Earnings Call Transcript - NTLA Q3 2021

Operator, Operator

Good morning and welcome to the Intellia Therapeutics Third Quarter 2021 Financial Results Conference Call. My name is Drew and I will be your conference operator today. Following formal remarks, we will open the call up for a question-and-answer session. This conference is being recorded at the Company's request and will be available on the Company's website following the end of the call. As a reminder, all participants are currently in listen-only mode. 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, SVP of Investor Relations and Corporate Communications

Thank you, and good morning, everyone. Welcome to Intellia Therapeutics third quarter 2021 earnings call. Earlier this morning, Intellia issued a press release outlining the Company's progress this quarter, as well as topics for discussion on today's call. This release can be found on the Investors & Media section of Intellia's website at intelliatx.com. This call is being broadcast live and a replay will be archived on the Company's website. At this time, I would like to take a minute to remind listeners that during 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 on the call today are Dr. John Leonard, Chief Executive Officer; Dr. David Lebwohl, Chief Medical Officer; Dr. Laura Sepp-Lorenzino, Chief Scientific Officer; and Glenn Goddard, Chief Financial Officer. On today's call, John will lead with the Company's third quarter and recent business highlights; followed by David, who will provide an update on clinical efforts surrounding NTLA-2001, NTLA-2002 and NTLA-5001. Laura will then recap the Company's R&D progress. And Glenn will review Intellia's financial results for the quarter. John will close with final remarks. And then, we will open the call for Q&A. With that, let me turn the call over to our CEO. John?

Dr. John Leonard, CEO

Thank you, Ian, and good morning, everyone. Following the landmark clinical data earlier this year, demonstrating the first systemically delivered CRISPR-based therapy in patients, our team at Intellia has remained intently focused on advancing our full spectrum pipeline, and building upon our industry-leading scientific capabilities to realize the full potential of CRISPR-based medicines. Our modular platform deploys differentiated solutions for both in vivo and ex vivo therapeutic applications. For genetic diseases, our in vivo approach leverages our proprietary owned fee-based platform for systemic gene editing. Our ex vivo approach is designed to produce homogeneous robust cell products that epitomize the patient's natural immune system for the treatment of cancer and autoimmune diseases. We've generated a robust pipeline that continues to grow, and now includes multiple clinical candidates and an expansive research stage portfolio to fuel future opportunities. And today, we're pleased to share an update on recent progress against our core strategic priorities for this year and look forward to upcoming catalysts. Our lead program, NTLA-2001, for the treatment of transthyretin amyloidosis or ATTR amyloidosis, we've made important progress in establishing the dose response relationship in our first-in-human study. Notably, we began dosing patients in Cohort 4 earlier in the quarter at a 0.7 mg/kg dose level and believe we are closing in on identifying the recommended dose to move forward into Part 2. We remain highly encouraged for the safety profile, consistency of TTR reduction and the ongoing effect of NTLA-2001 thus far in the Phase 1 study. Additionally, while this has long been our plan to develop NTLA-2001 for all forms of ATTR amyloidosis, we're accelerating the evaluation of NTLA-2001 in patients whose primary clinical manifestation is cardiomyopathy. Based on the strength of our interim data presented in June, we're happy to share that we intend to include patients with cardiomyopathy in our current Phase 1 study. This could leapfrog what would have been a separate study, and as a result, we believe will produce the necessary information we see in this patient population earlier. As compared to patients with polyneuropathy, cardiomyopathy represents the larger opportunities in terms of patient numbers, level of unmet need and commercial potential. We're excited to begin evaluating NTLA-2001 in patients with cardiomyopathy as quickly as possible, once we received regulatory approval. We continue to believe NTLA-2001 has the potential to dramatically transform the future treatment landscape. In terms of next steps, we plan to present interim data from all four cohorts from Part 1 in Q1 of 2022 at a company-hosted event. Taking this approach allows us to provide a comprehensive dataset from Part 1, which will include safety and serum TTR knockdown for cohorts, 3 and 4, as well as meaningful extended observation across all four cohorts. It lays the foundation for next steps, which includes selecting a recommended dose for Part 2 of the trial and beginning dosing in patients with cardiomyopathy. Our decision to slightly adjust the timings to present the interim data reflects our commitment to the principles we've established from the beginning, which is to present data when we've accumulated a robust body of information. We also plan to initiate Part 2, a single dose expansion cohort in the first quarter of next year. Beyond NTLA-2001, we've made tremendous progress across our full spectrum pipeline. First, we received regulatory clearance to advance our second in vivo knockout candidate, NTLA-2002, for hereditary angioedema or HAE, into first-in-human studies. This is a significant step forward, improving our platform modularity for treating a variety of genetic diseases that originate in the liver with our non-viral delivery technology. Second, now that we've clinically validated our ability to safely inactivate a gene in the liver, we're committed to moving ahead with our targeted insertion approach. If successful, this will unlock treatment for a whole new category of diseases that require restoring a missing or defective protein. In the past quarter, we nominated two in vivo gene insertion development candidates. This includes our first and wholly-owned gene insertion candidate, NTLA-3001 for alpha-1 antitrypsin deficiency or AATD, and as a result of our co-development efforts with Regeneron, we have nominated a Factor 9 gene insertion development candidate for hemophilia B. In both programs, we've demonstrated our ability to durably restore a functional protein to normal human levels in non-human primates. These results, if reproducible in humans, highlight the promise of CRISPR-mediated gene insertion in solving key limitations of traditional gene therapy. Third, we made equally substantial progress on our ex vivo pipeline with the FDA’s approval of IND for NTLA-5001 for the treatment of acute myeloid leukemia, or AML. This pipeline development was further enhanced with the presentation of new preclinical data, highlighting our proprietary LNP-based cell engineering process and novel allogeneic solution at last month's ESGCT Annual Congress. These technology enhancements provide us the opportunity to shape the landscape of next-generation cell-based therapies. In summary, the third quarter has been incredibly productive for Intellia as we continue to advance our leading genome editing pipeline. In the coming weeks, we will have three programs in clinical development and look forward to sharing interim clinical data from our lead program, NTLA-2001 in Q1 of 2022. With that introduction, I'll now hand over the call to our Chief Medical Officer, David Lebwohl, who will provide an update on our progress for NTLA-2001 and other programs entering the clinic.

Dr. David Lebwohl, Chief Medical Officer

Thanks, John, and welcome everyone. Our lead candidate, NTLA-2001 is the first systemically delivered CRISPR-based therapy to be dosed in patients and a potentially curative treatment for ATTR amyloidosis. NTLA-2001 applies our in vivo LNP delivery technology to knock out the TTR gene in the liver, which is a source of circulating TTR protein, thereby permanently reducing amyloid deposition after a single dose. We shared landmark interim data from the first two dose cohorts of Part 1 of the ongoing Phase 1 trial of NTLA-2001 earlier this year. These positive results not only support NTLA-2001’s therapeutic potential as a one-time treatment for ATTR amyloidosis but also offered a proof-of-concept for our non-viral delivery platform. These data demonstrated an encouraging safety profile and dose-dependent reduction in serum TTR. At 0.3 milligram per kilogram dose level, we achieved an average TTR reduction of 87% among the three patients at day 28, exceeding current standard of care for patients with polyneuropathy. During the third quarter, we began dosing patients in Cohort 4 at the 0.7 milligrams per kilogram dose level, as we continue to evaluate the dose response relationship of NTLA-2001. As John noted, we remain very encouraged by the safety and activity profile of NTLA-2001 thus far. To date, we've not observed concerning safety signals from any cohort. Once we select the recommended dose, we expect to initiate Part 2, a single dose expansion cohort to further characterize the activity of NTLA-2001. This includes an assessment of clinical measures of neuropathy and neurologic function. Furthermore, based on the interim clinical data and continued confidence in this program, we are accelerating the evaluation of NTLA-2001 for the treatment of patients that ATTR amyloidosis with cardiomyopathy. Currently, the only approved drug for patients with cardiomyopathy is ATTR stabilizer, which slows disease progression but does not address its underlying cause. We believe NTLA-2001 has the potential to treat all forms of the disease since it targets both the wild type and mutant TTR gene. The Company is intending to expand the population to include patients with cardiomyopathy. If approved, this expansion accelerates gaining clinical data in patients with cardiomyopathy and expedites our path to registrational trial. We plan to present interim data from all four cohorts of Part 1, including safety and serum TTR knockdown for Cohorts 3 and 4, as well as an early look at durability across all cohorts in the first quarter of 2022. Additionally, we also expect to initiate Part 2 of the study in the first quarter of 2022. Finally, we were pleased to share that in October, NTLA-2001 was granted orphan drug designation by the FDA for ATTR amyloidosis. Given the modularity of our platform, we have accelerated development of additional in vivo programs targeting the liver, such as NTLA-2002, and we believe with increased probability of technical success. NTLA-2002, our wholly owned candidate in the development for HAE leverages the same LNP delivery system as NTLA-2001, but targets the KLKB1 gene in the liver to permanently reduce plasma kallikrein protein. This approach is intended to provide continuous suppression of kallikrein activity, as we've demonstrated in our preclinical work, which we anticipate will eliminate HAE attacks. In October, we received authorization of our clinical trial application from both, the UK and New Zealand regulatory authorities to initiate our Phase 1/2 study of NTLA-2002. The study will evaluate safety, tolerability and activity, including levels of kallikrein knockdown in adults with Type 1 or Type 2 HAE. As previously guided, we expect to enroll the first patients by year-end. Our lead ex vivo program, NTLA-5001, a potential best-in-class engineered T cell therapy for AML leverages our TCR-based approach. With this approach, we target intracellular antigens not accessible by CAR-T. NTLA-5001, an autologous T-cell therapy targets the Wilms' Tumor 1 intracellular antigen, which is overexpressed in more than 90% of AML patients regardless of mutation subtype. Despite recent therapeutic advances, delivering improved response rates in subsets of AML, long-term outcomes continue to be poor with overall five-year survival below 30%. Between our proprietary cell engineering process, which Laura will speak to in a moment, and the frequent expression of WT1 on AML cells, we believe NTLA-5001 will be a highly active and well-tolerated agent to improve outcomes for patients with AML. In September, we announced that the FDA accepted our IND application for NTLA-5001. We remain on track to begin screening patients by year-end for a Phase 1/2a study evaluating NTLA-5001 for safety, tolerability, cell kinetics and antitumor activity in adults who have detectable AML after having received standard first-line therapy. I'll now turn over the call to our Chief Scientific Officer, Laura Sepp-Lorenzino to provide updates on our platform and R&D efforts.

Dr. Laura Sepp-Lorenzino, Chief Scientific Officer

Thanks, David. I’ll start with some of our recent advances with our in vivo pipeline. As John noted, we're excited today to introduce our newest wholly-owned development candidate NTLA-3001 being developed as a potentially curative treatment for AATD associated lung disease. NTLA-3001 is designed to insert a functional copy of the SERPINA1 gene, which encodes the alpha-1 protein with the potential to permanently restore functional protein after a single dose. We believe this will dramatically advance the treatment of alpha-1 deficiency and eliminate the need for sub-optimal weekly IV infusions of augmentation therapy or transplant in severe cases. At ESGCT, Intellia presented data showing that the insertion of SERPINA1 led to normal levels of human alpha-1 protein in non-human primates which were durable through one year in an ongoing study. The Company is advancing towards IND-enabling activities for NTLA-3001. In addition, in collaboration with Regeneron, we have also just nominated a Factor 9 gene insertion development candidate for hemophilia B. With these two new insertion nominations, we're continuing to deliver against the ambitious goals we set out at the beginning of the year. Further, we believe our CRISPR-based gene insertion platform represents a potential best-in-class modality for permanently restoring high levels of therapeutic protein. If successful, we could revolutionize gene replacement therapy and open the opportunity to intervene early in the patient's life across a host of genetic diseases. Moving on to additional developments, at ESGCT, we shared important preclinical data featuring the benefits of our LNP-based sequential CRISPR cell engineering platform that avoids the use of electroporation. Commonly used electroporations have several limitations that we face for product development. Beyond the well-recognized cytotoxicity of the procedure, electroporation also introduces random DNA base alterations contributing to genotoxicity. If multiple edits are required, these edits, if introduced simultaneously, further contribute to unintended translocations and structural variants. In contrast, our proprietary process utilizes LNP-based delivery for highly efficient sequential editing of cells for ex vivo applications. As presented for T-cells, our platform allows efficient sequential editing knockouts and insertions, leading to a high yield of cell product with desired characteristics and functional performance while minimizing the risk for genotoxicity. We believe our platform solution will translate to meaningful advantages in terms of hosting, cell genetics, persistence and ultimately efficacy for ex vivo therapies. Additionally, for the first time, we presented data on our allogeneic cell engineering platform that can be deployed for TCR-T and CAR-T therapies. By utilizing our approach, we're able to address these three immunological requirements for allogeneic therapy, not currently addressed by alternative approaches in clinical development. Our allogeneic approach is designed to not only avoid graft versus host diseases, and graft elimination by hosts CD8 and CD4 T-cells, but also to avoid rejection by host natural killer or NK cells without the need for host immune-suppression. Data presented at ESGCT clearly demonstrated T-cell performance, including efficient editing rates, robust expansion, persistence against NK mediated killing in vivo and no impairment in the tumor-killing ability in vitro and in vivo mouse models. We look forward to nominating our first allogeneic development candidate by the first half of next year. Outside our wholly owned efforts, our partnering strategy includes 11 pipeline options outside our core areas of focus, and as you see, novel technologies. These strategies reflected in our previous announcements to form a new company, along with Blackstone Life Sciences and Cellex, focused on developing allogeneic universal CAR-T therapies. And more recently, we also announced our collaboration with SparingVision, a genomic medicines company to develop another CRISPR-based treatment for ocular diseases using viral and non-viral delivery strategies. With that, I will hand the call to Glenn, our CFO, who will provide an overview of our third quarter financial results.

Glenn Goddard, Chief Financial Officer

Thank you, Laura, and good morning. Intellia is in a strong financial position as we aggressively advance and extend our pipeline. Our cash, cash equivalents and marketable securities were approximately $1.1 billion as of September 30, 2021, compared to $597.4 million as of December 31, 2020. The increase was mainly driven by net proceeds of $648.3 million from our July follow-on offering, $45.3 million of net proceeds from the Company's ATM agreement, $40.8 million in proceeds from employee-based stock plans, and $4.2 million from Regeneron cost-sharing. These increases were offset in part by cash used to fund operations of approximately $187.3 million. Our collaboration revenue decreased by $15 million to $7.2 million during the third quarter of 2021 compared to $22.2 million during the third quarter of 2020. The decrease was driven by $15.3 million of revenue recognized for our one-time catch-up adjustment related to the amendment and expansion of our Regeneron collaboration in Q2 of last year. Our R&D expenses increased by $20.7 million to $60.5 million during the third quarter of 2021 compared to $39.8 million during the third quarter of 2020. This increase was mainly driven by the advancement of our lead programs and the expansion of the R&D organization to support these programs. Our G&A expenses increased by $8.1 million to $18.7 million during the third quarter of 2021 compared to $10.6 million during the third quarter of 2020. This increase was mainly due to employee-related expenses, including stock-based compensation of $3.8 million. Finally, we expect our current cash balance to fund our operating plans beyond the next 24 months. With that, I will turn the call back over to John for closing remarks.

Dr. John Leonard, CEO

Thank you, Glenn. In summary, our team at Intellia continues to execute across the pipeline and platform as we move into the fourth quarter and beyond. We look forward to sharing an interim update from a Phase 1 study at a Company-hosted event in Q1 of 2022 with additional details to follow. In the coming weeks, we plan to initiate our first-in-human studies for NTLA-2001 and NTLA-5001, as well as advance the first insertion candidate, NTLA-3001, towards IND-enabling activities. As we approach 2022, we look forward to updating you on new programs as we continue to leverage our industry-leading genome editing platform. With that, we'll conclude our prepared remarks. Operator, you may now open the call for questions.

Operator, Operator

We will now begin the question-and-answer session. The first question comes from Maury Raycroft with Jefferies. Please go ahead.

Maury Raycroft, Analyst

Hi. Good morning, everyone. Congrats on the quarter. And thanks for taking my questions. For the plans to accelerate that clinical development in the cardiomyopathy patients, can you say if you collected cardiac exploratory biomarkers for many patients that have been dosed so far, and is this change supported by those biomarkers?

Dr. John Leonard, CEO

David? First of all, good morning, Maury. Nice to hear your voice. David, do you want to touch on that?

Dr. David Lebwohl, Chief Medical Officer

In the current study, we are focusing on patients who mainly exhibit symptoms of polyneuropathy without significant signs of cardiomyopathy. Nevertheless, we are aware that some patients may experience amyloid infiltration in their hearts. We are collecting MRIs for this, but the timeframe for that analysis extends beyond the schedule for starting the amendment for cardiomyopathy. Our approach is based on the understanding that a reduction of TTR is closely linked to symptom improvement, which is our main objective as we move forward.

Maury Raycroft, Analyst

Okay, makes sense. And also wondering if you can provide more specifics on what protocol changes will be made to include the cardiomyopathy patients. How many patients will you enroll? And can you talk more about the cardiomyopathy profile you aim to enroll? I guess, will you select for a certain NT-proBNP range?

Dr. David Lebwohl, Chief Medical Officer

We're not going to talk about the details right now. But we have said we do expect, based on the biology that the dosing will be the same in these patients. As you know, we've had a very good safety profile so far. So, we also expect that to go well in patients with cardiomyopathy. But the details of that will be coming out later.

Operator, Operator

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

Joon Lee, Analyst

Regarding your dosing for the ATTR program, does the fact that you're dosing down for Cohort 4 imply that you have already achieved 90% to 95% TTR knockdown, as you had hoped, in Cohort 3? Can you share anything about durability from Cohort 2 so far? And any plans to re-dose Cohort 1 patients? Thank you.

Dr. John Leonard, CEO

I would wait until we share the full complement of information in Q1, as we said. I think then, you'll get a chance to see exactly what we're looking at. And you'll see why we're excited. And I’d just remind you that the purpose of the study has been to explore the dose response curve, which we think just addresses good quality drug development, knowing the safety and efficacy profile with each respective dose, so that as we move forward, we can feel confident about how the drug is likely to perform in the set of patients, et cetera. With respect to re-dosing, I think we'll talk more about that as we go forward. But, as we said from the outset, once we establish what we consider to be the optimal biological dose, we'll make that available for patients who did not receive it.

Joon Lee, Analyst

Just a quick question on 3001 for AATD, where are you targeting for the insertion of the wild-type gene? Is that endogenous SERPINA1 locus to achieve the dual purpose of knock-in and knock-out, or are you targeting a different region? I'm just curious, because you mentioned it as a sequential editing, but it seems like you can achieve that with the single shot approach. Just if you can provide any expectation or color?

Dr. John Leonard, CEO

Let me turn to Laura. Laura, you want to just give a little more detail in terms of what genes you're targeting with the gene insertion?

Dr. Laura Sepp-Lorenzino, Chief Scientific Officer

Sure, yes. So, for NTLA-3001, we are inserting in the albumin locus following the same platform approach that we're taking for Factor 9, the other development candidate that has recently been nominated. So, we have for both programs demonstrated that. With this approach we can achieve normal levels of both proteins and the ability to carefully select doses that will allow us...

Operator, Operator

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

Rick Bienkowski, Analyst

Hey. Good morning. This is Rick on the line from Mani. Congrats on all the progress. Just two quick questions from us. So, first, could you maybe expand on the follow-up data we'll see for the earlier cohorts of the NTLA-2001 patients in the interim readout? And, I do understand that the durability implies, you'll be looking at serum TTR levels. But, if you could just expand on what other metrics will be evaluated here to get a read on longer-term safety and durability, that would be helpful. And second, how should we think about the pace of the dose escalation for the cardiomyopathy cohort? Do you anticipate that you could potentially start one of the mid doses evaluated in polyneuropathy, or will the full dose escalation need to be repeated here?

Dr. John Leonard, CEO

David, do you want to address Rick’s question?

Dr. David Lebwohl, Chief Medical Officer

The main focus for the long-term analysis includes two key aspects. We need to carefully consider safety, which is integrated into the trial. The primary measurement regarding activity will be the TTR levels, which we have found to be correlated with the benefits we anticipate for patients. Regarding the second question about dose escalation, we believe we can utilize the information gained from patients with polyneuropathy to adjust the doses we test in patients with cardiomyopathy.

Operator, Operator

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

Unidentified Analyst, Analyst

Hey. Good morning. This is Matt on for Salveen. Congrats on the quarter. Just a couple of questions. Could you remind us what the expectations are for the additional ATTR data? And then, separately, could you also share your thoughts on translocation risk observed recently for a gene editing company and the differentiation of Intellia's approach? Thank you.

Dr. John Leonard, CEO

So, why don't we start with Laura? Do you want to speak about how we think about translocations and how we avoid them with our approach? And then, we can turn to the other question, David, that will go to you.

Dr. Laura Sepp-Lorenzino, Chief Scientific Officer

Yes. And thank you, Matt, for the question. So, at Intellia, whatever the programs are in vivo or ex vivo, the approach for safety starts at the beginning, selecting guides that will not have any detectable validated off-targets at multiples of the intended pharmacological dose. So, that's a given and that's what applies throughout all of our programs. I think that the recent data you're referring to, for ex vivo, right? So, there are a number of differences that differentiates what's going on from that program, starting with careful selection of the guides, the mode of introducing the CRISPR machinery. In our case, we have a proprietary method that we described at ESGCT, looking at sequential editing, using an LNP-based method. And that minimizes any potential for translocations or other structural variants. This is different from what others are using, whether they're using multiplex or that one's using electroporation, just by having multiple editing events at once, that leads to translocations. And in addition, we’re different in electroporation, that by itself, even in the absence of gene editing machinery, with studying CRISPR leads to significant levels from breaks that are random. And that can contribute to structural variants and translocations that we are avoiding.

Dr. John Leonard, CEO

David, do you want to take the first question?

Dr. David Lebwohl, Chief Medical Officer

Yes. Thank you. So, what we've said is that we now have patients treated at both 1 milligram per kilogram and 0.7 milligrams per kilogram. So, with this next release, we'll be able to talk to you about really the whole range of dose escalation, as well as the follow-up on the patients. And certainly, just to get early follow-up on the higher doses, we'll be able to do that in a couple of months. That will also allow us to talk about the dose of Part 2, which we’ll be starting in the first quarter. So, you'll get a really pretty complete picture of where we are with the study.

Operator, Operator

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

Xiaobin Gao, Analyst

Hi. This is Xiaobin on for Gena. Thanks for taking our questions. Maybe two, one on NTLA-2001 and one on NTLA-2002. For the ATTR program, it's just down from 1 milligram per kilogram to 0.7. Could you elaborate more on whether that was driven primarily by efficacy or by safety reasons? And the HAE, question is on for the patient's characteristics, the baseline, do you have any criteria on their background attack rates and do you need to maybe implement running phase, to collect data or by patients reporting? Thanks.

Dr. John Leonard, CEO

Thank you for the question. Let me begin with NTLA-2001, and David will discuss NTLA-2002. Our approach to the study has focused on establishing the relationship between dose and response, where response is primarily measured by TTR reductions. As we presented in June, we observed significant reductions in TTR with the second dose. We aimed to explore higher doses to better understand the drug's performance and potential for additional TTR knockdown. We have conducted this work and are now interpreting data from Cohort 4. We believe we are nearing our plans for the future. The drug has performed very well in terms of efficacy, as indicated by TTR, and has a favorable safety profile. It is crucial to accurately establish this relationship, as it will inform all subsequent studies. In February, we will share the specifics of our approach and our goals as we move forward with the program. While we aim to present this in February, we cannot commit to a specific timeline at this moment. David, would you like to address the HAE aspect?

Dr. David Lebwohl, Chief Medical Officer

Yes. Thank you. You'll begin to see the details of the HAE study when the trial starts, although they may not be available very soon. The key baseline characteristics include the attack rate, which will be collected as patients enter the trial. Additionally, kallikrein levels will be monitored. This provides both a biomarker and a clinical effect to track, offering a bit more than what we have with TTR. That’s the plan.

Xiaobin Gao, Analyst

Maybe just a quick follow-up, so for the NTLA-2001 trial, would you also report any reduction in the attack rates when you present the data?

Dr. David Lebwohl, Chief Medical Officer

Yes, we will be monitoring the attack rate after treatment as well. Although it is not one of the main endpoints, we will be collecting that data.

Dr. John Leonard, CEO

Yes. I’d characterize it as descriptive more than anything else. These early stages, Xiaobin, it's hard to get the precision of the measurements that we'd be looking forward that you get across a larger population. But, of course, we'll be looking at that, but it's not a major determinant of the study.

Operator, Operator

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

Luca Issi, Analyst

I have two, one on NTLA-2001, the one on hemophilia B. So, in TTR, wondering if you have shared the data with FDA yet, again, wondering if you can comment on what is gating to file an IND in the U.S.? And then, for hemophilia B, obviously, few companies are in the space, I think uniQure is going to file next year, Pfizer's Phase 3, Freeline also is in the clinic. Can you just remind us sort of the key differentiating factors of your approach versus others?

Dr. John Leonard, CEO

So, with respect to regulatory interactions, that's something that we don't want to characterize at this point in time. And as we have a more complete picture, we'll share that when we think it's pertinent. With respect to hemophilia B, and more broadly, I would say, with respect to gene insertion, which we relate to gene therapy, we think that there's very significant advantages to the approach that we're advancing here. So, step back and remember what gene therapy is. Typically, what you're trying to do is deliver a transgene, often in form of a virus, which persists in the cell for some period of time as an episome, in dividing cells that can be lost and it can be lost even in non-dividing cells. So, the durability of that effect, it seems and seems to be corroborated by some clinical data that's been emerging is incomplete. I mean, it doesn't appear to be lifelong. So, when we think about the advantage that we can bring, particularly the disease like hemophilia, which manifests in childhood, a permanent insertion that one hopes normalizes, or very, very significantly improves on existing therapy that a child can grow up with, represents a very significant advantage, we think over the episome approach that just is not ideally suited for that patient population. And as we know, in hemophilia, a lot of the damage occurs in youngsters, and that is lifelong. So, we're excited about having that kind of an outcome. And that's the endgame for a program like this. And, again, we're starting in the early stages here, but that's the destination.

Operator, Operator

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

Liisa Bayko, Analyst

Hi, there. Thanks for taking the question. Just based on some follow-up work we've done with KOLs and such, I wanted to get a sense of how you're thinking about the level of TTR knockdown that you're trying to achieve. And I know you're exploring different doses. So, it's kind of a relevant question here. Some of the feedback has been that obviously there's a function for wild-type TTR that may be important over the longer term, and sort of the balance between knocking it down and keeping some potential wild-type of TTR available. So, maybe you could comment on that, how you're thinking about it? Thank you.

Dr. John Leonard, CEO

Sure. This is something we've considered from the beginning. As you can imagine, we carefully analyze other programs to see if we can gain insights from the data they collect over time. To our knowledge, there have been no reports related to TTR knockdown. It's important to note that no one, including us, has reduced TTR to zero. We don’t believe that’s possible since some TTR is produced outside the liver. As we observe the field and learn more about TTR's functions, we believe that any potential risk, if it exists, is minimal. Additionally, the primary role of the protein is to transport vitamin A, and all patients are supplemented with vitamin A as we move forward. With each passing month, we become increasingly confident that this risk is truly minimal.

Operator, Operator

The next question comes from Yanan Zhu with Wells Fargo. Please go ahead.

Yanan Zhu, Analyst

So, first question, it seems like you have further accelerated the cardiomyopathy program. I know you have always intended to move quickly on that program, but it appears the schedule has moved up even more. I’m curious if any information from the polyneuropathy study has influenced this acceleration. Additionally, do you expect any differences in TTR reduction between cardiomyopathy patients and polyneuropathy patients? Thanks.

Dr. John Leonard, CEO

The second question is related to the first because we believe there is no biological reason for cardiomyopathy patients to respond differently to TTR. The data we presented in June excited us about advancing the cardiomyopathy program more rapidly. David and his team have explored alternative strategies to achieve this. The options range from initiating a new study, which involves significant administrative work, to integrating patients directly into the ongoing study. We opted for the latter, as you mentioned. This approach allows us to gather data more quickly and build on what we already know. We hope this prepares us for the next crucial phase of larger studies that will hopefully lead to drug approval.

Yanan Zhu, Analyst

I have two additional questions. First, regarding the translocation for ex vivo therapy, how much reduction do you anticipate the sequential editing approach will achieve? Also, how much reduction do you believe the LNP approach will contribute to minimizing translocation? My second question pertains to the hemophilia program. Have you assessed hemophilia A, given that you and Regeneron are evaluating it, and what prompted the focus on hemophilia B at this time?

Dr. John Leonard, CEO

Yes. Let me address the second question first. With Regeneron, we are collaborating on both hemophilia A and B. You may have seen data we've presented for hemophilia B for some time now, and that program gained momentum ahead of some of our other projects, although they are closely related. We are not ready to share data and timelines for hemophilia A yet, but it remains a top priority for us. The work on hemophilia B lays the groundwork that will be relevant to the hemophilia A program. Regarding our proprietary approach to cell transduction, I'll let Laura discuss the quantitative aspects of the different elements of the approach. I want to emphasize that our methodology focuses on fundamental principles, aiming to understand the underlying mechanisms rather than relying on assumptions about what is currently regarded as the standard practice. Laura and her team have done an excellent job revisiting these basics and analyzing what is often accepted without question concerning translocations, regardless of the editing technique being utilized. By maintaining an open mind and demonstrating creativity, we believe we are making significant advancements over the conventional methods used throughout the field. Now, Laura, could you elaborate on how much of the translocation reduction is attributable to LNP as opposed to gentler techniques like electroporation versus sequential methods?

Dr. Laura Sepp-Lorenzino, Chief Scientific Officer

Yes. We have shared most recently at ESGCT actual data that we'll be happy to share with you, you will have access to, and really comparing electroporation versus our sequential methods versus untreated cells. And we minimize any translocations on target translocations significantly. The data we shared, it's one log lower as compared to electroporation and basically distinguishable from unedited cells. Happy to discuss that more offline.

Operator, Operator

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

Dae Gon Ha, Analyst

I guess, just delving into NTLA-2001, for the first part of the question, and then circling back on hemophilia plan. So, with regards to NTLA-2001, the two words I've heard repeatedly from your team has been between depth and consistency. So, to what degree is your decision to pursue Cohort 4, the 0.7 mg reflective of depth or consistency? And I guess, if we think about the timeline in 1Q with both, Part 1 update as well as initiation of Part 2, I guess what additional information are you hoping to derive from Cohort 4 before making that decision into Part 2? And then, with regards to hemophilia, recognizing Regeneron, and you guys are both juggling hem B and hem A, but just wanted to get your thoughts around is this reflective of maybe the underlying biology of the endothelial expression versus hepatocyte expression, and how that might be perhaps interfering with long-term durability? Thanks so much.

Dr. John Leonard, CEO

With respect to NTLA-2001, those words obviously apply as we look at the data. To the extent that determines what we do is something that we'll share more when we present a more complete data set here in the first quarter. And you can see exactly what we're looking at and why we make the decisions we make. I don't know, Laura, if you want to speak to the hemophilia question in terms of where the gene is expressed, and why hem B versus hem A for, go forward?

Dr. Laura Sepp-Lorenzino, Chief Scientific Officer

Yes, to address your question, it relates to the attack rate and the larger gene that is expressed in endothelial cells, which has been linked to stretch during expression and delivery. One key aspect of our approach is that we aim to introduce a copy of the gene into the chromosome in a stable manner. This means we don't require the over-expression or excessive delivery of multiple episomal copies, which can lead to inappropriate expression and potentially cause toxicity. This distinguishes our strategy from traditional AAV gene therapies that we are exploring. Regarding your question about why we chose hemophilia B first, I would recommend reaching out to Regeneron for more details, as they are leading both programs with us and are making progress on both fronts.

Operator, Operator

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

Timur Ivannikov, Analyst

Yes, hi, this is Timur Ivannikov on for Steve Seedhouse. And so, this question was sort of asked, but just to clarify further, in terms of the data in Q1 '22, I'm not sure I saw a description of functional endpoints to be disclosed. And they are listed day 168 and day 365, which seems to be achievable for patients in Cohorts 1 and 2. So, can you just talk about why the functional endpoints would or would not be available, especially with respect to endpoint?

Dr. John Leonard, CEO

David, do you want to speak to that?

Dr. David Lebwohl, Chief Medical Officer

Yes, thank you. As you can imagine, there may be data for Cohorts 1 and possibly 2. However, Cohort 1 received inadequate results because they didn't achieve a significant enough reduction in TTR to be relevant for those endpoints. We believe the most critical range is from 0.3 to 1.0. We do consider TTR to be very important, and it's been mentioned several times regarding the depth of TTR reduction. The 87% reduction we observed at 0.3 exceeds the average standard-of-care benchmark of 80%. Furthermore, all our patients demonstrated an 80% or greater reduction, while half of those receiving standard care exhibited a lesser TTR reduction. We believe this will be crucial for achieving consistent reductions, which we anticipate will lead to observable outcomes.

Operator, Operator

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

Jay Olson, Analyst

Could you talk about how the excitement surrounding the initial clinical data for NTLA-2001 may have influenced the pace of enrollment at existing clinical sites? And then, if you plan any geographic expansion into additional study sites?

Dr. David Lebwohl, Chief Medical Officer

We have noticed an extraordinary interest coming from the investigators as well as patients calling into those investigators. So, it's been very helpful to the study. And in fact, we don't need additional sites, based on what's been happening at the sites already. So, we're really in good shape in terms of enrollment of the trial.

Dr. John Leonard, CEO

And then, for NTLA-3001, can you comment on the doses you're considering in the Phase 1 study? And should we expect that clinical trial to be conducted initially at ex-U.S. study sites?

Operator, Operator

Keep going, David.

Dr. David Lebwohl, Chief Medical Officer

Yes. So, this is in clinicaltrials.gov at this point. So, there are two populations that we have, patients with minimal residual disease, so less than 5% blasts; and then patients who have full relapse which is considered as greater than 5% blasts. Otherwise, the trial design is fairly standard for oncology trial, 3 plus 3 design, at various doses. But there are some more details now available for you.

Operator, Operator

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

Ian Karp, SVP of Investor Relations and Corporate Communications

Great. Thanks so much, Drew. And thank you all for joining us today and for your continued interest and support in Intellia. And we look forward to updating you on our progress in the future. Have a great day, everyone.

Operator, Operator

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.