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spk02: Good morning and welcome to the Intellia Therapeutics second quarter 2023 earnings conference call. My name is Drew and I will be your conference operator today. 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. If anyone requires operator assistance during the conference, please press star zero on your telephone keypad. I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intelia. Please proceed.
spk09: Thank you, Operator, and good morning, everyone. Welcome to Intellia Therapeutics' second quarter 2023 earnings call. Earlier this morning, Intellia 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. This call is being broadcast live, and a replay will be archived on the company's website. At this time, I would like to take a minute to remind listeners that during this call, Intelia 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 Intelia undertakes no duty to update this information unless required by law. Joining me from Intelia are Dr. John Leonard, Chief Executive Officer, Dr. David Lebwal, Chief Medical Officer, Dr. Laura Sepp-Lorenzino, Chief Scientific Officer, and Glenn Goddard, Chief Financial Officer. John will begin with an overview of recent business highlights. David will provide an update on our clinical programs. Laura will review our R&D progress, and Glenn will review Intellia's financial results for the second quarter of 2023 before we open up the call for your Q&A. With that, I'll now turn the call over to John.
spk05: Thank you, Ian, and thank you all for joining us this morning. At Intelia, we're leading the genome editing revolution with the broadest and deepest toolbox of novel editing and delivery solutions. 2023 continues to be another year of important progress across our clinical pipeline and differentiated genome editing platform. We're particularly pleased with the significant advancement of our two lead clinical programs. Not only are these two programs potentially paradigm-shifting treatments for patients with ATTR, amyloidosis, and HAE, But our success and learnings from these investigational therapies will help set the foundation for our broader long-term goals and strategic priorities. Starting with NTLA-2002 in development for the treatment of hereditary angioedema, today we announced that in just a handful of months, we were able to identify all patients required to fully enroll the ongoing Phase II portion of the study. Notably, we now expect to initiate the Phase III program as early as the third quarter of next year subject to regulatory feedback. In addition to the exceptional clinical development execution and recent positive data update for NTLA-2022, we're getting very close to submitting our second in vivo IND application. This next IND submission, expected in September, will support the planned pivotal trial of NTLA-2001 for people with a cardiomyopathy manifestation of ATTR amyloidosis. Some estimates indicate there may be as many as 500,000 people around the world who suffer from this disease. Subject to regulatory feedback, we expect to initiate the global phase three by year end. We believe all this progress positions us well to deliver on initiating pivotal studies for both programs, a core strategic priority over this year and next. Lastly, I'd like to take this opportunity to thank Jean-Francois Formella, one of our founding board members who retired from our board in June. Jeff's vision and leadership over the past decade have been integral to our growth and recent achievements. I'll now hand the call over to our chief medical officer, David Leblon, who will review the lead clinical programs in greater detail. David?
spk10: Thanks, John, and welcome, everyone. I'll begin with 2001, our in vivo CRISPR-based candidate with the potential to halt and reverse disease in people living with ATTR-MOA doses after a single dose. For ATTR-CM, consistent with our prior guidance for a midyear submission, we are on track to submit an IND application in September for a global pivotal study of 2001. We are in the final stages of preparing the comprehensive IND package and expect to initiate the study by year end subject to regulatory feedback. For hereditary ATTRPN, we are continuing to make steady progress with the preparations for a Phase III study. Looking ahead, we plan to present additional data from both arms of the ongoing study later this year. Moving to 2002 and development for HAE, we have been really pleased with the interest and enthusiasm for the 2002 program from investigators and patients alike both in the US and internationally. The updated phase one data presented in June has fueled this enthusiasm even further. Across all 10 patients, a 95% mean reduction in monthly attack rate was observed after a single dose of 20-02 through the latest follow-up. The medium duration of follow-up was nine months. And at all three dose levels, 20-02 has been well tolerated and any adverse events were grade one or two in severity. Earlier this morning, we announced that we have identified all patients needed to complete enrollment in the phase two portion of the study. Based on the high level of interest for 2002, all slots have been allocated to current ex-US sites. Other sites planned for phase two, including US sites, will now be part of the planned phase three study. Following the clearance of our IND, we received a request from the FDA to provide supplemental preclinical data related to the inclusion of female patients of childbearing potential. While we could have proceeded with enrolling U.S. patients outside of this subgroup with a protocol amendment, the study was already rapidly enrolling at ex-U.S. sites and soon to finish. After discussion with the FDA, we have come to an agreement on the design of a reproductive study in mice to supplement the data that we have already supplied in our initial IND submission. Such data are often required as part of a registrational program and will now be submitted along with additional data being generated in advance of the initiation of the Phase III study. The main objective of the Phase II is to confirm the optimal dose for Phase III. By enrolling a diverse patient population ex-US, including women of childbearing potential, we are in a great position to move forward to do just that. Further, we announced today that we now expect to begin the Phase III study as early as the third quarter of 2024, subject to regulatory feedback. We are full steam ahead and look forward to updating you on our progress for initiating the 2002 Global Pivotal Study. I'll now hand the call over to Laura, our Chief Scientific Officer, who will provide updates on our R&D efforts.
spk12: Thank you, David. Beyond our lead programs, we're advancing a pipeline of in vivo and ex vivo programs towards the clinic. For NTLA-301, our first wholly owned in vivo insertion program, we continue to conduct IND enabling activities and plan to submit a CTA by year end. We're excited to be moving this program into the clinic for a number of reasons. First, there are few effective therapeutic options for patients suffering from Alpha-1 antitrypsin deficiency, a frequently debilitating and fatal disease. Based on our preclinical work, we believe NTLA-30-01 can normalize Alpha-1 levels for patients following a single dose. Additionally, NTLA-30-01 will be INTELLiA's first gene insertion program to enter the clinic. If successful, we believe we can apply this modular approach to a host of diseases caused by a missing functional protein where there is high and met need. We look forward to updating you on our progress across our R&D platform more broadly as we move through the second half of the year. I'll now hand over the call to Glenn, our Chief Financial Officer, who will provide an overview of our second quarter 2023 financial results.
spk04: Thank you, Laura. Good morning, everyone. Intelia continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform. Our cash, cash equivalents, and marketable securities were $1.1 billion as of June 30, 2023, compared to $1.3 billion as of December 31, 2022. The decrease was driven by cash used to fund operations of approximately $227.3 million. The decrease was offset in part by $24.6 million of interest income, $8 million of collaborator reimbursements, $3.3 million of proceeds from employee-based stock plans, and $1.5 million of net equity proceeds from the Companies at the Market program. Our collaboration revenue decreased by $.4 million to $13.6 million during the second quarter of 2023. compared to $14 million during the second quarter of 2022. R&D expenses increased by $25.1 million to $115.3 million during the second quarter of 2023, compared to $90.2 million during the second quarter of 2022. The increase was mainly driven by the advancement of our lead programs and personnel growth to support these programs. Stock-based compensation included in R&D expenses was $22.4 million for the second quarter of 2023. G&A expenses increased by $8.5 million to $30.7 million during the second quarter of 2023, compared to $22.1 million during the second quarter of 2022. This increase was primarily related to an increase in stock-based compensation of $5.1 million. Stock-based compensation included in G&A expenses was $14 million for the second quarter of 2023. Finally, we expect our cash balance to fund our operating plans beyond the next 24 months. It has certainly been a very productive first half of the year. We have a number of additional milestones still to come in the months ahead. With that, we will now open the call for your questions. Operator, you may now open the call for Q&A.
spk02: We will now begin the question and answer session. 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. To withdraw your question, please press star then two. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Maury Raycroft with Jefferies. Please go ahead.
spk20: Hi, good morning. Congrats on the progress and thanks for taking my question. When you get the 2001 Pivotal IND cleared after filing the IND in September, can you clarify if you will disclose details of the trial design and is base case that the trial size and duration will be similar to L-Nilam's Helios B or based on the Bridge Bio results recently, do you have more confidence you can run a smaller study compared to Helios B?
spk05: Thanks, Mari, for the question. Good morning to you and all the listeners. As we've done in the past, when we get to a state of some finality with protocols, we share the details, and we would expect to do the same here. With respect to the particulars of the study, maybe, David, you could tell us whether or not the BridgeBio or IONIS approach is more or less in focus for us.
spk10: Yeah, thanks. Yeah, so the Bridge Bio result is obviously very encouraging to us that after their first result, people were concerned that this area was hard to improve the patient's status. They were too healthy. It's clearly not true from what we see in their overall results. We do need to see the details of what they have, and that will be coming up. Those details are going to be very helpful to us in the design of our trial. We'll know more about event rates. We'll know more about the status of patients. Now the drug itself, the BridgeBio compound, is obviously very similar to faminus. It works by a different mechanism, and we do think that these are likely not as good as reducing TTR. As you know, we've been able to get to very low levels of TTR. So we use all the information coming from this, as well as later studies, to size the trial. But we do think it'll be about the size, pretty similar to the El Nile trial to Helios.
spk02: The next question comes from Luca Isi with RBC Capital. Please go ahead.
spk11: Hi, this is Reyna on for Luca. Thanks for taking my question. Just wanted to ask, could you remind us what the latest thinking is on gene editing outside the liver? If I recall, I think you showed us some tantalizing data last year for in vivo editing of CD34 hematopoietic stem cells, so wondering if you had any update there.
spk05: Generally speaking, I can tell you that we continue to work very, very hard on moving in vivo editing outside the liver. You're right, we've presented some really encouraging data, particularly with respect to hematopoietic stem cells, thinking down the road in terms of things like sickle cell disease, et cetera, where, you know, the preferred approach would be not to do a moment of transplant, but to actually use an LNP in vivo editing approach to, you know, avoid the morbidity that typically accompanies a pulmonary transplant. We continue to do that work. I will say that we are pursuing a variety of different modalities that target even beyond HSCs. and has been typical for us in the past is we think that we have a body of work that is ready to be presented scientifically. We will share that. But rest assured, there's more to come.
spk02: The next question comes from Joseph Thorn with TD Cowan. Please go ahead.
spk17: Hi there. Good morning, and thank you for taking my question. Maybe just one on the additional data for the women in childbearing age. I guess was there anything that spurred this ask by the FDA? And then as you think about applicability to your other programs, obviously TTRCM is, you know, more predominantly a male disorder in older patients. I guess is there any implications for this for the upcoming IND submission?
spk05: Thank you. There's no safety data that's provoked this particular request of the extensive work that we supplied in the IND, which includes very large breeding studies and careful analysis of that data. We've looked at germline cells specifically. We know that they're unaffected. Our view is that this is the FDA taking a very considered view of the space and looking for us to fill out what is a typical set of data that usually supplied a little later in a program. But from the standpoint of, you know, the study itself, this is something that is commonly done. No clinical data, et cetera, has appeared that speaks to this at all. And we're well on our way to completing the work and supplying it to the FDA so we can get on with the study, as we said. I guess, I'm sorry, before I forget, you asked about implications with respect to 2001. At this point, we don't see that, and certainly your point of you look at the demography of that disease, it's typically a set of patients that are older, biased to men in general, and so we just don't see it playing out in any really fundamental way with respect to the program.
spk17: Great. Thank you.
spk05: Sure.
spk02: The next question comes from Greg Harrison with Bank of America. Please go ahead.
spk14: Hey, good morning. This is Mary Kato for Greg. Thank you so much for taking our questions. It's great to hear the interest from the HAE program. I guess looking at your other programs, what feedback have you received from physicians and patients in the ATTR programs ongoing?
spk05: Maybe, David, you can speak to your interactions that are becoming pretty extensive at this point. What are you learning?
spk10: Yeah, thanks. The biggest group that we hear from, of course, is investigators who we're in touch with around the world. I would say we've talked with every investigator who treats patients at the leading centers with this disease. And there is a lot of excitement. We do know most of those sites, or maybe all those sites, will end up joining the study. And as you've seen in some of the other studies, these studies do enroll quite briskly. And there really is an increasing population of patients with ATTR, amyloidosis, and cardiomyopathy. We also hear about patients through through some of these physicians, the excitement that's there. We actually are starting to hear directly from patients, people trying to get into studies. And of course, we want to satisfy that need as soon as possible. So we're, as you know, we're working to get to the phase three study opened as quickly as possible and estimated to be at the end of this year.
spk02: The next question comes from June Lee with Truist Securities. Please go ahead.
spk16: Hi, good morning, and thanks for taking our question. This is Mehdi on for June. So earlier this year, arrowhead fuzzy serum in Sequoia phase 2 study achieved very high 90% reduction in ZAAT. But the impact on liver fibrosis improvement is still unclear, and Takeda is doing phase 3 study with 160 patients. So could you please elaborate on your plans and expectations for NTLA-203? Thanks.
spk05: David, any thoughts in terms of how other data is affecting your thinking for 2003?
spk10: We've been encouraged by the data that we're seeing coming from the CATA studies, and we do think it's important. Obviously, it's not a phase three, a definitive study, but it is very supportive of the benefit of reducing the mutant protein and the benefit for the liver. So we are, for that program, completing our IND enabling studies this year, and we'll be talking soon about when that will be getting into the clinic.
spk02: Thanks. The next question comes from Gina Wang with Barclays. Please go ahead.
spk00: Hi, good morning. This is Hershita on for Gina. Thank you for taking our questions. Just a quick clarification. I think you covered this in the prepared remarks, but I just wanted to confirm. Is that right for 2002 you've identified all the patients in Phase II and all of the patients in this study will be enrolled at CUS and you'll be waiting until the Phase III? to enroll U.S. patients. Can you clarify again what's the reason for this and why you're waiting to enroll U.S. patients in Phase 3 and not in Phase 2 right now? Thank you.
spk05: Thank you. You're correct that the study is fully enrolled. We've identified all the patients, as we've said. The study has been moving extremely quickly, as you can see. I mean, we began enrolling patients just in March of this year, and here we are at the very beginning of August, and we've identified all of the patients and then some to come into the trial. So, this is one of those things that's moved very, very aggressively, and we're excited about that and what that means. By the way, that same enthusiasm is reflected with U.S. investigators and patients who contact us. The reason for the particular choice was with the feedback from the FDA after the successful clearance of the IND to complete the work that we would have needed to do to allow women with child-bearing potential in the U.S., Remember, we're enrolling women of child-bearing potential in every site, every country outside the U.S. We would have delayed the study substantially. And given that the objective of the program is to capture the demographics, which we're doing, range of different disease states, range of ages, women of child-bearing potential and not, and men, et cetera, we were accomplishing that, especially with the primary goal of identifying the dose to take into phase three. So rather than delay, the idea was to complete the work, submit that to the FDA, and bring U.S. patients into the study in phase three. By the way, there are many U.S. sites who have wanted to participate, and given, again, the rapidity of the enrollment, they weren't able to come online fast enough anyway. So we think we're going to be very well situated in the U.S. We will have an abundance of U.S. patients, and I think we'll be well prepared to begin the phase three program, potentially as early as the third quarter of next year, and that's what we're working towards.
spk02: The next question comes from Devjit Chattopadhyay with Guggenheim Partners. Please go ahead.
spk23: Hey, good morning, and thanks for taking my question. With 2001, do you think a mid-90% TTR knockdown and the very tight control that you have over the TTR, will that translate into survival advantage? And could you remind us where you stand with respect to manufacturing as you prep for two Phase III studies over the next 12 months? Thanks.
spk05: Well, I'll have David address why we're excited about As you pointed out, the very, very deep reductions and critically for the study, the very low variance that we see across all the patients treated so far, we're quite convinced that that's going to be a meaningful advantage for patients. But with respect to phase three readiness, we put a lot of work into preparing for that IND that will enable that phase three program. And your point about, you know, having commercial material readiness, As one carries out these phase three trials is a really important observation. So the idea is, you know, to complete this trial, get the results that we're looking for, have the final material in the study, and be in a position that when we achieve approval for the product to move forward as quickly as possible to the marketplace. And we've always been shooting ahead of the duck, so to speak, and this is very much a part of how we've been thinking about it. David, if you have something to add with respect to CPR levels and how that translates into clinical benefit.
spk10: We do believe that these deep reductions we're getting, not only being at the 90% and greater range, but also having the great consistency, means that we have the potential to benefit all patients. There aren't patients who are having lesser amounts. When you have an average of 80% with other agents, half the patients have less than 80% reductions. That's very important. The other thing we're learning in terms of survival advantage, I think, is what we've seen in the bridge bio study. We've talked a lot about how we don't think the six-minute walk is a great test, and in fact, their study failed on that test. What we're seeing is that you do need a longer period to see the benefit of these agents, and we do think by having a large study with long follow-up we will come out positive on the most important endpoints. That will include cardiovascular events and mortality. That's what we're looking forward to in our phase three study.
spk02: The next question comes from Yanan Zhu with Wells Fargo Securities.
spk22: Please go ahead. Thanks for the questions. What would be the timeline for completing the supplemental preclinical data that, you know, FDA has agreed upon about the design of? And do you think, you know, do you plan to collect certain data from the female patients of childbearing age in the upcoming Phase II study? And if so, what might those data points be? Thanks.
spk05: Well, the particular studies that we're doing are in abbreviated form of what are typical studies that look at embryological development. That will be done well in advance of what would be the earliest phase three study start for us, which I said earlier could be as early as third quarter. With respect to precise month and all that, it's just not going to have an effect in terms of how the program proceeds. So I think we're well on our way. David, anything different that we're doing for collecting patient data on women?
spk10: They get the same complete data collection that other patients get. Of course, we'll look at all patients. We look at studies by gender and other things to see if there's any difference in the effect. We don't expect to see any difference between males and females or older or younger women. Of course, another part of follow-up in these studies is looking at pregnancies that may occur after the study. We know we have a number of those patients who are specifically getting on the trial so they can move on to have successful pregnancies. Of course, we look forward to bringing that great result forward in the future if we can.
spk05: Just a reminder to the audience here that in the preclinical work, there's been zero that there's any germline involvement in any way.
spk10: One other point there is, of course, we've talked about before, the pre-calocrine gene is not needed at all for normal lifespan or development or fetal development. So we know very well from humans that this gene is not essential for embryo development.
spk02: Got it.
spk22: Very helpful. Thank you.
spk02: The next question comes from Dagon Ha with Stifel. Please go ahead.
spk19: Hey, good morning, guys. Thanks for taking the question. Just staying with this preclinical idea, I guess one of your peers in the Boston area also provided a pretty substantial data from animals, I believe it was NHPs as well as mice, looking at a pretty robust set of data demonstrating the germline but still got a clinical hold. any additional color you can provide in terms of the size and breadth of this experiment that you think will be sufficient? Has the FDA clearly outlined exactly how many sample size that they want to see before they kind of confirm that it is substantial or kind of related to that? Have they expressed any N from the phase two that might substantially get their questions answered? Thanks so much.
spk05: Yeah, I would draw a distinction between what I've seen reported in terms of breeding studies and litters, et cetera, that is not what this is. That question has been addressed with information that was supplied with the already cleared INB. So, as far as we can tell in our dealings with the FDA and every other regulatory agency, that particular germline question has been put to rest with the data that we supplied. This particular study asks a different question, which is, Does the embryological development of a fetus in mice be affected potentially in any way by having been exposed to, call it the chemicals even, that are part of an LNP? This is something that is typically done with many agents. The distinction in this case is that this is being done a little earlier than would typically be the case. which, as we said at the outset, I think is just FDA taking a very considered view. We do have agreement with the study. It's, as I said, a modified, or I'm sorry, an abbreviated study, which is quite readily addressed and something that we're well on our way to completing. So it's standard stuff, and we look forward to sharing that information with the FDA. Great. Thanks so much. Sure.
spk02: The next question comes from Miles Minter with William Blair. Please go ahead.
spk13: Hi. Thanks for taking our question. Just another one on the preclinical studies. Since the platform approach is similar between several of your programs, just using a different guide, does this particular reproductive study need to be generated per product, or do you believe just once for the platform, and that should sort of cover several
spk05: Well, I can't speak for what the FDA will ultimately require. It is generally applicable. As you point out, it's the LNP itself that determines where the material goes. We've characterized that extensively. As we said, we've done the breeding studies, and we would expect the results to be no different with any other guide. So I do think, in many respects, this should be a platform answer. Whether or not the FDA will immediately see it that way remains to be seen. But our sense is that's how we think about it, and they may ultimately as well.
spk02: The next question comes from Brian Chang with JPMorgan. Please go ahead.
spk15: Hi, this is Songin. I'm working with Brian Chang. Thank you for taking our questions. What's the latest for ATTR polyneuropathy, and when do you think you will be able to give a bit more granularity on the timeline for a pivotal study in polyneuropathy? And what are some of the gating factors, if any? Thank you.
spk05: David, do you want to address that?
spk10: Yeah, what we've been saying and have said is that we are preparing the design of the pivotal studies. This is, obviously, we now have a lot of information from patients followed more than two years. We'll be talking more about that data later this year. And so that's where it is at this point. We're not guiding exactly to when that trial will start yet. In terms of... Gating factors. Oh, the gating factors. You know, this is what will be great going into this next study, of course, is all the CMC issues will all be resolved. We know a lot about safety in both patients with polyneuropathy and cardiomyopathy. So there are very few gating factors other than getting regulatory agreement on the trial design.
spk05: And that's the primary thing we're looking for is the regulatory feedback at this point. Yeah. Thank you.
spk02: The next question comes from William Pickering with Bernstein. Please go ahead.
spk21: Hi, good morning. Thank you for the question. As you think about the CM trial design and the time that it will take to show an outcomes benefit, are there other endpoints that you might be able to update investors on as the trial progresses and use these to point towards a differentiated clinical profile even before we see the outcomes data? Very quickly, could you share what sorts of clinical endpoints you were thinking of sharing towards the end of this year? Thank you.
spk05: David, what could we share during a blinded pivotal trial?
spk10: Yeah. Unfortunately, I think as you probably recognize, you can't share anything from a blinded trial because we don't say anything about the data by arm. So we'll have patients who are on the drug and patients who are off the drug. However, we should say we expect to have other studies that will go at the value of the deep reductions in TPR, generally called these mechanistic studies or that type of study, and we will bring that data forward as soon as we can. You do recognize from the phase 3s that are going on, these results do take a while to mature. The changes don't happen very quickly. But as you've seen in everything we've done, we bring forward data when we have meaningful, interpretable, and consistent results that we can show you what the story is. So, we will wait for that as we, whenever we bring up new data.
spk02: The next question comes from Rick Binkowski with Cancer Fitzgerald. Please go ahead.
spk25: Hi, good morning. Congrats on the progress. And just a quick question for me. Last quarter, it was noted that the redosing of patients from the low-dose polyneuropathy arm of 2001 has started. I'm curious if we could expect to see any of these data from the redosing cohort in the end-of-year update, and what type of data could potentially be shared from these patients?
spk05: David, do you want to comment on redosing?
spk10: Yeah. I mean, what we know, all three patients have been dosed at this point. It's gone well. I don't think we've decided whether to put that into the next update or future update, but we will talk about it as soon as we can.
spk25: Got it. Thank you.
spk02: The next question comes from Jay Olson with Oppenheimer. Please go ahead.
spk03: Oh, hey, congrats on all the progress, and thanks for taking the question. Can you talk about the rationale and the strategy behind pursuing a CTA for 3001 this year, but not an IND? And what are the gating factors and timeline to filing an IND? Thank you.
spk05: David, do you want to speak to that?
spk10: Yeah. As we've done in the past, I think what you've seen is we look at several things in the first country that we go to. We look at the sites that are available, the investigative sites. That's very key to us, getting high-quality sites. We look at the regulatory environment. And all those are pieces of what we put together. And in this case, we did decide, as we have in several of the other compounds, that going with a CTA is the best choice. Gating factors for an IND are similar to what we've had for other INDs. Of course, you need the pieces of CMC components. picture is a big piece of our applications. And of course, getting agreement on trial designs. So all those things are possible for a later submission as an IND.
spk03: Great. Thank you very much.
spk02: The next question comes from Sylvan Turkan with J&P Securities. Please go ahead.
spk24: Good morning and thanks for taking my question. I just have a more general question. With the CRISPR-XSL potential approval coming up in the U.S. by the end of the year, and then potential subsequent reimbursement, is there anything from those models that we can learn that will be applicable to, for example, your HDR programs, or is that too far off at this point? Thank you.
spk05: Well, obviously, we watch those spaces very, very carefully. I don't think that the world has converged on a final model for drugs like this that are potentially curative, but I see emerging trends, and there's going to be some really interesting, I think, examples that, of course, we will study very, very carefully. Our view right now is to have the best possible drug that moves the efficacy bar substantially forward and captures savings for the healthcare system, et cetera. And I think that that'll be the basis for whatever pricing model we ultimately come up with. But we're confident that the health advantages and the efficacy that we expect to deliver will be of value to payers, whether it's in the US or ex-US.
spk02: Thank you. The next question comes from Steve Seathouse with Raymond James. Please go ahead.
spk06: Hi, good morning. This is Nick for Steve. A couple questions on AATD. So are both knock-in and knock-out products intended to target patients with the homozygous Z genotype?
spk05: David, you want to address that?
spk10: Yeah, that's really where the need is for the patients who are homozygous Z. And in terms of the knockout, this is patients where the predominant issue is liver disease. That's the main thing that the knockout addresses. It doesn't address the lung disease. And there are a substantial group, maybe, well, I guess it's certainly 15% overall of the patients who tend to have liver disease. And that includes some patients with lung diseases. The big majority of patients are the patients who need the deficiency as affecting the lungs, and that is what the knock-in is going to help with by putting in the wild-type gene. Many patients will end up getting both because as they start to live longer, the liver disease may become more important. The liver disease can be subtle in some patients, and a lot of the physicians feel that they would want to give their patients both agents over time, and both these agents be given I should say in either order, one can be given before the other. Either one can be given before the other so that we have a lot of flexibility in how we treat patients.
spk05: It might be important for some of the listeners to remember that these are independent programs that can be brought together, but we're pursuing them as independent development programs.
spk10: These are two separate drugs that are going to be fully developed with all the requirements that you have for each drug. It's not a combination program per se.
spk06: Okay, got it. Thank you. And then so from your preclinical work, do you expect the same level of neutrophil elastase inhibition with the AAT protein induced by 3001 compared to wild-type MAAT protein?
spk05: What we've presented in non-human primate work is this approach was able to reproduce levels seen in non-human primates that were essentially indistinguishable from normal human levels of circulating Alpha-1. So, our, you know, target is to accomplish just that in patients. And, you know, the preclinical model suggests that we may well be able to do that. Laura, is there anything you want to add to how we're thinking about Alpha-1?
spk12: Yeah, no, so you need to ensure that not only you have protein levels, but those, you know, proteins are active, right? That the activity is what you need to have. You know, as John just described, that's what we accomplish in the non-human primate. And the expectation is that that's going to translate to humans.
spk02: Got it. Thank you. The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
spk01: Hi, this is Srinath Rao for Salveen. Thank you for taking our question. So a couple of questions, the first on NTLA 2002. In your data update at EACI, you mentioned that patients were allowed to withdraw from HA prophylaxis and they have not experienced subsequent attacks. Any further updates on these patients, as in have they remained attack-free to date? And on your 2001 program, could you provide some color on the regulatory discussions with the FDA on CM and PN? Have they spoken about what they would like to see in the pivotal study? Thank you.
spk05: Maybe you could remind the questioner about the data we presented on 2002, and I'm sure we'll be having updates as time goes on.
spk10: Yeah, so I think you recall we did give updated data fairly recently on 2002. Recall all the patients who had received prophylaxis were able to withdraw it, and none of those patients have had a subsequent attack in that report. I should mention that we didn't use lanodelumab as one of the withdrawals because it would affect our biomarker measures. However, what we're seeing in the phase two is we did allow lanodelumab withdrawal in and that is we have a number of patients who'll be treated after that withdrawal. So stay tuned, more data's coming for that as well. When we talk to regulators about the phase three, the IND is, we've had preliminary discussions, but of course to get agreement that involves the IND submission that we're doing in September for the FDA, we've also had extensive discussions regulated outside the US, we feel very good that our trial design will address the questions that they will have. For PN, we are a little earlier. We did push first on CM as a much larger medical need, more patients needing this. But also with PN, we will bring you forward more details as we get agreement to the pivotal trial design.
spk02: The next question comes from Richard Law with Credit Suisse. Please go ahead. Hey guys, good morning.
spk07: Can you discuss the market opportunity for XAE outside the US based on the reimbursement and usage rates for brand products so far? And what are the learnings for 2002 as you think about XUS market that you would need to include in your studies?
spk05: The bulk of the HAE market today resides inside the United States. We're well aware of that. We do have an eye to what we can deliver outside the United States. What we've seen through the course of our phase one and now phase two work is that there's a great desire to have these products. And we will do our very best to show that not only do the product does the product work very, very well, but that it can be resource sparing to those typically centralized systems. So to the extent that that market opportunity exists, we want to participate in it to the greatest extent possible.
spk07: Can you compare and contrast the reimbursement for U.S. versus ex-U.S.? Just curious to see how the different markets would affect the product.
spk05: I think that's something we can address later on as we get further down the road. But generally speaking, this is information that's well publicized and available. The market has been disproportionately a U.S. market with reimbursement rates that are higher. That's typically the case for most drugs, and again, we see that here. But again, we're trying to think through how this particular approach can be demonstrated to be resource sparing to what are typically centrally reimbursed approaches, and we'll present that data to those, you know, different systems, and we expect it will be of potential value to them.
spk07: Great. Thanks.
spk02: This concludes our question and answer session. I would like to turn the conference back over to Ian Karp for any closing remarks.
spk08: Great. Thanks for all the terrific questions and for your continued interest in Intellia and our progress. And we look forward to future updates. So have a great day and a great rest of the week.
spk02: The conference has ended. You may now disconnect your line. Thank you.
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