Intellia Therapeutics Inc

NASDAQ:NTLA

Earnings Call Transcript 2021-Q2

[Operator]

Good morning and welcome to the Intellia Therapeutics Second Quarter 2021 Financial Results Conference Call. My name is Jason and I will be your conference operator today. As a reminder, all participants are currently in listen-only mode. [Operator Instructions]

Following formal remarks, we will open the call up for questions. 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. I will now turn the conference over to Ian Karp Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please, proceed.

[Ian Karp]

Thank you, Operator, and good morning, everyone. Welcome to Intellia's Second 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 and Media section of Intellia's website at intelliatx.com. This call is being broadcast live and a replay will be archived on the company's website.

At this time, I 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 second quarter and recent business highlights; followed by David, who will provide an update on clinical efforts surrounding NTLA 2001; Laura will then recap the company's R&D progress; followed by Glenn, who will review Intellia's financial results for the quarter. John will then make some closing remarks and we'll open up the call for Q&A.

With that let me turn the call over to our CEO. John?

[John Leonard, Chief Executive Officer]

Thank you, Ian, and thank you all for joining us today. The past few months have been incredibly exciting for both Intellia, as well as for patients battling diseases that may be addressable with our genome editing therapies. Most notably, in June we became the first company to report clinical data for a systemically delivered CRISPR-based therapy in patients. This milestone represents a significant advance in our mission to develop curative genome editing treatments.

At Intellia, we've set out to build the broadest and deepest toolbox to fully-realize the promise of revolutionary CRISPR-based medicines. To that end, our platform deploys differentiated modular solutions across in vivo and ex vivo therapeutic applications of our Nobel prize-winning technology.

For genetic disease, we're leveraging a lipid nanoparticle or LNP-based delivery system to selectively inactivate disease causing genes or precisely insert genes to produce desired proteins. Our ex vivo approach is designed to produce a homogeneous robust cell product that epitomizes a patient's natural immune system to eliminate cancer cells. Across these efforts we've made significant progress advancing our full spectrum strategy since last quarter's call.

Our landmark data presented in June highlighted the interim clinical data from the first two cohorts of the dose escalation portion of our ongoing Phase 1 trial for NTLA-2001. These data indicate an encouraging safety profile and dose-dependent protein knockdown response. In the second dose level, treatment with NTLA-2001 in the three patients in the cohort led to a mean serum TTR reduction of 87% at day 28, with a maximum 96% production.

Notably, these results exceed the current standard of care for ATTR amyloidosis patients with polyneuropathy. At both dose levels, NTLA-2001 was generally well-tolerated by the six patients included in the interim analysis with no serious adverse events by day 28. We view this as a profoundly important outcome for patients, for Intellia, and for medicine.

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. It gives us added confidence to pursue other targets to treat diseases that originate in the liver via reproducible development path. More broadly, we believe these results open a new era in medicine in which curing genetic disease may be within reach. Shortly, David will elaborate more detail on the landmark data and next steps for this program.

Beyond the NTLA-2001 readout, NTLA-2002, our in vivo knockout candidate for hereditary angioedema or HAE and NTLA-5001, our lead-engineered TCR T cell therapy for acute myeloid leukemia or AML continue marching towards the clinic. In June, we shared that we submitted our first CTA for NTLA-2002 to regulatory authorities and we're pleased to announce this morning that we have submitted our first CTA for NTLA-5001 as well. Pending regulatory authorization, both first in human trials are on track to begin by the end of this year.

In addition, together with Cellex cell professionals in Blackstone Life Sciences, we launched a new Universal CAR T company. This new company combines Intellia's allogeneic cell engineering platform with a clinically-validated universal CAR T construct from GEMoaB. Additionally, this company which aims to develop differentiated immuno-oncology and autoimmune therapies is resourced with up to a $250 million financing commitment from Blackstone. In exchange for a license to our technology, Intellia will receive a significant equity stake of this new company along with two options to co-develop and co-commercialize two allogeneic Universal CAR T candidates in the U.S. and key European countries.

Collaborations like this one are a key instrument of our broader corporate strategy to enable us to realize the full scope and potential of our technology for patients. They can extend the reach of our technology beyond our core areas of strategic focus, while retaining rights across a diverse ex vivo landscape. In this collaboration brings the additional benefit of a concurrent manufacturing agreement with Cellex, which Laura will expand on a bit later.

Finally, before passing the call on, I'd like to extend a warm welcome two two ew members of our leadership team: Jim Basta, Executive Vice President and General Counsel; and Ian Karp, Senior Vice President of Investor Relations and Corporate Communications. We're thrilled to have them join Intellia and I have no doubt that their expertise and support will prove to be a great value as our company continues to mature.

I will now hand over the call to our Chief Medical Officer, David Lebwohl, who will recap our NTLA-2001 [ph] data and providing more in-depth update on our progress in the clinic. David?

[David Lebwohl, Chief Medical Officer]

Thank you, John. I'll start with a bit of background on ATTR amyloidosis and our approach with 2001. The ATTR amyloidosis is a rare, progressive and fatal disease caused by the buildup of TTR proteins in multiple organs. People living with the disease can have either the hereditary or wild-type form, resulting in a diverse range of disease manifestation, the most frequent being, polyneuropathy and cardiomyopathy.

Our lead candidate, 2001, is the first systemically delivered CRISPR-based therapy, dosed in the patient and a potentially curative state treatment for ATTR amyloidosis. 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, therefore permanently reducing amyloid deposition after a single dose.

Although the current standard of care has achieved meaningful therapeutic impact with roughly 80% knockdown of serum TTR, there remains unmet medical need in this population. Moreover, as Dr. Gilmore shared at our June Investor event, beyond the benefits of a one-time treatment as demonstrated in ATTR amyloidosis as well as other types of amyloidosis, greater TTR knockdown is anticipated to improve clinical outcomes.

We therefore believe a single-dose therapy that most importantly produces greater and durable TTR reduction will offer a significant benefit to patients and value to our healthcare system over the current standard of care. The 2021 Peripheral Nerve Society's Annual Meeting and concurrently published in The New England Journal of Medicine, we shared positive interim data from a Phase 1 study evaluating 21 inpatients living with hereditary ATTR amyloidosis with polyneuropathy that support this hypothesis.

Data representing six patients from the first two dose cohorts of Part 1 of the study, the single ascending dose portion were highly encouraging, showing that 2001 induced a dose-dependent reduction in serum TTR. In our second dose level, 0.3 milligrams per kilogram, we achieved an average TTR reduction of 87% at day 28, reaching a maximum TTR reduction of 96. 2001 was generally well-tolerated at both doses with adverse events all being grade one and mostly unrelated to the treatment.

Altogether, the data suggests that we can achieve targeted in vivo editings for the desired pharmacological effect, supporting 2001 as a first-in-class single-dose treatment for ATTR amyloidosis, validating our LNP technology and unlocking treatment of diseases that originate in the liver.

In terms of next steps for this program, we are continuing enrollment in the dose escalation portion of the Phase 1 study. We plan to provide additional data from Part 1 of the study at a scientific or medical conference later this year, including additional durability data beyond 28 days from the initial cohort. For Cohort 3, each subject will receive a single dose of 2001 at 1 milligram per kilogram. For Cohort 4, we have flexibility in the protocol to proceed to a higher dose or exploring intermediate dose.

Once we identify the recommended dose, we plan to initiate Part 2 of the trial, a single-dose expansion cohort. In this portion of the study, eight patients will be administered the recommended dose identified in Part 1 with the objective to further characterize the activity of 2001, including an initial assessment on clinical measures of neuropathy and neurologic function. We expect to advance into Part 2 of the study later this year.

In addition, we plan to engage with regulators, including the FDA to move into later phase clinical trials in which we aim to include both patients with polyneuropathy and cardiomyopathy. While we recognize these are interim Phase 1 results, with much more to learn, observations so far are quite meaningful, offering support that substantially derisks our in vivo efforts. We look forward to keeping you updated on our progress.

With that, I will now turn over the call to our Chief Scientific Officer, Laura Sepp-Lorenzino to provide updates on our two additional development candidate: 2002 and 5001, and across our R&D effort.

[Laura Sepp-Lorenzino, Chief Scientific Officer]

Thanks, David. Given the modularity of our platform, we're equally excited about what the interim clinical data imply for our efforts beyond NTLA-2001. Know that we have demonstrated we can deliver two hepatocytes [ph] in humans, we believe this accelerates the development of additional in vivo programs and increases their probability [ph] of technical success. This applies to several programs and especially to our in vivo knockout programs such as NTLA-2002, our wholly-owned candidate in development for HAE.

NTLA-2002 leverages the same LNP delivery system as NTLA-2001, but targets the KLKB1 gene in the liver to permanently reduce plasma kallikrein protein and thereby its activity, a key mediator of the disease. This approach is expected to provide continuous suppression of kallikrein activity and eliminate HAE attacks.

In June, alongside results from NTLA-2001, we announced the submission of our first clinical trial application to the New Zealand Medicines and Medical Devices Safety Authority to initiate a first in human study for NTLA-2002. We are submitting additional applications for this program and expect to enroll the first patient by year-end.

The first in human study will evaluate NTLA-2002 for safety, tolerability and activity, including levels of kallikrein knockout [ph] in patients with AHE. This program has leveraged insights from NTLA-2001 from its inception throughout its development and on the basis of our preclinical data and clinical results from NTLA-2001. We expect to determine the recommended those with a very limited number of those in cohorts.

Now turning to our ex vivo efforts. Here we're using CRISPR-Cas9 as a tool to create engineered cell therapies. Similar to our efforts in vivo, our proprietary approach to cell engineering serves as a foundation to our modular platform. This approach allows us to mix and match cell types targeting modality and the edits necessary for eliciting the desired pharmacology.

Regardless of therapeutic format, we expect to achieve highly efficient sequential editing, high yields, optimal cell performance and scalable manufacturing. Our will lead program NTLA-5001 is a potential best-in-class engineered T cell therapy designed to trade all genetic subtypes of AML. This investigation in the [ph] candidate is an autologous T cell receptor or TCR T cell therapy targeting the [inaudible 16:01] antigen and restricted to the HLA-A*0201 allele. Importantly, WT-1 is over-expressed in more than 90% of AML patients regardless of mutation subtype. And HLA-A*0201 is one of the most common serotypes.

Furthermore, NTLA-5001 utilizes our proprietary cell engineering [ph] process to replace patient's endogenous TCRs with the WT-1 targeting TCR, creating a homogeneous cell product with high intrinsic potency and improved safety by eliminating TCR in its pairing [ph].

By utilizing our sequential editing process, the resulting cell product has the desired attributes of high variability, robust levels of expansion, desirable memory phenotype, increased functional activity, and reduced translocations [ph].

Despite [inaudible 17:02] therapeutic advances, delivering improved response rates in subsets of AML, long-term outcomes continue to be poor with overall five-year survival below 30%. With our proprietary cell engineering process and the prevalence of WT-1, we believe NTLA-5001 will be a highly-active and well-tolerated agent to improved outcomes for AML patients.

As John mentioned, today, we're excited to share that we have submitted our first CTA to the United Kingdom's Medicine and Healthcare Products Regulatory Agency for Phase 1 study of NTLA-5001 in the United Kingdom. This first-in-human trial will evaluate the safety and activity of NTLA-5001 in patients with persistent or recurrent AML who have previously received first-line therapies. We expect to be screening patients for the Phase 1 study by year-end.

Beyond NTLA-5001, we plan to share more information on our allogeneic solution later this year. We believe our approach is differentiated from others currently in the clinic that typically address only Graft versus host rejection. We have focused on creating allogeneic cells that not only avoid Graft versus host disease, but also persist by avoiding elimination by host T cells and NK cells. This approach should avoid the aggressive [inaudible 18:39] and the induced profound immunodefficiency current implored to address a significant challenge in adoptive cell therapy.

In June, concurrent to launching a new universal CAR T cell therapy company, we entered into a preferred partnership agreement with Cellex. This agreement provides Intellia access to dedicated GMP [ph] manufacturing capacity and high-quality donor cells for our allogeneic programs [ph]. Our access to both will be of great value in supporting and accelerating the development of our wholly-owned ex vivo program.

All the R&D progress along with demonstrations earlier this year, such as preclinical data introducing our proprietary base editor and our first demonstration of in vivo editing outside the liver, reflects both the breadth of our technologies reached and our steadfast commitment to drive our pipeline forward through continued platform innovation. To that end, we plan to present additional in vivo and ex vivo update for scientific conferences later this year.

We remain on-track to nominate at least one new development candidate this year and we continue to work towards nominating the company's first allogeneic development candidate by the first half of 2022.

With that, I would like to hand over the call to our CFO, Glenn Goddard, who will provide an overview of our second quarter financial results.

[Glenn Goddard, Chief Financial Officer]

Thank you, Laura, and good morning. Our cash, cash equivalents and marketable securities were $551.3 million as of June 30, 2021 compared to $597.4 million as of December 31, 2020. The decrease was driven by cash used to fund operations of approximately $115.1 million, which was offset in part by $45.3 million of net proceeds from the company's at-the-market agreement, $20.5 million in proceeds from employee-based stock plans and $3.2 million of funding from cost-sharing agreements with Regeneron. Following the disclosure of our NTLA-2001 clinical data, we completed a successful follow-on offering in July, raising $648.1 million in net proceeds, putting Intellia in a strong position to aggressively advance and expand our pipeline.

Our collaboration revenue decreased by $9.7 million to $6.6 million during the second quarter of 2021 compared to $16.3 million during the second quarter of 2020. The decrease was driven by $8.4 million of revenue recognized for a one-time catch-up adjustment related to the amendment and expansion of our 2016 Regeneron collaboration agreement in Q2 of last year.

Our R&D expenses increased by $21.1 million to $58.9 million during the second quarter of 2021 compared to $37.8 million during the second quarter of 2020. This increase was driven by a $10 million one-time payment related to the amendment of our 2014 Novartis agreement, as well as employee-related expenses due to the continued expansion of our development organization.

Our G&A expenses increased by $5.2 million to $16.7 million during the second quarter of 2021, compared to $11.5 million during the second quarter of 2020. This increase was mainly due to employee-related expenses including stock-based compensation of $2.1 million. And finally, we expect our current cash balance to fund our operating plans beyond the next 24 months as Intellia is well-positioned to drive long-term growth and execute on our upcoming milestones.

And now, I will turn the call back over to John for closing remarks.

[John Leonard, Chief Executive Officer]

Thank you, Glenn. As you can see, we've made significant progress executing against the ambitious goals and strategic priorities set forth at the beginning of this year. Our presentation of proof of concept clinical data from the first-ever study of a systemically-administered CRISPR genome editing therapy in humans was clearly a highlight. Not only is this data important for the ATTR amyloidosis community, but it helps us advance our growing full spectrum pipeline. Moreover, this milestone represents just one key stat in unlocking the full therapeutic potential of our CRISPR platform.

Following the positive interim data from our Phase 1 study of NTLA-2001, we look forward to sharing additional interim results into initiating Part 2 of the study, a single-dose expansion cohort later this year. We've continued to progress our pipeline with CTA submissions for our second in vivo candidate, NTLA-2002 and our lead ex vivo candidate NTLA-5001 and we anticipate initiating both first-in-human trials by the end of this year. With validation of our CRISPR-Cas9 platform, we remain on-track to nominate at least one new development candidate by the end of the year. Additionally, we plan to share preclinical data on our allogeneic solution this year and expect to nominate the company's first allogeneic development candidate for the first half of next year.

And across our R&D efforts, we look forward to sharing additional in vivo and ex vivo updates at upcoming scientific and medical conferences. We are eager to carry this momentum forward as our recent progress offers a springboard from which to advance our long-term vision for Intellia.

Operator, you may now open the call for questions.

[Operator]

Thank you. We will now begin the question-and-answer session. [Operator Instructions]

Our first question comes from Maury Raycroft from Jefferies. Please, go ahead.

[Maury Raycroft, Jefferies]

Hi, good morning, everyone. Congrats on the progress and thanks for taking my questions. To start off, I was wondering if you can talk more about when you aim to engage with FDA about next step trials. Would that be after the eight-patient expansion data? Or can you have those meeting sooner? And for the eight-patient expansion, any new thoughts on how many mixed patients will be included in that and if you will assess for cardiovascular measures and biomarkers like NT-proBNP.

[John Leonard, Chief Executive Officer]

Thanks, Maury. Good morning. Nice to hear from you. Maybe I'll turn it to David. David, can you just tell us a little bit about your plans for progression to work?

[David Lebwohl, Chief Medical Officer]

Thank you, John. Thank you, Maury. So, with the data that we have from the Phase 1 so far, we're seeing that we've achieved 87% reduction in TTR. So, this result is as you know, is better than with available therapy. So, in the trial, we think we are getting close to where we need to be with dosing. We will be reporting on that before the end of the year. We are, at the same time, planning on the next studies at this time. We don't think we need any particular additional data to be able to engage with regulators, both the FDA and other regulators around the world about our next plans. In terms of the expansion, what is in the trial is described in these patients with polyneuropathy, if you look iin clinicaltrials.gov, we talked about some of the measures. There are measures of cardiac function, because as you know, many of these patients do as well have cardiac involvement, but they don't have heart failure. Their main involvement is neuropathy.

[Maury Raycroft, Jefferies]

Got it. That's all helpful. And so, it sounds like you could potentially engage with regulators sooner than later to get some additional feedback on what next step trials could look like?

[David Lebwohl, Chief Medical Officer]

That is a reasonable assumption.

[Maury Raycroft, Jefferies]

Okay. And then follow-up question, just on Cohort 4. What are gating factors to determine if you decide to assess an intermediate dose at dose level in that cohort and what could that dose look like?

[David Lebwohl, Chief Medical Officer]

We are going to look at the data from Cohort 3. We mentioned Cohort 4, but it's not required within the study. If we think we have the right dose to go forward based on the first three doses, we can do that, but we also do have the flexibility to go to either an intermediate dose that's higher or lower than that 1 milligram per kilogram. So we'll be looking at all the data that comes in from the third cohort and then decide what to do after that.

[Maury Raycroft, Jefferies]

Okay. Makes sense. Thanks for taking my questions and I'll hop back in the queue.

[David Lebwohl, Chief Medical Officer]

Thanks.

[Operator]

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

[Unidentified Analyst]

Hi. Thank you so much for taking our question. This is Sonia [ph] on for Salveen. We just have two questions. The first is on Intellia 2001. How should we think about the upcoming data for Cohorts 3 and 4. Just if you could help us frame expectations there? And then the second one is on the trial design for WT-1 AML and just if you could remind us what that is again, that would be helpful. Thank you.

[John Leonard, Chief Executive Officer]

I think I will turn to David again. David, could you say a little bit about our expectations for the end of the year? And I know it's early for WT-1 trial designs, but maybe you can just speak to where we are in the regulatory process just to remind our listeners?

[David Lebwohl, Chief Medical Officer]

Okay. Thank you, John. What we'll be reporting before the end of the year is additional data from the dose escalation portion of the trial. What you know from our report so far is that we will have data from patients receiving 1 milligram per kilogram and we've also said that we'll be talking more about the durability in the cohort in the existing patients in the trial. Of course, we'll bring forward as much information as we can from the trial and let people know where we are with that. Looking at 5001, we have announced that we've made our first regulatory submission that is. With that, we will be talking about the trial design after we are really getting started with the trial, after we have our first approval to move forward in the trial.

[Operator]

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

[Unidentified Analyst]

Hi. This is Sheldon [ph], on for Gena. Thank you for taking our question. We have two. One on 2001. So, for the second half updates, could you narrow it down a little bit for us, whether it's third quarter or fourth quarter and could you update us on the enrollment progress?

[John Leonard, Chief Executive Officer]

Yes. This is John. Thanks, Sheldon [ph]. We are really not going to be able to give more specificity other than we'll give you an update by the end of the year. We will apply the principles that we've been applying throughout the study to-date. We want those updates to be interpretable, meaningful and consistent, and that's what's been guiding us throughout the work. So, that's certainly our expectation to share more information, but as we did with the first go around, we'll give people advanced notice on where we're going to do that and how we're going to do that. So, stay tuned for that. We're not going to catch [ph] you by surprise.

[Unidentified Analyst]

Great. They're helpful. My second question is on HAE. So, when do you share the data? How should we think about the gating factors about when you will be able to share, is like to achieve certain follow-up or to achieve certain knockdown level?

[John Leonard, Chief Executive Officer]

Yes, I think that's premature at this time. I understand what's behind the question. We've begun the regulatory process as we laid out, and we're excited about moving that forward very, very expeditiously. As Laura commented, we think we're in a very good position to benefit from the work that's been done with 5001 and that will find its way into the clinical program. Once we've cleared on the regulatory side, we'll talk about the specifics of the program and the protocol and at that point, we can start to think ahead about what we'll share and when we'll share it. But I think as you know in these first-in-human studies, it's all very much a function of the protocol design and the rate of progression of enrollment that dictates what you can talk about. So, stay tuned again. I think you should just expect that we'll do it in a fashion that's quite similar to what we did with 2001.

[Sheldon]

That's very helpful, thank you.

[Operator]

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

[Joon Lee, Truist Securities]

Hi. Thanks for taking our questions and for the update. For the patients in the Cohort 1, if you look at the data, they didn't look like they plateaued. Have you collected more data beyond day 28, and if so, as you see a further knockdown in TTR? And related to that when who will you be able to share clinical updates, which could be particularly interesting given the completely different PK/PD profile compared to ASO? And I have a follow-up.

[John Leonard, Chief Executive Officer]

I'll take that. As David said in his comments, we'll provide more information as the study progresses and we've committed to doing that before the end of this year. We presented the data that we had. It's an ongoing study and what we try to do is present information that we think is meaningful. Generally speaking, we expect the TTR effects to settle out by day 28. But subsequent work and edit collection I think will corroborate that at least based on preclinical work, but with an upcoming update, we'll share the information that we have. So, stay tuned. It's an ongoing process. With respect to the clinical information, that's something that we'll collect more robustly in the second stage of the study. Although there is some descriptive work in this first phase, which as you know, will speak to the particular doses that the patients have received. So, as we shared with our update a few weeks ago, that Cohort 1, we think has very, very meaningful knockdown, but I don't think presents the drug with the maximal effect that one would hope to see from a clinical point of view. So that better, more robust description really is going to come to Stage 2.

[Joon Lee, Truist Securities]

Got it. And then as you advance 2001 towards commercialization, can you discuss your freedom to operate in the U.S., specifically to commercialize that in the U.S. unencumbered? Or do you foresee a need to negotiate with another company, or paired royalty? That's something [inaudible 35:18] that we'll be tackling? Thank you.

[John Leonard, Chief Executive Officer]

I think we're in a really good position to commercialize the product at this point, anything to share specifically with respect to dealings with other companies.

[Joon Lee, Truist Securities]

Thank you.

[Operator]

The next question comes from Luca Issi from RBC Capital Markets. Please, go ahead.

[Luca Issi, RBC Capital Markets]

Great. Thanks so much for taking my question. Congrats on all the progress here. [inaudible 35:49] question on durability. I know gene therapy is an imperfect comp, but we have seen the FDA asking for at least two years durability before considering approval, at least for liver. And if you look at the BioMarin data in hemophilia A as a comp, conceptually, do you anticipate the FDA to ask shorter timeline for heading [ph] given its permanent nature, or maybe do you expect them to ask in a longer timeline given we don't really understand the long-term consequences of potential off-target effects? Thanks so much.

[John Leonard, Chief Executive Officer]

That is not only philosophical, but also speculative. I think, Luca, in the spirit of your question, the specifics of what's goiing to take for this particular therapy to be approved by regulators is something that will be subjected to ongoing and future regulatory studies. I think that in the case of gene therapy, in terms of how we view it, the particular approach has inherent tendencies to at least be susceptible to waning over time and that I think as you know, tied to the notion of having an episome that is not integrated into the genetic material to sell. It's our expectation and we've certainly shared a lot of preclinical work to support this, that the effects should be in the case of gene editing, lifelong over the life of the patient. And we have no evidence to the contrary at this point. So, we'll see what the FDA is looking for, but I think that certain principles that are analogous to gene therapy are likely to be applied, but a lot of that is just looking for the clinical outcomes that come with it and sufficient information to indicate that the assumptions are correct.

[Luca Issi, RBC Capital Markets]

Great. Thanks so much, John.

[Operator]

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

[Unidentified Analyst]

Good morning. This is Greco [ph], on for Mani. Thanks for taking my question. What is your current thinking around the regulatory path for 2001 in cardiomyopathy and polyneuropathy, phenotype in the context of existing treatment options like stabilizers and [inaudible 38:21] that are becoming standard of care. Are you guys expecting to do non-inferiority studies for one or both phenotypes?

[John Leonard, Chief Executive Officer]

I'd say at this time, it's far from a foregone conclusion that in the cardiomyopathy space in particular, we'll be required to do comparative studies. And obviously, we watch this space carefully to learn whatever we can from the progress of other agents. I don't think that most KOLs would agree that there is a standard of care and certainly from a knockdown point of view, there is not even an improved product yet for cardiomyopathy. So, that basis of thinking, I think for regulatory sites for us is probably quite premature. So, with respect to the polyneuropathy space, that's work that we're thinking through at this point, but where the program stands today is we're especially interested in getting information in the cardiomyopathy patients. After David selects his optimal biological dose and we collect that information, then I will progress that as efficiently as we can.

[Unidentified Analyst]

My second question is so far we've seen NHP data from three different programs, I think ATTR, AHE and AATD, but the tested doses were not disclosed. But in terms of knockout efficiency, are you seeing similar knockout across different genes at similar dose levels or are you seeing some meaningful differences and knockout efficiency depending on the gene of interest, and how does this in combination with 2001 clinical data inform both [40:16] design and knockout expectations for 2002 in HAE.

[John Leonard, Chief Executive Officer]

Well, one of the benefits of the modular approach is that we use the same lipid shell that contains essentially the same cargo and by that I mean specifically the mRNA that encodes the Cas9 enzyme and for that matter of the guide RNA is virtually identical with the exception of the last 20 nucleotides, what we found is that from a product efficiency point of view in our preclinical models, there is great consistency across all of the different targets that we pursued. So we're excited that the logic that we employed at the very beginning about modularity appears to be holding true and I think the first real test of that is going to be as we move to 2002 and ideally, hopefully corroborate the results that we've already seen with 2001, but our preclinical stage, which have been a very good guidance thus far had been very, very helpful in terms of predicting where we go in humans.

[Unidentified Analyst]

Thanks. Really appreciate the detail. And thanks again for taking my question.

[Operator]

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

[Jay Olson, Oppenheimer & Co.]

Thank you for taking the questions. Maybe just a follow-up on 2001 and cardiomyopathy. Do you think that the greater TTR knockdown can lead to improved clinical benefits in both cardiomyopathy and polyneuropathy, and then maybe just a quick question on 5001 for AML. Since you're planning to do your early clinical work in the UK, can you remind us sort of the pros and cons of doing that work in the UK versus submitting an IND in the US. Thank you.

[John Leonard, Chief Executive Officer]

Let me speak to the whole knockdown question. Our central thesis, and I think it's a thesis that's broadly held in the amyloidosis field is that you want to reduce the offending protein to the greatest extent possible. And by that I mean to the greatest extent possible and there is clinical evidence when you look broadly across different proteins that cause different forms and amyloidosis to indicate that that's the case and there is even existing clinical data for the agents that currently exists that suggests that deeper responses lead to better effects. There is no reason that we can think off and no good reason that we've heard and we certainly discussed this extensively with people who are experts in the field to indicate that that's going to be any less true for cardiomyopathy than it is for polyneuropathy, and so the goal of our program is to achieve those greatest responses in TTR that we possibly can and we believe clinical trials and will bear that out and that is, as I said, the central thesis of the overall program. With respect to 5001 or the TCR program, I would point out that the regulatory submissions are in their early stages and I would not view this as limited in any way and certainly not limited to the UK. However, our experience in the UK and we anticipate that we will continue this way has been excellent with standards of care that are essentially indistinguishable from those that would be expected here in the US. So, from a limitation point of view, we don't see any.

[Jay Olson, Oppenheimer & Co.]

Thanks for taking the questions.

[Operator]

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

[Steve Seedhouse, Raymond James]

Hi. This is Ryan Deschner for Steve Seedhouse. Just wanted to ask you guys expect to report [44:50 inaudible] in the ATTR trial by end of the year in patients with clinically relevant dose, and had a follow-up question.

[John Leonard, Chief Executive Officer]

David. The question is do you expect any [45:03] data from this trial by the end of the year.

[David Lebwohl, Chief Medical Officer]

I think we are measuring [45:12] as part of [45:14] its part of the with the early patients course and dose escalation so there'll be very limited follow up. So it's a sufficient follow up to the meaningful we presented, but we're not sure we'll have that yet.

[Steve Seedhouse, Raymond James]

Okay, thanks for that. And then also have you or do you plan to assess the 2001 propensity for chromothripsis ex-vivo and is there a way to monitor this in vivo.

[John Leonard, Chief Executive Officer]

This work has been done extensively in the preclinical setting and that has been characterized and even reported on with respect to any off target analysis in the New England Journal paper out, I refer you to the supplement where it's far longer than the paper itself speaks to how this work is done, the data that's resulting, the testing at concentrations that far exceed those that are expected to be achieved in the clinic and from the standpoint of chromothripsis, I think the word even applies actually. But we're looking for is any evidence of off targets and what we find is that there are none at the doses and concentrations that we're administering to patients.

[Steve Seedhouse, Raymond James]

Okay, thank you very much.

[Operator]

Our next question comes from Silvan Tuerkcan from JMP. Please go ahead.

[Silvan Tuerkcan, JMP Securities]

Good morning and thanks for taking my question. I have two questions please. Just on the NTLA-5001, I know you can't tell us much about the trial, but would there be any reason to believe that there will be major differences from the Fred Hutchinson trial that included pre and post-transplant patients, were there any reason why you would exclude one of them or not. And then as a follow-up.

[John Leonard, Chief Executive Officer]

I want to make sure I understand the question. Are you asking from an outcome point of view or you asking about from a design point of view.

[Silvan Tuerkcan, JMP Securities]

From a design point of view.

[John Leonard, Chief Executive Officer]

Yeah, I'd say it's still a little early to speak specifically about the design of what we're going to be doing with 5001. I think there are general principles that people broadly apply that you should anticipate in the early studies, but once we get regulatory clearance, we will go into greater detail as to exactly what we're going to do. We certainly looking ahead when as you referred to the University of Washington, Fred Hutchinson results, we look to that as a helpful guide to set some expectations in terms of what might work and some of that logic supports our thinking about WT1, but there is differences between our particular approach and the one that they apply.

[Silvan Tuerkcan, JMP Securities]

Great, thank you. And maybe if you can speak to the high level strategy for the new company that you've created with Jim [48:37] Blackstone, did you think this new CAR T-cells will they explore new targets or you plan to just produce better sales with existing well established CAR T targets, if you could just speak to that. Thank you.

[John Leonard, Chief Executive Officer]

So the ___ NTLA will have its own story to tell as it moves along. It's an independent company, which we have significant ownership position and we're very, very excited about that and I'll remind you that we're supplying the allogeneic platform that we have not broadly disclosed, it is available to them, and you should look forward to hearing a bit more about that as we go forward here. But it's our expectation that they will pursue whatever they think the modality best addresses and that could apply to existing CAR T targets and with the switchable protein that actually target this lymphocytes certainly in a position where they could potentially explore other targets that I think that technology uniquely helps them to do, but that will be their story to tell us they lay out their plans going forward.

[Silvan Tuerkcan, JMP Securities]

Great, thank you for taking my question.

[Operator]

The next question comes from Jack Allen from Baird. Please go ahead.

[Jack Allen, Robert W. Baird & Co,]

Thank you so much for taking the questions. And congratulations on all the progress this quarter. We wanted to ask about your most recent thoughts concerning the potential for re-dosing with your O&P platform. How are you thinking about the potential need to re-dose NTLA-2001, this is something that's on the radar or are you very confident that one dose is going to be enough to drive meaningful clinical benefit, and then a quick follow-up question was how frequently are you receiving data from the study of NTLA-2001. I know it's a single-arm study and I imagine you're receiving data on some sort of rolling basis, any color you could provide there would be great as well. Thank you so much.

[John Leonard, Chief Executive Officer]

I will take that. We certainly look very, very carefully at the data as it comes in and it's not ongoing interaction with the investigation sites and our development team is in daily contact with them as such study progresses. It's not a blinded studies, so we have the benefits of getting information and interacting with investigators as we go and you're going to have to remind me the first question that you asked me, I just lost, I'm sorry. Oh, re-dosing, I'm sorry. Yeah, the way we think about re-dosing is the LMP is certainly enables that and that's by their very nature and one of the reasons that we chose them way back at the very beginning. They are not inherently immunogenic and they do not raise neutralizing antibodies, which means that if we need to re-dose we can re-dose, re-dosing approach in the case of 2001 for the patients participating in our first-in-human study has been to say the patients that once we determined an optimal biological dose, we will make that available to patients who did not receive that. That's not formally a part of this particular protocol, but that is something that will be made available to patients as the program proceeds. And going forward as we think about dosing patients in generally, once we have the final format and final dosing, again, it's our expectation and this is based on the preclinical results that we have that the likelihood of the require re-dose assuming an optimal dose given in the first place is remote. Probably not necessary.

[Jack Allen, Robert W. Baird & Co,]

Awesome. Thank you so much for the color.

[Operator]

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

[Yanan Zhu, Wells Fargo]

Hi. Thanks for taking my question. So, I was wondering for AML patients for the 5001 program, is there anything that might be different from the T cells from AML patients compared with B cell lymphoma patients that might affect the ability to grow out and manufacturing CAR Ts from those patients? Thanks.

[John Leonard, Chief Executive Officer]

David, do you want to try to address that? Is there any reason that we should be aware of underlying differences and sales based on what we're doing, relative to other cell types in other programs?

Dl:

Thanks. We don't think that patients with AML have any contradict [ph] issue, let's say with their T cells if they can't be manufactured well. Of course, we'll get more experience in the trial when we go forward, but so far we have no evidence of that.

[Yanan Zhu, Wells Fargo]

Got it. And a quick follow-up on your transduction method. I think in the past you mentioned that you have a gentler approach to transduction and manufacturing either the TCR or the CAR T-cells. Could you elaborate a little more on that? And what might be the advantage to traditional CAR T manufacturing? Thanks.

[John Leonard, Chief Executive Officer]

Yes, thanks for the question. It's something that we're really proud of, that our scientific team has worked on and developed. We don't share the specifics of how we do that. We think that that is an area of competitive advantage for us for the simple reason that standard out-of-the-box electroporation damages cell. Certainly an effective way of getting material into cells and it's widely used, but the approach that we've taken does that at least as well maintains cell viability, allow cells to behave as if they had never been transduced in the first place. From a division point of view, we think that's going to translate into dosing advantages for patients and importantly when you look at the genetic architecture of those cells, once they've been transduced, it's maintained. There's no inherent damage done to the genetic architecture by our transduction technique, irrespective of the editing itself, which is certainly not the case for standard electroporations. Our approach is that the editing is part of the story. How you do the editing is also critically important and what you want to do ultimately is have cells that are as normal as possible in advantaged to the greatest extent so that they will behave well once the patient is dosed.

[Yanan Zhu, Wells Fargo]

Great. Thanks for taking the question.

[Operator]

The next question comes from Tony Butler from ROTH Capital. Please, go ahead.

[Tony Butler, ROTH Capital]

John, 5001 or maybe the first program in cell therapy, I wanted to address what may be a very simplistic question and that is back when you and the team sat down to think about what would be your first target, you arrived at AML and WT-1 which is great. The question is, was there any specific reason for that particular program that is a blood tumor target versus maybe say, a solid tumor target? And I'm asking not because it's WT-1 or because it's AML. But just based upon the way that I perceive, you've laid out all the other programs. There may be some learnings you want to take from a particular set of experiments and this may give you this target and a blood tumor may give you the answer to those particular questions. And I'm curious if that's correct and if you may share that? Thank you.

[John Leonard, Chief Executive Officer]

I think it's an astute observation of how we think about our work. We try very hard to isolate the key variable, get the clearest answer that we can with respect to that variable, and then move on from there. So, in the case of engineered cells, we believe as we presented extensively and other venues that a T cell receptor-based approach brings with the tremendous opportunities and moves outside the fairly limited space that CAR T cells are active in. What we wanted to determine was, could wewith our approach isolate healthy donor TCRs, develop an editing paradigm that introduce those TCRs into cells and that we can show that they could work. What we tried to do is strip away all of the other potential confounding factors -- solid tumors have some, liquid tumors tend to be less -- they have their own complexity for sure, but there are other factors that characterize cell tumors that don't apply in liquid tumors. And we thought with AML and the high levels of WT-1 expression that characterize this, that would be a wonderful test case for the overall thinking and we're excited to see if our preclinical work is on target. Then as David shared, we're at the point where we're going to find those things out because we're moving to the clinic by the end of this year.

[Tony Butler, ROTH Capital]

I'm grateful for your comment.

[Operator]

There are no more questions in the queue. This concludes our question-and-answer session. I'd like to turn the conference back over to Ian Karp for any closing remarks.

[Ian Karp]

Great. Thank you so much and thank you, everyone, for joining us today and for your continued interest and support in Intellia. We look forward to updating you on our progress and we hope everyone has a great day. Bye now.

[Operator]

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