Intellia Therapeutics Inc

NASDAQ:NTLA

Earnings Call Analysis

Intellia Therapeutics Advances CRISPR-based Treatments and Prepares for Significant Trials

In the latest earnings call, Intellia Therapeutics highlighted promising developments in its CRISPR-based therapies. Notably, NTLA-2002 demonstrated efficacy in a Phase II study for hereditary angioedema, potentially leading to functional cures without ongoing treatment. The company is set to submit a Biologics License Application in 2026 based on data from an ongoing Phase III trial. Additionally, the FDA approved IND for the MAGNITUDE-2 trial, targeting hereditary ATTR amyloidosis. With a strong cash position of $944.7 million, Intellia expects to fund operations through late 2026 while advancing their clinical pipeline with significant investor interest.

Intellia's Ambitious Journey into Gene Editing

Intellia Therapeutics is making significant strides in the world of CRISPR-based gene editing treatments. The company is focusing on innovative therapies, particularly for hereditary angioedema (HAE) and transthyretin amyloidosis (ATTR). Their lead program, NTLA-2002, has shown promise in its Phase II clinical trials, where a single infusion could potentially eliminate the need for chronic treatment, marking it as a 'functional cure' for HAE. This sets a new standard for patient outcomes by demonstrating that, out of 15 patients treated in a 50-milligram dose cohort, 80% were attack-free and did not require further therapies.

Positive Phase II Results and Future Expectations

The encouraging results from the Phase II study of NTLA-2002 have reinforced confidence in the drug's efficacy. Notably, the company aims to progress to a Phase III study, with rapid patient enrollment anticipated due to its compelling profile. The team plans to submit a Biologics License Application (BLA) in 2026 for NTLA-2002, indicating a clear path forward in bringing this potential treatment to market.

Advancements in ATTR Therapies

Intellia has also received FDA clearance for its MAGNITUDE-2 Phase III trial, targeting hereditary ATTR amyloidosis with polyneuropathy. This study is structured to be a randomized, double-blind, placebo-controlled trial with 50 patients. The primary endpoints focus on assessing clinical benefits through serum TTR (transthyretin) reduction and neurological function over an 18-month period. The ongoing enthusiasm from physicians and patients reflects strong underlying demand for effective treatments in this space.

Financial Overview and Strategic Insights

Intellia maintains a robust financial footing with approximately $944.7 million in cash and marketable securities as of September 30, 2024. Although the company has experienced a cash burn of roughly $100 million over the past quarters, the existing cash reserves are projected to support operations into late 2026. This financial stability allows Intellia to continue investing in its promising clinical pipeline and platform.

Key Challenges and Competitor Landscape

Amidst their progress, Intellia faces competition from existing therapies that are already in use for ATTR and HAE. The company is focused on demonstrating that its gene editing therapies provide deeper reductions in TTR compared to competitors' treatments. The recent momentum in their patient enrollment indicates a strong belief among doctors that Intellia’s offerings may surpass the efficacy of traditional therapies. Observations about the high enthusiasm for their drug highlight the anticipated benefits that lie ahead.

Earnings Call Transcript 2024-Q3

[Operator]

Good morning, and welcome to Intellia Therapeutics' Third 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. [Operator Instructions]

I will now turn the conference over to Lina Li, Senior Director of Investor Relations and Corporate Communications at Intellia. Please proceed.

[Lina Li, executive]

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics Third 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 Investors and Media section of Intellia's website at intelliatx.com. This call is being broadcast live, and a replay will be archived on the company's website. At this time, I would like to take a minute to remind listeners that during this call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law.

Joining me from Intellia are John Leonard, Chief Executive Officer; David Lebwohl, Chief Medical Officer; Laura Sepp-Lorenzino, Chief Scientific Officer; and Ed Dulac, Chief Financial Officer. John will begin with recent business highlights. David will provide updates on our clinical pipeline progress. Laura will then provide R&D updates. And Ed will review our financials before we open the call for questions.

With that, I will now turn the call over to John, our Chief Executive Officer.

[John Leonard, executive]

Thank you, Lina. Good morning, everyone, and thank you all for joining us today. At Intellia, we are ushering in a new era of medicine. During the third quarter and more recent period, we've made substantial progress in our efforts to bring promising, highly differentiated and potentially curative CRISPR-based gene editing treatments to patients. In October, at the American College of Allergy, Asthma and Immunology Annual Scientific Meeting, we presented unprecedented positive results from our Phase II study of NTLA-2002 for the treatment of hereditary angioedema. These results show that a simple onetime infusion of NTLA-2002 offers patients the potential for a functional cure.

For people living with HAE, current treatment options are limited to chronically administered prophylactic therapies to prevent or manage attacks and the use of on-demand therapy to control breakthrough attacks. Because of this, available therapies place emphasis on attack rate reductions for their lifelong treatments. However, our market research is clear. Patients want to lead a normal life, one that is free of attacks, free of chronic treatment and free of mental burden around potential triggers and the loss of access to their therapies. The emerging profile for NTLA-2002 provides hope that a single intervention may lead to the complete elimination of angioedema attacks and remove the need for subsequent prophylaxis therapy for most patients. The opportunity to deliver such a profile will create significant value for patients and the health care system as a whole.

We're extremely encouraged by our Phase II results, and we're actively screening patients in the Phase III HAELO study. The strong enthusiasm for NTLA-2002 from patients and our investigators strengthens our conviction that the Phase III will enroll rapidly, enabling us to submit a planned BLA in 2026.

In addition, we're making excellent progress across our other late-stage trials. As announced this morning, the FDA cleared our IND application for MAGNITUDE-2, our Phase III trial of nex-z for patients with hereditary ATTR amyloidosis with polyneuropathy. We expect to initiate the study in the coming days. Since dosing our first cardiomyopathy patient in March, we continue to see strong momentum in our Phase III MAGNITUDE study and enrollment is tracking ahead of our internal projections. With 3 active Phase III studies expected by year-end, we are leading the field of in vivo CRISPR-based medicines. Intellia is ushering in a new era of medicine with the prospect of functional care for patients suffering from HAE and a treatment that may change the course of the disease for people with ATTR amyloidosis. I'll now hand the call over to our Chief Medical Officer, David Lebwohl, who will provide an update on our clinical programs. David?

[David Lebwohl, executive]

Thanks, John. I'll begin with 2002, in development for hereditary angioedema or HAE. As John noted, we presented Phase II data, which demonstrated that a single dose of 2002 could both eliminate attacks and eliminate the need for further treatment. In the 50-milligram arm, 8 of 11 patients had no attacks during the 16-week primary observation period after a single dose of 2002. These groundbreaking results highlight how 2002 has the potential to reset the standard of care for HAE. We are encouraged by the findings thus far from the post-primary observation period in the Phase II as well. The 8 patients who are attack-free in the 50-milligram cohort remain attack-free with no HAE-directed therapy for a median of 8 months so far. Moreover, the 3 patients who are not yet attack-free achieved clinically meaningful attack rate reduction. Based on our Phase I observations, we expect these patients to show continued improvement or become attack-free as they have more time to adjust to their new normal. We are continuing to follow all patients and look forward to presenting longer follow-up data next year.

With 2002, we believe we are creating a new standard for patient outcomes in HAE, where 12 out of 15 patients or 80% of patients who received the 50-milligram dose in the Phase I/II study appear functionally cured of their disease, that is patients who were attack-free without the need for further treatment. This is unprecedented and suggests an emerging product profile that is unmatched by other HAE therapies either currently approved or in development. Importantly, our market research indicates that 2002's emerging product profile aligns directly with the needs and priorities of patients and physicians. As such, we expect broad interest and demand for 2002 that will drive rapid enrollment of our Phase III study and commercial uptake once approved.

We are now actively screening patients in the HAELO Phase III study, a global randomized, double-blind, placebo-controlled study. Importantly, our Phase III study will extend the primary observation period and look at the number of HAE attacks from weeks 5 through 28 as its primary endpoint. This is designed to provide a cleaner read into the drug's effects once kallikrein reduction has reached its steady state about a month after therapy. As previously guided, we expect to submit a BLA filing in 2026 from the 60-patient study. In summary, we believe 2002 is well-positioned to be the first approved in vivo CRISPR gene editing treatment and a truly transformative onetime treatment for people living with HAE.

Switching to nex-z, also known as 2001, in development for the treatment of ATTR amyloidosis. This multisystem disease primarily manifests as either cardiomyopathy due to amyloid deposits in the heart or polyneuropathy through the progressive accumulation of protein deposits in the nervous system. We announced today that the U.S. FDA cleared our IND application to initiate a Phase III trial in patients with hereditary ATTR amyloidosis with polyneuropathy. This marks our fourth consecutive IND clearance within 30 days of submission for in vivo therapies we have developed, an unparalleled regulatory track record in the field of gene editing and testament to our high standard for drug development.

Our MAGNITUDE-2 Phase III trial is an international randomized, double-blind, placebo-controlled study. 50 patients will be enrolled and randomized 1:1 to receive a single 55-milligram infusion of nex-z or placebo. Patients randomized to the placebo arm will be eligible for optional crossover to receive nex-z. The primary endpoints are the change from baseline in mNIS+7 at month 18 and serum TTR at day 29.

In polyneuropathy, there is a positive correlation between greater TTR protein reduction and improved clinical benefit. To date, no other agent approved or in clinical development has demonstrated consistent, deep and durable TTR reduction like nex-z, which gives us tremendous confidence in our ability to positively impact patient outcomes in the MAGNITUDE-2 study. We expect to initiate the study at ex U.S. sites in the coming days. Simultaneously, the rapid enrollment of the MAGNITUDE trial in patients with cardiomyopathy continues to track ahead of our internal projections based on strong patient and physician interests. In total, we are actively enrolling patients at over 60 sites and have received regulatory clearance in more than 20 countries for the Phase III study.

Findings in a recent publication of a competitor's clinical data in ATTR-CM indicate that there is a major opportunity to improve patients' clinical outcomes beyond what current therapies provide. In our ongoing Phase I study, we demonstrated that all patients with cardiomyopathy achieved rapid, deep and durable TTR reduction with nex-z, more consistent and greater mean reductions than that reported with TTR silencers. As such, our early clinical data suggests nex-z could significantly reduce total TTR exposures, which in turn might provide greater clinical benefit for patients.

Next Saturday, November 16, we will be presenting new findings from the ongoing Phase I study as a late-breaking oral presentation at the American Heart Association Scientific Session. On the occasion of AHA's 100th anniversary, we will be presenting data at the opening session titled Celebrating a Century of Cardiovascular Science: From Prevention to Treatment to Cure. These data will provide insights into the emerging clinical profile of nex-z and the hypothesis that greater TTR reduction leads to better clinical outcomes. The update will include data from all 36 patients within the cardiomyopathy arm, including important measures of clinical and functional benefit. This includes safety, reduction of TTR and disease progression markers such as NT-proBNP, Troponin, 6-minute walk test at month 12 compared to baseline. We look forward to reviewing these data on an investor webcast taking place that same day, where we will also provide an update on the polyneuropathy arm.

I'll now hand the call over to Laura, our Chief Scientific Officer, who will provide updates on the 3001 program and our R&D efforts.

[Laura Sepp-Lorenzino, executive]

Thank you, David. Good morning, everyone. We're advancing our science beyond in vivo knockout therapies and into our first in vivo gene insertion programs in the clinic. NTLA-3001 is our first wholly owned in vivo gene insertion program for alpha-1 antitrypsin deficiency associated lung disease. It is designed to precisely insert the wild-type SERPINA1 gene, which encodes the alpha-1 antitrypsin protein. In previously presented nonhuman primate data, we've demonstrated the ability to produce fully functional alpha-1 protein at normal levels after a single dose. Notably, these normal levels of alpha-1 protein were durable through 2 years of follow-up in the completed study. We're on track to dose the first patient in the Phase I/II study of 3001 by year-end. If we're able to translate what we have seen in nonhuman primates to humans, we believe this will be a major step forward for alpha-1 patients and the field of gene editing. Assuming success, it would unlock a whole new category of diseases which require a gain of function that we could pursue with our modular insertion platform.

In parallel, we're continuing to advance our toolbox of novel gene editing and delivery technologies to extend the reach of CRISPR-based gene editing for in vivo and ex vivo therapeutic applications. This includes advancing gene editing programs in 5 different tissues outside the liver, either independently or in collaboration with partners. We're proud of all the recent progress and look forward to providing more updates as we advance our platform and pipeline.

I'll now hand over the call to Ed, our Chief Financial Officer, who will provide an update on our financial results as of third quarter 2024.

[Edward Dulac, executive]

Thank you, Laura, and good morning, everyone. Intellia continues to maintain a solid balance sheet that allows us to execute on our pipeline and platform. Our cash, cash equivalents and marketable securities were approximately $944.7 million as of September 30, 2024, compared to $1 billion as of December 31, 2023. The decrease was driven by cash used to fund operations of approximately $335 million. The decrease was offset in part by $176.9 million of net equity proceeds from the company's at-the-market program, $47 million of collaborator reimbursement, including a onetime $30 million payment received in April related to the company's technology collaboration with Regeneron, $37.2 million of interest income and $6.5 million in proceeds from employee-based stock plans.

Our collaboration revenue was $9.1 million during the third quarter of 2024 compared to $12 million during the third quarter of 2023. The $2.9 million decrease was mainly driven by a reduction in revenue related to the AvenCell license and collaboration agreement. R&D expenses were $123.4 million during the third quarter of 2024 compared to $113.7 million during the third quarter of 2023. The $9.7 million increase was primarily driven by the advancement of our lead programs. Stock-based compensation included in R&D expense was $24.2 million for the third quarter.

G&A expenses were $30.5 million during the third quarter of 2024 compared to $29.4 million during the third quarter of 2023. The $1.1 million increase was primarily related to stock-based compensation. Stock-based compensation included within G&A expense was $15.4 million for the third quarter of 2024.

Finally, we expect our cash balance to fund our operating plans into late 2026.

[John Leonard, executive]

Thanks, Ed. In conclusion, Intellia continues to deliver on the promise of gene editing, and we look forward to presenting the nex-z Phase I update next week at AHA. With that, we will 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.

[Operator]

[Operator Instructions] The first question comes from Rick Bienkowski with Cantor Fitzgerald.

[Rick Bienkowski, analyst]

I was just hoping to get more color on the pace of enrollment into MAGNITUDE-1. Just looking at the clinical trial record on clinicaltrials.gov, the estimated primary completion is listed at December 2027. So could you just walk me through the assumptions there for the pace of enrollment given that the primary endpoint is event-driven?

[John Leonard, executive]

Thanks for the question, Rick. As we've said, you can use the HAELO study as a good proxy with similar assumptions. You know that the study has 765 patients. We have global sites activated and the final sites are being activated as we speak here. So as we said in our comments here, we're enrolling ahead of our projections. And as we get further insight, there may be an opportunity to update that down the road. But in the meanwhile, things are progressing very, very well.

[Operator]

The next question comes from Alec Stranahan with Bank of America.

[Unknown Analyst]

This is [ Matthew ] on for Alec. Just one quick one for us. As you think about extending into later-stage clinical trials, just thinking about your capital allocation priorities given you have a lot going on in the pipeline and sort of how you're thinking about in vivo versus ex vivo going forward?

[John Leonard, executive]

So maybe Ed can address that, and we'll follow up as necessary.

[Edward Dulac, executive]

Yes. Thanks for the question. I mean we exited the third quarter with about $945 million in cash and -- as we look at our 2- or 3-year plan, I think we've laid out at JPMorgan earlier this year, 3-year priorities, strategic priorities through 2026. And so as I look at the company today, we clearly have a focus on the 3 Phase III studies, which will be up and running before the end of the year, and that's clearly a focus. We do have some exciting programs related to 3001, our first gene insertion program, which is an important proof of concept for us as well as sort of burgeoning ex vivo opportunities as well. And then we've been very prominent in just investing across the platform. So I look at our existing cash burn at roughly $100 million over the last couple of quarters as a reasonable estimate, that should go up. But I feel like we have a very conservative plan in place, one that takes our existing cash balance and gets us well into fourth quarter of 2026.

[Operator]

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

[Yanan Zhu, analyst]

Great. First, congrats on the clearance from FDA to conduct the Phase III study in ATTR polyneuropathy. I was just struck by 2 things from the trial design. One is that it is a placebo-controlled study and not, for example, active arm controlled study. And the other is that the patient -- the study size is very small, 50 patients. That's not even half of the size of the silencer studies. So could you comment on this, the ability to obtain such a study design? What does it mean? And also will patients on either arm allowed to receive silencer or other active treatment during the study?

[John Leonard, executive]

So thanks for the question, Yanan. First of all, it's important to note that the effect size of TTR reduction is very, very large in patients with polyneuropathy. That's been established. We have pretty good insight as to the effects as a function of TTR reduction. And as we've shared elsewhere, our TTR reduction is profound, and we expect that to continue into this patient population in Phase III. A placebo-controlled trial is possible based on our agreement with the FDA and other regulatory agents. It will give us a very solid readout on the performance and safety of the drug. And by carrying it out outside the United States, where many of these other therapies are not currently available, it allows the study to be enrolled promptly, and we'll be in a position to share the data when we have it. And David, you can speak to any other details that you think are pertinent to that study or silencers.

[David Lebwohl, executive]

Yes, thank you, John. I think what you're seeing in this small study is a great collaboration with the FDA as we talk to them about the best way to go forward. All the other drugs have been approved with placebo-controlled study. So that makes a lot of sense as well for our drug. And again, silencers are not available in the country where the studies are being conducted, so patients will not be receiving silencers.

[Operator]

The next question comes from Mani Foroohar with Leerink.

[Unknown Analyst]

This is CJ on for Mani. My question is regarding the Phase III HAELO study. I just noticed that patients are randomized 2:1 there versus 1:1 in magnitude. So I was just wondering if you thought this 2:1 enrollment was thought to accelerate patient enrollment in the study.

[John Leonard, executive]

David, do you want to speak to the randomization scheme?

[David Lebwohl, executive]

Yes. The benefit of a 2:1 randomization is for the patients themselves. It's attractive to them that they'll have 2/3 chance to start on the active drug right away. They also -- all these patients will be able to cross over if they wish as well at the end of the primary observation period. So it's also attractive to patients for that reason. With all that in place, we do anticipate very rapid enrollment as we saw in the Phase II as well. The number of patients -- by having 2:1 also, you have more information on the active arm as part of the BLA submission that will be coming up in 2026.

[Operator]

The next question comes from Konstantinos Biliouris with BMO Capital Markets.

[Konstantinos Biliouris, analyst]

Congrats on the progress. One question from us on the AATD program. Given that the gene that you inserted isn't under the control of the natural promoter and under infection, patients need about 2 to 3x more AAT protein. Can you remind us how do you ensure that this additional AAT protein is there during infections?

[John Leonard, executive]

Thanks for the question, Kostas. We base our excitement over the alpha-1 program on the preclinical [indiscernible] where as you point out, the natural transgene is driven by the albumin promoter. And with that in nonhuman primates, we've achieved normal levels of the protein. I would not expect that to be the module -- the typical response to infection because it will be driven by the albumin promoter. But what we prioritized is normalizing the protein because it's primary -- it's the primary defect in patients with the disease. And we think that, that's going to be the primary determinant of the success of the product.

[Operator]

The next question comes from Joseph Thome with TD Cowen.

[Joseph Thome, analyst]

Congrats on the progress. Maybe just on the MAGNITUDE-2 study, as the TTR serum reduction is going to be a day 29 read and the mNIS is 18 months, are you able to take a look at serum TTR ahead of that 18-month time point while maintaining some sort of blind? Or should we anticipate both of those readouts coming at once? And then secondly, on a submission for PN, how much does the submission in PN depend on also success in MAGNITUDE-1 for CM? Or are these completely uncoupled?

[John Leonard, executive]

Maybe I can address that, and David can fill in blanks. The 2 programs, polyneuropathy and cardiomyopathy are independent of each other and are determined by the study designs in each of those particular indications. We talked earlier on the call here about the cardiomyopathy program and how to think about that. Polyneuropathy program, as was pointed out, we'll have an 18-month observation period that's set in time sort of a landmark design. But the 2 are independent of each other. We would expect that safety will be supplementary from each of the programs as data accumulates, but in terms of the efficacy read, they're entirely independent. The study is blinded, and we will not be in a position where we'll be sharing data prematurely before the complete data readout. So don't look for TTR. And then the ultimate clinical outcomes, it will be the full set of data as it becomes available. David, if you have anything to add to that, be my guest.

[David Lebwohl, executive]

Just to add to the observation that you've seen in our data that all patients have a major reduction in TTR. So though we won't be looking at that data, what we know from our experience is that all patients will be able to achieve a rapid and deep reduction in TTR and that is maintained probably permanently as far as we know, but certainly over 2 years at this point. So we will see that at the time of unblinding, as John says, and we pretty much know what to expect in that data.

[Operator]

The next question comes from Gena Wang with Barclays.

[Unknown Analyst]

It's Tony on for Gena. So on ATTR, can you remind us of your assumptions for silencer drop-in rate and any strategies to address this if it ends up being higher than expected?

[John Leonard, executive]

David, do you want to speak to the silencer drop-in rate?

[David Lebwohl, executive]

Yes. We have figured that into a trial. We haven't given the exact way that will happen. We should mention, we think it's less likely now that we've seen the HAELOs data that there will be much drop in. What we've seen is that there is some addition to TTR to the tafamidis in that trial, but probably not enough to justify payers to pay for both drugs together. So what we expect to see is that patients will continue on their tafamidis in our study. They possibly may switch to vutrisiran if payers allow that. But even that switch, we don't think will have any effect on our primary endpoint.

[Operator]

The next question comes from Maurice Raycroft with Jefferies.

[Maurice Raycroft, analyst]

Congrats on the progress. I was wondering if you could just talk more about how you're setting expectations for the AHA update for biomarkers and the relationship or correlation to functional capacity. I'm wondering if you'll show individual patient data, potentially cardiac remodeling or imaging data as well.

[John Leonard, executive]

I think I can start with that question, and David can fill in some additional information. As we said in our comments, we're very enthusiastic about sharing the data at the upcoming AHA meeting, and we're honored to be featured in the opening session of the meeting, which is something that is addressing the next century of cardiac therapies. Very excited to be a part of that. As we've long said, we'll share biomarker data, functional data and clinical information on these patients. And in terms of how we think about that, the meaning of that information, first, we're excited about what we see because it relates for the first time, the extent of the TTR reduction that we're achieving with those particular readouts. And we think it will yield real insights into how we think about the MAGNITUDE study and how we expect that -- the drug to perform in that particular study. David, if you want to share any other comments?

[David Lebwohl, executive]

Yes. Just to add, you see the data on November 16. Recall that in the recent Phase IIIs, the active arms continue to show worsening in terms of these biomarkers. ProBNP continues to rise, 6-minute walk continues to go down. Even though they're better than placebo, they are still worsening in the populations as a whole. So it's important to observe as you see our data. Our data is also a very robust test of this -- of the ability of deep TTR reductions to make a big clinical difference. And that's because 50% of our patients are Class III instead of the 10% or so you see in the other studies and a full 31% of the patients have variant disease, which is really the very aggressive disease in this -- in ATTR-CM. And those patients as well in the other studies in the around 10% to 12%. So you will be seeing all 36 patients in the study because they've reached -- all reached 1 year, and you will see the data for these patients comparing baseline to 1 year.

[Operator]

The next question comes from Ry Forseth with Guggenheim.

[Ry Forseth, analyst]

This is Ry from Debjit's team. What factors do you think are the major contributors to enrollment being ahead of schedule in the MAGNITUDE ATTR-CM study? And do you think these factors apply to MAGNITUDE-2 for PN?

[John Leonard, executive]

What investigators tell us is they've been extremely excited with the extent of the TTR reduction and the safety profile that they see with the drug to this date. We've seen confirmation with competitor programs that lowering TTR is meaningful for patients. And the deep, consistent and enduring reductions that we've achieved with the drug thus far, I think, is really excited treating physicians around the world. We would anticipate that this will apply also to the MAGNITUDE study. And recall that in many of these countries, this kind of therapy is not available for patients, generally speaking. And we know that there's great enthusiasm with all the sites that we've spoken to.

[Operator]

The next question comes from Dae Gon Ha with Stifel.

[Dae Gon Ha, analyst]

Congrats on the progress. A question on AATD. Just thinking about the Phase I that's going to embark by the end of the year. If you can comment on any flexibility in that trial protocol to include any liver disease patients. I know that was supposed to be more of a 2003 purview, but given the biology and the potential, say, facilitation of polymer excretion from the cells once you have more M protein. Just wondering if you can add in a little bit of that sentinel cohort, if you will, just to see the benefit there.

[John Leonard, executive]

David, any

[Audio Gap]

including liver disease in the 31 trial?

[David Lebwohl, executive]

Yes, these patients will not be having a major -- any kind of major liver disease. Those patients with liver disease really are best addressed by reducing the mutant protein as well as, of course, giving the increased alpha-1 antitrypsin would be valuable to them as well. But without our ability to reduce the Z protein, we don't think we're doing them full justice.

[John Leonard, executive]

Well, just to add, we're taking an extended approach to going after alpha-1. And in addition to 3001, which we think will teach us a lot about the insertion approach for alpha-1 disease and reads to a multiplicity of other diseases for which insertion may be the path forward, we're also bringing forward a gene writing program that would address not only the lung but also the liver.

[Operator]

The next question comes from Luca Issi with RBC.

[Lisa Walter, analyst]

This is Lisa on for Luca. Congrats on all the progress here, team, and getting the IND cleared for TTR polyneuropathy. Just one question on the study. I know the primary endpoint is mNIS+7 at 18 months. However, I believe Alnylam was able to file on just 9 months of follow-up. So I'm just curious if the 18-month endpoint was mostly needed to satisfy European regulators? Or did the FDA also request the longer follow-up? Any color here would be helpful.

[John Leonard, executive]

David, any comments to share on 18 months versus a different follow-up time?

[David Lebwohl, executive]

Yes, we felt 18 months was -- looking at the trials, we felt 18 months was the optimal time to really see the full benefit of the drug. It was not required by regulators, but it was really our own decision to do that.

[Operator]

The next question comes from Salveen Richter with Goldman Sachs.

[Unknown Analyst]

This is Mark on for Salveen. First, congrats on the quarter. The recently presented Phase II data from NTLA-2002 in HAE, can you discuss the data in the context of read-through to the recently initiated Phase III HAELO study? And any takeaways that you're applying to HAELO?

[John Leonard, executive]

Well, thanks for the question. And I think it's really important to step back and consider what we've actually presented for 2002 thus far. If you take the 50-milligram doses from both the Phase I and Phase II studies, we now have -- we've reported on 12 of 15 patients who have achieved what we're considering a functional cure. That means patients following a single dose and no other therapy thereafter have no attacks. That is unique in the space. It's a new category of response. It is achieved in, to our knowledge, only with 2002 in this class of drugs. We expect that similar outstanding results will come from our Phase III trial. The study design is similar with the exception that we have an even longer follow-up period to see further insights into how patients would respond with even a longer observation period. What we've seen in our Phase I study is that while many patients get to a functional cure fairly quickly, there are some patients that reach that only with some additional time. So we expect that we'll have very favorable results in our Phase III program and look forward to sharing that as we go forward.

[Operator]

The next question comes from Myles Minter with William Blair.

[Unknown Analyst]

This is John on for Myles. So for 3001, I was just wondering if you could give us any idea of how many patients you are looking to dose before reporting initial data? And what kind of target are you looking for, for serum AAT levels in those lower dose cohorts?

[John Leonard, executive]

Thanks for the question. We've had a principle that we've applied since the outset with all of the clinical work that we've done here, which is that we report data when it's meaningful, consistent and interpretable, and we'll apply that same standard here. Obviously, we're looking for a biomarker here, which is readily measured. That's the production of the native protein, wild type. And we've said from the outset that our objective here is to normalize the levels of that protein. And that will be the basis for our determining the success of the project.

[Operator]

The next question comes from Joon Lee with Truist Securities.

[Mehdi Goudarzi, analyst]

This is Mehdi on for Joon. Given your great progress for in vivo programs that you have, any color on your future plans for using gene writing technology is really appreciated. For example, do you plan to use it for in vivo or this is more for your ex vivo programs?

[John Leonard, executive]

Thanks for the question. It really goes to the heart of the strategy of the company where it's a 3-pronged approach. We start with a platform that has a complete set of tools not only on the editing side, but also on the delivery side, so that as we look at any particular editing problem, we're in a position to choose what we think will be the best tool for the particular problem. And we apply those tools in both the in vivo and the ex vivo setting. We think that there are conditions for which gene writing is well suited. I don't think that's universally true. We think that there are certain instances, especially in the ex vivo setting where base editing is useful where one is going to multiplex. And then, of course, as we've shown with our ongoing Phase III programs, arcotypeal CRISPR as exemplified by 2001 and 2002 has profoundly successful results in terms of achieving the editing objectives that we're going after. So in short, we'll look at the particular programs and the editing that they need and apply the gene writing to that. One of the places where we think it's well suited is as an adjunct to our alpha-1 program, and that would be the first place where I would expect to see it.

[Operator]

The next question comes from Jay Olson with Oppenheimer.

[Jay Olson, analyst]

Congrats on all the progress. How are you thinking about the ex U.S. opportunity and strategy for 2002? Are you interested in partnering the program ex U.S.?

[John Leonard, executive]

Thanks for the question. Behind that is the assumption that there's a substantial commercial opportunity around the world, certainly in the developed markets, and we see that starting in the U.S. and going beyond the U.S., into Europe and perhaps beyond that. Our current plans are to be in a position to launch the drug ourselves. As we evaluate partnerships, we consider what they can bring to the table to extend our own reach. And as appropriate, as we learn more about that, we would share that strategy as we go forward.

[Operator]

The next question comes from Brian Cheng with JPMorgan.

[Unknown Analyst]

This is Sean on for Brian. Just speaking on the AATD program, just curious about your thoughts on the back of some of the RNA editing data from your peers. How do you view 3001's differentiation versus theirs?

[John Leonard, executive]

Thanks for the question. As we've said elsewhere, we think the key determinant of success for the pulmonary pathology of the disease will be achieving high essentially normal levels of wild-type protein. Thus far, we are the only company that we're aware of that's presented that in the setting of a nonhuman primate. That is what we're looking for in our Phase I study to determine whether or not we achieve those same similar proteins in humans. Obviously, we'll watch the space. There are competitive programs playing out, but it's very, very early. We'll see how successful people are at even delivering their technologies and then the performance of production of the normal protein over time.

[Operator]

The next question comes from Silvan Tuerkcan with Citizens JMP.

[Silvan Tuerkcan, analyst]

Congrats on the progress. Just a quick one, and I may have missed this. But for MAGNITUDE-2, congrats on the IND. But when do we plan the initiation in the U.S. here for this trial? And what is the eventual split of patients enrolled in this trial in considering U.S. versus ex U.S.

[John Leonard, executive]

Thanks for the question. We've tried to make it clear elsewhere that the study will be done outside the United States. It's there where one can readily conduct a placebo-controlled trial. Standards of care otherwise for these patients are similar around the world. We've worked on developing this protocol with the Food and Drug Administration in the United States. And they will accept the program coming from patients that are studied outside the United States.

[Operator]

The next question comes from William Pickering with Bernstein.

[William Pickering, analyst]

For the AATD program, do you have any plans to expand the study beyond the New Zealand site? And is it a reasonable base case that we would see data in 2025?

[John Leonard, executive]

David, do you want to speak to any other sites besides New Zealand?

[David Lebwohl, executive]

Yes. We will be having other sites, and we'll put them on [ clinicgov.com ] as they come up. I should say it is possible that we'll have data, reasonable to think we have data in 2025.

[Operator]

The next question comes from Andy Chen with Wolfe Research.

[Brendan O'Brien, analyst]

Brendan on for Andy. So we know docs are excited about your ATTR therapy. But can you please compare the excitement relative to their excitement for stabilizers and silencers? So let's say, you achieve similar efficacy on endpoints based on feedback now. Are docs much more likely to use gene editing compared to a silencer, for example? Any safety concerns about using gene editing in a very old population?

[John Leonard, executive]

David is on the front line talking to investigators. Can you speak to the enthusiasm for the investigators that we work with who, by the way, many of them have worked with silencers already? So they are in a position to be thinking about both those compounds.

[David Lebwohl, executive]

Yes. Thanks, John. I think you've heard our hypothesis for a number of years that deeper reductions in TTR will lead to better results. Our drug is also more rapid in getting down to low levels than silencers, as well as getting to those deeper levels. And it is continuous. So the levels are staying continuously low instead of what might happen if you give infusions of drugs periodically. So based on that excitement about the low levels we're achieving, we have heard a lot of excitement from physicians thinking this could be better than silencers. That is something we want to prove in Phase III, but that is -- that's what we hear from investigators, and that's why we think it's enrolling quite briskly. There hasn't been any safety concerns raised in an elderly population. We've seen it well tolerated in all the patients, including Class III patients and some very sick patients. And all the patients were able to receive a full dose of the drug as part of their therapy in the trial.

[John Leonard, executive]

Maybe something to add is that we now have over 3 years of follow-up in our earliest dose patients and the excellent safety profile that we reported in the early days has continued. We think many of the questions that surrounded gene editing are being addressed as these programs enroll. I think another thing to keep in mind with respect to patients who are older, which typifies the wild-type patient population. These patients live for a long time. And you can look at the recently reported results and see that there's high levels of survival years after the patients have been dosed. And I think that speaks importantly to the role of these agents and what they can do for these patients, the evolving care of them, and ultimately a pharmacoeconomic argument for treating patients like this who should derive the full benefit of the therapy. One other thing with respect to older patients, it's common to think of TTR cardiomyopathy as a heritable disease. In fact, in most cases, it's a disease of aging. 90-plus percent of the patients who suffer from the disease have wild-type protein. And you can see that in the Phase III trials that have been reported. So unfortunately, we're making many more of these patients annually as the population ages. And so it's not correct to think about it as a typical sort of genetic disease.

[Operator]

The next question comes from Whitney Ijem with Canaccord Genuity.

[Joohwan Kim, analyst]

This is Joohwan on for Whitney. Just trying to understand the rationale for the 2001 polyneuropathy IND given that the Phase III will be run ex U.S. Any color you can provide on that? Just want to make sure we're not missing any nuance here.

[John Leonard, executive]

Why do we have an IND and do the study outside the United States?

[David Lebwohl, executive]

Yes. The reason is that when you plan a BLA in the United States, it's a good idea to get agreement with the FDA on the design of that study. And that's what we've obtained with this IND. They agreed to the study you're seeing presented today, and this will go forward to a BLA in the U.S. as well as around the world.

[Operator]

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

[Lina Li, executive]

Thanks, Drew, and thanks, everyone, for your question today. We appreciate all of your continued support and look forward to connecting with everyone again after the AHA presentation on Saturday, November 16. Have a great day.

[Operator]

The conference has concluded. Thank you for attending. You may now disconnect your line.