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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 a listen-only mode. [Operator Instructions]. 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; and 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'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 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 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 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. 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 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 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 1 or 2 in severity, 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 the 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 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 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 a 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 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 in patients who are tafamidis naive at baseline. Patients will be randomized 2:1 to 2001 or placebo. Patients randomized to the active drug arm receive a single 55-milligram infusion of 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. 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 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 enrolment 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 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 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 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 success of our recent 2001 regulatory process as we prepare for the 2002 Phase 3. The strong momentum continues for Intellia with two active Phase 3 studies for a lead in vivo program expected in 2024. I'll now hand it over to Laura, our Chief Scientific Officer who will provides updates on our R&D efforts.

thank you, David. Good morning, everyone. We're entering the next stage of innovation with our [indiscernible] delivery solutions. In the EV setting we have premier priorities, this includes clinically validating our gene insertion platform, moving our gene editing capabilities outside the lever 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 efficiency. 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, a leading expertise we're making strong progress with additional LED [ph] modalities. As we announced today, we will be halting further INDNA brain 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 [ph]. In October, Intellia and Regeneron announced an expanded research collaboration to jointly develop in vivo programs for a treatment of neurological and muscular diseases. This collaboration leverages our proprietary NMA 2 [ph] 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 innovation to 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 handover 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 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 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 privatization 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 officially 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 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 Trail Blazers 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.

[Operator Instructions]. 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 power to demonstrate statistical significance of 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 [indiscernible]. The percentage of patients we estimate will be about half the patients who will be on tafamidis. As you know tafamidis is becoming a favorite care and then we place it around the world, so the world be -- extensive use of tafamidis. In terms of powering, the study has 765 patients, its 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 sub group analyses, which will be 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 the NTLA 2001 leads to a deep and durable reduction in TTR that is the connected best because it's efficient' 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, very, garbled. Just give it another shot.

Yeah, yeah, sure. Do you think the incremental debt in reduction will be efficient to differentiate [Question Inaudible]?

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 having the amount of TTR thinking about its absolute levels that 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 silencer of course have about double that with 80% reduction. If you look at an [indiscernible] 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 patient, and that's what we will plan to prove in our Phase 3 trial.

Thank you.

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 -- 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 day after that and obviously we'll be monitoring this during the trial.

Great. And obviously you guys have taken a slightly different approach around sort of flexibility around reaching an event rate on time horizon as opposed to setting a very prescriptive 30 months end point 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 they'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 not as you say they attract study used a different statistical methodology. But the recent studies are looking at reduction and risk of both composites of cardiovascular events and cardiovascular mortality for us. The other studies are suddenly 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.

Great, that's helpful. Thanks guys.

The next question comes some Rhys Forcep [ph] with Guggenheim. Please go ahead.

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

David, do you want to?

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, of course 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.

Thank you.

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 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 of that, 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. 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 -- about 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 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 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 is that when you will be following patients beyond the 30 month point. So 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?

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 the -- and be able to decide whether to keep the interim analysis or not depending from on how historical data is going with other studies.

Got it. Okay, thanks for taking my question.

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 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 had change. Just wondering why can’t you or didn’t you think about just 100% every patient will pass and now we'll have a 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 expanding a more patient numbers or will you be planning to wait a few 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 and to follow them for a longer period of time. I think as you have 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 stats methodology but as I said, it is similar to what the other studies are using. And we don't think -- there are a lot of countries that still do not have tafamidis, we think that looking at the benefit in patients don't have tafamidis 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 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, Sophie, no, I'll take that. It is 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% upto 15%, actually experienced that. And so as we balance that opportunity, versus the progress we're making with the CI [ph] writing approach. We thought that the better deployment of our resources was to the CI 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 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 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.

Okay, yeah, in terms of the 2:1 randomization, this was 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 these patients will likely get placebo if the trial is positive, we will likely allow them to go on to active drug or if we have an 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 drug. The CB mortality, we think is the more important endpoint here. It won't be -- an 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 Yanan

Great. Thanks for taking our questions. Just following up on the 2:1 ratio, given that if the trial size is similar as the [indiscernible] 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, so 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 is 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. The -- 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 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.

Great, thanks for the color.

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?

So we think, as we've seen in other studies, reducing TTR it's 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 would complete response as 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 levels, almost all patients achieved that low level, which is something that hasn't been achieved well with RNA silencers. We can't -- 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 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 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 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 says 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 ACB at all for 3001?

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

Thank you.

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 2001. So then kind of how to 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 tafamidis in the placebo arm. There are couple of things. We do ask that the patients start this after a year of therapy that they are not planning to go at the beginning of the study not to plan to start tafamidis 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 tafamidis 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 tafamidis.

Okay, thanks.

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 the 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 this 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. So 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.

Great, thanks for the color. The next question comes from Terrence 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 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 2001, we knew we were going to need to those many patients. So we began for the Phase 3 for the people on 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 I suppose mentioned by both Glenn and David, 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, 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 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 cut off in your Phase 3 is higher than the one seen in the LLB [ph] and attributes CM. Can you comment on the cut off here, how might that higher cut off 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 don't 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 BPP tends to be around 2000 and all the trials. So it is around where most patients sort of leave. Most patients are but we did want to have make it important that we could show a benefit to patients.

Thanks, David. Operator The next question comes from Myles Minter with William Blair. Please go ahead.

Good morning. This is Stephanie, on for Myles. Just took me on for miles. We just had a quick question. Our answers took me on for miles. We just had a quick question on the follow up from the Phase 1 study of NTLA-2001. Do you have any additional details [indiscernible] share those clinical modules of efficacy? And what sort of like the 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, yeah, none of the things that we looked at 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 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 2001 relative to an RNA silencer? Thank you.

We haven't given a quality, and quantitation of reduction. So that 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 our 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 spin 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, 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 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 [ph] and I think it's most likely to, the dosing regimen, is there any read across to until you're 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 folks are infused or self-administered or whatever. So convenience, certainly figures into this. It's just 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 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 them number one, in the inclusion criteria for patients right now, which is just TAF, but also for dropping patients at a subsequent point.

We deal with potential -- in the future. So, additional stabilizers, one additional stabilizer make them available, we will be able to modify the protocols to allow those patients into the trial. For silencers of course this is a wild offer in the trial but we do anticipate that some patients will go on for 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 reason adcom when they certainly focus the 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, top 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 inserts of programs whether it is -- Factor 9 and first you start with a guide. So the insertions needs to be driven. You know the double trend that's introduced by your selected guide. Recently guides that do not have target so 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 [indiscernible] insertion where it's going to be very effective location for insertion. And yes, all of that is part of our IND teamwork.

Well, thank you for taking my questions.

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 Acusol [ph] specifically do you have plants for patient level hold genomes so you can see across any year programs to evaluate off target edits in future studies, even 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 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 6 million is part of preliminary endpoints and I guess what's your take on requiring this?

Will we include 6-minute walk tests as a secondary endpoint.

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

What's the utility of other secondary endpoints I think what else was asked?

yeah, we think the most important secondary endpoints include quality of life is at high level of interests 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 and roll out our pipeline and technologies. Have a great day, everyone.