Good morning. My name is Andrew and I will be your conference operator today and welcome to the Intellia Therapeutics Fourth Quarter 2020 Earnings Conference Call. [Operator Instructions] At this time, I would like to turn it over to Josh Rappaport, Managing Director at Stern Investor Relations. Please go ahead..

Thank you, operator. Good morning, everyone and welcome to Intellia’s fourth quarter and full year 2020 earnings call. Earlier today, Intellia issued a press release outlining the company’s progress this quarter and the topics for discussion on today’s call.

This release can be found on the Investors and Media section of Intellia’s website at intelliatx.com. This call is being broadcast live and a replay will also be archived on the company’s website.

Before we get started, I would like to remind you that during this call, Intellia management may make certain forward-looking statements and ask that you refer to 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 today’s call from Intellia are Dr. John Leonard, Chief Executive Officer; Dr. David Lebwohl; Chief Medical Officer; Dr.

Laura Sepp-Lorenzino, Chief Scientist Officer; and Glenn Goddard, Chief Financial Officer.

For today’s call, John will begin by discussing the company’s highlights, David will provide an update on clinical efforts with NTLA-2001, Laura will recap the company’s R&D progress, and Glenn will review financial results from the fourth quarter and full year 2020. Following their prepared remarks, we will open the call up for Q&A.

With that, let me turn the call over to John..

Thank you, Josh and thank you all for joining us this morning. This is an exciting time to be in the genomics field. There has never been greater appreciation for the revolutionary applications of gene editing technologies in medicine and beyond.

We at Intellia are proud to be at the forefront of this movement, developing curative genome editing treatments to transform the lives of people with severe disease. Our leading CRISPR/Cas9-based platform supports a full spectrum strategy, which deploys differentiated modular solutions across in vivo and ex vivo therapeutic applications.

For genetic disease, we utilize our in vivo approach, which leverages a lipid nanoparticle-based delivery system to selectively knockout disease-causing genes or precisely insert genes to produce normal proteins.

Our ex vivo T-cell receptor or TCR-based approach is designed to produce a homogeneous robust cell product that epitomizes a patient’s own natural immune system to eliminate cancer cells. Across these efforts, we have generated a broad pipeline, including emerging clinical candidates and an expansive research stage portfolio.

2020 was a landmark year for our team. We submitted our first clinical trial application and shortly thereafter, dosed the first patient in our global Phase 1 study for NTLA-2001. It’s the first systemically-delivered CRISPR-based therapy to enter clinical development.

This was a tremendous milestone for Intellia from the gene-editing field and for patients with genetic disease.

In addition, we advanced IND-enabling activities for our next two development candidates, NTLA-5001, our first engineered TCR T-cell therapy and NTLA-2002, our second in vivo knockout candidate, which nicely demonstrates the modularity of our platform.

We built on our Nobel prizewinning scientific foundation, broadened our platform capabilities and further differentiate Intellia’s solutions for gene editing, delivery and cell engineering. And we strengthened our corporate position with the expansion of our Regeneron collaboration and significant support from both new and existing investors.

Today’s call is an opportunity not only to reflect on these achievements, but also to review our key priorities and anticipated milestones for this year. Our top three priorities are demonstrating clinical validation of our approach with NTLA-2001, advancing and expanding our plan; and continuing to build our platform capabilities.

This year, we will continue the evaluation of the clinical profile of NTLA-2001 that we began last year both as a potentially curative treatment option for ATTR patients and as validation of our non-viral approach to in vivo delivery.

In addition, we will continue to advance and expand our pipeline with first-in-human regulatory submissions planned for NTLA-5001 and NTLA-2002 and we also expect to nominate at least one new development candidate. Finally, we will continue building a complete gene editing toolbox to enable the next wave of pipeline candidates.

At our founding, we have set out to develop modular platform components that could serve as the engine powering and expansive portfolio of curative therapeutics. Our progress since has paved a rapid and reproducible development path, both in vivo and ex vivo, that should play out in additional programs moving forward.

In anticipation of first-in-human data this year and as our investment in R&D matures into a broad pipeline of clinical candidates, we are building for long-term growth and remain steadfast in our commitment to unlock genome editing’s full therapeutic potential.

With that, let me turn the call over to our Chief Medical Officer, David Lebwohl, who will provide an update on our progress in the clinic with NTLA-2001.

David?.

Thank you, John and good morning everyone. I will start with a bit of background. Transthyretin amyloidosis, or ATTR, is a progressive and fatal disease, followed by the buildup of TTR protein in multiple organs.

People living with the disease can have either the hereditary or wild-type form of ATTR, which results in diverse disease manifestations, most frequently, polyneuropathy and cardiomyopathy. Globally, there are an estimated 50,000 people with hereditary ATTR and between 200,000 and 500,000 with wild-type ATTR.

NTLA-2001, our investigational therapy for the treatment of all manifestations of ATTR, applies our in vivo approach to knockout the TTR gene in the liver, which is the source of circulating wild-type ATTR protein.

Although there are two chronic therapies for this condition, there remains significant unmet medical need in this population as patients are at best stabilized and not cured of the underlying condition.

Leading investigators in the field are enthusiastic to bring a potentially curative treatment to their patients and may tell us 2001 will deliver meaningful value to both patients and our healthcare system.

Our robust preclinical data showing deep and long-lasting TTR reduction support 2001 potential as a one-and-done treatment to halt and possibly reverse disease progression.

Following authorization to initiate our Phase 1 trial with the UK’s clearance of our CTA in October, we dosed the first patient in this study in November, marking our transition into a clinical stage company.

We continue to enroll patients across sites in the United Kingdom and New Zealand and are submitting additional clinical trial applications in other countries as part of our ongoing global development strategy.

As a reminder, this is a two-part open-label multi-center Phase 1 trial that is designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of 2001 in adult patients with hereditary ATTR with polyneuropathy. We will enroll up to 38 patients who each receive a single dose of 2001 to an intravenous infusion.

Part 1 is a single-ascending dose study with up to 4 cohorts, following a traditional 3 plus 3 design and aimed at identifying the optimal biologically active dose.

Then we plan to quickly move into the second part, which will be a single dose expansion cohort of 8 additional patients to characterize further the activity of 2001, including an initial assessment on clinical measures of neuropathy and neurologic function and obtain additional safety data at the optimal biologically active dose.

This trial design includes the measurement of serum TTR levels, a key biomarker of the disease. We expect to share interim results from Part 1 of this study at a scientific or medical meeting this year.

The results from the initial doses in the trial will give us a preliminary view of the safety and activity profile of the drug as the study progresses. Importantly, we believe our interim results will establish clinical proof-of-concept for our modular LNP delivery platform.

In addition, we expect this data to represent an important milestone towards identifying the optimal biological dose for 2001. Once we have evaluated safety and identify the optimal biologically-active dose, we plan to run studies assessing 2001 and ATTR patients with polyneuropathy and with cardiomyopathy.

In the cardiomyopathy patient population, we expect to be able to start at the optimal dose identified in our Phase 1 study in polyneuropathy patients as we anticipate the editing activity will be the same across these different disease manifestations.

Before passing the call off, I want to acknowledge the momentous achievement in dosing our first patient with 2001. We look forward to sharing our first glimpse into clinical data later this year.

Now, I will turn this over to our Chief Scientific Officer, Laura Sepp-Lorenzino, for updates on our two additional development candidates, 2002 and 5001 and across our R&D efforts..

Thanks, David. I will begin with our second in vivo knockout candidate, NTLA-2002, in development for the treatment of hereditary angioedema, or HAE. HAE patients experience recurrent, unpredictable and painful swelling in multiple tissues. While there are acute and prophylactic therapies for HAE, [indiscernible] patients remain significant.

We believe there is additional opportunity for a therapy that not only further reduces frequency and intensity of attacks, but which can prevent and eliminate them altogether. NTLA-2002 is designed to knockout the KLKB-1 gene in the liver, leveraging the same LNP delivery system used for NTLA-2001.

We will be sharing clinical results from this program this week at the American Academy of Allergy, Asthma & Immunology Annual Meeting, confirming greater reductions in serum kallikrein protein levels and activity in non-human primates versus the current standard of care for HAE.

In addition, the data will capture durability of this effect, sustained so far through 15 months following a single dose in an ongoing non-human primate study.

We also confirm the therapeutic hypothesis in a humanized KLKB-1 mouse model of bradykinin-mediated vascular permeability, where a single administration of NTLA-2002 resulted in robust KLKB-1 gene editing, subsequent reductions in total test in kallikrein and prevention of captopril-induced vascular leakage.

It’s translatable to patients we expect NTLA-2002 could effectively free patients from a lifetime of disease and its debilitating symptoms by permanently reducing kallikrein levels after a single course of treatment.

We commenced GMP manufacturing activities and remain on track to submit a regulatory application to begin clinical trials for NTLA-2002 in the second half of this year.

To my earlier point, we are leveraging insights from NTLA-2001 and therefore anticipate being able to start NTLA-2002 at the higher dose for our first-in-human study, which we expect will evaluate safety, tolerability and measures of activity, including levels of kallikrein model arm.

Turning now to our ex vivo efforts, here we are using CRISPR/Cas9 as a tool to create engineered cell therapies.

Similar to our efforts to in vivo, our proprietary approach to cell engineering underpins a modular platform with versatility to mix and match across cell type, targeted modality and ability to introduce the edits necessary for eliciting the pharmacology.

Regardless of solution, we can achieve highly-efficient sequential editing, high yields, open and full performance and scalable manufacturing. Our lead program, NTLA-5001, employs a TCR-based approach. We have shared great deal of data differentiating our process to precisely edit and replace the patient’s T-cell receptors with tumor targeting TCR.

This process reduces safety risk and should translate to potency and function versus other technologies for multiplex editing. NTLA-5001 is targeting WT1 and we have initially developed to treat AML.

Despite recent therapeutic advances delivering improved response rates in subsets of AML, long-term outcomes continue to recur with overall 5-year survival below 30%. And if you recall, WT1 is over-expressed in over 90% of AML patients regardless of SAT types.

So, our hope is a period advantages of our proprietary cell engineering process with this broken prevalent target, NTLA-5001 will be a well generated solution capable of improving long-term outcomes for patients across all mutational subtypes and forms of AML.

Core to this approach is to ensure patients receive a high-quality robust product that mimics natural T-cells and enhances their natural immune response.

At the American Society of Hematology Annual Meeting in December, we shared additional preclinical data showing NTLA-5001 produced high anti-tumor activity in proof-of-concept mouse models of acute leukemia. The data also showed factor expansion and superior function compared to T-cells engineered with standard gene editing process.

We continue to make steady progress with IND-enabling activities and we are on track to submit an IND or equivalent for NTLA-5001 midyear. Our first human clinical trial is expected to evaluate the safety and activity of NTLA-5001 in patients with persistent or recurrent AML who have previously received first-line therapy.

Moving now to our research programs and platform advances, across our wholly-owned and partner efforts, we are developing new specific candidates for genetic diseases and next generation engineered cell therapies for cancer. The versatility of our platform enables full spectrum approach allows us to move quickly with pipeline expansion.

And as John noted, we plan to nominate at least [indiscernible] candidate this year. Further, we have broader applications of our technology leveraging this modular toolbox. Within our in vivo work, we are pursuing research efforts across multiple liver targets, including for targeted transgene insertion.

In December, we presented a second nonhuman primate proof-of-concept study, building off our work with Factor IX for hemophilia B. Insertion of the SERPINA1 gene into the albumin locus produce normal levels of circulating human alpha-1 antitrypsin, or AAT after a single administration.

This is an important demonstration further differentiating our approach through insertion, which we are advancing against both wholly-owned and partnered targets.

Additionally, in November, we received a grant from the Bill & Melinda Gates Foundation to explore in vivo genome editing of hematopoietic stem cells as a potential cure for sickle cell disease. Importantly, this sets the stage for a mixed wave of in vivo genome editing, enabling us to treat diseases across multiple tissue types.

Ex vivo, we are evaluating potential use of the same NTLA-5001 contract to treat WT1-positive solid tumors in the clinical studies and we are working towards some allogeneic solution for the development of off-the-shelf T-cell therapies.

In developing our cellular therapies, we believe it is important to optimize for cell health and function, but it’s only in response with targeted reinforcements against resistant cancers and to ensure the engineered cells are not rejected.

Enhanced T-cell products with the cell characteristics should yield additional benefits for patients, improved safety and efficacy. Finally, we continue to expand the genome editing tools at our disposal, supporting the optionality to apply the most appropriate tool for a given therapeutic application.

We look forward to sharing more details in the coming year as we plan to present at scientific conferences across all these efforts. And with that, I would like now to hand over the call to Glenn, who will provide an overview of our fourth quarter and full year 2020 financial results..

Thank you, Laura and good morning. Intellia is well-positioned for our upcoming milestones. Our cash, cash equivalents and marketable securities were $597.4 million as of December 31, 2020 compared to $284.5 million as of December 31, 2019.

The increase was mainly driven by net proceeds of $346.1 million from external financing activities, $100 million from the expanded Regeneron collaboration and $31.4 million from our Regeneron and Novartis collaborations, offset in part by cash used to fund operations of $164.6 million.

Our collaboration revenue decreased by $4.3 million to $6.6 million during the fourth quarter of 2020 compared to $10.9 million during the fourth quarter of 2019. The decrease was mainly driven by a decrease in Novartis revenue as the resource portion of the collaboration ended in December of 2019.

Our R&D expenses increased by $6.5 million to $38.2 million during the fourth quarter of 2020 compared to $31.7 million during the fourth quarter of 2019. This increase was mainly driven by the advancement of our lead programs, research personnel growth to support these programs, and the expansion of the development organization.

Our G&A expenses increased by $1.8 million to $10.8 million during the fourth quarter of 2020 compared to $9 million during the fourth quarter of 2019. This increase was mainly due to employee-related expenses, including stock-based compensation of $1.3 million.

Finally, we expect our current cash balance to fund our operating plans for at least the next 24 months. And now, I will turn the call back over to John to briefly summarize our upcoming milestones..

Thanks, Glenn and to David and Laura as well for your updates. As you can see, there is a lot going on here at Intellia. Coming off of productive 2020 in which we dosed the first patient with a systemically-delivered CRISPR therapy and advanced our portfolio, we are poised to carry this momentum forward in 2021.

We are progressing our Phase 1 study of NTLA-2001 and look forward to sharing the interim results later this year for clinical validation of our platform. Across wholly-owned and partnered efforts, we continue to progress our pipeline.

This includes first-in-human regulatory submissions anticipated midyear for NTLA-5001 and in the second half of this year for NTLA-2002 as we advanced our research stage portfolio towards the clinic.

And we will further differentiate our capabilities with new platform innovations across multiple in vivo targets in the liver, in vivo editing of other tissues and an allogeneic approach enabling next-generation engineered cell therapies as we continue to expand our genome editing toolkit for research and therapeutic development.

As we keep focused on these core priorities for 2021, we are committed to making genome editing’s promise a reality for patients. We will now open the line to any questions.

Operator?.

[Operator Instructions] The first question comes from Salveen Richter with Goldman Sachs. Please go ahead..

Hi, thank you so much for taking our questions. This is Sonia on for Salveen.

Laura, could you talk a little bit about the AAP asset in terms of the knockdown and what the benchmark will be? Will you have to match the RNAi knockdowns or would you need to show something higher? And then also, when can we expect additional data through the year? Are there particular conferences that you are targeting? Thank you..

Sonia thanks and good morning, it’s John. We have always paid very, very careful attention to the other products that are out there as they provide really important benchmarks and goalposts for the work that we are doing.

And as we do our initial Phase 1 study here, which is progressing as we have said, we have in mind 80% or thereabouts as a benchmark, which we think is competitive, but the aspiration is to exceed that.

The way we think about that particular program and amyloidosis in general is that certainly advances have been made and we think that’s really wonderful for amyloidosis patients, but there is more to get and it’s really in the form of additional improved outcomes, there is we think unmet medical need in the form of efficacy that’s yet to get, so if we can not just delay the progression of disease, but actually reverse it, which we think comes with reductions beyond 80%, that’s very much what we are going to look for.

With respect to data this year, the study is underway. And as we accumulate that, we will look for medical conferences that will be appropriate venues to share that, but at this point, we can’t guide to any particular one..

Alright, thank you.

I think I was asking more about the alpha-1 antitrypsin assets in terms of, I guess, the other [indiscernible] assets, etcetera?.

I am sorry I misheard your question. The beta we presented thus far has been not a knockdown data, which maybe is the basis of the confusion here. We have presented insertion data that shows production of the normal human protein.

And that work has demonstrated that not only can we get production of that normal human protein, but we get it at normal human levels. And so as we look at the benchmarks that are out there, we are all ready well beyond anything that’s therapeutically available to patients, including replacement therapy.

So, from that standpoint of replacement therapy, we think we are in a wonderful position. The approach we are taking does not directly address production of the abnormal protein and that’s separate from the work that we are currently doing..

Thanks.

And will we see any additional data through the year from that program?.

There is a good possibility we will have more to share as the year goes on, but we are not guiding to any particular release at this point..

Okay, thank you so much..

The next question comes from Maury Raycroft of Jefferies. Please go ahead..

Hi, good morning and congrats on the progress and thanks for taking my questions. First question is on ATTR, just wondering if you can provide anymore specifics on where you are at with enrollment and dosing? I guess are you still at the first dose level.

And are there specific reasons why you now have clarity and confidence into providing data in 2021?.

Thank you for the question. We appreciate it. As you know, we started enrolling November of last year and things have progressed pretty much as per plan.

We are not sharing progression by patients or by cohort group, but where we have taken a position that as we get a body of clinical data that we think is meaningful and representative that that’s what we would choose to disclose.

So, I think what you should take is that we are moving forward and we have laid out that study plan and we look forward to sharing it when we have more complete story developed..

Got it. That makes sense.

And John, you mentioned 80% or greater knockdown for ATTR, I guess should we expect that degree of knockdown in the initial emerging data or I guess how many cohorts of data will we see in the initial data? And the right way to think about that is that, that should provide a line of sight into getting to that 80% or greater optimal knockdown?.

Yes. Thanks again. I – really I am not going to be in a good position to give you clarity with respect to outcomes per cohort, which is somewhat implicit in your question, Maury. The way we set the program up in the first place is that each of these different cohorts has some reasonable likelihood of having a therapeutic effect.

And as you know, this is the first time we have moved from preclinical work into human.

So, some of this is a good time to validate the thinking and the modeling that we have done, but each of the different doses that was chosen was done with the intention of seeing an effect and that effect will – the optimal biological effect is something that we will determine as we escalate across the different cohorts.

So – but we have something that we think is meaningful and that is readily interpretable, that’s what we’ll share, and we would expect that, that will be while the study is still taking place..

Got it. And so the initial update should give us a level or a line of sight into the trajectory of the knockdown that you are getting with each dose.

Is that fair?.

The sort of data that we would anticipate sharing with you would be a dose and a TTR effect and, of course, the safety that goes with that. With respect to extrapolating what subsequent doses will be, I think we can speculate together on that, but you would certainly be in a position to see what we’ve achieved at a given particular dose..

Got it. Okay. And maybe last quick question just on the regulatory applications being submitted, so just wondering if you can say if you submitted a U.S.

IND? And will you provide an update 1Q or 2Q on whether some of the additional regulatory applications are accepted or should we just keep an eye on clinical trials back out?.

So we haven’t shared yet exactly which regulatory filings we’ll have for the programs are subsequent to the TTR program. As those are cleared, we’ll definitely share that information with you..

Got it. Okay, thank you for taking my questions..

Of course..

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

Hey, good morning. This is Rick on the line for Mani. Thanks for taking my questions. For my first question, there was an earlier comment about submitting clinical trial applications for the TTR program in additional countries as a part of the global development strategy. I was hoping maybe you could just expand on the strategy a bit.

We were wondering how many countries the study might eventually extend into? And how many clinical sites you anticipate you might need in order to complete the Phase 1 study?.

Yes. So currently, we’re conducting the study in both the UK and New Zealand. We have a couple other applications that were progressing. Whether or not we will actually activate them to finish the Phase 1 study is something that’s a matter of discussion. And as the study unfolds, we’ll share that with you.

But we believe that, as currently structured, we are positioned to conduct the Phase 1 study and get the information that we need. We’re always interested in expanding the regulatory network because the program, ultimately, from let’s say program broadly, Phase 1 and beyond, certainly will be broad-based and global.

We have had multiple regulatory interactions as we played the basis for the advancement of the program..

Got it. Thanks. My second question was just focused more on forward-looking financials and how we should think about R&D spend in 2021, I understand in the ‘21 is currently in the clinic and two additional INDs are expected by year-end.

So I guess we’re wondering if we should expect a steady increase in R&D spend throughout the year or if changes in R&D spend might be more lumpy as the company hits specific milestones quarter-to-quarter?.

Yes. So let’s turn to our CFO.

Glenn, do you want to take that, please?.

Sure. Yes. We – as you noted, as we noted in the call, we have a very strong cash position as of the end of the year. We’ve guided that, that will get us through at least the next 24 months. We’re not giving specific kind of year-by-year OpEx guidance out, but I think it is fair to assume that the R&D operating expenses will drift up over time.

We don’t expect it to be lumpy. I think it will be similar to the trend you saw going from 2019 into 2020. You could expect a similar trend going into next year..

Great. That’s really helpful. Just want to congratulate you guys on all the progress and thank you for taking the questions, again..

Thank you..

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

Hi, good morning. This is Romit on for Gena.

So one clarification question, for the cardiomyopathy patients that you plan to enroll in the TTR trial, would that be included in the Part 2 in the 8 patients or is that the plan of the larger pivoting study?.

Yes, I will take that. That’s – the way you should think about this is we have a Phase 1 study that is patients with predominantly polyneuropathy. There are patients, as you know, there’s a mixed phenotype that has some degree of cardiomyopathy, although that’s not the predominant manifestation in this first-in-human study.

We will not be mixing patients with predominantly cardiomyopathy into the first-in-human study. But as David said in his comments, we believe that the optimal biological dose that we are planning will be readily applicable to cardiomyopathy patients, which we would address in a subsequent study..

Okay. And then just a follow-up to that, can you tell us like what is your definition of optimal dose? So you have these four dose escalation part in the Part 1.

So what exactly would you be looking for? And what constitutes an optimal dose to move into the Part 2 of the trial?.

David, do you want to address how you are thinking about optimal biological dose?.

Yes. Thanks, John. The idea for optimum buybacks which has really two pieces, one, of course, it has to be a phased dose. So this is a Phase 1 study, we’re characterizing the safety carefully, and that will be important at whatever dose we choose to that.

But even – the big piece of this is what is the potential activity and ultimately, efficacy of the dose. And as we’ve talked about, we do want to get a deep reduction in TTR as we go forward because we think it can make a bigger difference for patients.

And what you saw in the non-human primate studies is a 95% reduction we think getting towards that range would be valuable to patients, and that’s – we’re looking for something between, of course, the 80% that’s now being paid with current therapy, but potentially getting to higher degrees of reduction..

Okay, got it. Thanks for the taking questions..

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

Yes. Hi, good morning. This is Timur Ivannikov on for Steve Seedhouse.

And so we have a question about Phase 1 ATTR study slightly different – asked slightly differently, but in terms of your procedure for reviewing data and assessing knockdown and other metrics? Could you talk about at what time points you take those measurements, NHP study that it looks like weakly? Is that sort of similar time line that you have for the human study? Thank you..

Yes. The – broadly, the assessments were laid out on clinictrials.gov where you can get a lot of these details.

But maybe, David, you could just summarize some of the articulation of the study so people can relate that to the preclinical work?.

I think an important measure in this is really TTR, which is measured by the gold standard of ELISA. And said it’s measured intermittently through the study, as you mentioned, but as you – what we see from preclinical models and what we expect in PPO as well, is that you reach the lower point at around 28 days.

So you really have a good idea by 28 days what the ultimate reduction will be. We will continue to follow it. And as you know, this is expected to be permanent based on all the work that we’ve done previously, but we will have a good idea of how the patients are doing in terms of TTR reduction at that early point..

Okay. Thank you for that. And then a follow-up question in terms of the mix polyneuropathy, cardiomyopathy phenotype. Are you doing anything differently for those patients in terms of monitoring and maybe in the future for cardiomyopathy patients? Will you be doing any different monitoring versus polyneuropathy? Thank you..

David, do you want to take on that?.

Got it, John. Yes. So these patients, we are doing some standard monitoring that’s done for patients with cardiomyopathy. It turns out that almost all patients do have involvement to the heart even it may not have a functional effect in these patients, so we will learn something about that in the early study.

And going forward to this next study dedicated to pay for patients with cardiomyopathy, we haven’t fully designed that, but we will give you more details as that design is being prepared..

Okay, great. Thank you very much for taking the questions..

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

Hi, thanks for taking our question.

In light of the weaker update from bluebird bio, remind us again, what gives you comfort that you won’t see any tensor signal 5 to 6 years down the road regarding off-target effects of CRISPR/Cas? And with regards to your partnership with Gates Foundation to develop in vivo approaches for sickle cell, is that triggered by safety concerns around preconditioning or just to broaden the scope of the therapeutic? I’m pretty sure it’s in the latter, but just wanted to make sure given the recent updates from bluebird bio.

Then I have a follow-on..

So thanks. It’s a really important question. But I don’t think the bluebird bio results really even relate to the work that we’re doing. Certainly, on the in vivo side, I would contrast two really important different approaches.

Number one is the nature of a precise editing as opposed to a lentivirus sort of random insertion, which is somewhat difficult to control with respect to where the gene lands and what happens thereafter. And I think we’re seeing possibly some of the outcomes that may come with that, but maybe just trying to sort that out.

And then secondly, the in vivo approach that we’re taking with our TTR and related other programs doesn’t utilize the conditioning regimen at all, so whatever other safety questions that are provoked by taking that type of chemotherapeutic approach doesn’t even apply to the in vivo sorts of things.

So when you turn to the ex vivo side of the equation for us, again, everything that we’ve done and Laura’s team has done, I think, a really wonderful job of controlling the process, demonstrating that genetic architectures preserved that the insertion goes exactly where we want it to go, so we feel really good about that.

And when you think about preparing those patients for receiving NTLA-5001, the conditioning regimen is just very different from what you see with the bone marrow transplant, so we feel really good about our approach.

Now with respect to the Gates Foundation, I think and increasingly, people looked at, I think, the wonderful opportunities there are to apply gene editing to diseases like sickle cell disease and thalassemia. And we’ve demonstrated as a field that, from an editing point of view, you can address the problem.

The challenge is exactly what we’re talking about here, which is all those patients with current therapy is required a bone marrow transplant.

And that brings with it, whatever consequences of – if you’re using an imprecise approach, the safety issues that come with that, but across all of the bone marrow transplant approaches, the conditioning regimen that is inherently morbid and sometimes springs with it mortality.

So we, as a company, from the standpoint of editing and delivery, believe that we can leapfrog the current approaches to bone marrow, capture the highly desirable outcomes that would come with gene editing and potentially avoid the bone marrow transplant all together.

And with that, we think you can bring genome editing to many, many thousands of patients with sickle cell disease, which we, again, believe current therapies are not going to be able to do..

Great. Thanks for the clarification. And on the follow-up question, is the new development candidate, A1AT program or hemophilia or something different altogether? You saw a lot of presentation on ESGCT it’s very impressive, just curious what we can look forward to on that front? Thank you..

Thanks. Well, we have a lot to choose from, and I think that’s the point that you’re making. We ask Laura to make sure that both sides of the company are advancing, both on the in vivo side and the ex vivo side, and we have very active programs there.

And as you point out, we have a very exciting relationship with Regeneron that’s moving forward as well. So the particular development candidate, we’re not going to point to just yet. But there’s at least one in that list, and we’re very, very excited about it and some of the others that we’re sorting through as we go.

So that’s one I would just stay tuned for. We will give you a little bit more clarity as we get further into the year..

Thank you..

[Operator Instructions] The next question comes from Jay Olson of Oppenheimer. Please go ahead..

This is Shawn on the line for Jay. Thanks for taking our question and congrats on the progress.

Just one more question on 2001, wondering, is there any key genome you’ll be monitoring for the clinical trial? And if like side effect arrives, how would you eke out is that a consequence of on target of target gene editing or it could be something else like the vector RNA? Thank you..

David, do you want to address that? What particular things are you monitoring for in this off-target even figure into the realm of the discussion at this point?.

Right. Thank you, John. Yes, in terms of off-target, we feel we’ve addressed this really with the program that we’ve done clinically. And we could – you’ll hear more about that as we move forward, how we do.

But this is a comprehensive, both in vitro and in vivo study, to establish that we are precisely editing the right target and knocking it out, but not affecting other genes. In the study itself, the main safety thing that we’re looking at is the immediate effects of lipid nanoparticles. A lipid nanoparticle was really pretty well characterized.

That is somewhat different and proprietary to what we’re doing, so we do want to understand its safety.

But based on the non-human primate studies, we do feel that we can get to the deep reductions of the 95% range reduction that we’re seeing in non-human primates with doses that would be tolerated in people because they were tolerated in the non-human primates as well..

And was there a follow-up? Okay, continuing the next question comes from Yanan Zhu with Wells Fargo. Please go ahead..

Hi, thanks for taking my questions. So first, maybe a couple of quick one on the TTR program, does the cadence of enrollment so far meet your internal expectations? And could you remind us whether repeat dosing is allowed by protocol? And if it is then at what time point can repeat dosing be considered? Thanks..

Yes. I can take that. Thanks. Yes, the study has been going well. We’ve been really quite satisfied and excited with the progress that we’ve made and the interactions that we’ve had with investigators who we think are just doing a phenomenal job, so that’s just been a really gratifying sort of thing to be involved with.

With respect to – I think, I forgot the second question, just repeat it. I want to make sure....

That’s it, repeat dosing..

Yes. Thank you. Yes. Repeat dosing like formally a part of this particular study across the program where we’re working on provisions so that if patients who came early into a study did not receive an optimal biological dose, there will be other means for those patients to receive that. So that’s something that we’re working on..

Got it. On the WT1 TCR program, could you talk about any consideration for whether following the IND in the U.S. or an equivalent outside the U.S.

just curious about what the thought process for determining where to file?.

Yes. So we’re not guiding yet to precisely where and what we’re filing, although we want to have a broad-based, ultimately, global program there. We’re confident that we’re going to be able to do that, and we’re confident that we’re going to be in a position to meet the requirements to get into the clinic this year, so that’s going very, very well.

There are complexities to the program, and we’re making sure that we have the most robust regulatory package possible. And we’ve had extensive regulatory interactions to prepare for that. And so we’re really in the final stages of completing those submissions and packages.

So stay tuned, and as those filings clear, we’ll show that information more broadly..

And lastly, maybe a question on the in vivo sickle cell approach collaborated with the Gate Foundation.

Just curious, what would be the delivery vehicle for that approach? Is it going to be non-viral? And if it is, then what kind of visibility do you have? The feasibility of a non-viral delivery approach to the bone marrow hematopoietic stem cells, do you have any initial data preclinical data there? Thanks..

Yes. Thanks. Yes, we believe that the in vivo approach in the end is the winning approach for patients with sickle cell. And as you know, from the origins of the company, we’ve emphasized non-viral delivery approaches. That may not address every single tissue in the body, but it can certainly address many of them, including the bone marrow.

So the emphasis of this program and the basis of the collaboration with the Gates Foundation is, in fact, non-viral delivery because they see the merits of that approach as do we. We’ve shared some preclinical information with them, which I think was the basis for their enthusiasm.

And as we make more progress, we’ll be in a position to share that more broadly with a more general audience..

Great. Thank you..

And the last questioner today will be Tony Butler with ROTH Capital Partners. Please go ahead..

Good morning. This is Tash on for Tony.

Just a follow-up question – well, a question about follow-up about the TTR program, can you tell us about the duration of, let’s say, safety for of the patient must undergo before your – those patients begin? And also any word on the long-term follow, please?.

Can I just make sure we understand the question? Are you talking about the safety evaluation before dose escalating? And then the ongoing safety characterization of a patient once dosed? I think that’s what you asked, is that correct?.

Just first – and the dose escalation is the throughout dose this one patient. And then I am assuming here that first patient in that in a specific dose cohort, they are going to be followed for a set amount of time could be something like 8 weeks, but I was hoping if you would be able to give us any details about that. That’s the first part..

Yes.

So David, do you want to give some general guidance with respect to how the protocol is?.

Yes, John. I said the main safety – again, looking for due to the lipid nanoparticle, so these are events that are, again, well-characterized in the past. And they occur in a short period of time. So our follow-up is relatively short, most of it within a few weeks that you could see.

So this does allow us to sort of the first – these different intervals for the different dose levels. But basically, it’s a typical the PIC design with a short look between each patient to make sure that, that does is safe..

Thank you for that.

And then after the first patient again specific dose cohort, what about the following two patients? Are you able to dose them simultaneously or do you have to wait to – for a sequential dosing in a specific cohort?.

In the initial call, we did wait, but in the subsequent cohorts, they can be dosed together..

Thank you.

And lastly, what about the long-term follow-up, do we have a window here, for example – well, for certain therapies that FDA requires patients deal for approximately 15 years, give or take, is there any such requirement?.

Yes, really around the world, that regulatory agencies are looking for, let’s say, a 15-year period. It’s not completely defined, but it’s in that range. So we will be having a planning a long-term follow-up..

And what about – well, lastly, yes, what about any possible shortening of this initial safety follow-up based on data generated from lower based cohorts? Do you envision having a shorter follow-up period in the subsequent higher doses at those cohorts?.

The period is short enough that it wouldn’t significantly affect the trial, so we are – no, we are going to go forward as we see..

Thank you very much. I am grateful for your time..

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

I’d like to thank all of our listeners today for their questions and for following us. We appreciate it. I wish you all a good day, and we can certainly follow-up offline as necessary. Thank you..

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