Q4 2023 Intellia Therapeutics Inc Earnings Call

Operator: The Bulletproof Executive, 2013 Good morning, and welcome to the Intellia Therapeutics fourth quarter and full year 2023 financial results conference call. My name is Drew, and I will be your conference operator today.

Yes.

Good morning, and welcome to the intelligent therapeutics fourth quarter and full year 2023 financial results Conference call. My name is drew and I will be your conference operator today.

Operator: 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.

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.

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

I'll now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and corporate communications at until you. Please proceed.

Thank you operator, and good morning, everyone.

Ian Karp: Welcome to Intellia Therapeutics' fourth quarter and full year 2023. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter as well as topics for discussion on today's call. This release can be found on the Investors & Media section of Intellia's website at intelliatx.com. The call is being broadcast live, and a replay will be archived on the. At this time, I would 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. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information

Welcome to Italian therapeutics fourth quarter, and full year 2023 earnings call.

Earlier, this morning, and telling you issued a press release outlining the companys progress this quarter as well as topics for discussion on today's call.

This release can be found on the investors and media section of <unk> website at intaglio, TX Dot com.

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

At this time I would like to take a minute to remind listeners that during the call and Telia management may make certain forward looking statements and ask that you refer to our SEC filings available at SEC Gov for a discussion of potential risks and uncertainties.

All information presented on this call is current as of today and then tell you undertakes no duty to update this information unless required by law.

Ian Karp: Joining me from Intellia are John Leonard, Chief Executive Officer, David Leboil, Chief Medical Officer, Laura Sepp Lorenzino, Chief Scientific Officer, and Glenn Goddard, Chief Operating Officer. John will begin with an overview of recent business highlights. David will provide an update on our clinical trials, the Laurel Review, our R&D update, and Glenn will review our financials before we open up. With that, I'll now turn the call over to John. Thank you, Ian. Good morning, everyone, and thank you all for joining us.

Joining me from Intaglio, John Leonard Chief Executive Officer, David Loeb Wall, Chief Medical Officer, Laura step Lorenzi, now Chief Scientific Officer, and Glenn Goddard, Our Chief Financial Officer.

John will begin with an overview of recent business highlights David will provide an update on our clinical pipeline progress.

Laura will review, our R&D updates and Glenn will review our financials before we open up the call for questions.

With that I'll now turn the call over to John <unk>, Our Chief Executive Officer.

Thank you Ian and good morning, everyone and thank you all for joining us today.

John M. Leonard: 2023 was an outstanding year for Intellia, and that strong momentum has carried into 2020, with our two lead programs either in or approaching phase three clinical. We're now closer than ever to the first in vivo CRISPR-based therapies reaching the Notably, our one-time treatment, offering potentially unmatched clinical profiles, would address significant patient unmet need in two large and rapidly growing commercial markets. Having clinically validated our in vivo CRISPR gene editing technology by inactivating genetic targets in the liver, we're now bringing forth the next wave of innovation. This new frontier will come in two dimensions, broadening what we can do and expanding where we can go, all of which will allow us to treat more diseases. The genome editing revolution is only made possible by the unique properties of Intellia's expertise with CRISPR-Cas9 is unsurpassed and serves as a foundation for the diverse set of editing tools that we have developed and continue to advance. Whether using base editing or DNA writing tools, each of these technologies relies on the specificity and versatility of the CRISPR system.

2023 was an outstanding year for Kelly and that strong momentum has carried into 2024.

With our two lead programs either in or approaching phase III clinical development, we're now closer than ever to the first in vivo CRISPR based therapy, just reaching the market.

We've made critical advances for the field of genome editing and for patients suffering from a T. T. R amyloidosis sorry he.

Notably, our one time treatment offering potentially unmatched clinical profiles would address significant patient unmet need in two large and rapidly growing commercial markets.

Having clinically validated our in vivo CRISPR gene editing technology by Inactivating genetic targets in the liver, we're now bringing forth. The next wave of innovation. This new frontier will come in two dimensions broadening what we can do and expand where we can go all of which will allow us to increase the number of diseases. We can pursue.

The genome editing Revolution is only made possible by the unique properties of CRISPR Cas.

Kelly is expertise with CRISPR Cas night is unsurpassed and serves as a foundation for the diverse set of editing tools, we have developed and continued to advance.

Well, they're using base editing or DNA, writing tools each of these technologies rely on the specificity and versatility of the CRISPR system.

John M. Leonard: With our wide range of editing and delivery capabilities, we can apply the best tool for each therapeutic application. This allows us to address diseases where there is a meaningful opportunity to improve the standard of care. In some cases, we may even be able to address diseases that would otherwise be considered untreatable if not for the power of medicine.

With our wide range of editing and delivery capabilities, we can apply the best tool for each therapeutic applications. This allows us to address diseases, where there is a meaningful opportunity to improve the standard of care in some cases, we may even be able to pursue diseases that would otherwise be considered untreatable, if not for the power.

Christopher.

John M. Leonard: It is this expansive and modular platform, coupled with our strong balance, that will allow us to achieve the three-year strategic priorities announced earlier this year. Our focus remains on both near-term clinical execution as well as value-creating platform innovation. With this as a backdrop, we expect the following by the end of this year: two in vivo knockout programs and active phase three. Two in vivo gene insertion programs, first in human studies, and 5 different tissues outside the liver.

It is this expansive and modular platform coupled with our strong balance sheet that will allow us to achieve the three year strategic priorities announced earlier this year, our focus remains on both near term clinical execution as well as value creating platform innovation.

This is a backdrop, we expect the following by the end of this year.

Two in vivo knockout programs in active phase III studies, two in vivo gene insertion programs in the first in human studies and five different tissues outside the liver with active research programs in.

John M. Leonard: Additionally, we expect to have six or more collaborations with at least a dozen potential drug products utilizing our technology in research and development. We're confident in our ability to deliver on these ambitions. We have a proven track record of success with regulators in advancing CRISPR-based therapies in clinical trials. And we've consistently delivered on our commitments to the scientific, patient, and investment communities. And finally, we have a world-class team of drug developers who have pioneered some of the most innovative and commercially successful medicines in history. In summary, Intellia is the company with the most advanced and expansive in vivo and ex vivo pipeline in the industry, and with potential BLA submission in 2026, we're well-positioned to bring forth the first ever in vivo CRISPR-Basin. I'll now hand the call over to our Chief Medical Officer, David Levwall, who will provide an update on our clinical program. Thanks, John, and welcome, everyone.

And Additionally, we expect to have six or more collaborations with at least a dozen potential drug products utilizing our technology and research and development.

We're confident in our ability to deliver on these ambitious goals.

A proven track record of success with regulators and advancing CRISPR based therapies and clinical trials, we consistently delivered on our commitments to the scientific patient and investment communities.

Finally, we have a world class team of drug developers, who have pioneered some of the most innovative and commercially successful medicines in history.

In summary, and Kelly is the company with the most advanced and expansion of in vivo and ex vivo pipeline in the industry with the potential BLA submission in 2026, we're well positioned to bring forth the first ever in vivo CRISPR based therapy.

I'll hand, the call over to our Chief Medical Officer, David Loeb Wall, who will provide an update on our clinical programs David.

Thanks, John and welcome everyone.

David Neil Lebowitz: I'll begin with 2001, our in vivo CRISPR candidate for the treatment of ATTR amyloidosis. In December, we initiated the Phase III Magnetry Trial for patients with cardiomyopathy. Since then, we're hitting the aggressive timelines we have set for ourselves, including multiple sites opening and regulatory approvals in geographies with large patient numbers. Notably, we have our first U.S. site actively enrolling patients and on track to dose the first patient in the first quarter. We are making great progress and expect many additional sites to ramp up throughout.

I'll begin with 'twenty, one our in vivo CRISPR candidate for the treatment of H T. T. R amyloidosis.

In December we initiated the phase III magnitude trial for patients with cardiomyopathy.

Since then we're hitting the aggressive timelines, we have set for ourselves, including multiple sites opening and regulatory approvals in geographies with large patient numbers.

Notably we have our first U S sites actively enrolling patients and on track to dose the first patient in the first quarter.

We're making great progress and expect many additional sites to ramp up throughout the year.

David Neil Lebowitz: At the same time, we are actively preparing for a global, pivotal, phase 3 study in 2001 for the treatment of patients with polyneuropathy. We expect to provide additional information on our Phase 3 plans later this year. Finally, we plan to present new data from the ongoing Phase I study this year. I'll now turn to 2002, our in vivo CRISPR candidate for the treatment of hereditary angioedema or HAE. A few weeks ago, the New England Journal of Medicine published our landmark Phase I data. This marks the second consecutive Intellia in vivo program to have initial clinical data published in this prestigious medical journal.

At the same time, we are actively preparing for a global pivotal phase III study of 20th one for the treatment of patients with Polyneuropathy we.

We expect to provide additional information on our phase III plan later this year.

Finally, we plan to present, new data from the ongoing phase one study this year.

I'll now turn to 'twenty or to our in vivo CRISPR candidate for the treatment of hereditary angioedema or H E E.

A few weeks ago, the New England Journal of Medicine, published our landmark phase one data.

This marks the second consecutive and Telia in vivo program to have initial clinical data published in this prestigious medical journal.

David Neil Lebowitz: We are continuing to follow the Phase I patients and plan to present additional data this year. As previously announced, high interest in 2002 allowed us to identify all patients for the Phase II study in only six months. We have since completed enrollment and those

We are continuing to follow the phase one patients and plan to present additional data this year.

As previously announced high interest in 20 O two allowed us to identify all patients for the phase two study in only six months, we have since completed enrollment and dosing.

David Neil Lebowitz: We look forward to presenting the initial results for the first time later this year. Importantly, these data will determine the dose selected for the pivotal phase 3 study. We expect to initiate the phase three study in the second half of this year. Of course, this is subject to regulatory feedback, but we think we're in an excellent position. With five special regulatory designations granted in 2002, we've taken advantage of the opportunities for additional interactions with the FDA and other agencies to gain early alignment on our Phase III plan. In summary, we believe both programs could reset the standard of care for people living with ATTR amyloidosis or HAE. I'll now hand over the call to Laura, our Chief Scientific Officer, who will provide updates on our R&D efforts. Thank you, David. Good morning, everyone.

We look forward to presenting the initial results for the first time later this year.

Importantly, these data will determine the dose selected for the pivotal phase III study.

We expect to initiate the phase III study in the second half of this year.

Of course this is subject to regulatory feedback we think we're in an excellent position with.

With five special regulatory designation granted to <unk> 20 O. Two we've taken advantage of the opportunities for additional interactions with the FDA and other agencies to gain early alignment on our phase III plans.

In summary, we believe both programs could reset the standard of care for people living with H T T R amyloidosis or H E.

I'll now hand over the call to Laura our Chief Scientific Officer, who will provide updates on our R&D efforts.

Thank you David good morning, everyone.

Laura Sepp: We're continuing to advance novel gene editing and delivery technologies for both in vivo and ex vivo therapeutic applications. Building on the success of our in-vivo gene inactivation programs, we're leading the development of CRISPR-based targeted gene insertion. Here, we're leveraging the same NMP platform using our gene knockout programs to deliver the CRISPR machinery, along with an AAV to deliver a functional gene. Unlike traditional gene therapy, we expect our approach will permanently restore a missing or defective protein without a waning of effect over time. Earlier this month, our collaborator, Jenneron, announced that the Sector 9 gene insertion program for hemophilia B has achieved IND clearance. This milestone puts Intellia at 3-for-3 in vivo A&E clients within 30 days of submission, a testament to our high standards for drug development.

The novel Gene editing and the degree of technologies for both in people and XD.

Needless to say if you take applications building.

Building on the success of our N V, Virginia, and Canadian Province, where leading ladies element of Crazy Crazy.

So we're leveraging the same LNP platform using our email got programs to deliver the great spring machinery, along with an AAV to then either.

Unlike traditional gene therapy, we expect our approach with permanent store in D. C on the protein and weight.

Agree.

And do you have any spring our collaborator.

And now it's at the Center 90 communication program for Hemophilia a knee has achieved these.

These milestone puts in Columbia recently.

Marine VPN says within 30 days of submission it gets them into our high standards for drinking.

Laura Sepp: In parallel, we also expect to begin this year the Phase I study of our wholly-owned program, NTLA-30.01, for alpha-1 and titrypsin deficiency. Based on our preclinical data, NTLA-30.01 could potentially achieve normal human levels of the alpha-1 protein after a single dose. Further, the potential human proof of concept of our modular gene insertion platform would open a whole new category of diseases that require restoring a missing or defective protein. This may include diseases that are not addressable by either base editing or DNA writing. Beyond our liver-directed program, our goal is to harness the full potential of gene editing by extending the reach of our industry-leading platform to other tissues. Recently, we announced a collaboration with Ricoh Therapeutics to accelerate the development of CRISPR-based treatments targeting genes in the lung for cystic fibrosis.

Even though we also expect to initiate the phase <unk> study of our wholly owned program and nearly 31 for Alpha one antitrypsin deficiency.

Another preclinical data and really again, one could potentially achieve normal human levels excellent.

After a single dose.

Further they potentially human proof of concept, where much attention because you've got some would open a whole new category in D. C that we quietly Stein.

Where do you think they'd probably this meeting can be she says that argument and drink combo, they either pay anything or anything.

Beyond our leaving they might get program. Our goal is to harden the full potential of gene editing by extending the reach of our industry leading platform to other dishes.

Recently, we announced the collaboration with Leeco therapeutics to accelerate the development of CRISPR based treatments kind of get things in line for cystic fibrosis.

Laura Sepp: This collaboration provides yet another example of our partnering strategy to enable pipeline optionality outside our core areas of focus while retaining attractive commercialization value. With this new collaboration, alongside our own and other partner programs, we're actively pursuing gene-editing programs across five different disciplines. Finally, in the ex vivo setting, we're continuing to advance multiple programs, both wholly owned and with collaborators. For example, Advancel is now dosing patients in their first in-human study of an allogeneic candidate. Kiberna is utilizing our allogeneic platform to advance a next-gen CAR-T program for autoimmune disease.

These collaborations are like yet. Another example of how we're partnering strategy to enable pipeline of personality outside our core areas of focus while retaining attractive commercialization right.

With this new collaboration alongside our own and other partner programs were actively pursuing gene editing programs across five different insurers.

Finally in the ex vivo setting we're continuing to advance multiple programs both wholly owned and with collaborators for example, I've been traveling now dosing patients in the phase two study.

Allogeneic car, meaning they're not utilizing our allogeneic platform.

And in Mexico, and country program for autoimmune disease.

Glenn G. Goddard: Both collaborators are using Intellia's proprietary Allo solution, which is designed for both T-cell and NK-cell-mediated rejection, a previously unsolved challenge for the field of cell therapy. I'll now hand over the call to Glenn, our chief financial officer, who will provide an update on our financial results as of fourth quarter 2023. 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 equivalents, and marketable securities were approximately $1 billion as of December 31, 2023, compared to $1.3 billion as of December 31, 2018. The decrease was driven by cash use to fund operations of approximately $448.8 million.

Both collaborators are using kind of a proprietary solution, which is designed for both both T cell and NK cell mediated rejection. It previously and some challenge for the field.

I'll now hand over the call to Glenn what did you say.

You mentioned officer will provide an update on our financial results for fourth quarter 2023.

Thank you Laura good morning, everyone and tell you continues to maintain a strong balance sheet that allows us to execute on our pipeline and platform.

Our cash cash equivalent to marketable securities were approximately $1 billion as of December 31, 2023, compared to $1 $3 billion as of December 31, 2022.

The decrease was driven by cash used to fund operations of approximately 448.8.

$8 million the decrease was offset in part by $119 $8 million of net equity proceeds from the company's aftermarket program.

Glenn G. Goddard: The decrease was offset in part by $119.8 million of net equity proceeds. $49.8 million, that's interesting. $18.7 million of collaborator reimbursement, and $10.5 million in proceeds from employee-based stock. Our collaboration revenue decreased by $15.5 million to negative $1.9 billion during the fourth quarter of 2023, compared to $13.6 million during the fourth quarter of 2020. This decrease was mainly driven by a $10.3 million one-time revenue recognition adjustment related to Regeneron extending the technology collaboration to April 2026. Intellia will receive a $30 million payment due in April as part of the Regeneron extension. R&D expenses increased by $9 million to $109 million during the fourth quarter of 2023, compared to $100 million during the fourth quarter of 2022.

$49.8 million of interest income.

$18 $7 million of collaborator reimbursements.

And $10 $5 million and proceeds from employee based stock plans.

Our collaboration revenue decreased by $55 million to negative $1 $9 billion during the fourth quarter of 2023.

Compared to $13 $6 million during the fourth quarter of 2022.

This decrease was mainly driven by a $10 3 million dollar one time revenue recognition adjustment related to the general on extending the technology collaboration to April 2026, and tell you, where we received a $30 million payment due in April as part of that where general an extension.

R&D expenses increased by $9 million to $109 million during the fourth quarter of 2023.

Compared to a $100 million during the fourth quarter of 2022.

Glenn G. Goddard: The increase was mainly driven by the advancement of our LEAD programs and personnel growth to support these programs. Stock-based compensation included in R&D expenses was $21.7 million for the fourth quarter of 2020. G&A expenses increased by $5.4 million to $29 million during the fourth quarter of 2023, appearing to $23.6 million during the fourth quarter. This increase was primarily related to an increase in stock-based compensation of $4.3 million. Stock-based compensation included in G&A expenses was approximately $13.3 million for the fourth quarter.

The increase was mainly driven by the advancement of our lead programs and personnel growth to support these programs.

Stock based compensation included in R&D expenses was $21.7 million for the fourth quarter of 2023.

G&A expenses increased by $5 $4 million to $29 million during the fourth quarter of 2023 compared to $23 $6 million during the fourth quarter of 2022.

This increase was primarily related to an increase in stock based compensation of $4 $3 million.

Stock based compensation included in G&A expenses was approximately $13 $3 million for the fourth quarter of 2023.

Glenn G. Goddard: Finally, we expect our cash balance to fund our operating plans into mid-2026. 2024 will be another productive and catalyst-rich year for Intellia, and we look forward to updating you on our continued progress. With that, we will now open the call for your questions, operator. You may now open the call. We will now begin the question-and-answer session. To ask a question, you may press star, then 1 on your touch-tone phone. If you're using a speakerphone, please pick up your handset before pressing the keys.

Finally, we expect our cash balance to fund our operating plans until mid 2026.

'twenty 'twenty four will be another productive and catalyst rich year for intaglio.

And we look forward to updating you on our continued progress.

With that we will now open the call for your questions. Operator, you May now open the call for Q&A.

Okay.

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.

Operator: To withdraw your question, please press star then 2. Please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. Our first question comes from Mari Raycroft with Jeff... Please go ahead. Hi, good morning.

Please limit yourself to one question.

At this time, we will pause momentarily to assemble our roster.

The first question comes from Maury Raycroft with Jefferies. Please go ahead.

Hi, good morning, Congrats on the progress and thanks for taking my question.

John M. Leonard: Congratulations on the progress, and thanks for taking my question. As you accumulate data from the Phase 1, 2001 cardiomyopathy study, are you getting a sense of how TTR levels are tied to CV events in individual patients and how this compares to silencers, potentially as it relates to Apollo B and Helios B? And how much data and follow-up do you aim to collect before providing your update? And maybe we can talk more about what you'll report in the update later. Thanks, Mauri. It's John.

As you accumulate data from the phase one and 2001 cardiomyopathy study are you getting a sense of how T. T. Our levels are tied to C V events in individual patients and how this compares to silence or is potentially as it relates to Apollo B Helios B and how much data and follow up do you.

To collect before providing your update and maybe talk more about what Youll reported net the update later this year.

Thanks, Maury, it's John I appreciate your question.

John M. Leonard: Appreciate your question. Remember, the Phase I study is limited in size, so the amount of information it'll provide from a clinical point of view and the ability to tie TTR levels to clinical progression is going to be inherently limited. We look at what we see other competitors doing in the space and use that as a complement to what we see with her own work.

Remember that the phase one study is limited in size. So that the amount of information will provide from a clinical point of view and the ability to tie T. T. Our levels to clinical progression is gonna be inherently limited.

We look to what we see.

Other competitors doing in the space.

And use that as a tough.

A complement to what we see on our or with her own work.

John M. Leonard: I don't think that anything that we've seen thus far that's been put out there is really changing fundamentally how we're thinking about prosecuting the Phase 3 program, but I'm sure we'll be talking a little bit more about that as the call progresses. I don't know, David, if you wanted to add anything to what might be presented later this year. Yeah, I think you've given the most important points.

I don't think that anything that we've seen thus far that's been put out there is really changing fundamentally how we're thinking about prosecuting the phase III program, but I'm sure, we'll be talking a little bit more about that.

As the call progresses, I don't know David if you wanted to add anything to what might be presented later this year.

Yes, I think you've given the most important point people to just recall that the with the dose expansion just completed it towards the end of 'twenty. Two so the patients have had just a little bit over a year and we've seen in other studies that even.

David Neil Lebowitz: People should just recall that the dose expansion just completed it towards the end of 22. So, the patients have had just a little bit over a year, and we've seen in other studies that even the difference between placebo and treated patients in the phase threes of other compounds starts to diverge at about one year. So, we do need significant follow-up to see trends. Of course, we don't.

The just the difference between placebo and <unk> treated patients in the phase threes of other compounds start to diverge at about one year. So we do need significant follow up.

To see trends and of course, we don't this is a single arm trial. So we don't have the quite the right controls to compare any of our results to though we do have the results of course from the other studies to look at.

David Neil Lebowitz: This is a single-arm trial, so we don't have quite the right controls to compare any of our results to, but we do have the results, of course, from the other studies to look at. Got it. Thanks for doing my question. The next question comes from Luca Isi with RBC. Please go ahead. Oh, great. Thanks for taking our question. This is Lisa from LUCA.

Got it thanks for taking my question.

The next question comes from Luca <unk> with RBC. Please go ahead.

Yeah.

Oh, great. Thanks for taking our question this is <unk>.

Uh huh.

That's just a Q a question again on kicked here cardiomyopathy.

John M. Leonard: Just a question again on TTR cardiomyopathy. We know an island celiac B study is going to be published this summer, so just wondering, should this read out positively? Could this result in... an early termination of your TTR cardiomyopathy study with NTLA-2001? Any color there would be helpful.

In Island East.

Is going to read out this summer.

Just wondering you shouldn't just read out positively.

Resolved and.

Early termination of your GTR cardiomyopathy study with M. P. L. A to outline any color there would be helpful. Thanks.

John M. Leonard: I don't see how the HELIOS results are going to affect, you know, the early termination of our own work. I mean, just to remind you what David went through in his earlier comments, we're actively enrolling the 21 Phase III trial, which we call Magnitude, and we're aggressively opening up sites. We've got multiple sites open and enrolling now, and we'll communicate some more about the progress later this year.

I don't see how the Helios results are going to affect.

The early termination of our own work I mean, just to remind you what David went through in the earlier comments, we're actively enrolling the 'twenty one.

Phase III trial, which we call magnitude, we're aggressively opening up sites, we've got multiple sites open and enrolling now and we will communicate more about the progress later this year, obviously, we look to information as its presented weather.

John M. Leonard: Obviously, we look at information as it's presented, whether, you know, the HELIOS study or other studies, but think about how we conduct our own program. But based on everything we've seen thus far, based on our own data, and the data that's accumulated by others, we're very confident and satisfied with the trial design that we have. I'll remind you it's an endpoint study, so whatever happens from a time point of view at Helios really doesn't relate to the work that we're doing. This is an events-driven study. We sized the study appropriately, and we're gonna have patients that we expect to present clinical endpoints just based on the stage of their disease, which is somewhat more advanced in our study. So, all things considered, we think we're in a really good position. Of course, we'll watch Helios as it comes out, but it doesn't really fundamentally change anything that we're doing.

The Helios study or other studies to think about.

How we conduct our own program, but based on everything we've seen thus far based on our own data.

Data that's accumulated by others were very confident and satisfied with the trial design that we have I'll remind you. It's an endpoint study so whatever happens from a time point of view with Helios really doesn't relate to the work that we're doing this is an events driven study we size the study appropriately and we're gonna have patients. So we.

To.

Present clinical endpoints just based on the stage of their disease, which is somewhat more advanced in our study. So all things considered we think we're in a really good position of course, we'll watch Helios as it comes out but it doesn't really fundamentally change anything that we're doing.

John M. Leonard: The next question comes from Greg Harrison with Bank of America. Please go ahead. Hey, good morning, and thanks for taking the question. Could you give some color on your latest thinking on 2002's potential place in the treatment landscape given recent competitor data? Yeah, it's an important question because we acknowledge there are other drugs out there that have some activity in HAE, and certainly, over the last few years, progress has been made in the pharmacopoeia for HAE patients, which is great news. But the fundamental problem, the challenge for patients that we hear from doctors and from patients themselves is to make attacks go away, to make them be in a position where they never have to worry about an attack and So as new forms of on demand therapy come out, that fundamentally, we don't think address what patients are looking for.

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

Hey, good morning, and thanks for taking the question could.

Could you give some color on your latest thinking on a 20 O twos potential place in the treatment landscape given recent competitor data up there.

Yeah. It's an important question because we acknowledge there is other drugs out there that have some activity in H E E.

Certainly over the last few years progress has been made in the pharmacopoeia for the H.

<unk> patients, which is great news.

The mental problem.

Challenge for patients that we hear from doctors from patients themselves is too.

To make it tax go away make them be in a position where they never have to worry about an attack and don't have to carry.

On demand therapy, so as new forms of on demand therapy come out that fundamentally we don't think addresses.

What patients are looking for from a prophylactic point of view as long as those drugs need to be a re administered.

John M. Leonard: And from a prophylactic point of view, as long as those drugs need to be re administered, that is going to be a continuing burden for those patients. So as we look at where we are with the data that we've seen thus far and look forward to continuing to expand, we believe that we're going right to the heart of the matter, which is preventing attacks once and for all, which we anticipate, assuming the success we've seen thus far continues, patients will be able to dispense with their therapy once and for all. And I think that's the solution patients are looking for. That's helpful. Thanks again.

As can be continuing burden for those patients. So as we look at where we are with the data that we've seen thus far and look forward to continuing to expand we believe that we're going right to the heart of the matter, which is preventing attacks once and for all which we anticipate.

Homing the success, we've seen thus far continues.

Patients will be able to dispense with their therapy once and for all and I think that's the the solution patients are looking for.

Makes sense that's helpful. Thanks again.

David Neil Lebowitz: The next question comes from Gena Wang with Barclays. Please go ahead. Hi, good morning. This is Hershida on behalf of Gena.

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

Hi, Good morning. This is hershey it on for Gena. Thank you for taking our question.

David Neil Lebowitz: Thank you for taking our questions. I just had one on the magnitude APTR serum trial. For clinicaltrials.gov, your secondary outcomes included change from baseline to month 18 in serum TTR and also KPPQ. So first, I wanted to confirm that these were the only secondary endpoints being measured. And if so, I wanted to get your thoughts on why these were selected as the sole secondary endpoints versus, you know, some other common ones such as the six minute walk and write your class and T-score BNP echo parameters. So any color you could provide there would be really helpful.

I just had one on the magnitude achy Trc them trial I'm right about that.

Bob Your secondary outcomes included change in baseline to month, 18, and CMT T R and although cases EQ. So first I wanted to confirm that these were the only secondary endpoints being my shirt and if so I wanted to get your thoughts on why these were selected as the sole secondary endpoints, where he says you know some other common ones such as <unk>.

When you walk in major class and Heathrow Bnb Echo parameters. So any color you could provide there would be really helpful. Thank you.

David Neil Lebowitz: Thank you. David, do you want to speak about how we think about secondary endpoints and why we included the ones we chose? Yeah, those were chosen as being the most important secondary endpoints, of course, in consultation with regulatory agencies. The important things for patients we think of, first of all, we see in the primary endpoints, reduction in cardiovascular events and mortality. Of course, that's the most important thing, will be associated, we think, with an improvement in quality of life, and, of course, quality of life is, therefore, an important endpoint for these patients. The other measures, like the six-minute walk, have had inconsistent results in recent studies, as you've seen, and we don't think it's a really important part of what's happening to patients, especially because they may have other things, other than their heart disease, that's really affecting their six-minute walk, as these are older patients.

David do you want to speak to how do we think about secondary endpoints and why we included in the ones we chose.

Those were chosen as being the most important secondary endpoints of course and consultation as well with regulatory agencies.

The important things for patients we think of first of all what we see in the primary endpoints reduction in cardiovascular events and mortality of course, that's the most important thing this.

We will be associated we think that the improvement in quality of life and of course quality of life is therefore, an important endpoint for these patients.

The other measures like six minute walk are have been have had inconsistent results and recent studies as you've seen and we don't think is a really important part of whats happening for patients.

Especially because they may have other things other than their heart disease that has really affected their six minute walk as well these are older patients.

David Neil Lebowitz: Same for ProBNP; it's a biomarker that indicates something about heart function but not really getting to the heart of what's important to patients. The next question comes from Troy Lankford with TD Kala. Please go ahead. Hi, congrats on all the progress this quarter and thanks for taking our question. For 2002, do you all expect that you could file a regulatory application in Europe at around the same time as in the U.S.? And do you see European regulators, or do you think that European regulators seem mostly aligned with what the FDA wants at this point? Or do you see any divergence?

Name for Probuphine P. It's it's a biomarker that.

Indicate something about heart function, but not really getting to the heart of what's important to patients.

The next question comes from Troy Lankford with TD Cowen. Please go ahead.

I guess on all the progress this quarter and thanks for taking our question for 20th two do you expect that you could file a regulatory regulatory application in Europe at around the same time as in the U S and do you see European regulators or do you think that European regulators seamlessly aligned with what the FDA wants at this point or do you see any divergences there.

Yeah.

David Neil Lebowitz: David, you want to address the conjugate filing of 2002. So, this is, you know, for 2002; the design of phase 3s is fairly well established for this indication. You've seen a number of drugs going forward, both with approvals or with new phase 3 studies, and they all have a really similar design, and that includes the feature that they tend to be very small studies. They could be well under 100 patients and are really looking to, in our case, the idea that we may be able to prevent any events in these patients. This is in coordination with the FDA filing, which would be sort of an end-of-phase-2 meeting. In Europe, they don't have that kind of meeting, but we have other types of discussions that indicate that the designs that we have moving forward will be acceptable in Europe as well.

David do you want interests.

<unk>.

And you get filing of 'twenty two.

So this is for 'twenty two.

The design of Phase III is fairly well set for this indication you've seen a number of drugs.

Going forward, both with approvals or with new phase III studies, and they all really similar design.

That includes a future that they're they tend to be very small studies that could be well under 100 patients.

And and really looking to in our case.

Idea that we may be able to prevent any events in these patients.

This is in coordination with the FDA filing.

Which would be sort of an end of phase two meeting in Europe. They don't have that kind of meeting, but we have other types of discussions that indicate that the design that we have moving forward will be acceptable in Europe as well.

Yeah.

Okay.

David Neil Lebowitz: The next question comes from Costas Bilouri with BMO Capital. Please go ahead. Good morning, everyone.

The next question comes from cost as Laurie with BMO capital. Please go ahead.

Good morning, guys. Congrats on the progress and thanks for taking our question maybe one question on your recent call about H O C codes can you provide any additional color on our approximately when we can see that first the early data that and how are you thinking about the competitive landscape, especially.

Laura Sepp: Congratulations on the progress, and thanks for taking our question. Maybe one question on your recent collaboration with Recode. Can you provide any additional color on approximately when we can see the first early data there?

Laura Sepp: And how are you thinking about the competitive landscape, especially other gene editing approaches that are being developed for this disease? Thank you. Thanks for the question. We're really excited about the work that we're embarking on with ReCODE. I think it's a little early at this time to project exactly what we're going to have and when we're going to have it, but we're convinced that the work that they've done with LNP delivery to the lung puts us into a really interesting position where we can take the gene writing approach that we've developed and go and address a variety of different genetic lesions that are currently unsatisfied for patients with CF.

Other gene editing approaches that are being developed for these disease. Thank you.

Thanks for the question, we're really excited about the work that we're embarking on with re code I think it's a little early at this time to project exactly what we're going to have and we're going to have it but we're convinced that the work that they've done with LNP delivery to the lung puts us into a really interesting pause.

<unk>, where we can take the gene writing approach that we've developed and go and address a variety of different genetic lesions that.

I'm currently unsatisfied for patients with CF, obviously, that's a landing pad from which one can expand it can think more broadly about what might be possible.

That space in terms of other competitive approaches.

Laura Sepp: In terms of other competitive approaches, I think there's obviously a race to get to solving once and for all the problem that these patients suffer from, and we think we've chosen the best partner to be in a position to be highly competitive and ultimately prevail. Thank you. Very helpful. The next question comes from Daegon Ha with Stiefel, please go ahead. Hello, this is Benazir. I'm on behalf of Dagon.

I think there is.

Obviously, a race to get to.

Solving once and for all the problems that these patients suffer from and we think we've chosen the best partner to be in a position to be highly competitive and ultimately prevail.

Thank you very helpful.

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

Hello. This is been out there I'm on for Dana.

Laura Sepp: Maybe a couple questions on NTLA-3001: given the rapid, like, crowding of gene therapy and gene editing approaches in ATD, what is the ideal product profile for NTLA-3001? And can you remind us again that the Serapina-1 gene insertion is directional, and what are some supportive pieces of evidence or tools that are available to detect the correct insertion?

A couple of questions on <unk> 3001.

The rapid like crowding of the gene therapy gene editing approaches and H D D.

What is the ideal product profile for <unk> 3001.

Can you remind us again that the therapy no one gene insertion.

Is it directional and letters in support of pieces of evidence or tools that are available to detect correct insertion epigene. Thank you.

John M. Leonard: So we'll turn to Laura to speak to what the insert is and if there's any sort of directionality to it. We think we've addressed it nicely, just with respect to the product profile.

So we'll turn to allow her to speak to what the insert is and if there's any sort of directionality to it we think we've addressed it nicely just with with respect to the product profile.

John M. Leonard: Our objective is to get to essentially normal human levels of wild-type protein. Once one does that, which we've accomplished preclinically in non-human primates, those patients should be essentially the same as patients without the mutation in the first place, at least with respect to their lung disease. So, whether or not we'll get to that in humans is the basis of the Phase I trial that we're embarking on now as we speak. And, of course, we're really excited about getting that information, which we think will address not only what we're doing with 30.01 but a whole plethora of other sorts of insertion programs that will be associated with that. Laura, do you want to say a word about the insert and how that works?

Our objective is to get to essentially normal human levels of wild type protein.

Once one does that which we've accomplished pre clinically in nonhuman primates.

Those patients should be essentially the same as patients without the mutation in the first place at least with respect to their lung disease, so whether or not we'll get too bad in humans as the basis of the phase one trial that we're embarking on now as we speak and of course, we're really excited.

Getting that information, which we think will address not only what we're doing with 31, but a whole plethora of other sorts of insertion programs that will.

Be associated with that or do you want to say a word about the uncertain how that wasn't sure and this is where you've seen that we're inspection platform, where we're inserting into the internal one off the albumin locus. So the expression is driven by I mean, when she said really strong promote there and of course the gene babies.

Laura Sepp: Sure. And this is, we're using our insertion platform where we're inserting into the intron one of the albumin locus. So, the expression is driven by albumin, which is a really strong promoter. And, of course, the gene, right, is wild type. So, this is, you know, a fully functional wild type.

It's wild type so in D. C. As you know fully functional wild type and so the snow issues. When you know Amy ericsson's sequencing or bystander and it's for example that do interviews with other editing modality.

Laura Sepp: So, there are no issues with, you know, any errors in sequencing or bystander edits, for example, that you introduce with other editing modalities. Okay, thank you very much. The next question comes from June Li with Truist Securities. Please go ahead. Hi, good morning. This is Median for June, and thanks for taking that question.

Yeah.

Okay. Thank you very much.

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

Hi, Good morning. This is Matthew on for June and Thanks for taking our question. This one also maybe for Lora on anything.

Very old one so could you.

Laura Sepp: This one also may be for Laura on NTLA-3001. So, could you please talk about a potential risk of exacerbation in the liver manifestation of a patient treated with 3001 based on the heteropolymerization capacity of the normal form with the mutant form? Thank you. Do you want to address? Yeah, we haven't seen any in our preclinical models.

So you just talked about.

Potential risks golf exacerbation.

The liver manifestation of Ah patients treated with a parity or one based on a preliminary.

Preliminary renovation capacity off the normal forum with amusement park.

Yeah.

Do you want to address so yeah, we haven't seen any in our preclinical models have seen you know cell lines, where they used expression of the mutant farms that would lead us to.

Laura Sepp: You've seen, you know, cell lines where there is expression of the mutant form that, you know, would lead us to a concern with regard to exacerbation of aggregation after third day one treatment. Thank you. The next question comes from Brian Chang with J.P. Morgan. Please go ahead. Good morning.

<unk>, a concern with Omega successfully patient enough Hum aggregation.

After Thursday, one treatment.

Thank you.

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

Hey, guys. Good morning, Thanks for taking my question, what's the latest thought around a 30 year old one so I'm traveling fine.

David Neil Lebowitz: Thanks for clarifying my question. What's the latest thought around the 30.01 phase one trial design, specifically, how do you sequentially space out the AAB and the LNP administrations? And can you touch on the bar of CMAAT that you're aiming to achieve?

Secondly, how do you sequentially space out the a b and Kim Initiations and can you touch on I saw the bottom from a cheap.

Hum.

David Neil Lebowitz: David, can you summarize the essence of the phase one design? I think that it was a little hard to hear, but I think part of the question was how much time elapses between AAV and LNP administration in a particular patient. You know, we haven't told the exact sign of the clinical study, but they are both going to be, they're not given exactly at the same time because, you know, we do want to separate them a bit, but they are given sequentially, and both the CRISPR mechanism and the AAV will be present in the cells at the same time once they are administered.

But can you summarize the.

The essence of the phase one design I think it was a little hard to hear but I think part of the question was.

How much time elapsed between AAV and LNP.

Administration within a particular patient.

We haven't totally exact sign a clinical study, but they are both going to be they're not give an exactly at the same time because.

You want a separate them a bit but the.

They are given sequentially and both the CRISPR mechanism in the AAV will be present in the cells at the same time once they are administered in that and that's the key feature to be successful to get the gene insertion.

David Neil Lebowitz: And that's a key feature to be successful in getting the gene insertion. Otherwise, it really is a standard phase one study with a dose escalation based on the preclinical findings that we have. And again, we'll be giving more details of that once the trial is fully approved. The next question comes from Salveen Richter of Goldman Sachs. Please go ahead. Excuse me, Salveen at Goldman Sachs; your line is open. Is it needed accidentally on your side?

Otherwise it really is a standard phase one study with a dose escalation.

Based on the preclinical findings that we have and again, we'll be giving more details of that once the trial is fully approved.

Yeah.

And the next question comes from Sal <unk> Richter with Goldman Sachs. Please go ahead.

Excuse me.

<unk> at.

At Goldman Sachs. Your line is open.

Is it muted accidently on your side.

Operator: Can you hear me? Go ahead. Thank you. Hi, sorry, this is Lydia on behalf of Salveen.

Can you hear me.

Go ahead. Thank you.

Hi, sorry. This is lidia on for Sylvian. Thank so much for taking our question just another on 2001 could you just speak to your comfort around the powering for the magnitude trial and when do you expect to complete enrollment. Thanks, so much.

David Neil Lebowitz: Thanks so much for taking our question. Just another on 2001, could you just speak to your comfortability around the powering for the magnitude trial and when you expect to complete enrollment? Thanks so much.

David Neil Lebowitz: David, do you want to address that? Sure. So, we're very confident in the design. I recall that we used an event-based study rather than having follow-up on patients. So, the advantage of this, of course, is that you would not need to extend the time of the study based on perhaps slower event rates than you predict. But given that, we did make a very conservative estimate both on our powering and predicted event rate.

David My Dresser sure.

We're very confident in the design a recall that we've used and event space study rather than having to follow up on patients. So the advantage of this of course is that you would not need to extend the time of the study.

Based on.

Perhaps slower event rates that makes new predict but given that we did make a very conservative estimate both on our powering and predicted event rate. So again, we're confident in what we have with the design with a larger study than our Helios B are at 750 patients.

David Neil Lebowitz: So, again, we're confident in what we have with the design, with a larger study than Helios B at 750 patients. The completion of enrollment is going to be in the, Yeah, it would be looking at some of the other studies to get a sense. And you've seen that these studies enroll very quickly, and so that would give you a good idea when we do expect to complete enrollment. Thanks so much. The next question comes from Debjit Chattopadhyay with Guggenheim. Please go ahead. Good morning, this is Rai. I'm for Debjit.

The the completion of enrollment.

Sure.

We've said, it's going to be in the yeah.

Yeah, we'd be looking at some of the other studies to get a sense and you've seen that these studies enroll very quickly.

And so that would that would give you a good idea of when we do expect to complete enrollment.

Thanks, so much.

The next question comes from Doug.

<unk> China.

Kind of pet <unk> with Guggenheim. Please go ahead.

Good morning. This is ray on for Doug Jet do you see opportunity for 20 O. One differentiation by potentially enriching the magnitude trial with N Y H a class III subjects.

David Neil Lebowitz: Do you see opportunity for 2001 differentiation by potentially enriching the magnitude trial with NYHA Class 3 subjects or other patient demographics that capture a sicker population relative to contemporary ATTR-CM trials? David, do you want to speak to the mix of patients we've allowed in, patients who have more advanced disease? What does that do for us?

Or other patient demographics that capture a sicker population relative to contemporary E. T. T. R. C M trials.

David do you want to speak to the mix of patients we have allowed in patients who are.

I have more advanced disease, what does that do for US Yeah. We do allow of course class III patients an important feature of what we looked for is patients who are somewhat.

David Neil Lebowitz: We do, of course, allow Class III patients. An important feature of what we look for is patients who are somewhat sicker than in other studies. And the way we did this was to have the baseline pro-BMP be greater than 1,000 and to not have an upper limit on the pro-BMP. This could differentiate us in a few ways. We did this because by the events occurring more rapidly, the trial will be completed more rapidly.

Somewhat sicker than the other studies and the way. We did this is to have the baseline pro BNP be greater than a 1000 and to not have an upper limit on the pro BNP. This could differentiate us in a few ways first we did this because the.

By the events occurring more rapidly the trial will be completed more rapidly. In addition, we do think these sicker patients. So the one most likely to benefit from GTR reduction if you're if you have a very healthy patients. They wont have events in either arm of the trial and they they really won't contribute to.

David Neil Lebowitz: In addition, we do think these sicker patients are the ones most likely to benefit from TTR reduction. If you have a very healthy patient, they won't have events in either arm of the trial, and they really won't contribute to what we learn about the trial. So we do think that by choosing these patients, we will be able to differentiate our treatment of getting to lower TTRs than the other treatments in this study.

What we learned about the trial. So we do buy things do think that by choosing these patients we will be able to differentiate our treatment of getting to lower T T ours and the other treatments in.

In this study.

Laura Sepp: Thank you. The next question comes from William Pickering, with Bernstein. Please go ahead. Hi, thanks for taking my question. In AATD, what dose level of AAV was used in your NHP studies? And how would the human dose equivalent compare to what we see from traditional AAV gene therapies that aren't integrating into the genome? And how much margin for error do you have on not lowering albumin in terms of the insertion efficiency that you're expecting versus the levels that would be required to make a meaningful dent in albumin levels?

Got it thank you.

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

Hi, Thanks for taking my question in a T D. What dose level of AAV was used in your NH Pea studies, and how with the human dose equivalent compared to what we see from a traditional AAV gene therapies that arent integrating into the genome.

And how much margin for error do you have on not lowering albumin in terms of the insertion efficiency that you're expecting versus the levels that would be required to make a meaningful dent in albumin levels. Thank you.

Laura Sepp: Thank you, but we're not speaking about the precise dose of AAV, but it's lower than what's used for standard gene therapy. Laura, maybe you could say a word about the strength of the albumin promoter and why just a few integrins are necessary to get to the levels we need. Yeah, so, albumin promoter is, you know, the strongest promoter in the liver. So you just need a few percentage of cells to have productive insertion to achieve normal levels. You know, here we're looking at 22 micromolar, you know, as an average, right?

Well, we're not speaking to the precise dose of AAV, but it's lower than what's used for standard.

Gene therapy, Laura maybe you could say a word about the strength of the albumin promoter and why.

Just a few immigrants are necessary to get to the levels. We need yes. So you know I didn't even promoter as you know the strongest promoter in the liver. So you. Just mean you know a few percentage of cells to have presenting insertion duet chief normal levels.

I can tell you what happens in that 22 micro molar you know are not already trained.

So.

Laura Sepp: So, you know, the preclinical data, of course, we did matrices of LMPs and AAV, keeping the goal, as John just said, to ensure that the AAV dose is low. We don't need to hit all the cells in the liver, just a few. And that gives us safety.

The preclinical data of course, we we did matrices of M P's N and AAV keeping the goal as John just said to ensure that the AAD those ease slow we don't need to hit all of the Oh. This all seem to neighboring countries here.

And that gives US safety you know we feel very good about the margin.

Laura Sepp: You know, we feel very good about the margin. Oh, and with regard to albumin, we do not see significant decreases in albumin, right? Because you're only editing, you know, a few cells.

And with regards to I mean, we do not see significant decreases in I've been involved because you are only anything even if his house. So I didn't mean expansion remains constant and that we've seen in preclinical models and that was further evaluated in our G&P Tox studies.

Laura Sepp: So albumin expression remains constant, and that we've seen in preclinical models, and that was further evaluated in our GLP drug studies. Thank you. The next question comes from Rick Benkowski with Cancer Fitzgerald. Please go ahead. Great. Good morning, everyone.

Thank you.

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

Great. Good morning, everyone. Thanks for taking the questions.

David Neil Lebowitz: Thanks for taking the question. For the pivotal study in HAE, given the timelines for the potential 2026 BOA filing, I wanted to ask about the degree of confidence in being able to use a six-month primary endpoint in the pivotal study, just given the gene editing mechanism is so different from the competitors here. And also, in the Phase 1 data, there was the initial 16-week period after dosing where some patients experienced breakthrough attacks. I was wondering if this phenomenon could be accounted for in the pivotal trial design in any way. David, do you want to speak about six-month endpoints? I mean, obviously, you've been on the front line, talking to regulators around the world.

Or is that a pivotal study in <unk> given the timelines for the potential 2026 filing.

Wanted to ask about the degree of confidence in being able to use our six months primary endpoint in the pivotal study just given the gene editing mechanism is so different from the competitors here.

Also in the phase one data there was the initial 16 week period after dosing, where some patients experienced breakthrough attacks I was wondering if this phenomenon could be accounted for in the pivotal trial design in any way.

Yeah.

Do you want to speak too sick.

Six months endpoints I mean, obviously you've been on the front line I'm.

Talking to regulators around the world.

David Neil Lebowitz: Do you think that there will be the need to extend beyond these standard sorts of approaches? Yeah, what we believe is that the six-month endpoint, which has been standard in these studies, will be the same endpoint that we apply to this study. In terms of longer follow-up, of course, we will have phase one and phase two patients with longer follow-up when we file the DLA, and as well as a very extensive safety database from our other gene knockout program with QTR. So we do feel very confident that the safety database we're bringing will satisfy what the regulators want.

Do you think that to be the need to extend beyond these two standard sorts of approaches what we believe is at the six month endpoint, which has been standard in these studies will be the same standards that we apply to this study in terms of a longer follow up of course, we will have a phase one and phase two.

With longer follow up when we file the BLA and as well as a very extensive safety database from our other.

Do knockout program with Q T. R. So we do feel very confident that the safety database with breathing will be satisfied what the regulators want of course for all gene therapies. We will continue to follow the patients for the standard 15 year period.

David Neil Lebowitz: Of course, for all gene therapies, we will continue to follow the patients for the standard 15-year period. In terms of breakthrough attacks, we are looking at how to account for this in the pivotal study. We're not talking about the exact design.

In terms of the breakthrough attacks, we are looking at how to account for this in the in the pivotal study we're not talking about the exact design you have to recall those patients are only the patients who had very unusual number of attacks Oh, that's up to 15 attacks a month because you recall so that this we don't expect that that's an unusual patients kind of pay.

David Neil Lebowitz: You have to recall, those patients are only the patients who had a very unusual number of attacks, up to 15 attacks a month, as you recall. So this, we don't expect; that's an unusual patient, kind of patient who is waiting for the phase one study. Most of the patients in the study will be more like the other patients where the attacks were pretty much gone after the infusion. Rick, I appreciate your noting the BLA in 2026.

And who is waiting for the phase one study most of the patients in this study would be more like the other patients where the attacks.

We're.

Pretty much gone after the infusion Rick.

Richard I appreciate you're noting the BLA in 2026. It is one of our key strategic objectives for the company in the next two to three years and we're very excited about being in a position to take.

John M. Leonard: It is one of our key strategic objectives for the company in the next two to three years, and we're very excited about being in a position to take, you know, what we think will be the very first in vivo CRISPR-based approach to approval and go into what we think is a marketplace that we can be extremely successful in. All right, I appreciate the color.

But we think will be the very first in vivo CRISPR based approach to approval and go into what we think is a marketplace that we can be extremely successful.

Alright, I appreciate the color. Thank you.

David Neil Lebowitz: Thank you. The next question comes from Yanan Zhu with Wells Fargo Security. Please go ahead. Great. Thanks for taking our questions. So, just wondering, a very quick one on magnitude.

The next question comes from you know Jan on Jew with Wells Fargo Securities. Please go ahead.

Great. Thanks for taking our questions.

So just wondering a very quick one on a magnitude what is the percentage of onto Fabulous patient you target in the trial.

John M. Leonard: What is the percentage of ontofamidase patients you target in the trial? And also wondering if you could talk a little bit about your DNA writing technology. I think this is the first time we hear about a program since you acquired the technology in 2022. So, wondering, for example, if there are correction templates and whether it is in RNA or DNA format.

And also wondering if you could talk a little bit a little bit about your DNA, writing technology. I think this is the first time, we hear about a program.

Since you acquired the technology in 2022.

So wondering if for example is there a correction template and whether it is a RNA or DNA.

John M. Leonard: Thank you. Maybe I can say a word about the DNA writing approach, and David will address how we think about the famitis and the magnitude study. The way we think about gene editing in general is in terms of capabilities. By that, I mean introducing the particular type of change that one is interested in introducing into the genome for whatever therapeutic purpose. There are different ways to introduce those changes. When we think about gene writing tests, that's a category that brings with it a variety of approaches to introduce a string of nucleotides.

Format. Thank you.

Well, maybe I can say a word about the rating DNA, writing approach and David will address how we think about <unk> and <unk>.

The magnitude study.

The way we think about.

Gene editing in general is capabilities by that I mean.

Introducing the particular type of change that one is interested in.

And introducing them to the genome for whatever therapeutic purpose theres different ways to introduce those changes.

When we think about gene writing to us that's a category that brings with it.

Variety of approaches to introduce a string of nucleotide.

John M. Leonard: As you commented, we acquired work that was complementary to the work that we were doing a couple of years ago, and we're excited about what that brings us to add to the work that we're already doing. And at the right time and the right place, we'll talk about exactly what we're doing and how it fits into our pipeline, but I think it's just important to note at this point that we're making excellent progress in doing everything that we want the technology to do. David, do you want to say a word about the famitis?

As you commented we acquired a work that was complementary to the work that we're doing a couple of years ago, and we're excited with what that brings.

Just to add to the work that we're already doing.

And at the right time in the right place, we will talk about exactly what we're doing and how it fits into our pipeline, but I think it's.

It's just important to note at this point that we're making excellent progress and doing everything that we want the technology to do that for you.

Want to say a word about the families.

David Neil Lebowitz: Yeah, for the famitis, we expect about half the patients to be treated with famitis, and this is similar to what's been seen in the pivotal studies that have been reported so far as well. Great. Thanks for the answer.

Yeah for the Fabs, we expect about half the patients to be treated with us to families and this is similar to what's been seen in the pivotal studies that have been reported so far as well.

Great. Thanks for the answers.

David Neil Lebowitz: The next question comes from Steve Seedhouse with Raymond James. Please go ahead. Hi, good morning. This is Timur Ivannikov on behalf of Steve Seedhouse.

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

Hi, Good morning. This is tomorrow, but it goes on for Steve Steve House. So we have a question and a T. D. I've historically, it's been difficult to show improvement in lung function with augmentation therapies and other therapies on endpoints, such as SD Wan or pulmonary exacerbations.

David Neil Lebowitz: So we have a question in AATD. Historically, it's been difficult to show improvement in lung function with augmentation therapies and other therapies on endpoints, such as SAV1 or pulmonary exacerbation, and even more advanced augmentation therapies haven't attempted to show this improvement. So how do you think about improvement in lung function? Do you expect regulators to require you to show improvement? David, do you want to speak on it? Yeah, you know, the regulatory standard hasn't been set here yet.

And even more advanced augmentation therapies haven't attempted to show this improvement.

So how do you think about improvement in lung function do you expect regulators to requiring you to show an improvement.

David you on that sure Yeah. There you know the regulatory standard hasn't been set here there have been some reports publicly that the FDA may accept having normal levels of of Alpha one antitrypsin could be a way to move forward of course with some associated clinical findings, but not that slayer thoroughly a definitive <unk>.

David Neil Lebowitz: There have been some reports publicly that the FDA may accept having normal levels of alpha-1 antiretropin could be a way to move forward, of course, with some associated clinical findings, but not necessarily a definitive improvement. And we do think because our program can get to normal levels, really the only gene editing program that's shown this so far, that this may be something that the regulators will work with us on and give us a way forward to approval, mostly based on the high levels that we'll be achieving. Thank you. The next question comes from Jay Olson with regard to Oppenheimer.

<unk> and we do think because our program can get to normal levels really the only gene editing program. That's shown this so far that this may be something that the regulators will work with us on and how it gives us a way forward to an approval mostly based on that on the high levels that will be achieving.

Thank you.

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

Laura Sepp: Please go ahead. Oh, hey, thanks for providing the update and congratulations on the recent collaboration with Recode and Cystic Fibrosis. Can you just talk about some of the features of the LNP platform that you found attractive and what is the route of administration, and does the collaboration only focus on Cystic Fibrosis, or could you potentially leverage the collaboration to study additional targets and diseases? Thank you. Laura, do you want to take that?

Oh, hey, thanks for providing the update and congrats on the recent collaboration with re Cogent cystic fibrosis can you just talk about some of the features of the LNP platform that you found attractive and what is the route of administration and is the collaboration.

<unk> focus on cystic fibrosis or could you potentially leverage the collaboration to study additional targets and diseases. Thank you.

Laura you want to take that yeah sure. So we called has been pioneering and Newcastle sleeping nanoparticles are that are hard to get into different Oregon's he's had the sort of the beds.

Laura Sepp: Yeah, sure. So, RECODE has been pioneering a new class of lipid nanoparticles that are targeted to different organs. These are called sword lipids.

Laura Sepp: They have, we were quite interested in what they were doing in the lung. And as you may know, they're already in the clinic with two inhale LNP mRNAs for PCV and cystic fibrosis. Actually, I think they dosed the first patient with an mRNA yesterday. So, with these LNPs that go to the lung, for which they already have preclinical and clinical data, and, you know, the manufacturing and the route of administration of inhalation, they have demonstrated that they can get to not only the mature cells but also the target cells that, you know, you need to edit to have long-lasting benefits if you're looking after So, when we're looking at partnerships, we're looking to marry technologies. You know, we have a strong gene editing technology that allows us to target, you know, specific mutations, and they bring in, you know, validated delivery modalities. So, I think it's a great partnership.

They have we were quite interested in what they what do they want in their lungs are and as you may know they are already in the clinic with two N Hell LNP mrna is for a B C D and cystic fibrosis actually I shouldn't say that was the first patient with any man it yesterday.

So with this M P that goes to lung for which they already have preclinical and clinical data and you know the manufacturing and the route of administration of emulation. They have demonstrated that they can get to not only the mature sounds but also the paragon sounds.

And you know you would need to edit does have long lasting.

Yeah, you know benefit even if they're looking after is he Afghan correction. So when we're looking at partnerships. We're looking to marry the technologies. You know we have a strong gene editing technology that allows us to.

It's hard to get specific mutations and they bring in you know validated delivery modality. So I think it's a great partnership and we're looking forward to make quick progress.

Laura Sepp: And, you know, we're looking forward to making quick progress. The next question comes from Silvan Tuerkcan with JMP Securities. Please go ahead. Yeah, good morning.

The next question comes from Silvan <unk> with JMP Securities. Please go ahead.

Hey, good morning, congrats on the quarter and congrats on the progress and thanks for taking my question.

David Neil Lebowitz: Congratulations on the quarter and, Progress, www.globalonenessproject.org Transcribed by ESA, translated by — program. What are some of the considerations that you're thinking about, you know, selecting the dose for phase three and what? I'll give you data a bit later this year.

Just a quick one on on the HIV program.

What are some of the considerations that you're thinking about them you know selecting the dose for the phase III.

What can we see in the phase II data. That's later this year towards you know give us confidence about dose selection and then regarding the phase III design overall is there any impact or any information that well.

David Neil Lebowitz: Confidence in that dose selection. And then regarding the Phase 3 design overall, is there any impact or any information that we'll get from the Phase 3 OASIS-HAE study from IONIS that will be presented mid-year that will help us also in the design or think about the design of the phase 3 trial here?

From the phase II Oasis, which of your study for my honest that'll be presented.

Mid year.

That will help us also like in the design or thinking about the design of the phase III trials here. Thank you.

David Neil Lebowitz: David, how are you going to choose your dose for Phase 3? Yeah, so recall that we've completed enrollment in a Phase 2 study in which there are 10 patients on 25 milligrams, 10 patients on 50 milligrams, and 5 patients on placebo. So we have a very good setting in which to evaluate those two doses. We chose those two doses because, in the dose escalation phase, as you recall, all patients basically achieved no events after the infusion, except a single event in one patient a year after treatment, which was related to a sports injury.

Is it are you going to choose your dose for phase III.

Yeah. So so recall that we've completed the enrollment through a phase two and which the patients. There are 10 patients on 25 milligrams 10 patients on 15 milligrams and five patients on placebo.

Have a very good setting in which to evaluate.

Those two doses, we chose those two doses because in the dose escalation phase as you recall all patients basically achieved no events after the infusion except a single event.

And one patient a year after treatment, which.

It was related to a sports injury.

David Neil Lebowitz: So with Phase 2, we'll have a very extensive database of these two doses. The things we'll be looking at, of course, are the clinical findings, the event rate, but also the consistency of the pharmacodynamic effect we'll be looking at as part of this. There was more variability at the lower dose. So, on first principles, we would tend to think that the 50 dose is going to be better, but we want to look at all the data and make a decision about Phase 3, and it will be a very robust decision based on this Phase 2 study. The next question comes from David Lebowitz with Citi. Please go ahead. Thank you for taking my question. A competitor has a switch study for its HAE trial, and I'm curious as to whether there is a similar type of study that would be needed or what that would look like. I'll speak to that. You know, we haven't talked about doing a switch study. In pivotal studies, what usually happens is that you withdraw from any kind of prophylactic therapy. In our study, we have seen patients withdrawing from lanicellumab as well as other prophylactic therapies.

The.

Yeah, we haven't talked about doing a switch study.

And the pivotal studies, what usually happens is that you withdraw from any kind of prophylactic therapy, we have seen of our study patients withdrawing from <unk>.

As well as other prophylactic therapies, and we do think that will be.

David Neil Lebowitz: And we do think that will be of interest to patients when this is an approved therapy to get off the therapies that they have to take repeatedly and go on to a one-time therapy. So we haven't yet gotten to the point of there being a switch therapy, but this is something obviously that would be considered a switch study. Thanks for taking my... The next question comes from Jack Allen with Baird.

Of interest in patients. When this is an approved talk therapy to get off the therapies that they have to take repeatedly and go onto a onetime therapy.

So.

We haven't yet guided to there being a switch therapy, but this is something obviously that would be considered a switch study.

Thanks for taking my question.

The next question comes from Jack Allen with Bird.

David Neil Lebowitz: Please go ahead. Great, thanks for taking my question and congratulations on the progress. I wanted to ask if you could comment a bit more about your plans to enroll slightly more advanced patients in Magnitude as compared to Helios B. And how do you expect positive results from Helios B could affect enrollment in Magnitude, being that Magnitude will be a placebo-controlled study? The idea of enrolling more advanced patients is that these are the patients who can really benefit from the therapy. If you imagine some of the studies we've seen, some patients who are quite healthy despite having some early heart failure, those patients have very few events and therefore contribute very little to the findings in the study.

Please go ahead.

Alright, Thanks for taking my question and congratulations progress I wanted to ask if you could comment a bit more about your plans to enroll slightly more advanced patients in magnitude as compared to heal the S. B.

And how do you expect a positive results from Helios b could affect enrollment in magnitude being magnitude will be a placebo controlled study.

Is it.

Yeah. The idea of enrolling more advanced patients is that these are the patients who can can really benefit from the therapy. If you imagine some of the studies we've seen some patients who are.

Can be quite healthy despite having some early heart failure and those patients have very few events and therefore contribute very little to the findings in the study.

David Neil Lebowitz: So that's the idea of doing that. We do think a positive Helios B study is good for us as well. It would show that TTR reduction is beneficial for patients with cardiomyopathy, the hypothesis that really all the experts really believe in.

The idea of doing that.

We do think positive Helio speed study is is a positive for us as well it would show that PTR reduction.

Is a value to patients with cardiomyopathy. The the hypothesis that really all the experts really believe in so we do think as well that it's very likely that helios will be positive.

David Neil Lebowitz: So we do think as well that it's very likely that Helios will be positive. The physicians are already very excited about our therapy because, first of all, they've seen that we have a very consistent and deeper reduction in TTR. It could be the best-in-class agent, so we expect the enrollment to be brisk in any case. Of course, having a positive study demonstrating that TTR reduction is important may be a further value in driving our enrollment as well.

The physicians are already very excited about our therapy so that.

First of all they seem that we have a very consistent and deeper reduction in ctr could be the best in class agent.

So expect the enrollment to be brisk in any case of course, having a positive study demonstrating the TCR reduction is important maybe for maybe a further value and driving our enrollment as well.

David Neil Lebowitz: Great, thanks so much to my colleagues. This concludes our question-and-answer session. I would like to turn the conference back over to Ian Karp for a closing remark. All right. Thanks so much, Drew, and thank you, everyone, for joining us this morning. It's certainly been an eventful and successful start to the year, and we look forward to updating you throughout the year with additional progress. So thanks again, and I look forward to talking with everyone soon.

Alright next question Okay.

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

Great. Thanks, so much drew and thank you everyone for joining us. This morning, it's certainly been a eventful and successful start to the year and we look forward to updating you out updating this throughout the year with additional progress. So thanks, again and look forward to talking with everyone. Soon.

Thank you the conference has come to a close he may disconnect. Your line. Thank you.

Ian Karp: Thank you. The conference has come to a close. You may disconnect your line.

Yeah.

[music].

Operator: Thank you. The Ultimate Parody Site! The Bulletproof Executive 2013, The Ultimate Parody Site!

Mmm.

Mhm.