Q2 2024 Intellia Therapeutics Inc Earnings Call

August 8, 2024

Operator: Good morning and welcome to Intellia Therapeutics' second quarter 2024 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 Intellia. Please proceed.

Operator: 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 Intellia. Please proceed.

Ian Karp: Thank you operator, and good morning everyone. Welcome to Intellia Therapeutics' second quarter 2024 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 Investor 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'd like to take a minute to remind listeners that during the 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.

Ian Karp: At this time, I'd like to take a minute to remind listeners that during the 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.

Ian Karp: 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, Laura Sepp Lorenzino, Chief Scientific Officer, Ed Dulac, Chief Financial Officer. Also in the room and available for the Q&A is Lioran Walsh, Head of Development for Indievo programs. Our Chief Medical Officer, David Lebwohl, is unable to join us today, but he will be participating in upcoming investor conferences. John will begin with updates on our clinical pipeline progress and recent business highlights. Laura will then provide R&D updates, and Ed will review our financials before we open the call for questions. And with that, I'll now turn the call over to John, our Chief Executive Officer.

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, Laura Sepp Lorenzino, Chief Scientific Officer, Ed Dulac, Chief Financial Officer. Also in the room and available for the Q&A is Lioran Walsh, Head of Development for Indievo programs. Our Chief Medical Officer, David Lebwohl, is unable to join us today, but he will be participating in upcoming investor conferences.

John will begin with updates on our clinical pipeline progress and recent business highlights. Laura will then provide R&D updates, and Ed will review our financials before we open the call for questions. And with that, I'll now turn the call over to John, our Chief Executive Officer.

John M. Leonard: Thank you, Ian. Good morning, everyone, and thank you all for joining us today. At Intellia, we're harnessing the power of CRISPR-based gene editing for developing potentially curative treatments. Now, with over 150 patients dosed with our investigational therapies and multiple programs in clinical development, we're undoubtedly at the forefront of the gene editing revolution. We're proud to report another quarter of substantial progress and continued innovation across our full-spectrum pipeline and platform. I'll start with NTLA-2002 for the treatment of hereditary angioedema, also known as HAE. It is a debilitating and potentially fatal condition that manifests as recurrent episodes of unpredictable swelling.

John M. Leonard: I'll start with NTLA-2002 for the treatment of hereditary angioedema, also known as HAE. It is a debilitating and potentially fatal condition that manifests as recurrent episodes of unpredictable swelling.

John Leonard: Despite existing treatments, we've heard loud and clear from patients and physicians and through our market research that HAE patients are seeking improved efficacy and convenience. Beyond that, patients tell us that what they want most is to live a life free from their disease and the many challenges that come with it, even while on chronic treatments available today. While current and other emerging therapies attempt to differentiate themselves with modest improvements in attack rate reduction or extending dosing intervals for prophylactic therapy, what we are pursuing is a total paradigm shift in the treatment of HAE.

John Leonard: Our goal for NTLA-2002 is to provide a complete response, that is, a treatment outcome in which patients are both free from attacks and untethered from the requirements of chronic treatment after a single administration. This is the outcome patients and physicians seek, and with the revolutionary advancement of our gene editing technology, we believe we are making it a reality.

John Leonard: In June, we reported positive long-term data from the Phase 1 study of NTLA-2002. Of the 10 patients treated, eight continued to be completely attack-free for 18 to 26 months following a single administration of the drug. And across all patients, we observed a 98% reduction in attacks with the latest follow-up. Importantly, the data from these 10 patients continue to demonstrate a favorable safety profile. The most frequent adverse events were infusion-related reactions and fatigue, but for mostly grade ones. These unprecedented results reinforce the potential of NTLA-2002 to be a one-time functional cure for this life-threatening disease.

John Leonard: Today, we are thrilled to announce that NTLA-2002 met its primary efficacy and all secondary endpoints in the 16-week primary observation period of the Phase II study. As a reminder, the ongoing phase II was a randomized placebo controlled study to further evaluate the safety and efficacy of the 25 milligram and 50 milligram doses. The key objective of the Phase II was to determine which of the two doses to move forward into the Global Pivotal Phase III trial.

John Leonard: The primary efficacy endpoint was the reduction in the number of angioedema attacks per month during the 16-week primary observation period. Key secondary endpoints included safety, the number of angioedema attacks per month during weeks 5 to 16, the number of angioedema attacks per month requiring acute therapy, and the change from baseline and the total plasma calotrene protein level. We plan to present the detailed results at a medical meeting in the fourth quarter of this year. As such, we will be limiting our discussion of the top line results to what we disclosed in today's press release.

John Leonard: A single 25 or 50 milligram dose of NTLA-2002 led to deep reductions in attacks for patients with HAE. No new safety findings were observed. We have now selected the 50 milligram dose to advance into the global phase III trial because we saw a greater calocrine reduction and importantly, a higher number of patients who achieved complete elimination of attacks compared to the 25 milligram dose cohort, which is consistent with the prior phase I results. In addition to the positive results, we recently completed a successful end-of-Phase II meeting with the FDA. We believe we have completed addressing their questions and have a clear understanding of the path forward.

John Leonard: We are on track to begin the Phase III trial in the second half of this year, and if positive, plan to submit the BLA for NTLA-2002 in 2026. We anticipate that NTLA-2002 will be the first in vivo gene editing therapy to come to market. And most importantly, we strongly believe it will reset the standard of care for HAE. Switching now to NTLA-2001 for the treatment of ATTR amyloidosis, the drug now has a new name, Nexigoransaclumaran, or NEX-V for short.

We are on track to begin the Phase III trial in the second half of this year, and if positive, plan to submit the BLA for NTLA-2002 in 2026. We anticipate that NTLA-2002 will be the first in vivo gene editing therapy to come to market. And most importantly, we strongly believe it will reset the standard of care for HAE.

Switching now to NTLA-2001 for the treatment of ATTR amyloidosis, the drug now has a new name, Nexigoransaclumaran, or NEX-V for short. Recent competitor data confirmed our longstanding hypothesis that TTR reduction leads to a clinically meaningful improvement in patients with cardiomyopathy. This is an important advancement in the field's understanding of the disease, and this result further increases our confidence that NEX-Z could lead to even better clinical outcomes for patients. Our belief is based on the consistently deep and durable TTR reductions observed in the Phase 1 study. Further, the competitor clinical data recently reported reaffirmed that the ongoing magnitude trial is well-designed. As appropriate, we will incorporate additional learnings into our trial as they become available.

John Leonard: Recent competitor data confirmed our longstanding hypothesis that TTR reduction leads to a clinically meaningful improvement in patients with cardiomyopathy. This is an important advancement in the field's understanding of the disease, and this result further increases our confidence that NEX-Z could lead to even better clinical outcomes for patients. Our belief is based on the consistently deep and durable TTR reductions observed in the Phase 1 study. Further, the competitor clinical data recently reported reaffirmed that the ongoing magnitude trial is well-designed. As appropriate, we will incorporate additional learnings into our trial as they become available.

John Leonard: The rapid enrollment of the MAGNITUDE trial continues to track well ahead of our internal projections. In addition to the significant physician and patient interest in the trial, we're also progressing well with global regulatory approvals for the study. In total, we've now received regulatory clearance in over a dozen countries and are actively enrolling at over 35 sites around the world.

John Leonard: Building on our significant progress in cardiomyopathy, we are on track to initiate the pivotal trial for polyneuropathy by year-end. As previously announced, the study is expected to be a small, placebo-controlled trial of approximately 50 patients conducted in ex-US regions with limited or no access to TTR silencers. Finally, we look forward to presenting data from the ongoing Phase I study in the second half of 2024. We plan to include safety and TTR reduction data from both the CM and PN arms, as well as other clinical endpoints, such as NT, ProB, and P, 6-minute walk test, and MNIST plus 7.

Building on our significant progress in cardiomyopathy, we are on track to initiate the pivotal trial for polyneuropathy by year-end. As previously announced, the study is expected to be a small, placebo-controlled trial of approximately 50 patients conducted in ex-US regions with limited or no access to TTR silencers.

Finally, we look forward to presenting data from the ongoing Phase I study in the second half of 2024. We plan to include safety and TTR reduction data from both the CM and PN arms, as well as other clinical endpoints, such as NT, ProB, and P, 6-minute walk test, and MNIST plus 7.

John Leonard: We anticipate these data will build upon insights recently reported in other TTR silencer clinical trials, with three pivotal phase III trials and our first gene insertion study, all expected to be active by year end. Intellia is closer than ever to transforming the future of medicine with our one-time in vivo gene editing therapies. In parallel to our clinical execution, we're making strategic investments for our exciting evolution from late stage clinical development to a commercial organization.

We anticipate these data will build upon insights recently reported in other TTR silencer clinical trials, with three pivotal phase III trials and our first gene insertion study, all expected to be active by year end. Intellia is closer than ever to transforming the future of medicine with our one-time in vivo gene editing therapies.

In parallel to our clinical execution, we're making strategic investments for our exciting evolution from late stage clinical development to a commercial organization. This is exemplified by the recent appointment of Brian Goff to our Board of Directors, and Ed Dulac as Chief Financial Officer and Treasurer. Brian's extensive global commercialization experience, coupled with his track record of success leading rare disease product launches, will be invaluable.

John Leonard: This is exemplified by the recent appointment of Brian Goff to our Board of Directors, and Ed Dulac as Chief Financial Officer and Treasurer. Brian's extensive global commercialization experience, coupled with his track record of success leading rare disease product launches, will be invaluable. Similarly, Ed's deep financial and business development experience at clinical and commercial stage biotech companies will be critical as we enter the next chapter in our evolution. I'll now hand the call over to Laura, our Chief Scientific Officer, who will provide updates on the NTLA-3001 program and our R&D efforts.

This is exemplified by the recent appointment of Brian Goff to our Board of Directors, and Ed Dulac as Chief Financial Officer and Treasurer. Brian's extensive global commercialization experience, coupled with his track record of success leading rare disease product launches, will be invaluable.

Similarly, Ed's deep financial and business development experience at clinical and commercial stage biotech companies will be critical as we enter the next chapter in our evolution. I'll now hand the call over to Laura, our Chief Scientific Officer, who will provide updates on the NTLA-3001 program and our R&D efforts.

Laura Sepp-Lorenzino: Thank you, John. Good morning, everyone. At Intellia, we're deploying the industry's broadest toolbox of novel gene editing and delivery technologies for in vivo and ex vivo therapeutic applications. Let me begin with NTLA-3001.

Laura Sepp Lorenzino: At Intellia, we're deploying the industry's broadest toolbox of novel gene editing and delivery technologies for in vivo and ex vivo therapeutic applications. Let me begin with NTLA-3001. As we announced last week, we received regulatory approval from the United Kingdom's Medicine and Healthcare Products Regulatory Agency to initiate the first in-human study in patients with Alpha-1 antitrypsin deficiency associated lung disease. Following the IND clearance of Regeneron's Factor IX program, this marks the second program leveraging our modular gene insertion platform set to enter the clinic, another accomplishment from our industry-leading research engine. Unlike traditional gene therapy, we expect our approach will permanently restore a missing or defective protein without a waning effect over time.

At Intellia, we're deploying the industry's broadest toolbox of novel gene editing and delivery technologies for in vivo and ex vivo therapeutic applications. Let me begin with NTLA-3001.

As we announced last week, we received regulatory approval from the United Kingdom's Medicine and Healthcare Products Regulatory Agency to initiate the first in-human study in patients with Alpha-1 antitrypsin deficiency associated lung disease. Following the IND clearance of Regeneron's Factor IX program, this marks the second program leveraging our modular gene insertion platform set to enter the clinic, another accomplishment from our industry-leading research engine. Unlike traditional gene therapy, we expect our approach will permanently restore a missing or defective protein without a waning effect over time.

Laura Sepp Lorenzino: As a reminder, NTLA 3001, is designed to precisely insert the wild-type Serpin A1G to permanently restore production and the destruction of fully functional Alpha-1 Pro. Our goal is to replicate what we demonstrated in non-human primates, to restore patients to normal alpha-1 levels after a single dose. The Phase I/II study will be a two-part, open-label, multi-center study to evaluate the safety, tolerability, PK, and PD of NTLA-3001. Up to 30 patients will be enrolled. Phase I will be a single assembly in those designed with up to three cohorts.

As a reminder, NTLA 3001, is designed to precisely insert the wild-type Serpin A1G to permanently restore production and the destruction of fully functional Alpha-1 Pro. Our goal is to replicate what we demonstrated in non-human primates, to restore patients to normal alpha-1 levels after a single dose.

The Phase I/II study will be a two-part, open-label, multi-center study to evaluate the safety, tolerability, PK, and PD of NTLA-3001. Up to 30 patients will be enrolled. Phase I will be a single assembly in those designed with up to three cohorts. Patients will receive a single infusion of NTLA-3001, which consists of a sequential dose of AAV and LNP. The AAV delivers a 13A1 DNA template, and the LMP delivers a CRISPR machinery. Based on our learnings from NTLA-2001 and NTLA-2002, we will be evaluating a 6-LMP dose of 50 mg. The only variable component from cohort to cohort in the dose escalation will be the dose of AAV.

Laura Sepp Lorenzino: Patients will receive a single infusion of NTLA-3001, which consists of a sequential dose of AAV and LNP. The AAV delivers a 13A1 DNA template, and the LMP delivers a CRISPR machinery. Based on our learnings from NTLA-2001 and NTLA-2002, we will be evaluating a 6-LMP dose of 50 mg. The only variable component from cohort to cohort in the dose escalation will be the dose of AAV.

Laura Sepp Lorenzino: We will begin with doses of AAV that we expect will show some level of activity even in the first cohort. Once we've identified the optimal dose, we plan to move into the Phase II, which will be a single-dose expansion cohort to further characterize the activity of NTLA-3001. We're on track to dose the first patients in the second half of this year.

Laura Sepp Lorenzino: Assuming success, NTLA-3001 could redefine how Alpha-1 is treated and unlock a whole new category of diseases we can pursue with our in vivo gene insertion platform. Turning to another exciting development with our in vivo platform, in June, Intellia achieved yet another landmark milestone for the field of gene editing. We presented the first ever clinical data demonstrating that redosing with CRISPR when utilizing Intellia's LNP-based delivery platform enabled an additive pharmacodynamic effect. Critically, the follow-on dose was generally well-tolerated.

Laura Sepp Lorenzino: Overall, the safety and pharmacodynamics of redosing with NTLA-2001 were consistent with those observed after a single dose. The ability to successfully re-dose these patients is a testament to our high standard in developing our proprietary LNP formulation to ensure both safety and activity. Going forward, while not planned for our current clinical programs, the option to read those could be an important advantage for Intellia as we continue to push the boundaries of what we can do and expand where we can go outside the labor with CRISPR-based technology.

Laura Sepp Lorenzino: We look forward to updating you on our progress across our R&D platform more broadly this year. I'll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results as of second quarter 2024.

Edward Dulac: Thank you, Laura. Good morning, everyone.

Ed Dulac: Intellia continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform. Our cash, cash equivalents, and marketable securities were approximately $939.9 million as of June 30, 2024, compared to $1 billion as of December 31, 2023. The decrease was driven by cash used to fund operations of approximately $234.4 million. The decrease was offset in part by $96.4 million of net equity proceeds from the company's at-the-market program, $35.9 million of collaborator reimbursements, including a one-time $30 million payment received in April related to the company's technology collaboration with Regeneron, $25.1 million of interest income and $4.8 million in proceeds from employee-based stock. Our collaboration revenue was $7 million during the second quarter of 2024, compared to $13.6 million during the second quarter of 2023. The $6.6 million decrease was mainly driven by a reduction in revenue related to the [inaudible] license and collaboration agreement.

Ed Dulac: $35.9 million of collaborator reimbursements, including a one-time $30 million payment received in April related to the company's technology collaboration with Regeneron, $25.1 million of interest income and $4.8 million in proceeds from employee-based stock. Our collaboration revenue was $7 million during the second quarter of 2024, compared to $13.6 million during the second quarter of 2023. The $6.6 million decrease was mainly driven by a reduction in revenue related to the [inaudible] license and collaboration agreement.

Ed Dulac: R&D expenses were $114.2 million during the second quarter of 2024, compared to $115.3 million during the second quarter of 2023. The $1.1 million decrease was primarily driven by a decrease in employee-related expenses. Stock-based compensation, including an R&D expense, was $25.4 million for the second quarter of 2024. G&A expenses were $31.8 million during the second quarter of 2024, compared to $30.7 million during the second quarter of 2023. The $1.1 million increase was primarily related to stock-based compensation. Stock-based compensation included in G&A expense was $15.4 million for the second quarter of 2024. Finally, we expect our cash balance to fund our operating plans into late 2026.

R&D expenses were $114.2 million during the second quarter of 2024, compared to $115.3 million during the second quarter of 2023. The $1.1 million decrease was primarily driven by a decrease in employee-related expenses. Stock-based compensation, including an R&D expense, was $25.4 million for the second quarter of 2024. G&A expenses were $31.8 million during the second quarter of 2024, compared to $30.7 million during the second quarter of 2023. The $1.1 million increase was primarily related to stock-based compensation.

Stock-based compensation included in G&A expense was $15.4 million for the second quarter of 2024. Finally, we expect our cash balance to fund our operating plans into late 2026.

John M. Leonard: Thanks Ed. In conclusion, Intellia continues to deliver on the promise of gene editing, and we are looking forward to several important clinical milestones in the second half of this year. With that, we'll now open the call for your questions. To do our best to address as many questions as possible, we will only be able to take one question per caller. 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 one on your touchtone phone.

Operator: We will now begin the question-and-answer session. To ask a question, you may press star, then one on your touchtone phone. If you're using a speaker phone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Terence Flynn with Morgan Stanley. Please go ahead.

Operator: If you're using a speaker phone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Terence Flynn with Morgan Stanley. Please go ahead. Hi, thank you for taking our question. This is Chris on for Terence and congratulations on the progress. Regarding the HAE phase II data, can you talk about how competitive it is against Iona's drug? Thank you.

If you're using a speaker phone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Terence Flynn with Morgan Stanley. Please go ahead. Hi, thank you for taking our question.

Unknown: Hi, thank you for taking our question. This is Chris on for Terence and congratulations on the progress. Regarding the HAE phase II data, can you talk about how competitive it is against Iona's drug? Thank you.

This is Chris on for Terence and congratulations on the progress. Regarding the HAE phase II data, can you talk about how competitive it is against Iona's drug? Thank you.

John M. Leonard: Thanks, Chris. As we said in our earlier comments, we're very excited about the profile of 2002. The way we're approaching the disease is we're trying to reset what is the current therapeutic regimen that's available to patients and that starts with having a deep understanding of what patients are actually looking for. They're not looking for minor improvements in prophylactic therapy. They're not looking for primarily extensions and dosing intervals. What they're looking for is to be as normal as possible and that means not having to take any medicine.

John Leonard: So as we look at HAE and its development, that is the profile we're looking for, single dose that leads to a complete elimination of tax, and patients no longer to take any medication at all. That is the profile we're shooting for. That's what we've seen in our early phase I program. And as information becomes available for our phase II program, you'll be able to see for yourself in terms of our ability to achieve that profile. We think we're resetting the bar. And with that, in an entirely new category of responses for patients, we think the drug will be without equal. Great, thank you.

So as we look at HAE and its development, that is the profile we're looking for, single dose that leads to a complete elimination of tax, and patients no longer to take any medication at all. That is the profile we're shooting for. That's what we've seen in our early phase I program. And as information becomes available for our phase II program, you'll be able to see for yourself in terms of our ability to achieve that profile. We think we're resetting the bar. And with that, in an entirely new category of responses for patients, we think the drug will be without equal.

Unknown: Great, thank you.

Operator: The next question comes from Mary Kate Davis with Bank of America. Please go ahead. Good morning. Thank you for taking our question. Looking at the AATV program here, could you comment on how impact the wholly-owned [inaudible] program could be for the current market given unmet need in the space? Thank you.

Operator: The next question comes from Mary Kate Davis with Bank of America. Please go ahead.

Mary Kate Davis: Good morning. Thank you for taking our question. Looking at the AATV program here, could you comment on how impact the wholly-owned [inaudible] program could be for the current market given unmet need in the space? Thank you.

John M. Leonard: Well, our assessment of alpha-1 antitrypsin deficiency therapies as they currently exist is that it's almost a complete absence of effective therapy. So our view is that it's essentially wide open in terms of resetting the bar. Remember what we're trying to do. We're trying to have the production of a fully normal protein that is the wild type alpha-1 antitrypsin deficiency, sorry, alpha-1 antitrypsin protein that has normal activity. That doesn't exist yet today. And so we view this very large market as one that we can be very, very successful in. And we're very excited about beginning a clinical program with 3001.

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

Dae Gon Ha: Hey, good morning, guys. Thanks for taking our question as well. I'll also stick with AAT. Maybe a question for Laura. As we think about the 3001, specifically on the AAV component, I guess, can you speak to what your learnings are or what your derivations are from the Astellas-Odenti's experience when it comes to AAV-8 and how that gets factored into your dose? And specifically, can you also talk about sort of the biology behind wild-type AAT and still having Z-AAT production, whether the Z-AAT lingering might have some pro-inflammatory effects on the lung pathology? Thanks so much.

Operator: I'll also stick with AAT. Maybe a question for Laura. As we think about the 3001, specifically on the AAV component, I guess, can you speak to what your learnings are or what your derivations are from the Astellas-Odenti's experience when it comes to AAV-8 and how that gets factored into your dose? And specifically, can you also talk about sort of the biology behind wild-type AAT and still having Z-AAT production, whether the Z-AAT lingering might have some pro-inflammatory effects on the lung pathology?

Operator: Thanks so much.

John M. Leonard: So Laura, do you want to take that and start with some of the dosing differences?

Laura Sepp-Lorenzino: Yeah, sure. So thank you for the question. So here we're using the AAV to deliver the template for insertion. So it's quite a different approach when we're using traditional gene therapy where you need to load the cells with epizomes to ensure that you have long duration of effect. So given that our doses are much, much lower, not only to what [inaudible] has used, but what others have used, including for liver directed diseases using AAV-8.

Laura Sepp Lorenzino: So, again, the thing is we need to have enough template to have exertion in a few percentage of hepatocytes that's going to drive the levels of alpha-1 that we believe are going to be fully therapeutic. Based on our data and not all the patients who have alpha-1 antitrypsin deficiency have liver disease, right? That's a minority of the patients, so we don't expect any issue by having expressing the wild-type protein in patients who have [inaudible]. John, anything you would like to add?

John M. Leonard: No, I think that speaks to it. Thank you Laura.

John Leonard: The next question comes from Joseph Thome with T.D. Cowen. Please go ahead. Hi there. Good morning. And thank you for taking my question. Maybe one quickly on the 2001 PN proposed study. You indicated that it would be ex-US which obviously makes sense given the [inaudible]. But do you think the FDA would like to see dosing of any ex-US patients prior to an approval in this setting or do you think ex-U.S patients for the entire program will be sufficiently enrolled in an open label extension or anything like that? Thank you.

Operator: The next question comes from Joseph Thome with T.D. Cowen. Please go ahead.

Operator: The next question comes from Joseph Thome with T.D. Cowan, please go ahead. Hi there, good morning and

Joseph Thome: Hi there. Good morning. And thank you for taking my question. Maybe one quickly on the 2001 PN proposed study. You indicated that it would be ex-US which obviously makes sense given the [inaudible]. But do you think the FDA would like to see dosing of any ex-US patients prior to an approval in this setting or do you think ex-U.S patients for the entire program will be sufficiently enrolled in an open label extension or anything like that? Thank you.

John M. Leonard: Thanks for the question, Joe. We've reviewed this extensively with the FDA. We have a very good understanding of what they're looking for. We have agreements in alignment on how we're conducting the study outside the United States. They're not requiring patients to be dosed in that particular indication inside the United States. Remember that they're going to see many other patients that will come from our cardiomyopathy study, where already we're enrolling patients in the United States, so they'll see a very extensive prior exposure to the drug.

Operator: Perfect, thank you. The next question comes from Luca Issi with RBC. Please go ahead. Oh, great. Thanks so much for taking my question. Congrats on all the progress. Laura, maybe one more here on alpha-1. Obviously the competitor landscape continues to evolve. Obviously Vertex giving up on their approach but we're seeing a lot of other innovations coming down the pipeline including clinical data for the first time for ADAR and RNA editing towards the end of the year. I wonder if you can kind of compare and contrast that approach versus your approach and why you think your approach is better. Any thoughts there much appreciated. Thanks so much.

Operator: The next question comes from Luca Issi with RBC. Please go ahead. Oh great!

Laura Sepp-Lorenzino: Thank you for the question. Look, based on the preclinical data that we have seen, right, we believe that with 3001 we have demonstrated in non-human primates the ability to achieve not just 11 micromolar, right, but the full normal dose. And I think that if we can translate that in humans, that's going to be differentiating. And because of the mechanism of action, right, this is going to be potentially one-and-done, right? So you're looking for a single solution that will achieve normal levels. Of course, there are other modalities that are being advanced. At the end of the day, the proof of the pudding will be in the clinic, so I'll await the clinical data.

Laura Sepp Lorenzino: Thank you for the question. Look, based on the preclinical data that we have seen, right, we believe that with 31 we have demonstrated, you know, in non-human primates the ability to achieve not just 11 micromolar, right, but, you know, the full normal dose. And I think that that's, if we can translate that in humans, that's going to be differentiating. And because of the mechanism of action, right, this is going to be potentially one-and-done, right? So you're looking for a single solution that will achieve normal levels.

Laura Sepp Lorenzino: Of course, there are other modalities that are being advanced. At the end of the day, the proof of the pudding will be in the clinic, so I'll await the clinical data.

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

Gena Wang: Thank you. I will ask one question regarding the HAE program. What is the status of the partial clinical hold in HAE for the women of the reproductive age? And also for the phase II HAE full data, I assume you will be presenting at the medical conference is the ACAAI in Boston a good venue for the full data?

John M. Leonard: Thanks Gena. As soon as we're in a position to share where we're presenting the data, we will, of course, do that, as we've always done. And we look forward to seeing you in the audience as we go through what we think is very exciting data. With respect to the women with childbearing potential, I just want to clear up one thing. There was no partial clinical hold. That's not correct. But as we said, we've addressed all of the issues with the FDA. We have complete alignment with respect to the phase III study. And we will be including women of childbearing potential not only in the United States, but around the world, as we've been doing up until now, with the exception of the United States. So we look very, very much forward to beginning that trial and collecting results on the full population.

Operator: But as we said, we've addressed all of the issues with the FDA. We have complete alignment with respect to the phase III study. And we will be including women of childbearing potential not only in the United States, but around the world, as we've been doing up until now, with the exception of the United States. So we look very, very much forward to beginning that trial and collecting results on the full population.

Operator: I would add that beyond just women of childbearing potential, the goal of that trial is to be very expansive and to include the largest set of patients with different degrees of the illness to begin with, so we can have a very expansive label when we're done.

Operator: The next question comes from Maury Raycroft with Jeffries. Please go ahead. Hi, congrats on the update and thanks for taking my question. I'm wondering if there's more you can say on feedback from the HAE in the phase II meeting and your latest thoughts on the pivotal trial design. And in particular, I'm wondering how big the study will need to be and if there's anything more you could say about effect size or placebo response expectations.

Operator: The next question comes from Maury Raycroft with Jeffries. Please go ahead.

Maury Raycroft: Hi, congrats on the update and thanks for taking my question. I'm wondering if there's more you can say on feedback from the HAE in the phase II meeting and your latest thoughts on the pivotal trial design. And in particular, I'm wondering how big the study will need to be and if there's anything more you could say about effect size or placebo response expectations.

John M. Leonard: Thanks Maury. I guess I would characterize the FDA meeting as profoundly successful. We presented, as they've seen earlier, preclinical data, we've shared our manufacturing approach, and they've seen the clinical data from not only the phase I but the phase II program. The key decision there was to decide on which dose to take into phase III. We've done that. And as we shared here, that will be the 50 milligram dose. And as per the prior question from Gena, we will expose the full population of people with the disease to the drug, so we're very, very excited about that.

John Leonard: And as we shared here, that will be the 50 milligram dose. And as per the prior question from Gena, we will expose the full population of people with the disease to the drug, so we're very, very excited about that.

Operator: We now know the size of the trial, and we expect that this will be fewer than 70 patients. It will be a placebo-controlled trial, as is the standard. We'll look for a variety of different outcomes, not only attack rate reduction, but of course, the number of patients who achieve that complete response that we think is so fundamental to the profile of the drug. And these things will be measured over a six-month interval, as opposed to the 16 weeks that we've done in phase I and phase II.

Operator: Again, just to make the point, we're on track to begin this before the end of the year, and we're very, very excited about advancing this program, because we believe it will be the very first in vivo approved agent for any CRISPR program. Got it, thank you.

Again, just to make the point, we're on track to begin this before the end of the year, and we're very, very excited about advancing this program, because we believe it will be the very first in vivo approved agent for any CRISPR program.

Maury Raycroft: Got it, thank you.

Operator: The next question comes from Mani Foroohar with Leerink. Please go ahead.

Mani Foroohar: Hey, thanks for taking the question. I know you have been more reticent than others to use the phrase functional cure, which is realistically, what we're talking about for HAE is you're going to take patients off all therapy. The competitive program for Ionis, which is a chronic therapy, so not pursuing a curative and functional cure, has a number of studies. They had to do a switch study, etc. They chose to do a switch study. When you think about the path to commercialization or what's meant to be a one-time, functionally-curative therapy for at least some, if not the majority of patients, how do you think about providing data for patients to switch, for patients moving off of prophylactic therapy, discontinuing the practice of keeping on-demand therapy on them, etc.? More broadly, will there be a couple of other studies as part of your larger strategy to inform physicians about how to enroll patients on therapy or do you think you would take advantage of datasets produced by others in terms of providing the operation in terms of how physicians move patients off of current poly pharmacy to your therapy and eventually nothing on top of it?

John Leonard: When you think about the path to commercialization or what's meant to be a one-time, functionally-curative therapy for at least some, if not the majority of patients, how do you think about providing data for patients to switch, for patients moving off of prophylactic therapy, discontinuing the practice of keeping on-demand therapy on them, etc.? More broadly, will there be a couple of other studies as part of your larger strategy to inform physicians about how to enroll patients on therapy or do you think you would take advantage of datasets produced by others in terms of providing the operation in terms of how physicians move patients off of current poly pharmacy to your therapy and eventually nothing on top of it?

John M. Leonard: That may have been six questions, Mani, and I don't know if I can speak to all of them, but let me try to give some perspective on what I think you're getting at. First of all, we're being very judicious with the words that we use to describe the outcomes for these patients. You yourself are calling it a functional cure. We think that that's something that we're achieving with these patients. What we'll be able to say from a regulatory point of view remains to be determined as we work with the Food and Drug Administration, but the evidence will speak for itself. Again, the goal is to have patients following a single application of the drug no longer take therapy, and you can decide what you want to call that. With respect to moving forward with the agent into the marketplace, we expect that there will be a set of patients immediately who won't have access to the drug and these are patients who are not responding well to existing therapy of whatever form. Doctors tell us and patients tell us that they very much look forward to having the drug available to them. Then there's a set of patients who have responses that are incomplete, that have a propensity to switch. And the mechanism by which that plays out is something that we'll learn with the investigators and our key opinion leaders as we work with them.

Operator: What we'll be able to say from a regulatory point of view remains to be determined as we work with the Food and Drug Administration, but the evidence will speak for itself. Again, the goal is to have patients following a single application of the drug no longer take therapy, and you can decide what you want to call that. With respect to moving forward with the agent into the marketplace, we expect that there will be a set of patients immediately who won't have access to the drug

Operator: and these are patients who are not responding well to existing therapy of whatever form. Doctors tell us and patients tell us that they very much look forward to having the drug available to them. Then there's a set of patients who have responses that are incomplete, that have a propensity to switch. And the mechanism by which that plays out is something that we'll learn with the investigators and our key opinion leaders as we work with them.

Operator: We may be in a position to do a switch study that's not currently laid out but as we complete our thinking and get more information, as we work with leaders in the field, we'll get back to you and the larger community and talk about the way forward there. Either way, we believe that the drug will be extremely successful in the marketplace given a profile that is unmatched.

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

Unknown: Hi, good morning, everyone. This is Mehdi on for Joon. Congrats on the progress and thanks for taking our question. So, on NTLA-2001, given [inaudible] now has a PDUFA date of November 19th, and shows 50% CVS reduction with 81% survival, so what do you expect to see the outcome of 2001? Basically, what do you think is the bar now for our phase III MAGNITUDE study.

John M. Leonard: Well, we based on the TTR results that we presented in multiple forums, which are the deepest have been reported, and the most prolonged that have been reported, we expect that we'll be able to meet or achieve any profile that's been put forward by any of the other competitive agents, whether a stabilizer or a silencer. We've designed a phase III trial that is designed to demonstrate that and we have looked at patients with a range of different degrees of stability from their cardiomyopathy. And we think that that patient population, whether on existing therapy or on monotherapy with 2001, will have outcomes that are superior to what's been reported to any of the other agents. So stay tuned.

John Leonard: And we think that that patient population, whether on existing therapy or on monotherapy with 2001, will have outcomes that are superior to what's been reported to any of the other agents. So stay tuned. As we said in our comments earlier, there's a lot of enthusiasm in the marketplace with investigators and patients now essentially around the world coming into the study very, very quickly, well above our own expected accrual rate. So we're excited

And we think that that patient population, whether on existing therapy or on monotherapy with 2001, will have outcomes that are superior to what's been reported to any of the other agents. So stay tuned.

As we said in our comments earlier, there's a lot of enthusiasm in the marketplace with investigators and patients now essentially around the world coming into the study very, very quickly, well above our own expected accrual rate. So we're excited and as we get that information down the road, obviously we'll share it, and I'm sure it will be much watched. So we'll proceed as quickly as we can.

John Leonard: and as we get that information down the road, obviously we'll share it, and I'm sure it will be much watched. So we'll proceed as quickly as we can.

Operator: The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead. Hi, this is [inaudible] on for Kostas. Thank you for taking our question. Just one question from us. Under Intellia's 3001 program, how do you think the biotech competition for patient enrollment given that Beam and also other RNA adding companies are also recruiting in the United Kingdom. Thank you.

Operator: The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead.

Unknown: Hi, this is [inaudible] on for Kostas. Thank you for taking our question. Just one question from us. Under Intellia's 3001 program, how do you think the biotech competition for patient enrollment given that Beam and also other RNA adding companies are also recruiting in the United Kingdom. Thank you.

John M. Leonard: Thanks for the question. We work with investigators who know the patients they have, and we're quite confident that certainly in a phase I setting, not only in the UK, but other countries where we will have sites, including New Zealand and Ireland, that we'll be in a position to recruit the study expeditiously and look for the results that tell us how the drug is performing. We don't see this being a competitive situation.

Rick Bienkowski: Hey, good morning and congrats on the update on HAE. So one of the observations from the phase I data was there was a small number of breakthrough attacks during the primary observation period and then complete depression of attacks afterwards, so for this whole phase II presentation later this year, will we see any follow ups for patients that's longer than the primary observation period? And could you just discuss if there are any plans to follow these patients for a longer term and maybe present those data at a later date?

Operator: The next question comes from Rick Bienkowski with Cator Fitzgerald. Please go ahead.

John M. Leonard: We'll present data through the 16-week observation period. Remember that there's a couple differences in the Phase II from the Phase I. In the case of the Phase II study, there are two different doses, but a placebo arm as well. And what we offered all patients in the study was a switch, so we're not going to be in a position to look at ongoing placebo patients over time. We will follow all of these patients, as we've done with every single one of the patients that we've dosed, irrespective of the program. And I would expect that down the road at the appropriate times, we'll present follow-up information on every single one of the patients that we've treated thus far.

John Leonard: And I would expect that down the road at the appropriate times, we'll present follow-up information on every single one of the patients that we've treated thus far.

Operator: The next question comes from Jay Olson with Oppenheimer. Please go ahead. Hey, congrats on all of the progress and thanks for taking the question. For 2001, can you talk about the number of study sites you plan to activate for the MAGNITUDE study and how could that be impacted by other competing trials that are ramping up and then what you'll be looking for in the HELIOS-B results when they report it at ESC? Thank you.

Operator: The next question comes from Jay Olson with Oppenheimer. Please go ahead.

Jay Olson: Hey, congrats on all of the progress and thanks for taking the question. For 2001, can you talk about the number of study sites you plan to activate for the MAGNITUDE study and how could that be impacted by other competing trials that are ramping up and then what you'll be looking for in the HELIOS-B results when they report it at ESC? Thank you.

John M. Leonard: Thank you for the question. We anticipate around 100 or so sites spread around the world with a variety of different countries participating. As we said in our comments, there's about a dozen so far that have given the regulatory approval to begin enrolling, and that number will increase in the coming weeks. About 35 of the overall 100-plus sites are now active, and so we expect to see enrollment actually even accelerating beyond our strong start already.

Operator: As we put the study together and thought about where and how we were doing the study, we were cognizant of what was going on around the world, and we were very thoughtful about which sites to participate and which countries to carry out the work in. And thus far, with the accumulated experience over the last few months, we don't see that we're really in a different competitive situation from the one that we surmised. In fact, as I said, we're ahead of our expectations and we expect that to continue to be the case as time goes on.

Operator: we don't see that we're really in a different competitive situation from the one that we surmised. In fact, as I said, we're ahead of our expectations and we expect that to continue to be the case as time goes on.

Operator: The next question comes from Brian Cheng with J.P. Morgan. Please go ahead. Hey guys, thanks for taking our questions this morning. Just on the back of your recently reported redosing data, is there any plan to build in redosing for those patients that can achieve perhaps certain biomarker reduction thresholds if it happens in the next set of studies for TTR polyneuropathy, HAE or AATV? Thanks for taking our question.

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

Brian Cheng: Hey guys, thanks for taking our questions this morning. Just on the back of your recently reported redosing data, is there any plan to build in redosing for those patients that can achieve perhaps certain biomarker reduction thresholds if it happens in the next set of studies for TTR polyneuropathy, HAE or AATV? Thanks for taking our question.

John M. Leonard: One of the things that I think is really noteworthy of all of the patients that we've treated thus far, certainly those that have been treated at the doses that we deem to be therapeutic is that, almost without exception, every single patient has achieved the level of reductions that we're looking for, which is a remarkable outcome that I think is sometimes lost, particularly when you look across other drugs and the variability that you see with not only the pharmacokinetic outcome, but the pharmacodynamic outcome. I mean, what we're seeing here is quite unique.

John Leonard: The way I would think about redosing is that it doesn't apply to the amyloidosis program. It doesn't apply, we don't think to the caliprene program or HAE, but there may be instances where in certain situations, if the level of editing is lower than what we're shooting for, you may want to walk up to a particular effect. And I can think of instances outside the liver where that might be the case, but that doesn't apply to any program that we're currently doing. And for all practical purposes, we think every one of the patients participating in the ongoing studies will be a one and done case.

Operator: The next question comes from Steve Seedhouse with Raymond James. Please go ahead. Hi, this is Timur Ivannikov on for Steve. For AATV lung disease, historically it's been difficult to show improvements in [inaudible] and pulmonary [inaudible]. So do you think the FDA will require showing improvements from those end points besides just showing the reduction in neutrophilic [inaudible]?

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

Timur Ivannikov: Hi, this is Timur Ivannikov on for Steve. For AATV lung disease, historically it's been difficult to show improvements in [inaudible] and pulmonary [inaudible]. So do you think the FDA will require showing improvements from those end points besides just showing the reduction in neutrophilic [inaudible]?

John M. Leonard: It's an evolving space. And as far as we can determine in our interactions, as well as talking to experts in the space, is that the FDA is likely to approach this as a function of the degree of normality that's achieved. If patients achieve normal levels of the protein, the requirements we expect for functional aspects of that may be different from those instances in which either an abnormal protein or less than a complete normalization effect is achieved because in those cases, you're going to need supplementary information to indicate that less than a complete response is actually beneficial to the patient. That's why we want to normalize patients. We think that the best we can do is put them in a position as if they never had the disease in the first place, and that's the objective for the program.

John Leonard: because in those cases, you're going to need supplementary information to indicate that less than a complete response is actually beneficial to the patient. That's why we want to normalize patients. We think that the best we can do is put them in a position as if they never had the disease in the first place, and that's the objective for the program.

Operator: Thank you. The next question comes from Silvan Tuerkcan with Citizens JMP. Please go ahead.

Silvan Tuerkcan: Yeah, good morning and thanks so much for taking my question and congrats on the data update. Just about the open label trial with the phase I in HAE, the [inaudible] attack rate post the most recent presentation. I don't know if you can comment on it, but do you still have [inaudible] temptations with no attacks post the observation period?

John M. Leonard: Thank you for the question, Silvan. I would say watch for updates as they come. As we said to one of the earlier questions, we'll follow all of these patients and as we collect the information, we'll share it. We continue to be very, very excited about what we see and how these patients are performing after their single dose of 2002. Great, thank you so much. Looking forward to the data. The next question comes from William Pickering with Bernstein. Please go ahead.

Silvan Tuerkcan: Great, thank you so much. Looking forward to the data.

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

William Pickering: Hi, good morning. Congrats on all the progress and thank you for taking my question. Now that it looks increasingly likely that a silencer will become available during your MAGNITUDE trial and potentially even before enrollment completes, can you speak to your assumptions on silencer drop in rate? Is there a cap? And can you just confirm that patients who are already on a silencer would not be eligible to enroll? Thank you.

John M. Leonard: We will look at the data as it becomes available from Helios B, which we're very interested in confirming some of the assumptions that we have in terms of the design of our trial. And as that study becomes available and our own study evolves, we'll address what we think may be appropriate, if at all, for any drop-ins for patients on silencers. So stay tuned, but as it stands now, those drugs are not available, and we've made provisions for tefamidus use, which is integral to the study, as well as monotherapy. So the story will evolve, and as it changes, we will adapt as necessary.

Operator: So the story will evolve, and as it changes, we will adapt as necessary.

Operator: Thank you. The next question comes from Salveen Richter with Goldman Sachs. Please go ahead. Hi, this is [inaudible] on for Salveen. Thanks for taking our question. Just a quick one from us on ATTR cardiomyopathy. Just as it regards to the enrollment progression for the MAGNITUDE trial, I think that last quarter you said there were 30 patients enrolled, can you just provide an update on the figures here and then when you expect to complete enrollment. Thanks so much.

Operator: Thank you. The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.

Unknown: Hi, this is [inaudible] on for Salveen. Thanks for taking our question. Just a quick one from us on ATTR cardiomyopathy. Just as it regards to the enrollment progression for the MAGNITUDE trial, I think that last quarter you said there were 30 patients enrolled, can you just provide an update on the figures here and then when you expect to complete enrollment. Thanks so much.

John M. Leonard: Thank you for the question. What we won't be doing is giving updates on a quarterly basis. We share that information because it was the first time we had reported after we began the study, and we wanted people to see the very strong start in enrollment, which, as I said, continues to be above our expectations. Again, we have more than 35 sites up and running in 12 countries that will continue to expand in the weeks that lie ahead. In terms of the complete enrollment, I would encourage you to look at proxies for the work that we've done, and the Helios study would be, I think, a good place to look in terms of overall rate of enrollment, but of course our objective is to improve upon that.

Operator: We share that information because it was the first time we had reported after we began the study, and we wanted people to see the very strong start in enrollment, which, as I said, continues to be above our expectations. Again, we have more than 35 sites up and running in 12 countries that will continue to expand in the weeks that lie ahead. In terms of the complete enrollment, I would encourage you to look at proxies for the work that we've done, and the Helios study would be, I think, a good place to look in terms of overall rate of enrollment, but of course our objective is to improve upon that. The next question comes from Myles Minter with. William Blair, please go ahead. Uh, hey, thanks for taking the question. Just on Alpha One, just-

Operator: The next question comes from Myles Minter with William Blair. Please go ahead. Hey, thanks for taking the question. Just on alpha-1, just curious what your definition of normal AAT levels are because there's a wide range of 20-50 micromolar and if that range will be achievable with your initial 50mg dosing you're going with. And final question is just on the risk of albumin reduction, just with the fact that you're [inaudible] and if that's going to be material or not. Thanks very much.

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

Myles Minter: Hey, thanks for taking the question. Just on alpha-1, just curious what your definition of normal AAT levels are because there's a wide range of 20-50 micromolar and if that range will be achievable with your initial 50mg dosing you're going with. And final question is just on the risk of albumin reduction, just with the fact that you're [inaudible] and if that's going to be material or not. Thanks very much.

John M. Leonard: We'll turn to Laura who can speak to what we're shooting for in terms of normal, but just one thing you said, you referred to a 50 milligram dose, we will be holding the LNP dose constant in our phase one study in varying the AAV dose, which again, is at levels that are significantly below what's typical for gene therapy, at least in recent examples. Maybe Laura, you can speak to--

Laura Sepp-Lorenzino: Right, so normal levels, right, and what you quoted is right, so they vary from 20 to 50, and that's the goal that we want to achieve. In the [inaudible] we were in the 20s so that's what we expect we're going to be able to achieve in humans. With regards to albumin, that was obviously extensively evaluated in our GLP toxicology studies, and we do not see a decrease in albumin expression that in any way could put patients in danger. So we believe that, again, the doses that we're going to be investigating, even the first dose, we expect, we designed the trial for even the first dose to have lead to alpha-1 levels that will be therapeutically relevant, and then we expect that the safety of the approach 3001 will be pristine.

Miles Minter: Thank you.

Operator: The next question comes from Lisa Bayko with Evercore ISI. Please go ahead.

Unknown: Hi, this is Jamie on for Lisa. Thanks so much for taking our questions and congrats on the progress. So, we just have a question for Phase III MAGNITUDE study. What method do you plan to use for analysis of the composite endpoint? Something like Finkelstein or Anderson-Gill like in Helios B. Thank you.

John Leonard: Thank you.

Operator: The next question comes from Ry Forseth with Guggenheim. Please go ahead. Hey, this is Ry from [inaudible] team. Across HAE, ATTR PN and CN, what's your temporary market internal research suggesting for uptake or enthusiasm to switch for gene editing? Is there any notable inter-indication differences that you've seen?

John M. Leonard: Thanks for the question. Those are details that lie ahead and we'll disclose at the appropriate time, but we appreciate your interest.

John M. Leonard: Those are very different diseases, cardiomyopathy and hereditary angioedema. One in the case of cardiomyopathy and polyneuropathy, those are progressive diseases. HAE is episodic in nature and any one episode can be a fatal event. What our market research tells us is that, as we said in earlier comments, patients with HAE want to be normal. They're otherwise, in most cases, between attacks, normal, and they want to have that in every day of their life as much as possible.

John Leonard: So ranging from patients who have poorly controlled disease to patients who want to improve how they live their lives, which is most of the patients taking the drug, what our market research tells us is that 2002 will be very, very attractive to the preponderance of patients suffering from HAE. In the case of amyloidosis, whether polyneuropathy or cardiomyopathy, these are progressive diseases with patients getting worse and worse and ultimately succumbing to their disease.

So ranging from patients who have poorly controlled disease to patients who want to improve how they live their lives, which is most of the patients taking the drug, what our market research tells us is that 2002 will be very, very attractive to the preponderance of patients suffering from HAE.

In the case of amyloidosis, whether polyneuropathy or cardiomyopathy, these are progressive diseases with patients getting worse and worse and ultimately succumbing to their disease. The objective here is for us to demonstrate not only stopping the progression of the disease, but we believe that in several instances, perhaps many of the cases, we'll actually have some degree of reversal. As the year goes on, I would encourage you to look at the Phase I results that we'll be presenting, which patients have been followed now for a couple of years. We think that that may be indicative of what lies ahead. In the end, patients want the best drugs available for whatever disease they suffer from, and it's our goal at Intellia to meet that need.

John Leonard: The objective here is for us to demonstrate not only stopping the progression of the disease, but we believe that in several instances, perhaps many of the cases, we'll actually have some degree of reversal. As the year goes on, I would encourage you to look at the Phase I results that we'll be presenting, which patients have been followed now for a couple of years. We think that that may be indicative of what lies ahead.

John Leonard: In the end, patients want the best drugs available for whatever disease they suffer from, and it's our goal at Intellia to meet that need.

Operator: The next question comes from David Lebowitz with Citi. Please go ahead. Thank you very much for taking my question. Certainly understanding that you can't speak directly to anything with the MAGNITUDE trial and the potential adaptations, but could you indicate what specific items are most interesting to you in the upcoming HELIOS-B detailed readout at FC what things you're focusing on and how I guess that might inform further aspects of the design of the trial.

Operator: The next question comes from David Lebowitz with Citi. Please go ahead.

David Neil Lebowitz: Thank you very much for taking my question. Certainly understanding that you can't speak directly to anything with the MAGNITUDE trial and the potential adaptations, but could you indicate what specific items are most interesting to you in the upcoming HELIOS-B detailed readout at FC what things you're focusing on and how I guess that might inform further aspects of the design of the trial.

John M. Leonard: Sure, David. It's an important question. And we and many others, I think, will be very interested in learning more details about what we think are exciting initial results. What's of great interest to us, and the field in general, is some relationship between the level of TTR reduction and overall event rates and how that plays out in particular patient populations. That's a function of the stage of their disease. Patients who are early in the disease have a slower rate of events taking place, and how that plays out in patients with more severe disease will be of great interest to us.

Operator: Patients who are early in the disease have a slower rate of events taking place, and how that plays out in patients with more severe disease will be of great interest to us. Remember that when we constructed our trial, we included patients who have been excluded in many of the other studies that have been done. We're allowing and, in fact, requiring higher levels of ProBNP at baseline, as well as allowing patients with Class III heart disease.

Patients who are early in the disease have a slower rate of events taking place, and how that plays out in patients with more severe disease will be of great interest to us.

Remember that when we constructed our trial, we included patients who have been excluded in many of the other studies that have been done. We're allowing and, in fact, requiring higher levels of ProBNP at baseline, as well as allowing patients with Class III heart disease.

Operator: We will be very interested in understanding the nature and extent of the effect in patients receiving a drug on top of tefamidus, and that will be something that we consider with our own study as it proceeds. Remember that we designed the study in a way that if we need to adapt it based on what we learn, we can adapt it. And because we're early in enrollment here, we think that we're in a really strong position to come up with what we think will be the strongest study in the space. Thank you for taking my question.

We will be very interested in understanding the nature and extent of the effect in patients receiving a drug on top of tefamidus, and that will be something that we consider with our own study as it proceeds. Remember that we designed the study in a way that if we need to adapt it based on what we learn, we can adapt it. And because we're early in enrollment here, we think that we're in a really strong position to come up with what we think will be the strongest study in the space.

David Neil Lebowitz: Thank you for taking my question.

Operator: Our last question will come from Andy Chen with Wolf Research. Please go ahead. Hey, this is Brandon on for Andy. Congrats on the success as you move to phase III. Based on our understanding, the HAE market is somewhat saturated, although there is still a chunk of patients who have not signed up for [inaudible] treatments, competitors don't seem to be [inaudible] those patients, so all your competitors are competing for the same pie right now. Do you think gene editing could expand the pie for prophylactic treatment?

John M. Leonard: In a word, yes. And with respect to saturation, I would be careful in terms of how I think what that means. The presence of therapy does not mean that the therapy is ideal. And again, as we look to our market research, and this involves extensive discussions with leading investigators in the space, multiple patient interviews, if you ask patients, most of them want to be normal. And that means never having to take any of those drugs that currently saturate the market that you referred to. It is our objective to meet that need and we think that we'll be able to normalize the vast preponderance of patients with this disease.

John Leonard: I would be careful in terms of how I think what that means. The presence of therapy does not mean that the therapy is ideal. And again, as we look to our market research, and this involves extensive discussions with leading investigators in the space, multiple patient interviews, if you ask patients, most of them want to be normal. And that means never having to take any of those drugs that currently saturate the market that you referred to. It is our objective to meet that need. And we think that we'll be able to normalize the vast preponderance of patients with this disease.

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

Ian Karp: Great. Thanks so much, Drew, and thank you everyone for joining us and for your continued interest in Intellia. I'd also like to give a special thanks for everyone's discipline in asking one question today, because I think this may be the first time in a while that we've gotten through everyone's questions. So we look forward to continued updates as the year continues. And with that, we wish everyone a great rest of the summer.

Operator: The conference has ended. You may now disconnect your line. Thank you.

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Drew: Good morning and welcome to Intellia Therapeutics' second quarter 2024 financial results conference call. My name is Drew and I will be your conference operator today.

Operator: --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 Intellia. Please proceed.

Drew: Following formal remarks, we will open the call up for a question and answer session.

Drew: 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.

Drew: I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.

Ian Karp: Thank you operator, and good morning everyone. Welcome to Intellia Therapeutics' second quarter 2024 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 Investor 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'd like to take a minute to remind listeners that during the 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.

Ian Karp: Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics' second quarter 2024 earnings call.

Speaker Change: 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.

Speaker Change: This release can be found on the Investor and Media section of Intellia's website at IntelliaTX.com

Speaker Change: This call is being broadcast live and a replay will be archived on the company's website.

Ian Karp: At this time, I'd like to take a minute to remind listeners that during the 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.

Speaker Change: At this time, I'd like to take a minute to remind listeners that during the 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.

Speaker Change: All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law.

Ian Karp: 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, Laura Sepp Lorenzino, Chief Scientific Officer, Ed Dulac, Chief Financial Officer. Also in the room and available for Q&A are Lioran Walsh, Head of Development for Indivo. Our Chief Medical Officer, David Lebwohl, is unable to join us today, but he will be participating in upcoming investor conferences. John will begin with updates on the clinical pipeline progress and recent business highlights. Laura will then provide R&D updates and Ed will review our financials before we open the call for questions. And with that, I'll now turn the call over to John, our Chief Executive Officer.

Speaker Change: Joining me from Intellia are John Leonard, Chief Executive Officer, Laura Sepp Lorenzino, Chief Scientific Officer, Ed Dulac, Chief Financial Officer.

Speaker Change: Also in the room and available for the Q&A is Liron Walsh, Head of Development for INDIBO Programs.

Speaker Change: Our Chief Medical Officer, David Lebwohl, is unable to join us today, but he will be participating in upcoming investor conferences.

Speaker Change: John will begin with updates on our clinical pipeline progress and recent business highlights. Laura will then provide R&D updates, and Ed will review our financials before we open the call for questions.

Speaker Change: And with that, I'll now turn the call over to John , our Chief Executive Officer.

John M. Leonard: Thank you, Ian. Good morning everyone and thank you all for joining us today. At Intellia, we're harnessing the power of CRISPR-based gene editing for developing potentially curative treatments. Now, with over 150 patients dosed with our investigational therapies and multiple programs in clinical development, we're undoubtedly at the forefront of the gene editing revolution. We're proud to report another quarter of substantial progress and continued innovation across our full-spectrum pipeline and platform. I'll start with NTLA-2002 for the treatment of hereditary angioedema, also known as HAE. It is a debilitating and potentially fatal condition that manifests as recurrent episodes of unpredictable swelling.

John Leonard: And thank you all for joining us today. At Intellia, we're harnessing the power of CRISPR-based gene editing for developing potentially curative treatments. Now, with over 150 patients dosed with our investigational therapies and multiple programs in clinical development, we're undoubtedly at the forefront of the gene editing revolution. We're proud to report another quarter of substantial progress and continued innovation across our full-spectrum pipeline and platform. I'll start with NTLA-2002 for the treatment of hereditary angioedema, also known as HAE. It is a debilitating and potentially fatal condition that manifests as recurrent episodes of unpredictable swelling.

John Leonard: Thank you, Ian. Good morning, everyone, and thank you all for joining us today.

Speaker Change: At Intellia, we're harnessing the power of CRISPR-based gene editing for developing potentially curative treatments.

John Leonard: Now, with over 150 patients dosed with our investigational therapies and multiple programs in clinical development, we are undoubtedly at the forefront of the gene editing revolution.

John Leonard: We're proud to report another quarter of substantial progress and continued innovation across our full-spectrum pipeline and platform.

John Leonard: I'll start with NTLA-2002 for the treatment of hereditary angioedema, also known as HAE.

John Leonard: It is a debilitating and potentially fatal condition that manifests as recurrent episodes of unpredictable swelling.

John Leonard: Despite existing treatments, we've heard loud and clear from patients and physicians, and through our market research, that HEE patients are seeking improved efficacy and convenience.

John Leonard: Beyond that, patients tell us that what they want most is to live a life free from their disease and the many challenges that come with it, even while on chronic treatments available today.

John Leonard: While current and other emerging therapies attempt to differentiate themselves with modest improvements in attack rate reduction or extending dosing intervals for prophylactic therapy, what we are pursuing is a total paradigm shift in the treatment of HAE.

John Leonard: This is the outcome patients and physicians seek, and with the revolutionary advancement of our gene editing technology, we believe we are making it a reality.

John Leonard: In June, we reported positive long-term data from the Phase I study of M2A2002. Of the 10 patients treated, 8 continued to be completely attack-free for 18 to 26 months following a single administration of the drug. And across all patients, we observed a 98% reduction in attacks with the latest follow-up. Importantly, the data from these 10 patients continue to demonstrate a favorable safety profile. The most frequent adverse events were infusion-related reactions and fatigue, which were mostly grade one. These unprecedented results reinforce the potential of NTLA-2002 to be a one-time functional treatment for this life-threatening disease.

John Leonard: In June , we reported positive long-term data from the Phase 1 study of MTLA-2002.

John Leonard: Of the 10 patients treated, 8 continued to be completely attack-free for 18 to 26 months following a single administration of the drug.

John Leonard: And across all patients, we observed a 98% reduction in attacks with the latest follow-up. Importantly, the data from these 10 patients continue to demonstrate a favorable safety profile.

John Leonard: The most frequent adverse events were infusion-related reactions and fatigue, which were mostly grade 1.

John Leonard: These unprecedented results reinforce the potential of NTLA-2002 to be a one-time functional care for this life-threatening disease.

John Leonard: Today, we are thrilled to announce that NTLA-2002 met its primary efficacy and all secondary endpoints in the 16-week primary observation period of the Phase II study. As a reminder, the ongoing phase II was a randomized placebo-controlled study to further evaluate the safety and efficacy of the 25 milligram and 50 milligram doses. The key objective of the phase II was to determine which of the two doses to move forward into the Global Pivotal Phase III trial.

John Leonard: Today, we are thrilled to announce that NTLA-2002 met its primary efficacy and all secondary endpoints in the 16-week primary observation period of the Phase II study.

John Leonard: As a reminder, the ongoing Phase II was a randomized, placebo-controlled study to further evaluate the safety and efficacy of the 25mg and 50mg doses.

John Leonard: The key objective of the Phase II was to determine which of the two doses to move forward into the Global Pivotal Phase III trial.

John Leonard: The primary efficacy endpoint was the reduction in the number of angioedema attacks per month during the 16-week primary observation period. The key secondary endpoints included safety, the number of angioedema attacks per month during weeks 5 to 16, the number of angioedema attacks per month requiring acute therapy, and the change from baseline and the total plasma calotrene protein level. We plan to present the detailed results at a medical meeting in the fourth quarter of this year. As such, we will be limiting our discussion of the top line results to what we disclosed in today's press release. A single 25 or 50 milligram dose of MTLA2002 led to deep reductions in attacks for patients with HAE.

The primary efficacy endpoint was the reduction in the number of angioedema attacks per month during the 16-week primary observation period. The key secondary endpoints included safety, the number of angioedema attacks per month during weeks 5 to 16, the number of angioedema attacks per month requiring acute therapy, and the change from baseline and the total plasma calotrene protein level. We plan to present the detailed results at a medical meeting in the fourth quarter of this year. As such, we will be limiting our discussion of the top line results to what we disclosed in today's press release.

John Leonard: The primary efficacy endpoint was the reduction in the number of angioedema attacks per month during the 16-week primary observation period.

John Leonard: Key secondary endpoints included safety, the number of angioedema attacks per month during weeks 5 to 16, the number of angioedema attacks per month requiring acute therapy, and the change from baseline and the total plasma calotrene protein level.

John Leonard: We plan to present the detailed results at a medical meeting in the fourth quarter of this year.

John Leonard: As such, we will be limiting our discussion of the top-line results to what we disclosed in today's press release.

A single 25 or 50 milligram dose of NTLA2002 led to deep reductions in attacks for patients with HAE. No new safety findings were observed. We have now selected the 50 milligram dose to advance into the global phase three trial because we saw a greater calocrine reduction and, importantly, a higher number of patients who achieved complete elimination of attacks compared to the 25 milligram dose cohort, which is consistent with the prior phase one results. In addition to the positive results, we recently completed a successful end-of-phase II meeting with the FDA. We believe we have completed addressing their questions and have a clear understanding of the path forward.

John Leonard: A single 25 or 50 milligram dose of MTLA-2002 led to deep reductions in attacks for patients with HAE.

John Leonard: No new safety findings were observed. We have now selected the 50 milligram dose to advance into the global phase three trial because we saw a greater calocrine reduction and, importantly, a higher number of patients who achieved complete elimination of attacks compared to the 25 milligram dose cohort, which is consistent with the prior phase one results. In addition to the positive results, we recently completed a successful end-of-phase II meeting with the FDA. We believe we have completed addressing their questions and have a clear understanding of the path forward.

John Leonard: No new safety findings were observed.

John Leonard: We have now selected the 50 milligram dose to advance into the global phase 3 trial because we saw a greater calocrine reduction and importantly

John Leonard: A higher number of patients who achieved complete elimination of attacks.

John Leonard: compared to the 25 mg dose cohort, which is consistent with the prior Phase I results.

John Leonard: In addition to the positive results, we recently completed a successful end-of-Phase II meeting with the FDA.

John Leonard: We believe we have completed addressing their questions and have a clear understanding of the path forward. We are on track to begin the Phase 3 trial in the second half of this year, and if positive, plan to submit the BLA for NTLA-2002 in 2026.

John Leonard: We are on track to begin the Phase III trial in the second half of this year, and if positive, we plan to submit the BLA for NTLA2002 in 2026. We anticipate that NTLA-2002 will be the first in vivo gene editing therapy to come to market. And most importantly, we strongly believe it will reset the standard of care for HAE. Switching now to NTLA2001 for the treatment of ATTR amyloidosis, the drug now has a new name, Nexigorin Ziclumarin, or NEX-Z for short.

We are on track to begin the Phase III trial in the second half of this year, and if positive, we plan to submit the BLA for NTLA2002 in 2026. We anticipate that NTLA-2002 will be the first in vivo gene editing therapy to come to market. And most importantly, we strongly believe it will reset the standard of care for HAE.

John Leonard: We anticipate that NTLA-2002 will be the first in vivo gene editing therapy to come to market, and most importantly, we strongly believe it will reset the standard of care for HAE.

Switching now to NTLA2001 for the treatment of ATTR amyloidosis, the drug now has a new name, Nexigorin Ziclumarin, or NEX-Z for short.

John Leonard: Switching now to Antel-A20-01 for the treatment of ATTR amyloidosis, the drug now has a new name, Nexigorin Ziclumirin.

John Leonard: Recent competitor data have confirmed our longstanding hypothesis that TTR reduction leads to a clinically meaningful improvement in patients with cardiomyopathy. This is an important advancement in the field's understanding of the disease. And this result further increases our confidence that NEX-Z could lead to even better clinical outcomes for patients. Our belief is based on the consistently deep and durable TTR reductions observed in the Phase I study. Further, the competitor clinical data recently reaffirmed that the ongoing magnitude trial is well-designed.

John Leonard: or NEX-Z for short. Recent competitor data confirmed our longstanding hypothesis that TTR reduction leads to a clinically meaningful improvement in patients with cardiomyopathy.

John Leonard: This is an important advancement in the field's understanding of the disease, and this result further increases our confidence that NEX-Z could lead to even better clinical outcomes for patients.

John Leonard: Our belief is based on the consistently deep and durable PTR reductions observed in the Phase I study.

John Leonard: Further, the competitor clinical data recently reaffirmed that the ongoing magnitude trial is well designed. As appropriate, we will incorporate additional learnings into our trial as they become available.

John Leonard: As appropriate, we will incorporate additional learnings into our trial as they become available. The rapid enrollment of the MAGNITUDE trial continues to track well ahead of our internal projections. In addition to the significant physician and patient interest in the trial, we're also progressing well with global regulatory approvals for the study. In total, we've now received regulatory clearance in over a dozen countries and are actively enrolling at over 35 sites around the world. Building on our significant progress in cardiomyopathy, we are on track to initiate the physical trial for polyneuropathy by year end.

As appropriate, we will incorporate additional learnings into our trial as they become available. The rapid enrollment of the MAGNITUDE trial continues to track well ahead of our internal projections. In addition to the significant physician and patient interest in the trial, we're also progressing well with global regulatory approvals for the study. In total, we've now received regulatory clearance in over a dozen countries and are actively enrolling at over 35 sites around the world.

John Leonard: The rapid enrollment of the MAGNITUDE trial continues to track well ahead of our internal projections.

John Leonard: In addition to the significant physician and patient interest in the trial, we are also progressing well with global regulatory approvals for the study. In total, we have now received regulatory clearance in over a dozen countries and are actively enrolling at over 35 sites around the world.

Building on our significant progress in cardiomyopathy, we are on track to initiate the physical trial for polyneuropathy by year end. As previously announced, the study is expected to be a small placebo-controlled trial of approximately 50 patients conducted in ex-US regions with limited or no access to TTR silencers. Finally, we look forward to presenting data from the ongoing Phase 1 study in the second half of 2024. We plan to include safety and TTR reduction data from both the CM and PN arms, as well as other clinical endpoints, such as NT, ProB, and P, 6-minute walk test, and MNIST plus 7. We anticipate these data will build upon insights recently reported in other TTR silencer clinical trials. With three pivotal phase III trials and our first gene insertion study all expected to be active by year end, Intellia's closer than ever to transforming the future of medicine with our one-time in vivo gene editing therapies. Parallel to our clinical execution, we're making strategic investments to our exciting evolution from late stage clinical development to commercial organization. This is exemplified by the recent appointment of Brian Dobbs to our Board of Directors and Ed Doulag as Chief Financial Officer and Treasurer. Brian's extensive global commercialization experience, coupled with his track record of success leading rare disease product launches will be invaluable. Similarly, Ed's deep financial and business development experience at clinical and commercial stage biotech companies will be critical as we enter the next chapter in our evolution. I'll now hand the call over to Laura, our Chief Scientific Officer, who will provide updates on the NTLA3001 program and our R&D efforts. Thank you John. Good morning everyone. [inaudible] the industry's broadest toolbox of novel gene editing and delivering technology for in vivo and ex vivo therapeutic applications. Let me begin with NTLA3001.

John Leonard: Building on our significant progress in cardiomyopathy, we are on track to initiate the pivotal trial for polyneuropathy by year-end.

John Leonard: As previously announced, the study is expected to be a small placebo-controlled trial of approximately 50 patients conducted in ex-US regions with limited or no access to TTR silencers. Finally, we look forward to presenting data from the ongoing Phase 1 study in the second half of 2024. We plan to include safety and TTR reduction data from both the CM and PN arms, as well as other clinical endpoints, such as NT, ProB, and P, 6-minute walk test, and MNIST plus 7. We anticipate these data will build upon insights recently reported in other TTR silencer clinical trials.

John Leonard: As previously announced, the study is expected to be a small, placebo-controlled trial of approximately 50 patients conducted in XUS regions with limited or no access to TTR silencers.

John Leonard: Finally, we look forward to presenting data from the ongoing Phase 1 study in the second half of 2024.

John Leonard: We plan to include safety and TTR reduction data from both the CM and PN arms, as well as other clinical endpoints, such as NT, ProB, and P, 6-minute walk test, and MNIST plus 7.

John Leonard: We anticipate these data will build upon insights recently reported in other TTR silencer clinical trials.

John Leonard: with three pivotal phase three trials and our first gene insertion study.

John Leonard: all expected to be active by year-end and Intellia is closer than ever to transforming the future of medicine with our one-time in vivo gene editing therapies.

John Leonard: In parallel to our clinical execution, we're making strategic investments for our exciting evolution from late-stage clinical development to a commercial organization.

Speaker Change: This is exemplified by the recent appointment of Brian Goff, who are Board of Directors, and Ed Dulac, the Chief Financial Officer and Treasurer.

Speaker Change: Brian's extensive global commercialization experience, coupled with his track record of success leading rare disease product launches, will be invaluable.

Ed Dulac: Similarly, Ed's deep financial and business development experience at clinical and commercial-stage biotech companies will be critical as we enter the next chapter in our evolution.

John Leonard: I'll now hand the call over to Laura, our Chief Scientific Officer, who will provide updates on the Intel A31 program and our R&D efforts.

Laura: Thank you, John . Good morning, everyone. At Intellia, we're deploying the industry's broadest toolbox of novel gene editing and delivery technologies for in vivo and ex vivo therapeutic applications.

John Leonard: As we announced last week, we received regulatory approval from the United Kingdom's Medicine and Healthcare Products Regulatory Agency to initiate the first in-human study in patients with Alpha-1 antidepressant deficiency-associated lung disease. Following the IND clearings of Regeneron's [inaudible] program, this marks the second program leveraging our modular gene insertion platform [inaudible] the clinic; another accomplishment from our industry leading research engine. Unlike [inaudible] gene therapy, we expect our approach will permanently restore a missing or defective protein without a [inaudible] effect overtime. As a reminder, NTLA3001 is designed to precisely insert the wildtype [inaudible] A1 gene to permanently restore production and secretion of fully functional alpha-1 produce. Our goal is to replicate what we demonstrated in non-human primates; to restore patients to normal alpha-1 levels after a single dose. The phase I/II study will be a two part, open label, multi center study to evaluate the safety tolerability, PK and PV of NTLA3001. Of the 30 patients we've enrolled, phase I will be a single ascending dose designed with up to three cohorts. Patients will receive a single infusion of NTLA3001, which consists of a sequential dose of AAV and NMP. The AAV delivers the 3001 DNA template and the NMP delivers the CRISPR machinery. Based on our learnings from NTLA2001 and NTLA2002, we will be [inaudible] a 6th NMP dose of 50 mg. The only variable component from cohort to cohort into dose escalation will need a dose of AAV. We will begin with doses of AAV that we expect will show some level of activity even in the first cohort. Once we've identified the optimal dose, we plan to move into the phase II, which will be a single dose expansion cohort to further characterize the activity of NTLA3001. We're on track to dose the first patient in the second half of this year. Assuming success, NTLA3001 could redefine how [inaudible] is treated and unlock a whole new category [inaudible] we can pursue with our in vivo gene insertion platform. Turning to another exciting development with our in vivo platform, [inaudible] Intellia achieved yet another landmark milestone for gene editing. We presented the first ever clinical data demonstrating that dosing with CRISP when utilizing Intellia's NMP [inaudible] platform, enable an additive pharmaco dynamic asset. [inaudible] the follow on dose was generally well tolerated. Overall, the safety and pharmaco dynamics of dosing NTLA2001 was consistent with those observed after a single dose. The ability to successfully [inaudible] patients is a testament to our high standard in developing our proprietary NMP formulation to ensure both safety and activity. Going forward, while not planned for our [inaudible] clinical programs, the option to readout could be an important advantage for Intellia as we continue to push the boundaries of what we can do and expand where we can go outside the level with CRISPR based technology. We look forward to updating you on our progress across our R&D platform more broadly this year. I'll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results as of the second quarter 2024. Thank you Laura. Good morning everyone. Intellia continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform. Our cash, cash equivalent and marketable securities were approximately $939.9 million as of June 30, 2024 compared to $1,000,000,000 as of December 31, 2023. The decrease was driven by cash use to fund operations of approximately $234.4 million. The decrease was offset in part by $96.4 million of net equity proceeds from the company's after market program, $35.9 million of collaborator reimbursement, including a one time $30 million dollar payment received in April related to the company's technology cloud relation with Regeneron, $25.1 million of interest income and $4.8 million in proceeds from employee based [inaudible]. Our collaboration revenue was $7 million during the second quarter of 2024, compared tp $13.6 million during the second quarter of 2023. The $6.6 million decrease was mainly driven by a reduction in revenue related to the [inaudible] license and collaboration agreement. R&D expenses were $114.2 million during the second quarter of 2024, compared to $115.3 million during the second quarter of 2023. The $1.1 million decrease was primarily driven by a decrease in employee related expenses. Stock based compensation included in R&D expense was $25.4 million for the second quarter of 2024. G&A expenses were $31.8 million during the second quarter of 2024, compared to $30.7 million during the second quarter of 2023. The $1.1 million increase was primarily related to stock based compensation. Stock based compensation included in G&A expense was $15.4 million for the second quarter of 2024. Finally, we expect our cash balance to find our operating plans into late 2026. Thanks Ed. In conclusion, Intellia continues to deliver on the promise of gene editing and we are looking forward to several important clinical milestones in the second half of this year. With that, we'll now open the call for your questions. We'll do our best to address as many questions as possible. We will only be able to take one question per caller. 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 one on your touchtone phone. If you are using a speaker phone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster.

Speaker Change: Let me begin with MDLA-3-D01.

Speaker Change: As we announced last week, we received regulatory approval from the United Kingdom's Medicine and Healthcare Products Regulatory Agency to initiate the first in-tune study in patients with Alpha-1 antiretroviral deficiency-associated lung disease.

Speaker Change: Following the IND clearance of Regeneron's Factor IX program, this marks the second program leveraging our modular gene insertion platform set to enter the clinic, another accomplishment from our industry-leading research engine.

Speaker Change: Unlike traditional gene therapy, we expect our approach will permanently restore a missing or defective protein without a waning effect over time.

Speaker Change: as a reminder and the l thirty one is designed to precisely insert the wildtype serin a one gene to permanently with store production and sticion of fully functional alpha one project

Speaker Change: Our goal is to replicate what we demonstrated in non-human primates, to restore patients to normal alpha-1 levels after a single dose.

John Leonard: The Phase 1-2 study will be a two-part, open-label, multi-center study to evaluate the safety, tolerability, PK, and PD of MDLA-30.1.

Speaker Change: Up to 30 patients will be enrolled. Phase 1 will be a single ascending dose designed with up to 3 cohorts.

John Leonard: Patients will receive a single infusion of MDLA-31, which consists of a sequential dose of AAV and LMP.

Speaker Change: The AAV delivers the SERPIN-A1 DNA template and the LMP delivers the CRISPR machinery.

Speaker Change: thised our learnings from inlay twenty or one and twent and two we will be evenval weightiting a sixx lnb low of fifty milligrams

Speaker Change: The only variable component from cohort to cohort in the dose escalation will be the dose of AAV.

John Leonard: We will begin with doses of AAV that we expect will show some level of activity, even in the first couple. We are on track to those first patients in the second half of this year. We presented the first-ever clinical data demonstrating that re-dosing with CRISPR when utilizing Intellia's LNP-based delivery platform enabled an additive pharmacodynamic effect. Intellia continues to maintain a strong balance sheet that allows it to execute on our pipeline and platform. The decrease was offset in part by $96.4 million of net equity proceeds from the company's at-the-market program, compared to $115.3 million during the second quarter of 2023.

Speaker Change: We will begin with doses of AAV that we expect will show some level of activity even in the first cohort. We will begin with doses of AAV that we expect will show some level of activity even in the first cohort.

Speaker Change: once with identify the optimon those we plan to move into a sie two which will be a single those expansion cohort to further characterizethe activity of ndlater thir one

Speaker Change: We are on track to those first patients in the second half of this year.

Speaker Change: Assuming success, MPLA-31 could redefine how Alpha-1 is treated and unlock a whole new category of experiences we can pursue with our in vivo gene insertion platform.

Speaker Change: Turning to another exciting development with our in vivo platform, in June Intelli achieves yet another landmark milestone for the field of gene editing.

John Leonard: We presented the first ever clinical data demonstrating that redosing with CRISPR when utilizing Intellia's LNP-based delivery platform enabled an additive pharmacodynamic effect.

John Leonard: Critically, the following dose was generally well-tolerated.

John Leonard: Overall, the safety and pharmacodynamics of re-dosing with NTLA-21 were consistent with those observed after a single dose.

John Leonard: The ability to successfully re-dose these patients is a testament to our high standard in developing our proprietary LNP formulation to ensure both safety and activity.

John Leonard: Going forward, while not planned for our current clinical programs, the option to read those could be an important advantage for Intellia as we continue to push the boundaries of what we can do and expand where we can go outside the lever with CRISPR-based technologies.

John Leonard: We look forward to updating you on our progress across our R&D platform more broadly this year. I'll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results as of second quarter 2024.

Ed Dulac: Intellia continues to maintain a strong balance sheet that allows it to execute on our pipeline and platform. The decrease was offset in part by $96.4 million of net equity proceeds from the company's at-the-market program, compared to $115.3 million during the second quarter of 2023.

Ed Dulac: Thank you, Laura. Good morning, everyone.

Ed Dulac: Intellia continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform.

Ed Dulac: Our cash, cash equivalents, and marketable securities were approximately $939.9 million as of June 30, 2024, compared to $1 billion as of December 31, 2023.

Ed Dulac: The decrease was driven by cash used to fund operations of approximately $234.4 million.

John Leonard: The decrease was offset in part by $96.4 million of net equity proceeds from the company's at-the-market program.

John Leonard: $35.9 million of collaborator reimbursements, including a one-time $30 million payment received in April related to the company's technology collaboration with Regeneron.

John Leonard: $25.1 million of interest income and $4.8 million in proceeds from employee-based stock plans.

John Leonard: Our collaboration revenue was $7 million during the second quarter of 2024, compared to $13.6 million during the second quarter of 2023.

John Leonard: The $6.6 million decrease was mainly driven by a reduction in revenue related to the Avancel license and collaboration agreement.

John Leonard: rn d expenses were one hundred and fourteen point two million dollars during the second quarter of two thousand and twenty four compared to one hundred and fifteen point three million dollars during the second quarter of two thousand and twenty three

John Leonard: The $1.1 million decrease was primarily driven by a decrease in employee-related expenses.

John Leonard: stock-based compensation included in r nd expense was one with twenty-five point four million dollars for the second quarter of two thousand and twenty- four

John Leonard: G&A expenses were $31.8 million during the second quarter of 2024, compared to $30.7 million during the second quarter of 2023.

John Leonard: The $1.1 million increase was primarily related to stock-based compensation.

John Leonard: Stock-based compensation included in G&A expense was $15.4 million for the second quarter of 2024.

John Leonard: finally we expect our cash balance the fundour operating plans into late two thousand and twenty-six

Speaker Change: s said

Speaker Change: In conclusion, Intellia continues to deliver on the promise of gene editing, and we are looking forward to several important clinical milestones in the second half of this year.

Speaker Change: With that, we'll now open the call for your questions. To do our best to address as many questions as possible, we will only be able to take one question per caller. Operator, you may now open the call for Q&A.

Speaker Change: 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 are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then 2.

Speaker Change: Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster.

Operator: The first question comes from Terence Flynn with Morgan Stanley. Please go ahead. Hi, thank you for taking our question. This is Chris on for Terence and congratulations on the progress. Regarding the HAE phase two data, can you talk about how competitive it is against Iona's drug? Thank you. Thanks Chris. As we said in our earlier comments, we're very excited about the profile of 2002. The way we're approaching the disease is we're trying to reset what is the current therapeutic regimen that's filled with patients. And that starts with having a deep understanding what patients are actually looking for. They're not looking for minor improvements in prophylactic therapy, they're not looking for primarily extensions and dosing intervals. What they're looking for is to be as normal as possible and that means not having to take any medicines.

Speaker Change: The first question comes from Terence Flynn with Morgan Stanley . Please go ahead.

Chris Ahn: Hi, thank you for taking our questions. This is Chris Ahn for Terence and congratulations on the progress. Regarding the HAE Phase 2 data, can you talk about how competitive it is against Iona's drug?

Speaker Change: Thank you.

Speaker Change: Thanks, Chris. As we said in our earlier comments, we're very excited about the profile of 2002.

Speaker Change: The way we're approaching the disease is we're trying to reset what is the current therapeutic regimen that's available to patients.

Speaker Change: And that starts with having a deep understanding of what patients are actually looking for.

Speaker Change: they're not looking for minor improvements in in proactic therapy they're not looking for primarily extensions and dosing intervals what they're looking for us to be as normal as possible and that means not having to take any medicines

John Leonard: So as we look at HAE and its development, that is the profile we're looking for: a single dose that leads to a complete elimination of tax and patients no longer to take any medication at all. That is the profile we're shooting for, that's what we've seen in our early phase one program and as information comes available for a phase two program you'll be able to see for yourself in terms of our ability to achieve that profile. We think we're resetting the bar and with that, in an entirely new response for patients, we think the drug will be without [inaudible]. Great, thank you. The next question comes from Mary Kate Davis with Bank of America. Please go ahead. Good morning. Thank you for taking our question. Looking at the AATV program here, could you comment on how impactful the [inaudible] program could be for the current market given unmet need in the space? Thank you. Well, our assessment of alpha one antitrypsin deficiency therapies that currently exist is that it's almost a complete absence of effective therapy. So our view is that it's essentially wide open in terms of resetting the bar. Remember what we're trying to do. We're trying to have the production of a fully normal protein that is the wild type alpha one antitrypsin protein that has normal activity. That doesn't exist yet today, and so we view this very large market as one that we can be very, very successful in. And we're very excited about beginning a clinical program with 3001. The next question comes from [inaudible] with Stifel. Please go ahead. Hey, good morning guys. Thanks for taking our question as well. I'll also stick with AATV. Maybe a question for Laura. As we think about the 3000 [inaudible], specifically on the AAV component, I guess, can you speak to what your learnings are or what your derivations are from the [inaudible] when it comes to AAV and how that gets factored into your dose. And specifically, can you also talk about sort of the biology behind wild type AAT and still having ZAAT production, whether the ZAAT lingering might have some proinflammatory effect on the lung pathology. Thanks so much. So Laura, do you want to take that and start with the dosing differences?

Speaker Change: So, as we look at HAE and its development, that is the profile we're looking for, a single dose that leads to a complete elimination of tax.

Speaker Change: and patients no longer to take in any medication at all that is the profile we're shooting for that's what we've seen in our early phase one program and as information becomes available for a phase two program you'll be able to see for yourself in terms of our ability to achieve that profile

Speaker Change: We think we're resetting the bar, and with that, in an entirely new category of responses for patients, we think the drug will be without equal.

Speaker Change: Great, thank you.

Speaker Change: The next question comes from Mary Kate Davis with Bank of America. Please go ahead.

Speaker Change: Good morning. Thank you for taking our question. Looking at the AATD program here, could you comment on how impactful the wholly-owned insertional program could be for the current market given unmet need in the space? Thank you.

Speaker Change: Well, our assessment of alpha-1 antitrypsin deficiency therapies as they currently exist is that it's almost a complete absence of effective therapy.

Speaker Change: So our view is that it's essentially wide open in terms of resetting the bar.

Speaker Change: Remember what we're trying to do. We're trying to have the production of a fully normal protein that is the wild-type alpha-1 antitrypsin protein that has normal activity.

John Leonard: That doesn't exist yet today, and so we view this very large market as one that we can be very, very successful in. And we're very excited about beginning a clinical program with 301.

Speaker Change: That doesn't exist yet today. And so we view this very large market as one that is one that we can be very, very successful in. And we're very excited about beginning a clinical program with 301.

Speaker Change: The next question comes from Dagon Hopp with Stiefel. Please go ahead.

Dagon Hopp: Hey, good morning guys. Thanks for taking our question as well. I'll also stick with AAT. Maybe a question for Laura. As we think about the 3001, specifically on the AAV component, I guess, can you speak to what your learnings are or what your derivations are from the Astellas Adentes experience when it comes to AAV8 and how that gets factored into your dose? And specifically, can you also talk about sort of the biology behind

Speaker Change: Wild Type AAT and still having ZAAT production, whether the ZAAT lingering might have some pro-inflammatory effects on the lung pathology. Thanks so much.

Laura Sepp Lorenzino: Yes, so thank you for the question. So here we're using the AAV to deliver the template for insertion. So it's quite a different approach when we're using traditional gene therapy where you need to load the cells with epizomes to ensure that you have a long duration of effect. So given that our doses are much, much lower, not only [inaudible], including for liver directed diseases [inaudible]. So again, the thing is, we need to have enough templates, have insertions John, anything you would like to add? No, I think that speaks to...

Speaker Change: So Laura, do you want to take that and start with some of the dosing differences? Yeah, sure.

Laura: Yes, so thank you for the question. So, you know, here we're using the AAV to...

Laura: To deliver the template for insertion, so it's, you know, quite a different approach when we're using traditional gene therapy where you need to load the cells with epizomes to ensure that you have, you know, long duration of effect.

Speaker Change: So, you know, given that, our doses are much, much lower, not only to what our dentist, you know, has used, but what, you know, others have used, including for, you know, liver-directed diseases, you know, using AAV-8.

Speaker Change: So, again, you know, the thing is we need to have enough template to have exertion in a few percentage of hepatocytes that's going to drive the levels of alpha-1 that we believe are going to be fully therapeutic.

Speaker Change: Based on our data, not all the patients who have alpha-1 and atrial fibrillation deficiency have liver disease, right? That's a minority of the patients.

John Leonard: So, we don't expect any issue by, you know, having, expressing the wild type protein in patients who have, you know, it's said a little. John , anything you would like to add? No, I think that speaks to it. Thank you, Laura.

Joseph Thome: The next question comes from Joseph Thome with T.D. Cowan. Please go ahead.

Speaker Change: The next question comes from Joseph Thome with TD Cowan. Please go ahead.

Unnamed: Hi there, good morning, and thank you for taking my question. Maybe one quickly on the 2001...

Joseph Thome: Hi there, good morning and thank you for taking my question. Maybe one quickly on the 2001 PN proposed study, I think you indicated that it would be ex-US, which obviously makes sense given the availability of silencers.

Speaker Change: Do you think the FDA would like to see dosing of any US patients prior to an approval in this setting? Or do you think ex-US patients for the entire program would be sufficient? Would you do an open label extension or anything like that? Thank you.

John Leonard: Thanks for the question, Joe. We've reviewed this extensively with the FDA. We have a very good understanding of what they're looking for. We have agreements in alignment on how we're conducting the study outside the United States. They're not requiring patients to be dosed for that particular indication inside the United States. Remember that they're going to see many other patients that will come from our cardiomyopathy study where we're already enrolling patients in the United States, so they'll see a very extensive prior exposure to the drug.

Speaker Change: Thanks for the question, Joe. We've reviewed this extensively with the FDA. We have a very good understanding of what they're looking for.

Speaker Change: We have agreement and alignment.

Speaker Change: Our research focuses on how we are conducting the study outside the United States. They are not requiring patients to be dosed in that particular indication inside the United States.

Speaker Change: Remember that they're going to see many other patients that will come from our cardiomyopathy study, where already we're enrolling patients in the United States, so they'll see a very extensive prior exposure to the drug.

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

Speaker Change: Perfect, thank you.

Speaker Change: The next question comes from Luca Issi with RBC. Please go ahead.

Laura Sepp Lorenzino: Oh, great. Thanks so much for taking my question. Congratulations on all the progress. Maybe, Laura, one more here on Alpha One. Obviously, the competitive landscape continues to evolve with Vertex giving up on their approach, but we are seeing a lot of other innovations coming down the pike, including, I think we're going to see clinical data for the first time for ADAR and RNA editing toward the end of the year.

Luca Issi: Oh great Doug, thanks so much for taking my question, congrats on all the progress, maybe Laura one more here on Alpha 1.

Speaker Change: Obviously the competitive landscape continues to evolve of the Vertex giving up on their approach, but we are seeing a lot of other innovations coming down the pike.

Speaker Change: I think we're going to see clinical data for the first time for ADAR and RNA editing toward the end of the year. I'm wondering if you can just kind of compare and contrast that approach versus your approach and why you think your approach is better. Any thoughts there? I much appreciate it. Thanks so much.

Laura Sepp Lorenzino: Wondering if you can just kind of compare and contrast that approach versus your approach and why you think your approach is better. Any thoughts there? I would very much appreciate it. Thanks so much.

Speaker Change: Thank you for the question. Look, based on the preclinical data that we have seen, right, we believe that with 31 we have demonstrated, you know, in non-human primates the ability to achieve not just 11 micromolar, right, but, you know, the full normal dose.

Speaker Change: And I think that if we can translate that in humans, that's going to be differentiating. And because of the mechanism of action, right, this is going to be potentially one-and-done, right? So you're looking for a single solution that will achieve normal levels.

Speaker Change: Of course, there are other modalities that are being advanced. At the end of the day, the proof of the pooling will be in the clinic, so along with the clinical data.

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

Speaker Change: Thanks a lot.

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

Gena Wang: Thank you. I will ask one question regarding the HAE program. What is the status of a partial clinical hold in HAE for the women of a reproductive age and also for the phase 2 HAE full data? I assume you will be presenting at the medical conference. You know, is the ACAEI in Boston is a good venue for the full data?

Speaker Change: Thanks, Gena. As soon as we're in a position to share where we're presenting the data, we will, of course, do that as we've

Speaker Change: I was done, and we look forward to seeing you in the audience as we go through what we think is very exciting data. With respect to the women with childbearing potential, I just want to clear up one thing. There was no partial clinical hold. That's not correct.

Speaker Change: But as we said, we've addressed all of the issues with the FDA.

Speaker Change: Complete alignment with respect to the Phase 3 study, and we will be including women of childbearing potential, not only in the United States, but around the world, as we've been doing up until now, with the exception of the United States. So we look very forward to that.

Speaker Change: Very much forward to beginning that trial and collecting results from the full population. I would add that

Speaker Change: Beyond just women of childbearing potential, the goal of that trial is to be very expansive and to include the largest set of patients with different degrees of the illness to begin with, so we can have a very expansive label when we're done.

Maury Raycroft: The next question comes from Maury Raycroft with Jeffreys. Please go ahead.

Speaker Change: Thank you.

Speaker Change: The next question comes from Morrie Raycroft with Jeffreys. Please go ahead.

Morrie Raycroft: Hi, congrats on the update and thanks for taking my question. I'm wondering if there's more you can say on feedback from the HAE and the Phase II meeting and your latest thoughts on the pivotal trials design. And in particular, I'm wondering how big this study would need to be and if there's anything more you could say about effect size or placebo response expectations.

John Leonard: Thanks, Maury. I guess I would characterize the FDA meeting as profoundly successful. We presented, as they saw earlier, preclinical data. We shared our manufacturing approach, and they saw the clinical data from not only the phase one, but the phase two program. The key decision there was to decide on which dose to take into phase three. We did that.

Speaker Change: Thanks, Maury. I guess I would characterize the FDA meeting as profoundly successful.

Speaker Change: We presented, as they've seen earlier, preclinical data. We've shared our manufacturing approach.

Speaker Change: and they've seen the clinical data from not only the Phase I but the Phase II program.

Speaker Change: The key decision there was to decide on which dose to take into Phase 3. We've done that, and as we shared here...

John Leonard: And as we shared here, that will be the 50 milligram dose. And as per the prior question from Gina, we will expose the full population of people with the disease to the drug. So we're very, very excited about that.

Speaker Change: that will be the 50 milligram dose and as per the prior question from Gina we will expose the full population of people with the disease to the drug so we're very very excited about that

John Leonard: We now know the size of the trial, and we expect that it will be fewer than 70 patients. It will be a placebo-controlled trial, as is the standard. We'll look for a variety of different outcomes, not only attack rate reduction but, of course, the number of patients who achieve that complete response that we think is so fundamental to the profile of the drug. And these things will be measured over a six-month interval, as opposed to the 16 weeks that we did in phase one and phase two.

Speaker Change: We now know the size of the trial and we expect that this will be fewer than 70 patients.

Speaker Change: It will be a placebo-controlled trial, as is the standard. We'll look for a variety of different outcomes, not only attack rate reduction, but of course the number of patients who achieve that complete response that we think is so fundamental to the profile of the drug.

Speaker Change: And these things will be measured over a six-month interval as opposed to the 16 weeks that we've done in phase one and phase two.

John Leonard: Again, just to make the point, we're on track to begin this before the end of the year, and we're very, very excited about advancing this program because we believe it will be the very first in vivo approved agent for any CRISPR program.

Speaker Change: Again, just to make the point, we're on track to begin this before the end of the year, and we're very, very excited about advancing this program because we believe it will be the very first in vivo approved agent for any CRISPR program.

Mani Foroohar: The next question comes from Mani Foroohar on Lyrinc. Please go ahead.

Speaker Change: got thank you

Speaker Change: The next question comes from Mani Foroohar with Lyrinc. Please go ahead.

John Leonard: Thanks for taking the question. I know you have been more reticent than others to, uh, use the phrase functional cure, which is... Realistically, what we're talking about for HAE is that you take patients off all therapy. The competitive program for Ionis, which is a chronic therapy, so not pursuing a curative and functional cure, has a number of studies. For example, they had to do a switch study, etc. They chose to do a switch study on your therapy and eventually nothing on top.

Mani Foroohar: Thanks for taking the question.

Mani Foroohar: I know you have been more reticent than others to use the phrase functional cure, which is

Speaker Change: realistically what we're talking about for HAE is you're going to take patients off all therapy

Speaker Change: The competitor program from Ionis, which is a chronic therapy, so not pursuing a curative and functional cure, has a number of studies. They had to do a switch study, etc. They chose to do a switch study.

Speaker Change: when you think about the pastic commercialization for what's meant to be a onetime funct chred to therapy for at least momed on with the majority of patients

Speaker Change: How do you think about providing data...

Speaker Change: For patients to switch, for patients moving off of trophillactic therapy, discontinuing, you know, the practice of keeping on-demand therapy on them, etc. Will there be a couple of other, more broadly, will there be a couple of other studies as part of your larger strategy?

Speaker Change: To inform physicians on how to roll patients off therapy, or do you think you can take advantage of data sets produced by others in terms of providing the operational input of how physicians move patients off of current polypharmacy to your therapy and eventually nothing on top of it?

John Leonard: That may have been six questions, Mani, and I don't know if I can speak to all of them, but let me try to give some perspective on what I think you're getting at. First of all, you know, we're being very judicious with the words that we use to describe the outcomes for these patients. You know, you yourself are calling it a functional cure. We think that that's something that we're achieving with these patients.

Mani: That may have been six questions, Mani, and I don't know if I can speak to all of them, but let me try to give some perspective on what I think you're getting at.

Mani Foroohar: First of all, we're being very judicious with the words that we use to describe the outcomes for these patients.

Speaker Change: You know, you yourself are calling it a functional cure. We think that that's something that we're achieving with these patients. What we'll be able to say from a regulatory point of view remains to be determined as we work with the Food and Drug Administration, but the evidence will speak for itself.

John Leonard: What we'll be able to say from a regulatory point of view remains to be determined as we work with the Food and Drug Administration, but the evidence will speak for itself. Again, the goal is to have patients following a single application of the drug no longer take therapy, and you can decide what you want to call that. With respect to moving forward with the agent into the marketplace,

Speaker Change: again the goal istohave patients following a single application of the drug no longer take therapy and we can decide what you want to call that with respect to moving forward with the eight with the agent into the marketplace

Speaker Change: We expect that there will be a set of patients immediately who want to have access to the drug.

Speaker Change: and these are patients who are not responding well to existing therapy of whatever for

Speaker Change: Doctors tell us and patients tell us that they very much look forward to having the drug available to them. Then there's a set of patients who have responses that are incomplete that have a propensity to switch.

Speaker Change: And the mechanism by which that plays out is something that we'll learn with the investigators and our key opinion leaders as we work with them.

Speaker Change: We may be in a position to do a switch study that's not currently laid out, but as we complete our thinking and get more information, as we work with leaders in the field, we'll get back to you and the larger community and talk about the way forward there.

Speaker Change: Either way, we believe that the drug will be extremely successful in the marketplace given a profile that is unmatched.

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

Speaker Change: The next question comes from Joon Lee with Truist Securities. Please go ahead.

Unnamed: Hi, good morning everyone. This is Mehdi on 4th June.

Speaker Change: Hi, good morning everyone, this is Mehdi on 4th June , congrats on the progress and thanks for taking our questions. So, on NTLA-201, given Aquarimidis now has a PDUFA date of November 19th,

John Leonard: Congratulations on the progress and thanks for taking our question. So, on NTLA-201, given Acquiramidis now has a PDUFA date of November 19th and showed 50% CVH reduction with 81% survival, what do you expect to be the outcome of NTLA-201 in this regard? Basically, what do you think is the bar now for a Phase 3 magnitude study?

Mehdi: and show fifty percent cvs reduction with eighty-one percent arrival so what do you expect to be the outcome of our tool one ind this regard basically what do you think is the bar now for phase three magnitde study

John Leonard: Well, based on the TTR results that we presented in multiple forums, which are the deepest that have been reported, and the most prolonged that have been reported, we expect that we'll be able to meet or achieve any profile that's been put forward by any of the other competitive agents, whether a stabilizer or a silencer. We've designed a phase three trial that is designed to demonstrate that. And we have looked at patients with, you know, a range of different degrees of stability from their cardiomyopathy.

Speaker Change: well we based on the t results that we presented in multiple forums

Speaker Change: We expect that we'll be able to meet or achieve any profile that's been put forward by any of the other competitive agents, whether a stabilizer or a silencer.

Speaker Change: We've designed a phase 3 trial that is designed to demonstrate that and we have looked at patients with a range of different degrees of stability from their cardiomyopathy.

Kostas Biliouris: And we think that that patient population, whether on existing therapy or on monotherapy with 2001, will have outcomes that are superior to what's been reported with any of the other agents. So, stay tuned. As we said in our comments earlier, there's a lot of enthusiasm in the marketplace, with investigators and patients now essentially around the world coming into the study very, very quickly, well above our own expected accrual rates. So, we're excited.

Speaker Change: and we think that that patient population with on existing therapy or on mondel therapy with twent thousand and one will have outcomes their superior to what's been reported to any of the other agents so stay tuned the pro as we said in our comments earlier

Mehdi: there's a lot of enthusiasm in the marketplace with investigators and patients now essentially around the world

Mehdi: coming into the study very very quickly well above our own expected apaccrualval right so we're excited and as we get that information down the roadobviously we'llshare it and i'm sureit willll be much watched so we'll proceed as quickly as we can

Kostas Biliouris: And as we get that information down the road, obviously, we'll share it, and I'm sure it will be much watched. So, we'll proceed as quickly as we can. Thank you. The next question comes from Kostas Biliouris with BMO Capital Markets. Please go ahead.

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

Speaker Change: thank you

Mehdi: The next question comes from Costas Berdouris with BMO Capital Markets. Please go ahead.

Hi, this is Theo for Costas. Thank you for taking our question. And just one question from us. So on the IntelliEd 3.0.1 program, how do you think about the competition for patient enrollment, given that Beam and also other R&D companies are also recruiting in the United Kingdom? Thank you.

John Leonard: Thanks for the question. We work with investigators who know the patients they have, and we're quite confident that, certainly, in a phase one setting, not only in the UK but other countries where we will have sites, including New Zealand and Ireland, we'll be in a position to recruit the study expeditiously and look for the results that tell us how the drug is performing. We don't see this as being a competitive situation.

thanks for the question we work with investigators who know the patients they have

and we're quite confident that certainly in a phase one setting not only in the UK but other countries where we will have sites including New Zealand and Ireland that will be in a position to recruit the study expeditiously and look for the results that tell us how the drug is performing. We don't see this being a competitive situation.

Rick Bienkowski: The next question comes from Rick Bienkowski with Cancer Fitzgerald. Please go ahead. Hey, good morning.

Rick Bienkowski: The next question comes from Rick Bienkowski with Cancer Fitzgerald. Please go ahead. Hey, good morning, and congrats on the update in HAE.

the next question comes from rick and kosk with cancer fzgerald please go ahead

Rick Keskosk: good morning and congrats on the update and h ha e

So one of the observations from the phase one data was there was a small number of breakthrough attacks during the primary observation period and then...

complete suppression of attack afterwards so for the full phase two presentation later this year will we see any follow up ientsthats longer than the primary observation period and could you discuss if there are any plans to follow of these patients for a long term and maybe present those data at at a later date

John Leonard: We'll present data through the 16-week observation period. Remember that there are a couple differences in Phase II from Phase I. In the case of the Phase II study, there are two different doses, but a placebo arm as well. And what we offered all patients in the study was a switch, so we're not going to be in a position to look at ongoing placebo patients over time. We will follow all of these patients, as we have done with every single one of the patients that we've dosed, irrespective of the program.

We'll present data through the 16-week observation period.

Remember that there's a couple differences in the Phase II from the Phase I.

in the case of the phase i study there are two different doses but a plplaceussevble arm as well

And what we offered all patients in the study was a switch.

So we're not going to be in a position to look at, you know, ongoing placebo patients over time.

We will follow all of these patients, as we've done with every single one of the patients that we've dosed, irrespective of the program, and I would expect that down the road, at the appropriate times, we'll present follow-up information on every single one of the patients that we've treated thus far.

John Leonard: And I would expect that down the road, at the appropriate times, we'll present follow-up information on every single one of the patients that we've treated thus far. The next question... The next question comes from Jay Olson with Oppenheimer. Please go ahead. Oh, hey, congrats on all.

Jay Olson: The next question comes from Jay Olson with Oppenheimer. Please go ahead.

The next question comes from Jay Olson with Oppenheimer. Please go ahead.

Oh, hey, congrats on all the progress and thanks for taking the question. For 2001, can you talk about the number of study sites you plan to activate for the magnitude study and how could that be impacted by other...

Competing trials that are wrapping up, and then what you'll be looking for in the Helios B results when they're reported at ESC. Thank you.

John Leonard: Thank you for the question. We anticipate around 100 or so sites spread around the world with a variety of different countries participating. As we said in our comments, there are about a dozen so far that have received regulatory approval to begin enrolling, and that number will increase in the coming weeks. About 35 of the overall 100-plus sites are now active, and so we expect to see enrollment actually accelerate beyond our strong start already.

Thank you for the question.

we anticipate around one hundred or so sites spread around the world with

a variety of different countries participating. As we said in our comments, there's about a dozen so far that have given the regulatory approval to begin enrolling, and that number will increase in the coming weeks.

About 35 of the overall 100 plus sites are now active, and so we expect to see enrollment actually even accelerating beyond

John Leonard: As we put the study together and thought about where and how we were doing the study, we were cognizant of what was going on around the world, and we were very thoughtful about which sites to participate in and which countries to carry out the work in. And thus far, with the accumulated experience over the last few months, we don't see that we're really in a different competitive situation from the one that we estimated.

Our strong start already. As we put the study together and thought about where and how we were doing the study, we were cognizant of what was going on around the world and we were very

thoughtful about which sites to participate in which countries to carry out but work it in thus far as as with the accumulate experience over the last few months

we don't see that we're really in a different competitive situation from the one that we surmised in fact as i said we're ahead of our expectations and we continue we expect that to continue to be the cases time goes on

John Leonard: In fact, as I said, we're ahead of our expectations, and we expect that to continue to be the case as time goes on. The next question comes from Brian Cheng with J.P. Morgan. Please go ahead. Hey guys, thanks for taking our questions this morning.

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

the next question comes from brian chank with jp morgan please go ahead

Hey guys, thanks for taking our questions this morning.

Just on the back of your recently reported re-dosing data, is there any plan to build in re-dosing for those patients that didn't achieve perhaps a certain biomarker reduction threshold if it happens?

in a nextix set of study for t polling what the x hae or at thanks working our questions

John Leonard: Thanks for the question, Brian. One of the things that I think is really noteworthy of all of the patients that we've treated thus far, particularly those that have been treated at the doses that we deem to be therapeutic is that almost without exception, every single patient has achieved the level of reductions that we're looking for, which is a remarkable outcome that I think is sometimes lost, particularly when you look across other drugs and the variability that you see with not only the pharmacokinetic outcome but the I mean, what we're seeing here is quite unique.

Thanks for the question Brian . One of the things that I think is really noteworthy of all of the patients that we've treated thus far

Certainly, those that have been treated at the doses that we deem to be therapeutic is that

almost without exception

Every single patient has achieved the level of reductions that we're looking for.

Which is a remarkable outcome that I think is sometimes lost, particularly when you look across other drugs and the variability that you see with not only the pharmacokinetic outcome but the pharmacodynamic outcome. I mean, what we're seeing here is quite unique.

John Leonard: The way I would think about re-dosing is that it doesn't apply to the amyloidosis program. It doesn't, we don't think, apply to the calocrine program or HAE. But there may be instances where, in certain situations, if the level of editing is lower than what we're shooting for, you may want to walk up to a particular effect. And I can think of instances outside the liver where that might be the case, but that doesn't apply to any program that we're currently doing. And for all practical purposes, we think every one of the patients participating in the ongoing studies will be a one-and-done case.

The way I would think about re-dosing is that it doesn't apply to the amyloidosis program.

it doesn't apply we don't think to the caliaterarine program or ha

but there may be instances where in certain situations if the level of editing is lower than what we're shooting for

You may want to walk up to a particular effect.

and i can think of instances outside deliver where that might be the case but that doesn't apply to any program that we're currently doing and for all practical purposes we think every one of the patients participating in the ongoing studies will be a one in done case

Steve Seedhouse: The next question comes from Steve Seedhouse with Raymond James. Please go ahead. Hi, this is Timur Ivannikov on first.

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

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

Hi, this is Timur Ivannikov on for Steve.

for ad long disease historically has been difficult to show improvements and at thed one and puulminaryy excesserurbations

So do you think the FDA will require showing improvements on those endpoints besides just showing the reduction in neutrophil elastase activity?

John Leonard: It's an evolving space, and as far as we can determine from our interactions, as well as talking to experts in the space, the FDA is likely to approach this as a function of the degree of normality that's achieved. If patients achieve normal levels of the protein, the requirements we expect for functional aspects of that may be different from those instances in which either an abnormal protein or less than a complete normalization of effect are achieved.

It's an evolving space and as far as we can determine in our interactions as well as talking to experts in the space.

is that the fda is likely to approach this as a function of the degree of normality that's achieved

If patients achieve normal levels of the protein...

The requirements we expect for functional aspects of that

The patient may be different from those instances in which either an abnormal protein or less than a complete normalization of effect is achieved, because in those cases you're going to need supplementary information to indicate that less than a complete response is actually beneficial to the patient.

John Leonard: Because in those cases, you're going to need supplementary information to indicate that less than a complete response is actually beneficial to the patient. That's why we want to normalize patients. We think that the best we can do is put them in a position as if they never had the disease in the first place, and that's the objective of the program.

That's why we want to normalize patients. We think that the best we can do is put them in a position as if they never had the disease in the first place, and that's the objective for the program.

Silvan Tuerkcan: Thank you. The next question comes from Silvan Tuerkcan with Citizens JMP. Please go ahead. Good morning, and thanks

Silvan Tuerkcan: The next question comes from Silvan Tuerkcan with Citizens JMP. Please go ahead. Good morning, and thanks so much for joining us.

Thank you.

The next question comes from Silvan Tuerkcan with Citizens JMP. Please go ahead.

good morning and thanks so much for taking my questions and congress from the data date and just about the open lil trial the phase one in he the lot long to attack rate

Post the most recent presentation, I don't know if you can comment on it, but do you still have 8 out of 10 patients with no attacks post the observation period?

John Leonard: Thank you for the question, Silvan. I would say watch for updates as they come. As we said with one of the earlier questions, we'll follow all of these patients, and as we collect the information, we'll share it. We continue to be very, very excited about what we see and how these patients are performing after their single dose in 2002.

thank you for the question sovan i would say watch for updates as they come as we said to one of the earlier questions will follow all of these patients and as we collect the information will share it we continue to be very very excited about what we see and how these patients are performing after their single bells of two y o two

William Pickering: Great, thank you so much; I'm looking forward to the data. Thank you. The next question comes from William Pickering with Bernstein. Please go ahead. Hi, good morning.

William Pickering: The next question comes from William Pickering with Bernstein. Please go ahead. Hi, good morning.

Great, thank you so much, looking forward to the data. Thank you.

the next question comes from william pickering with ernstein please go ahead

Hi, good morning. Congrats on all the progress and thank you for taking my question. Now that it looks increasingly likely that a silencer will become available during your magnitude trial and potentially even before enrollment completes,

Can you speak to your assumptions on silencer drop-in rate? Is there a cap? And can you just confirm that patients who are already on a silencer would not be eligible to enroll? Thank you.

John Leonard: We will look at the data as it becomes available from Helios B, which we're very interested in confirming some of the assumptions that we have in terms of the design of our trial. And as that study becomes available and our own study evolves, we'll address what we think may be appropriate, if at all, for any drop-ins for patients on silencers. So stay tuned, but as it stands now, those drugs are not available, and we've made provisions for tefamidus use, which is integral to the study, as well as monotherapy.

We will look at the data as it becomes available from Helios B, which we're very interested in.

confirming some of the assumptions that we have in terms of the design of our trial.

And as that study becomes available and our own study evolves, we'll address what we think may be appropriate, if at all, for any drop-ins for patients on silencers, so stay tuned, but as it stands now,

those drugs are not available and we've made provisions for to famitous use which is integral to the study as well as monotherapy so the story will evolved as it changes we will adapt us necessary

Salveen Richter: So the story will evolve, and as it changes, we will adapt as necessary. Thank you. The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.

Thank you.

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

Hi, this is Lydia. I'm from Salveen. Thanks so much for taking our question. Just a quick one from us on APHR cardiomyopathy.

Just with regard to the enrollment progression for the magnitude trial, I think that last quarter you said that there were 30 patients enrolled, could you just provide an updated figure here and then when you expect to complete enrollment? Thanks so much.

John Leonard: Thank you for the question. What we won't be doing is giving updates on a quarterly basis.

thank you for the question what we won't be doing is giving updates on a quarterly basis

We share that information because it was the first time we had reported after we began the study, and we wanted people to see the very strong start in enrollment, which, as I said, continues to be above our expectations.

Again, we have more than 35 sites up and running in 12 countries that will continue to expand in the weeks that lie ahead.

John Leonard: We share that information because it was the first time we had reported results after we began the study, and we wanted people to see the very strong start in enrollment, which, as I said, continues to be above our expectations. Again, we have more than 35 sites up and running in 12 countries that will continue to expand in the weeks that lie ahead. In terms of complete enrollment, I would encourage you to look at proxies for the work that we've done.

In terms of the complete enrollment, I would encourage you to look at proxies for the work that we've done, and the Helios study would be, I think, a good place to look in terms of overall rate of enrollment, but of course our objective is to improve upon that.

John Leonard: And the Helios study would be, I think, a good place to look in terms of overall rate of enrollment. But, of course, our objective is to improve upon that. The next question comes from Myles Minter with. William Blair, Uh, hey, thanks for taking the question. Just on Alpha One, just-

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

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

he thanks for taking the question just on alpha one just curious what your definition of normal a levels are because there's a wide range i think twenty to fifty three micrmala and if that range will be achievable with your initial fifty me dose that you're going with and final question is just on the risk of alpum and reduction

Just with the fact that you're inserting into the album and locus and if that's going to be material or not. Thanks very much.

John Leonard: We'll turn to Laura, who can speak to what we're shooting for in terms of normal, but just one thing you said, you referred to the 50 milligram dose. We will be holding the LNP dose constant in our phase one study, and varying the AAV dose, which again is at levels that are significantly below what's typical for gene therapy, at least in recent examples. Maybe, Laura, you can speak to that.

We'll turn to Laura who can speak to what we're shooting for in terms of normal, but just one thing you said.

you refer to a fifty milillgram dose we will be holding the l np dose constants in our phase one study in varying the avdose which again is at levels that are significantly below what's typical for gene therapy at least

Laura Sepp Lorenzino: Right, so normal levels, right? And what you quoted is right, right? So they vary from 20 to 50.

in recent examples. Maybe, Laura, you can speak to...

Laura Sepp Lorenzino: Right.

Right, so normal levels, right, and what you quoted is right, right, so they vary from 20 to 50, and that's the goal that we want to achieve, right, in the monkeys we were in the, you know, 20s to, so that's what we, you know, expect we're going to be able to achieve in humans.

Laura Sepp Lorenzino: And that's the goal that we want to achieve, right? In the monkeys, we were in the, you know, 20s to, so that's what we, you know, expect we're going to be able to achieve in humans. With regard to albumin, that was obviously extensively evaluated in our GLP toxicology studies, and you know, we do not see a decrease in albumin expression that could, in any way, put patients in danger. So, we believe that, again, the doses that we're going to be investigating, even the first dose, we expect, we designed the trial for even the first dose to lead to alpha-1 levels that will be therapeutically relevant. And then we expect that the safety of approach 30-1 will be, you know, pristine.

with regards to al and that was obviously extensively evvaluin our gp to psychology studiesand

we do not see a decrease in albeum an expression that in anyway could put patients in the danger

So, we believe that, again, the doses that we're going to be investigating, even the first dose, we expect, we designed the trial for even the first dose to have

lead to ultrha one levels that will be repeutically relevant and then we expect that the safety of the approach thirty-one will be chrisistine

Liisa Bayko: The next question comes from Liisa Bayko with Evercore ISI. Please go ahead.

Thank you.

the next question comes from lisa bacco with evercore i please go ahead

John Leonard: Hi, this is Jamyung for Liisa. Thanks so much for taking our questions and congratulations on the progress. So, we just have a question for the Phase 3 Magnitude Study. What method do you plan to use for analysis of the composite endpoint? Something like Finkelstein or Anderson-Gill, like in Helios B.

John Leonard: Thank you.

hey this is stream for lisa thanks so much for taking our questions and congresss on the progress so which is of a question for bas three magnitude study well method do you pun to use for analysis of the composite andpoint something like singinkcoine or anders and go likeand kil speed thank you

Ry Forseth: Thanks for the question. Those are details that lie ahead, and we'll disclose at the appropriate time, but we appreciate your interest. Thank you. The next question comes from Ry Forseth with Guggenheim. Please go ahead. This is Rye from Debjit's team.

it's really the question those are details that lie ahead and we'll disclose at the appropriate time but we appreciate your interest

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

Thank you.

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

This is Rai from Debjit's team. Across HAE, ATTRPN, and CM, what's your contemporary internal market research suggesting for uptake or enthusiasm to switch for gene editing? Is there any notable interindication differences that you've

John Leonard: Those are very different diseases, cardiomyopathy and hereditary angioedema. In the case of cardiomyopathy and polyneuropathy, those are progressive diseases.

those are very different disease it card on my opathy in heredit ange themma one in the case of carry my oppiteity ploy roapaththy those are progressive diseases h episodic in nature in any on episode can be a tatal evthat

John Leonard: HAE is episodic in nature, and any one episode can be a fatal event. What our market research tells us is that, as we said in earlier comments, patients with HAE want to be normal. They're otherwise, in most cases, between attacks, normal, and they want to have that in every day of their life as much as possible.

What our market research tells us is that, as we said in earlier comments, patients with HAE want to be normal.

They're otherwise, in most cases, between attacks normal

John Leonard: So, ranging from patients who have a poorly controlled disease to patients who want to improve how they live their lives, which is most of the patients taking the drug, what our market research tells us is that 2002 will be very, very attractive to the preponderance of patients suffering from HAE. In the case of amyloidosis, whether polyneuropathy or cardiomyopathy, these are progressive diseases with patients getting worse and worse and ultimately succumbing to their disease.

every day of their life as much as possible.

So, ranging from patients who have poorly controlled disease to patients who want to improve how they live their lives, which is most of the patients taking the drug.

What our market research tells us is that 2002 will be very very attractive to the preponderance of patients suffering for HAE

In the case of amyloidosis, whether polyneuropathy or cardiomyopathy, these are progressive diseases with patients getting worse and worse and ultimately succumbing to their disease.

John Leonard: The objective here is for us to demonstrate not only stopping the progression of the disease, but we believe that in several instances, perhaps many of the cases, we'll actually have some degree of reversal. As the year goes on, I would encourage you to look at the Phase I results that we'll be presenting, patients who have been followed now for a couple of years, and we think that those may be indicative of what lies ahead. In the end, patients want the best drugs available for whatever disease they suffer from, and it's our goal at Intellia to meet that need.

The objective here is for us to demonstrate not only

Stopping the progression of the disease, but we believe that in several instances, perhaps many of the cases, will actually have some degree of reversal.

As the year goes on, I would encourage you to look at the Phase I results that we'll be presenting, which patients have been followed now for a couple of years.

And we think that that may be indicative of what lies ahead. So, in the end, patients want the best drugs available for whatever disease they suffer from, and it's our goal at Intellia to meet that need.

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

Thank you.

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

John Leonard: Thank you very much for taking my question. Certainly understand that you can't speak directly to anything about the Magneti trial and the potential adaptations, but could you indicate what specific items are most interesting to you in the upcoming Heliospeed detailed readout here at the EFC? What things are you focusing on and how I guess that might inform further aspects of the design of the Magneti trial?

thank you very much for taking my question certainly understanding that that you can't speak to directly to anything with the magnnetity trial and the potential ad aptations but could you

Indicate what specific items are most interesting to you in the upcoming webinar.

Heliospeed detailed readout at the EFC, what things you're focusing on and how I guess that might inform further aspects of design of the magnitude trial.

John Leonard: David, it's an important question, and we and many others, I think, will be very interested in learning more details about what we think are exciting initial results. What's of great interest to us and the field in general is some relationship between the level of TTR reduction and overall event rates and how that plays out in particular patient populations. That's a function of the stage of their disease. Patients who are early in the disease have a slower rate of events taking place, and how that plays out in patients with more severe disease will be of great interest to us.

David, it's an important question and we and many others I think will be very interested in learning more details about what we think are exciting and initial results.

What's of great interest to us, and the field in general, is some relationship between the level of TTR reduction and overall event rates.

and how that plays out in particular patient populations that's a function of the stage of their disease

Patients who are early in the disease have a slower rate of events taking place and how that plays out in patients with more severe disease will be of great interest to us.

John Leonard: Remember that when we constructed our trial, we included patients who have been excluded in many of the other studies that have been done. We're allowing and, in fact, requiring higher levels of ProBNP at baseline as well as including patients with class 3 heart disease. We will be very interested in understanding the nature and extent of the effect in patients receiving other drugs on top of tefamidus, and that will be something that we consider with our own study as it progresses.

Remember that when we constructed our trial...

We included patients who have been excluded in many of the other studies that have been done.

we'are allowing and fact requiring higher levels of prob m pat baseline as well as allowing patients with class three heart disease

We will be very interested in understanding the nature and extent of the effect in patients receiving drug on top of tefamidus.

And that will be something that we consider with our own study as it proceeds. Remember that we designed the study in a way that if we need to adapt it based on what we learned, we can adapt it.

John Leonard: Remember that we designed the study in a way that if we need to adapt it based on what we learn, we can adapt it, and because we're early in enrollment here, we think that we're in a really strong position to come up with what we think will be the strongest study in the space.

And because we're early in enrollment here, we think that we're in a really strong position to come up with what we think will be the strongest study in the space.

Andy Chen: Thank you for taking my question. Our last question will come from Andy Chen with Wolf Research. Please go ahead. Hey, this is Brandon on behalf of Andy. Congratulations on the phase two success and move to phase three.

Andy Chen: Our last question will come from Andy Chen with Wolf Research. Please go ahead. Hey, this is-

thank you for taking a question

Our last question will come from Andy Chen with Wolf Research. Please go ahead.

Hey, this is Brandon on for Andy. Congrats on the Phase 2 success and move to Phase 3. Based on our understanding, the HEE market is somewhat saturated. Although there's still a chunk of patients who have not signed up for prolactive treatments, your competitors don't seem to be activating those patients.

So all of your competitors are competing for the same pie right now. Do you think gene editing could expand the pie of prophylactic treatment?

John Leonard: In a word, yes. And with respect to saturation...

in a word yes

John Leonard: I would be careful in terms of what I think that means. The presence of therapy does not mean that the therapy is ideal. And again, as we look at our market research, which involves extensive discussions with leading investigators in the space, and multiple patient interviews, most patients say that they want to be normal. And that means never having to take any of those drugs that currently saturate the market that you referred to. It is our objective to meet that need. And we think that we'll be able to normalize the vast preponderance of patients with this disease.

and with respect to saturation

I would be careful in terms of how I think what that means.

the presence of therapy does not mean that but therapy is ideal and again as we look to our market research and this involves exexpensive discussions with leading an investigators in the space multiple patient interviews

If you ask patients, most of them want to be normal. And that means never having to take any of those drugs that currently saturate the market that you referred to.

It is our objective to meet that need, and we think that we'll be able to normalize the vast preponderance of patients with this disease.

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

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

Ian Karp: Great. Thanks so much, Drew, and thank you, everyone, for joining us and for your continued interest in Intellia. I'd also like to give a special thanks for everyone's discipline in asking one question today because I think this may be the first time in a while that we've gotten through everyone's questions. So we look forward to continued updates as the year continues. And with that, we wish everyone a great rest of the summer.

Great. Thanks so much, Drew, and thank you, everyone, for joining us and for your continued interest in Intellia. I'd also like to...

Give a special thanks for everyone's discipline in asking one question today, because I think it's, this may be the first time in a while that we've gotten through everyone's questions. So, we look forward to continued updates as the year continues, and with that, we wish everyone a great rest of the summer.

Unnamed: The conference has ended. You may now disconnect your line. Thank you.

The conference has ended. You may now disconnect your line. Thank you.

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