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..

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?.

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 freedom 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, it 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, plus as a result of our co-development efforts with Regeneron, where they are the lead party, we have dominated 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 and 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.

David?.

Thanks, John, and welcome everyone. Our lead candidate, 2001 is the first systemically delivered CRISPR-based therapy to be dosed in patients and a potentially curative treatment for ATTR amyloidosis.

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 2001 earlier this year.

These positive results not only support 2001’s therapeutic potential as a one-time treatment for a TTR 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 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 2, 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 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 2001 has the potential to treat all forms of the disease, since it targets both for 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, 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 liver, such as 2002, and we believe with increased probability of technical success.

2002, our wholly owned candidate in the development for HAE leverages the same LNP delivery system as 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 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 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. 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 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 5001.

We remain on track to begin screening patients by year-end for a Phase 1/2a study evaluating 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..

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 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 pre-clinical 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 contributing to genotoxicity. If multiple edits are required, these edits, if introduced simultaneously, further contribute to on and off translocation 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 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 that 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..

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..

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..

We will now begin the question-and-answer session. 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 that clinical development in the cardiomyopathy patients, can you say, if you collected cardiac exploratory biomarkers from -- for many patients that have been dosed so far, and is this change supported by those biomarkers?.

David? First of all, good morning, Maury. Nice to hear your voice.

David, do you want to touch on that?.

Yes. Hi. Yes. In the current study, as you know, this is patients who have predominantly -- have 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 do -- 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.

So, this is really based on our knowledge that reduction of TTR is strongly associated with improvement of symptoms. And that's what we want to see obviously going forward..

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?.

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..

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

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..

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..

Just a quick question on 3001 for ATT, 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?.

Let me turn to Laura.

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

Sure, yes. So, for 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 denominated. 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....

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

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 2001 patients in the interim readout? And, I do understand that the durability implies, you'll be looking at serum TCR 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?.

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

So, the main readout, the longer term readout are two things. Of course, we want to 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. And that's what we've learned. And actually we'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..

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

Hey. Good morning. This is Matt on for solving. 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..

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..

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 guys, 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 is a number of differences that differentiates what's going on from that program, starting with careful selection of the guys, 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 variance.

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..

David, do you want to take the first question?.

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..

The next question comes from Gena Wang with Barclays. .

Hi. This is Xiaobin on for Gena. Thanks for taking our questions. Maybe two, one on 2001 and one on 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..

Thanks for the question. So, let me start with 2001 and David can address 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.

And 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. So, 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.

So, we've done that work. We continue to now interpolate with Cohort 4 and we think we've -- as we've said, we think we're closing in on what we're going to want to do going forward.

So, the drug has performed in ways that we've been really very, very, very gratified by in terms of not only the efficacy, again, as determined by TTR, but also by safety profile. And so, this is the time to get that relationship right, because it lays the foundation for all subsequent studies going from where we are.

So, 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 our goal would be to do this in February, but we can't guide at this point, any specific point in time.

David, do you want to speak to HAE?.

Yes. Thanks. So, you'll start to see the details of the HAE study on -- when trial start -- may not quite be out very soon. But, the most important baseline characteristics are, as you mentioned, the attack rate. This will be obviously collected as we -- patients enter into the trial. And the other piece is kallikrein level.

So, you both have a biomarker in this case and a clinical effect that you can follow, giving a bit more than what we have with TTR in a way. So, that's the plan..

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?.

Yes. Obviously, we will be following the attack rate after treatment as well. So, whether that will be -- it's not really a prime, one of the primary endpoints but yes, we'll be collecting it..

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..

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

I have two, one on TTR, 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 fall next year, Pfizer's Phase 3, Freeline also is in clinic.

Can you just remind us sort of the key differentiating factors of your approach versus others?.

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..

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 TCR 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..

Sure. This is something we thought about from the outset. And as you might imagine, we look carefully across other programs to see if there's any insights that we can gain from data that they collect over time. And to our knowledge thus far, there's been no reports anywhere of any kind that relates 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’s produced outside the liver. And 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, we -- the primary function of the protein is to carry vitamin A, and as we know, this patients are all supplemented with vitamin A, as we proceed. And 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..

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

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? And also related to the question is that is whether -- TTR reduction, do you expect any difference in cardiomyopathy patients compared with polyneuropathy patients? Thanks..

Well, the second question airs 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.

So, David and his team has looked at the alternative ways to do that. And the range of choices there go from starting a new study and all of the administrative efforts that go with that, or looking for bring patients directly into the study that's ongoing. And 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. And one hope sets us up for that next really important phase of studies which will be larger studies that hopefully will move us in the direction getting the drug approved..

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? And how much reduction do you think the LNP approach brings to reducing translocation? And the other question is on the hemophilia program.

Wondering if you have evaluated hemophilia A that -- you and Regeneron have evaluated the hemophilia A, and what's the reason to move with hemophilia B currently?.

Yes. So, 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 got the jump, I would say, on some of the other work that we're doing, although they're highly related.

So, we're not giving data and timelines yet for hemophilia A. But rest assured, that's something of great interest to us. And obviously, hemophilia B sets us up for some foundational work that should apply to that program.

With respect to the proprietary approach to transducing cells, I'm going to let Laura speak to any quantitative aspects that one or the other elements of the approach can take.

But, 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 what represents the standard approach in any given point in time.

And 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.

And by being open minded and I think pretty creative that what we believe are very, very substantial improvements on, 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 kind of gentler than electroporation versus sequential, why don’t you take a shot at that?.

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 share, it's one log lower as compared to electroporation and basically distinguishable from unedited cells, happy to discuss that more offline..

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

I guess, just delving into 2001, for the first part of the question, and then circling back on hemophilia plan. So, with regards to 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..

With respect to 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?.

Yes. No, no, and what you're bringing it up forward hem A, right? So, it’s the attack rate, it’s larger gene expressed, endothelial cells, and it has been associated with stretch, right, when you -- for expression and deliver. I think that one of the differences -- and I should make sure that Regeneron is the -- program here.

So, I will point -- you should be asking them additional color on this. But for one of the benefits of our approach is that we're aiming to introduce a copy of the gene in the chromosome, right, in the genome stably.

And we don't need to have over-expression or over-delivery of multiple episomal copies, right, that would lead to inappropriate -- aggravated expression that could lead to toxicity. So, I think that's different from traditional AAV gene therapy that we're trying to explore here. And then, your other question was why hemophilia B first.

I think, again, I would point that question to Regeneron. Both programs -- they're leading both programs with us and progress we make for both..

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

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 and 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?.

David, do you want to speak to that?.

Yes. Thank you. So, as you can imagine, right, there may be data for Cohort 1 and maybe even Cohort 2. But of course, Cohort 1 got an inadequate, because they don't have enough of a reduction in TTR to be interesting for those endpoints. And really where we -- the most important range we think is from 0.3 to 1.0. We do think that TTR is very important.

It's been talked about couple of times about the depth of TTR reduction. What we saw at 0.3 with 87% reduction, so this is already greater than 80% average that seems the standard-of-care.

And if you think about that, and we also stated every patient has 80 or greater percent, while half the patients getting standard-of-care have a lesser degree of TTR. So, we think that's what's going to make the big difference for this -- getting to consistent reduction, we think we can see manifestation..

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

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

David, I'll invite you to respond that..

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 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..

And then, for 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?.

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 they come into more focus and we get further down the regulatory paths and lay out a protocol. We'll share the information as it solidifies. But at this point, that's pretty mature..

And the last question today will be from Silvan Tuerkcan with JMP Securities. Please go ahead..

Could you please tell us where you're at with the process for your TCR program, as you're moving into the clinic by year-end? And also will there be any modifications in the near-term to this process based on the data that you've presented at ESGCT with lipid nanoparticle transfection, or is that already incorporated perhaps? Thank you..

David, is that something you want to address?.

Yes. So, the process is set -- 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. So, that is going forward, as planned. It does incorporate the LNP process. So, we want to have the advantages of the LNP process in this manufacturing..

Okay. Thank you. And 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..

Yes. So, this is -- it 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..

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. And 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..