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 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 after the call concludes. As a reminder, all participants are currently in a listen-only mode. I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics' third 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 & 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 a 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 Intellia are John Leonard, Chief Executive Officer; David Lebwohl, 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 progress, 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 Intellia, we are 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 3 trial of an in vivo CRISPR-based therapy. This marks Intellia’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 3 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 are only weeks away from the planned completion of patient enrollment for the NTLA-2002 Phase 2 study for HAE, which 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 are 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 Lebwohl, who will provide an update on our clinical programs.

Thanks, John, and welcome everyone. I'll begin with NTLA-2001, our in vivo CRISPR-based candidate for the treatment of ATTR amyloidosis. We were pleased to present updated interim data from the Phase 1 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 and will be reported at a future date. Starting with safety, NTLA-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 1 or 2 in severity, transient, and resolved spontaneously. All patients received a full dose of NTLA-2001 and remain on study. In summary, the NTLA-2001 safety data continue 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 NTLA-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 doses of 0.7 milligrams per kilogram and 1.0 milligrams per kilogram, respectively. Across the 62 patients who received the dose of 0.3 milligrams per kilogram or higher, the mean and median serum TTR reductions were 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 the 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 NTLA-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 continue to show long-lasting responses 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 NTLA-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 3 trial. Now I will share for the first time more information about the pivotal trial design. The NTLA-2001 Magnitude 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 tafamidis and patients who are tafamidis naive at baseline. Patients will be randomized 2:1 to NTLA-2001 or placebo. Patients randomized to the active drug arm receive a single 55-milligram infusion of NTLA-2001. 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. 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 3 study. To start as quickly as possible, we began preparation 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 NTLA-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 NTLA-2002, our in vivo CRISPR candidate for the treatment of hereditary angioedema. In October, the EMA granted PRIME designation to NTLA-2002 based on the positive interim data from the Phase 1 portion of the ongoing Phase 1-2 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 NTLA-2002 to patients as quickly as possible. As John mentioned, we are on track to complete enrollment of the Phase 2 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 3 as early as the third quarter of next year. One of the key advantages of our modulate platform is our ability to apply the learnings from one program to another. We will certainly be incorporating the learnings from the successes of our recent NTLA-2001 regulatory process as we prepare for the NTLA-2002 Phase 3. The strong momentum continues for Intellia, with two active Phase 3 studies for our lead in vivo program expected in 2024. I'll now hand it 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 advanced delivery solutions. In the in vivo setting we have premier 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-3001 in Q1 of next year. If successful, we believe NTLA-3001 will be a major advancement for people living with a long manifestation of Alpha 1 antitrypsin deficiency. In parallel, our collaborators at Regeneron plan to initiate a clinical study next year for our jointly developed Factor 9 gene insertion program for Hemophilia B. Next, building on our CRISPR/Cas9 expertise, we're making strong progress with additional delivery modalities. As we announced today, we will be halting 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 lab. In October, Intellia and 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 NMA 2 CRISPR/Cas9 systems and Regeneron’s antibiotic-targeted viral vector delivery technology. We're excited to deploy NMA 2 Cas9, a compact CRISPR enzyme well-suited for AAV delivery in combination with Regeneron technology to potentially solve delivery to other tissues outside the liver. Regeneron has also exercised its option to extend the existing technology collaboration term with Intellia for an additional two years until April 2026. Alongside our work with Regeneron earlier this quarter, SparingVision announced a selection of its second target as part of our collaboration to develop novel genomic medicines for the treatment of ocular diseases. Looking ahead, in advancing our own in vivo and ex vivo programs, we will continue to seek partners to maximize their value and impact of our proprietary technologies. I will 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, Laura, and good morning, everyone. Intellia 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 marketable 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 a $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 NTLA-2003, as Laura mentioned earlier, to prioritize our 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 3 up and running at Intellia. We have built a modular LNP-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 within 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 the same process in a commercial setting. As a reminder, Regeneron covers 25% of the NTLA-2001 costs. Finally, for NTLA-2002, we anticipate the Phase 3 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 Intellia, we're already focused on what lies ahead. We're only weeks away from the anticipated start of our Phase 3 study for NTLA-2001 and expect to begin the Phase 3 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 Intellia, as well as our 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 will now open the call for your questions. Operator, you may now open the call for Q&A.

The first question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead.

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

Well, I will ask David to address that. Part of the question was how much tafamidis do we think will be in the trial and how we're powering it versus patients on tafamidis we are including. The percentage of patients we estimate will be about half the patients who will be on tafamidis. As you know, tafamidis is becoming a favored care and then we place it around the world, so there will be extensive use of tafamidis. 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 tafamidis or no tafamidis. The benefit in patients with tafamidis can be discerned by looking at the subgroup analyses, which will be conducted because patients are stratified by the use of tafamidis.

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

Hey, congrats on the progress and thanks for taking my questions. I appreciate that NTLA-2001 leads to a deep and durable reduction in TTR that is the connection to differentiate versus one AI drugs clinically? Thank you.

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

Yeah, sure. Do you think the incremental decrease in reduction will be sufficient to differentiate against RNA silencers clinically?

I think I know, yeah, this is David. I got you. The reduction that we're seeing and you've seen here some median of 98% is really significant compared to the absolute levels you see with silencers. The silencers get about an 80% reduction. What we've shown in this recent presentation is absolute levels about 17 micrograms, and the silencers of course have about double that with an 80% reduction. If you look at other studies 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 3 trial.

The next question comes from Mani Forooher with Leerink Partners. Please go ahead.

Hey guys, thank you very much for taking the question. A couple of quick follow ups. Regarding that approximately half tafamidis number I presume that is the proportion of the patients you expect to be on tafamidis on a matched basis at baseline or is that your estimate of the proportion of patients that will be on tafamidis 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 tafamidis 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 the time horizon as opposed to setting a very prescriptive 30 months 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 tafamidis study, are you thinking in terms of absolute reduction in terms of number of mortality, how do you think about the target product profile you're trying to generate from this study presuming you continue to see a robust benefit in lockdown that you have seen thus far?

Yeah, as we understand the analyses of the more recent studies, as you say, the attract study used a different statistical methodology. But the recent studies are looking at reduction in risk of both composites of cardiovascular events and cardiovascular mortality for us. The other studies are certainly 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 we will be looking at the benefit in a similar way.

The next question comes from Rhys Forcep with Guggenheim. Please go ahead.

Hey everyone this is Rhys from Debjit's team. So for enrollment objectives in the Magnitude Study, what is the target for inclusion of the NYHA Class 3 subjects?

David, do you want to address that?

Yeah, we have not set a target for that. We will be monitoring the number of Class 3 patients. In our study, I think what you see is we are looking for patients who are at risk. We think that if you have two healthy patients, the drug doesn’t make much difference because there aren’t any events either with or without active drug. But in terms of Class 3 patients, we do think we have a potential to benefit them with our deep reductions in TTR or consistent reductions in TTR, and we will be looking at that in the clinical trial.

The next question comes from Dae Gon Ha with Stifel. Please go ahead.

Great, good morning, guys. Thanks for taking the question. I will just pivot a little bit to the latest presentation at the 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.

Yes, these are patients in the trial who have congestive heart failure. And these are patients, of course, who are at risk of having exacerbation in the course of their disease. So these are patients who, in the course of their disease, did have a worsening. That's really what we can say about them. 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 about half of which are patients with cardiomyopathy.

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 Helio Speed, 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, I will try to get all that. So we are not setting a particular number of patients that will be at 30 months, but a large proportion will be at 30 months even with an event-driven trial. The advantages of an event-driven trial are that when you will be following patients beyond the 30-month point, your patients who are going longer, get more information from them. And there will be some patients who have less than 30 months. We are 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?

I believe the interim analysis will certainly involve reviewing data from other studies to assess the benefits of reducing TTR with silencers, and it will help determine whether to continue with the interim analysis based on how historical data from other studies is progressing.

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

Thank you for taking my questions. I also have a few regarding the Phase 3 study design particularly for NTLA-2001. So just from a philosophical point of view, all the other studies they enroll by 50%, close to 50% on the baseline task is because actually was earlier studies and took a few years. So now the dynamic has changed. Just wondering why can’t you, or didn’t you think about just 100% of every patient will pass and now we'll have definitive results whether you will be 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 3 study, and the flexibility when you can modify in the way you be planning to expand more patient numbers or will you be planning to wait for a few more events to reach?

Let's start with the last point. Yes, we have the ability to adjust the design before it's unblinded. We will monitor the results from other trials as we determine the best approach. It seems less probable that we would want to increase the patient count and observe them for an extended duration. As seen in other studies, the benefits typically manifest later in the trials, usually after about a year of treatment. We hope to see these benefits appear earlier in our trial, but there appears to be a delay in the effectiveness of reducing amyloid. While we're not discussing the specific statistical methodology, it is somewhat aligned with what other studies are employing. Additionally, many countries still lack access to tafamidis, so assessing the benefits in patients who do not have it will also be a significant aspect of the trial.

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 NTLA-2003, can you just walk us through what you saw pre-clinically to discontinue this program? And just your thoughts about why gene writing is the technology to move forward with here? Thank you.

Thanks, Salveen. No, I'll take that. It is John. As we looked at the strict liver manifestations of Alpha 1 antitrypsin deficiency, which is what NTLA-2003 would address, we see that as what is a pretty small subset of all patients; it's estimated that only 10% to 15% actually experience 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 opportunities 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 Issi with RBC. Please go ahead.

Oh, great. Thanks so much for taking my questions and David, apologies. We're coming back to you, I guess. But can you just talk about the two-to-one randomization here, is that something that you proactively pitched the FDA, or did they ask you to do a 2:1 randomization trial, so you can collect more safety data from the active arm, given the novelty of the technology? Any thought there would be much appreciated? And then maybe if I may, can you just talk, you've already alluded to it, can you talk about why cardiovascular mortality, and not all-cause mortality? Thanks so much.

In terms of the two-to-one randomization, this was our decision and it was approved by regulators worldwide. This approach is beneficial for patients entering a trial. Many of these patients may receive a placebo if the trial shows positive results, and if we have an active drug available at that time, we will likely allow them to transition to it. Ultimately, this is in the best interest of the patients. We believe we can gather more safety data by transitioning patients to the active drug. We consider cardiovascular mortality to be the more significant endpoint here, as all-cause mortality can be influenced by other factors in this elderly population. Therefore, we want to focus closely on the impact we have on cardiovascular events and mortality.

The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.

Great. Thanks for taking our questions. Just following up on the 2:1 ratio, given that if the trial size is similar as the other studies but the randomization is 2:1 as opposed to 1:1, does that imply that your assumed effect size could be greater than RNA silencers? And also just wondering when might we have an insight or understanding of the treatment effect versus silencer, do you think we have to wait until the conclusion of the Phase 3 study or perhaps there could be early signals from your Phase 1 study, such as evidence from NT-pro BNP, or other evidence, if you can comment on that, that would be great? Thank you.

So we do think that the effect size will be greater than seen with RNA silencers. You can, we felt this will be very well powered even if the effect size is similar to the RNA silencers; it is a large trial and it has very high power to look at differences of the two arms. Can you give me a second, we do think there will be some insights coming from the Phase 1 study. Of course, it's a non-randomized study with a relatively small number of patients. What we do with sufficient follow-up will have some evidence perhaps, we might have evidence that this is better than what's happening with RNA silencers.

The next question comes from Greg Harrison with Bank of America. Please go ahead.

Hey, good morning, and 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?

We believe, as indicated in other studies, that reducing TTR is crucial for any clinical benefit. Additionally, we have observed that lower levels provide even greater benefits, particularly as they reach very low levels. A relevant example outside of TTR is light chain disease, where patients achieving a complete response tend to have survival rates that are nearly normal, with minimal heart failure incidence. Furthermore, our reduction results are quite consistent. Nearly all patients have achieved these low levels, which is a significant improvement over what has been accomplished with RNA silencers. We are exploring various approaches to understand disease reversal better, as this phenomenon has not been documented before; we will need to analyze our own data to gain deeper insights as we progress.

The next question comes from Joseph Thome with TD Cowen. Mr. Thome, not sure if it's possible to lower the volume in the background. 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 with regards to the HAE, the preclinical data that you need to allow dosing in women of childbearing age and if that has any implication for the Q1 2024 anticipated IND submission for AATD given the gender dispersion and the age of onset for that medication as well? Thank you.

So the study states it's going to be completed well before the Phase 3 starts in the first quarter of next year 2024. And so it's on track for the first half. The second question was about Alpha 1, I think about that.

Yeah, completion of that relates to the Q1 filing and AATD at all for 3001?

They're unrelated. It's not related to that right now.

The next question comes from Liisa Bayko 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 TAFA 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 and the people who are not on NTLA-2001. So then kind of how to account for that statistically? Thank you.

Yes, that is a possibility. Since we anticipate the active treatment arm will perform better, there may be a tendency for patients in the placebo group to begin tafamidis. There are a few points to consider. We require patients to start tafamidis after one year of therapy; they will not begin tafamidis at the study's onset. To address this, we can assume that those patients who start tafamidis after a year will show some improvement in the placebo group due to the number of patients switching to tafamidis.

The next question comes from Rick Bienkowski with Cantor Fitzgerald. Please go ahead.

Hey, good morning. Congrats on all the progress. Also, I have a question about tafamidis. So in the Apollo Billion trial, the benefit in the active arm was driven by patients who are not also treated with tafamidis. 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 that's also something that could potentially emerge from cardiovascular endpoints?

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 these small differences that we saw on the two arms, it's hard to attribute it to whether benefit combination with tafamidis or not was important or other factors. We do hope as that trial matures, they may be able to get additional results. Of course, that may be highly diluted by the fact that they crossed patients over to silencer or the placebo patients. 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 tafamidis. So it will be the Helios B trial, which they said will be coming in the first half of 2024. But we should have much more information with longer follow-up about combinations with tafamidis or without tafamidis.

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

Hi, thanks for taking the question. Maybe just one clarification on NTLA-2001 manufacturing, it sounds like you're obviously making product now ahead of the Phase 3. 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 3, so that everything from this process that's been used in the Phase 3 is what you're going to use for the commercial product? Thank you.

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

Yeah. Good morning, and thank you for the questions. So when we initiated the Phase 1 trial for NTLA-2001, we knew we were going to need to those many patients. So we began activities to scale up the manufacturing process and bring it to the facilities where we intend to commercialize. So as both Glenn and David mentioned, we already manufacture the majority of the product that we need and manufacture it with the manufacturing processes that we intend to use in the commercial setting as well as 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 we enter commercialization, we will take as many of these processes and these facilities.

The next question comes from Brian Cheng with J.P. Morgan. Please go ahead.

Good morning, guys. Thanks for taking my question. The NT pro BNP cutoff in your Phase 3 is higher than the one seen in the LLB, and attributes CM. Can you comment on the cutoff here, how might that higher cutoff potentially affect the distribution of the NYHA class and baseline TTR level? Thank you.

Yeah, so we did choose a higher level of 1000. And the idea here, talking to our experts around the world or leading 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 effects of the drug. Patients should be somewhat sicker though we should say in all these trials; the average pro BNP tends to be around 2000 in all the trials. So it is around where most patients sort of leave. But we did want to make it important that we could show a benefit to patients.

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

Good morning. This is Stephanie, on for Myles. Just a quick question. Our analysts took me on for Myles. We just had a quick question on the follow-up from the Phase 1 study of NTLA-2001. Do you have any additional details to share about the clinical modules of efficacy? And what sort of follow-up would be planned for that?

Could you talk about some of the clinical endpoints that we look forward to seeing from the Phase 1 work in 2011?

Okay, none of the things that we looked at in this trial include pro BNP and MRI of the heart. For most patients with cardiomyopathy, they have not reached one year yet. And we're not yet giving 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 NTLA-2001 relative to an RNA silencer? Thank you.

We haven't given a quality and quantitation of 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 Huan for Will. Thanks for taking my question. Could you provide information on how the timeline for the magnitude study aligned with your cash runway? And how do you plan to keep investors interested in Intellia 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 3. Just as a reminder, Regeneron is subsidizing 25% of the costs here on this program.

The next question comes from Silvan Tuerkcan 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 Alnylam’s earnings call where there's increasing switching from patisserie into rotisserie, and I think it's most likely to due to the dosing regimen. Is there any read across to NTLA-2001?

Well, this is John. I'll take that. The fundamental premise of what we're doing with NTLA-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 folks are infused or self-administered or whatever. So convenience certainly figures into this. It's just part of NTLA-2001. As we look at NTLA-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 Lebowitz 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 TTR silencer on the market at some point in the future for cardiomyopathy, how would you consider dealing with the number one, in the inclusion criteria for patients right now, which is just TAF, but also for dropping patients at a subsequent point?

We are considering potential future developments. Therefore, if additional stabilizers become available, we will be able to adjust the protocols to include those patients in the trial. As for silencers, they will be part of the trial, and we expect that some patients may start treatment with a silencer during the trial, and we have planned for that in the trial design. Maybe we can turn to Laura, who can speak to unique approaches to target analyses with an insertion candidate versus a non-insertion candidate, and just generally how we approach our targets versus what's been presented at the recent AATD.

Yeah, I'm not sure. Thank you for the questions. So for any of our insertion programs, whether it is Factor 9 to start with a guide, the insertions need to be driven. You know the double strand that's introduced by your selected guide. Recently guides that do not have target. Here we're looking at on-target. And, of course, in spite of the character extension you look for insertion, particularly on that side, but then you look more broadly. But again the goal is that we should at least ensure that the insertion is in a very effective location, and yes, all of that is part of our IND teamwork.

The next question comes from Steve Seedhouse with Raymond James. Please go ahead.

Hi, good morning. This is Nick on for Steve. I actually have a broader question related to CRISPR technologies. Do you have plans for patient-level hold genomes so you can see across any year programs to evaluate off-target edits in future studies, even if it's of 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 with that assessment. I think the approach that we've taken from how we look at off-targets versus what was presented also differs in there 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 Juan on for Whitney. Thanks for taking our question. Just wanted to ask about the magnitude trial, also says functional endpoints like the six-minute walk test as part of preliminary endpoints, and I guess what's your take on requiring this?

We will include the six-minute walk tests as a secondary endpoint.

The six-minute walk test will be an exploratory endpoint in our trial. The second question?

Yeah, we think the most important secondary endpoints include quality of life as a high level of interest 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.

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 and roll out 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.