patients for whom 24 months of follow up was available.
Nex-z has continued to demonstrate a favorable safety and tolerability profile. In recognition of the potential clinical importance of Nex-z for the treatment of ATTR VPN, the FDA granted Nex-z regenerative medicine advanced therapy designation or RMAT. This will enable closer collaboration with the FDA as we approach a BLA filing in 2028.
We look forward to presenting longer term data from both ATTR CM and ATTR VPN patients in the Phase 1 study later this year. The data will include updated measures of clinical efficacy and safety. Regarding our research platform, we're dedicated to using our toolbox to bring forward breakthrough products both in vivo and ex-vivo. You'll hear more about that in the time to come.
I'll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results as of fourth quarter 2024.

Edward Dulac

Thank you, David. Good morning, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our pipeline and platform. Our cash equivalents, and marketable securities were approximately $861.7 million as of December 31, 2024, compared to $1 billion as of December 31, 2023. Our collaboration revenue was $12.9 million during the fourth quarter of 2024 compared to negative $1.9 million during the fourth quarter of 2023. The $14.8 million increase was mainly driven by the Regeneron license and collaboration agreement.
R&D expenses were $116.9 million during the fourth quarter of 2024 compared to $109 million during the fourth quarter of 2023. The $7.9 million increase was primarily driven by the advancement of our lead programs.
Stock-based compensation included in R&D expense was $24.4 million for the fourth quarter of 2024. G&A expenses were $32.4 million during the fourth quarter of 2024 compared to $29 million during the prior year quarter. The $3.4 million dollar increase was primarily related to stock-based compensation. Stock-based compensation included in G&A expenses was $15.2 million for the fourth quarter.
As we turn our focus to the future, I want to share a few thoughts regarding the restructuring we announced on January 9 and how this changes the complexion of our GAAP operating expenses. In the first quarter of 2025, we expect to incur wind down costs associated with certain programs like NTLA-3001 that have been discontinued or deprioritized. We expect the difficult decisions made to reduce our workforce and focus our pipeline will result in year over year declines in GAAP operating expenses of approximately 5% to 10%.
The operating leverage and savings created in 2025 are expected to benefit the company over the next couple of years and allow us to make important investments in commercial infrastructure and capabilities while keeping total company expenses below the level of reported results in 2024.
While we anticipate greater sales and marketing investments in 2027 to support a successful commercial launch of NTLA-2002 and HAE, the company's capital needs to support multiple Phase 3 studies will begin to diminish during that year as some of these programs complete enrollment and supporting costs naturally wind down. We expect to occur approximately $8 million in severance and other employee termination related costs. Finally, we expect our cash balance to fund our operating plans into the first half of 2027.

John Leonard

Thanks, Ed. In conclusion, Intellia continues to deliver on the promise of gene editing, and we look forward to sharing more clinical progress with you mid-year.
With that, we will now open the call for your questions. To do our best to address as many questions as possible, we will only be able to take one question per caller. Operator, you may now open the call for Q&A.

Question and Answer Session

Operator

(Operator Instructions)
Mani Foroohar, SVB Securities.

Mani Foroohar

Thanks for taking the call, guys. . Can we have -- can you help to give us a little bit of an update on the tempo of OpEx decline over the course of this year? And as you execute on the restructuring and looking out over the course of the next several years, there's been a lot of concern around from investors around OpEx ramps as you have large pivotal studies growing. Can you clarify that a little bit to the extent to which that OpEx ramp is going to happen or the extent to which we should think more in terms of stabilization from clinical trial costs around the pivotal stage?
I know this is a little bit of a compound question, but broadly if you could help people help us, I suppose, trace out. Trajectory of that OpEx over the course of those pivotal trials, that was really helpful.

John Leonard

So Mani from Leerink, thank you for the question. Obviously, Ed made some comments about the rate of spend and how the restructuring addresses that, but maybe Ed, you can give some additional details what you think the trajectory of spend is going to be over the coming years here.

Edward Dulac

Yeah, so I'll say a few things. Thanks for the question, Mani. As we reported operating results this morning, operating expenses on a GAAP basis were up, I think, 7% year over year. That's pretty consistent with how the company has had momentum in terms of supporting this evolution from a research-based company into a clinical stage organization. That evolution as is expected to continue. So we are committed to fully investing in the clinical programs that we have. That's reflected in the financial guidance that we have provided for 2025, and we are very committed to building the US infrastructure, at least initially, to support the launch of NTLA-2002 in the US.
In my prepared remarks, I gave commentary to help with 2025 guidance. If I could put a little bit more color on this year in particular, the first quarter will be a little bit noisy. Having announced this in January 9, we have some wind down costs associated with some of the programs. But you'll begin to see the effect already in the first quarter, and that benefit will continue to accrue throughout the course of 2025.
What makes this dynamic and complicated to be overly prescriptive at this point is the reality of what you described as the three Phase 3 studies that we have ongoing. So those costs are well underway for magnitude and cardiomyopathy. There are costs now associated with the HAELO study for which we dose the first patient, and we still expect to dose the first patient in our third Phase 3 study MAGNITUDE-2. So you'll see some increase in costs that are offsetting the benefits that will come with the restructuring. So too will offset the cost of the restructuring will be the investment that we make in the US for the commercial infrastructure that's required.
As you get beyond 2025 though, we kind of hit steady state. We're fully enrolled in HAELO at that point by 2026. We'll be well on our way within the MAGNITUDE-2 study and we'll be substantially on our way with MAGNITUDE. So we kind of hit steady state in 2026. And for which we'll get into 2027, costs will begin to naturally sunset and wind down for the HAELO program, then MAGNITUDE-2, and then ultimately, MAGNITUDE.
So I think it's important just to take a step back. We have made significant restructuring efforts that allows us to make the investments we need in the new priorities for the company, particularly clinically and commercially oriented. And it's hard for me to see a scenario in 2025-2026 or at least through the first part of 2027, where our OpeEx is at the level of what we've seen this past year in 2024. So I do think peak operating expenses are behind us. The only thing we'll have to assess closer to the launch will be what incremental investments we need to support NTA 2002 and HAE.

Mani Foroohar

That's very helpful. I take the question. I know you guys have a lot of other people online as well.

Operator

Maury Raycroft, Jefferies.

Maury Raycroft

Hi, good morning. Thanks for taking my question. For for Nex-z or 2001, what's the latest regarding your assumptions on Phase 3 events or rate based on longer-term data that you have? And are you saying more on what would enable the interim analysis for the MAGNITUDE-3 study at this point?

John Leonard

Maybe David, you can address how we're thinking about the event rates for the magnitude study and lay out some of our initial thinking for the interim analysis.

David Lebwohl

Yeah. So this study is enrolling at a very good rate. We're ahead of what our projections were. And the evolution of events, we expect to be similar to the other recent studies [Acarainus and lutricerin] So now there is a lot of data available on events rates in this disease. The management of disease has not changed significantly from the time of that trial -- of those trials. So that's what we're expecting. We haven't said exactly what that is publicly, but you could see it from the historical data.
In terms of the interim analysis, what we have said is what we've seen in our trial is that from the Phase 1 are results that look quite favorable. They look very good. There is a low event rate in this population, suggesting that the patients are benefiting from therapy both in terms of stabilization and even improvement. And this does look different from all the other treatments for TPR that are out there in which the patients as a population continue to get worse.
So based on that, we are obviously going to follow up this data carefully this year. We'll be seeing the evolution of the events in our in our magnitude trial. But based on that, we will be able to in the future give more better estimates about the interim. But there is, based on what we're seeing, a good possibility that we could see favorable findings at the interim analysis that would allow us to stop the program earlier. So we will, but there'll be more details about this from us as as time goes on.

Maury Raycroft

Got it. That's helpful. Thanks for taking my question.

Operator

Luca Issi, RBC.

Oh great, thanks so much for taking our question. This is Lisa on for Luca. We saw earlier this week that an [Nilon] is moving forward with the next generation TTR silencer, and they're proceeding with a pivotal trial design which is about 2 times the size of their [Helios B trial]. So, we're just curious if this larger trial sizes made you reflect on the MAGNITUDE study. And if you are considering making any trial changes such as increasing your patient population size, any color here would be helpful. Thanks.

John Leonard

Thanks, Lisa. Maybe I can make a couple of comments and David, if you see fit to add, be my guest.
We always look at data and we always look at what the competition is doing and think about that very carefully in terms of what it means for the program that we're carrying out. Any information that we can gather that helps us think more clearly and accurately about where we're going is always helpful.
We do see important differences, however, and David has touched on, how we're using some of the clinical data that we've accumulated already in observations that come from patients who've been treated with our own drug. I think for details in terms of how Eylum is approaching their work, I would encourage you to ask them.
However, I imagine that one of the considerations will be they're looking to achieve an effect on top of [TAFF], which was not seen, in the earlier study, and I'm sure they're doubling down to try to capture that. We think we'll be in a really strong position with respect to that category of patients. And also, my guess would be that the proportion of patients who are taking [tefamitus] will only increase over time and so there'll be a far greater proportion of patients taking that drug in their study as that plays out. Those are some top line comments.
I'm sure they have their reasons for some additional details. But with respect to our own work, we're quite pleased with the design we have. And as David said, As we continue to look at event rates as they occur in our own Phase 1 patient population, that influences how we think about adjusting, if at all, the trial that we're doing.

David Lebwohl

You just mention one observation about the I announcement is that you see that they are talking more and more about how important it is to get to lower levels of TPR. And that was actually used slides very close to our slides showing that as an AL amyloidosis, you see that patients who get very low levels have a better result, as well as in polyneuropathy, the greater the TTR reduction the better result. So this is good to see in the sense that they are now agreeing with the hypothesis that we have about lowering of TTR.

Operator

Kostas Biliouris, BMO Capital Markets.

Hi, this is Yuri on Kostas. Congrats on the progress and thanks for taking a question. So we have another question on [Eresteron]. Can you provide your thoughts on the potential competition from Eresteron and ATTR CM that has (inaudible) dosing saying strong TPR knockdown and can launch around the same time as Nex-z? Thank you.

John Leonard

(multiple speakers) I'm sorry, it was a little unclear. Well, I don't know if it'll launch around the same time. We'll see how that all plays out. Clearly, people are trying to move very quickly, to get improved therapies to the market. Our basic perspective, I think, was captured by David, which is this is all about reading TTR levels from the body to the greatest extent possible. And what we've seen thus far, certainly in the patient population is that we've gotten to extremely low levels.
We've presented not just percentage reduction, but the absolute levels of TTR, which I think is the more meaningful measure, just with respect to [Bambootra], which is what we expect to be in the market sooner. We're talking about levels that are about a third with Nex-z that compared to what's been reported for drug. So we'll see how it plays out with the compound for (inaudible)
But we think that certainly a one and done therapy that allows physicians and patients being treated by them to have access to the drug that will have benefits essentially that are in place we suspect for the rest of their lives will be critically important. And I would point out that when it comes to pricing of these drugs, access to insurance, the authorization procedures that are necessary to have year-on-year dosing, we think we'll be in an advantage position. So we like where we are. And as you heard from David, the study is progressing well. We expect that, we will meet our objectives and look forward to bringing the product to the market.

Operator

Gena Wang, Barclays.

Gena Wang

Thank you. What makes you feel confident to pick 550 patient numbers by year end for the enrollment regarding the ATTR (inaudible) trial? Does that mean you will complete your trial enrollment in first half '26 for the total 765 patients?

John Leonard

Gena, thanks for the question. You know us well, we underpromise and overdeliver. And that's been the guidelines for how we've run the company and how we talk about who we are, where we're going, and how we do our work. When I say 550 patients by the end of the year, you can count on that being a very highly likely outcome.
Yes, we've said that we expect enrollment of the study to be done by 2027 in almost any scenario that we can imagine, even if we were to adjust the trial once we see the (inaudible) data or as we get additional exposure to our own event rates, we are confident that we will fall within that time frame. But meanwhile, you can count on those 550 patients being enrolled because I see the enrollment rates and we're not going to give patient by patient updates, but it's rolling robustly and doing very well.

Operator

Joseph Thome, TD Cowan.

Joseph Thome

Hi, there. Good morning and thank you for taking my question. Maybe just one sort of a commercial approach here. We've seen some gene therapies enter the market for chronic conditions where there's an established standard of care, and some of them had some issues with reimbursement and leading the company to even discontinue it. Pfizer did with [13AB gene] therapy last week, I guess.
What can you do now to kind of make sure that the reimbursement environment is favorable and you can drum up patient interest, so that specifically in HAE where there is that established standard of care, you'll be commercially viable? Thank you.

John Leonard

Well, it's an important question, and when we think about -- I would start by pointing out that we don't think gene therapy, certainly the application of AAV to supply missing genetic function is the relevant comparator. Gene editing, which is a really readily straightforward application procedure, is something quite different from the compounds that you mentioned.
I just remind you and the other listeners that when we think about dosing patients with their drug, there is a very straightforward treatment regimen that consists of a single dose of dexamethasone the day before therapy. And then on an outpatient basis and I repeat, outpatient basis, patients come in, get another dose of dexamethasone, some antihistamines, a two to four-hour infusion, and go home. That is the regimen.
Extended steroids, biological product handling, etc, just doesn't apply in this case. So with respect to, as you said, drumming up interest, it starts with the performance of the drug. And in the case of HAE, remember what we've presented thus far, an entirely new category of response for these patients. We're talking about following a single application, patients having, what we have been calling, a functional cure, which is the absence of attacks and the absence of the need to take any ongoing therapy.
If you ask patients what they want, that is exactly what they're looking for. So I think a good proxy for how the drug will be received in the marketplace will be the enrollment of the study. And I can report at this time that, well, we've certainly talked about dosing our first patient, we have patients waiting at multiple clinical trial sites, so we expect this to go very well. And I think that's an indication of patient response.
With respect to payers, that work is already underway. And we think we will have a very favorable profile that we'll be able to present to the not just the patients themselves but to the physicians and the payers. And so we look forward to talking more about that as the year goes on.

Joseph Thome

Great. Thank you very much.

Operator

Alec Stranahan, Bank of America.

Hey guys, this is Matthew on for Alec. Thanks for taking our question. Maybe a quick one from us on the HAE phase 12 follow-ups. Looking at sort of the incomplete responders, any color on how these patients are doing currently with a longer follow up period and what you're expecting or hoping to see in the next update in 2025?

John Leonard

Thanks for the question. I'll start with a topic sentence or two and then David can fill in some of the details, but I would just point out that the nomenclature used is probably inappropriate. Every single patient has responded and every single patient is better off than the patient was before they came into the trial. Most of the patients that we reported in that short 16-week observation period for Phase 2 had a response that we've have been terming a functional cure, that is, they've been able to abandon their therapy and they have no ongoing attacks.
We've treated patients or offered to patients who are in the placebo arm in the Phase 2 study or in the 25 mg dose, the opportunity to be redosed at the Phase 3 dose of 50 mg. And we'll be in a position to report on those patients and the extended follow up of the other patients from both for the duration of those patients who have already achieved a functional cure and those patients who had not yet achieved that during the 16 week observation period. I would point out in our phase one work we've seen that patients mature in terms of the response over time. And we expect that to be occurring as well for patients in the Phase 2 stage.
David, if you want to provide any other color?

David Lebwohl

Yeah, that's the most important thing, obviously we're going to wait until we give our report about how those patients are doing. But to just reiterate what John has mentioned, what we've seen over time is that patients improve. It may be related to the fact that they now know they're on the drug. But it certainly is what we've been seeing, and we will talk to you more about that and these patients from the Phase 2 later this year.

Thanks.

Operator

Brian Cheng, JPMorgan.

Brian Cheng

Thanks for taking our questions, good morning. Maybe going back to HAE, how should we think through the gating factor as you get ready for the BLA filing? Outside of the clinical package that we're waiting for from HAELO, What are some of the other important items that you need to align between now and then? Thank you.

John Leonard

Maybe I'll say a few words and then David you could add just in terms of being in a position to file the BLAs. I mean, we've said that our objective is to file a BLA in 2026. I can say next year now, it's becoming quite close. And obviously, based on some of the earlier questions, we're thinking about the market and being prepared for that. But in terms of the product itself and the filing that we're putting in place, obviously that will consist of the pre-clinical package which is done.
It has the continued observation of our Phase 1 and Phase 2 patient population and then the Phase 3 data that will come from the phase -- from the HAELO study, which we'll be reporting out in the first part of next year, as that study completes.
It's important to note that the product itself is in really good shape. We're using the commercial form of the product in our Phase 3 trial. So some of those things that can take place where some companies try to bridge the commercial product, that work is done. And we think we're going to be in a really good position to move very quickly. I would add that we have RMAT designation for the product and that already puts us in a strong position to deal in an accelerated fashion with the FDA. We've been using that designation to our advantage, and we expect that that will be very meaningful as the review ensues.

David Lebwohl

Just to add that we've had multiple interactions with the FDA, very favorable interactions, and all the things that John is saying we think we will be ready for the BLA.

Operator

Rick Bienkowski, Cantor Fitzgerald.

Rick Bienkowski

Hey, good morning and thanks for taking the question. I wanted to follow up on Ed's comments around the marketing build out for 2002 and the associated cost. Could you comment on how big of a sales force you anticipate needing to launch 2002 and what other preparations need to be built out prior to a commercial launch?
And if I heard correctly, it sounded like most of the spend would take place in 2027. So I just wanted to confirm you don't anticipate significant spend here in 2026.

Edward Dulac

Yeah, thanks, Rick. So we're not going to describe the size of the sales force. I think we look at the opportunity as a well defined market, patients know each other. There's good patient advocacy groups. It's a well established market opportunity. We think the footprint to operationalize that is relatively tidy and neat for a company our size, and so we're very confident in our ability to create that infrastructure and have a very successful launch.
The investment in this broader commercial consideration started already in 2024. We've brought in senior leadership that has very relevant experience, particularly in HAE, and we have very clear plans in 2025 and 2026 to further extend that leadership team. We've had a number of questions today already on market access and pricing considerations. We've made that important higher. So we have more senior leadership coming on board in 2025.
As we get into 2026, with the BLA filing, we're sort of at T-minus 24 or 12 months and in, and so we'll think about hiring additional marketing and salesforce at that time. So we don't think it's a significant investment relative to the other aspects of our business, particularly the clinical expenses, but we've got a very clear two year plan on the expertise we need hiring plan to achieve that such that we're ready for launch in 2027.

Operator

William Pickering, Bernstein.

William Pickering

Hi, thank you for taking the question also on HAE, you talked about how some patients may be experiencing pseudo attacks that will potentially go away with the longer follow up, especially if they know they have been treated. So it sounds like the data you collect in the long term observation portion of Phase 3 could be pretty important to demonstrating functional cure, and I think that will be collected after you submit the original BLA.
So I was wondering if you thought about how long you'd want to follow those patients, in the long-term observation before submitting a supplemental filing, would it need to be the full 104 weeks, or could you do it sooner if it's clearly apparent that all the attacks have stopped? Thank you.

John Leonard

David, can you outline how we think of long term follow up and what's shared with the FDA and when?

David Lebwohl

Yeah, so, it is true we won't have 104 weeks at the time of the initial filing. However, by the time we do have the approval, we will be close to having all that data on the patients, including recall many patients crossing over in the Phase 1 and 2 experience or receiving the drug in Phase 1 and 2. So we would think about a supplemental BLA fairly soon after the initial approval as we think about it right now.

John Leonard

And of course we'll be following those patients for 15 years. Lots of data to come over there.

David Lebwohl

Beyond the 104, yeah, but we'll have the 15 year follow up.

Operator

Jay Olsson, Oppenheimer.

Jay Olson

Oh hey, thanks for providing this update. I wanted to follow up on the commercialization of 2002. It sounds like you're planning on building out a commercial infrastructure in the US. I was wondering what your thoughts are for commercializing 2002 outside the US and whether or not that might be a partnership opportunity? Thank you.

John Leonard

Thanks for the question. We are focusing primarily on the US, and we want to make sure that that is well conceived and well carried out. We are thinking through our options for how we would extend outside the United States, and there's a variety of different approaches that we might pursue and a partnership option is one of those possibilities. But we haven't decided exactly how we're going to pursue that just yet.

Jay Olson

Great, thanks for taking the question.

Operator

Silvan Tuerkcan, Citizens JMP.

Silvan Tuerkcan

Thanks for taking my question. Just a quick question about, I guess, the upcoming quad AI presentation where you plan to show additional quality of life data in HAE. Can you just characterize a little bit like what we may see there and how that could help us understand your opportunity in HAE? Thank you.

John Leonard

David, do you want to speak (multiple speakers)

David Lebwohl

-- your details of the results yet. Please stand by and watch that presentation. As you can imagine, a therapy that is very easy to take from the beginning and then patients having no events after that, think about you being a patient is very favorable. So look forward to seeing those results.

Silvan Tuerkcan

Thank you.

Operator

Yanan Zhu, Wells Fargo Securities.

Yanan Zhu

Great. Thanks for taking our questions. Just wondering for the long-term ATTR data readout this year, what might be the incremental learnings to inform -- further inform product profile? Thank you.

John Leonard

Maybe I can address that. We would present essentially the results the categories of assays, etc. That you've already seen extended over on the order of a year or so. What does that mean? As David referenced in earlier comments, we're looking for a continued low rate of progression of the disease. I think it would be very interesting to see if any additional patients have approved, improved relative to where they were at baseline. I certainly wouldn't rule that out.
And we'll look for continued confirmation of what we think is a very low event rate and think through how that relates to our own Phase 3 trial. But bottom line, what we're seeing is the first clinical manifestations of what we think is a very low TTR level. And what that means for these patients. And thus far with the results that were published in the New England Journal and presented at AHA in November, those results are very exciting, and we think very important for these patients with severe cardiomyopathy.

Yanan Zhu

Great, thanks for the color.

Operator

Liisa Bayko, Evercore ISI.

Liisa Bayko

Hi, there. Thanks for taking the question. I'd love to just get a little bit more color on how you're thinking about the attack free rate in the context of your reduction in cal crime and how you -- how you're thinking about potentially trying to of all this number so it can be a little bit even greater number of patients who are attack free and Phase 3? Any color additional work you've done there and what's been the preliminary feedback I guess on the data as well at this point from the community physicians, etc? Thanks.

John Leonard

Maybe a general comment on [Calacrine] and its relationship to attacks. It's not strictly linear. There may be some patients that for just variability in the patient population reasons react a little bit differently. But what we do know is that as you go below 60% reduction, attack rates start to fall precipitously. And as you get to the very low levels that we've achieved, it's even beyond that.
Part of the challenge for observing these attacks are the consequences of a double blind study and medical treatment for patients who don't know if they receive drugs or not, act on any, let's say, twitch or early indication that they may or may not be having an attack, which is what the medical guide is for them to behave. So Smaller, shorter-term studies can be influenced by bad behavior, which again is appropriate medical therapy. We think that with extended observation, that will likely lessen.
I think that an important aspect from what we've seen in work already presented, particularly when we look at the Phase 1 results and add that to the phase 2 results, is the longer patients go, the more confident they are, and we see attack rates falling to very low levels. And I think there'll be an opportunity later this year to see how that plays out with the additional patients and the additional follow up that we've accumulated.

David Lebwohl

Just mentioning the Phase 3, difference in the Phase 3 is we do follow the patients for a longer period of time. Instead of the 16-week follow-up, the follow-up is between weeks 5 and 28. We also think we'll support, seeing a better result there.

Liisa Bayko

Thank you.

Operator

Myles Minter, William Blair.

Hey team, this is John on for Miles. Thanks so much for taking our question. I was just wondering if you could give us any updates on how stabilizer usage in the MAGNITUDE study is tracking compared to your original projections, which I believe were for around 50% usage in the study? Thanks.

John Leonard

Yeah, I think we had said it would be at least 50%, but David, you want to give some insight here.

David Lebwohl

What we are seeing is greater usage of families around the world, in particular, the UK has now supplied that to the patients there. We actually think this is actually going in a good direction in terms of our ultimate results, because what we think is important to show is that we can have a significant benefit over to formatuve, that hasn't been shown yet for any other agent. And that finding we think will be part of superior efficacy that we might see that would drive the usage of our drugs.

Helpful, thank you.

Operator

David Lebowitz, Citi.

David Lebowitz

Thank you very much for taking my question. This is a follow up from my earlier question. On HAE, there's a lot of talk about the possibility of a functional cure. I would imagine that that's not the bar ultimately that you see for success. What do you see as the bar for success?

John Leonard

Well, we think the functional cure aspect is the key driver for how patients are going to want to use this drug. But what we see in our market research, whether it's patients or physicians, is that patients are not looking for marginal improvements in the interval between using prophylaxis or on demeaning therapy that takes effect faster than existing therapy. That's -- that market is largely satisfied as what we can tell.
What patients are looking for is a completely new category of response, and that is, in fact, a functional cure basis. We think we will have many patients who are achieving functional care. In fact, what we've seen thus far is the a large majority of patients already have achieved that in early observation. So that I think will be a very important driver.
I would add that on the more routine measurements of attack rate reductions, we have data that is competitive with any other agent that's been presented. And as observation periods are extended, what we see is that attack rates for any of those patients thus far who have continued to have attacks, the attack rate is very low. So we think on any category of potential competition, we're in a really strong position.

David Lebowitz

Thank you so much for the answer.

Operator

Andy Chen, Wolf Research.

Hey, Brandon on for Andy. Another question from us on competition and rolling. So by our calculation, Helios be enrolled about 380 patients per year. You're planning to do 375 here as a follow-up therapy, which appears to be quite fast. It's -- is it reasonable to use the ratio between that 380 and 275 to determine doctor enthusiasm and patient enthusiasm for your TTR gene therapy? And Do you have any other hard quantitative metrics to show the magnitude of patient enthusiasm for your product compared to competition? Thank you.

John Leonard

Not unreasonable to use ratios like that, but at best that is a very blunt instrument in terms of determining how enrollment's going. I would start by just using the numbers we've provided. As I said earlier in the call, there's a very high likelihood that we will have in excess of those 550 patients. And we expect to be in a position where the study finishes well within the guidance that we've already given. So if there's reason to give additional updates as time goes on, we'll consider that. But I would not look for routine updates in terms of the numbers of patients that are coming into the study.

David Lebwohl

And just to mention what we're saying, there is a very high level of enthusiasm from the physicians, and we're hearing it coming through as well from their patients joining the trial. So we're excited about what we're seeing in the field.

Thank you.

Operator

Terence Flynn, Morgan Stanley.

Terence Flynn

Hi, thanks for taking the questions. I was just wondering on the [Regeneron] collaboration, just wondering if you can walk us through kind of the next milestones that we should anticipate here or when we could learn more about the profile. Thank you.

John Leonard

Just a couple of high-level comments. The regenerating collaboration with Nex-z is a 25% interest on their part and 75% interest on ours. That's been in place for some time now. There is a point where they'll need to make a determination whether or not they're going to opt in for a coke commercialization partnership and we look forward to seeing that decision and planning around that so. I don't know, Ed, if you think there's any other milestones that are important to mention at this point.

Edward Dulac

I think that's it. And just to double down on John's point, it's a co-promotion in the US that they have the right. The economics don't change. And so what's going to drive that is sort of the timeline to commercialization as we think about PN indication in particular. I think we've been very prudent in sort of providing guidance on timelines for that. But if you think about alternatives in terms of interim analysis or accelerated approval processes, that timeline could come in. So we're not necessarily terribly far away from that, but that next milestone for them to opt into a US code promote is an important one and that's on the horizon.

Operator

Salveen Richter, Goldman Sachs.

Hey, this is Mark on Salveen and thanks so much for taking our question. You guys briefly mentioned earlier that you, discontinued until like 3001 for a second-generation approach. I was wondering if you could talk more about that. Were there any signals you were seeing with the original 2001 that were unfavorable and any commentary on the second generation approach?

John Leonard

There was nothing on 3001 from a clinical point of view. We stopped just short of dosing a patient. The pre-clinical studies we've talked about in the past. We -- as we look at that area, we made a decision on how to pursue 3001 in the context of the prioritization and restructuring that we announced in January. And we think that the gene writer approach that we've described elsewhere has significant utility in the disease and at an appropriate time, we'll be in a position to talk about that.

Operator

This concludes the question-and-answer session and Intellia Therapeutics' fourth quarter and full year 2024 financial results conference call. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect your line.