Q4 2024 Intellia Therapeutics Inc Earnings Call
Drew: Good morning and welcome to Intellia Therapeutics' fourth quarter and full year 2024 financial results conference call. My name is Drew and I will be your conference operator today.
Drew: Following formal remarks, we will open the call up for a question and answer session. This conference is being recorded at the company's request and will be available on the company's website following the end of the call. As a reminder, all participants are currently in listen-only mode.
Drew: If anyone requires operator assistance during the conference, please press star zero on your telephone keypad. I will now turn the conference over to Brittany Chavez, Manager of Investor Relations at Intelia. Please proceed.
Brittany Chavez: Thank you, operator, and good morning everyone. Welcome to Intelia Therapeutics' fourth quarter and full year 2024 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.
Brittany Chavez: This release can be found on the Investors & Media section of Intelia's website at inteliatx.com.
Brittany Chavez: This call is being broadcast live and a replay will be archived on the company's website.
Brittany Chavez: At this time, I would like to take a minute to remind listeners that during this call, Intelligent 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.
Brittany Chavez: All information presented on this call is current as of today, and Intelia undertakes no duty to update this information unless required by law.
Speaker Change: Joining me from Intelia are John Leonard, Chief Executive Officer, David Lebwohl, Chief Medical Officer, Ed Dulac, Chief Financial Officer, and Birgit Schultz, our Chief Scientific Officer, who will join for Q&A.
Speaker Change: John will begin with recent business highlights, David will then provide updates on our clinical pipeline progress, 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.
Speaker Change: Thank you, Brittany. Good morning, everyone, and thank you all for joining us today.
Speaker Change: We're off to a strong start in 2025 with renewed focus on our operational execution.
Speaker Change: With growing support and interest from investigators and patients, we're making remarkable headway with enrollment across our late-stage studies.
Speaker Change: We see significant promise with NTLA-2002 for the treatment of hereditary angioedema, where we expect a complete enrollment in our Phase III study, HALO, in the second half of 2025.
Speaker Change: We are similarly encouraged by the pace of enrollment with our Phase 3 studies for trans-diuretin amyloidosis and expect enrollment in magnitude, our cardiomyopathy study, to exceed 550 total patients by year-end.
Speaker Change: 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.
Speaker Change: In November, we presented positive extended follow-up data from patients in the ongoing phase 1 trial of NEXE, previously known as NTLA-2001, in patients with transthyretin or ATTR amyloidosis.
Speaker Change: The Phase 1 data offered compelling evidence that deep and persistently low levels of TTR reduction achieved with NEXE may favorably impact disease progression for people living with ATTR amyloidosis.
David will review these results in greater detail.
Speaker Change: 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.
Speaker Change: As you may recall, this pivotal trial is an efficient study with expected enrollment of 50 patients. We plan to measure MNIST plus 7 at 18 months and serum TTR levels as key endpoints in the study.
Speaker Change: We expect enrollment to be completed in 2026, enabling our second BLA filing by 2028.
Speaker Change: Last month, we announced the first patient had been dosed with NTLA-2002 in HALO, our phase 3 study in HAE.
Speaker Change: 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.
Speaker Change: 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 until A2002 and next year.
Speaker Change: We discontinued our work on NGLA 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.
Speaker Change: As we look ahead to the rest of the year, we are well positioned for near-term value creation.
Speaker Change: We have three Phase III 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.
Speaker Change: So we look forward to sharing data from both of our programs later this year.
Speaker Change: Lastly, I would like to take this time to welcome Birgit Schultz, our newly appointed Chief Scientific Officer.
Speaker Change: She's an outstanding scientist with over 20 years of experience in drug development and biotechnology, including the clinical development of self-therapies and complex biologic products.
Speaker Change: She has experience with our entire suite of gene editing technologies and is leading our more concentrated in vivo and ex vivo research efforts.
Speaker Change: I'll now hand the call over to our Chief Medical Officer, David Lebwohl, who will provide an update on our clinical programs.
David?
Speaker Change: Thanks, John. I'll begin with 2002 in development for HAE. As John noted, we dosed the first patient with 2002 in our HALO phase 3 study last month.
Speaker Change: As a reminder, the HALO study is a 60-patient, global, randomized, double-blind, placebo-controlled study.
Speaker Change: This is an exciting milestone for Intelia and the HAE community.
Speaker Change: We see high interest for 2002, which we believe will drive rapid enrollment of our Phase III study and commercial uptake once approved.
Speaker Change: 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.
Speaker Change: We plan to present longer-term data from the Phase I-II study later this year, including patients in the Phase II portion who initially received a 25 mg dose or placebo and were subsequently given the 50 mg dose of 2002 selected for the Phase III study.
Speaker Change: With HALO well underway, we believe 2002 is well positioned to be the first ever one-time treatment for people living with HAE.
Speaker Change: The therapy is administered with a simple infusion and no need for extended steroids or other preparative drugs.
Speaker Change: This transformative therapy would also be the first approved using in vivo CRISPR gene editing.
Speaker Change: Let's move on to NXVI and development for the treatment of ATTR amyloidosis.
Speaker Change: Starting with ATTR amyloidosis with cardiomyopathy, enrollment in the pivotal phase through magnitude study is progressing ahead of our target enrollment projections.
Speaker Change: And we expect cumulative enrollment to exceed 550 total patients by year end.
Speaker Change: In November, we presented data from the Phase I study at the 2024 American Heart Association Scientific Sessions and published the findings in the New England Journal of Medicine.
Speaker Change: 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.
Speaker Change: At month 12, the mean serum TTR reduction was 90% from baseline, and the mean absolute residual serum TTR concentration was 17 micrograms per ml.
Speaker Change: All patients achieved deep and durable TTR reduction after a one-time infusion.
Speaker Change: Notably, the TPR reduction occurred rapidly, with the NADER reached at 28 days.
Speaker Change: When every day matters, achieving PTR reduction as quickly as possible is crucial in this life-threatening illness.
Speaker Change: With KTR silencers, the reported mean reduction was approximately 80%, which is not reached until six months after starting chronic treatment.
Speaker Change: Now, we have observed that 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 12 compared to baseline.
Speaker Change: 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.
Speaker Change: This is a significant insight because when patients are untreated, disease progression as measured by these markers is typically evident within 12 months.
Speaker Change: 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 I study, despite the advanced patient population treated with NEX-Z.
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: At last November's Investor event, we presented data from the Phase I study.
Speaker Change: Across all 33 patients who received a dose of 0.3 mg per kilogram or higher, the mean serum TTR reduction was 91%.
Speaker Change: And the mean absolute residual serum TTR concentration was 20 micrograms per ml at month 12.
Speaker Change: 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 this.
Speaker Change: MNIST Plus 7 and MDMI, they were favorable trends of clinical benefit at month 12 compared to baseline levels with further improvements noted in this and MDMI in the part 1 patients for whom 24 months of follow-up was available.
Speaker Change: Nexi has continued to demonstrate a favorable safety and tolerability profile.
Speaker Change: 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.
Speaker Change: This will enable closer collaboration with the FDA as we approach a BLA filing in 2028.
Speaker Change: We look forward to presenting longer-term data from both ATTR-CM and ATTR-VPN patients in the Phase I study later this year.
Speaker Change: The data will include updated measures of clinical efficacy and safety.
Speaker Change: 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.
Speaker Change: 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.
Thank you, David. Good morning, everyone.
Speaker Change: Intellia continues to maintain a solid balance sheet that allows us to execute on our pipeline and platform.
Speaker Change: Our cash, cash equivalents, and marketable securities were approximately $861.7 million as of December 31st, 2024, compared to $1 billion as of December 31st, 2023.
Speaker Change: 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.
Speaker Change: The $14.8 million increase was mainly driven by the Regeneron License and Collaboration Agreement.
Speaker Change: R&D expenses were $116.9 million during the fourth quarter of 2024, compared to $109 million during the fourth quarter of 2023.
Speaker Change: The $7.9 million increase was primarily driven by the advancement of our LEAD programs.
Speaker Change: Stock-based compensation included in R&D expense was $24.4 million for the fourth quarter of 2024.
Speaker Change: 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 increase was primarily related to stock-based compensation.
Speaker Change: The box-based compensation included in G&A expenses was $15.2 million for the fourth quarter.
Speaker Change: As we turn our focus to the future, I want to share a few thoughts regarding the restructuring we announced on January 9th and how this changes the complexion of our GAP operating expenses.
in the first quarter of 2025.
Speaker Change: We expect to incur wind-down costs associated with certain programs, like NTLA 3001, that have been discontinued or deprioritized.
Speaker Change: 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 percent.
Speaker Change: 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.
Speaker Change: While we anticipate greater sales and marketing investments in 2027 to support a successful commercial launch of NTLA, 2002, and HAE,
Speaker Change: The company's capital needs to support multiple Phase III studies will begin to diminish during that year as some of these programs' complete enrollment and supporting costs naturally wind down.
Speaker Change: We expect to incur approximately $8 million in severance and other employee termination-related costs.
Speaker Change: Finally, we expect our cash balance to fund our operating plans into the first half of 2027.
Speaker Change: Thanks, Ed. In conclusion, Intelia 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.
Speaker Change: 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
We will now begin the question and answer session.
Speaker Change: To ask a question, you may press star then 1 on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys.
Speaker Change: To withdraw your question, please press star then 2. Again, please limit yourself to one question. At this time, we will pause momentarily to assemble our roster.
The first question comes from Mani Foroohar with SVB Securities.
Please go ahead.
Mani Foroohar: Well, I don't know about SCB Securities, but thanks for taking the call, guys.
Speaker Change: Can we have, can you help give us a little bit of an update on...
Mani Foroohar: the tempo of OPEC's decline over the course of this year.
Mani Foroohar: 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 from investors around OPEX ramps as you have large pivotal studies growing.
Speaker Change: 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?
Speaker Change: are on 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 would be really helpful.
So, Mani from Littering, thank you.
for the question.
Speaker Change: Yeah, obviously I'd made some comments about the rate of spend and how the...
Speaker Change: organization. That evolution, as you know, is expected to continue, so we are committed to fully investing in the clinical programs that we have.
Speaker Change: 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, to support the launch of NTLA-2002 in the U.S.
Speaker Change: 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.
Speaker Change: The first quarter will be a little bit noisy. Having announced this in January 9th, 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.
Speaker Change: What makes this dynamic and complicated to be overly prescriptive at this point is the reality of what you described as the three phase three studies that we have ongoing. So those costs are well underway for magnitude and cardiomyopathy.
Speaker Change: There are costs now associated with the HILO study, for which we dosed the first patient, and we still expect to dose the first patient in our third phase 3 study magnitude 2.
Speaker Change: So, you'll see some increase in cost that are offsetting the benefits that will come with the restructuring. So, too, 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.
Speaker Change: 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 II study and we'll be substantially on our way with Magnitude. So we kind of hit steady state in 2026.
Speaker Change: and for which we'll get into 2027, costs will begin to naturally sunset and wind down for the HALO program.
Speaker Change: then magnitude 2, and then ultimately magnitude. So I think it's important just to take a step back.
Speaker Change: 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.
Speaker Change: And it's hard for me to see a scenario in 2025, 2026, or at least through the first part of 2027, where our OPT-X is at the level of what we've seen this past year in 2024. So I do think peak operating expenses are behind us.
Speaker Change: The only thing we'll have to assess closer to the launch will be what incremental investments we need to support NTLA-2002 and HAE.
Speaker Change: That's really helpful. Thanks for taking the question. I know you guys have a lot of other people online as well.
Speaker Change: The next question comes from Maury Raycroft with Jeffreys. Please go ahead.
Maury Raycroft: Hi, good morning. Thanks for taking my question. For NEXE or 2001, what's the latest regarding your assumptions on phase 3 events or cruel raid 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?
Maybe, David, you can address...
Maury Raycroft: how we're thinking about the event rates for the magnitude study and layout some of our initial thinking for
the interim analysis.
Yeah. Or me. Or me. Yeah. Yeah. Yeah.
Yeah, so this study is...
Speaker Change: As you know, enrolling at a very good rate. We're ahead of what our projections were.
Maury Raycroft: and the evolution of events we expect to be similar to the other recent studies acaraminas and verticillin. So now there is a lot of data available on events rates in this disease.
Maury Raycroft: The management of disease has not changed significantly from the time of that of that trial of those trials so that's that's what we're expecting. We haven't said exactly what that is publicly but you could see it from from the historical data.
In terms of the interim analysis,
Maury Raycroft: from the Phase I 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.
Maury Raycroft: 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.
Maury Raycroft: So based on that, we are obviously going to follow up this data carefully this year.
Maury Raycroft: We'll be seeing the evolution of the events in our magnitude trial.
Maury Raycroft: 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.
Maury Raycroft: There will be more details about this from us as time goes on.
Got it. That's helpful. Thanks for taking my question.
Luca Isi: The next question comes from Luca Isi with RBC. Please go ahead.
Speaker Change: Oh, great. Thanks so much for taking our question. This is Lisa on Toluca.
Speaker Change: 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.
Speaker Change: Thanks Lisa. Maybe I can make a couple of comments and David if you see fit to add be my guest.
Thank you very much. Thank you.
Speaker Change: 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.
Speaker Change: We do see important differences, however, and, you know, David has touched on
Speaker Change: how we're using some of the clinical data that we've accumulated already in observations that come from patients who have been treated with with our own drug.
Speaker Change: I think for details in terms of how LLM is approaching their work, I would encourage you to ask them.
Speaker Change: However, I imagine that one of the considerations will be, you know, they're looking to achieve an effect 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.
Speaker Change: We think we'll be in a really strong position with respect to that category of patients.
Speaker Change: And also, my guess would be that the proportion of patients who are taking tefamidus 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.
Speaker Change: 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,
Speaker Change: As we continue to look at event rates as they occur in our own phase one patient population, that influences how we think about adjusting, if at all, the trial that we're doing.
Speaker Change: I just want to mention one observation about the on-island announcement is that you see that they are talking more and more about how important it is to get to lower levels of TPR.
Speaker Change: And that was, actually these slides are very close to our slides, showing that as in A. al.
Speaker Change: 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.
Speaker Change: So this is good to see in a sense that they are now agreeing with the hypothesis that we have about lowering of GTR.
Speaker Change: The next question comes from Costas Belouris with BMO Capital Markets. Please go ahead.
Costas Belouris: Hi, this is Yuri Onferkasas. Congrats on the progress and thanks for taking our question. So, we have another question on the grass around. Can you provide your thoughts on the potential competition?
Speaker Change: from Newcrestone and APPR-CM that has Q6M dosing, strong PPR knockdown and can launch around the same time as NEG-Z. Thank you.
Speaker Change: Were you asking about Amvutra? The next chapter. Yeah, I'm sorry, it was a little unclear.
Speaker Change: 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, very quickly to get, you know, improved therapies to the market.
Speaker Change: Our basic perspective, I think, was captured by David, which is, you know, this is all about
reading
Speaker Change: We've been able to get 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.
Speaker Change: presented not just percentage reduction but the absolute levels of TTR which I think
is the more meaningful measure.
Speaker Change: Just with respect to VUTRA, which you know is what we expect to be in the market sooner, we're talking about levels that are about a third with DEXE compared to what's been reported for VUTRA.
Speaker Change: So we'll see how it plays out with the follow-on compound for L-Nylum.
but you know we think that certainly a one-and-done therapy
that allows physicians and patients being treated by them.
Speaker Change: 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.
Speaker Change: And I would point out that when it comes to pricing of these drugs, access to insurance,
Speaker Change: The authorization procedures that are necessary to have year-on-year dosing, we think will be in an advantageous position. So, we like where we are, and as you heard from David, the study is progressing well.
Speaker Change: I expect that we will meet our objectives and look forward to bringing the product to the market.
Speaker Change: The next question comes from Gena Wang with Barclays. Please go ahead.
Thank you. What makes you feel confident to pick?
Speaker Change: Thanks for the question. You know us well. We under-promise and over-deliver. 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.
Speaker Change: When I say 550 patients by the end of the year, you can count on that being a very highly likely outcome.
Speaker Change: 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.
Speaker Change: I see the enrollment rates and you know we're not going to give patient by patient updates but it's rolling robustly and doing very well.
Speaker Change: The next question comes from Joseph Thome with TD Cowan. Please go ahead.
Joseph Thome: 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, you know, enter the market for
Joseph Thome: chronic conditions where there's a established standard of care and you know some of those had some some issues with reimbursement and Leading the companies even discontinue it. Pfizer did with their Hinkley be gene therapy last week I guess what can you do now to kind of make sure that the reimbursement is
Joseph Thome: 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 partially viable. Thank you.
Joseph Thome: Well, it's an important question and when we think about, I would start by pointing out that we don't think gene therapy
Speaker Change: Certainly, the application of AAV to supply missing genetic function is the relevant comparator.
Speaker Change: Gene editing, which is a really readily straightforward application procedure, is something quite different from the compounds that you mentioned.
Speaker Change: I just remind you and the other listeners that when we think about dosing patients with our drug.
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: And in the case of HAE, remember what we've presented thus far.
Speaker Change: an entirely new category of response for these patients. We're talking about following a single application.
Speaker Change: 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 you're looking for.
Speaker Change: So, I think a good proxy for how the drug will be received in the marketplace.
will be the enrollment for the study.
Speaker Change: And I can report at this time that, well, we've certainly talked about dosing our first patient.
Speaker Change: We have patients waiting at multiple clinical trial sites. So we expect this to go very, very well. And I think that's an indication of patient response.
Speaker Change: 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 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 on.
Great, thank you very much.
Alex Ranahan: The next question comes from Alex Ranahan with Bank of America. Please go ahead.
Alex Ranahan: Hey guys, this is Matthew on for Alec. Thanks for taking our question. Maybe a quick one from us on the HAE Phase 1-2 follow-ups.
Alex Ranahan: 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?
Speaker Change: 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.
David Lebwohl: Every single patient has responded and every single patient is better off than the patient was before they came into the trial.
David Lebwohl: Most of the patients that we reported in that short 16-week observation period for phase 2 had a response that we have been terming a functional cure. That is, they've been able to abandon their therapy and they have no ongoing attacks.
David Lebwohl: 25 milligram dose the opportunity to be redosed at the phase 3 dose of 50 milligrams
David Lebwohl: and we'll be in a position to report on those patients and the extended follow-up.
David Lebwohl: of the other patients from the phase two group, both for the duration of those patients who have already achieved a functional cure.
David Lebwohl: and those patients who had not yet achieved that during the 16-week observation period.
David Lebwohl: I would point out that in our Phase I work, we've seen that patients mature in terms of their response over time.
David Lebwohl: And we expect that to be occurring as well for the patients in the Phase II site.
David Lebwohl: I don't know, David, if you want to provide any other color as any other. Yeah, that's the most important thing. You know, 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.
David Lebwohl: 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 in a patient from the phase two later this year.
Thanks.
Speaker Change: The next question comes from Brian Cheng with J.P. Morgan. Please go ahead.
Thanks for taking our questions this morning.
Speaker Change: Maybe going back to HAE, how should we think through the gating factor as we get ready for the BLE filing? Outside of the clinical package that we're waiting for from HALO, what are some of the other important items that you need to align between now and then? Thank you.
Speaker Change: Maybe I'll say a few words and then David you could add just in terms of being in a position to file the BLA as I mean we've said that our objective is to file a BLA
Speaker Change: 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.
Speaker Change: But in terms of the product itself and the filing that we're putting in place,
Speaker Change: Obviously that will consist of the preclinical 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
Speaker Change: will come from the phase from the HALO study which will be reporting out in the first part of next year as that study completes.
Speaker Change: 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
Speaker Change: Some companies try to bridge to the commercial product. That work is done.
Speaker Change: And we think we're going to be in a really good position to move very quickly.
Speaker Change: With the FDA, we've been using that designation to our advantage.
Speaker Change: And we expect that that will be very meaningful as the review ensues. 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 DLA.
Speaker Change: The next question comes from Rick Bienkowski with Cancer Fitzgerald. Please go ahead.
Rick Bienkowski: Hey, good morning, and thanks for taking the question. I wanted to follow up on Ed's comments around the marketing buildout for 2002 and the associated costs.
Rick Bienkowski: Can 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?
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: The investment in this broader commercial consideration started already in 2024, we've brought in senior leadership.
Speaker Change: 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 hire. So we have more senior leadership coming on board in 2025.
Speaker Change: As we get into 2026 with the BLA filing, we're sort of at T-24.
Speaker Change: or T-12 months and in, and so we'll think 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 very clear two-year plan on the expertise we need, the hiring plan to achieve that, such that we're ready for launch in 2027.
Speaker Change: The next question comes from William Pickering with Bernstein. Please go ahead.
Hi, thank you for taking the question also on HAE.
William Pickering: 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 3 could be pretty important to demonstrating functional cure, and I think that would be collected after you submit the original BLA.
Speaker Change: 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.
Speaker Change: 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.
David Lebwohl: 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 I and II experience or receiving the drug in Phase I and II.
David Lebwohl: So we would think about a supplemental BLA fairly soon after the initial approval as we think about it right now.
David Lebwohl: And, of course, we'll be following these patients for 15 years, so there'll be lots of data to come. Beyond the 104, yeah, we'll have the 15-year follow-up.
Speaker Change: The next question comes from Jay Olson with Oppenheimer. Please go ahead.
Jay Olson: Well, 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 U.S. I was wondering what your thoughts are for commercializing 2002 outside the U.S. and whether or not that might be a partnership opportunity. Thank you.
Jay Olson: Thanks for the question. We are focusing primarily on the U.S. and we want to make sure that that is
well-conceived and well-carried-out.
Jay Olson: We are thinking through our options for how we would extend outside the United States and there is a variety of different approaches that we might pursue and
Jay Olson: You know, 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.
Speaker Change: The next question comes from Silvan Tuerkcan with Citizens JMP. Please go ahead.
Thanks for taking my question.
Silvan Tuerkcan: Just a quick question about, I guess, the upcoming SQuAD AI presentation, where you plan to show additional quality-of-life data in HAE. Can you just characterize a little bit, like, what's going to happen in the future?
Speaker Change: what we may see there and how that, you know, could help us understand, you know, your opportunity. Thank you.
Speaker Change: David, do you want to speak? We haven't really shared details of the results yet.
Speaker Change: 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 your being a patient, is very favorable. So look forward to your seeing those results.
Thank you.
Speaker Change: The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.
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 further inform product profile? Thank you.
Maybe I can address that.
Yanan Zhu: 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,
Yanan Zhu: How youre thinking about potentially trying to hit.
Yanan Zhu: Above this number so it can be a little bit even greater number of patients were attack free in phase III any color on what additional work you've done there and what's been the preliminary feedback I guess on the data as well.
Yanan Zhu: At this point from kind of the community physicians et cetera.
Yanan Zhu: Maybe a general comment on <unk> and its relationship to attacks, it's not strictly linear.
Yanan Zhu: 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 paper attack rates start to fall precipitously and as you get to the very low levels that we've achieved.
Yanan Zhu: Even beyond that so.
Yanan Zhu: Hi.
Yanan Zhu: Part of the challenge for observing these attacks are.
Yanan Zhu: The consequences of a double blind study in medical treatment for patients, who don't know if they've received drug or not act on any.
Yanan Zhu: Let's say twitch early indication that they may or may not be having attack, which is what's the medical guidance as presented to behave so.
Smaller shorter term studies can be influenced by that behavior, which again as appropriate medical therapy.
Yanan Zhu: Think that with extended observation that will likely lessen.
Yanan Zhu: I think that.
Speaker Change: An important aspect from what we've seen and work already presented particularly when we look at the phase one results and add that to the phase II results as the longer patients go the more confident they are and we see a tac rates falling to very very low levels I think there'll be an opportunity later this year to see how that.
Speaker Change: Plays out with additional patients and the additional follow ups that we've accumulated.
Speaker Change: Oh sure.
You mentioned in the phase III, one difference in the phase III as we do follow the patients for a longer period of time instead of the 16 week follow up the follow up is between <unk> five and 28.
Speaker Change: So think will support.
Speaker Change: Seeing a better result, there.
Speaker Change: Okay.
Speaker Change: The next question comes from Myles Minter with William Blair. Please go ahead.
Speaker Change: Hey, Tim This is John on for Myles. Thanks, So much for taking my question I was just wondering if you could give us any updates on how stabilize their usage and the magnitude studying is tracking compared to your original projections, which I believe were for around 50% usage on the study. Thanks.
Speaker Change: Yes, I think we had said it would be at least 50%, but David do you want to give some insight to what we are seeing is greater usage of families around the world in particular of the U K has now supplied that to the patients there.
Speaker Change: Do you 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 fabless.
Speaker Change: That hasnt been shown yet for any other agent and that finding we think it will be part of a superior efficacy that we might see that would drive the usage of our drug.
Speaker Change: Helpful. Thank you.
Speaker Change: The next question comes from David Lebowitz with Citi. Please go ahead.
David Lebowitz: Thank you very much for taking my question. This is a follow up from my earlier question.
David Lebowitz: Hey, there's a lot of talk about the possibility of a functional cure.
David Lebowitz: I would imagine that that's not a bar ultimately that you see for success.
David Lebowitz: Do you see as the bar for success.
Speaker Change: Well, we think the functional cure aspect is the key driver for how patients are going to want to use this drug.
Speaker Change: 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 demand therapy that takes effect faster than existing therapy.
Speaker Change: That market is largely satisfied as we can tell with.
Speaker Change: Patients are looking for.
Speaker Change: A completely new category spots and that is in fact, a functional cure basis. We think we will have many patients who are achieving functional cure in fact, what we've seen thus far is the.
Speaker Change: Yes Laurie.
Speaker Change: Majority of patients already have achieved that and 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.
Speaker Change: 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 a tax the attack rate is very very low. So we think on any category of potential.
Speaker Change: Competition, we're in really strong position.
Speaker Change: Thank you so much for the answer.
Speaker Change: 75.
Andy Chien: The next question comes from Andy Chien with Wolfe Research. Please go ahead.
Hey, Brandon on for Andy Another question from Us on competition and rolling them Tomorrow calculation Helios B enrolled.
Andy Chien: 380 patients per year.
Andy Chien: Turning to do 375 years of follow her therapy.
Andy Chien: It appears to be quite fast.
Andy Chien: Is it reasonable to use the ratio between that 380, and $2 75 to determined doctor enthusiasm and patient enthusiasm for your two tier of gene therapy.
Speaker Change: And do you have any other hard quantitative metrics to show the magnitude of patient enthusiasm for your product compared to competition. Thank you.
Andy Chien: Oh.
Andy Chien: 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 I would start by just using the numbers we provided.
Andy Chien: Does say as I said earlier in the call. There is a very very high likelihood that we will have in excess of those 550 patients.
Speaker Change: And we expect to be in a position where the study finishes well within the guidance that we've already Kevin So.
Speaker Change: If there is reason to give additional updates as time goes on we'll consider that but.
Speaker Change: I would not look for routine updates in terms of the numbers of patients that are coming into the study.
Speaker Change: And just mentioned might be saying there is a very high level of enthusiasm from 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.
Speaker Change: Thank you.
Terence Flynn: The next question comes from Terence Flynn with Morgan Stanley. Please go ahead.
Speaker Change: Hi, Thanks for taking the questions.
Speaker Change: 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.
Speaker Change: Just a couple of high level comments the regeneron.
Speaker Change: Collaboration with NEC C.
Speaker Change: As a 25% interest on their part and 75% interest on ours.
Speaker Change: That's been in place for some time now there is a point, where they will need to make a determination whether or not they're going to opt in for a co commercialization.
Speaker Change: Partnership and we look forward to.
Seeing that decision and planning around that so.
Speaker Change: Don't know Ed if you think there's any other milestones that are important to mention at this point no I think I'd say that and just to double down on John's point, It's a co promotion in the U S that they have the right. The economics don't change and so what's going to drive that as sort of the timeline to commercialization as we think about pn indication in particular, I think we've been very prudent and sort of providing.
Speaker Change: Guidance on timelines for that but as we think about alternatives in terms of interim analyses 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 U S. Co promote is an important one and that's on the horizon.
Speaker Change: The next question comes from <unk> Richter with Goldman Sachs. Please go ahead.
Speaker Change: Hey, this is mark on for Sally and thanks, so much for taking our question.
Speaker Change: You guys briefly mentioned earlier that you discontinued.
Speaker Change: <unk> 3001 for a second generation of Roche I was wondering if you could talk more about that or are there any signals you were seeing with original 2001 that were unfavorable and any commentary on the second generation fresh.
Speaker Change: There was nothing.
Speaker Change: <unk>.
Speaker Change: <unk> hundred one from a clinical point of view, we stop just short of dosing a patient.
Speaker Change: The preclinical studies, we've talked about in the past.
Speaker Change: We as we look at that area, we made a decision on how to pursue 31 in the context of the prioritization.
Speaker Change: Restructuring that we announced in January and we think that the gene writer approach that we've described elsewhere.
Speaker Change: Significant utility and that sees in an appropriate time, but we will be in a position to talk about that.
Speaker Change: This concludes the question and answer session and until your therapeutics fourth quarter and full year 2024 financial results Conference call. The conference has now concluded. Thank you for attending today's presentation.
Speaker Change: You may now disconnect your line.
Speaker Change: Okay.
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