Intellia Therapeutics, Inc. Price & Performance (NTLA)

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics' fourth quarter and full year twenty twenty four Earnings Call. Earlier this morning, Intelia issued a press release outlining the company's progress this quarter as well as topics for discussion on today's call. This release can be found on the Investors and Media section of Intellia's website at intelliatx.com Intellia. This call is being broadcast live and a replay will be archived on the company's web At this time, I would like to take a minute to remind listeners that during this call, Intelli management may make certain forward looking statements and ask that you refer to our SEC filings available at sec.gov for discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. Joining me from Intelliya are John Leonard, Chief Executive Officer David Lebewell, Chief Medical Officer Ed Dulak, Chief Financial Officer and Birgit Schulz, our Chief Scientific Officer, who will join for Q and A. John will begin with the recent business highlights. David will then provide a and Ed will review our financials before we open the call for questions.

With that, I will now turn the call over to John, our Chief Executive Officer.

Thank you, Britney. 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. Withdrawing support and interest from investigators and patients, we're making remarkable headway with enrollment across our late stage studies. We see significant promise with NTLA-two thousand and two the treatment of hereditary angioedema where we expect to complete enrollment in our Phase three study HALO in the second half of twenty twenty five. We are similarly encouraged by the pace of expect enrollment in magnitude or cardiomyopathy study to exceed five fifty 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 one trial of Nexeo previously known as NTLA-two thousand and one in patients with trancyretin or ATTR amyloidosis. The Phase one data offered compelling evidence that deep and persistently low levels of TTR reduction achieved with Nexi may favorably impact disease progression for people living with ATTR amyloid David will review these results in greater detail.

We are actively screening patients with ATTR amyloidosis with polyneuropathy in our Phase three magnitude two 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 fifty patients. We plan to measure MNIST plus seven at eighteen months and serum TTR levels as key endpoints in the study. We expect enrollment to be completed in 2026 enabling our second BLA filing by 2028. Last month, we announced the first patient had been dosed with NGLA-two thousand and two in HALO, our Phase three study in HAE. Enthusiasm for NTLA-two thousand and two from patients and our investigators is high and we believe this Phase three study will enroll rapidly enabling us to submit a BLA filing 2026. At the beginning of this year, we conducted a pipeline prioritization to focus our on these late stage and high value programs until 08/2002 and Nexi. We discontinued our work on NxStage 03/2001, favor of a second generation approach and will 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 three programs actively recruiting and one singular focus getting the work done to enable three launches between 2027 and 02/1930. 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 Pergett Schultz, our newly appointed Chief Scientific Officer.

She's an outstanding scientist with over twenty years of experience in drug development and biotechnology, including the clinical development of therapies and complex biologic products. She's experience 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 Leblau, who will provide an update on our clinical programs. David?

Thanks, John.

Begin with 02/2002 in developments for HAE. As John noted, we dosed the first patient with 02/2002 in our HALO Phase three study last month. As a reminder, the HALO study is a 60 patient global randomized double blind placebo controlled study. This is an exciting milestone for Intelia and the HAE community. See high interest for 02/2002, which we believe will drive rapid enrollment of our Phase three study and commercial uptake once approved. Based on the promising data we 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. Plan to present longer term data from the Phase onetwo study later this year including patients in the Phase two portion who initially received a twenty five milligram dose or placebo and were subsequently given the fifty milligram dose two thousand and two, selected for the Phase three study. [indiscernible] With HALO well underway, we believe 02/2002 is well positioned to be the first ever one time treatment for people living with HAE. 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 Nexi in development for the treatment of eight amyloidosis. Starting with ATTR amyloidosis with cardiomyopathy, enrollment in the pivotal Phase II magnitude study is progressing ahead of our target enrollment projections. And we expect cumulative enrollment to exceed five fifty total patients by year end. In November, we presented data from the Phase one study at the twenty twenty four 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 twelve, the mean serum TTR reduction was 90% from baseline. And the mean absolute residual serum TTR concentration was 17 micrograms per mL. All patients achieved deep and durable TTR reduction after a one time infusion. Notably, the TTR reduction occurred rapidly with the nadir reached at twenty eight days. When everyday matters, achieving TTR reduction as quickly as possible is crucial in this life threatening illness. With QTR silencers, the reported mean reduction was approximately which is not reached until six months after starting chronic treatment.

Now we have observed at the very low levels of circulating TTR seen with Nex Z are associated with disease stabilization or improvement across several markers of cardiac progression at month twelve compared to baseline. These favorable results were observed even though half of the patients met criteria for Class III heart failure. About thirty percent 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 twelve 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 one 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 three 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 one study. Across all thirty three patients, who received a dose of zero point three milligram per kilogram or higher, The mean serum TTR reduction was ninety one percent.

And the mean absolute residual serum TTR concentration was twenty micrograms per mL at month twelve.

We Consistent with the observations of ATTR Centimeters, 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. [indiscernible] Across NIS, MNIST Plus seven and 12 compared to baseline levels with further improvements noted in NIS and MDMI in the Part one patients for whom twenty four months of follow-up was available. Nexe has continued to demonstrate a favorable safety and tolerability profile. In recognition of the potential clinical importance of neck for the treatment of ATTR VPN the FDA granted Nexz 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 Centimeters ATTRVPN patients in the Phase one study later this year.

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 twenty twenty four. 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 cash equivalents and marketable securities were approximately $861,700,000.0 as of December 31, 2024.

Compared to $1,000,000,000 as of 12/31/2023. [indiscernible] Our collaboration revenue was $12,900,000 during the fourth quarter of twenty twenty four, compared to negative $1,900,000 during the fourth quarter of twenty twenty three a $14,800,000 increase was mainly driven by the Regeneron license and collaboration agreement R and D expenses $116,900,000 during the fourth quarter of twenty twenty four, compared to $109,000,000 during the fourth quarter of twenty twenty three. $7,900,000 increase was primarily driven by the advancement of our lead programs.

Stock based compensation included in R and D expense was $24,400,000 for the fourth quarter of twenty twenty four. [indiscernible] G and A expenses $32,400,000 during the fourth quarter of twenty twenty four, compared to $29,000,000 during the prior year quarter.

The $3,400,000 increase was primarily related to stock based compensation Box based compensation included in G and A expenses was $15,200,000 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 twenty twenty five, we expect to incur wind down costs associated with certain programs like NTLA 3,001 that have been discontinued or deprioritized. 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, support a successful commercial launch, of NTLA two thousand and two in HAE the company's capital needs to support multiple Phase three studies we'll begin to diminish during that year as some of these programs complete enrollment and supporting costs naturally wind down. We expect to occur approximately $8,000,000 in severance and other employee termination related costs.

Finally, we expect our cash balance to fund our operating plans into the first half of twenty twenty seven. Thanks, Ed. Conclusion, Intelia continues to deliver on the promise of gene editing 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 and A. The first question comes from Manny Bruhaut with SVB Securities. Please go ahead. I don't know about SCB Securities. But thanks for taking the call guys.

Can we have can you help us give us a little bit of an update on the tempo of OpEx decline over the course of this year [indiscernible] 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 just think more in terms of stabilization from clinical trial costs 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 would really help So Manny from Leerink, thank you. For the question. Obviously, I had made some comments about the rate of spend and how the restructuring addresses that, but maybe Ed you can give additional details what you think the trajectory of spend is going to be over the the coming years here? So I'll say a few things. Thanks for the question, Manny.

As we reported operating results this morning, operating expenses on a GAAP basis were up 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 [indiscernible] That evolution as you know 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 U. S. Infrastructure at least initially support the launch of NTLA-two thousand and two in The U. S. 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 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 the reality of what you described as the three Phase three studies that we have ongoing.

So those costs are well underway for magnitude or in cardiomyopathy. There are costs now associated with the HILO study for which we dosed the first patient. We still expect to dose the first patient in our third Phase three study, Magnitude two. You'll see some increase in costs that are offsetting benefits that will come with the restructuring. So two, we'll offset the cost of the restructuring will be the investment that we make in The U. S. For the commercial infrastructure that's required. As you get beyond 2025 though, we kind of hit steady state. We're fully enrolled in HALO at that point by 2026. We'll be well on our way within the magnitude two study and we'll be substantially on our way [indiscernible] and for which we'll get into 2027 costs will begin to naturally sunset and wind down for the HALO program then magnitude two 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 twenty twenty seven where our OpEx 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 NTLA-two thousand and two and HAE. That's very helpful.

Thanks for taking the question. I know you guys have a lot of other Zoom line as well.

The next question comes from Maury Raycroft with Jefferies.

Please go ahead.

Hi, good morning. Thanks for taking my question. For Nexi or 02/2001, what's the latest regarding your assumptions on Phase three events accrual rate based on longer term data that you have? And are you saying more on what would enable the interim analysis for the MEGT-three study at this point? 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 Yes.

So this study is as you know, 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, Achoramidis and Vutrisiran. So now there is a lot data available on events rates in this disease. The management of disease has not changed significant that trial of those trials 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, We have said is what we've seen in our trial is from the Phase one 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 TTR 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 we will be seeing the evolution of the events in our magnitude trial based on that, we will be able to, in the future, give more better estimates about the Intellia. But there is a based on what we're seeing a good probable a good possibility that we could see favorable findings at the Intellia analysis that would allow us to stop the program earlier.

So we will, but there will be more details about this from us as time goes on. Got it. That's helpful. Thanks, Georgina.

Question. The next question comes from Luca Issey with RBC.

Please go ahead.

Great. Thanks so much for taking our question. This is Lisa on for Luca. We saw earlier this week that Anilum is moving forward with the next generation TTR silencer. And they're proceeding with a pivotal trial design, which is about two times the size of their HELIOS B trial. So we're just curious if this larger trial size has 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.

Thanks, Lisa. Maybe I can make a couple of comments and David if you see fit to add. [indiscernible] We always look at data and we always look at what the competition is doing and think about that very careful. The program that we're carrying out, any information that we can gather that helps us think more clearly and accurately about 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 aldilumab 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 on top of TAF, 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 tafamidis will only increase over time. And so there will 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 [indiscernible] 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 one patient population that influences how we think about adjust doing.

I just mentioned one observation about the Onileum announcement. Is that you see that they are talking more and more about how important it is to get to lower levels of TTR. Actually used slides very close to our slides showing that as in 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 a sense that they are now agreeing with the hypothesis hypothesis that we have about lowering FTR.

The next question comes from Kostas Beluris with BMO Capital Markets. Please go ahead.

Hi, this is Yuri on for Kasimov. Congrats on the progress and thanks for taking our question. So we have another question on the recurrence around. Can you provide your thoughts on the potential competition Nucresiran and ATTR centimeters that has Q6 m dosing, strong TTR knockdown and can launch around the same time Were you asking about INVUTRA? Yes.

I'm sorry, it was a little unclear.

Well, I don't know if it will launch around the same time. We'll see how that all plays out. Clearly, people are trying to move very, 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 VENVUTRA, which is what we expect to be in the market sooner, We're talking about levels that are about a third with Nexi that compared to what's been reported for VUTRAC. So we'll see how it plays out with the the follow on compound for Alnylam, 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. Expect that we will meet our objectives and look forward to bringing it to the product to the market. The next question comes from Gena Wang with Barclays.

Please go ahead.

Thank you. What makes you feel confident to pick five fifty patient number by year end for the enrollment regarding the ATTR cardiomyopathy trial. Does that mean you will your trial enrollment in first half twenty six? The total seven sixty five patients.

Tina, 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 five fifty 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 site 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 Amphutra data or as we get additional exposure to our own event rates, we are confident that we will fall within that timeframe. But meanwhile, you can count on those five fifty 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 and doing very well.

The next question comes from Joseph Tumme with TD Hi there. Good morning and thank you for taking my question.

Maybe just one on sort of the commercial approach here. We've seen some gene therapies enter the market for chronic conditions where there's a established standard of care and some of those had some issues with reimbursement and leading the companies even discontinue it, Pfizer did with their HUZY with 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 HE where there is that a 7% of care you'll be commercially viable?

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 that you mentioned. I just remind you and the other listeners that when we think about dosing patients with our drug, there is a very straightforward treatment regimen that consists of a single dose of dexamethasone the day before therapy patients come in, get another dose of dexamethasone, some antihistamines, a two to four hour infusion, That is the regiment. Extended steroids, biological product handling, etcetera, 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 for 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, very well 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 patients themselves, but to the physicians and the payers. And so we look forward to talking more about that as the year goes The next question comes from Alec Stranahan with Bank of America. Please go ahead.

Hey, guys. This is Matthew on for Alex. Thanks for taking our question.

Maybe a quick one from us.

On the HAE Phase onetwo follow ups. Looking at sort of the incomplete responders, any color on how these patients expecting or hoping to see the next update in 2025?

Thanks for the question. I'll start with topic sentence or two and then David can fill in some of the details. But I would just point out that the nomenclature used 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 sixteen week observation period for Phase two had a response that we've 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 two study twenty five milligram dose, the opportunity to be redosed at the Phase three dose of fifty milligrams and we'll be in a position to report on those patients and the extended follow-up of the other patients from the Phase two group.

Both for the duration of those patients who have already achieved a functional cure and those patients who who had not yet achieved that one hundred and week observation period.

Would point out in our Phase one work, we've seen that patients mature in terms of the response over time. And we expect [indiscernible] David, if you want to provide any other color or any other Yes, 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 Jon 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 a what we've been seeing and we will talk to you more about that in these patients from the Phase two later this year. Thanks.

The next question comes from Brian Cheng with JPMorgan. Please go ahead.

Thanks for taking our questions this morning.

Maybe going back to H. J. Yi, how should we think through the gaining factor as you get ready for the BLA filing outside of the clinical package that we're waiting for from HALO, what are some of the other items that you need to align between now and then?

Maybe In 2026, I can say next year now, it's becoming quite close and obviously based on some of the earlier questions thinking about the market and being prepared for that. But in terms of the product, it's [indiscernible] Obviously, that will consist of the preclinical package, which is done It has the continued observation of our Phase one and Phase two patient population and then the Phase three data that will come from the Phase from the HALO study. 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 three trial. So some of those things that can take place where some companies try to bridge to the commercial that work is done. And where 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 a 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 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. The next question comes from Rick with Cantor Fitzgerald. Please go ahead. Hey, good morning and thanks for taking the question. I wanted to follow-up on Ed's comments around the marketing build out for 02/2002 and the associated cost Could you comment on how big of a sales force you anticipate needing to launch 02/2002 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 2020 just wanted to confirm, you don't anticipate significant spend here in 2026?

Yes. 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.

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.

We have very clear plans in twenty twenty five 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 hire. So we have more senior leadership coming on board in 2025. As we get into 2026 with the BLA filing, we're sort of that T minus 24 or T minus twelve months and in. And so we're thinking about hiring additional marketing and sales force 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 clear two year plan on the expertise we need, hiring plan to achieve that such that we're ready for launch in 2027.

The next question comes from William Pickering with Bernstein.

Please go ahead. Hi. Thank you for taking the question. Also on HAE.

You've 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've been treated. So it sounds like the data you collect in the long term observation portion of the Phase three could be pretty important to demonstrating functional cure and I think that would 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 and four weeks or could you do it sooner if it's clearly apparent that all the attacks have stopped?

David, can you outline how we think of long term follow-up and what shared with the FDA when Yes.

So, it is true we won't have one hundred and four weeks at the time of the initial borrowing. 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 one and two experience or receiving the drug in Phase one and two. So we would think about it as supplemental being a BLA fairly soon after the initial approval we think about it right now.

And of course, we'll be following those patients [indiscernible] Beyond the 104, yes, we'll have the the fifteen year follow-up.

The next question comes from Jay Olson with Oppenheimer.

Please go ahead.

Hey, thanks for providing this update. I wanted to follow-up on the commercialization of 02/2002. It sounds like you're planning on building out a commercial infrastructure in The U. S. I was wondering what your thoughts are for commercializing 02/2002 out Thanks for the question. We are focusing S. 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.

Great. Thanks for taking the question. The next question comes from Sylvan Turkan with Citizens JMP.

Please go ahead.

Thanks for taking my question. Just a quick Question about I guess, the upcoming Squared AI presentation where you plan to show it additional quality of life data in HAE. Can you just characterize a little bit what we may see there and how that could help us understand your opportunity in SG and A? Thank you. David, do you want to speak If we haven't yet, we haven't really shared details of 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 look forward to you seeing those results.

Thank you.

The next question comes from Yan Anju with Wells Fargo Securities. Please go ahead.

Great. Thanks for taking our questions.

Just wondering for the long term ATTR data readout, this year, what might be the incremental learnings [indiscernible] [indiscernible] Maybe I can address that. We would present essentially the the categories of assays, etcetera, that you've already seen extended over on the order of a year or so. What does that mean? As David referenced in earlier We're looking for a continued low rate of progression of the disease I think it will be very interesting to see if any additional patients have approved improved relative to where they were at baseline. 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 III trial. But bottom line, what we're seeing is the first clinical manifestations of what we think is a very, very low TTR level and what that means for these patients. And thus far with the results that were published at the New England in the New England Journal and presented in November, those results are very, very exciting and we think very, very Import for these patients with severe cardiomyopathy Great. Thanks for the color.

The next question comes from Lee Please go ahead.

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 CaliCran and how you you're thinking about potentially trying to evolve this number, so it can be a little bit even greater number of patients who are attack free in Phase three. Any color or additional work you've done there? And been the preliminary feedback, I guess, on the data as well, at this point from the community physicians, etcetera? Thanks.

Maybe a general comment on Caltrain 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.

So 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 drug 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 medical types is for them to behave. So you know Smaller, shorter term studies can be influenced by that behavior, which again is appropriate medical therapy. We think that with extended observation that I 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 one results and add that to the Phase two results is the longer patients go, the more confident they are and we see attack rates falling to very, very low levels. And I think there'll be an opportunity later this year to see how that plays out with additional patients and the additional follow-up that we've accumulated Just as you mentioning the Phase three, one difference in the Phase three is we do file the patients for a longer period of time. Instead of the sixteen week follow-up, the follow-up is between weeks five and twenty eight.

We also think will support seeing a better result there.

Thank you. The next question comes from Myles Minter with William Blair. Please go ahead. Hey, team. This is John on for Myles. 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? Yes.

I think we had said it would be at least 50%, but David want to take some insights? Yes. 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 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 tafamidis. 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 drug. The next question comes from David Lebowitz with Citi.

Please go ahead.

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

Well, we think the functional cure aspect is the key driver for how patients are going to want to use this drug. What 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 demand therapy that takes effect faster than existing therapy. That's That market is largely satisfied as what we can tell with what patients are looking for is a completely new category response and that is in fact the functional care based We think we will have many patients who are achieving functional care. In fact, what we've seen thus far is large majority of patients already have achieved that early observation. So that I think will be a very, 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 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, very low. So we think on any category of potential competition, we're in really strong position.

Thank you so much for the answer. $75,000,000 to the Chinese The next question comes from Andy Chen with Wolfe Research.

Please go ahead. Hey, Brandon on for Andy.

Another question from us on competition and rolling. So by our calculation, Helios B enrolled about three eighty patients per year. And you're planning to do three seventy five here as a follow-up therapy, which appears to be quite fast. Is it reasonable to use the ratio of and two seventy five to determine doctor enthusiasm and 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.

Not unreasonable to use ratios like that, but at best that is a very, very blunt instrument in terms of determining how enrollment is going. Would start by just using the numbers we've provided There's a, as I said earlier in call, there's a very, very high likelihood that we will have in excess of those five fifty 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.

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.

The next question comes from Terence Flynn with Morgan Stanley. Please go ahead.

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 Just a couple of high level comments. The Regeneron collaboration with [indiscernible] is a 25% interest on their part and 75% interest on ours. That's been in place for some time now. [indiscernible] point where they'll need to make a determination whether or not 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.

I think that's it. And just to double down on John's point, it's a co promotion in The U. S. That they have the right 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 time lines for that. But as we think about alternatives in terms of Intellia analysis or accelerated approval processes, timeline could come in. So we're not necessarily terribly far away from that. But that next milestone for them to opt into a U. S. Co promote is an important one on the horizon. The next question comes from Salveen Richter with Goldman Sachs.

Please go ahead.

Hey, this is Mark on for Selby and thanks so much for taking our question.

You guys briefly mentioned earlier that you discontinued NTA-three thousand and one for a second generation Roche. I was wondering if you could talk more about that. Were there any signals you were seeing with original 2,001 that were unfavorable and any commentary on the second generation Roche?

There was nothing on 3,001 from a clinical point of view. We stopped to short of dosing a patient. The preclinical studies we've talked about in the past We as we look at that area, we made a decision on how to pursue 3,001 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 also [indiscernible] has significant utility in the disease and at an appropriate time we'll be in a position to talk about them.

This concludes the question and answer session. And as Teletherapeutics' fourth quarter and full year twenty twenty four Financial Results Conference Call.

The conference has now concluded.