Intellia Therapeutics, Inc.

Q1 2023 Earnings Conference Call


spk06: Good morning and welcome to the Intellia Therapeutics first quarter 2023 financial results 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. I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intelia. Please proceed.
spk10: Thank you, Operator, and good morning, everyone. Welcome to Intelia Therapeutics' first quarter 2023 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 investor and media section of Intelia's website, at 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, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at 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 Intelia are Dr. John Leonard, Chief Executive Officer, Dr. David Lebwall, Chief Medical 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, and Glenn will review financial results for the first quarter of 2023 before we open up the call for Q&A, at which time Dr. Laura Sepp-Lorenzino, our Chief Scientific Officer, will also be available. With that, I'll now turn the call over to John.
spk08: Thank you, Ian, and thank you all for joining us this morning. At Intelia, we're continuing to lead the genome editing revolution with the broadest and deepest toolbox of novel editing and delivery solutions. We've had a productive start to the year in the recent successful clearance of our first IND for an investigational in vivo CRISPR-based therapy. Alongside that regulatory accomplishment, we continue to make important progress across both our in vivo and ex vivo pipeline and platform. Today, we're pleased to announce dosing has begun in the Phase 2 study of NTLA-2002 for the treatment of hereditary angioedema, or HAE. Additionally, based on strong interest from investigators and patients, we expect to complete study enrollment in the second half of this year. Both the FDA's acceptance of our IND application and the rapid clinical progression of NTLA-2002 move us one step closer to our goal of introducing a potential functional cure for people living with HAE. Simultaneously, we're working towards submitting our second in vivo IND. This next IND is for the planned pivotal trial of NTLA-2001 for people with the cardiomyopathy manifestation of ATTR amyloidosis. Some estimates indicate there may be as many as 500,000 people who suffer from this disease around the world. Subject to regulatory feedback, we expect to initiate the global pivotal trial by year end. Both NTLA-2001 and NTLA-2002 represent potentially paradigm shifting treatments as supported by the initial groundbreaking clinical data presented last year. As the first and only company to demonstrate successful systemic CRISPR gene editing in humans to date, we now look forward to presenting new interim data from each phase one study at upcoming medical meetings later this year. Lastly, we're very happy to welcome Bill Chase to our Board of Directors. Bill brings over three decades of financial management expertise and a strong track record for building leading biopharmaceutical companies. He was formerly the CFO of AbbVie and spearheaded its successful spin-out from Abbott Laboratories. Bill will succeed Carolyn Dorsa as Audit Committee Chair following her retirement from the Board. I would also like to take this opportunity to thank Carolyn Dorsa for her long and dedicated service on Intellia's board and her many contributions to the company's growth and success as its first independent director. We wish her well in her future pursuits. With that summary of the excellent progress we've made so far this year, I'll hand the call over to our Chief Medical Officer, David Leblal, who will review the lead clinical programs in greater detail. David?
spk04: Thanks, John, and welcome, everyone. I'll begin with an update for 2001, an in vivo CRISPR-based candidate with the potential to halt and reverse disease in people living with ATTR amyloidosis after a single dose. As we shared back in February, we have now completed the planned enrollment in the dose expansion portion of the cardiomyopathy and polyneuropathy arms of the two-part phase one study. Data from these expansion cohorts will be used to inform our dose selection decision for subsequent pivotal studies. For ATTR-CM, we remain on track to submit an IMD application mid-this year. We are currently in the process of preparing the IMD package. Similar to 2002, we are putting together a robust filing, including the extensive preclinical work and available clinical data. Subject to regulatory feedback, we plan to initiate the global pivotal study by year end. For hereditary ATTR amyloidosis with polyneuropathy, we are preparing for a future phase 3 study and discussions with regulatory authorities. Separately, we also recently began redosing patients who received the 0.1 mg per kg dose of in the dose escalation portion of the Phase I study. As you may recall, the first three patients in the first inhuman study received a relatively low dose. Our objective for testing this low dose in the first cohort of patients was primarily to examine the lower bounds of 2001 safety and activity profile. Patients in this cohort achieved a mean TTR reduction of 52% by day 28. This is in comparison to patients who achieved near or greater than 90% CTR reduction in the subsequent dose escalation cohorts. Patients who elect to receive a follow-on dose will receive a 55 milligram dose, the sixth dose corresponding to 0.7 milligrams per kilogram. While we are developing 20-01 as a one-time treatment, we believe that the ability to potentially redose with our CRISPR-based candidates is an important advantage of our LNP-based delivery system. As such, this redosing feature may provide valuable clinical validation for our platform in other therapeutic applications, including those outside the liver. Finally, we plan to present additional data from both arms of the study this year, For ATTR-CM, we expect to include longer-term safety and durability data, as well as emerging clinical endpoints. I'll turn now to our second in vivo program, 2002, our investigational therapy for the treatment of hereditary angioedema, or HAE. Despite the availability of chronic treatments, people living with HAE face high treatment burden and many still experience breakthrough attacks. With 2002, we aimed to prevent attacks by providing lifelong reduction of plasma calocrine activity with just a single dose. We were very pleased to announce in March that the FDA cleared the 2002 IND application. This was our first in vivo IND submission, and the FDA's clearance within the initial 30-day review period speaks to the extraordinary work from the team here at Intelia. Importantly, this marks the first time the FDA has cleared an IND for a systemically administered in vivo CRISPR-based candidate using LNP delivery. Shortly after IND clearance, we also received RMAT designation for 2002 for treatment of HAE. The FDA confers RMAT designation to certain promising therapeutic candidates, and includes important benefits to expedite development and review. It is recognition by the FDA for our early clinical data and indicates that 2002 has the potential to address serious unmet medical needs for people living with HAE. Significant progress we've made with the 2002 program doesn't stop there. More recently, we have begun dosing patients in the global phase two study. We've seen strong interest and enthusiasm from investigators and patients alike following our early clinical data suggesting 2002 may provide durable prevention of swelling attacks after a single dose. Today, we announced that we expect to complete enrollment in the second half of this year. As a reminder, the goal of the phase two is to identify the dose to move forward into a future registrational trial. We look forward to presenting new additional data from the phase one portion of the first in human study later this year. Data expected to be presented include new safety, durability, and attack rate measures from all three cohorts. As John mentioned, it's been a very productive first quarter, especially for the 2002 program. As 2001 and 2002 continue to progress, we believe that we are moving closer to setting a new standard of care for people living with these serious diseases. Beyond our two lead programs, we're advancing a pipeline of in vivo and ex vivo programs towards the clinic. Notably, we remain on track to submit an IND or IND equivalent to 3001, our first wholly owned in vivo insertion program in the second half of this year. I'll now hand over the call to Glenn, our CFO, who will provide an overview of our first quarter 2023 financial results.
spk07: Thank you, David. 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 $1.2 billion as of March 31st, 2023. compared to $1.3 billion as of December 31st, 2022. The decrease was driven by cash used to fund operations of approximately $120.9 million. The decrease was offset in part by $12 million of interest income, $3.4 million of collaborative reimbursements, $1.5 million of net equity proceeds from the companies at the market program, and $0.8 million in proceeds from employee-based stock plans. Our collaboration revenue increased by $1.3 million to $12.6 million during the first quarter of 2023, compared to $11.3 million during the first quarter of 2022. Our R&D expenses decreased by $36 million to $97.7 million $1.1 million during the first quarter of 2023 compared to $133.1 million during the first quarter of 2022. This decrease was mainly driven by $56 million of expense related to the acquisition of Rewrite Therapeutics during the first quarter of 2022. This decrease was offset by an increase in expenses of $20 million driven by the advancement of our lead programs and personnel growth to support these programs. Our G&A expenses increased by $5 million to $27.4 million during the first quarter of 2023, compared to $22.4 million during the first quarter of 2022. This increase was primarily related to an increase in stock-based compensation of $2.1 million. Finally, we expect our cash balance to fund our operating plans beyond the next 24 months. It's certainly been a very productive start to the year. We look forward to a number of additional key milestones and data presentations throughout the remainder of the year. With that, I will now open the call for your questions. Operator, you may now open the call for Q&A.
spk06: We will now begin the question and answer session. To ask a question, you may press star then 1 on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star then 2. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster? The first question comes from Joseph Thorn with TD Cowan. Please go ahead.
spk22: Hi there. Good morning, and thank you for taking my question. Maybe could you give us a little bit more of an indication in terms of what that ILAP designation means for the development program for 2002? And maybe just broadly, Peter Marks has obviously been a little bit more in terms of accelerated approval for gene therapies in the U.S. Do you think this speaks through to gene editing, and does this impact your development strategy at all? Thank you.
spk08: David, do you want to speak to that question? And I guess more broadly, the FDA's outlook as we see it for gene editing in the U.S.?
spk04: Yeah, no, thank you. The ILAP designation refers specifically to the UK, as mentioned. So this is a program in which they're trying to advance innovative therapies. I think we talked to you in the past about how closely we have worked with UK authorities. They've been very interested in gene editing as a class and have been very helpful in moving our program forward. In this case, they officially have a program in which they They make the designation for programs which they think will be very valuable to their populations, the people in their country, and they help move along the approval process. This is fairly new. We don't know exactly how it's going to affect the advancement in the UK, but they really have taken a very innovative approach to try to move this type of program forward. We've also noted that Peter Marks has been very positive towards accelerated approvals for gene therapies. In general, we talked about our registration programs. In these cases, we generally do think we need at least a randomized study because of the nature of assessing the response to these diseases. But we will certainly talk to them about ways to accelerate the approval using the data that we are gaining in these studies.
spk22: Perfect. Very helpful. Thank you.
spk06: The next question comes from Maury Raycroft with Jefferies. Please go ahead. Hi.
spk13: Good morning, and thanks for taking my question. For the IND filing midyear for ATTR cardiomyopathy, You likely have to have a near final plan in place for the study when you file, but there are two key events in the space mid-year with Alnylums, ADCOM, and BridgeBio's phase three outcomes data. I'm wondering, will you wait for those events to inform your IND, or will you file and adjust if need be? I guess, how are you thinking about the timing and strategy?
spk08: I'll take that, Mari. Thanks for the question. Our plan is to move forward as we've guided with the IND filing mid this year. We think that we have much of the information that we're going to need to move the program forward. And, you know, it's of highest priority for us to get to an agreement on what that protocol is actually going to be in the U.S. with the FDA. So the sooner we move on that, the better for everybody. Got it.
spk13: Thanks for taking my question.
spk06: Sure. The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.
spk21: Thanks for taking my question. So I think you made this interesting comment that enrollment interest has been high for the 2020 the 2002 HAE Phase II Global Study. I think one thing that has been mentioned by others is that HAE has fairly good standard of care, at least in the U.S. And therefore, you know, there has been a question of interest in receiving a one-time once and done gene editing treatment. And can you comment on what you make of the strong interest that you have seen for this study and whether part of that interest includes in developed markets like the U.S. market?
spk08: Thank you. Thanks for the question. we're seeing broad-based interest, really, irrespective of geography. We are in developed markets. The IND obviously brings the program here to the U.S., and we've been really quite gratified by the clinical interest that we've seen from investigators. You know, I guess the, you know, core of your question is, why might that be? I think there's really a couple of very fundamental points that speak to the program. Number one, what we've seen thus far for efficacy is at least equal to what has been put out there by competing companies and perhaps surpasses that. We'll see as the program moves on. But I think one underappreciated factor for patients with HAE is that, remember that they're frequently diagnosed when they're young. and they require lifelong therapy. And that translates into what patients view as a very burdensome treatment regimen, whether it's infusions or the materials that they need to carry with them, and the uncertainty that they contend with as they go about their daily lives. But what we're seeing, and this is what both patients and physicians tell us, that the prospects of dispensing with that therapy, potentially, and being essentially functionally cured, which means approximating disease-free status is something of great interest to patients. And we'll see as our phase one data continues to mature, but that prospect is very, very exciting to patients. So stay tuned. You know, as the work goes on, we'll see how far we get to achieving those goals, but It certainly, we've learned, is alluring to patients.
spk21: Great to hear. Thanks for the update.
spk06: The next question comes from Daegun Ha with Stifel. Please go ahead.
spk16: Great. Good morning. Thanks for taking our question. I'll switch gears to 3001, if I may. So with regards to the IND plans, looking back at the 2002 and your soon-to-be-filed overall IND experience. I guess, can you talk about your confidence in IND submission for that 3001 program and eventual clearance? I guess I'm just wondering how much of this IND or IND equivalent decision will be driven by regulatory requirements as opposed to other considerations like availability of standard of care in certain geographies? Thanks so much.
spk08: David, do you want to speak to how we're approaching the regulatory filings to begin clinical work with 3001?
spk04: Yeah. So, first, recall with 3001 that with the knock-in of the F1 antitrypsin, we're able to get what look like normal levels of non-human primates. So, we have seen a lot of enthusiasm from investigators to be able to start to use this therapy, to test this therapy. in people because of the potential that with the single dose, we would be able to achieve normal levels of the enzyme. Putting that together, this IND, and that also motivates regulators, I should say, so that's what's important there. In terms of the IND, there are really two pieces, major pieces of this. One is the lipidana particle, able to target at the albumin site. And what we've learned from the 2002 application is that we are doing the things that the FDA is interested in, in that aspect of the gene editing. The second piece of it is new to us, but not new to the FDA at all. And this is the AAV virus that's part of that program. That way forward for IND is very well established. So putting the two together, we think that the the IND or IND equivalent has a good chance of passing. We don't think that's a major hurdle in terms of going forward.
spk06: The next question comes from Debjit Sripadhyay with Guggenheim. Please go ahead.
spk09: Good morning, everyone. This is Rai Forseth. I'm for Debjit. Thinking about the 2001 data that you'll share later this year, do you anticipate providing information around NT-ProBNP with that data set? And secondly, just one clarification for those patients that were redosed, I think you said a fixed dose equivalent to 0.7 mg per kg. I think you also said the flat dose, but I missed that.
spk08: David, maybe you can speak to some of the clinical information that we expect to share. I guess the question was specifically about some biomarkers. In the meanwhile, we can say that, yes, the redosing is with the 55 flat dose. It's not going to be weight-based. What we're doing is following up these patients in the first cohort with the same dose that everyone else has been receiving in the expansion phase of the program. David, do you want to speak to some of the clinical information for 2001 that we expect to share this year?
spk04: What we're going to show from the trial is information from both the polyneuropathy and cardiomyopathy arms. What we think you know is that we completed enrollment to the cardiomyopathy at the end of last year and the polyneuropathy early this year. Those patients have had We'll have had some follow-up as we move to the year. We haven't said exactly when that presentation will be, but it will be early for some patients who started in that late period. Of course, we have longer information on the patients in the trial who were in the Part 1 of the trial. In general, we will present safety and TTR results. Those come very quickly in the trial, so that will be available really for all patients. But the other measures like pro-BNP and cardio MRI of the heart do take longer, and of course, with the varying follow-up, the various degrees of follow-up in different patients. In general, we do want to report data when there's substantial and complete information, so we can't say exactly what we're presenting right now, but we will come forward with the important information that we find.
spk06: Thank you. The next question comes from Lisa Baco with Evercore ISI. Please go ahead.
spk20: Hi there. Thanks for taking the question. I was really curious about your redosing strategy. Is there anything specifically you're looking for for this particular program, or is it more a safety evaluation for other programs? How will you know if it's doing what you're expecting, what you're looking for, if there's anything beyond safety. Thank you.
spk08: David, do you want to speak to that?
spk04: Yeah, so the redosing, in general, we don't think is needed for either the TTR program or the HAE program. We've seen with a single dose that we can achieve the results that we want, greater than 90% reduction of TTR at the appropriate doses in general. And for HAE, What we've seen for higher doses is 80% to 90% reduction in the biomarker with a complete elimination of the events. So we don't think they need redosing. Those effects should be permanent based on everything we know. The redosing that is being done is really being done for the benefit of those patients who joined our trial, particularly patients who joined as the first people in the world to receive a CRISPR-based in vivo therapy. So we had committed to them. that if they didn't get the type of effect that we wanted them to, that we would offer them a redose. We proved that this is feasible in the preclinical situation, that if we went to the full dose, that we would be able to achieve very good editing in first non-human primates. But for these patients, by giving them 55 milligrams, we do think we'll be able to achieve the type of result that the the other patients in this trial have had at the higher doses. We did mention that could this be useful in some other indications. We haven't found that yet, but you could imagine some place where you may want to redose, perhaps a titration type of thing, but we haven't found that indication yet. It will be good to know that this is safe to give the drug again. And it's especially outside the liver where we're interested in whether that might be necessary to give an additional dose. We haven't seen that, of course, as you've seen in the liver so far.
spk20: Okay. Makes sense. Thank you.
spk06: The next question comes from William Pickering with Bernstein. Please go ahead.
spk11: Good morning. Thank you for taking my question. David, at an investor conference in March, you stated your expectation that the pivotal trial in cardiomyopathy could be smaller than others that we have seen. Could you share more about what gives you that confidence and how do you see that translating into study duration? Thank you.
spk04: Yeah, so what I was indicating is that we have first the fact that because we're seeing deeper reductions in TTR, we expect to see better efficacy. That's the correlation that's been seen already for neuropathy and has been seen in other types of cardiomyopathy. Deeper reductions could translate into that better efficacy. When you do have a greater treatment effect, you don't need as many people to establish a positive endpoint, to achieve a primary endpoint that is statistically significant. So, for example, we do think the trial will be not very different from the Helios B, but, of course, there's other trials like IONIS that are now at 1,400 patients. You'd have a very small treatment effect that, you know, you could see a very small treatment effect when you go to a size trial such as that. So that's what I was talking about.
spk11: Thank you.
spk06: The next question comes from June Lee with Truist Securities. Please go ahead.
spk02: Hi, good morning and thanks for taking our questions. This is maybe on for June. So you showed that ex vivo base editing is capable of like multiplexing, very safe and efficient. So would you expect the same or similar efficacy in vivo And if that's the case, would you choose base editing for your next in vivo candidate? And if there are any notable considerations in this domain? Thank you.
spk08: Yeah, thanks for the question. I think we should just go back to the basics here and think through how we approach programs. Remember, we have our platform where we've been aggregating tools that we think provide us the capabilities to address any specific gene editing necessary to go after a particular disease state. Obviously, you know, we've built out a platform that starts with a deep understanding of CRISPR and what it can do and guide RNA formations. We've added to that the ability to do base editing. and we're well on our way to doing what we think is very advanced forms of gene writing. So we have a toolbox that we can draw on to address what we think is the most appropriate tool for whatever the particular disease might be. So if base editing were the right approach, we would choose that. We think, as we look at it today, that base editing is best suited for ex vivo uses when one is multiplexing. which is inherent to some of the aspects of base editing in terms of its activity, but also how one goes about assessing its off-target effects. So I would look to our pipeline as it continues to develop, see where we deploy base editing. We think it has a place, but right now we're very, very excited about what our approach does and the diseases that we're currently advancing in the clinic.
spk06: Thank you very much. The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
spk12: Hi, thank you for taking my question. This is Srinath Rao on for Salveen. Can you provide some color on how you're thinking about the trial design for the Phase III study in ADDR-CM, and what have you learned from your discussions with regulators on that front, and what do you think the FDA would like to see in a pivotal study?
spk08: David, how are you thinking about the Phase III program for cardiomyopathy?
spk04: Yeah, thank you for that question. We think, firstly, to think about the primary endpoints of the trial. What's important to patients? What's important to the doctors and the payers? And we think that is the clinical benefit that you can achieve. So this is reducing cardiovascular events, reducing cardiovascular mortality. So first and foremost, what can this do for patients? In terms of the design of the trial, we do think it will be similar to the other trials that are out there. You've seen that tefamilis is part of the background therapy for many patients around the world. That continues to be a growing trend, and we think that the fact that you'll be combining TTR reduction with stabilization certainly is an antagonistic and possibly could be quite beneficial to patients. If you get, for example, with our drug, down to less than 10% of the initial protein to very low levels of TTR, and you even want to avoid any of that protein getting into organs, the stabilization may be helpful there. We don't know at this point, but it certainly won't hurt. So what we want to see is the benefit over what's currently out there. So it'll be, obviously, a randomized study looking at the benefit of 20-01 in those patients. The size of the trial we do think will be similar to other trials. As mentioned, it could be somewhat smaller because of the greater treatment effect. However, we do need to learn from the ongoing trials. We've learned really from the Apollo B that that was probably too small a trial with too short a follow-up in order to see the full clinical benefit of the drug, and so they do not really establish the clinical benefit with that type of trial. We do think you need a good follow-up on patients as well as probably a larger number of patients than the Apollo B. Luckily, we will be seeing the results of some of these trials before we unblind our trial. This will also help us make sure that we have the right trial design as we go and unblind and get our primary endpoint for our trial. So those are the main features that we are looking to. We will gain agreement with regulators on that and then go forward to the trial starting later this year.
spk12: Thank you.
spk06: The next question comes from Brian Chang with JPMorgan. Please go ahead.
spk17: Hey, guys. Thanks for taking my question this morning. Given the genetic heterogeneity in AATD and the mix of associated clinical phenotype, is there a specific variant basket that you see more of a lower hanging fruit for 3001? In other words, would you exclude those that also have presentation of liver disease in your planned phase one study for 3001? Thank you.
spk08: David, do you want to? talk about just the basics of how we're thinking about the phase one program for 3001?
spk04: Yeah, so you're right that there are different varieties of alpha-1 atripsin. Some patients really have a very predominant lung issue, loss of function in the lung. Other patients have a predominant liver dysfunction, particularly some of the younger patients. And some patients have those. Going into a phase one study, we would avoid patients who we think have liver disease in general because you're not treating it when you put in the new gene. You're not getting rid of the mutant gene in the initial program. Similarly, for our second program, 2003, which knocks out the Z allele, this also would be predominantly for patients who have the liver disease as their main manifestation initially Of course, those patients later on could get lung disease as well. The advantage of our program is ultimately we will treat both aspects of the disease, not only the lung disease but also liver disease, and that these drugs can be used together as we advance the program even further. But initially, that would be appropriate to avoid patients with liver disease.
spk17: Thanks, David.
spk06: The next question comes from Rick Minkowski with Cancer Fitzgerald. Please go ahead.
spk05: Hi, good morning. Thanks for taking the question. So for the Phase II program of INTELLiA 2002, given this is the first time that patients will be dosed in the U.S., could you just help us with our expectation for the pace of dosing here? Will you be required to space out the dosing for each of the patients in the initial U.S. cohort, or can you dose more rapidly given the safety data that was generated from the phase one outside of the U.S.?
spk08: I'll take that. What we're seeing is, as we discussed earlier in the call, very high interest in the program here in the U.S. and outside the U.S. We're actively enrolling. The study We expect we'll finish this year. And with respect to the pacing of patients, we think that that's going to go very, very fast without the requirement to space as is typically done in a phase one program. So overall, I would expect this study to move quite quickly, and we'll update as the program unfolds.
spk05: Great. Congrats on all the progress here.
spk06: The next question comes from Greg Harrison with Bank of America. Please go ahead.
spk01: Good morning. This is Mary Kate Onford. Greg, thanks for taking our question. Just looking at some of the upcoming medical conferences, you have multiple abstracts in collaboration with Regeneron for the preclinical hemophilia program at ASGCT. Maybe how are you looking at this early stage program and what impact could a gene editing product have in this indication? Thanks.
spk08: You're asking specifically about hemophilia?
spk01: Yes.
spk08: Yeah, I'll take that. The way we think about that is there's a couple of aspects to the program. First of all, hemophilia obviously is a lifelong disease that starts in children as they deal with the manifestations of the disease. They accumulate morbidity as their lives unfold. Our objective is ultimately to be able to get to a curative approach for the pediatric population. So as we think about the progression of studies here, what we would want to do is establish that we're able to carry out gene insertion. We've got a couple of programs that are looking at that. 3001, as David just discussed, with alpha-1 antitrypsin. Factor IX with our collaborators at Regeneron. And the objective there would be as quickly as reasonable to get to the pediatric population. And we think that that addresses, potentially, if we're able to achieve what our objectives are, the ability of getting into kids before the disease takes its ultimate toll. The therapies that are available that are single-dose applications today are really best suited for the adult population, we're seeing. And so we think that there's an important advantage that comes with having a stable gene that's integrated that can grow with the patient, the pediatric patient, as he or she, or he in this case, sorry, develops.
spk06: The next question comes from Luca Isi with RBC. Please go ahead.
spk18: Hi. This is Rina on for Luca. Thanks for taking my question. I just wanted to ask on HAE, you commented earlier that there's been broad-based interest irrespective of geography regarding enrollment. So we're just wondering if you could add more color on the first patient dose. Was this at a U.S. or ex-U.S. trial site and what proportion of the trial sites are based in the U.S.? ?
spk08: You're correct that we've begun dowsing. You're correct that there's broad-based interest. What we're not going to do is talk about individual sites and individual patients. Our approach is to provide updates as we collect information in aggregate, and we've done that with all the programs to date, and we'll continue doing that, so stay tuned.
spk18: Okay, thanks for taking my question.
spk06: The next question comes from Gina Wang with Barclays. Please go ahead.
spk00: Hi, good morning. This is Hershida on for Gina. Thank you for taking our questions. We had a quick one. So for 3001, your insertion program, as you're nearing the IND or IND equivalent in second half of 2023, we just wanted to get your thoughts on how you're thinking about dose selection for this program, given that you'll be dealing with both LNP and AAV components when it comes to gene insertion. Thank you.
spk08: I can address that. I mean, the principles are, as you say, there's a couple of things that need to be assessed, both the LMP as well as the AAV. So our preclinical program is addressing those variables. And the objective in a Phase III program would be to reduce the number of variables to the greatest extent possible. Obviously, we've learned a lot about how to dose LMPs with 2001 and 2002 thus far, and so we think we have a pretty good understanding of how those are likely to behave. My guess at this point, and obviously we haven't finalized this yet, would be that there's probably more to explore on the AAV side of the equation. But as we finalize that program, we'll share more details.
spk00: Great. Thank you so much.
spk06: The next question comes from Steve Seathouse with Raymond James. Please go ahead.
spk19: Good morning. Thank you. For the AATD program, it seems optimal in theory to just correct the Serpina 1 gene at the mutated locus. And it sounds like ultimately you do want to combine the insertion and the knockdown therapeutics you have into one approach that addresses both lung and liver. So I'm curious, what are the technical hurdles that just prevent a single therapeutic here making correction of the mutation and Are those limitations specific to AATD, or would they apply for gene correction in general? Next.
spk08: Well, the way we've approached alpha-1 antitrypsin deficiency is looking at the two primary manifestations of the disease, as has been referenced here earlier in the call. One is knocking out the gene as it causes liver problems. The other one is providing a basis to replace essentially normal levels of circulating alpha-1 antitrypsin. With the work that we've done, which relies on two approaches, as you rightly point out, what we've been able to see in our preclinical work is that you can essentially achieve normal levels of the circulating protein and essentially complete knockout. So we've looked at what we're able to accomplish with this program thus far. And what we think we have something that offers for many patients an opportunity to have something that approximates normality. It's correct, as you say, that if one can do this all in one maneuver, it may be possible to achieve both steps simultaneously. And as we think about our own alpha-1 antitrypsin program, I see it as a progression of technologies starting with what we've already achieved, which we think is very appealing for many patients in advance over what's currently available today. But with our gene writing work, we can imagine down the road at some point potentially addressing both in a single maneuver using solely an LNP-based system. So stay tuned as that work unfolds. What we see here is a significant opportunity in the disease that is currently poorly treated.
spk06: The next question comes from Sylvain Turcan with JMP Securities. Please go ahead.
spk14: Good morning, and thanks for taking my question. Just a quick one on your initiated Phase II HAE trial. Is there any specific goal of achieving a specific number or percentage of U.S. patients versus ex-U.S. so that you can engage with regulators following the first results of that trial? Thank you.
spk08: No, we have not pre-specified any particular proportion of patients by geography. I'd say this, Sylvain, we, as we said at the outset, we've got Many, many patients interested in participating in the trial. Right now our primary objective is to get to the right dose so that we can move into what we believe will be registrational studies at the next step. We're absolutely committed to having U.S. patients in this program, and that is absolutely a priority for us. But getting to the answer for the right dose is something that we think we can do very, very quickly this year. Thank you.
spk06: The next question comes from Richard Law with Credit Suisse. Please go ahead.
spk03: Good morning and thanks for taking my question. So you mentioned before that there's a possibility of doing an interim analysis for 2001 in ATTR-CM and then possibly show a positive CP outcomes then. Is there a possibility to file a BLA early if that's the case and not when the trial to completion And then just based on your preliminary thinking right now, what would be the timing of an interim analysis? Thanks.
spk08: David, how are you thinking about interim steps and what might you do with the information?
spk04: Yeah, so it goes back to the question, greater interest in accelerated approvals for important new therapies in the U.S. and elsewhere. So there is a potential to have an interim analysis in the study. We'll learn more about whether this could be valuable based, again, on other people's trials as they come forward. Would an interim analysis be a place to see a positive result? But we can't say exactly the timing of what that would be at this point. But if we do it, it would be for the purpose of achieving an earlier BLA. But that's the details we have at this point.
spk06: This concludes our question and answer session. I would like to turn the conference back over to Ian Karp for any closing remarks.
spk10: Great. Thanks so much, Drew. And thank you everyone for joining us today. We look forward to continuing to keep you informed on our progress. But until then, we wish you all a great day and we'll talk again soon. Bye now.
spk06: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

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