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 begin with 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. 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 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 one-time 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 five, 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 one 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 four cohorts. Since our first disclosure from the initial six patients, we are now reporting updated interim data from an additional nine patients. Furthermore, in the initial cohorts, we've collected serum TTR data out 9 months-12 months post-treatment. Importantly, NTLA-2001 was generally well-tolerated at all dose levels. At the 1 mg/kg dose, which is the highest dose evaluated, a mean serum TTR reduction in the six 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 months-6 months.
At these deep and persistent levels of TTR reduction, we believe NTLA-2001 has the potential to halt and perhaps even reverse the course of this disease. NTLA-2001 continues to represent a potential best-in-class, one-time 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. If we move to slide seven, 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 five development candidates, including two that are in clinical development and two 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 eight, 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. 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's Liver Transplant Unit, as well as an author on 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 two 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 years-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 one-time 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 a single-guide RNA molecule that targets the human TTR gene and a human optimized mRNA sequence of Streptococcus pyogenes 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, where they are taken up via the LDL receptor on the hepatocytes.
After endocytosis and release into the cytoplasm, the Cas9 mRNA is translated, producing the Cas9 enzyme, which then interacts with a single guide RNA to form the CRISPR-Cas9 ribonucleoprotein complex. This complex enters the nucleus, and a 20-nucleotide sequence at the five prime end of the guide RNA binds to the patient's DNA double helix at the complementary target site. This leads to precise knockout of the targeted TTR gene sequence, which consequently stops production of the transthyretin protein. An extensive genome-wide search using computational and laboratory-based techniques for loci with the potential for off-target editing identified seven 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 the concentration at 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 non-human 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 mg/kg, 3 mg/kg, and 6 mg/kg on day 0 and followed for over 360 days. A control cohort receiving no treatment was included for comparison. The vertical lines represent standard deviations across the three 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 one 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 mg/kg in non-human primates corresponds approximately to the 1 mg/kg dose in humans. This arm in the first-in-human study with NTLA-2001 is a two-part, open-label, multi-center study in patients with hereditary ATTR amyloidosis with polyneuropathy. Part one is a single ascending dose portion of the study with a minimum of three patients in each of the four dose-escalating cohorts of 0.1 mg/kg, 0.3 mg/kg, 0.7 mg/kg, and 1 mg/kg.
Part two will consist of administration of the dose selected from part one to a dose expansion cohort, initially for eight subjects. The primary objectives of this 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 four dose escalation cohorts included in part one. This table summarizes the demographics of the 15 study participants. The median age is 55, with a range of 19 years-70 years. Nine men and six women were enrolled. Most subjects self-reported as Caucasian. Median weight was 83 kg, with a range from 59 kg-111 kg. Seven 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.
Two subjects had peripheral neuropathy with a disability score of two, and one subject had cardiomyopathy with a NYHA class II. Seven of the 15 subjects had elevated NT-proBNP measurements at baseline. The next two slides summarize the safety data from this study. NTLA-2001 was generally well-tolerated across all dose levels. All adverse events, regardless of relationship to treatment, 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 one. 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 mg/kg cohort to a total of six 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 in columns 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 one.
The next four slides summarize the pharmacodynamic effects from part one 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 four dose cohorts. Doses of 0.3 mg/kg and above achieved mean reductions of more than 80%, and the highest dose of 1 mg/kg achieved a mean reduction of 93%. There was a dose-response relationship, but increasing the dose from 0.1 mg/kg- 0.3 mg/kg results in a larger incremental decline in serum TTR than from increasing from 0.3 mg/kg- 1 mg/kg. I should note that the 0.1 mg/kg was the first ever in-human systemic administration of a lipid nanoparticle CRISPR-Cas9 gene-editing therapeutic. The purpose of this dose cohort was to evaluate safety.
It was encouraging that not only was the agent safely administered, but that all three 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 mg/kg cohort reveals that four of the six subjects had reductions greater than 93%. All subjects had 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 the finding that the 0.3 mg/kg and 0.7 mg/kg, suggest 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 four dose cohorts.
Similar to the non-human 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 blue bars depicts the mean percentage reduction for a dose cohort, with the hatched bars showing the mean reductions at day 28 and the solid bars the mean reductions for the latest measurement from each patient. The duration of follow-up ranges from two months for the most recent cohort, up to 12 months for the first cohort. The mean reduction in TTR observed at day 28 was sustained through the latest available time points. For example, in the 1 mg/kg 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 mg/kg, 0.7 mg/kg, and 1 mg/kg cohorts receiving a mean decrease from baseline of 87%, 86%, and 93% respectively. Reductions 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 one, a fixed dose of 80 mg has been selected for evaluation in part two of the study.
80 mg is expected to result in consistent and deep reductions in TTR comparable to the 1 mg/kg 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 co-investigators and their teams on this study. I'd like to thank Dr. Georg Thorwirth, Björn Pilebro, Julian Gillmore, Justin Kao, and Marianna Fontana, and the research staff at New Zealand Clinical Research, Richmond Pharmacology, and Umeå University. 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 NTLA-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 NTLA-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 NTLA-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 one of the polyneuropathy arm, we have selected the fixed dose of 80 mg, which is expected to deliver a similar exposure to 1 mg/kg 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're planning to initiate part two, a single-dose expansion cohort later this quarter, where we expect to enroll eight patients. On the cardiomyopathy arm, we continue to dose patients in separate dose escalation cohorts, starting at the 0.7 mg/kg dose, with plans to evaluate the 1 mg/kg 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 designs. 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 NTLA-2001's potential as a treatment for ATTR amyloidosis. Key insights from the ongoing phase I study include, first, NTLA-2001 was generally well-tolerated at all dose levels. Next, NTLA-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. Finally, early indications are that these reductions are durable, which is consistent with our preclinical model. Further, in every type of amyloidosis that has been studied, there has been a strong correlation between degree of knockdown of the relevant 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 NTLA-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. 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.
Thank you. We will now begin the question-and-answer session. To ask a question, you may press star then one on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. The first question today will be from Salveen Richter with Goldman Sachs. Please go ahead.
Good evening, and thank you for taking our question. This is Elizabeth on for Salveen. Just wanted to ask about the two 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, you wanna speak to that?
Yeah, 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.
Great. Thank you.
Thank you. The next question will come from Maury Raycroft with Jefferies. Please go ahead.
Hi, congrats on the update today, and thanks for taking my questions. 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. That's where most of the patients are, and it's our interest to go address that gap as quickly as we can. I don't wanna give any impression whatsoever that we're uninterested in pursuing polyneuropathy. We will of course work on sweeping that up as well.
Got it. Maybe just a quick follow-up. In December, I believe you said you started dosing in the cardiomyopathy population. Just wondering if you can say how many 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 gonna 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 espoused since the beginning. Look to hear more from us when things start coming into focus, and we'll be happy to share at that time.
Got it. Okay. Thanks for taking my questions, and congrats again.
Of course. Thank you.
Thank you. The next question will come from Mani Foroohar with Leerink Partners. Please go ahead.
Hey, thanks. Thanks for taking the question. Congrats on the data again. A couple of quick ones. I'm looking at slide 26, and it gives a breakdown for the individual patients. The 1.0 mg/kg. Can you give a sense whether or not it's as wide or a little tighter amongst the smaller patients 0.7 mg/kg, and secondarily, I see a little bit of a gap from the 2%- 41% knockdown 1.0 mg/kg. Is that just a variation in function of just measurement? You know, or is there a particular reason that, you know, in terms of thinking about mechanism 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 think two questions to start with.
Mani, it's John Leonard. 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 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 of editing, there's a fair amount of bounce from time point to time point. You can bounce up a little bit, bounce down a little bit. But generally speaking, you know, animals over time stay pretty flat with respect to where they set out. We think that that's what this is gonna 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. We see that if you go and you look at the 1.0 mg/kg dose, the variance is actually very, very small around that. While there are a few patients that are up, you know, 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. We're really quite pleased with the results. Maybe you could. I think I addressed your questions at least to the extent that we could hear them. Back to you.
Sure. I'm just gonna scream into my phone 'cause I clearly have reception problems on my end. We saw challenges in terms of finding adequately severe patients based on the unusually strong placebo response seen in the ATTRibute-CM study by BridgeBio, progressively milder patients in clinical trials in the HELIOS-A study versus APOLLO-B from Alnylam. 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 this therapy?
Yeah. 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.
Yeah, 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. 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. We will be talking about that trial, you know, in the future.
You might add that we're also looking at patients of varying severity of their heart failure.
Yeah.
In the cardiomyopathy arm as well.
Certainly, yeah. In our cardiomyopathy arm, you'll recall we're looking at patients both Class I and II, as well as Class III patients.
All right. Thanks, guys. That's really helpful. I'll hop back in the queue.
Thank you.
Thank you. The next question will be from Gena Wang with Barclays. Please go ahead.
for taking my questions. Also congrats on the data. I have three 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? My second question is regarding the polyneuropathy patient. You do have a few cohorts had a nine months follow-up. Just wondering, is NIS score maintained at least flat throughout these times? Then lastly, regarding-
Do you wanna do the mNIS+7?
Yeah.
I will hold my last question until you answer these two.
Thank you, Gina. Maybe we can ask Dr. Gane to give some color on the gastroparesis patient, and the patient's prior history was, and then we can come back to the other questions. Dr. Gane?
Sounds good.
Thank you. Yes. This patient was not at our site, but this patient did have a history of quite severe autonomic neuropathy. Part of the problems with that is delayed gastric emptying or what we call gastroparesis. This had been a very difficult management problem in the past. The patient had required admission to hospital for control of emesis. This is many months prior to involvement, participation in this study. 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. It hasn't been an issue after discharge.
Thanks, Dr. Gane. David, you wanna tell us about the mNIS+7?
Yeah. In the first part of the study, we're actually measuring NIF, and it moves to mNIS+7 in the second part. Part of the measurement of neuropathy in these type of studies is it doesn't change rapidly and that the measurement of NIF is at one year in part one. Just the first patient who had very low dose is reaching that one-year point at this right now. We don't have data now on NIF.
Okay, very helpful. The last question is cardiomyopathy. You say you will expand from 0.7 mg- 1 mg. First, you know, did you see similar level of knockdown at the 0.7 mg/kg ? Also, why expand it to 1 mg/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. The patient cardiomyopathy, we're testing both doses, yes, 0.1 mg/kg and 1 mg/kg. 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 two, either with kilogram-based dosing or with fixed dosing. We do think the effects and we don't have the effects yet in patient cardiomyopathy. We'll be obviously reporting that at a later time. 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 two doses are 0.7 mg/kg and 1 mg/kg point-
Yeah. Okay. Yeah.
Yeah, just.
Good.
Very helpful. Thank you very much.
Thank you, Gena.
Thank you. The next question will be from Joon Lee with Truist. Please go ahead.
Hi. Thanks for taking our questions, and congrats on the very strong data. You know, what was the decision behind dosing down from cohort three, you know, which was at 1.0 mg/kg to, you know, cohort four testing 0.7. Was it driven by that one gastroparesis patient with grade three vomiting? And how were you able to rule out NTLA-2001 as the contributor to grade three vomiting? And is gastroparesis one of the manifestations of ATTR? Thank you.
Yeah. What we saw going from 0.3 mg/kg- 1 mg/kg, as you've seen in the data, was a greater reductions in TTR. But of course, that is a threefold change in the dose. We really what we wanted to do is fill in that dose response and really know, do we need to go to 1 mg? Is .7 mg/kg 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 on at the time. The patient's coming into the study, they're changing their medication, they're going, they're traveling, they're stopping, they're getting dexamethasone.
As is, you know, 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.
Is gastroparesis one of the clinical manifestations of ATTR?
Yes, it is. That's part of the disease. It's autonomic neuropathy involving the gut, basically. You can imagine when that happens, you get vomiting, you know, that's what happens with gastroparesis.
It's a really common manifestation-
Yeah.
of a polyneuropathy in patients with amyloidosis.
Right.
Got it. Do you plan to have something in place to sort of preclude this or, you know, how? Can you just tell us just a flavor of what grade three 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. 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. We don't think there's any reason to exclude these patients.
Yeah.
In fact, these are some of the patients we think who may benefit most from the therapy.
Got it. Thank you so much. One more question follow-up. I know that you guys thought about redosing, you know, patients with the lowest dose, 0.01 mg/kg, 0.1 mg/kg I mean, could you envision maybe more titrated gradual dosing up to maybe avoid some of these side effects or SHs? Thank you so much.
Yeah. No. 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 do be very helpful to those patients. The idea on those patients who got the lower dose would be to give them a full dose in the future.
Thank you. The next question will come from Dae Gon Ha with Stifel. Please go ahead.
Great. Good afternoon. Thanks for taking our questions, and congrats from me as well. Two-part question from me. I wanted to drill down on this 80 mg fixed dose a little bit more. Just looking at the dose response, 1 mg/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 kg and 100 kg. So that, I guess, arithmetic would bring us to about 0.7 mg/kg . Just trying to get a sense for how much efficacy we can expect from these patients that would surpass that 100 kg or even 90 kg weight. 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? Thank you.
Dr. Gane, you wanna go first just with respect to what is a typical patient with polyneuropathy and amyloidosis in terms of their weights? 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-matched population, certainly in the early phases of the disease. In this study, most patients were Euro-Caucasian, but of course, all ethnicities can be affected. As patients get sicker and they get more marked effects on their digestive tract and malnutrition, their weight will fall off, but that is in the late stages of disease. 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.
Yeah.
Yeah, let me take the first question. We've looked very carefully at this and have a lot of pharmacokinetic information, which we'll review at a later meeting this year. People can see some of the same information that we've been looking at. 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. You know, at the most extreme upper ends, you're going to be adjusting in a way that's not appropriate for clearance of the drug. We just want to bear that in mind.
As we look across exposures in the patient weights that are in this trial, essentially, we're achieving something pretty close to a bioequivalence at either end of the spectrum that we've chosen here. 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. We'll give more pharmacokinetic information so people can see that at the extremes, you know, the heaviest patients and the patients that weigh the least.
In fact, the overall exposures that they get at this 1 mg/kg dose would be expected to be pretty much equivalent to what you get at the 80 mg 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/kg data points. If I eyeball it's between 87 and 97. Are you able to comment on what you saw with the 0.7 mg/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/kg going forward. You can get a sense from the variance that we've, 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. That's why we made the comment about getting to what are saturating doses. What you wanna have is the consistency, not just, you know, high levels of reduction that we've achieved. We think at the 1 mg/kg dose, we're getting exactly what we're looking for and preserving the safety profile. That's the dose that we're excited about moving forward.
Right. Depth and consistency. Thank you very much, and congrats.
Thank you.
Thank you. Ladies and gentlemen, in the interest of time, we please ask that you limit yourself to one question, please. The next question will come from Liisa Bayko with Evercore ISI. Please go ahead.
Hi there. Thanks for taking my question. I just had a question about durability. You know, you know, overall, it looks pretty consistent, but I wanted to just inquire how comfortable you are. When I look at the 0.1 mg/kg, it does look like, you know, you lose about, you know, 9 percentage points, and that's the longest duration of follow-up. Can you maybe comment on kind of when that transition to -52% -51% occurred? How comfortable are you with the sort of durability at this point at the higher doses? 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 mg/kg, and that's the issue. If you go and you look at the animal data we presented previously, when you have intermediate levels of editing, you can get variance on either side up or down just related to the assay. In fact, that's what we think we're seeing at the 0.1 mg/kg dose, which again, as we said earlier, is therapeutically irrelevant. As you move to these higher levels, you get to, as you are asymptotically approaching almost 100% reduction, the variability collapses.
You know, we would just emphasize that variance is really shrinking, which is, you know, 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. As we look at the 0.3 mg/kg, which, you know, we have 9 months of data on all of the patients there, you see the level is really very, very significantly maintained. As we go to, you know, the 0.7 mg/kg and 1 mg/kg doses, you know, we see similar results.
Just thinking about it biologically in terms of hepatocytes and where they come from and how they're edited, this conforms with what we had seen preclinically, what we would expect to see biologically. Of course, you know, we'll follow these patients as they go out, and we would expect these effects to be maintained.
Okay, great. That's helpful. Just a quick one for Dr. Gane. What percentage of patients do you think would be interested in a profile like this and be interested in going on this gene editing curative approach?
Dr. Gane, that one's for you.
I'm incredibly excited about these results, and I think, the population affected by the disease are as well. I certainly know from some of the, amyloidosis, support organizations that they are obviously following this study very closely. Yes, there is a lot of interest from people affected with this terrible disease in accessing such groundbreaking treatment.
Thank you.
Thank you, Dr. Gane. Yep.
Thank you. The next question will come from Luca Issi with RBC Capital. Please go ahead.
Oh, great. Thanks so much for taking my question, and 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 have done some great work, obviously, primary human hepatocytes. Wondering if that is sufficient or maybe the FDA at some point will ask you for some human evidence of non-target editing. Any thoughts there would be great. 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 thyroxine, I should say. Any comment there would be great. Thanks so much.
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 within, you know, and reported in the New England Journal with the extensive pre-clinical assessment of off-targets. You know, when you think about what there is to learn in a biopsy relative to what we've already shown pre-clinical, I think everybody who's looked at it is convinced that, you know, that is not gonna be a meaningful assessment. I don't know, Dr. Gane, if there's something you wanna 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 aspirate, so it would be a core liver biopsy. That's not without risk. I think you'd 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.
Thank you. Maybe David, you wanna say a word about coagulopathy? Has that even been, you know, relevant in the study?
There have been no significant change in the coagulation profile of the patients. That's where we are at this point. As mentioned in Dr. Gane's presentation, the only significant change is with transient increase in AST.
Nothing on thyroxine, right?
Thyroxine, there's nothing significant there.
Great. Thanks so much. Appreciate it.
The next question is from Steve Seedhouse with Raymond James. Please go ahead.
Hi, this is Timur Ivannikov on for Steve. We just had another follow-up on flat dosing because, you know, there does appear to be a difference between 0.7 mg/kg and 1 mg/ kg in terms of TTR response. 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 take it above 1 mg/ kg? Thanks.
David, you wanna speak to our plans?
Yeah. The plan is, you know, with the flat dosing, when we looked at the data, weight had no significant effect on exposure. That's the fundamental finding you have to make it clear that flat dosing is the best way to go. We mentioned you avoid mis-dosing. When you do dosing by kilogram, there is that risk that it will be mixed wrong, it'll be applied wrong. It's much more convenient as well for administration of the drug. The fact that 0.7 mg/kg has more variability could, you know, is likely other factors other than the patient that certainly we're looking at, but that, you know, as we come out with all the data, you'll see the justification that flat dosing is really much better here.
Okay. Thank you.
The next question is from Yanan Zhu with Wells Fargo Securities. Please go ahead.
Hi. Thanks for taking my question, and congrats on the data. So I just have a question with regard to dose and efficacy relationship. As you mentioned, higher reduction leads to higher efficacy. 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%.
I'm guessing, you know, with your chosen dose, is there a degree of overlap in terms of the reduction in those patients' efficacy, the TTR reduction could be similar between these two approaches? How do you think of, you know, value proposition among those patients? Thanks.
Yeah. 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. Yeah, as we go and think broadly about where we wanna go, deeper is better, and I think everybody agrees with that. 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.
We think that that is what's going to drive the clinical benefit for patients that we hope to observe in subsequent clinical work. Keeping, you know, just as you look across data sets, just look at that variability and keep that in mind and I think that'll be an important aspect here.
Got it. If I may, a very quick question. The flexibility of the 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 a flexibility to then, you know, go back to a weight-based dosing or, you know, without generating additional clinical data?
We will continue to learn in part two of the study. We're collecting additional information clearly with our cardiomyopathy patients. As the dataset expands, we think we'll be in an increasingly more and more informed view with respect to how we administer and what dose we administer for our ultimate pivotal trials. 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. This is, you know, not final until we say it's final, and we move into clinical into pivotal work.
Got it. Thank you.
Sure.
Thank you. The next question will come from Debjit Chattopadhyay with Guggenheim Securities. Please go ahead.
Hi, 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, you wanna speak to that?
Yeah. Yeah. Thank you. Yeah, 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. 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.
Okay. Thank you.
Thank you. The next question will come from Jay Olson with Oppenheimer. Please go ahead.
Oh, hey, congrats on these results, and thanks for taking the question. I'm curious about the TTR reduction with the 0.7 mg/kg dose. Could you share any thoughts on why the TTR reduction for 0.7 mg/kg is similar to that for 0.3 mg/kg? And I noticed that in the baseline characteristics, the NT-proBNP level was lower for the patients in the 0.7 mg/kg cohort. Do you think that had any influence on the level of TTR reduction that can be achieved with NTLA-2001? And finally, related to that, can you comment on the NT-proBNP level before and after treatment with NTLA-2001?
David, do you wanna speak to.
First, your question about 0.7 mg/kg. You know, this is just a relatively small number of patients, three patients at 0.3 mg/kg, three patients at 0.7 mg/kg. There is some variability in the amount of reduction you get. 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. We have not yet. We're not reporting at this point on any BNP changes over time.
Okay. Thank you.
Yeah. I mean, just to add to that, I would point out the data are remarkably consistent. And so.
Yeah.
You know, looking between 0.3 mg/kg a nd 0.7 mg/kg, you know, just consider some of the statistical 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. 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.
Thank you. 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 of your 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.
Thank you. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.