Study Result

Jun 28, 2021

And welcome to Intellia Therapeutics Investor Event to discuss the interim clinical data from the Phase 1 study of NTLA 2,001. 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 1 clinical trial of NTLA-two thousand and one. 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 and 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. Doctor. John Leonard, our Chief Executive Officer, will begin with brief introductory remarks. Doctor. Julian Gilmore, Professor of Medicine at the National Amyloidosis Centre and physician at the Royal Free Hospital in the U. K, will review the interim results. Doctor. Gilmore is a respected key opinion leader on the treatment of amyloidosis and the National Coronary Investigator on our clinical trial in the U. Doctor. David Leadwall, our Chief Medical Officer, will then speak to the next steps in the clinical development of NTLA-two thousand and one. And Doctor. Laura Seplaranzino, 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 today. 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 Intelli 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, Lena Welcome everyone. Today we're incredibly proud to share positive interim data from Part 1, the dose escalation portion of our Phase 1 study evaluating NTLA-two thousand and one as a potential one time treatment for transthyretin amyloidosis also known as ATTR amyloidosis. NTLA-two thousand and one is not only our lead candidate, but also the 1st systemically delivered CRISPR based therapy to enter clinical development. That is the 1st CRISPR based drug candidate to be intravenously administered and edit the human genome in the target cells inside the body, to severe in vivo approach. As such, the study is intended both to evaluate NTLA-two thousand and one as a potentially curative treatment option for ATTR amyloidosis and to validate our in vivo editing and delivery platform. Over 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-two thousand and one the only treatment with curative potential that may both halt and reverse disease progression with a single dose. Despite availability of chronically administered therapies, there remains unmet need in patients with ATTR amyloidosis. We believe a single dose therapy that this is greater TTR reduction will offer significant benefit to patients and value to our healthcare system over the current standard of care. For Intellia, this is a profoundly important milestone. We've worked hard to advance our platform the point of clinical validation. We recognize that these results are significant to our broader in vivo pipeline development 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 are 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 are grateful to the patients who are participating in the trial. And for the field, as 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 1 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 sought to harness the power of CRISPR as a therapeutic modality by developing in vivo and ex vivo approaches. For genetic thesis, we've utilized an in vivo approach where CRISPR is the medicine. We leverage our proprietary non viral lipid nanoparticle based CRISPR delivery 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 at a genes from patient derived cells 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 in CRISPRCas9 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 a presentation at the Peripheral Nerve Society with today and we note the publication of this work in the New England Journal of Medicine on Saturday. Based on interim data and 6 patients from Part 1 of our first in human study evaluating NTLA-two thousand and one, treatment with NTLA-two thousand and one led to a dose dependent response and serum TTR reduction. In our second dose level, we achieved an average TTR reduction of 87% at day 28, including one patient with a 96% TTR reduction. These deep TTR reductions support our view that NTLA-two thousand and one has clear potential to deliver life changing benefits for patients with ATTR amyloidosis. Importantly, We observed encouraging safety and tolerability for our proprietary lipid nanoparticle or LNP delivery technology and RNA CRISPR cargo with no serious adverse events in the first six patients by day 28. Altogether, the data suggests that we can achieved targeted in vivo editing for desired pharmacological effect. And although there's 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 Doctor. Julian Gilmore who will take us through the data in detail and offer his perspective as the National Coordinating Investigator on our Phase 1 trial in the U. K. And a leading physician specializing in treatment of ATTR amyloidosis. Doctor. Gilmore, Over to you. Thank you very much. So for listeners who may not be familiar with trans thyroid amyloidosis, 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 transpiratin 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 caused debilitating symptoms with a high burden of disease for patients and caregivers. Intellia's Phase 1 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-two thousand and one. However, there's no conceivable reason to believe that the effects of NTLA-two thousand and one 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 percent 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've achieved a greater than 50% reduction, but less than 90% reduction. The Next line up is patients who've achieved what hematologists call a VGPR, which is a greater 90% reduction in the 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 octiles of serum amyloid A protein, that's the protein that is amyloid falling 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 uropathy score. We see that lower serum TTI has been observed to be associated with better subsequent control of symptoms from disease. So taken together these data form a 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 1st in human trial of an in vivo CRISPR Cas9 based gene editing therapy, NTLA-two thousand and one, designed to edit the TTR gene in patients with transthyroid 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 transpiritin. 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 a particularly attractive treatment strategy. NTLA-two thousand and one 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 is transported directly to the liver where it's taken up by the LDL receptor on hepatocytes. After endocytosis released into the cytoplasm, the Cas9 mRNA is translated producing the Cas9 enzyme, which interacts with the single guide RNA to form the CRISPR Cas9 ribonuclear protein or RNP complex. The RNP complex enters the 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 bases in the target site. These frameshift alterations 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-two thousand and one. This was performed in cultured primary human hepatocytes. The vertical line here marks the concentration at which we routinely observe 90% reduction in TTR protein production in the EC90. Above the EC90, NTLA demonstrated saturating levels of TTR gene editing accompanied by greater than 95% reduction and NTTR 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 titrations. 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-two thousand and one. 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-two thousand and one threefold greater than the EC90. Preclinical in vivo studies were conducted in 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 in monkeys received the NNP at doses of 0, 1.5, 3, and 6 milligrams per kilogram of the RNA cargo on day 0 and followed for 3 in 67 days. Vertical lines represent standard deviations across 3 main animals in each group. Now the single dose of 3 milligrams per kilogram achieved a durable reduction in circulating TTR protein of approximately 95% after day 28. Safety studies established dose range at which no adverse effects of NTLA-two thousand and one were observed with near complete sustained reduction in serum TTR following a single administration. Higher doses, the adverse effects in the monkeys were dose dependent, transient, reversible and monitorable. 1st in human study with NTLA-two thousand and one is a 2 part open label multicenter study in patients with hereditary ATTR amyloidosis and polyneuropathy. Part 1 is 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 tenth 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 objectives of the first interhuman study are to evaluate safety, tolerability, PK and PD, the latter by serial measurements of TTR levels. I will report data on the first six patients from the first two dose escalation cohorts included in Part 1. Bear in mind, participants received a one time infusion of NTLA-two thousand and one on day 1 of the study. Here are the demographics of these first six 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 Flinoxart 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-two thousand and one was generally well tolerated in the acute phase with AEs all being Grade 1 and mostly unrelated 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 excursions 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 range 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 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-two thousand and eleven 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-two thousand and one treatment was well tolerated in the acute phase with all AEs being of 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 would like to acknowledge the patients, contract research organizations involved in the trial, my co investigators at the National Amyloidosis Center, Richmond Pharmacology and the University of Auckland and of course the many members of Intellia Therapeutics and Regeneron Pharmaceuticals who are responsible for the development of NTLA-two thousand and for the development of NTLA-two thousand and one. Now I'd like to turn the call over to David Lebowle. Thank you, Doctor. Gilmore. Your leadership in this trial has been critical for its success. We also appreciate your vision for 2,001's potential improve on patient 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 2,001 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 as indicators of proof of concept for our platform, an important step towards identifying the recommended dose for 2,001. As you can see, we have achieved our goal. We're highly encouraged by these interim results, which to date show that 2,001 was associated with only grade 1 adverse events in the first 2 dose cohort. 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 experiment, we believe 2,001 has the potential to be a 1st in class single dose treatment for patients with ATTR amyloid doses. 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 2,001 at 1 milligram per kilogram dose level. We plan to provide additional data from Part 1 of this 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 2,001 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 this 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 this 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, Lara Sephoraanzino, will review today's update in context of our platform and broader in vivo pipeline. Thank you, David. These results are significant in terms of what they mean for ATTR amyloidosis patients. We're equally excited about what they may imply for our efforts beyond NTLA-two thousand and one. As John noted, Intellius 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 treatment for multiple diseases both rare and prevalent. These results demonstrate we can deliver to hepatocytes and by swapping out the target site 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-two thousand and two, our candidate in development for hereditary androedema or AJE. NTLA-two thousand and two leverages the same LNP and RNA cargo now targeting the KLKV1 gene in the liver to permanently reduce plasma kaliqrine protein and activity, a key mediator of the disease. This approach is designed to provide continued suppression of Kallikrein activity and eliminate HAE attacks. Today, alongside the NTLA-twenty one interim results, we're very excited to share that we have filed our first CTA NTLA-two thousand and two in New Zealand. And on the basis of learnings from NTLA-two thousand and one, including the results discussed today, we expect to move faster and begin evaluation at the higher dose with NTLA-two thousand and two. We plan to enroll our first patient in a Phase 1 study of NTLA-two thousand and two 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 hypotheses 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 meaningful validation for our modular platform and programs well beyond NTLA-twenty 1. It takes a path forward de risking 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 Doctor. Gilmore. We appreciate the time you spent with us today. As you can see, observations so far from our Phase 1 study of NTLA-two thousand and one are very encouraging, offering support at both program and platform levels. For patients with ATTR amyloidosis, we believe these interim results point to NTLA-two 101'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 in to 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 and 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-two thousand and one, we plan to provide additional data from Part 1 of 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-two thousand and two or HAE, now that we've filed our first CTA, we plan to enroll our 1st patient in a Phase 1 study by the end of this year. For NTLA-five thousand and one for AML, we are on track to submit an IND or equivalent regulatory filing in mid-twenty 21. And across our R and 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 inactivation 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 to 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 sharing more from NTLA-two thousand and one 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. Thank you. We will now begin the question and answer session. Our first question comes from Maury Raycroft from Jefferies. Please go ahead. Hi, good morning everyone and congrats on the update. Let's see, just starting off, I'm assuming you have 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 are seeing beyond 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 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, more 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 virological 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 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. Great. Okay. Thanks for taking my questions. I'll hop back in the queue. Sure. The next question comes from Salveen Richter from Goldman Sachs. Please go ahead. Good morning and congratulations on the data. Just a couple of questions for me. How are you monitoring Potential off target edits for patients in this study and if you could comment on the read through to cardiomyopathy and then as well given you have read through 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? Thank you. Thanks, Helane. 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 supra pharmacologic concentrations. I think Doctor. Gilmore 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 patients ever going to get. What we've demonstrated is that at those That give the results reported today, there's no interaction with sequences other than the targeted ones. So we're quite confident that from the standpoint of off targets, we know exactly what we're doing. We know exactly where CRISPR is producing its effects. 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 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 2,001 or 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, The second dose where we've seen only grade 1 safety events in this population, in the TTR population. The 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 1 yet. I think you 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 Wong from Barclays. Please go ahead. NTLA. I wanted to say that this is a transformative for the 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 off targets, we understand that I think Doctor. Gilmore also mentioned human satellite has 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 non human primates data. It seems like translation from non human primates data to HUMI seems much better. When we look at Alnylam actually showed pretty consistent with FDA guidance basically threefold differences and our non data showed very consistent, but in your case seems much better. So any thoughts on like did you optimize the lipid nano 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, Gina. There's a lot there. First of all, the work that we do with our targets It 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 yet to take that into consideration relative to the non human 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 preclinical models to the clinic and benefit from those insights and then capture the additional data that's particular to the a test article that we're doing. So we're quite excited. I give my preclinical team a strong A with the work that they've done and we think That puts us in a really good position for where we go with HAE. 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. What that particular dose will be is 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 Faroohar from SVB Leerink. Please go ahead. Hey, 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 and an indication with many therapies available or soon to be available as TTR. The players who approved RNAi have been able to reach into the placebo They had some 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 as a potential control arm or would you expect an active control? And then I have a quick follow-up question. We will look at a database that we have access to. There is proprietary databases that we can access. Well that's just the way it is. Obviously we're going to work with Experts like Doctor. Gilmore 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, I mean that's something that we'll 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 Our studies will be while we're still working to complete the Phase 1 study, but interesting discussions I'm sure lie ahead. Great. And a separate pushback having spoken to yourselves, well, each of the companies in the TTR space already has been around commercialization. Some of the existing players have argued that the cost of a gene editing approach would be prohibitive given one time expense and particularly 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 Ferrari's a year currently on a net basis. And the difference in the COGS 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 NTLA. 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 straw man 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 it will bring value to the healthcare system and that's our objective here. Thanks for clarifying that. I'll hop back. I'm sure there are other questions. Congrats again. The next question comes from Liisa Bayko Ko from Evercore ISI. Please go ahead. Hi, congratulations on the data and thanks for taking the question. Can you maybe talk about as you sort of envision the journey from here to sort of Phase 3, What are the 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? And 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 endpoints to be looking at? Thanks. Thanks, Lisa. I'm going to ask David to give some general concepts that we're Thank you, John. So the next step is really to get to the recommended dose for the Phase 3 studies. So as you know we're already at a point where we're getting a mean of 87% reductions. 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 Doctor. Gilmore in his presentation. So once we do have that dose based on all the data coming from our Phase 1 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 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 wanted 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 material difference in terms of clinical Gomzer, 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 from 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? I think one thing to think about is what Doctor. Gilmore showed is that for other diseases 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 another way going from 80% to just 90% is already a 50% reduction. You've gotten rid 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 Doctor. Gilmore. So we think that's an important piece. Okay, thanks. And then just on the as you think about that duration, that was my follow-up question. Yes. Thanks. 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 of the non human primates that looking as long as you can look beyond a year, you see no change in the reduction in TTR. In addition, we've done another experiment in mice. It's shown in New England Journal. And if you take out 2 thirds of an edited mouse's liver, it will regenerate. And what we see is in the regeneration, new cells are still edited. So the precursor cells are getting edited and what we think that means and that will be permanent. Of course we need to show that We will be bringing you data later in the year, but that's what we expect based on the mechanism of action. Okay. Thank you. The next question comes from Joon Lee from Truist. Please go ahead. Hi, thanks for taking our questions and congrats on the impressive data. Have you harvested and sequenced different tissues, specifically the testes and the ovaries of non human primate models that were dosed with the NTLA-two thousand and one 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? Thank you. As part of the preclinical work, we do biodistribution studies and what we see is that the LMPs go where you would expect them to go, which is primarily to liver and a few other related tissues at 2 very, very low levels. The risk of transgenerational passage we think is de minimis and 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. Please go ahead. Good morning. Congrats to everyone involved at Intellia and in the trial. I have two questions about NTLA-two thousand and one and 2 very quick and related ones about and the guide RNA. First, as part of the TTR development program, any plans on enrolling switch patients from RNAi therapy? David, do you want to speak? Yes, thanks. Yes, as part of in part 2, we do allow patients to switch from RNAi 2R therapy. Awesome. Thank you. And Doctor. Gilmore, you also showed the TTR reduction versus MNIST plus 7 dot 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 thank you. There's a very clear correlation as I showed in every type of amyloidosis that's ever 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 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 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? This is very good. Okay. And for the company, the TTR knockdown that you're seeing or reduction rather that you're Jing, so far in 6 patients, looks like it's tracking with your guide RNA adjusted PKPD 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 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 partnered now with the data that we have that those models are very, very good guides to what to expect to see in the clinic. And we'll take all of that information including preclinical work for HAD 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 4 even if you've optimized TTR reduction in cohort 3 just you can get the LNP safety data in the event that HAE or some other indication down the road doesn't have or 4 to 5 fold more potent guide RNA or would you just dose to higher LNPs down the road if you need to and stop at Cohort 3 here? Thank you. 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 In the protocol however for us to explore intermediate doses should we desire to do that that's something that we'll confer for with our investigators and experts to think through what the merit of that actually is. Obviously, we want to be in a position and 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 decision. So lots of interesting assessments lie ahead And as the information comes in, David and his team, I'm confident we'll make a good decision. Thanks. Congratulations. Thank you. The next question comes from Mike King from H. C. Wainwright. Please go ahead. Good morning, guys. Sorry, I lose my voice here a little bit. Thanks for taking my call and let me add to the Congratulations, especially by you guys hitting the marks so nicely on the initial dosing levels. Couple of science geek questions. I'm just curious, when you look at the supplemental data from the 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 one 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 it'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 one half 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, 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 have looked into that maybe from a preclinical standpoint of there is 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 invariant over the course of we believe the patient's life. So while the compartments are interesting probably in the 1st few days relative to how you think NTLA pharmacokinetically about a standard drug, it really doesn't apply thereafter. Right. Okay. Well, thanks for indulging me on that. 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? Thank you. David, how are you thinking about wild type? 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 iGTR. So that will be you'll be hearing more about that in the coming months. Great. Thanks so much. This concludes our question and answer session as well as the conference. Thank you for attending today's presentation. You may now disconnect.