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. If anyone requires operator assistance during the conference, please press star then zero on your telephone keypad. I will now turn the conference over to Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.
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 Investor and the 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 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.
Thank you, Ian, and good morning, everyone. Following our 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 LNP-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. It now includes multiple clinical candidates and an expansive research stage portfolio to fuel future opportunities.
Today, we're pleased to share an update on recent progress against our core strategic priorities for this year and to look forward to upcoming catalysts. For 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 four earlier in the quarter at a 0.7 mg per kg dose level and believe we are closing in on identifying the recommended dose to move forward into part two. We remain highly encouraged by the safety profile, consistency of TTR reduction, and the ongoing effect of NTLA-2001 thus far in the phase I study. Additionally, while it 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 I study. This could leapfrog what would have been a separate study, and as a result, we believe will produce the necessary information we seek in this patient population earlier. As compared to patients with polyneuropathy, cardiomyopathy represents the larger opportunity 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 receive 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 one in Q1 of 2022 at a company-hosted event.
By taking this approach, it allows us to provide a comprehensive data set from part one, which will include safety and serum TTR knockdown for cohorts three and four, 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 two of the trial and beginning dosing in patients with cardiomyopathy. Our decision to slightly adjust the timing 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 two, 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. During 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.
Plus, as a result of our co-development efforts with Regeneron, where they are the lead party, we have nominated a factor IX 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 our 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 with NTLA-2001 and other programs entering the clinic. David?
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 the 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 one of the ongoing phase I 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 offer proof of concept for our non-viral delivery platform. These data demonstrated an encouraging safety profile and dose-dependent reduction in serum TTR.
At the 0.3 mg/kg 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 four at the 0.7 mg/kg dose level as we continue to evaluate the dose response relationship of 2001. As John noted, we remain very encouraged by the safety and activity profile of 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 two, a single-dose expansion cohort, to further characterize the activity of 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 with ATTR amyloidosis with cardiomyopathy. Currently, the only approved drug for patients with cardiomyopathy is a TTR 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 One, including safety and serum TTR knockdown for cohorts three and four. As well as an early look at durability across all cohorts in the first quarter of 2022. Additionally, we also expect to initiate part two 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 the 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 of 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 U.K. and New Zealand regulatory authorities to initiate our phase I/II study of NTLA-2002. The study will evaluate safety, tolerability, and activity, including levels of kallikrein knockdown in adults with type one or type two HAE. As previously guided, we expect to enroll the first patient 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 -Ts. 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 Sepp-Lorenzino 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 I/IIa 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 update on our platform and R&D efforts.
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 could dramatically advance the treatment of alpha-1 deficiency and eliminate the need for suboptimal 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 IX 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 share important preclinical data featuring the benefits of our LNP-based sequential CRISPR cell engineering platform that avoids the use of electroporation. Commonly used electroporation has several limitations that impair our product development.
Beyond the well-recognized cytotoxicity of the procedure, electroporation also introduces random DNA breaks contributing to genotoxicity. If multiple edits are required, these edits, if introduced simultaneously, further contribute to on- and off-target 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 high yield of a 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 safety, 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 the 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 disease and graft elimination by host CD8 and CD4 T cells, but also to avoid rejection by host natural killer, or NK cells, without the need for host immunosuppression. 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 their tumor killing ability in 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 enabling pipeline options outside our core areas of focus and accessing novel technologies.
This strategy is 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. More recently, we also announced our collaboration with SparingVision, a genomic medicines company, to develop novel CRISPR-based treatments 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.
Thank you, Laura, and good morning. Intellia is in a strong financial position as we aggressively advance and expand our pipeline. Our cash equivalents and marketable securities were approximately $1.1 billion as of September 30th, 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 an 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 - $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 a 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 - $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 in the expansion of the R&D organization to support these programs.
Our G&A expenses increased by $8.1 million - $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.
Thank you, Glenn. In summary, our team at Intellia continues to execute across our pipeline and platform as we move into the fourth quarter and beyond. We look forward to sharing an interim update from our phase I 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-2002 and NTLA-5001, as well as advance our 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.
We will now begin the question-and-answer session. To ask a question, you may press star then one on your touch tone phone. If your using speakerphone, please pick up your handset before pressing the key. To withdraw your question, please press star then two. At this time, we will pause momentarily to assemble our roster.
The first question comes from Maury Raycroft with Jefferies. Please go ahead.
Hi. Good morning, everyone. Congrats on the quarter, and thanks for taking my questions. For the plans to accelerate the clinical development in the cardiomyopathy patients, can you say if you collected cardiac exploratory biomarkers from any patients that have been dosed so far? Is this change supported by those biomarkers?
David. Well, first of all, good morning, Maury. Nice to hear your voice. David, do you wanna touch on that?
Yeah. Hi. Yeah, in the current study, as you know, this is patients who have predominantly the predominant symptoms of polyneuropathy, so that they don't have in general significant signs of cardiomyopathy. Even though that's true, we do know they can have infiltration of their heart with the amyloid, and we are collecting MRIs, but the time points to look at that are longer than the time points of getting this amendment started for cardiomyopathy. This is really based on our knowledge that reduction of TTR is strongly associated with improvement of symptoms, and that's what we wanna see, obviously, going forward.
Okay. Makes sense. I'm 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? Can you talk more about the cardiomyopathy profile you aim to enroll? I guess, will you select for a certain NT-proBNP range?
Maury, we'll let David lay that out. Yeah. Go ahead, David. That's. Keep going.
Sorry. Yeah. No, you're right. Yeah. No, we're not gonna 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 the patients with cardiomyopathy. But the details of that will be coming out later. Thanks, John. Yeah.
Okay. Thanks for taking my questions. I'll hop back in the queue.
The next question comes from Joon Lee with Truist Securities. Please go ahead.
Hi. Thanks for taking the question, and congrats on all the progress. Regarding your dosing for the ATTR program, does the fact that you're dosing down for cohort four imply that you have already achieved 90%-95% TTR knockdown as you had hoped in cohort three? Can you share anything about durability from cohort two so far, and any plans to read those cohort onw patients? Thank you.
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. You know, I 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, you know, 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 redosing, I think we'll talk more about that as we go forward.
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.
Just a quick question on NTLA-3001 for AAT. You know, where are you targeting for the insertion of the wild-type gene? Is that the endogenous SERPINA1 locus to achieve the dual purpose of knock-in and knockout, or are you targeting a different region? I'm just curious because you mentioned it as sequential editing, but it seems like you can achieve that with a single shot with the approach. Just if you can provide any additional color. Thank you.
Why don't we turn to Laura? Laura, you wanna give us a little more detail in terms of what gene you're targeting with the gene insertion?
Sure. Yeah. For NTLA-3001, we are inserting in the albumin locus, following the same, you know, platform approach that we're taking for factor IX, you know, the other development candidate that has recently been nominated. You know, we have for both programs, right, demonstrated that, you know, with this approach, we can achieve, you know, normal levels of both proteins and the ability to, you know, carefully select doses that will allow us to achieve that in patients.
Got it. Thank you.
The next question comes from Mani Foroohar with SVB Leerink. Please go ahead.
Hey, good morning. This is Rick on the line for 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? You know, I do understand that the durability implies you'll be looking at certain 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. Second, how should we think about the pace of the dose escalation for the cardiomyopathy cohort? Do you anticipate that you could potentially start at one of the mid doses evaluated in polyneuropathy, or will the full dose escalation need to be repeated here?
David, do you wanna address Rick's question?
Hi. The main readout, the longer term readout are two things. Of course, we wanna look carefully at the safety and that's part of built into the trial. But the main readout in terms of activity will be the TTR levels. That's what we'll learn. As you've seen, that is correlated with the benefit we expect to see in patients. For the patients with the second question was about oh, about dose escalation. No, we do think we can use the information we've learned in the patients with polyneuropathy to modify the doses that we study in patients with cardiomyopathy.
All right. Great. That's it from us. Thanks for taking our questions.
Thank you.
Thank you.
The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
Hey, good morning. This is Matt on for Salveen. Congrats on the quarter. Just a couple questions. Could you remind us what the expectations are for the additional ATTR data? 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.
Why don't we start with Laura? Do you wanna 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'll go to you.
Thank you, Matt, for the question. You know, at Intellia, whether the programs are in vivo or ex vivo, you know, the approach for safety starts at the beginning, selecting guide RNAs that will not have any detectable validated off targets at multiples of the intended pharmacological dose. Okay. That's a given, and that's what we apply throughout all of our programs. I think that the recent data you're referring to, for ex vivo, right? There is a number of differences that differentiates what we're doing from that program. You know, starting with, you know, careful selection of the guide RNAs.
The mode of introducing the CRISPR machinery, in our case, we have a proprietary method that we describe 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, where they're using multiplex all at once using electroporation. You know, just by having multiple editing events at once, you know, that leads to translocations. In addition to that, if you're using electroporation, that by itself, even in the absence of gene editing machinery, whether it's TALEN or CRISPR, leads to significant double-strand breaks that are random. Also, that can contribute to, you know, to structural variants and translocations that we are avoiding.
David, do you wanna take the first question?
Yeah. Thank you. What we've said is that we've now have patients treated at both 1 mg/kg and 0.7 mg/kg . 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. 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 Two, which will be starting in the first quarter. You'll get a really pretty complete picture of where we are with the study.
Great. Thank you very much.
The next question comes from Gina Wang with Barclays. Please go ahead.
Hi. This is Sheldon on for Gena. Thanks for taking our question. Maybe two, one on 2001 and one on 2002. For the ATTR program, you dosed down from 1 mg/kg- 0.7 mg/kg. Could you elaborate more on whether that was driven primarily by efficacy or by safety reasons? The HAE question is on, for the patient characteristics at baseline, do you have any criteria on their background attack rates? Do you need to maybe implement a run-in phase to collect those data or by patient reporting? Thanks.
Thanks for the question. Let me start with NTLA-2001, and David is gonna address NTLA-2002. The way we think about the study is, from the outset, it's been about establishing the relationship of dose and response, and response obviously is characterized by efficacy, which for the purposes of where we are in the program, is primarily measured by TTR reductions. As I think was clear from the data that we presented back in June, we were already at the second dose achieving pretty substantial reductions in TTR. We sought to further characterize higher doses just to make sure we had a good understanding of how the drug would perform and get some notion of what additional TTR knockdown there is to get. We've done that work.
We continue to now interpolate with cohort four, and we think we've, you know, as we said, we think we're closing in on what we're gonna wanna do going forward. The drug has performed in ways that we've been really very gratified by in terms of not only the efficacy, again, as determined by TTR, but also by the safety profile. This is the time to get that relationship right because it lays the foundation for all subsequent studies going on, you know, from where we are. You'll see in February exactly what we're looking at, and you'll understand what we're shooting for as we continue to advance the program.
I hasten to add that a goal would be to do this in February, but we can't guide at this point any specific point in time. David, do you wanna speak to HAE?
Yeah, thanks. We start. You know, you'll start to see the details of the HAE study on ClinicalTrials.gov. I think it may not quite be out, but very soon. The most important baseline characteristics are, as you mentioned, the attack rate. This will be filled, you know, obviously collected as patients enter into the trial. The other piece is kallikrein levels. You both have a biomarker in this case and a clinical effect that you can follow, giving us, you know, even a bit more than what we have with TTR in a way. That's the plan.
Yeah. Maybe just a quick follow-up. For the supplement to the trial, would you also report any reduction in attack rates when you present the data?
Yeah. You know, obviously we will be following the attack rate after treatment as well. You know, whether that will be, you know, it's not really one of the primary endpoints, but yeah, we'll be collecting it.
It would be yeah. I characterize it as descriptive more than anything else. You know, at these early stages, Sheldon, it's hard to get, you know, the precision of the measurements that we'd be looking for 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.
That's very helpful. Thank you so much.
The next question comes from Luca Issi with RBC. Please go ahead.
Oh, great. Thanks so much for taking my question. Congrats on all the progress. I have two, one on TTR, the other one on hemophilia B. On TTR, wondering if you have shared the data with the FDA yet. Again, wondering if you can comment on what is gating to file an IND in the U.S. Maybe for hemophilia B, obviously a few companies are right in the space. I think uniQure is gonna file next year. Pfizer's in phase III. Freeline also is in clinic. Can you just remind us what are the key differentiating factors of your approach versus others? Thanks so much.
With respect to regulatory interactions, that's something that we don't wanna characterize at this point in time. As we have a more complete picture, we'll share that when we think it's, you know, 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 some very significant advantages to the approach that we're advancing here. Step back and remember what gene therapy is. Typically, what you're trying to do is deliver a transgene, often in the form of a virus, which persists in a 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.
The durability of that effect, it seems, is corroborated by some clinical data that's been emerging, is incomplete. I mean, it doesn't appear to be lifelong. When we think about the advantage that we can bring, particularly to disease like hemophilia, which manifests in childhood, a permanent insertion that one hopes normalizes or very significantly improves on existing therapy that a child can grow up with represents a very significant advantage, we think, over, you know, the episomal approach that just is not ideally suited for that patient population. As we know, in hemophilia, a lot of the damage occurs in youngsters, and that is lifelong. We're excited about having that kind of an outcome, and that's the end game for a program like this.
Again, we're starting in the early stages here, but that's the destination.
Got it. Super helpful. Thanks, John.
Sure.
The next question comes from Liisa Bayko with Evercore ISI. Please go ahead.
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? I know you're exploring different doses, so it's kind of a relevant question here. You know, some of the feedback has been that obviously, you know, 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, you know, potential wild type TTR available. So maybe you could comment on that, how you're thinking about it? Thank you.
Sure. This is something we've thought about from the outset. As you might imagine, we look carefully across other programs to see if there's any insights that we can gain from, you know, data that they collect over time. To our knowledge, thus far, there's been no reports anywhere of any kind that relate to knockdown of TTR. I remind you that no one, including us, has knocked down TTR to zero. We don't think that's even possible because some TTR is produced outside the liver. You know, as we watch the space and as we understand more and more about how TTR functions, it's our belief that that risk, if it even is real, is remote at best.
By the way, you know, the primary function of the protein is to carry vitamin A, and as we know, these patients are all supplemented with vitamin A as we proceed. I think at this point, with each passing month across the field broadly, we get more and more confident that that risk is really remote.
Okay. Thank you.
Sure.
The next question comes from Yanan Zhu with Wells Fargo. Please go ahead.
Hi, thanks for taking my questions and congrats on the progress. So first question. It sounds like you have further accelerated the cardiomyopathy program. I know you have always planned to move quickly on that program, but seems like the schedule has been further moved up. Wondering if you have whether any information that you saw in the polyneuropathy study has informed this acceleration? Also related to the question is whether TTR reduction do you expect any difference in cardiomyopathy patients compared with polyneuropathy patients? Thanks.
Well, the second question bears on the first, right? Because we believe that there's no reason why, at a purely biological point of view, why cardiomyopathy patients should have a different TTR response. Given the data that we presented back in June, that made us very enthusiastic about moving forward more quickly with the cardiomyopathy program. David and his teams looked at alternative ways to do that. You know, the range of choices there, you know, go from starting a new study and all of the administrative efforts that go with that, or looking to bring patients directly into the study that's ongoing. We chose the latter for the reasons that you stated. We believe that that's a way of getting to the data faster and building on the information that we already have.
One hopes it sets us up for that next really important phase of studies, which will be, you know, larger studies that hopefully will move us in the direction of getting the drug approved.
Great. Maybe two additional questions, if I may. One, on the translocation for ex vivo therapy side, how much reduction do you think the sequential editing approach can bring? How much reduction do you think the LNP approach brings to reducing translocation? The other question is on the hemophilia programs, wondering if you and Regeneron have evaluated hemophilia A. What's the reason to move with hemophilia B as a first, you know, currently? Thanks.
Yeah. Let me do the second one first. With Regeneron, we're working on both hemophilia A and B. You will have seen data that we present for hemophilia B for some time now, and that program, you know, got the jump, I would say, on some of the other work that we're doing, although they're highly related. We're not giving data and timelines yet for hemophilia A, but rest assured, that's something of great interest to us. Obviously, hemophilia B sets us up to, for some, foundational work that should apply to that program. With respect to the proprietary approach to transducing cells, I'm gonna let Laura speak to any quantitative aspects that one or the other elements of the approach can take.
I would just start by saying that what we did and what we try to do with all the work that we did is just go back to basic principles and ask, "What's doing what?" Instead of making assumptions on, you know, what represents the standard approach at any given point in time. Laura and her team, I think, have just done a really nice job of going back to those basics and dissecting what many people accept from the outset, with respect to translocations, irrespective of whatever editing technique they're trying to bring. By being open-minded and I think pretty creative, they've made what we believe are very substantial improvements on, you know, what is the standard approach in the field that pretty much is used across all of the approaches that we're familiar with.
Now, Laura, maybe you can add a little more color on if you think with respect to translocations, how much of it is just LNP and kinder, gentler, you know, than electroporation versus sequential. Why don't you take a shot at that?
Yeah, no. We have shared most recently at ESGCT the actual data that we'll be happy to, you know, share with you if you don't have access to it. You know, really comparing electroporation versus our sequential methods and, you know, versus untreated cells. We minimize any off-target translocations, you know, significantly. You know, the data we share, it's you know, one log lower as compared to electroporation and basically indistinguishable from unedited cells. Happy to discuss that more offline.
Great, very helpful. Thank you.
The next question comes from Dae Gon Ha of BofA. Please go ahead.
Great. Good morning. Thanks for taking our questions, and congrats from me as well on all the progress. I guess just delving into NTLA-2001 for the first part of the question and then circling back on the hemophilia plans. With regards to NTLA-2001, the two words I've heard repeatedly from your team has been between depth and consistency. To what degree is your decision to pursue cohort four, the 0.7 mg, reflective of depth or consistency? And I guess if we think about the timeline in 1Q with both part one update as well as initiation of part two, I guess, what additional information are you hoping to derive from cohort four before making that decision into part two?
With regards to hemophilia, recognizing Regeneron and you guys are both juggling hemophilia B and hemophilia A, but just wanted to get your thought 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.
With respect to 2001, those words obviously apply as we look at the data. To the extent it determines what we do is something that we'll share more when we present the more complete data set here in the first quarter. 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?
Sure.
I think why hem B versus hem A. Go for it.
Yeah, no. What you're bringing it up for hemophilia A, right? It's, you know, the factor VIII is, you know, it's a larger gene. It's expressed in endothelial cells. It's, you know, and it has been associated with, you know, stress, right? When, you know, when you force expression in the liver. I think that, you know, one of the differences, and I should, you know, make sure that, you know, Regeneron is the program lead here. I would, you know, point that, you know, you should be asking them additional color on this. For, you know, one of the benefits of our approach is that we're aiming to introduce, you know, a copy of the gene, you know, in the chromosome, right? In the genome stably.
We don't need to have overexpression or over delivery of multiple episomal copies, right? That would lead to inappropriate, unregulated expression that could lead to toxicity. I think that's, you know, different from traditional AAV gene therapy that we're trying to exploit here. Your other question was why hemophilia B first? I think, again, you know, I would point that question to Regeneron. Both programs, you know, they're leading both programs as, you know, with us, and there is progress we make for both.
Great. Appreciate the color. Thanks for taking the question.
The next question comes from Steve Seedhouse with Raymond James. Please go ahead.
Yes, hi. This is Timur Ivannikov on for Steve Seedhouse. This question was sort of asked, but just to clarify further, in terms of the data in Q1 2022, I'm not sure I saw a description of functional endpoints to be disclosed, and they are listed at day 168 and day 365, which seem to be achievable for patients in cohorts one and two. Can you just talk about why the functional endpoints would or would not be available, especially with respect to mNIS+7 endpoint? Thank you.
David, do you wanna speak to that?
Yeah. No, thank you. As you can imagine, you're right. It may be data for cohort one and maybe even cohort two, but of course, cohort one got an inadequate dose. They just have, you know, they don't have enough of a reduction in TTR to be interesting for those endpoints. Really where we, you know, the most important range we think will be from 0.3 - 1.0, where we do think that TTR is very important. It's been talked about a couple of times about the depth of TTR reduction. What we saw at 0.3 was 87% reduction, so this is already greater than the 80% average that's seen with the standard of care.
If you think about that, what we also said is every patient had 80% or greater, while half the patients getting the standard of care have a lesser degree of TTR. We think that's what's gonna make the big difference for this drug. By getting to consistent TTR reduction, we think we can be able to benefit patients.
Okay. Thank you very much.
The next question comes from Jay Olson of Oppenheimer. Please go ahead.
Oh, hey. Congrats on the progress, and thank you for taking the questions. Can 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? If you plan any geographic expansion into additional study sites?
David, I'll invite you to respond to that.
Yeah.
Go for it.
Right at the positive. Thank you for that question. Yeah, no, there's been extraordinary interest coming from the investigators as well as patients, you know, calling into those investigators. So, it's been very helpful to the study. 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 to the trial.
Great. Thank you for that. For 3001, can you comment on the doses you're considering in the phase I study? Should we expect that clinical trial to be conducted initially at ex-U.S. study sites?
I think that's premature at this time. I would expect that we'll treat that exactly from a communication point of view as we've done the other programs. As you know, they come into more focus and we get further down the regulatory path and lay out a protocol, we'll share the information as it solidifies. At this point, that's premature.
Okay, great. Thanks for taking the questions.
Sure.
The last question today will be from Silvan Türkcan with JMP Securities. Please go ahead.
Hey, good morning, and thanks for taking my questions. Could you please tell us where you're at with the process for your TCR program as you're moving it into the clinic by year-end? Will there be any modifications in the near term to this process based on the data that you've presented at ESGCT with the lipid nanoparticle transfection? Or is that already incorporated, perhaps? Thank you.
David, is that something you wanna address?
Yeah. The process is set. You know, we've had an IND approved by the FDA, so they've obviously looked at what we plan to do in the study in terms of both manufacturing and the clinical study. That is going forward as planned. It does incorporate the LNP process, so we wanna have the advantages of the LNP process in this manufacturing.
Great. Thank you. Can you at this point tell us, I think you mentioned that the first patient will be screened by the end of the year. Can you characterize, kind of the trial design and the patient population at this point?
Keep going, David.
Yeah, this is in ClinicalTrials.gov at this point, right? There are two populations that we have, patients with minimal residual disease, so less than 5% blast, and then patients who have full relapse, which is considered as greater than 5% blast. Otherwise, the trial design is fairly standard for oncology trial, a 3 + 3 design at various doses. But there are some more details now available for you.
Great. Thank you very much.
This concludes our question-and-answer session. I would like to turn the conference back over to Ian Karp for closing remarks.
Great. Thanks so much, Drew, and thank you all for joining us today and for your continued interest and support in Intellia. We look forward to updating you on our progress in the future. Have a great day, everyone.
The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.