Intellia Therapeutics Inc

NASDAQ:NTLA

Earnings Call Analysis

Intellia's Q2 2024 Updates Spotlight CRISPR Advancements and Financial Health

Intellia Therapeutics reported solid progress in its Q2 2024, showcasing advances in its CRISPR-based gene editing programs. NTLA-2002's ongoing trials for hereditary angioedema (HAE) revealed a 98% reduction in attacks, reinforcing its potential for a one-time treatment. The company also announced the successful dosing milestone of NTLA-3001 for alpha-1 antitrypsin deficiency lung disease. Financially, Intellia maintains a strong balance sheet with $939.9 million available, expected to fund operations through late 2026. R&D expenses stood at $114.2 million, while collaboration revenue dipped to $7 million due to reduced contributions from the AvenCell partnership. The Phase III trial for NTLA-2002 is set for late 2024 with BLA submission targeted for 2026.

Intellia's Vision for Gene Editing

Intellia Therapeutics is positioning itself at the forefront of gene editing, particularly in the area of hereditary angioedema (HAE) and alpha-1 antitrypsin deficiency (AATD). CEO John Leonard articulated a strong commitment to delivering potentially curative treatments through its CRISPR-based platform. With over 150 patients treated in various investigational studies, Intellia is eagerly anticipating clinical results that could redefine treatment paradigms in these conditions. This approach promises a significant shift from existing therapies that focus on managing symptoms rather than addressing the root causes.

Promising Results from HAE Trials

Regarding NTLA-2002 for HAE, early results from the Phase I program are striking, with patients experiencing up to a 98% reduction in attacks after a single treatment. Most encouragingly, 8 out of 10 treated patients remained free from attacks for 18 to 26 months. The ongoing Phase II study aims to confirm these results and determine the optimal dose of the drug for future trials. Preliminary analysis indicates that both the 25mg and 50mg doses are viable candidates for subsequent pivotal studies, with full results expected to be presented later this year.

Financial Resilience Amidst Investment

Intellia's financial standing remains robust, with approximately $939.9 million in cash and equivalents as of June 30, 2024. This is a slight decrease from $1 billion at the end of 2023, primarily due to operational expenditures of $234.4 million. Notably, this budget was partially offset by $96.4 million in equity raise proceeds, showcasing the company’s ability to bolster its resources while advancing its innovative pipeline. The CFO, Ed Dulac, reassured investors that this cash balance is sufficient to fund operations through late 2026.

What Lies Ahead: NTLA-3001 and Market Potential

The company is set to begin human trials for NTLA-3001, which targets gene therapy for AAT deficiency-associated lung disease. This marks a crucial step as Intellia received regulatory approval to initiate this essential Phase I/II study. The goal is to permanently restore production of a fully functional protein with a 'one-and-done' treatment approach. Leonard emphasized that this represents an unmet medical need in a market they deem wide open, especially as existing therapies have not adequately addressed the disease’s progress.

Strategic Positioning in a Competitive Landscape

As Intellia advances its trials, the competitive landscape is evolving as well. Other companies like Ionis are developing parallel therapies, but Intellia's unique approach of seeking a complete cessation of medications after treatment positions it distinctively. Leonard argued that the demand for a treatment that allows patients to live as normally as possible without chronic medication would drive Intellia's success. This narrative aligns with patient desires highlighted in market research conducted by the company.

Guidance on Future Growth and Milestones

Looking ahead, Intellia's strategy includes multiple pivotal clinical trials with NTLA-2001 and NTLA-3001 expected to progress by year-end. The timeline for initiating these trials, combined with the anticipated presentation of comprehensive Phase I data in late 2024, indicates a structured approach to growth. Investors can look forward to significant updates that may enhance Intellia's standing in gene editing and regenerative medicine sectors.

Earnings Call Transcript 2024-Q2

[Operator]

Good morning, and welcome to Intellia Therapeutics Second Quarter 2024 Financial Results Conference Call. My name is Drew, and I will be your conference operator today.[Operator Instructions]. 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 Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.

[Ian Karp, executive]

Thank you, operator, and good morning, everyone. Welcome to Intellia Therapeutics Second Quarter 2024 Earnings Call. Earlier this morning, Intellia issued a press release outlining the company's progress this quarter as well as topics for discussion on today's call. This release can be found on the Investor and Media section of Intellia's website at intelliatx.com. This call is being broadcast live, and a replay will be archived on the company's website.

At this time, I'd like to take a minute to remind listeners that during the call, Intellia management may make certain forward-looking statements and ask that you refer to our SEC filings available at sec.gov for a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law.

Joining me from Intellia are John Leonard, Chief Executive Officer; Laura Sepp-Lorenzino, Chief Scientific Officer; Ed Dulac, Chief Financial Officer. Also in the room and available for the Q&A is Liron Walsh, Head of Development for in vivo programs. Our Chief Medical Officer, David Lebwohl, is unable to join us today, but he will be participating in upcoming investor conferences. John will begin with updates on our clinical pipeline progress and recent business highlights. Lauren will then provide R&D updates and Ed will review our financials before we open the call for questions.

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

[John Leonard, executive]

Thank you, Ian. Good morning, everyone, and thank you all for joining us today. At Intellia, we're harnessing the power of CRISPR-based gene editing for developing potentially curative treatments. Now with over 150 patients dosed with our investigational therapies and multiple programs in clinical development, we are undoubtedly at the forefront of the gene editing revolution. We're proud to report another quarter of substantial progress and continued innovation across our full spectrum pipeline and platform.

I'll start with NTLA-2002 for the treatment of hereditary angioedema, also known as HAE. It is a debilitating and potentially fatal condition that manifests as recurrent episodes of unpredictable swelling. Despite existing treatments, we've heard loud and clear from patients and physicians and through our market research that HAE patients are seeking improved efficacy and convenience. Beyond that, patients tell us that what they want most is to live a life free from their disease and the many challenges that come with it even while on chronic treatments available today.

While current and other emerging therapies attempt to differentiate themselves with modest improvements in attack rate reduction or extending dosing intervals for prophylactic therapy, what we are pursuing is a total paradigm shift in the treatment of HAE. Our goal for NTLA-2002 is to provide a complete response that is a treatment outcome in which patients are both free from attacks and untethered from the requirements of chronic treatment after a single administration. This is the outcome patients and physicians seek and with revolutionary advancement of our gene editing technology, we believe we are making it a reality.

In June, we reported positive long-term data from the Phase I study of NTLA-2002. Of the 10 patients treated 8 continue to be completely attack-free for 18 to 26 months following a single administration of the drug. And across all patients, we observed a 98% reduction in attacks in the latest follow-up. Importantly, the data from these 10 patients continue to demonstrate a favorable safety profile. The most frequent adverse events were infusion-related reactions and fatigue, which were mostly grade 1. These unprecedented results reinforce the potential of NTLA-2002 to be a onetime functional care for this life-threatening disease. Today, we are thrilled to announce at NTLA-2002 met its primary efficacy in all secondary endpoints in the 16-week primary observation period of the Phase II study.

As a reminder, the ongoing Phase II was a randomized, placebo-controlled study to further evaluate the safety and efficacy of the 25-milligram and 50-milligram doses. The key objective of the Phase II was to determine which of the 2 doses to move forward into the global pivotal Phase III trial. The primary efficacy endpoint was the reduction in the number of angioedema attacks per month during the 16-week primary observation period. Key secondary endpoints included safety, the number of angioedema attacks per month during weeks 5 to 16, the number of angioedema attacks per month requiring acute therapy and the change from baseline in the total plasma kallikrein protein level. We plan to present the detailed results at a medical meeting in the fourth quarter of this year. As such, we will be limiting our discussion of the top line results to what we disclosed in today's press release.

A single 25 or 50-milligram dose of NTLA-2002 led to deep reductions in attacks for patients with HAE. No new safety findings were observed. We have now selected the 50-milligram dose to advance into the global Phase III trial because we saw greater kallikrein reduction and importantly, a higher number of patients who achieve complete elimination of attacks compared to the 25-milligram dose cohort, which is consistent with the prior Phase I results.

In addition to the positive results, we recently completed a successful end of Phase II meeting with the FDA. We believe we have completed addressing their questions and have a clear understanding of the path forward. We are on track to begin the Phase III trial in the second half of this year and a positive plan to submit the BLA for NTLA-2002 in 2026. We anticipate that NTLA-2002 will be the first in vivo gene editing therapy to come to market. And most importantly, we strongly believe it will reset the standard of care for HAE.

Switching now to NTLA-2001 for the treatment of ATTR amyloidosis. The drug now has a new name, nexiguran ziclumeran or nex-z for short. Recent competitor data confirmed our long-standing hypothesis that TTR reduction leads to a clinically meaningful improvement in patients with cardiomyopathy. This is an important advancement in the field's understanding of the disease, and this result further increases our confidence that nex-z could lead to even better clinical outcomes for patients. Our belief is based on the consistently deep and durable TTR reductions observed in the Phase I study.

Further, competitor clinical data recently reported reaffirm that the ongoing MAGNITUDE trial is well designed. As appropriate, we will incorporate additional learnings into our trial as they become available.

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

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

Finally, we look forward to presenting data from the ongoing Phase I study in the second half of 2024. We plan to include safety and TTR reduction data from both the CM and PN arms as well as other clinical endpoints, such as NT-proBNP, 6-minute walk test and mNIS+7. We anticipate these data will build upon insights recently reported in other TTR silencer clinical trials.

With 3 pivotal Phase III trials and our first gene insertion study, all expected to be active by year-end, and telling us closer than ever to transforming the future of medicine with our onetime in vivo gene editing therapies. In parallel to our clinical execution, we're making strategic investments for our exciting evolution from late-stage clinical development to a commercial organization.

This is exemplified by the recent appointment of Brian Goff, to our Board of Directors; and Ed Dulac, as Chief Financial Officer and Treasurer. Brian's extensive global commercialization experience, coupled with this track record of success leading rare disease product launches will be invaluable. Similarly, its deep financial and business development experience at clinical and commercial stage biotech companies will be critical as we enter the next chapter in our evolution.

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

[Laura Sepp-Lorenzino, executive]

Thank you, John. Good morning, everyone. At Italia, we're deploying the industry's broadest toolbox of novel gene editing and delivery technologies for in vivo and ex vivo therapeutic applications. Let me begin with NTLA-3001. As we announced last week, we received regulatory approval from the United Kingdom's Medicine and Healthcare products, Regulatory Agency to initiate the first-in-human study in patients with alpha-1 antitrypsin deficiency associated lung disease.

Following the IND clearance of Regeneron factor IX program, this marks the second program leveraging our modular gene insertion platform set to enter the clinic, another accomplishment from our industry leading research engine. Unlike traditional gene therapy, we expect our approach will permanently restore and releasing of the effected protein without a waning effect over time.

As a reminder, NTLA-3001 is designed to precisely insert the wild-type SERPINA1 gene to permanently restore production and secretion of fully functional alpha-1 protein. Our goal is to replicate what we demonstrated in nonhuman primates to restore patients to normal alpha-1 levels after a single dose.

The Phase I/II study will be a 2-part open-label multicenter study to evaluate the safety, tolerability, PK and PD of NTLA-3001, up to 30 patients will be enrolled. Phase I will be a single ascending dose design with up to 3 cohorts. Patients will receive a single infusion of NTLA-3001, which consists of a sequential dose of AAV and LNP. The AAV delivers a SERPINA1 DNA template and the LNP delivers a CRISPR machinery. Based on our learnings from NTLA-2001 and NTLA-2002, we will be evaluating a 6 LNP dose of 50 milligrams. The only variable component from cohort to cohort in the dose escalation will be the dose of AAV. We will begin with doses of AAV that we expect will show some level of activity even in the first cohort.

Once we've identified the optimal dose, we plan to move into the Phase II, which will be a single dose expansion cohort to further characterize the activity of NTLA-3001. We are on track to dose the first patient in the second half of this year. Assuming success, NTLA-3001 could redefine how alpha-1 is treated and unlock a whole new category of diseases we can pursue with our in vivo gene insertion platform.

Turning to another exciting development with our in vivo platform. In June, Intellia achieved yet another landmark milestone for the field of gene editing. We presented the first ever clinical data demonstrating that redosing with CRISPR when utilizing Intellia's LNP-based delivery platform, enable an additive pharmacodynamic effect. Typically, the follow-on dose was generally well tolerated. Overall, the safety and pharmacodynamics of redosing with NTLA-2001 were consistent with those observed after single dose.

The ability to successfully redose these patients is a testament to our high standard in developing our proprietary LNP formulation to ensure both safety and activity. Going forward, while not planned for our current clinical programs, the option to redose could be an important advantage for Intellia as we continue to push the boundaries of what we can do and expand where we can go outside the liver with CRISPR-based technology. We look forward to updating you on our progress across our R&D platform more broadly this year.

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

[Edward Dulac, executive]

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 $939.9 million as of June 30, 2024, compared to $1 billion as of December 31, 2023. The decrease was driven by cash used to fund operations of approximately $234.4 million. The decrease was offset in part by $96.4 million of net equity proceeds from the company's At the Market program, $35.9 million of collaborator reimbursement including a onetime $30 million payment received in April related to the company's technology collaboration with Regeneron, $25.1 million of interest income and $4.8 million in proceeds from employee-based stock plans.

Our collaboration revenue was $7 million during the second quarter of 2024, compared to $13.6 million during the second quarter of 2023. The $6.6 million decrease was mainly driven by a reduction in revenue related to the AvenCell license and collaboration agreement.

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

[John Leonard, executive]

Thanks, Ed. In conclusion, Intellia continues to deliver on the promise of gene editing, and we are looking forward to several important clinical milestones in the second half of this year. With that, we'll now all 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 Terence Flynn with Morgan Stanley.

[Unknown Analyst]

This is Chris on for Terence and congratulations on the progress. Regarding the HAE Phase II data, can you talk about how competitive it is against Ionis drug?

[John Leonard, executive]

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

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

[Operator]

The next question comes from Mary Kate Davis with Bank of America.

[Mary Davis, analyst]

Looking at the AATD program here, could you comment on how impactful the wholly owned insertional program could be for the current market, given an unmet need in the space?

[John Leonard, executive]

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

[Operator]

The next question comes from Dae Gon Ha with Stifel.

[Dae Gon Ha, analyst]

I'll also stick with AAT. Maybe a question for Laura. As we think about the 3001, specifically on the AAV component, I guess, can you speak to what your learnings are or what your deviations are from the Astellas, Audentes experience when it comes to AAV8 and how that gets factored into your dose? And specifically, can you also talk about sort of the biology behind wild-type AAT and still having Z AAT production, whether the Z AAT lingering might have some pro-inflammatory effects on the lung pathology.

[John Leonard, executive]

So Laura, do you want to take that and start with some of the dosing differences?

[Laura Sepp-Lorenzino, executive]

Yes. So Dae Gon, thank you for the question. So here we're using the AAV to deliver the template for insertion. So it's quite a different approach when we're using traditional gene therapy where you need to load the cells with episomes to ensure that you have long duration of effect.

So given that, our doses are much, much lower, not only to what Audentes has used but what others have used including for liver-directed diseases using AAV8. So again, the thing is we need to have enough template to have insertion in a few percentage of hepatocytes that's going to drive the levels of alpha-1 that we believe are going to be fully therapeutic.

Based on our data and not all the patients who have alpha-1 antitrypsin deficiency have liver disease, right? That's minority of the patients. So we don't expect any issue by having expressing the wild type protein in patients who have it. John, anything you would like to add?

[John Leonard, executive]

I think that speaks it. Thank you, Laura.

[Operator]

The next question comes from Joseph Thome with TD Cowen.

[Joseph Thome, analyst]

Maybe one quickly on the 2001 PN proposed study. I think you indicated that it would be ex-U.S., which obviously makes sense given the availability of silencers. But do you think the FDA would like to see dosing of any U.S. patients prior to an approval in this setting? Or do you think ex-U.S. patients for the entire program would be sufficient? Would you do like an open-label extension or anything like that?

[John Leonard, executive]

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

[Operator]

The next question comes from Luca Issi with RBC.

[Luca Issi, analyst]

Great. Congrats on the progress. Maybe, Laura, one more here on alpha-1. Obviously, the competitive landscape continues to evolve, obviously, Vertex giving up on their approach. But we are seeing a lot of other innovations coming down the pipe, including, I think we're going to see clinical data for the first time for ADAR and RNA editing toward the end of the year. Wondering if you can just kind of compare and contrast that approach versus your approach and why you think your approach is better. Any thoughts there? Much appreciate it.

[Laura Sepp-Lorenzino, executive]

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

[Operator]

The next question comes from Gena Wang with Barclays.

[Huidong Wang, analyst]

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

[John Leonard, executive]

Thanks, Gena. As soon as we're in a position to share where we're presenting the data, we will, of course, do that as we've always done, and we look forward to seeing you in the audience as we go through what we think is very exciting data.

With respect to the women of childbearing potential, I just want to clear up one thing. There was no partial clinical hold, that's not correct. But as we said, we've addressed all of the issues with the FDA. We have complete alignment with respect to the Phase III study, and we will be including women of childbearing potential, not only in the United States, but around the world, as we've been doing up until now with the exception of the United States. So we look very much forward to beginning that trial and collecting results in the full population.

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

[Operator]

The next question comes from Maury Raycroft with Jefferies.

[Maurice Raycroft, analyst]

Congrats on the update. I'm wondering if there's more you can say on feedback from the HAE in the Phase II meeting and your latest thoughts on the pivotal trial's design. And in particular, I'm wondering how big this study would need to be and if there's anything more you could say about effect size or placebo response expectations?

[John Leonard, executive]

Thanks, Maury. I guess I would characterize the FDA meeting as profoundly successful. We presented, as they've seen earlier preclinical data. We've shared our manufacturing approach and they've seen the clinical data from not only the Phase I but the Phase II program.

The key decision there was to decide on which dose to take into Phase III. We've done that. And as we shared here, that will be the 50-milligram dose and as per the prior question from Gena, we will expose the full population of people with the disease to the drug, so we're very, very excited about that. We now know the size of the trial, and we expect that this will be fewer than 70 patients. It will be a placebo-controlled trial as the standard. We'll look for a variety of different outcomes, not only attack rate reduction, but of course, the number of patients who achieve that complete response that we think is so fundamental to the profile of the drug. And these things will be measured over a 6-month interval as opposed to the 16 weeks that we've done in Phase I and Phase II.

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

[Operator]

The next question comes from Mani Foroohar with Leerink.

[Mani Foroohar, analyst]

I know you have been more reticent than others to use the phrase functional cure, which is realistically what we're talking about for HAE, if you're going to take patients off all therapy. The competitor program from Ionis, which is a chronic therapy, for not pursuing curative event like functional cure has a number of studies, they have the SWITCH study, et cetera, they chose to do a SWITCH study. When you think about the path to commercialization for what's meant to be a onetime functional curative therapy for at least some, if not with the majority of patients.

How do you think about providing data for patients to switch, for patients moving off of prophylactic therapy discontinuing the practice of keeping on-demand therapy on them, et cetera. Will there be a couple of other -- more broadly, will there be a couple of other studies as part of your larger strategy to inform physicians on how to roll patients off therapy? Or do you think you can take advantage of data sets produced by others in terms of providing the operational input of how physicians move patients off of current polypharmacy to your therapy and eventually nothing on top of it?

[John Leonard, executive]

That may have been 6 questions, Mani, and I don't know if I can speak to all of them, but let me try to give some perspective on what I think you're getting at. First of all, we're being very judicious with the words that we use to describe the outcomes for these patients. You, yourself, are calling it a functional cure, we think that, that's something that we're achieving with these patients. What we'll be able to say from a regulatory point of view, remains to be determined as we work with the Food and Drug Administration, but the evidence will speak for itself. Again, the goal is to have patients following a single application of the drug, no longer take therapy, and you can decide what you want to call that.

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

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

[Operator]

The next question comes from Joon Lee with Truist Securities.

[Mehdi Goudarzi, analyst]

This is Mahdi on for Joon. Congrats on the progress. So on NTLA-2001, given Acoramidis now has a PDUFA date of November 19 and showed 50% CVS reduction with 81% survival. So what do you expect to be the outcome of 2001 in this regard? Basically, what do you think is the bar now for Phase III MAGNITUDE study?

[John Leonard, executive]

Well, based on the TTR results that we presented in multiple forums, which are the deepest that have been reported and the most prolonged that have been reported we expect that we'll be able to meet or achieve any profile that's been put forward by any of the other competitive agents, whether a stabilizer or a silencer.

We designed a Phase III trial that is designed to demonstrate that and we have looked at patients with a range of different degrees of stability from their cardiomyopathy. And we think that, that patient population whether on existing therapy or on monotherapy with 2001 will have outcomes that are superior to what's been reported to any of the other agents. So stay tuned.

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

[Operator]

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

[Unknown Analyst]

This is [ Dale ] for Costas. Just one question from us. So on the NTLA-3001 program, how do you think about the competition for patient enrollment, given that Beam and also other editing companies also recruiting in the United Kingdom?

[John Leonard, executive]

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

[Operator]

The next question comes from Rick Bienkowski with Cantor Fitzgerald.

[Rick Bienkowski, analyst]

Congrats on the update in HAE. So one of the observations from the Phase I data was there was a small number of breakthrough attacks during the primary observation period and then complete suppression of attacks afterwards. So for the full Phase II presentation later this year, will we see any follow-up for patients that's longer than the primary observation period? And could you just discuss if there are any plans to follow these patients for a longer term? And maybe present those data at a later date.

[John Leonard, executive]

We'll present data through the 16-week observation. Remember that there's a couple of differences in the Phase II from the Phase I. In the case of the Phase II study, there are 2 different doses, but a placebo arm as well. And what we offered all patients in the study was a switch. So we're not going to be in a position to look at ongoing placebo patients over time. We will follow all of these patients as we've done with every single one of the patients that we've dosed irrespective of the program. And I would expect that down the road at the appropriate times, we'll present follow-up information on every single one of the patients that we've treated thus far.

[Operator]

The next question comes from Jay Olson with Oppenheimer.

[Jay Olson, analyst]

Congrats on all the progress. For 2001, can you talk about the number of study sites you plan to activate for the magnitude study. And how could that be impacted by other competing trials that are wrapping up? And then what you'll be looking for in the HELIOS-B results when they're reported ESC?

[John Leonard, executive]

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

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

[Operator]

The next question comes from Brian Cheng with JPMorgan.

[Lut Ming Cheng, analyst]

Just on the back of your recently reported redosing data, is there any plan to build in redosing for those patients that didn't achieve perhaps a certain biomarker reduction threshold if it happens? In the next set of studies for TTR polyneuropathy HAE or AATD?

[John Leonard, executive]

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

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

[Operator]

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

[Timur Ivannikov, analyst]

This is Timur Ivannikov for Steve. For AATD lung disease, historically, it's been difficult to show improvements in FEV1 and pulmonary exacerbations. So do you think the FDA will require showing improvements on those end points besides just showing the reduction in neutrophil elastase activity?

[John Leonard, executive]

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

[Operator]

The next question comes from Silvan Tuerkcan with Citizens JMP.

[Silvan Tuerkcan, analyst]

Congrats on the data update. Just about the open-label trial, the Phase I in HAE, the long-term attack rate post the most recent presentation, I don't know if you can comment on it, but do you still have 8 out of 10 patients with no attacks post the observation period?

[John Leonard, executive]

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

[Operator]

The next question comes from William Pickering with Bernstein.

[William Pickering, analyst]

Congrats on all the progress. Now that it looks increasingly likely that a silencer will become available during your MAGNITUDE trial and potentially even before enrollment completes. Can you speak to your assumptions on silencer drop-in rate, is there a cap? And can you just confirm that patients who are already on a silencer would not be eligible to enroll?

[John Leonard, executive]

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

[Operator]

The next question comes from Salveen Richter with Goldman Sachs.

[Lydia Erdman, analyst]

This is Lydia on for Salveen. Just a quick one from us on ATTR cardiomyopathy, just with regard to the enrollment progression for the MAGNITUDE trial. I think that last quarter, you said that there were 30 patients enrolled. Could you just provide an updated figures here and then when you expect to complete enrollment?

[John Leonard, executive]

Thank you for the question. What we won't be doing is giving updates on a quarterly basis. We shared that information because it was the first time we had reported after we began the study, and we wanted people to see the very strong start in enrollment, which, as I said, continues to be above our expectations. Again, we have more than 35 sites up and running in 12 countries that will continue to expand in the weeks that lie ahead.

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

[Operator]

The next question comes from Myles Minter with William Blair.

[Myles Minter, analyst]

Just on alpha-1, just curious what your definition of normal AAT levels are because there's a wide range, I think, 20 to 50 micromolar. And if that range will be achievable with your initial 50 mg dose that you're going with? And final question is just on the risk of albumin reduction. Just with the fact that you're uncertainty into the albumin locus and if that's going to be material or not?

[John Leonard, executive]

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

[Laura Sepp-Lorenzino, executive]

Right. So normal levels, right? And what you quoted is right, right? So they vary from 20 to 50. And that's the goal that we want to achieve, right, in this case, we were in the 20s. So that's what we expect we're going to be able to achieve in humans.

With regards to albumin that was obviously externally evaluated in our GLP toxicology studies. And we do not see a decrease in albumin expression that in any way could put patients in danger. So we believe that, again, the doses that we're going to investigating even the first dose, we expect we designed the trial for even the first dose to have led to alpha-1 levels that will be therapeutically relevant. And then we expect that the safety of the approach to 3001 will be pristine.

[Operator]

The next question comes from Liisa Bayko with Evercore ISI.

[Unknown Analyst]

This is [ Jamie ] on for Liisa. Congrats on the progress. So we just have a question for Phase III MAGNITUDE study. What method do you plan to use for analysis of the composite endpoint, something like [ single stain ] or Andersen-Gill like HELIOS-B?

[John Leonard, executive]

The question, those are details that lie ahead, and we'll disclose at the appropriate time. But we appreciate your interest.

[Operator]

The next question comes from Ry Forseth with Guggenheim.

[Ry Forseth, analyst]

This is Ry from Debjit team across HAE, ATTR PN and CM, what's your contemporary internal market research suggesting for uptake or enthusiasm to switch for gene editing. Is there any notable inter indication differences that you've seen?

[John Leonard, executive]

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

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

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

[Operator]

The next question comes from David Lebowitz with Citi.

[David Lebowitz, analyst]

Certainly, understanding that you can't speak directly to anything with the MAGNITUDE trial and the potential adaptations. But could you indicate what specific items are most interesting to you in the upcoming HELIOS-B detailed readout at ESC? What things you're focusing on and how, I guess, that might inform further aspects of design of the MAGNITUDE trial?

[John Leonard, executive]

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

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

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

[Operator]

Our last question will come from Andy Chen with Wolfe Research.

[Brendan O'Brien, analyst]

This is Brendan on for Andy. Congrats on the Phase II success and move to Phase III. Based on our understanding, the HAE market is somewhat saturated, although still a chunk of patients who have not signed up for prophylactic treatments or your competitors don't seem to be activating those patients. So all of your competitors are competing for the same pie right now. Do you think gene-editing could expand the prophylactic treatment?

[John Leonard, executive]

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

[Operator]

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

[Ian Karp, executive]

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

[Operator]

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