Intellia Therapeutics, Inc. (NTLA) Earnings Call Transcript & Summary

Good morning, and welcome to Intellia Therapeutics Investor Event to discuss the Interim Clinical Data from the Phase I Study of NTLA-2001. 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 Lina Li, Director of Investor Relations at Intellia. Please proceed.

Thank you, operator, and good morning, everyone. Welcome to Intellia's investor event featuring interim data from our Phase I clinical trial of NTLA-2001. Saturday morning, we issued a press release detailing results presented at the 2021 Peripheral Nerve Society's Annual Meeting and published in the New England Journal of Medicine. This release and the accompanying presentation can be found on the Investors & Media section of Intellia's website at intelliatx.com. As a reminder, this call is being broadcast live, and a replay of the event will be archived on the company's website. Before we begin, allow me to introduce our speakers and share an outline for today's call. Dr. John Leonard, our Chief Executive Officer, will begin with brief introductory remarks. Dr. Julian Gillmore, Professor of Medicine at the National Amyloidosis Centre and physician at the Royal Free Hospital in the U.K., will review the interim results. Dr. Gillmore is a respected key opinion leader on the treatment of amyloidosis and the national coordinating investigator on our clinical trial in the U.K. Dr. David Lebwohl, our Chief Medical Officer, will then speak to the next steps in the clinical development of NTLA-2001. And Dr. Laura Sepp-Lorenzino, Chief Scientific Officer at Intellia, will outline the implications of these results, both for our proprietary LNP-based platform for systemic gene editing and for our pipeline of in vivo therapeutics in research and development. John then will return for closing remarks before we open up the call for Q&A. At this time, I would like to take a minute to remind listeners that during this call, we 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. With that, let me turn the call over to our CEO. John?

Thank you, Lina, and welcome, everyone. Today, we're incredibly proud to share positive interim data from Part 1, the dose escalation portion of our Phase I study evaluating NTLA-2001 as a potential onetime treatment for transthyretin amyloidosis, also known as ATTR amyloidosis. NTLA-2001 is not only our lead candidate, but also the first systemically delivered CRISPR-based therapy to enter clinical development. That is the first CRISPR-based drug candidate to be intravenously administered and edit the human genome in the target cells inside the body, the basis of our in vivo approach. As such, the study is intended both to evaluate NTLA-2001 as a potentially curative treatment option for ATTR amyloidosis and to validate our in vivo editing and delivery platform. For the past several months leading up to this announcement, we viewed this readout through 3 critical lenses: what it means for patients, what it means for Intellia and what it means for the field of medicine. For patients with ATTR amyloidosis, NTLA-2001 is the only treatment with curative potential that may both halt and reverse disease progression with a single dose. Despite the availability of chronically administered therapies, there remains unmet need in patients with ATTR amyloidosis. We believe a single-dose therapy that produces greater TTR reduction will offer significant benefit to patients and value to our health care system over the current standard of care. For Intellia, this is a profoundly important milestone. We've worked hard to advance our platform to the point of clinical validation. We recognize that these results are significant to our broader in vivo pipeline development efforts by helping to establish proof of concept for our modular approach that we incorporate into future programs. This announcement is our first clinical data readout. And for that alone, we're grateful to our team and partners at Regeneron for their shared and tireless commitment to bringing our technology to patients. But more than that, we're grateful to the patients who are participating in the trial. And for the field, it's the first-ever clinical data supporting the safety and efficacy of systemic in vivo CRISPR genome editing. We believe this opens the door to a new era in medicine. We recognize these are interim Phase I results, but we believe CRISPR/Cas9 and genome editing more broadly, is an immensely powerful tool with vast potential impact. And these results begin to demonstrate that. Moreover, our technical achievement of systemic administration marks the beginning of bringing CRISPR as a beneficial therapeutic to broad patient populations. This work is central to our mission to advance curative genome editing treatments for patients with severe diseases and is why we believe these data represent a momentous milestone for medicine. At Intellia, we've sought to harness the power of CRISPR as a therapeutic modality by developing in vivo and ex vivo approaches. For genetic diseases, we've utilized an in vivo approach where CRISPR is the medicine. We leverage our proprietary nonviral lipid nanoparticle-based CRISPR delivery system to selectively inactivate disease-causing genes or precisely insert genes to produce normal proteins. And although not the focus of today's call, our ex vivo approach where CRISPR creates the medicine, is designed to edit genes from patient-derived cells for treatment of immuno-oncology and autoimmune diseases. Implementing this full-spectrum strategy, we focused on building the broadest, deepest toolbox in the genome editing space, and we've developed a modular platform that we can leverage from one program to the next. These efforts have produced a rapidly expanding pipeline aimed at extending the benefits of our Nobel Prize-winning CRISPR/Cas9 technology to the broadest possible population of patients. This is, in part, what makes the platform lens of today's readout so meaningful and enables robust expansion of our pipeline over the next several years. With all this in mind, we're pleased to share our interim clinical data from our presentation at the Peripheral Nerve Society with you today, and we note the publication of this work in the New England Journal of Medicine on Saturday. Based on interim data in 6 patients from Part 1 of our first-in-human study evaluating NTLA-2001, treatment with NTLA-2001 led to a dose-dependent response in serum TTR reduction. In our second dose level, we achieved an average TTR reduction of 87% at day 28, including 1 patient with a 96% TTR reduction. These deep TTR reductions support our view that NTLA-2001 has clear potential to deliver life-changing benefits for patients with ATTR amyloidosis. Importantly, we observed encouraging safety and tolerability for a proprietary lipid nanoparticle or LNP delivery technology in RNA CRISPR cargo in these patients with no serious adverse events in the first 6 patients by day 28. Altogether, the data suggests that we can achieve targeted in vivo editing for desired pharmacological effect. And although there is still much left to learn from the study regarding this program and our platform, we believe these results substantially derisk our in vivo efforts, validating our nonviral approach to systemic delivery and unlocking treatment of diseases that originate in the liver. David and Laura will touch more on the implications of these results shortly. For now, it is my pleasure to welcome Dr. Julian Gillmore, who will take us through the data in detail and offer his perspective as the national coordinating investigator on our Phase I trial in the U.K. and a leading physician specializing in treatment of ATTR amyloidosis. Dr. Gillmore, over to you.

Thank you very much. So for listeners who may not be familiar with transthyretin amyloidosis or known -- also known as ATTR amyloidosis, it's a rare, progressive and fatal disease caused by the accumulation of amyloid deposits, which are composed of misfolded transthyretin or TTR protein. The disease may be hereditary caused by a mutation in the TTR gene, of which there are now more than 120 known. Hereditary ATTR amyloidosis is estimated to affect roughly 50,000 individuals worldwide and may predominantly affect the nerves causing polyneuropathy, or the heart referred to as cardiomyopathy or both in combination. ATTR amyloidosis can also be acquired, known as wild-type ATTR amyloidosis. This causes a predominant cardiomyopathy and is an increasingly recognized cause of heart failure. The exact prevalence remains unknown. Both conditions cause debilitating symptoms with a high burden of disease for patients and caregivers. Intellia's Phase I study is in the hereditary ATTR amyloidosis with polyneuropathy population. This is the population in whom knockdown of TTR protein has been shown to have clinical benefit. It is also the population that's most likely to provide clear data on safety whilst establishing a dose effect for NTLA-2001. However, there's no conceivable reason to believe that the effects of NTLA-2001 treatment will not translate to the entire ATTR amyloidosis population. Let me explain why. In every type of amyloid that's ever been treated, there has been a very strong correlation between the degree of knockdown of the relevant protein and clinical outcomes. The explanation is very simple. The turnover of amyloid deposits depends on the equilibrium between the rate of amyloid production and the rate of amyloid removal. The rate of removal is, by definition, very slow, such that in an untreated individual, the rate of amyloid production exceeds the rate of removal amyloid accumulates and results in clinical progression and death. The more one knocks down the concentration of the relevant protein, in other words, the rate of amyloid production, the greater the equilibrium in favor of amyloid removal. Initially, when we started treating light chain, also known as AL amyloidosis, we thought that a greater than 50% reduction in the amyloid-forming protein, in other words, the light chain, was sufficient because outcomes were better than in patients with no knockdown. Many years later, however, we now know that what hematologists need to aim for is what they call a complete response, in other words, a 100% reduction of the amyloid-forming protein. If you have a look at this graph, at the bottom, the line at the bottom is patients who've achieved a less than 50% reduction in the amyloid-forming protein. The next graph up is patients who have achieved a greater than 50% reduction but less than 90% reduction. The next lineup is patients who've achieved what hematologists call a VGPR, which is a greater than 90% reduction in their light chain. And the top line, the best survival is amongst patients who achieve what hematologists call a CR or a complete response. Exactly the same is true in AA amyloidosis, a different form of amyloidosis. This table shows the relative risk of death in patients as the octyls of serum amyloid A protein, that's the protein that is the amyloid-forming protein in this type of amyloid, decreases. And you can see that the relative risk of death decreases progressively as the SAA concentration decreases. In ATTR amyloidosis, we see exactly the same trend emerging, although the data at this point are less mature since TTR knockdown has only been possible in the last few years. This, however, shows the relationship between degree of TTR knockdown and change in neuropathy score. We see that lower serum TTR has been observed to be associated with better subsequent control of symptoms from disease. So taken together, these data form the basis for the hypothesis that knockout of the TTR gene to achieve deep TTR reduction may halt and potentially reverse this disease and the conviction behind my involvement with this study. I will now share the presentation from Saturday's 2021 PNS Annual Meeting. It's a privilege to share with you interim data from the first-in-human trial of an in vivo CRISPR/Cas9-based gene editing therapy, NTLA-2001, designed to edit the TTR gene in patients with transthyretin amyloidosis. These are my disclosures. As I said earlier, the main therapeutic strategy successful in all types of amyloidosis that are amenable to treatment is to reduce the concentration of the circulating amyloid-forming protein, in this case, transthyretin. The gene silencing therapy, patisiran, reduces serum TTR concentration by approximately 80% and being shown to benefit neuropathy in hereditary ATTR amyloidosis. However, gene silencing therapy requires chronic administration, and one would expect greater TTR knockdown to achieve better clinical outcomes. There is, therefore, an unmet need for better treatments in ATTR amyloidosis. Editing of the TTR gene, which has the potential to provide permanent and profound TTR knockdown after a single infusion, is a particularly attractive treatment strategy. NTLA-2001 is a CRISPR/Cas9-based in vivo gene editing therapy. It consists of a single-guide RNA molecule that targets the human TTR gene and a human-optimized mRNA sequence of strep pyogenes Cas9 protein encapsulated in a lipid nanoparticle or LNP. Following intravenous administration of the LNP, it's transported directly to the liver, where it's taken up by the LDL receptor on hepatocytes. After endocytosis and release into the cytoplasm, the Cas9 mRNA is translated producing the Cas9 enzyme, which interacts with the single-guide RNA to form the CRISPR/Cas9 ribonucleoprotein protein or RNP complex. The RNP complex enters this in nucleus, and a target-specific 20 nucleotide sequence of the 5 prime end of the guide RNA binds to the DNA double helix at the target site. This leads to precise cleavage in the targeted TTR gene sequence. Endogenous DNA repair results in introduction of insertions or deletions of basis in the target site. These frameshift operations reduce functional target gene mRNA and, consequently, production of the target protein. The plot here shows the in vitro therapeutic index with effects of concentration of the guide RNA on the percentage TTR gene editing by NTLA-2001. This was performed in cultured primary human hepatocytes. The vertical line here marks the concentration at which we routinely observed 90% reduction in TTR protein production of EC90. Above the EC90, NTLA demonstrated saturating levels of TTR gene editing accompanied by greater than 95% reduction in TTR protein. An important question the scientific team asked before bringing this agent to clinic was what is the level of off-target editing at these concentrations? The team performed extensive genome-wide screening with computational laboratory-based techniques to detect and validate the likeliest sites for potential off-target editing. These methods identified 7 sites all in non-coding regions. The experiment shown here compares the rate of on- and off-target editing following treatment with NTLA-2001. What you see marked down here by the colored lines, each representing 1 of the 7 sites, is that there was no detectable evidence of off-target editing even at concentrations of NTLA-2001 threefold greater than the EC90. Preclinical in vivo studies were conducted in the cynomolgus monkeys using a surrogate LNP incorporating a single-guide RNA specific to the monkey TTR gene. This graph shows the mean percentage reduction from baseline in serum TTR protein concentration, and monkeys received the LNP at doses at 0, 1.5, 3 and 6 milligrams per kilogram of the RNA cargo on day 0 and followed for 367 days. Vertical lines represent standard deviations across 3 main animals in each group. Now the single dose at 3 milligrams per kilogram achieved a durable reduction in circulating TTR protein of approximately 95% after day 28. Safety studies established dose range, which no adverse effects of NTLA-2001 were observed with near complete, sustained reduction in serum TTR following a single administration. At higher doses, the adverse effects in the monkeys were dose-dependent, transient, reversible and monitorable. The first-in-human study with NTLA-2001 is a 2-part open-label, multicenter study in patients with hereditary ATTR amyloidosis and polyneuropathy. Part 1 is a single-ascending dose design with a minimum of 3 patients in each of up to 4 dose escalation cohorts. The starting dose in humans was 1/10 of the allometrically scaled dose at which no adverse effects were observed in the monkey. The recommended dose selected in Part 1 will be administered to a dose expansion cohort in Part 2. The primary objective of the first-in-human study are to evaluate safety, tolerability, PK and PD, the latter by serial measurements of TTR levels. I will report data on the first 6 patients from the first 2 dose escalation cohorts included in Part 1. Bear in mind, participants received a one-time infusion of NTLA-2001 on day 1 of the study. Here are the demographics of these first 6 patients, 3 in each dose cohort: age range from 46 to 64, 3 different pathogenic TTR mutations were represented and 3 patients received prior to a series of therapy. All had early-stage polyneuropathy, and despite presence of cardiac ATTR amyloid by imaging in 5 of 6 patients accompanied in some by elevated NT-proBNP, they were all NYHA Class 1. Median time from diagnosis to treatment was 2.5 years. NTLA-2001 was generally well tolerated in the acute phase, with AEs all being Grade 1 and mostly unrelated to the treatment. One patient had a mild infusion-related reaction, but this did not require dose interruption. There were no SAEs. There was no evidence of liver toxicity or coagulopathy, and laboratory discussions were clinically insignificant. Serum TTR reduction was observed by day 7 and deepened further by day 28 in all patients at the first dose level of 0.1 milligram per kilogram. The reductions ranged from 47% to 56%. And the reductions were dose dependent with greater reductions detected in the 3 patients who received the higher 0.3 milligram per kilogram infusions. Here, the reductions range from 80% to 96%. At day 28, mean TTR reduction from baseline in the 0.1 milligram per kilogram cohort was 52%, and then the 0.3 milligram per kilogram cohort was 87%. In conclusion, systemic administration of NTLA-2001 in patients with hereditary ATTR amyloidosis and polyneuropathy caused a profound and dose-dependent reduction in serum TTR protein concentration. Of note, maximum reductions were 56% and 96%, respectively, in the 2 dose cohorts. NTLA-2001 treatment was well tolerated in the acute phase with all AEs being at mild severity. Further dose escalation is ongoing in this first-in-human study with the aim of achieving greater reduction in TTR than that provided by currently available agents, which is expected to translate into improved clinical benefit for patients. For example, improvement in autonomic symptoms, better mobility and fewer cardiac hospitalizations for heart failure. This is the first demonstration of CRISPR-based in vivo gene editing in humans. These findings provide proof of concept for a promising new therapeutic strategy. I'd like to acknowledge the patients, the contract research organizations involved in the trial, my current investigators at National Amyloidosis Center, Richmond Pharmacology in the University of Auckland and, of course, the many members of Intellia Therapeutics and Regeneron Pharmaceuticals who are responsible for the development of NTLA-2001. Now I'd like to turn the call over to David Lebwohl.

Thank you, Dr. Gillmore. Your leadership in this trial has been critical for its success. We also appreciate your vision for 2001's potential to improve on patient's health outcome compared to current standards of care by achieving deeper TTR reductions. Before outlining next steps for this program, I'd like to spend a minute reviewing our objectives for 2001 and specifically what we had hoped to achieve with this readout. Since initiating the study, we suggested that this readout would share data that is consistent, meaningful and interpretable although interim. And with this report occurring during the dose escalation phase of the trial, we're looking to demonstrate the initial safety and activity profile of the drug. We hope to see a consistent dose response and good tolerance of the LNP formulation and indicators of proof of concept for our platform, an important step towards identifying the recommended dose for 2001. As you can see, we have achieved our goal. We're highly encouraged by these interim results, which to date show that 2001 was associated with only Grade 1 adverse event in the first 2 dose cohorts. Equally important, we have already achieved a deeper TTR protein reduction on average in the second cohort than the current standard of care. We anticipate that a higher dose may further drive TTR levels consistently lower than any other therapy has been able to achieve with expected corresponding clinical benefit. Based on the safety and tolerability data observed to date, we are continuing to dose escalate. Taking these early results from part 1 of our study, together with our robust demonstrations in the preclinical experiments, we believe 2001 has the potential to be a first-in-class, single-dose treatment for patients with ATTR amyloidosis. In terms of next steps for this program, we're pleased to share that we are actively enrolling Cohort 3, where each subject will receive a single dose of 2001 at 1 milligram per kilogram dose level. We plan to provide additional data from Part 1 of the study at a scientific or medical conference in the second half of the year. In this next update, we plan to share data further along in our dose escalation as well as additional durability data beyond 28 days for the initial cohort. 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, 8 subjects 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 as well as additional safety data. We expect to advance into Part 2 of the study later this year. Our goal then is to expand the study and to engage with regulators, including the FDA, to move into later studies in which we aim to include both polyneuropathy and cardiomyopathy patients. This is an exciting first look as we continue to make steady progress in the clinical study, and we look forward to keeping you updated on our progress. Before passing this call along, although the trial is ongoing, we'd like to express our gratitude, first and foremost, to all the patients and their caregivers for their participation in the study and also to our investigators and their site support staff. With that, I'd like to turn the call over to our Chief Scientific Officer, Laura Sepp-Lorenzino, who will review today's update in context of our platform and broader in vivo pipeline.

Thank you, David. These results are significant in term of what they mean for ATTR amyloidosis patients. We're equally excited about what they may imply for our efforts beyond NTLA-2001. As John noted, Intellia's platform was built intentionally to enable modular solutions that would support the broadest possible therapeutic application for our editing and delivery technology. In the in vivo setting, we pursued systemic delivery to achieve this ultimate objective. In particular, we selected a lipid nanoparticle-based solution for the numerous advantages it presents, included transient expression, large cargo capacity and the potential to redose and also because it introduced a rapid and reproducible path to clinical development once we demonstrated proof of concept. This interim update offers just that. We believe we have unlocked the liver. Because many genetic diseases involve genes that are active in the liver, enabling systemic CRISPR delivery to this organ should allow us to develop treatments for multiple diseases, both rare and prevalent. These results demonstrate we can deliver to hepatocytes, and by swapping out the target side portion of the guide RNA, we're able to precisely edit different genes. We can, therefore, accelerate the development of additional in vivo programs with increased probability of technical success. This includes several indications we've already explored preclinically and numerous others and especially applies to follow-on in vivo knockout programs, such as NTLA-2002, our candidate in development for hereditary angioedema or HAE. NTLA-2002 leverages the same LNP and RNA cargo now targeting the KLKB1 gene in the liver to permanently reduce plasma kallikrein protein and activity, a key mediator of the disease. This approach is designed to provide continuous suppression of kallikrein activity and eliminate HAE attacks. Today, alongside the NTLA-2001 interim results, we're very excited to share that we have filed our first CTA for NTLA-2002 in New Zealand. And on the basis of learnings from NTLA-2001, including the results discussed today, we expect to move faster and begin evaluation at the higher dose with NTLA-2002. We plan to enroll our first patient in a Phase I study of NTLA-2002 by year-end. Further, we believe this interim data has applicability to our targeted insertion and consecutive editing strategies since it utilizes the same CRISPR delivery system. We continue to advance this work internally and in partnership with Regeneron and look forward to evaluating these hypothesis in the clinic as well. Finally, as this slide outlines, the next wave of growth for our in vivo efforts is to extend the applicability of our delivery platform and editing tools to pursue disease targets across multiple tissues. Once again, the data presented today offers meaningful validation for our modular platform and programs well beyond NTLA-2001. It paves the path forward, derisking our LNP delivery platform, accelerating our in vivo pipeline and offering a springboard to set up our long-term vision for Intellia. And with that, I'll turn the call back to John for closing remarks.

Thank you, Laura and David and especially to Dr. Gillmore. We appreciate the time you spent with us today. As you can see, observations so far from our Phase I study of NTLA-2001 are very encouraging, offering support at both the program and platform levels. For patients with ATTR amyloidosis, we believe these interim results point to NTLA-2001's potential to halt and reverse their disease with a single dose. We believe this demonstration of systemic in vivo genome editing substantially derisks our LNP platform and accelerates our in vivo pipeline. And we're proud to lead the way into this new era in medicine in which curing genetic disease may be within reach, and we're just getting started. We're executing against the ambitious goals and strategic priorities set out at the beginning of this year, having now checked boxes for clinical validation, advancement of our full-spectrum pipeline and continued platform innovation. And as our investment in R&D matures into a broad pipeline of clinical candidates, we remain steadfast in our commitment to harnessing CRISPR's full therapeutic potential. Turning our attention to the second half of this year and beyond. We hope to carry this momentum forward as we close in on a number of key upcoming milestones. For NTLA-2001, we plan to provide additional data from Part 1 of the study at a scientific or medical conference this year. And once the recommended dose has been identified, we expect to initiate Part 2, our single-dose expansion cohort later in 2021. For NTLA-2002 or HAE, now that we've filed our first CTA, we plan to enroll our first patient in a Phase I study by the end of this year. For NTLA-5001 for AML, we're on track to submit an IND or equivalent regulatory filing in mid-2021. And across our R&D efforts, we remain on track to nominate at least one new development candidate this year along with the nomination of our first allogeneic development candidate by the first half of next year. As Laura stated, today's update provides a springboard from which to advance our long-term vision for Intellia. As we look ahead for our in vivo approach, our interim data supporting the successful delivery to and an activation of a gene in the liver opens the door to targeted gene insertion and, ultimately, the next wave of therapy is targeting diverse tissues across multiple diseases with our proprietary delivery technology. Further, we continue to advance CRISPR cell engineering in the ex vivo setting. This includes introducing a differentiated allogeneic solution as well as applying our proprietary base editing technology introduced earlier this year as we continue to expand our pipeline. Taken together with today's announcement accelerating our in vivo strategy, we have a path forward to advance 1 to 2 new programs per year. Without a doubt, this is an exciting new chapter for Intellia, for genome editing and most importantly, for patients. We look forward to sharing more from NTLA-2001 and other parts of our pipeline as we continue to work toward fully realizing the promise at the heart of the genomic revolution. Operator, you may now open the call for questions.

[Operator Instructions] Our first question comes from Maury Raycroft from Jefferies.

Congrats on the update. Let's see, just starting off, I'm assuming you have a longer-term follow-up for some of the patients. How much total follow-up do you have at this point? And can you talk about what trends you're seeing down 28 days?

Thanks, Maury. It's John. That's information that we'll share later this year as we collect it. Remember that we are trying to share information on a cohort-by-cohort basis so we get a consistent readout. So as the year goes on, we'll be in a position to share that information when we have a more complete picture.

Got it. Okay. And then in the New England Journal of Medicine publication, it mentions plans for longer-term safety follow-up under a separate program in development. So I'm just wondering when we'll learn more about the separate program. And will this program enable you to redose Cohort 1 and potentially get biopsies from any of the patients treated?

Well, thanks, Maury, again. Biopsies are really not necessary nor informative, and so I don't think that's going to be relevant to the program. As we've laid out from the outset, given that this is a single-ascending dose phase of the program for those patients who turn out to have a dose that was less than maximally efficacious, we're making provisions for those patients to come back and get access to that dose, and that would be outside this particular protocol. The details of that are something that we'll share a little bit later on as we get more information. I think just to make sure everybody understands, one of the reasons we're excited about the LNP platform is that, in fact, you can redose. And this was a very important part of putting the modular system together and the chemical-based approach as opposed to a neurological delivery. And so as we learn how the lower doses behave, we're able to take the information that we gather at higher doses and make it available to those who came in early in the study. So we should all be in a good position for everybody to benefit from that information as we go.

The next question comes from Salveen Richter from Goldman Sachs.

Congratulations on the data. Just a couple of questions from me. How are you monitoring for potential off-target edits for patients in the study? And if you could comment on the readthrough to cardiomyopathy. And then as well, given you have readthrough here to HAE, anything you can give us around trial design there or starting dose given the work you've seen now in TTR polyneuropathy?

Thanks, Salveen. As we've tried to make clear in other venues, the off-target aspect is something that is substantially derisked preclinically by extensive work that's done in human cells at suprapharmacologic concentrations. I think Dr. Gillmore tried to address that. What we've showed is that using the most stringent assays that anybody is applying, we test concentrations that are far in excess of what any patient is ever going to get. What we've demonstrated is that at those concentrations that give the results reported today, there's no interaction with sequences other than the targeted one. So we're quite confident that from the standpoint of our targets, we know exactly what we're doing. We know exactly where CRISPR's producing its effect. So we think we're in quite good shape there. With respect to cardiomyopathy, the biology is the same. The edit that we get with this particular approach in these polyneuropathic patients is expected to be identical in the cardiomyopathic patients, and we expect to show that here quite soon as we move into that patient population. And maybe I'll turn it to David Lebwohl, our CMO. David, if you just want to give some basic ideas of how we're thinking about HAE and how these results relate to that protocol.

Yes. Thanks, John. So the HAE drug, I think you know, is part of the platform. So the only difference from 2001 are the 20 nucleotide sequence at the 5 prime end. So this is really the same lipid nanoparticle, the same messenger RNA and almost the same guide. So based on this, we think we know already a good bit about what the safety is expected to be with HAE. And on that basis, we do think we can potentially start at a higher dose, potentially at the second dose where we've seen only Grade 1 safety events in this population, in the TTR population. The HAE population is quite healthy as well, and we do expect them to do very well. So we're not talking about the exact design of the Phase I yet. I think you'll have some sense just from what you know already, but we will be talking more about that as we get close to the study.

The next question comes from Gena Wang from Barclays.

I wanted to say that this is a transformative for the full whole field. I'm really glad. I'm really excited to see this data. Congratulations. So I have 3 sets of questions. First, John, regarding the off-targets, we understand -- I think Dr. Gillmore also mentioned, human cell is a very good system to test the off-targets. And you did show very good limited off-targets. But from the FDA perspective, do you think that they wanted to see actual data from humans? That's the first question. And the second question is regarding nonhuman primate data. It seems like translation from nonhuman primate data to human seems much better. And when we look at our model actually showed pretty consistent with FDA guidance, basically threefold differences. And now data show very consistent, but in your case, it seems much better. So any thoughts on like did you optimize the lipid nanoparticle or the final drug product? Any thoughts there explaining that? And the last question is beyond -- for the HAE program, I assume your first dose will be 0.3 milligram per kg, if that's the case. And then also beyond HAE, what other knocking down indication you wanted to go after?

Thank you, Gena. There's a lot there. First of all, the work that we do with off-targets is done in primary hepatocytes, not cell lines. And we think that, that gives us far and away the best sort of determination and assessment of what's going on. This is information we've shared with the regulators. They've seen how provocative we've done our testing, again, at suprapharmacologic levels, and that's been satisfactory. There's been no request for testing in humans. And I think just about anybody who thinks about it for a while realizes that, that's not going to be particularly informative. So I would not look for that type of work as we go down the road here. With respect to nonhuman primates, the -- well, first of all, we were very pleased with the extent that we were able to predict or at least come close to what we hope to achieve in humans. There's lots of precedents. We have a great team that's done a lot of work extrapolating back and forth between different cell types and the preclinical models. We've also learned that our -- the human guide is quite active and you have to take that into consideration relative to the nonhuman primate guide, and there's an additional benefit if you have activity there. So I guess what we can take away from this is that standard allometric thinking is a very good guidepost, which is good news for us because we can take the information that's been built over the years as people think -- been thinking about going from preclinical models to the clinic and benefit from those insights and then capture the additional data that's particular to the test article that we're doing. So we're quite excited. I give my preclinical team as strong A with the work that they've done, and we think that it puts us in a really good position for where we go with HAE. With -- specifically with the HAE protocol, I wouldn't spend too much time trying to guess what dose we're going to start with. Just as we did with the TTR work, we try to be very thoughtful about the patient population, what we know from preclinical models, obviously, what we're learning from this particular study. But the takeaway, I think, should be that we can start at doses that are higher than the lowest dose here. But that particular dose will be something that we'll decide as we begin enrolling those patients. So overall, I think that the takeaway is that the preclinical work is solid. It teaches us a lot, and it's been an excellent guide for what we do in the clinic, and that's a very, very good place to be in.

Our next question comes from Mani Foroohar from SVB Leerink.

Congratulations on the data and for publishing in our small local medical journal here in Boston. A couple of quick questions for you on this one. One of the pushbacks that we've gotten is some of the complexity and challenges in terms of clinical development in an indication where there's many therapies available or soon to be available as TTR. The payers who approved RNAis have been able to reach into the placebo data they had from previous studies to accelerate and provide synthetic control arms for their next-generation products. Are there opportunities for you to look at existing placebo data from other studies in the potential control arm? Or would you expect an active control? And then I have a quick follow-up question.

We will look at any database that we have access to. If there's proprietary databases that we can access, well, that's the way it is. Obviously, we're going to work with experts like Dr. Gillmore and people who are very, very well versed in the space to design a protocol that builds on the information that's accumulated and with the particulars of what the control will be, and that's something that we'll think through. We have some ideas already on how to do that in a very, very efficient fashion. And I don't think today is the place to go into what those particular studies will be while we're still working to complete the Phase I study. But interesting discussions, I'm sure, lie ahead.

Great. And a separate pushback, having spoken to yourselves about each of the companies in the TTR space already, has been around commercialization. Some of the existing players have argued that the cost of the gene editing approach would be prohibitive given onetime expense and particularly, the structure of payers and reimbursement in the U.S. Could you lay out how you see potential cost offsets for the -- in the existing therapies priced at between 1 to 2 Ferraris a year currently on a net basis. And the difference in the [ COG ] and potential price flexibility that you have in LNP approach versus the gene therapy comps, which are producing -- which require large quantities of manufactured virus.

Well, first of all, Mani, just to be clear, we don't have a viral approach here. So if people are invoking that as a base of comparison, that would be misguided. This is a manufacturing process that starts with essentially with small molecules or nucleotides. We have a phenomenal tech ops team who are charged with bringing efficient manufacturing procedures to not only our clinical trial material, but also to the marketplace when we get there. And I'm quite confident we will have a very, very competitive offering. I hear a lot about pricing. Since we've never offered an approach or a price, that is a strawman put up by people who do that at their own peril. And so I would say that we're going to be in an excellent position to bring not only medical value to patients, but I fully expect that will bring value to the health care system, and that's our objective here.

The next question comes from Liisa Bayko from Evercore ISI.

Congratulations on the data. Can you maybe talk about, as you sort of envision the journey from here to sort of Phase III, what are kind of the next steps? And as you think about a pivotal design, can you maybe talk through sort of the duration, kind of what size? I know it's still TBD, but you must have some framework and sort of like guidepost on how you're thinking about that. And then also, what kind of end points we'd be looking at?

Thanks, Liisa. I'll ask David to give some general concepts that we're working through. David?

Yes. Okay. Thank you, John. So the next step is really to get to the recommended dose for the Phase III study. So as you know, we're already at a point where we're getting a mean of 87% reduction. We have already started the dose escalation, the next cohort, so that you have a sense of where we're going in terms of where we want to be with dose. We do think we're fairly close given that we're already have greater reduction than the existing agents, and we do think that there's a big advantage to that as explained by Dr. Gillmore in his presentation. So once we do have that dose, based on all the data coming from our Phase I study, we really want to be careful in that selection. We will go on to these more advanced pivotal studies. I should say, we're already planning for that. We are -- we will be discussing it with health authorities around the world, the design of that trial. I think you can get a sense of what it will be from some of the other studies that are already ongoing. We don't think they're very far off in the way they design the studies. But when we get closer, we will talk about more precisely what that design is.

And how do you think about duration? And then I just -- that's a follow-up to that question. And then I just want to get a sense on sort of what incremental efficacy do you foresee between, let's say, somewhere in the 80% reduction in TTR versus if you kind of migrate up into the 90s. Do you expect some -- do you expect a material difference in terms of clinical outcomes? Or how should we think about kind of as you have additional kind of reduction in TTR, how that might affect clinical outcomes as you go for this kind of 80% to maybe 90% range? And how we should think about other compounds that are kind of in the 80% versus thinking something a little bit higher than that?

Yes. I think one thing to think about is what Dr. Gillmore showed is that for other diseases of amyloid, when you go from 90% reduction to complete remission, you get a major improvement in survival in that case. And if you also think about it another way, going from 80% to just 90% is already a 50% reduction. You've gotten rid of half of the residual protein, so that if the body is trying to get rid of the amyloid and there's half as much protein in the serum, we -- that's why we think that's happening, as explained by Dr. Gillmore. So we think that's an important piece.

Okay. And then just on the -- as you think about the duration, that was my follow-up question.

Yes. So in duration, understanding the mechanism of action, we are precisely targeting the TTR gene, a gene is no longer an effective gene. What we've shown preclinically, first in the nonhuman primate that looking as long as you can look beyond the year, you see no change in the reduction in TTR. In addition, we've done another experiment in mice that's shown in the New England Journal. And if you take out 2/3 of the edited mouse's liver, it will regenerate. And what we see is in the regeneration, the new cells are still edited. So the precursor cells are getting edited. And what we think that means is that will be permanent. Of course, we need to show that. And we will be bringing new data later in the year, but that's what we expect based on the mechanism of action.

The next question comes from Joon Lee from Truist.

Congrats on the impressive data. Have you harvested and sequenced different tissues, specifically the testes and the ovaries of nonhuman primate models that were dosed with the NTLA-2001 equivalent for on- and off-target edits? And what will be the risk of transgenerational inheritance of these on- or off-target edits? And lastly, what are you doing prospectively to monitor for such outcome? What would the FDA want to see? And when can we expect the U.S. IND?

As part of the preclinical work, we do biodistribution studies. And what we see is that the LNPs go where you would expect them to go, which is primarily to liver and a few other related tissues to very, very low levels. The risk of transgenerational passage, we think, is de minimis. We have no evidence to indicate that, that is anything other than a theoretical concern at this point. I guess if we have offspring as a result of the study that subsequently, I'm sure there'll be some interest in testing those patients, but the likelihood of finding something, I think, is de minimis.

The next question comes from Steve Seedhouse from Raymond James.

Congrats to everyone involved at Intellia and in the trial. I have 2 questions about NTLA-2001 and 2 very quick and related ones about HAE and the guide RNA. First, as part of the TTR development program, any plans on enrolling switched patients from RNAi therapy?

David, do you want to speak on that?

Yes. Thanks. Yes, so as part of -- in part 2, we do allow patients to switch from RNAi to our therapy.

Awesome. And Dr. Gillmore, you also showed the TTR reduction versus mNIS+7 plot for patisiran RNAi. But the same chart for antisense shows no correlation with TTR reduction despite having some patients that are like 80%, 90% reduced. And I don't -- I've never found a good explanation for it. I'm just curious if you have any comment as to why there's no correlation for antisense or what the sources of uncertainty are in quantifying TTR reduction?

Julian, if you want to speak to that, feel free.

Yes, absolutely. So there's a very clear correlation as I showed in every type of amyloidosis that have been treated between the degree of knockdown and outcome. And I think the thing to say in ATTR amyloidosis is that the data are fairly immature. We've only been able to knock down TTR with gene silencers for about 5 or 6 years. And there's a correlation emerging, but at the same time, the rate at which a patient or a particular individual gets rid of amyloid is always slow. But it does vary a little bit, so it's not a linear correlation. So you need a good deal of data with a good deal of patients to really establish that correlation strongly, and I'm sure it will emerge as it already is doing so. But I'm sure it will become firmer and firmer as we get more experience.

Very good. Okay. And for the company, the TTR knockdown that you're seeing -- or reduction rather that you're seeing so far in 6 patients looks like it's tracking with your guide RNA-adjusted PK/PD model versus the equipotent assumption and you published both of those. So I'm curious for your HAE product, are you selecting dose levels that adjust for the sgRNA potency differences? And what is the potency difference for the HAE guide RNA in humans versus primates?

Thanks for the question, Steve. We're not going to go into relative potencies of guide versus NHP guides and different indications, other than to say the following. I spoke to it earlier. We think we have very robust preclinical models. We feel very heartened now with the data we have that those models are very, very good guide to what to expect to see in the clinic. And we'll take all of that information, including preclinical work for HAE as we figure out where we're going to start in the next study. And I hope to be able to report similarly robust findings, which we'll do when we have them.

Terrific. Last question. I do appreciate it. Is it important in the TTR study to enroll cohort for even if you've optimized TTR reduction in Cohort 3 just so you can get the LNP safety data in the event that HAE or some other indications down the road doesn't have our four to fivefold more potent guide RNA? Or would you just dose to higher LNPs down the road if you need to and stop a Cohort 3 here?

Thank you for the question. What we really like where we are right now is that we're well into a therapeutic desired target space. There's no obligation to treat or to work through all 4 cohorts. There is some flexibility in the protocol, however, for us to explore intermediate doses should we desire to do that. That's something that we'll confer with our investigators and experts to think through what the merit of that actually is. Obviously, we want to be in a position to have a good dose selected as we expand the patient population in step 2. And we're looking for as much information as we can get to make the best possible decisions. So lots of interesting assessments lie ahead. And as the information comes in, David and his team, I'm confident, will make a good decision.

The next question comes from Mike King from H.C. Wainwright.

Sorry, I'm losing my voice here a little bit. And let me add to the congratulations, especially by your guys hitting the mark so nicely on the initial dosing levels. A couple of science key questions. I'm just curious, when you look at the supplemental data from NEJ article, at the 0.3 mg per kg dose, you had a -- well, first of all, you had 3 different genetic subtypes. Is there any correlation between the genetic subtype and the 1 patient who had the 96% response reduction in TTR?

The answer is no, not that we can draw.

Okay. And then further to that, the spread between the responses seem to be quite a bit larger. I don't know if that's just the play of small numbers or whatever the case may be. But in siRNA dogma, the higher the dose, the lower the variability. So I wonder if you wanted to maybe comment on that.

Well, we were pleased with how tight the data is and really gratified with that. And you're right, as you reach a maximal effect, one would expect that whatever variability there is to really start to collapse. Once you hit the maximum effect, that's 1/2 of the variability. And we're very, very close to that now. So I would expect with the ongoing work that that's the sort of observation we'll have. But that lies ahead. And when we have the data to look at it, I'm sure we'll be sharing it.

Okay. Super. And also wanted to talk maybe about the decay curves. It seems like they're sort of biphasic. I'm just wondering why if you've looked into that maybe from a preclinical standpoint of there's some sort of biphasic effect going on. Or would we expect some more linear response rates as we get greater numbers?

Well, within a patient, there are different compartments. You have a protein that needs to be cleared. You have mRNA that needs to be cleared. And then at the beginning, there's the early effect on the gene itself. So there are compartments, but all that plays out very, very early on. And the idea here is that once the gene is inactivated, the maximal effect is the effect. And that's in variant over the course of, we believe, the patient's life. So while the compartments are interesting, probably in the first few days relative to how you think pharmacokinetically about a standard drug, it really doesn't apply thereafter.

Right. Okay. And then just finally, from a clinical standpoint, can you share with us your thoughts on the timing of when you might start looking at the wild-type TTR patient population? Do you want more dosing and safety experience? Or do you feel good enough with the data that you have now that the wild types might be on the docket fairly soon?

David, how are you thinking about wild types?

Yes. So we do expect those patients to have the same effect with the drug. So that's -- we think we'll know the right dose to go with. And as I sort of mentioned, we're already in discussions about how to expand the population to the patients with cardiomyopathy and wild-type TTR. So that will be -- you'll be hearing more about that in the coming months.

This concludes our question-and-answer session as well as the conference. Thank you for attending today's presentation. You may now disconnect.