Intellia Therapeutics, Inc.

Good morning and welcome to the Intellia Therapeutics third 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. 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.

Thank you, operator, and good morning, everyone. Welcome to Intelia Therapeutics' third 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 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, Intellia 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 John Leonard, Chief Executive Officer, David Lebwal, Chief Medical Officer, 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 pipeline progress. Laura will review our R&D updates, and Glenn will review our financials before we open up the call for questions, at which time Eliana Clark, our Chief Technical Officer, will also be available. With that, I'll now turn the call over to John, our Chief Executive Officer.

Thank you, Ian, and thank you all for joining us today. At Intelia, we're at the forefront of realizing the promise of genome editing in unprecedented ways. Through the remarkable efforts of our experienced team, we recently received FDA clearance to begin the first ever pivotal phase three trial of an in vivo CRISPR-based therapy. This marks Intelia's second in vivo IND that the agency has cleared this year, further demonstrating our deliberate and systematic approach to drug development. As a result of our commitment to high technical standards, whether in basic research, assessing safety, manufacturing, or in the clinical development of our drug candidates, we've moved another step closer towards ushering in a new era of medicine. With the imminent start of the phase three for NTLA-2001, Intellia is now a late stage drug development company. As David will go through in more detail, the latest interim data give us confidence that NTLA-2001 could potentially reset the standard of care for ATTR amyloidosis. These data, now from over 60 patients, showed a favorable safety profile, as well as consistently deep and durable TTR reductions following a single infusion. Alongside all the progress we've made with NTLA-2001, a broader pipeline and platform continue to advance as well. We're only weeks away from the planned completion of patient enrollment of the NTLA-2002 Phase 2 study for HAE. This means we are now approaching 100 patients dosed with either of our two lead in vivo candidates. Additionally, we expect to submit a regulatory filing to begin clinical development of our first wholly owned in vivo gene insertion program, NTLA-3001, in Q1 of next year. Overall, 2023 has already been a highly productive year, and there's still much more to come in the weeks and months ahead. In this challenging financial market that has impacted our entire sector, we continue to further tighten our financial management to turn the promise of gene editing into reality for patients. Our balance sheet remains strong and we are prioritizing programs and platform innovations we believe will address unmet needs and provide the greatest value to our shareholders. We're acutely focused on the efficient and rapid advancement of our two lead in vivo programs and their anticipated future commercialization. I'll now hand the call over to our Chief Medical Officer, David Leblall, who will provide an update on our clinical programs. David?

Thanks, John, and welcome, everyone. I'll begin with 2001, our in vivo CRISPR-based candidate for the treatment of ATTR amyloidosis. We were pleased to present updated interim data from the phase one study at the fourth international ATTR amyloidosis meeting for patients and doctors last week. The data presented from the largest in vivo gene editing study run to date were from the initial 65 out of 72 patients. The results from the final seven patients dosed were enrolled after the data cutoff will be reported at a future date. Starting with safety, 2001 was generally well tolerated across all patients and at all dose levels tested. The most commonly reported adverse events were infusion-related reactions. The majority of adverse events, including infusion-related reactions, were grade one or two in severity, were transient, and resolved spontaneously. All patients received a full dose of 2001 and remain on study. In summary, the 2001 safety data continues to be encouraging. Moving on to the activity data that begins on this slide. In the newly reported dose expansion portion, a single dose of 2001 at the 55 milligram and 80 milligram dose led to profound reductions of serum TTR levels. These results were consistent with the data previously reported from patients in the dose escalation portion, who received the corresponding weight-based dose of 0.7 milligrams per kilogram and 1.0 milligrams per kilogram, respectively. Across all 62 patients who received a dose of 0.3 milligrams per kilogram or higher, the mean and median serum TTR reductions was 90% and 91%, respectively, at day 28. The three initial patients who received the lowest dose of 0.1 milligram per kilogram have all received a follow-on dose of 55 milligrams, and these data will be presented in the future. On the next slide, you'll see for the first time the absolute residual TTR concentration levels for all 62 patients dosed with 2001. These data are striking in comparison to what you would expect to see with RNA silencers. Regardless of a patient's baseline TTR level, all patients reached a low level of residual TTR concentration and then, as expected with our gene editing modality, stayed at these low levels. With over 20 patients now having reached at least 12 months of follow-up, these patients continued to show long-lasting response with no evidence of loss in activity over time. As Dr. Gilmore highlighted in his talk last week, While the clearance of amyloid is invariably slow and occurs at different rates in different organs, the concentration of amyloid protein matters. As seen with other types of amyloidosis, achieving a greater reduction in circulating concentration of the amyloid precursor protein is associated with a better clinical outcome. And here, with ATTR amyloidosis, we anticipate seeing similar results. The persistently low levels of TTR concentration achieved with 2001 are expected to reduce the rate of ongoing amyloid formation and hold the possibility for amyloid clearance to reverse the symptoms of the disease. We have also observed early signs of clinical activity in the initial cohorts and look forward to presenting the first clinical data beyond TTR levels once we have longer follow-up across all cohorts. We believe these encouraging interim data bode well for what we'll see in the future. These data also support the selection of 55 milligrams as a dose for further evaluation in the Phase III trial. Now, I will share for the first time more information about the pivotal trial design. The 2001 Magnin-2 trial is a global randomized double-blind placebo-controlled study. It will enroll approximately 765 patients living with ATTR amyloidosis with cardiomyopathy who have either the hereditary or wild-type form of the disease. The study is designed to enroll patients on concomitant tefamidus and patients who are tefamidus naive at baseline. Patients will be randomized 2 to 1 to 20 to 1 or placebo. Patients randomized to the active drug arm receive a single 55 milligram infusion of 20-01. The primary endpoint is a composite endpoint of cardiovascular-related mortality and cardiovascular-related events, such as urgent heart failure visits and hospitalizations. The study will read out when both a pre-specified number of events have occurred, and the final patient has completed at least 18 months of follow-up. Secondary endpoints include serum TTR levels and the Kansas City cardiomyopathy questionnaire score. Notably, if needed, we'll be able to adjust the trial via protocol amendment based on learning from others in the space, and the protocol includes an optional interim analysis which could provide an earlier readout. Moving to the next slide, we are poised for rapid initiation and enrollment in the Phase III study. To start as quickly as possible, we began preparations for this pivotal trial months ago. We have selected the majority of our clinical sites around the world and have seen great enthusiasm from investigators. Additionally, patients themselves have expressed strong interest in enrolling in the program, including here in the United States. If enrollment goes as quickly as we hope it does, we are well prepared to supply the drug product needed. The majority of 2001 for use in the study has already been manufactured, employing the same process and facilities to be used in the commercial setting. As previously guided, we are on track to initiate the study by year end with patient dosing to commence early next year. I'll now turn to 2002, our in vivo CRISPR candidate for the treatment of hereditary angioedema. In October, the EMA granted PRIME designation to 2002 based on the positive interim data from the Phase I portion of the ongoing Phase I-II study. We're very pleased to receive PRIME designation because it is only awarded to drug candidates that may offer a major therapeutic advantage over existing treatments. With PRIME, we gain valuable regulatory benefits with a goal of getting 2002 to patients as quickly as possible. As John mentioned, we are on track to complete enrollment of the phase two portion by year end. We're also on track to complete in the first half of next year, the additional mouse study requested by the FDA and expect to initiate the phase three as early as third quarter of next year. One of the key advantages of our modular platform is our ability to apply the learnings from one program to another. We will certainly be incorporating the learnings from the success of our recent 2001 regulatory process as we prepare for the 2002 phase three. The strong momentum continues for Intelia with two active phase three studies for a lead in vivo program expected in 2024. I'll now hand over to Laura, our Chief Scientific Officer, who will provide updates on our R&D efforts.

Thank you, David. Good morning, everyone. We're entering the next stage of innovation with our editing and delivery solutions. In the in vivo setting, we have three near-term priorities. This includes clinically validating our gene insertion platform, moving our gene editing capabilities outside the liver, and continuing to expand our comprehensive gene editing toolbox. Starting with in vivo gene insertion, we plan to submit a CTA for NTLA-30-01 in Q1 of next year. If successful, we believe NTLA-30-01 will be a major advancement for people living with a lung manifestation of Alpha-1 antitrypsin deficiency. Our collaborators at Regeneron plan to initiate a clinical study next year for our jointly developed Factor IX gene insertion program for hemophilia B. Next, building on our CRISPR-Cas9 editing expertise, we're making strong progress with additional editing modalities. As we announced today, we will be holding further IND-enabling activities for NTLA-2003 our in vivo candidate for the treatment of the 10 to 15% of Alpha-1 patients with liver disease to prioritize a research program for Alpha-1 utilizing our DNA writing technology. Finally, we established a new collaboration to accelerate gene editing capabilities outside the liver. In October, Intellian Regeneron announced an expanded research collaboration to jointly develop in vivo programs for the treatment of neurological and muscular diseases. This collaboration leverages our proprietary NME2 CRISPR Cas9 systems and Regeneron's antibody-targeted viral vector delivery technology. We're excited to deploy NME2 Cas9, a compact CRISPR enzyme well-suited for AAV delivery in combination with Regeneron's technology to potentially solve delivery to other tissues outside the liver. Regeneron has also exercised its option to extend the existing technology collaboration term within Thalia for an additional two years until April 2026. Alongside our work with Regeneron, earlier this quarter, Sparing Vision announced the selection of a second target as part of our collaboration to develop novel genomic medicines for the treatment of ocular diseases. Looking ahead, in addition to advancing our own in vivo and ex vivo programs, we will continue to seek partners to maximize the value and impact of our proprietary technologies. And now hand over the call to Glenn, our Chief Financial Officer, who will provide an update on our financial results as of third quarter 2023.

Thank you, Lauren. Good morning, everyone. Intelia continues to maintain a strong balance sheet that allows us to execute on our plans to advance our pipeline and platform. As shown on this slide, our cash, cash equivalents, and markable securities were approximately $993 million as of September 30, 2023, compared to $1.3 billion as of December 31, 2022. Please note this does not include the $30 million tech collaboration extension payment from Regeneron expected in the first half of 2024. As we move forward in the current capital market environment, we will continue to be selective with how we deploy capital and will continue to make important portfolio prioritization decisions to support our continued growth. One such example is the decision to halt further IND-enabling activities for Intel A2003. As Laura mentioned earlier, to prioritize a research program using our DNA writing technology for Alpha 1. Looking ahead, we do not expect a significant uptick in our operating expenses as we get closer to having two Phase 3s up and running at Intelia. We have built a modular LMP-based platform where manufacturing processes and drug components are largely the same across multiple programs. Unlike viral-based gene therapies, our drug components are synthetic with well-established manufacturing readily available. Therefore, the cost to manufacture is significantly less expensive than traditional gene therapy. In addition, for NTLA-2001, we have finished scaling up our manufacturing process to meet the needs of the pivotal trial for which a majority of the drug product has already been manufactured. We anticipate being able to leverage this same process in the commercial setting. As a reminder, Regeneron covers 25% of the NTLA-2001 coughs. Finally, for NTLA-2002, we anticipate the Phase III study to be small, relatively quick to enroll and complete. In summary, we continue to efficiently deploy our resources with a heavy emphasis on advancing our two lead programs towards commercialization. We expect our cash balance to fund our operating plans beyond the next 24 months. And with that, I'll turn the call back over to John for closing remarks.

Thanks, Glenn. I want to close by acknowledging that while it's been an exciting year filled with many milestone achievements for Intelia, we're already focused on what lies ahead. We're only weeks away from the anticipated start of our phase three study for NTLA-2001 and expect to be in the phase three for NTLA-2002 next year. With the start of these two pivotal studies, we will move one step closer to commercialization and ultimately profitability. What was once a distant hope to turn CRISPR into medicines is now quickly within our grasp. Finally, I'd like to take a moment to thank the incredible team at Intelia as well as the physicians and patients involved in our clinical trials as the true trailblazers in this field. Without their passion, dedication, and courage, we would not be entering this next phase of innovation towards a new era in genomic medicine. With that, we'll now open the call for your questions. Operator, you may now open the call for Q&A.

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 2. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Costas Valouris with BMO Capital Markets. Please go ahead.

Hello, good morning, everyone. Thanks for taking our question. Maybe one question, I will restrict it to one question. Can you discuss a little bit about whether the trial is powered to demonstrate statistical significance of 2001 on top of the family's in this case, and what percentage of tefamidase baseline you allow in the trial? Thank you.

Well, I'll ask David to address that. Part of the question was how much tefamidase do we think will be in the trial and how we're powering it versus patients on tefamidase.

Thank you, Costas. The percentage of patients we estimate will be about half the patients will be on tefamidase. As you know, tefaminis is becoming a standard of care in many places around the world, so there will be extensive uses of tefaminis. In terms of powering, the study has 765 patients. It's powered to show an improvement of the active arm versus the placebo arm, including patients who have either tefaminis or no tefaminis. The benefit in patients with tefaminis can be discerned by looking at the subgroup analyses which will be because patients are stratified by the use of defaminus.

The next question comes from June Lee with Truist. Please go ahead.

Hey, congrats on the progress and thanks for taking our questions. We appreciate that the NCAA 2001 leads to a deep and durable reduction in TTR. but if the incremental death is sufficient to differentiate versus the RNAi drug clinically. Thank you.

June, I'm sorry. I'm going to have to ask you to say it again. The call was very, very garbled. Just give it another shot.

Yeah, sure. Do you think the incremental death and reduction will be sufficient to differentiate versus the RNAi drug?

I think I heard. Yeah, this is David. Thank you. Yeah, the reduction that we're seeing, and you've seen here, it's about a median of 90%, is really having the amount of PTR, thinking about it at absolute levels, that you see with the silencers. The silencers get about an 80% reduction. What we've shown in this recent presentation is absolute levels, about 17 micrograms, and the The silence, of course, have about double that with 80% reduction. If you look at Alnylam's data, for example, in polyneuropathy, you do see that there's actually a greater than proportional benefit as you reduce the TTR protein. So we do think this will make a significant clinical benefit for patients, and that's what we will plan to prove in our phase three trial. Thank you.

The next question comes from Mani Buruhar with Xerink Partners. Please go ahead. Hey, guys. Thank you very much for taking the question.

A couple of quick follow-ups regarding that approximately half the FAMIDIS number. I presume that is the proportion of the patients you expect to be on FAMIDIS. on a matched basis at baseline, or is that your estimate? Or is that your estimate of the proportion of patients that will be on to FAMINIS across the course of the study, including drop-in? And I have one more follow-up.

Do you want to address that, David?

Yeah, I was referring to the number of patients at baseline. We have anticipated that during the study, some patients may start on to FAMINIS after that, and obviously we'll be monitoring this during the trial.

Great. And obviously you guys have taken a slightly different approach around flexibility around reaching an event rate on time horizon as opposed to setting a very prescriptive 30-month endpoint, for example. How should we think about what is the target product profile you guys are looking for in terms of, Are you targeting a relative risk ratio on your label that looks like the original feminist study? Are you thinking in terms of absolute reduction in terms of number of mortality? How do you think about the target product profile that you're trying to generate from this study, presuming you continue to see a robust benefit knockdown that you've seen thus far?

Yeah, as we understand the analyses of the more recent studies, as you say, the TRACS study used a different statistical methodology, but the recent studies are looking at reduction in risk of both a composite of cardiovascular events and cardiovascular mortality for us. The other studies are subtly different. Some people look at total mortality and other small differences, but overall, the current studies that are ongoing are using a fairly similar endpoint and will be looking at the benefit in a similar way.

Great. That's helpful. Thanks, guys.

The next question comes from Rye Forseth with Guggenheim. Please go ahead.

Hi, everyone. This is Rai from Debjit's team. So for enrollment objectives in the magnitude study, what is the importance or target for inclusion of the NYHA Class III subjects?

David? Yeah, we have not set a target for that. We will be monitoring the number of Class III patients. In our study, I think what you'll see is we are looking for patients who are at risk. We think that if you have two healthy patients, of course, a drug doesn't make much difference because there aren't any events either with or without active drug. But in terms of class III patients, we do think we have the potential to benefit them with our deep reductions in TTR, our consistent reduction in TTR, and we'll be looking at that in the clinical trial.

Thank you. The next question comes from Dagon Ha with Stifold. Please go ahead.

Great. Good morning, guys. Thanks for taking the question. I'll just pivot a little bit to the latest presentation at ATTR amyloidosis meeting. I wanted to get a clarification on the safety data, specifically on the cardiac failure tabulation on slide 10 of the presentation. You saw grade 2 and grade 3s. Can you clarify when or what kind of events these were? Thanks so much.

Yeah, of course, these are patients in the trial who have congestive heart failure, and these are patients, of course, who are at risk of having exacerbation of that in the course of their disease. So these are patients who, in the course of their disease, did have a worsening, and that's really what we can say about them. It's just, as you can see, it's a very small number of patients among a group of now a total of 75 patients, more than half of which are patients with cardiomyopathy.

Great, thanks so much.

The next question comes from Maury Raycroft with Jefferies.

Please go ahead. Hi, good morning, and thanks for taking my question. The size of the pivotal is larger than Heliospeed, but it seems like the duration of the study has options in it where it could be stopped early. Can you talk about the proportion of patients you will need at 30 months and the pre-specified number of events needed? And what are your expectations for enrollment timelines and when an optional interim could occur?

Yeah, sorry to get all that. So we are not setting a particular number of patients to be at 30 months, but a large proportion will be at 30 months, even with an event-driven trial. However, the advantages of an event-driven trial is that you will be following patients beyond the 30-month point. So you have patients who are going longer, get more information from them. and there will be some patients who have less than 30 months. We're not yet giving guidance on completion of enrollment, and we're not talking in detail about the number of events at this point.

Okay. Is there anything more you can say about the optional interim and what would be factored into that?

Yeah, I think the interim analysis will be obviously looking at data from other studies to understand the benefit of reducing TTR with silencers, for example. and understanding and be able to decide whether to keep the interim analysis or not, depending on how the historical data is going with other studies.

Got it. Okay. Thanks for taking my question.

The next question comes from Gina Wang with Barclays. Please go ahead.

Thank you for taking my questions. I also have a few regarding the phase three study design for 2002-2001. So just, you know, from philosophical point of view, all the other studies, they enrolled 50%, close to 50% on the baseline TAF is because actually it was earlier studies and took a few years. So now the dynamic has changed. Just wondering why, you know, country or didn't you think about just 100% every patient on TAF, and that will have a definitive result whether you will be a superiority against the TAF monotherapy and also will help with the stats. And the second question is also regarding the stats methodology. What is the method you will use for the Phase III study and flexibility when you can modify Will you be planning to expanding more patient numbers, or will you be planning to wait until more events reach?

Let's start with the last one. Yes, we are. There is flexibility to modify the design before it's unblinded. So, again, we will be watching the results from other trials as we decide the best way to do that. I think it's less likely that we'd want to expand the number of patients than to follow them for a longer period of time. I think, as you've seen in the other studies, the benefit tends to come later in the trials after about a year of treatment. In those trials, we're hoping that will come earlier in our trial, but still, there does seem to be some delay in the benefit of reducing the amyloid. We're not talking about the exact methodology, but as I said, it is similar to what the other studies are using. There are a lot of countries that still do not have defamitis. We think that looking at the benefit in patients who don't have defamitis will be an important finding in the trial as well.

The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.

Good morning. Thanks for taking my question. With regard to the AAT program 2003, can you just walk us through what you saw clinically to discontinue this program and just your thoughts about why gene writing is the technology to move forward with here? Thank you.

Thanks, Sophie. I'll take that. It's John. As we looked at the strict liver manifestations of alpha-1 antitrypsin deficiency, which is what 2003 would address, we see that as what is a pretty small subset of all patients. It's estimated 10% to up to 15%. We actually experienced that. And so as we balance that opportunity versus the progress we're making with the gene writing approach, we thought that the better deployment of our resources was to the gene writing, which, again, is making good progress in the preclinical setting. We will have more opportunity to talk about that as time goes on, but one of the things that we're very excited about is deploying that technology even more broadly in other conditions.

The next question comes from Luca Isi with RBC. Please go ahead.

Oh, great. Thanks so much for taking my question, and David, apologies. We're coming back to you, I guess. Can you just talk about a two-to-one randomization here? Is that something that you proactively pitch the FDA, or did they ask you to do a two-to-one randomization trial so you can collect more safety data from the active arm, give it a novelty of the technology? Any thoughts there would be much appreciated. And then maybe if I may, can you just talk, you already alluded to it, can you talk about why cardiovascular mortality and not all-cause mortality? Thanks so much.

Okay, in terms of the two-to-one randomization, this is our decision. It was agreed by regulators around the world. It's favorable for patients, of course, entering a trial. So that's a lot of it. These patients will likely, the placebo, if the trial is positive, we will likely allow them to go on to active drug or make active drug available to them at that point. But it really is in the interest of the patients. We do get, as you say, more safety data as we possibly could get by crossing patients over to active drugs. The CV mortality, we think, is the more important endpoint here. It won't be, you know, all-cause mortality can have noise from other causes of mortality in this elderly population. So we do want this really to be looking sharply at the effect that we have on cardiovascular events and mortality.

Thanks so much.

The next question comes from Yann Anjou with Wells Fargo Securities. Please go ahead.

Great. Thanks for taking our questions. Just to follow up on the 2 to 1 ratio, given that if the trial size is similar as the Helios B, but the randomization is 2 to 1 as opposed to 1 to 1, does that imply that your assumed effect size could be greater than RNA silencers, and also just wondering when might we have insight or understanding of the treatment effect versus silencers? Do you think we have to wait until the conclusion of this Phase III study, or perhaps there could be early signals from your Phase I study, such as evidence from NT-proBNP, or other evidence. If you can comment on that, that would be great. Thank you.

We do think that the effect size will be greater than seen with RNA silencers. We felt this is very well powered, even if the effect size is similar to the RNA silencers. It is a large trial and has very high power to look at differences of the two arms. Can you hear the second? Yeah, we do think there will be some insights coming from the phase one study. Of course, it's a non-randomized study with a relatively small number of patients, but we do think with sufficient follow-up, we'll have some evidence perhaps. We might have evidence that this is better than what's happening with RNA silencers.

Great.

Thanks for the cover. The next question comes from Greg Harrison with Bank of America. Please go ahead.

Hey, good morning. Thanks for taking the question. For the absolute residual serum TTR concentration you've talked about, can you help us understand your view on what level is clinically meaningful and where you could potentially see disease reversal?

So we think, as we've seen in other studies, reducing TTR is important to see any clinical benefit. But what we've also seen is you get greater benefit with lower levels, you get greater benefit, particularly more than proportionally, as you get to very low levels. An example outside of TTR, of course, is light chain disease, where patients with complete response have a survival that looks close to normal. They don't get heart failure significantly. The other piece of what we have with our reductions is it's quite consistent. You've seen the standard error on our On our levels, almost all patients achieve that low level, which is something that hasn't been achieved well with RNA silencers. We are looking at different ways of understanding reversal of disease. Because it hasn't been seen before, we will have to look at our own data in order to understand that better as we move forward.

Got it. Thanks for taking the question.

The next question comes from Joseph Tome with TD Cowan. And Mr. Tome, not sure if it's possible to lower the volume in the background or sound. Please go ahead. Sorry about that.

I'm at the airport. But good morning. Thank you for taking my question. Maybe just one on AATD. Can you just give us an update on where you stand in regards to the HAE, the preclinical data that you need to allow dosing? in the women of childbearing age and if that has any implication for the Q124 anticipated IMD submission for AATD given the gender dispersion and the age of onset for that education as well. Thank you.

The study says it's going to be completed well before the phase three starts in the first quarter of next year of 24. It's on track for the first half. The second question is about Alpha 1, I think, about that.

Yeah, if completion of that relates to the Q1 filing in AATB at all for 3001.

They're unrelated. Yeah, it's not related to that right now.

Thank you. The next question comes from Lisa Beko with Evercore ISI. Please go ahead.

Hi, I just have a question about the study. Can you maybe describe for patients that do start on TAPA, how you're going to account for that in the trial? It seems to me that there's a risk that you might have more of that in the people who are not on 2001, so then how do you account for that statistically? Thank you.

Yeah, so that is possible. The patients who are, because we expect the active arm to be doing better, there might be a bias towards patients starting tofamidus in the placebo arm. There are a couple of things. We do ask that the patients start this after a year of therapy, that they not plan to, from the beginning of the study, not to plan to start tofamidus until the beginning of the study. And The way you can account for it is to assume that those patients, at least after a year, because it does take a year for tefamidus to have a benefit in terms of events, after that year there will be some improvement in the placebo arm due to the number of patients crossing to tefamidus.

Okay, thanks.

The next question comes from Rick Benkowski with Cancer Fitzgerald. Please go ahead.

Hey, good morning. Congrats on all the progress. I also have a question about defamitis. So in the Apollo B trial, the benefit in the active arm was driven by patients who were not also treated with defamitis. I was just curious to hear your thoughts on that observation and if you think that effect was specific to the six-minute walk test endpoint or if that's also something that could potentially emerge from cardiovascular endpoints.

Yeah, I think what we saw in Apollo overall is that they did not follow the patient long enough to understand the potential benefit of reducing TTR. So the small differences that we saw in the two arms, it's hard to attribute it to whether that combination with defaminants or not was important or other factors. We do hope that as that trial matures, they may be able to get additional results, though of course that may be highly diluted by the fact that they cross patients over. to silence the placebo patients. So we think we didn't learn a lot about benefit in that trial. We did learn about event rates and other things from it, but unfortunately not about the value with defaminus. Very different will be the Helios B trial, which they've said will be coming in the first half of 24, but we should have much more information with longer follow-up about combinations with defaminus or without defaminus.

Great. Thanks for the call.

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

Hi. Thanks for taking the question. Maybe just one clarification on 2001 manufacturing. It sounds like you're obviously making product now ahead of the phase three, but just wanted to ensure that there were no other changes planned on manufacturing. that you needed to make as you scale for a potential commercial product post the phase three, so that everything from this process that's being used in the phase three is what you're going to use for the commercial product. Thank you.

So we'll turn to Ileana Clark, our Chief Technical Officer, who can talk about where we stand with the manufacturing and supply.

Good morning, and thank you for the question. So when we initiated the Phase 1 trial for 2001, we knew we were going to need to those many patients. So we began for the Phase 3, for the pivotal trial. And so we began our activities to scale up the manufacturing process and bring it to the facilities where we intend to commercialize. So as was mentioned by both Glenn and David, we already manufacture the majority of the product that we need with the manufacturing processes that we intend to use in the commercial settings. and also in the facilities that we intend to use for the commercial setting. And this is what we included in our IND that we filed with FDA that was clear. We don't anticipate making any changes. Once, you know, we enter commercialization, we will stay with these processes and these facilities.

The next question comes from Brian Chang with KP Morgan. Please go ahead.

Good morning, guys. Thanks for taking my question. The NT-PRO-BNP cutoff in your Phase III is higher than the one seen in the POLO-B and the TPU-CM. Can you comment on the cutoff here? How might that higher cutoff potentially affect the distribution of the NYXH class and baseline TTR levels? Thank you.

Yeah, so we did choose a higher level, 1,000. And the idea here, talking to our experts around the world, including our steering committee, is that patients who are very healthy don't contribute to a trial like this because they have either no or very few events in the course of the trial. It's hard to get lower than no events, obviously, with your drug. So they did recommend that we have patients who are more at risk of having events. We think this will be valuable in seeing the effect of the drug. patients should be somewhat thicker, though we should say in all these trials the average pro-BMP tends to be around 2,000 in all the trials. So it is around where most patients are, but we did want to make it important that we could show a benefit to patients.

Thanks, David.

The next question comes from Miles Minter with William Blair. Please go ahead.

Good morning. This is Tiffany on 4 Miles. We just had a quick question on the follow-up from the Phase 1 study of 2001. Do you have any additional details on when you plan to sort of share those clinical measures of efficacy and what sort of length of follow-up would be planned for that?

Can you talk about some of the clinical endpoints that we can look forward to seeing from the Phase 1 work in 2001?

Okay, yeah, a number of the things that we looked on in this trial include pro-BMP and MRI of the heart. For most patients with cardiomyopathy, they have not reached one year yet, and we're not yet given guidance to when that data will be available. We do want to have data on the full cohorts of patients so that it's mature.

The next question comes from Jay Olson with Oppenheimer.

Please go ahead. Oh, hey, congrats on the progress, and thanks for taking the question. According to your models, to what extent do you expect to further reduce cardiovascular events, including mortality, with a deeper TTR knockdown with 2001 relative to an RNA silencer? Thank you.

We haven't given a quantity and quantitation of the reduction. So it's really hard to answer your question exactly there.

The next question comes from William Pickering with Bernstein. Please go ahead.

Hi, good morning. This is Wen for Well. Thanks for taking our question. Could you provide information on how the timeline for the magnitude study aligns with your cash runway? And how do you plan to keep investors' interest in Intelia over the likely three to five-year trial period? Thanks.

Glenn, do you want to address our spend rate and runway?

Sure, yeah. So thanks for the question. Yeah, so as we talked about, the current cash flow will get us beyond the next 24 months. We're not guiding specifically as to how far deep we'll get into the study with the runway, but we will get pretty deep into the phase three. Just as a reminder, Regeneron is subsidizing 25% of the cost here on this program.

The next question comes from Sylvan Thurken with JMP. Please go ahead.

Thank you. Thanks for taking my question and congrats on that progress. I just wanted to talk about a comment on Anilam's earnings call where there's increasing switching from patisserie to patisserie, and I think it's most likely to, you know, the dosing regimen. Does any read across to Entelia 2001? Thank you.

Well, this is John. I'll take that. The fundamental premise of what we're doing with 2001 is all about efficacy. And we expect to show that with the study that we've been discussing at length here today. So that's what drives physician decisions primarily. But it's also true that the patient experience is key to what doctors will take into consideration. And I don't think it's any secret that medications that are easy to take or that are taken only a single time are going to be easier to take than drugs that are infused or self-administered or whatever. So convenience certainly figures into this. It's part of 2001. As we look at 2002 and the HAE patient population, we've learned that that very much drives how the patients think about taking their medicine. So it's an important aspect for sure.

The next question comes from David Leibowitz with Citi. Please go ahead.

Thank you for taking my question. With respect to the ATTR trial, given the potential enrollment timelines and the fact that there could be another stabilizer on the market and even potentially a TTR silencer on the market at some point in the future for cardiomyopathy, how would you consider dealing with number one in the inclusion criteria for patients on, right now, which is just on TAF, but also for drop-in patients at a subsequent point.

How will we deal with potential trigger regurgles in the future?

Yeah, so for additional stabilizers, when additional stabilizers make them available, we will be able to modify the protocol to allow those patients into the trial. For silencers, of course, this is a while off within the trial. but we do anticipate that some patients will go on to silencer sometime in the trial, and we have designed that into the trial as well.

Got it. And jumping over to AATD and the insertion candidate, given the recent adcom when they certainly focused a lot on various risks associated with insertion, is there any particular nuance to the IND and clinical process that needs to be considered with this approach versus knockdown.

Maybe we can turn to Laura, who can speak to unique approaches to off-target analyses with an insertion candidate versus a non-insertion candidate, and just generally how we approach off-targets versus what's been presented at the recent ADCOM.

Yeah, no, sure. Thank you for the question. So for any of our programs, whether it is alpha one or factor nine, first you start with a guide, right?

So the insertion needs to be driven, the double trend break that's introduced by your selected guide. We select guides that do not have off target, so here we're looking at on target. And of course, as part of the characterization, You look for insertion particularly on that side, but then you look more broadly. But again, the goal is that this is a CRISPR-mediated insertion where it's going to be very specific location for insertion. And yes, all of that is part of our INDNA teamwork.

Well, thank you for taking my questions.

The next question comes from Seed House with Raymond James. Please go ahead.

Hi, good morning. This is Nick on for Steve. I actually have a broader question related to CRISPR's XSL-ICOM. Specifically, do you have plans for patient-level whole genome sequencing across any of your programs to evaluate off-target edits in future studies, even if it was an interest for some of the panel members?

We don't. That's not something that we think would be informative. It's been discussed extensively. with regulatory agencies who all concur in that assessment. I think the approach that we've taken from how we look at off-targets versus what was presented also differ, and that probably figures into the thinking.

The next question comes from Whitney Ijem with Canaccord Genuity. Please go ahead.

Hi, good morning. This is Juwan on for Whitney. Thanks for taking our question. Just wanted to ask, will the magnitude trial also set functional endpoints like six minute walk test as part of secondary endpoints? And I guess what's your take on requiring this?

David, will we include six minute walk test as a secondary endpoint?

Yeah, six minute walk test will be an exploratory endpoint in our trial.

Second question, what's the utility of other secondary endpoints, I think was what was asked.

Yeah, we think the most important secondary endpoints include quality of life. There's a high level of interest in that, both among regulatory agencies as well as other places, and as well TTR levels. Reduction in TTR will be important as a secondary endpoint. Great. Thank you.

This concludes our question and answer session. I would like to turn the conference back over to Ian Karp for any closing remarks.

Okay, well, thanks again, everyone, for joining us. We appreciate your time, and we look forward to continuing to update you as we make further progress with our pipeline and technologies. Have a great day, everyone.

The conference has now concluded. Thank you for attending today's conference. You may now disconnect.