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

Good afternoon, and welcome to Intellia Therapeutics investor event to discuss the interim clinical results 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 Ian Karp, Senior Vice President of Investor Relations and Corporate Communications at Intellia. Please proceed.

Thank you, operator, and good afternoon, everyone. Welcome to Intellia's presentation of additional interim data from the Phase I clinical trial of NTLA-2001 for the treatment of ATTR amyloidosis. Earlier this afternoon, we issued a press release detailing the results from our ongoing study. This release and the accompanying slide 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 Intellia's website. Before we begin, allow me to introduce our speakers and share an outline for today's call. First, Dr. John Leonard, our Chief Executive Officer, will bring introductory remarks and a brief overview of Intellia's full spectrum genome editing platform and pipeline; next, Dr. Ed Gane, Professor of Medicine at the University of Auckland, Chief Hepatologist at the Auckland City Hospital and clinical investigator for Intellia's Phase I study of NTLA-2001 in New Zealand will review the interim clinical results; Dr. David Lebwohl, Intellia's Chief Medical Officer, will then highlight the next steps in the clinical development of NTLA-2001; and finally, John will return for some closing remarks before we open up the call for your questions. At this time, I'd 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. As a reminder, this presentation contains interim data from our ongoing Phase I study. NTLA-2001 has not been approved by any health authority. With that, let me turn the call over to John.

Thank you, Ian, and welcome, everyone. Today, we're extremely pleased to share additional positive interim data from our ongoing Phase I study, evaluating NTLA-2001 as a potential onetime treatment for people living with transthyretin amyloidosis also known as ATTR amyloidosis. In June of last year, Intellia made history when we presented the first ever clinical data showing it's possible to edit a target gene inside the body or in vivo through a systemically delivered CRISPR-based candidate. It was a first for Intellia and our partner, Regeneron, and for the field of medicine. On Slide 5, you can see just a few of the headlines that followed the landmark data published in the New England Journal of Medicine that spoke to the transformative potential of our investigational therapy. The additional data reported today increases our enthusiasm for NTLA-2001 and our platform. It provides the first evidence that a single dose CRISPR-based investigational therapy may provide a lifelong effect for patients. In part 1 of the polyneuropathy arm, treatment with NTLA-2001 resulted in a rapid, deep and durable reduction of the disease-causing protein with dose-dependent responses across all 4 cohorts. Since our first disclosure from the initial 6 patients, we are now reporting updated interim data from an additional 9 patients, Furthermore, in the initial cohorts, we've collected serum TTR data out 9 to 12 months post treatment. And importantly, NTLA-2001 was generally well tolerated at all dose levels. At the 1 milligram per kilogram dose, which is the highest dose evaluated, a mean serum TTR reduction in the 6 patient study reached 93% by day 28. Notably, the mean TTR reduction remained at 93% through the observation period for this cohort, which ranged from 2 to 6 months. At these deep and persistent levels of TTR reduction, we believe NTLA-2001 has the potential to halt and perhaps even to reverse the course of this disease. NTLA-2001 continues to represent a potential best-in-class onetime treatment option for people living with ATTR amyloidosis. More broadly, these data provide important support for our broader pipeline and platform. Our technical achievement marks a significant step forward in bringing forth CRISPR-based therapies as a potentially curative treatment for people living with certain life-threatening diseases. This work is central to our mission, and I could not be prouder of the team at Intellia working tirelessly on behalf of patients. At Intellia, we're building a full spectrum genome editing company by deploying the industry's broadest and deepest toolbox to fully realize the promise of CRISPR-based medicine. Today's results are only possible because of this solid foundation, combining CRISPR with novel editing and delivery solutions. These data give us great confidence in the robustness of our platform which enables us to apply CRISPR both in vivo, as is the case with NTLA-2001, as well as ex vivo, where we are developing cell therapies to treat cancer and autoimmune diseases. Notably, with these interim data, we believe we have unlocked the liver with our lipid nanoparticle delivery system. We believe this modular platform significantly increases the probability of success of our in vivo programs as we apply our technology to other diseases. As we move to Slide 7, you can see the beginning of the output from our modular platform and robust research engine. In the last 6 months, we've expanded our in vivo pipeline. We're now advancing 5 development candidates, including 2 that are in clinical development and 2 that we recently nominated as our gene insertion candidates. We also continue to accelerate our research programs across a variety of indications. For our next most advanced program, NTLA-2002, we look forward to providing an update in the second half of this year with initial results from our ongoing Phase I/II trial in patients with hereditary angioedema. On the ex vivo side, which is highlighted on Slide 8, patient enrollment is underway in our first-in-human study of NTLA-5001, an engineered TCR T cell therapy for the treatment of acute myeloid leukemia. In addition, we were pleased to announce last week our first allogeneic development candidate NTLA-6001 for CD30-positive expressing hematologic cancers. Our research engine continues to yield novel CRISPR-based investigational candidates across in vivo and ex vivo applications. We look forward to sharing more about our pipeline and platform progress beyond NTLA-2001 as the year goes on. In a few moments, Dr. Ed Gane will review the latest NTLA-2001 data in detail. Before that, I'd like to highlight a few of our overarching principles that serve as the foundation for our approach to the development of genomic medicines. We begin by ensuring that we can deliver our CRISPR-based therapeutic candidates to the intended tissue and then precisely edit the target gene. Fundamental to this is our focus on achieving a favorable safety profile for each investigational candidate. From there, in the case of gene knockout candidates, we seek to reduce the levels of the disease-causing protein to therapeutically relevant levels. And of course, the ideal drug candidate will demonstrate consistent results across patients with an effect that is durable over time. With these key principles as a backdrop, I'd now like to invite Dr. Gane to review the latest data from the ongoing Phase I trial and offer his perspective on its significance. Dr. Gane is the national coordinating investigator of our Phase I trial in New Zealand and a leading physician specializing in treatment of ATTR amyloidosis. Dr. Gane is a Professor of Medicine at the University of Auckland, and Deputy Director of New Zealand Liver Transplant Unit as well as an author of more than 600 articles in peer-reviewed journals.

Thank you. I will present the interim data from the polyneuropathy arm of 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. NTLA-2001 is also being evaluated in patients with cardiomyopathy in an arm of this Phase I study. Interim results from this arm will be released at a future presentation. Here are my disclosures. Transthyretin amyloidosis is a rare, progressive and fatal disease caused by the accumulation of amyloid deposits composed of misfolded transthyretin protein. Transthyretin amyloidosis consists of 2 forms: hereditary and wild type, which cause a spectrum of clinical disease. The rate of new diagnosis is increasing where the hereditary type is estimated to affect 50,000 individuals worldwide. It has a variable phenotypic presentation that primarily features either peripheral and autonomic polyneuropathy or cardiomyopathy. To some extent, patients can have a mixed phenotype. Some neuropathy patients can have signs of cardiac involvement, and some cardiomyopathy patients can have neurological symptoms. The wild type is primarily a cardiomyopathy that is estimated to affect upwards of 500,000 people. It is an increasingly recognized cause of heart failure in individuals over the age of 50. It is progressive and typically fatal within 3 to 10 years. It has recently been recognized that the majority of affected individuals are never diagnosed. Therapy in ATTR amyloidosis is directed to reducing the circulating amyloid-forming protein. Long term, repeated administration of gene-silencing therapies such as siRNAs and antisense oligonucleotides decrease TTR mRNA and reduce serum TTR by around 80%. Long-term therapy can result in stabilization of neuropathy and greater reduction of TTR is expected to lead to better clinical outcomes, including improvements in the quality of life and more pronounced regression of the disease. NTLA-2001 is being studied as a potential onetime treatment to knock out the TTR gene for the treatment of ATTR amyloidosis. NTLA-2001 is an investigational CRISPR-Cas9 based in vivo gene editing therapy. It consists of the single guide RNA molecule that targets the human TTR gene and a human optimized mRNA sequence of CRISPR gene-edited Cas9 protein, both encapsulated in a lipid nanoparticle or LNP. This cartoon summarizes the mechanism of action of NTLA-2001. Following intravenous administration, the lipid nanoparticles are transported directly to the liver which are taken up via the LDL receptor on their hepatocytes of the endocytosis and released into the cytoplasm. The Cas9 mRNA is translated producing the Cas9 enzyme to interact with a single guide RNA to form the CRISPR CAS9 ribonucleoprotein complex. This complex acts as a nucleus as a 20 nucleotide sequence at the 5 prime ends of the guide RNA binds to the patient's DNA double helix at the complementary target size. This leads to precise knockout of the targeted TTR gene sequence, which consequently stops production of the transthyretin protein. Our extensive genome wide search using computational and laboratory-based techniques for loci with the potential for off-target editing identified 7 validated loci in non-coding regions with the potential for off-target editing by NTLA-2001. These loci were evaluated for off-target editing by treatment of primary human hepatocytes with NTLA-2001. No evidence of off-target editing was detected, even at NTLA-2001 concentration threefold greater than the EC90, which is a concentration of which 90% of TTR protein reduction is achieved. These data demonstrate the high specificity of NTLA-2001 for the TTR gene. Preclinical in vivo studies were conducted in nonhuman primates, specifically the cynomolgus monkey. This graph shows the mean percentage reduction from baseline in the serum TTR protein concentration against time. Following a single intravenous dose of 1.5, 3 and 6 milligrams per kilogram on day 0 and followed for over 360 days. Our controlled cohort receiving no treatment was included for comparison. The vertical lines represent standard deviations across the 3 animals in each group. Two important observations can be made from these results. Firstly, there was a dose response relationship with the highest doses achieving more than 95% reduction in circulating transthyretin, and lower doses demonstrating a more variable response. Secondly, the response was durable for at least 1 year after that single dose. Safety studies demonstrate that the adverse effects of NTLA-2001 were dose-dependent, transient, reversible and monitorable. A dose of 3 milligrams per kilogram in nonhuman primates corresponds approximately to the 1 milligram per kilogram dose in humans. This arm in the first-in-human study with NTLA-2001 is a 2-part open-label multicenter study in patients with hereditary ATTR amyloidosis with polyneuropathy. Part 1 is a single ascending dose portion of the study, with a minimum of 3 patients in each of the 4 dose-escalating cohorts on 0.1, 0.3, 0.7 and 1 milligram per kilogram. Part 2 will consist of administration of the dose selected from Part 1 to a dose expansion cohort initially for 8 subjects. The primary objectives of the first in-human study are to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics, the latter by serial measurement of serum TTR levels. I will report data on all 15 patients enrolled in the 4 dose escalation cohorts included in Part 1. This table summarizes the demographics of the 15 study participants. The median age is 55, with a range of 19 to 70 years, 9 men and 6 women were enrolled. Most subjects self-reported as Caucasian. Median weight was 83 kilograms with a range from 59 to 111 kilograms. 7 different mutations were represented in these 15 patients. The most common were T80A, E62D and S97Y. Most patients had early disease with mild neuropathy and minimal or no cardiomyopathy, 2 subjects have peripheral neuropathy with the disability scores 2, and 1 subject had cardiomyopathy with a NYHA Class II. 7 of the 15 subjects had elevated NT-proBNP measurement at baseline. The next 2 slides summarize the safety data from this study. NTLA-2001 was generally well tolerated across all dose levels. All adverse events regardless of relationships to treatments are presented. The most frequent adverse events were headache, infusion-related reactions, back pain, rash and nausea. In the majority of patients, the maximum severity of adverse events through the entire observation period was Grade 1. Infusion-related reactions were typical for those observed with LNP infusions, characterized by back pain, headache or fever. These were all graded as mild and resolved within 24 hours without clinical sequelae. All patients completed the infusions, received their full intended doses and remain on the study. There was a single serious adverse event of vomiting in a patient with a pre-existing history of autonomic neuropathy and prior hospitalization for gastroparesis management. This dose-limiting toxicity, considered possibly related to study drug, required expansion of the 1 milligram per kilogram cohort to a total of 6 subjects. The cohort completed enrollment with no additional DLTs. No clinically significant laboratory findings were observed. Transient grade 1 liver enzyme elevations were observed, which resolved shortly following the infusion and were not recorded as adverse events. The maximally tolerated dose was not reached. This table summarizes the most common clinical adverse events with reported grades and column for each dose level and for all subjects in the last column to the right encircled in blue. These adverse events were predominantly transient, reversible and most frequently grade 1. The next 4 slides summarize the pharmacodynamic effects from part 1 of this first in-human study. This first figure depicts the mean TTR reduction from baseline at 28 days post treatment for each of the 4 dose cohorts. Doses of 0.3 milligrams per kilogram and above achieved mean reductions of more than 80%, and the highest dose of 1 milligram per kilogram achieved a mean reduction of 93%. There was a dose response relationship but increasing the dose from 0.1 to 0.3 milligrams per kilogram resulted in a larger incremental decline in serum TTR than from increasing from 0.3 to 1 milligram per kilogram. I should note that the 0.1 milligram per kilogram was the first ever in-human specific administration of our lipid nanoparticle CRISPR/CAS9 gene editing therapeutics. The purpose of this dose cohort was to evaluate safety. It was encouraging that not only was the agent safely administered, but that all 3 subjects had measurable reductions in serum transthyretin. We intend to offer retreatment to these subjects with a higher dose of NTLA-2001 and report on these results in the future. Closer inspection of the data in the 1 milligram per kilogram cohort reveals that 4 of the 6 subjects had reductions greater than 93%. All subjects have reductions in serum TTR at day 28 that were within 10% of the mean and greater than 80%. These findings on magnitude and consistency as well as deciding that the 0.3 and 0.7 milligram per kilogram suggests that this dose has neared a saturable effect. This figure depicts the mean percentage reduction from baseline of serum TTR plotted at 7, 14, 28 and 56 days post infusion for each of the 4 dose cohorts. Similar to the nonhuman primate data shown earlier, dose-dependent reductions in serum TTR were observed with nadir reached at approximately day 28. This figure demonstrates the durability of effect of NTLA-2001. In the bar graph, each pair of bars depicts the mean percent reduction for a dose cohort, with the hash bars showing the mean reduction at day 28, and the solid bars the mean reduction for the latest measurement from each patient. The duration of follow-up ranges from 2 months for the most recent cohort, up to 12 months for the first cohort. The mean reduction in TTR of circa day 28 were sustained through the latest available time point. For example, in the 1 milligram per kilogram dose cohort, the mean reduction was 93%, both at day 28 and at the last available follow-up. In conclusion, a single intravenous administration of NTLA-2001 in patients with hereditary ATTR amyloidosis and polyneuropathy achieved rapid and profound dose-dependent reductions in serum TTR protein concentrations, with the 0.3, 0.7 and 1 milligram per kilogram cohort receiving a mean decrease from baseline of 87%, 86% and 93%, respectively. Reduction in serum TTR were maintained through the last available follow-up measurements. NTLA-2001 was generally well tolerated with nearly all AEs being of mild severity. The maximum tolerated dose was not reached. Based on the safety, activity and pharmacodynamic profile of NTLA-2001 observed in Part 1, a fixed dose of 80 milligrams has been selected for evaluation in Part 2 of the study. 80 milligrams is expected to result in consistent and deep reductions in TTR comparable to the 1 milligram per kilogram dose. These data confirm and extend the early findings reported last year on this pioneering trial, demonstrating the promise of CRISPR-based in vivo gene editing in humans. Contributions of numerous individuals made this project possible. Foremost, we thank the patients who participated in the study and their family and loved ones who have and continue to support them. I am grateful to my coinvestigators and their teams on this study. I'd like to thank Dr. Jorg Taubel, Björn Pilebro, Julian Gillmore, Justin Kao and Marianna Fontana and the research staff at New Zealand Clinical Research, Richmond Pharmacology and the University of Umea. I'm grateful for the support from multiple teams at Intellia Therapeutics and Regeneron Pharmaceuticals. My Intellia colleagues additionally appreciate support of their contractors and their vendors as listed here. With that, I'll turn over the next part of the presentation to Intellia's Chief Medical Officer, David Lebwohl. Thank you.

Thank you, Dr. Gane. We appreciate your leadership on this trial and your shared conviction in 2001's potential to be a transformative treatment for patients with ATTR amyloidosis. We're highly encouraged by these additional interim results from our ongoing Phase I trial of 2001. As a brief reminder, we have included a summary of the trial design on Slide 32. Our first-in-human study includes a polyneuropathy arm, which Dr. Gane just presented data. We also have recently expanded the study to include a cardiomyopathy arm. This portion of the study will be evaluating 2001 in patients with either hereditary or wild-type ATTR amyloidosis with cardiomyopathy. Please now turn to Slide 33, where I'll highlight our key next steps. Upon completing Part 1 of the polyneuropathy arm, we have selected the fixed dose of 80 milligrams, which is expected to deliver a similar exposure to 1 milligram per kilogram for further evaluation, pending regulatory feedback. The dose selection and change from weight-based dosing to fixed dosing is based on the safety, tolerability, pharmacokinetic and activity profile observed in the polyneuropathy arm. The fixed dose is simpler to administer and reduces risk of dosing calculation errors. We are planning to initiate Part 2, a single dose expansion cohort later this quarter where we expect to enroll 8 patients. On the cardiomyopathy arm, we continue to dose patients in separate dose escalation cohorts starting at the 0.7 milligram per kilogram dose and with plans to evaluate the 1 milligram per kilogram dose. Following the results from this dose escalation portion, we then plan to move to the dose expansion stage, which may also transition to a fixed dose. Based on the efficacy and safety data we have observed, we expect to move ahead towards pivotal studies for both forms of ATTR amyloidosis, with an initial focus on patients with cardiomyopathy manifestations of the disease. This includes engaging with regulatory agencies, including the U.S. FDA, to discuss later-stage trial design. We also plan to present additional clinical data from this Phase I study at a future medical meeting later in 2022. Finally, we expect to complete enrollment to both arms of the study before the end of this year. With today's updated interim data, we have begun to answer important questions consistent with the foundational principles that John set out earlier in the call. Based on the data presented by Dr. Gane, we have growing confidence in 2001's potential as a treatment for ATTR amyloidosis. Key insights from the ongoing Phase I study include: first, 2001 was generally well tolerated at all dose levels; next, 2001 had a dose response relationship with higher doses yielding even deeper serum TTR reduction. Importantly, these reductions occurred rapidly by day 28 and were consistent across patients with polyneuropathy treated to date; and finally, early indications are that these reductions are durable, which is consistent with our preclinical model. Further, in every type of amyloidosis that have been studied, there has been a strong correlation between degree of knockdown and development protein and clinical outcomes. The greater the reduction of disease-causing protein, the greater the rate of amyloid removal and subsequent control of disease symptoms. This relationship, coupled with the data presented today, support our hypothesis that 2001 may halt and potentially reverse the disease following a single dose. Of course, this hypothesis will need to be tested in future registrational clinical trials, and we look forward to providing updates on these plans at the appropriate time in the future. With that summary of the next steps, I'd like to turn the call back over to John for some closing remarks and broader perspective on the importance of the data presented today.

Thank you, David. And Dr. Gane, thank you for your leadership in the treatment of this disease. In closing, we believe Intellia is well on its way to opening a new era of medicine. In June, we were the first company to demonstrate that we can precisely inactivate a gene responsible for producing a disease-related protein following a systemically delivered CRISPR-based candidate. The interim data presented today reinforces this achievement with a growing body of evidence. The data presented demonstrate that treatment with NTLA-2001 was generally well tolerated and led to consistently deep and durable reductions of serum TTR protein through the observation period. This is great progress for medicine, and it offers new hope for people living with this disease. As pioneers of this new era, we're already leveraging key insights to the rest of our growing pipeline. We believe the learnings from NTLA-2001 are directly applicable to our other systemically administered in vivo drug candidates since the modular LNP-based delivery technology remains the same from candidate to candidate, except for a very small portion of the guide RNA specific to each target gene. We hope to confirm this hypothesis as we advance NTLA-2002 for hereditary angioedema following the principles we've laid out. We look forward to sharing initial clinical data from NTLA-2002's first-in-human study later this year. Our CRISPR-based approach represents new hope for others around the world whose lives are affected by diseases with genetic roots. We will continue to keep you updated on our future progress in the months ahead. Operator, you may now open the call for questions.

[Operator Instructions] The first question today will be from Salveen Richter with Goldman Sachs.

This is [ Elizabeth ] on for Salveen. Just wanted to ask about the 2 patients that didn't achieve greater than 90% reduction by day 28 at the highest dose. Wondering if there are certain patient characteristics for those patients that didn't quite get there? And congrats on the data.

David, do you want to speak to that?

Yes. Thank you. No, we haven't seen any particular characteristics in those patients. Of course, these numbers are actually very close between all the numbers, but we will continue to look and understand in more depth what determines the exact amount of TTR reduction each patient has.

And the next question will come from Maury Raycroft with Jefferies.

Congrats on the update today. In your press release, you mentioned you plan on moving toward pivotal studies for both ATTR polyneuropathy and cardiomyopathy with initial focus on cardiomyopathy. I'm just wondering if you can talk more about this decision to prioritize cardiomyopathy and what went into that?

Thanks, Maury. The way we think about it is both indications are of great interest to us, as you might imagine. As we look at the cardiomyopathy space, it's an area for which gene knockdown is completely open at this point in time. The only therapy available to patients is a stabilizer. And we view this as an area of the greatest unmet medical need. There's -- that's where most of the patients are. And it's our interest to go address that gap as quickly as we can. But I don't want to give any impression whatsoever that we're uninterested in pursuing polyneuropathy, we will, of course, work on sweeping that up as well.

Got it. And maybe just a quick follow-up. In December, I believe you said you started dosing in the cardiomyopathy population. And just wondering if you can say how many of those cardiomyopathy patients have been dosed at this point? And can we expect data from that cohort this year?

Well, Maury, thanks for the question again. As we've done in the past, we're not going to give updates in terms of the ongoing number of patients. When we get to a point where we're in a position to talk more about the data, we'll share that as appropriate and adhere to the principles that we've discussed since the beginning. So look to hear more from us when things start coming into focus, and we'll be happy to share at that time.

The next question will come from Mani Foroohar with SVB Leerink.

Congrats on the data again. A couple of quick ones. I'm looking at Slide 26, and you gave us a breakdown for [ the lives ] of individual patients [indiscernible]. Could you give us a sense whether or not [indiscernible] wide or a little tighter amongst the [ small number of ] patients [indiscernible] [ 0.7 mg per ] [indiscernible]. And secondarily, I saw -- you see a little bit of a gap [ from the 52% ] to the 41% [indiscernible] [ 0.1 mg per ] [indiscernible]. Is that just a variation [ and a ] function of just measurement? Is that -- or is there a particular reason that, [ in terms of thinking about ] [indiscernible] around that potential decline. I would presume, once hepatocytes are edited, they sort of stay that way. I have one quick study design follow-up, but [ I just have 2 questions to start with ].

Mani, it's John. We had terrible audio, but I think I got the gist of your question, which had to do with some of the variability in the lowest dose group. I'd just call your attention to the substantial variance around that data. If you go back and look at some of the preclinical data that we have in the animals, we know that when there's intermediate levels with editing, there's a fair amount of bounce. From time point to time point, it can bounce up a little bit, bounce down a little bit. But generally speaking, animals, over time, stay pretty flat with respect to where they set. And we think that, that's what this is going to be as well. As we go to higher and higher doses, as Dr. Gane commented, we believe we're getting to more saturating effects. And with that, the variance collapses. And we see that if you go and you look at the 1.0 mg per kilogram dose, the variance is actually very, very small around that. And while there are a few patients that are -- didn't reach 90%, as David pointed out in his comments, in fact, the numbers are actually unusually tight with respect to what you typically see with pharmacotherapy. So we're really quite pleased with the results. So maybe you could -- I think I addressed your questions, at least to the extent that we could hear them. So back to you.

Sure. I'm just going to scream into my phone because clearly the [ reception fault ] is on my end. So we saw challenges in terms of finding adequately severe patients based on the unusually strong placebo response seen in the ATTRibute study by BridgeBio, progressively milder patients in clinical trials in the HELIOS-A study versus APOLLO-A from Alnylam. So your competitors have had challenges finding adequately severe patients to show a strong drug effect. From that data, what lessons are you drawing and what patients should you be enrolling in the cardiomyopathy study arm to properly showcase the efficacy of the therapy?

Yes. So thanks for clarifying that. Maybe, David, you could speak to what we're learning in this study, which is different from what will ultimately be the pivotal design. But happy to hear your comments.

Yes. We are looking at the data that's coming in very carefully from BridgeBio, and there'll be some new data coming from Alnylam in the coming months. We do think that the things to look at include proBNP levels that are set, some of the function that the patients had coming into the trial. And so as we have the advantage now in our trial of having that information and we'll be incorporating that into the trial design that we present, and we will be talking about that trial in the future.

You might add that we're also looking at patients of varying severity of their heart failure, cardiomyopathy arm as well.

And certainly, yes. In our cardiomyopathy arm, you'll recall, we're looking at patients both Class I and II as well as Class III patients.

And the next question will be from Gena Wang with Barclays.

Also congrats on the data. I have 3 questions. The first one is regarding the gastroparesis patient. Can you give a little bit more color, what is the onset of gastroparesis and how quickly was it resolved? And was any medication applied to that patient? And my second question is regarding the polyneuropathy patient. You do have a few cohorts had a 9-month follow-up. Just wondering, is NIS score maintained at least flat throughout this time? And then lastly regarding...

Do you want to...

I will hold my last question until you answer these 2.

Thank you, Gena. Maybe we can ask Dr. Gane to give some color on the gastroparesis patient and what the patient's prior history was, and then we can come back to the other questions. Dr. Gane?

Thank you. Yes, this patient was not at our site, but this patient did have a history of quite severe autonomic neuropathy. And part of the problems with that is delayed gastric emptying or what we call gastroparesis. And this has been a very difficult management problem in the past. And the patient had required admission to hospital for control of emesis. This is many months prior to involvement -- participation in the study. So it seems that this patient had a further episode of emesis following treatment in the study. The patient had been within a Phase I unit and it didn't appear to be directly linked to therapy. We assume it was just a recurrence of this patient's long-standing [ effects of ] severe autonomic neuropathy [indiscernible] after discharge.

Thanks, Dr. Gane. David, do you want to tell us about the mNIS?

Yes. So the -- in the first part of the study, we're actually measuring NIS, and it moves to mNIS in the second part, but part of the measurement of neuropathy in these type of studies is it doesn't change rapidly and the measurement of NIS is at 1 year in Part 1. So just the first patient who had very low dosage is reaching that 1 year point at this right now. So we don't have data now on NIS.

Okay. Very helpful. And the last set of questions -- sorry, last question is cardiomyopathy. You said you will expand from 0.7 milligram to 1 milligram. First did you see similar level of knockdown at the 0.7 milligram per kg? And then also why expand it to 1 milligram per kg? Will you eventually also use fixed dose? Why not just go directly to fixed dose at a higher dose?

Yes. Thank you for that question. So in the patient with cardiomyopathy, we're testing both doses, yes, 0.1 and 1 milligram per kilogram. And we designed this actually before we had all the data from patients with polyneuropathy. We can use this data, though, to support going to Part 2, either with kilogram based dosing or with fixed dosing. We do think the effects -- and we don't have the effects yet in patient with cardiomyopathy. We'll be obviously reporting that at a later time. But given the biology, we expect it to look fully and exactly like what we see in patients with polyneuropathy. We just need to confirm that in our study.

Just to clarify, the 2 doses are 0.7 and [indiscernible] -- yes, yes, just...

And the next question will be from Joon Lee with Truist.

Congrats on the very strong data. What was the decision behind dosing down from cohort 3 of -- which was at 1.0 mg per kg to cohort 4, testing 0.7. Was it driven by that 1 gastroparesis patient with grade 3 vomiting? And how are you able to rule out NTLA-201 (sic) [ NTLA-2001 ] as the contributor to grade 3 vomiting? And is gastroparesis one of the manifestations of ATTR?

So what we saw going from 0.3 to 1, as you've seen in the data, was greater reductions in TTR. But of course, that is a threefold change in the dose. So we really -- what we wanted to do is fill in that dose response and really know, do we need to go to 1 milligram? Is 0.7 as good? And that's what we were looking for there. Now the event is possibly related to the drug. There are other things going at the time. The patients coming into the study, they're changing their medication, they're going -- they're traveling, they're stop -- they're getting dexamethasone. So as is not too uncommon in a Phase I study, when you have a very common event like vomiting, it's very hard to say, is it exactly due to the drug or is it due to other things that are going on in the patient.

And is gastroparesis one of the clinical manifestations of ATTR?

Yes, it is. So that's part of the disease. It's autonomic neuropathy involving the gut basically. So you can imagine when that happens, you can get vomiting, you get -- that's what happens with gastroparesis.

It's a really common manifestation of polyneuropathy in patients with amyloidosis.

Got it. Do you plan to have something in place to sort of preclude this? Or how -- can you just tell us just a flavor of what grade 3 vomiting is and how serious it is?

Well, it means that the patient needed to get hydration and watched temporarily in the hospital. It is not -- it's easily managed. It was completely reversible after a short period of time. So we think the main thing that would be done for patients is to carefully follow them after they're treated and to manage any patients who might develop either nausea or vomiting.

Right. And we don't think there's any reason to exclude these patients. In fact, these are some of the patients we think who may benefit most from the therapy.

Got it. One more question follow-up. I know that you guys thought about redosing patients with the lowest dose, 0.1. I mean could you envision maybe a more titrated gradual dosing up to maybe avoid some of the side effects or SAEs?

Yes. No, we -- the patients who received a low dose, as you saw, only have about a 50% reduction in TTR. We do think it's very important to get the deepest possible reductions. And the average of 93%, we think will be very helpful to those patients. So the idea on those patients who got the lower dose would be to give them a full dose in the future.

And the next question will come from Dae Gon Ha with Stifel.

Congrats from me as well. Two-part question for me. I wanted to drill down on this 80-milligram fixed dose a little bit more. Just looking at the dose response, 1 mg per kg is clearly the strongest on serum TTR reduction. But looking at the baseline characteristics on Slide 21, I do realize that the maximum weight surpasses 90 kilograms and 100 kg. So that, I guess, arithmetics would bring us to about 0.7 mg per kg. Just trying to get a sense for how much efficacy we can expect from these patients that would surpass that 100 or even 90-kilogram weight? And then second part question is for Dr. Gane. As we think about the natural, I guess, disposition of patients and their weights, what's the general kind of maximum kg weight that we can expect?

Dr. Gane, you want to go first just with respect to what is a typical patient with polyneuropathy and amyloidosis in terms of their weights? And I'll speak to the other question.

Okay. Thanks for the question. I would have thought the weight distribution would not be any different from age match population. Certainly, in the early phases of the disease, in this study, most patients were Caucasian, but of course, all ethnicities can be affected. As patients get sicker and they get more marked effects on their digestive track and malnutrition, their weight will fall off, but that is in the late stages of disease. So I would have thought the weight distribution for patients being considered for NTLA-2001 will be similar, certainly to the general population.

Maybe I can take -- yes, let me take the first question. So we've looked very carefully at this and have a lot of pharmacokinetic information, which we'll review at a later meeting this year, and people can see some of the same information that we've been looking at. And one of the, I think, really excellent findings is that across the weights that we've looked at, the drug behaves really, really well. Now at some point, as patients become very large, the body mass and the liver do not grow at the same rate. And at the most extreme upper ends, you're going to be adjusting in a way that's not appropriate for a clearance of the drug, so we just want to bear that in mind. But as we look across exposures in the patient weights that are in this trial, essentially, we're achieving something pretty close to bioequivalence at either end of the spectrum that we've chosen here. So we -- as we look at this, we feel that the right decision is to opt for simplicity, as was commented on some of the remarks that Dr. Lebwohl made during the course of the presentation, as opposed to having a strictly weight-based approach. And again, we'll give more pharmacokinetic information so people can see that at the extremes, the heaviest patients and the patients that weigh the least, in fact, the overall exposures that they get at this 1 mg per kg dose would be expected to be pretty much equivalent to what you get at the 80-milligram fixed dose that we're choosing to move forward with.

Got it. Makes sense to me. If I can ask just one, I guess, clarification question. On Slide 26, you show sort of the, I guess, distribution of the 1 mg per kg data point. If I eyeball it, it's between 87% and 97%. Are you able to comment on what you saw with the 0.7 mg per kg cohort, what the range was on the lower end as well as the higher end?

We're not going through those individual data sets here as we're interested in the 1 mg per kg going forward. But you can get a sense from the variance that we -- if you look at the data that's presented either at day 28 or later, you'll see that there's a higher variance there. And that's why we made the comment about getting to what are saturating doses. What you want to have is the consistency, not just the high levels of reduction that we've achieved. And we think at the 1 mg per kg dose, we're getting exactly what we're looking for and preserving the safety profile. So that's the dose that we're excited about moving forward.

[Operator Instructions] The next question will come from Liisa Bayko with Evercore ISI.

I just had a question about durability. And overall, it looks pretty consistent. But I wanted to just inquire how comfortable you are. When I look at the 0.1 mg per kg, it does look like you lose about 9 percentage points, and that's the longest duration of follow-up. Can you maybe comment on kind of when that transition to minus 52% to minus 51% occurred? And how comfortable are you with the sort of durability at this point at the higher doses? And is there any dose response here to think about? Just curious how you're thinking about that.

I would point out -- Liisa, thanks for the question. Just look at the variance on the 0.1, and that's the issue. If you go and you look at the animal data we've presented previously, when you have intermediate levels of editing, you can get variance on either side, up or down just related to the assay. And in fact, that's what we think we're seeing at the 0.1 mg per kg dose, which, again, as we said earlier, is therapeutically irrelevant. But as you move to these higher levels, you get to -- as you are asymptotically approaching almost 100% reduction, the variability collapses. And so we would just emphasize that, that variance is really shrinking, which is -- as you think of pharmacologic agents in general, it's a phenomenal profile, and one that we're really excited about. Now with respect to confidence, look, it only grows with time. We have the data that we have. Obviously, the most information at the lowest dose, the one that's therapeutically irrelevant. But as we look at the 0.3, which we have 9 months of data on all of the patients there, you see the level is really very, very significantly maintained. And as we go to the 0.7 and 1 mg per kg doses, we see similar results. So just thinking about it biologically in terms of hepatocytes and where they come from and how they're edited, this conforms with what we have seen preclinically, what we would expect to see biologically. But of course, we'll follow these patients as they go out, and we would expect these effects to be maintained.

Okay. Great. That's helpful. And then just a quick one for Dr. Gane. What percentage of patients do you think would be interested in the profile like this and be interested in going on this gene editing curative approach?

Dr. Gane, that one's for you.

I'm clearly excited about these results and, I think, the population affected by the disease are as well. And I see and know from some of the amyloidosis support organizations that they are obviously following this study very closely. And yes, we know there is a lot of interest from people affected with this terrible disease in accessing such groundbreaking treatment.

Thanks, Dr. Gane.

And the next question will come from Luca Issi with RBC Capital.

Congrats on the data. Maybe one on off-target editing. Any plan to evaluate off-target editing in humans? I know liver biopsies are no fun, and you've done some great work, obviously, primary human hepatocytes. But wondering if that is sufficient or maybe the FDA at some point will ask you for some human evidence of nontarget editing. So any thoughts there would be great. And then the second one, super quickly. I know in the past, you guys have showed us also no evidence of coagulopathy or no meaningful reduction in tyrosine -- thyroxine, I should say. Any color there would be great.

I'll speak to the off-target assessment. No regulatory authority has requested that. Maybe Dr. Gane can speak to what he sees as the clinical utility of it. But I would refer you to the work that was done with -- and reported in the New England Journal with the extensive preclinical assessment of our targets. When you think about what there is to learn in a biopsy relative to what we've already shown preclinical, I think everybody has looked at it is convinced that, that is not going to be a meaningful assessment. I don't know if Dr. Gane, if there's something you want to add to those comments, feel free.

Well, I guess, just commenting on the use of liver biopsy in clinical studies, liver biopsy is obviously an invasive procedure. You couldn't get the data you want, what you're requesting, from a fine-needle effort. So it would be a core liver biopsy, and that's not without risk. So I think you have to justify including in this situation, biopsies, possibly paired biopsies in the study design. I'm not sure that this would be necessarily advantageous.

So thank you. Maybe, David, do you want to say a word about coagulopathy? Has that even been relevant in the study?

Yes. So there have been no significant change in the coagulation profile of the patients. So that's where we are at this point. And as mentioned in Dr. Gane's presentation, the only significant change is with the transient increase in AST.

And nothing on thyroxine, right?

And thyroxine, there's no -- yes, nothing significant there.

And the next question is from Steve Seedhouse with Raymond James.

This is Timur Ivannikov on for Steve. So we just had another follow-up on flat dosing because there does appear to be a difference between 0.7 and 1 mg per kg in terms of TTR response. So we're just wondering, do you plan to control for liver volume somehow? And why is flat dosing so much better in your view? And do you plan to sort of rack it above 1 milligrams per kg?

David, do you want to speak to our plans?

Yes. So the plan is -- with the flat dosing, when we looked at the data, weight had no significant effect on exposure. So that's the fundamental finding you have to make it clear that flat dosing is the best way to go. We mentioned you avoid mixed dosing. When you do dosing by kilogram, there is that risk that will be mixed wrong, it will be applied wrong. And it's -- so it's much more convenient as well for administration of the drug. The fact that 0.7 has more variability is likely other factors other than the patient -- that certainly we're looking at. But that -- as we come out with all the data, you'll see the justification that flat dosing is really much better here.

And the next question is from Yanan Zhu with Wells Fargo Securities.

Congrats on the data. I just have a question with regard to dose and efficacy relationship. As you mentioned, higher reduction leads to higher efficacy. And if we look at the landscape for RNA therapeutics, I think in HELIOS-A, it was said the mean reduction in a steady state was 88%. So I'm guessing with the -- your chosen dose, is there a degree of overlap in terms of a reduction that could be -- in those patients, efficacy -- the TTR reduction could be similar between these 2 approaches? And how do you think of value proposition among those patients?

Maybe I'll start off with that. I would encourage you to look very closely at those data and understand the cohort effect and the number of patients that are reported on when those conclusions are drawn. So I'll leave that to you to go see. And I think you need to explore where those numbers are actually coming from and when they were achieved and whether or not they were actually maintained. So that's something for you to look at. As we go and think broadly about where we want to go, deeper is better, and I think everybody agrees with that. And so that's why the consistency of the effect and the depth of the effect is so critically important for what is the dose selection that we've moved forward with. And we think that, that is what's going to drive the clinical benefit for patients that we hope to observe in subsequent clinical work. So keeping -- just as you look across data sets, just look at that variability and keep that in mind. And I think that will be an important aspect here.

Got it. If I may, a very quick question. The flexibility of fixed dosing, I guess, as you look at data being generated with flat dosing, and you look at lighter body weight patients, do you have the flexibility to then go back to a weight-based dosing without generating additional clinical data?

We will continue to learn in part 2 of the study. We're collecting additional information clearly with our cardiomyopathy patients. And so as the data set expands, we think we'll be an increasingly more and more informed view with respect to how we administer and what dose we administer for our ultimate pivotal trials. But at this point, when we look at the totality of the data, the fixed dosing approach seems the right way to proceed when we consider all of those factors. But this is not final until we say it's final and we move into clinical -- into pivotal work.

And the next question will come from Debjit Chattopadhyay with Guggenheim Securities.

This is Ry Forseth on for Debjit. Congratulations on the data. We're curious about the IND strategy in the U.S. How does that fit into the overall clinical development landscape for 2001? And when would it be best to pull the trigger on that? Is there any need for having patients as part of your Phase I study evaluated in the U.S.?

David, do you want to speak to that?

Yes. Thank you. Yes. You do not need to have patients evaluated in the U.S. as part of Phase I to open a more advanced study in the U.S. So we're right now working on the design of the future pivotal studies, which will certainly include the U.S. as well as countries around the world.

And the next question will come from Jay Olson with Oppenheimer.

Congrats on these results. I'm curious about the TTR reduction with the 0.7 mg per kg dose. Could you share any thoughts on why the TTR reduction for 0.7 is similar to that for 0.3? And I noticed that in the baseline characteristics, the NT-proBNP level was lower for the patients in the 0.7 mg per kg cohort. Do you think that had any influence on the level of TTR reduction that can be achieved with 2001? And finally, related to that, can you comment on the NT-proBNP level before and after treatment with 2001?

David, do you want to speak to...

So the -- yes, first, your question about 0.7, this is just a relatively small number of patients, 3 patients at 0.3, 3 patients at 0.7. There is some variability in the amount of reduction you get. So I don't make much of it at this point that you get about the same reduction in both groups. The proBNP is not known, and we don't think it has any potential effect on TTR levels. And we have not yet -- we're not reporting at this point on any BNP changes over time.

Yes. I mean just to add to, I would point out the data are remarkably consistent. And so looking between 0.3 and 0.7, just consider some of the statistical just variance here. The hope for effect that I think you're asking about may well reside in those numbers. But again, back to what I think the lesson is here, is that, as you move to what we believe are saturating doses, that variability really starts to collapse. And that's what we're looking for is getting the deep consistent effects with a well-preserved safety profile. Those are excellent drug characteristics that we think are things to be quite proud of and are the basis for taking the program forward.

Ladies and gentlemen, this concludes our question-and-answer session. I would like to turn the conference back over to Ian Karp for any concluding remarks.

Great. Thanks so much. I know we went a few minutes over, but hopefully, we were able to answer all the questions. We appreciate your continued interest and support in Intellia, and we absolutely look forward to updating you as we progress on this program and the rest of our pipeline. Take care, and have a great night.

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