Good morning, and welcome to Intellia Therapeutics' investor event to discuss the updated interim clinical data from the phase 1 study of NTLA-2001. My name is Jason, and I will be your conference operator today. Please be advised that this call is being recorded at the company's request. At this time, all participants are in listen-only mode. Following the formal remarks, we'll open the call up for your questions. I'll 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 morning, everyone. I'm pleased to welcome you to Intellia's investor event, featuring updated interim data from the phase 1 clinical trial of NTLA-2001. Earlier today, Intellia issued a press release detailing these results. This release, along with the accompanying presentation, can be found on the Investors and Media section of Intellia's website at intelliatx.com. As a reminder, this call is being broadcast live and a replay of the event will be archived on the company's website. At this time, I'd like to take a minute to remind listeners that during this call, Intellia management 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.
Please note that NTLA-2001 has not yet been approved by any health authority. With that said, joining me today on the call are Dr. John Leonard, our Chief Executive Officer, and Dr. David Lebwohl, our Chief Medical Officer. We will begin with brief introductory remarks from John, followed by David's review of the updated interim results from the polyneuropathy arm of our phase one trial of NTLA-2001 for the treatment of transthyretin amyloidosis, also known as ATTR amyloidosis. John will then provide closing remarks before opening the call for questions where Laura Sepp-Lorenzino, our Chief Scientific Officer, and Glenn Goddard, our Chief Financial Officer, will also be available. I'll now turn the call over to John.
Thank you, Ian, and welcome everyone. Earlier today, updated interim data from the polyneuropathy arm of our phase 1 study of NTLA-2001 was presented at the International Liver Congress hosted by the European Association for the Study of the Liver. We're excited to highlight the latest data from the study of NTLA-2001, our lead in vivo genome editing candidate, which is being developed in collaboration with Regeneron for the treatment of transthyretin amyloidosis or ATTR amyloidosis. At Intellia, we're building a full spectrum genome editing company by deploying the industry's deepest and broadest toolbox. With each clinical data update, we're demonstrating the immense power of CRISPR-based technologies, which we believe have the potential to revolutionize the future of medicine.
The data that David will detail in a few moments helps support one of our core scientific hypotheses, namely that deep reductions in a disease-causing protein achieved by a one-time genome editing treatment are in fact durable over time. With clinical data now out a full year for all patients receiving the 0.1 and 0.3 mg/kg dose, and six to nine months for patients receiving the 0.7 and 1.0 mg/kg dose, we continue to see remarkable persistence and durability of serum TTR reduction. In addition to the growing body of durability data, David will review the safety and pharmacokinetic modeling data that provide the foundation for a highly desirable fixed dose we are further evaluating.
Overall, the safety, depth of TTR reduction, and durability profile demonstrated thus far further support NTLA-2001's potential to halt and reverse the disease after a one-time treatment. With that, I'll now pass the call to David. David?
Thank you, John, and welcome everyone. I'll begin with a brief reminder of the NTLA-2001 trial design. Our ongoing phase 1 trial is an open label, multi-center, two-part study of NTLA-2001 in adults with either hereditary ATTR amyloidosis with polyneuropathy or ATTR amyloidosis with cardiomyopathy. Today's update includes all the patients from part one of the polyneuropathy arm. These 15 patients were treated across dose escalation cohorts of 0.1, 0.3, 0.7, and 1.0 milligrams per kilogram. As previously shown, the highest doses led to greater and more consistent reductions in TTR. Similar to every type of amyloid disease that has been studied, greater protein reduction is expected to achieve better clinical outcomes and can potentially reverse progression of the disease.
The primary objectives from this first in human study are to evaluate safety, tolerability, pharmacokinetics, and pharmacodynamics following a single intravenous infusion of NTLA-2001. Following the positive interim results previously announced in February, we initiated part two of the study, an open label single dose expansion cohort in patients with polyneuropathy. Part two further characterizes the activity of NTLA-2001 at the selected dose of 80 milligrams, a fixed dose equivalent of 1 milligram per kilogram. Starting with safety, NTLA-2001 continues to be generally well tolerated across all four dose levels with no new safety signals identified as compared to our last update. The majority of adverse events were mild in severity and transient in nature. The most frequent adverse events across all doses were headache, infusion-related reaction, back pain, rash, and nausea.
All infusion-related reactions were considered mild, resolving without clinical sequelae, with 73%, or 11 out of the 15 participants, reporting a maximal adverse event severity of grade 1. As previously reported, 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. While this dose-limiting toxicity was considered possibly related to study drug, the expansion of the 1 mg/kg cohort to six patients did not result in any additional DLTs. No clinically significant laboratory findings were observed. Any transient grade 1 liver enzyme elevations resolved shortly following the infusion and were not reported as adverse events. All participating patients received the complete study dose of 2001 and remain on the study.
The median follow-up is 10 months for all subjects contributing to these findings and of course, we will continue to follow these patients. The maximum tolerated dose was not reached. This slide, which we shared in February, shows the mean TTR reduction from baseline for each of the four cohorts at 28 days post-treatment. A single administration of NTLA-2001 led to rapid, consistent, and dose-dependent reductions in serum TTR protein concentration. Notably, the higher doses yielded even deeper serum TTR reduction, with doses of 0.3 milligrams per kilogram and above achieving mean reductions of more than 85% and the highest dose of 1 milligram per kilogram leading to a 93% mean reduction by day 28. With this profound level of TTR reduction, it is our judgment that there is limited benefit of assessing doses beyond 1 milligram per kilogram.
Next, we can see the emerging durability profile of 2001's effect on serum TTR reduction across all four cohorts. At all dose levels, editing of the TTR gene with 2001 was durable with sustained reductions over the follow-up period. At 0.1 milligrams per kilogram, which was the lowest dose administered to evaluate safety, we observed moderate serum TTR reduction with sustained effect through 12 months. Consistent with our preclinical models, there was greater TTR variability at this dose as compared to higher doses. This was driven by lower levels of editing and subsequent higher residual levels of TTR production in the liver. Our plan remains to amend the current protocol such that all three patients in the 0.1 milligram per kilogram cohort will be given the option to receive a follow-on dose at the 80 milligram dose subject to regulatory approval.
As we now look at the data from the three higher dose cohorts, you can clearly see that the deep reductions in serum TTR which were observed at day 28 were consistently maintained through 6-12 months. Patients in the 0.3 milligram per kilogram cohort have now all reached 12 months of follow-up, and a consistent sustained response to treatment continues to be observed with a mean 89% reduction at month 12. In the 0.7 milligram per kilogram dose cohort, the 86% mean serum TTR reduction observed at day 28 also remained durable through 6 months. At the highest dose evaluated, 1 milligram per kilogram, the mean TTR reduction observed was 93% at 28 days. In all 6 patients, this deep reduction was maintained at 93% through 6 months.
In addition, we now have three of these six patients who have reached the nine-month measurement point, and the mean reduction also remains at 93% at this time point. While we await the results in the other three patients, we are pleased to share this preliminary data for the fixed-dose equivalent being evaluated in Part Two. In totality, we believe these data strongly support NTLA-2001's potential to provide a permanent reduction in the disease-causing protein after a one-time treatment. Now, given the favorable adverse event data and maximum pharmacodynamic effects observed, the 80 milligram dose or fixed-dose equivalent of 1 milligram per kilogram dose is currently being studied in Part Two in the expansion cohort.
The Part One data combined with pharmacokinetic modeling and simulation data suggest that an 80 milligram dose would provide similar exposure to the 1 milligram per kilogram dose, where we observed a 93% mean and 98% maximum serum TTR reduction by day 28. As shown here, there is a significant overlap in the area under the curve across weight quartiles following a weight-based 1 milligram per kilogram dose and an 80 milligram fixed dose of NTLA-2001. Based on the favorable therapeutic window, this model highlights the fixed dose of 80 milligrams is anticipated to produce similar therapeutic exposures to the 1 milligram per kilogram dose.
In summary, the latest data presented today provides early confirmation that a single systemic administration of NTLA-2001 resulted in deep, consistent, and notably durable reductions of serum TTR. Mean TTR reductions were sustained between six and 12 months at all dose levels without a loss in TTR reduction over time. Further, NTLA-2001 continues to be generally well tolerated through the latest follow-up. This growing body of data, which includes unprecedented levels of mean TTR reduction sustained over time, supports NTLA-2001's potential as a one-time treatment that could halt and possibly reverse the disease. Further, this reflects the promise of systemically administered CRISPR-based in vivo gene editing in humans. Now I will turn the call back to John for some closing remarks.
Thank you, David. We're excited to share the latest data from our landmark study with heightened confidence in NTLA-2001's potential as a transformative treatment for ATTR cardiomyopathy manifestations of the disease. We anticipate completing enrollment across both arms of the trial and reporting our first interim data from the cardiomyopathy arm later this year. In addition, we're engaging with regulatory agencies, including the U.S. FDA, to discuss a potential pivotal trial design. Moreover, as our lead candidate, NTLA-2001, helps validate our broader in vivo genome editing platform, we will continue to apply the learnings from this program to our other pipeline candidates. Although not the focus of today's call, we currently have additional pre-clinical and clinical programs in development, both in the in vivo and ex vivo settings, alongside numerous partner programs leveraging our technology.
We look forward to advancing our full spectrum pipeline and expanding our leadership position with several updates expected later this year. With that, we'd be happy to answer any questions. Operator, you may now open the call for Q&A.
Thank you. We'll now begin the question-and-answer session. To ask a question, you may press star then one on your touch-tone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. At this time, we'll pause momentarily to assemble our roster. Our first question comes from Luca Issi from RBC. Please go ahead.
Oh, great. Thanks so much for taking the question. Maybe one on dosing. I know super small number, but what is the best way to rationalize the 0.1 milligram per kilogram dose, which actually goes to 55% knockdown, then goes back to 30, and then goes back again to 40? Again, maybe just small numbers, but any thoughts there will be helpful. Then maybe for phase 3, how are you thinking about a study design, particularly in TTR cardiomyopathy? Can you still run a placebo control study, or do you need to run a trial as add-on to Tafamidis? Thanks so much.
David, do you want to address the variability that you see at the lowest dose group in contrast with the highest dose groups, and we'll come back to the phase three thinking?
Yes, sure. What we're seeing in the lowest dose group is that there's what we saw in the pre-clinical picture, which is variability in the pre-clinical setting, where the monkeys were either not edited or just had partial editing. The way you can think about that variability is these patients still have a lot of their liver still intact with their gene is still unedited, so that the natural variability you see in TTR is seen in that group. Now, we know there are various sources of variability. These include nutrition, inflammation, drugs, and that's what's going on there.
Now, when you go to the higher doses, you see that variability collapses because there's very little TTR being produced in the liver, so you don't see the natural variability that you see at the higher doses.
Luca was also asking about the phase 3 thinking. Maybe you could share some of the early thoughts, as we, you know, progress our thinking here, David.
Yeah. We are obviously with the phase 1 well underway, thinking carefully about what the next studies will be. As you know, there are currently no TTR reducing drugs that are approved in the area of cardiomyopathy, so we do believe that part of this could be a placebo-controlled study. Really, at this point, what we're doing is talking to key investigators around the world. We're talking to regulators, and when we do have our trial design, we'll be talking about that publicly.
Got it. Thanks so much, guys.
The next question comes from Joon Lee from Truist. Please go ahead.
Hi. Thanks for taking our questions and congrats on the data. Following the modeling studies showing the equivalence of an 80 milligrams flat dosing to 1 milligram per kilo weight-based dosing, have you also modeled how knocking down with your NTLA-2001 compares to Patisiran every three-week dosing?
Maybe I can take an attempt at that, Jun. Thanks for the question. We're taking, you know, an empirical approach here, which is looking at the dose and the TTR reduction that comes with it. Obviously, it's based on the preclinical work that we did, and we're corroborating that here in the clinical study. You know, it just goes back to maybe, you know, what's the thesis behind your question, which is, I think all indications are the lower you go, the more likely you'll have better outcomes. For us, what we're trying to do is get a very consistent effect, which we think we're seeing now, that is, you know, as substantial as possible with it. We're very, very pleased with the depth of the reductions that we're seeing at these highest doses.
I'll just point out that if you look across the body of work here, I mean, essentially all these patients are well below 80%, and most of them are below 90%. That effect, you know, once it's achieved at these low doses, doesn't vary. We think that that's what's going to drive, you know, the outcomes that we'll look for in subsequent regulatory studies.
A quick follow-up, if I may.
Sure.
Your 0.3 milligram dose arm continues to trend down. It's slightly, but it continues to improve knockdown over time. Is there any survival advantage of liver cells that has been knocked out with this toxic protein? If that's the case.
None.
Do you think the FDA might actually ask you to study a lower dose than the 80 milligrams flat dose? Thank you.
Yeah. First of all, TTR isn't a toxic protein, particularly in wild type. We've seen no evidence of any survival effect one way or the other in any of the work that we've done. Frankly, I don't think there's a reason to posit one. Obviously, as we talk with regulators, we'll present the body of data, which is what we're accumulating here, to make our recommendation about what should be studied in pivotal work. This is an ongoing study, but thus far, we think the higher doses are clearly the ones that will be preferred.
Thank you.
Sure.
As a reminder, in the interest of time, please limit yourself to one question. If you have any follow-up, you may reenter the queue. The next question will come from Mani Foroohar from SVB Securities. Go ahead.
Hey, guys. Thanks for taking the question. I guess I want to circle back on something that you and every other company in TTR have been asked about 40 times. As you think about what we've learned for TTR cardiomyopathy, from various studies, ATTR, what we are likely to learn one way or another from APOLLO, et cetera, how do you think about appropriate endpoints to evaluate cardiomyopathy patients, you know, either on an interim or on a longer-term basis that looks more like ATTR-ACT? And then secondarily, I notice you touched on earlier, what should we expect to see, when we see that first slug of cardiomyopathy data from you guys? Is it just knockdowns or other clinical endpoints? Help us understand our expectations right.
Maybe I'll take a shot at the first one. I would point out, Mani, if it's been 40 times, this will be 41. But thanks for the question nonetheless. You know, we think the six-minute walk test is, you know, has utility, although somewhat limited. It's not a particularly discerning endpoint. The far and away preferred endpoints, you know, from regulatory purposes, for physician purposes, for payer purposes, et cetera, and I think the ones that is most discriminating are the harder endpoints. We're actually looking at patient outcomes, you know, ranging from death to hospitalizations, exacerbations of the underlying disease. I would expect that that'll be the centerpiece of the work that we do.
I think that, you know, if you step back and consider the progression of the disease and, you know, the underlying biology, we think those are the kinds of readouts that give the drug the best opportunity to display what it has to offer patients. Maybe David, you know, if you want to amend that or add to that, feel free to do it. Maybe you could just say a word or two about what we hope to present later this year for the ongoing cardiomyopathy early work.
Yeah, I'll just reinforce that for patients, for doctors and payers and regulators, everyone thinks that the cardiovascular events and mortality are the most important endpoints in those trials. Obviously, we'll be watching that very closely as the new trials come forward. What we'll be able to show this fall for, or, you know, beginning of winter, for patients with cardiomyopathy will be the knockdown is, you know, really the important to confirm that this is the same as what we've seen in the patients with polyneuropathy. In addition, obviously the safety in these patients is important as we go forward to more advanced studies, so we'll do extensive look at safety. The clinical endpoints for cardiomyopathy don't change that quickly.
I think you can see that from the ATTR-ACT trial and other trials, so that you know, we're obviously measuring these things as we go along. With this first report, I wouldn't expect to have information on that. What we do know from other types of cardiomyopathies, of course, and may soon know from trials of TTR silencers, is that deeper reductions lead to better efficacy in these patients. If we can achieve the kind of deep reductions we've achieved in the phase 1 so far, we think that's a very good sign for what we'll see in future trials.
The next question comes from Swapnil Malekar from Piper Sandler. Please go ahead.
Hey. Congrats on the data, and thanks for taking my question. One, on the ALT elevation, if we look at day 28, one patient went beyond the upper limit of normal. Can you just provide a little bit of context about this patient? Was there something different at baseline, and was this patient the same as the patient with the grade 3 vomiting?
David, do you want to address that?
Yeah. This is a different patient from the one with the vomiting. The patient was completely asymptomatic. As you can see there was an elevation at day 28, but came back to normal completely at day 56. We can't say there's any clinical significance to this finding, but of course, you know, we are keeping it in mind as we go forward.
Got it. Thank you.
The next question comes from Maury Raycroft from Jefferies. Please go ahead.
Hi, good morning. I'll add my congrats, and thanks for taking my question. Just wondering if you've collected any functional measures for the Part One patients that have completed at least nine months post-dosing. Can you talk about what you're seeing there and maybe when we'll see data from Part Two?
David, that's for you.
Yeah. We don't have clinical data to report yet from Part One. As you mentioned, in this case, we don't even have mNIS+7. That's part of Part Two of the study. We do think in that part we will learn more. Again, just to repeat that we do think with the deeper reductions, it's been shown very, you know, clearly from the data with other agents that getting those deep reductions is associated with better outcomes for patients. As we go forward to future trials and Part Two of the study, we do hope to be able to talk more about that.
Got it. That's helpful. Do you guys plan on having a data update from Part Two this year, or is that more of a 2023 event?
I'd say stay tuned, Maury. You know, it really comes down to how the data accumulates, and as you know, there's accrual and collecting the observations, et cetera. We've tried to be very, very consistent with these principles that we've espoused from the beginning about, you know, having information that's complete and interpretable, meaningful, and we'll continue to apply that as we go on.
Got it. Okay. Thank you.
Sure.
The next question comes from Salveen Richter from Goldman Sachs. Please go ahead.
Hey, guys. Thanks for taking our question, and congrats on the data. This is Elizabeth on for Salveen. Just wondering if you could provide a little bit more details and walk us through the model simulation you used for the predictions for AUC for the fixed dose. You know, just on the NIS and the mNIS measures, if you could kind of help set expectations for what we should expect from the Part Two data on that. Thank you.
David, do you want to speak to how we approach the pharmacokinetics of this?
Yeah. If you look at that slide, what we're doing is taking the information we have about the patients on the trial with their weights, of course, not chosen by us, by randomly coming into the trial and the exposures that are exhibited and put it into a model in which you can actually predict, you know, you do 1,000 reiterations of this thing and predict what the expected exposure width is in the various weight quartiles. You see on the left of the slide, you recall that no matter what the weight, the exposures are very similar in all the quartiles.
We do the same model these by saying, "Well, what if we gave these patients 80 milligrams in all these weight quartiles?" What you see on the right is that, again, these exposures are very, very similar, completely, really overlapping, in those various quartiles. This gives us very good confidence that we can give a fixed dose and all the advantages of a fixed dose, certainly, safer for patients. You don't have someone trying to multiply out your weight by your milligrams. It also, of course, ultimately will be easier drug packaging and delivery to patients.
I think it's fair to point out that there's a weight minimum to come into the study. When you think about the lower bounds of this, you know, there's a cutoff in terms of what patients need to weigh to be in the study in the first place. That's one thing to bear in mind as we think about the fixed dose. But overall, what the model shows us, and I think it makes biological sense, is that at some point, as people get bigger, body mass changes faster than hepatocyte number, if you want to think about it in those terms.
At the limits of this, the extremes that we're testing in all the different dose groups, you're very close to being bioequivalent in terms of the exposure, which we think is a really good thing for patients. You know, as David said, it really simplifies how to think about this. As the study goes on, we're continuing to accumulate data. We'll continue to test those assumptions. You know, this is obviously an ongoing phase 1 study, and it's very much about data collection. David, I think there's a second part to this thing, which just, the mNIS+7 piece, so people understand, mNIS+7 only comes from the second part of the study.
People should not look, you know, for those kinds of data from the first ascending phase of the study because, again, we're testing doses just to get to a knockdown level. We characterized what might be the clinical consequences, again, in small numbers of patients only in part two. I don't know. Is there something to add to that, David, that might be illuminating here?
Yeah. No, that's completely right.
Okay.
The next question comes from Richard Law from Credit Suisse. Please go ahead.
Hi. Thanks for taking my question, and congrats on the data. Vutrisiran received approval earlier this month. Was there anything surprising in the label that stood out to you, like QoL-DN, they included, like, participants in the study, but the data were not mentioned in the label? Is there anything that you've learned from the label that can apply to NTLA-2001's approval pathway? For example, looking at that nine-month endpoint, do you think for NTLA-2001, can you use the nine-month or would it be longer because of gene therapy? Thanks.
I don't think we learned that much incremental new information. You know, I think it was helpful that, you know, the effect was formalized when the FDA looked at the data to see, you know, knockdown of about 80, low 80s%, which is what, you know, the silencer's been running previously. I think that that's helpful to make it clear, which is, you know, what we've seen in other presentations. Otherwise, in terms of how it works and to the extent it works, we really didn't see anything all that surprising.
The next question comes from Gena Wang from Barclays. Please go ahead.
Thank you for taking my questions. I wanted to go back to slide eight and to try to understand the durability more. I think it's very important for both, you know, scientific perspective and a clinical perspective. I know you mentioned a few hypotheses. Just wondering, have you thought about or have you tested, you know, the editing efficiency that you mentioned? Specifically, have you tested biallelic editing versus monoallelic editing? Like, when you edit cells, how complete you edit, like both copy of genes, did you knock out or only single copy? Could that explain the low dose why we'll have a rebound if you have a residual cell , like, say, like meaningful percentage of cells that has a monoallelic editing?
That's the first question and the comparison of a low dose versus high dose. My second question is regarding the status of IND filing. Just wondering what will be included in the IND package. I understand you have tons of clinical data now, ex US, you know, for the next step. Can you just lay out the data package you will be including for the global clinical trials next step?
Yeah. I mean, just before we start, I would point out that the study's ongoing. I appreciate you're referring to it as tons of data, and, you know, we think we're, you know, collecting a lot of information, but we're not done, you know? This is ongoing work and having a body of data that's meaningful and really lays the foundation for subsequent work is key to this thing. That's why we call these updates interim because we, you know, continue to collect that information, which we will continue to do, and that will be part of, you know, ongoing regulatory filings. You know, Laura, do you want to say a word about the, any, you know, even the relevance of thinking about, you know, differing editing profiles? It's just to address Gena's question.
Thank you for the question. In the phase 1, you know, there are a number of hepatocytes that are edited, and that results in, you know, these partial knockout from TTR. As you move higher, right, where you're achieving 93% as a mean and, you know, maximum of 98%, that means that we're getting to almost all of the hepatocytes and that we're achieving biallelic edits. That's the only way you would, you know, be able to achieve these really profound knockouts in TTR. Yeah. Thanks.
Laura, when you say 98%, was that biallelic editing?
Yes.
It has to be.
Right. It has to be. Yeah. You know, when we go back to the 0.1, like lower dose, what is that editing efficiency if only focusing on the biallelic editing?
For the humans, we don't have that data obviously because there is, you know, we're not doing any biopsies, right? You know, when there is partial knockout at the lower doses, it's a combination of cells that are unedited, cells that are, you know, monoallelic edited and biallelic edited. Anyway, you know, the end result at those, you know, lower doses is that you still have residual TTR, and that's not the dose that we're going to be moving forward, right? That's important for us to consider and that's why it's important that, you know, pending regulatory approval, that we will be able to reload those patients so we can achieve the profound TTR knockout that, you know, that we believe is going to be efficacious for disease.
The next question comes from Joseph Thome from Cowen and Company. Please go ahead.
Hi there. Good morning, and thank you for taking my question. I think historically, you indicated that you would go forward with both cardiomyopathy and polyneuropathy, but that cardiomyopathy would be prioritized. Maybe, when you're thinking about approaching the FDA about a pivotal design, what level of follow-up do you want to see from the fixed-dose expansion? Is it just a time period, or is it functional endpoints? Maybe when would you be in a place, do you think, to make those conversations? Thank you.
David, do you want to speak to data collection and what we hope to take to regulatory agencies?
Yeah. I think what you can see, we have a growing body of data, not only from the patients with cardiomyopathy but also polyneuropathy. This is important when you're bringing safety data to the FDA. Obviously, they are interested in seeing follow-up with patients. I can't talk today exactly to what the details of what that would be in the IND, but you could see that we do have many patients passing the one-year point at this moment, including at the higher doses, this will be valuable to support the safety. Another aspect of the safety is, of course, we're only giving this drug once. Unlike drugs that you're continuing to give that might have cumulative safety issues, that won't happen.
This is, you know, just a one-time therapy and then you're following it out. So far, what we're seeing is, you know, all of the things and anything that we may see in terms of safety related to the drug, such as the infusion-related reactions are very early in their course. So this is also helpful to say that, as far as we know, we don't expect to see very late safety questions coming up.
Thank you.
The next question comes from Steven Seedhouse from Raymond James. Please go ahead.
Yeah. Thanks for taking the question. I just wanted to go back to the discussion on the functional data 'cause you mentioned mNIS+7 is only being measured in Part Two, but there are obviously other assessments, whether it's polyneuropathy, 10-meter walk test, I think just NIS in both parts. It's just not clear why you aren't measuring mNIS+7 in Part One, and if that's always been the case, it seems like a new detail, at least that I wasn't aware of. It couldn't be a function of N because you have more patients in aggregate in Part One than you do in Part Two.
I just hoping you can elaborate on strategically why that's even the case and what you're going to do with the other functional data beyond mNIS+7 from Part One, when we'll see that. Thanks.
David, do you want to address that?
The protocol has not changed. You could see in ClinicalTrials.gov that we've always had NIS is the first part and mNIS+7 is the second part. The main reason for that is, when you're especially at low doses, you're not going to learn very much. It's actually complicated for sites to carry out mNIS+7. There's a whole training program and things that we wanted to get ready for them to reach that. That's part of what it is. Now, in terms of what you can even see with NIS, an earlier version of that test is that it is also measured first at one year.
We're just reaching the first people at the higher doses, having any data about NIS. We will obviously be now, you know, from now on, hopefully have some of that, but it's not none of that either or the walk tests are very sensitive, relative to the standard here, which is the mNIS+7. Again, though, you know, in terms of going to future studies, we don't feel we need that data. You know, this data is best collected in randomized studies in any case. Really, what we know from prior studies is that when you reduce the TTR, when you do reduce it more, you get better effects.
In fact, if you get it to very low levels, as you do with a small number of patients with silencers, they actually, those patients seem to get, you know, in a better direction from mNIS+7. We feel very confident about that our TTR reductions will translate into a good clinical benefit. It will, you know, it takes a rigorous study to do that, and we're, you know, we're getting ready for that.
Very helpful. Thank you. If I could just on the redosing question, I'm wondering if that's essentially, basically a courtesy to the patients that had the lower TTR reduction at the lower doses, or if you'd also be allowing high-dose patients redosing at any point, whether it's just their request or let's say they have 90% knockdown, they want more. If redosing is a strategy that you're planning to incorporate into a pivotal study and eventual label. Thanks for the question.
Yeah. Thank you for that. Yeah. This is really being offered to the patients at the lowest doses because it's part of our commitment to them that if, you know, being part of the study, we wanted to give them the best results that are available with this drug, and that is the drug at the now recommended dose of 80 milligrams. As you can see, all the patients above the lowest dose have had very good results, you know, really as good or better than any of the standard agents. We're very happy that patients joining this phase I trial have actually received what looks like potential for important benefits. We feel good about that, and we won't be offering them additional drug.
It's unlikely they can get additional editing getting, you know, getting a similar dose a second time.
The next question comes from Dae Gon Ha from Stifel. Please go ahead.
Yeah. Hi, good morning. Thanks for taking my questions, and congrats on the update. Had a couple of clarification questions on safety. If we look at your slide deck that I'm looking at on the safety table, it does have a little bit of a footnote. For the grade 3 COVID-19, which was also seen in February, that patient now has a chest pain at day 296. Can you maybe talk about that and how that may be just a complication or extension of COVID-19? And then secondly, on the grade 3 vomiting patient, recognizing he or she had the medical history, but it was previously characterized as related, and now it's possibly related. Maybe can you clarify that for me? And going forward, the draft guidance does include a long-term follow-up.
Just wondering, how frequently are you getting those patients monitored for any kind of safety updates? Thank you.
Yeah, let me start with the chest pain and the COVID. There is no apparent relationship between those two events. You can see they're pretty far apart. The chest pain was fully evaluated by the site. They did not find any evidence of ischemic disease. It's an event that they were evaluated. As far as we know, it has no relation to the COVID or of course, to the drug as well. For the patient with the vomiting, you know, the sites always put a rating of either possibly, probably, definitely related to study drug, basically. You know, the rating that the site gave was possibly related.
If you had heard just related in the past, it might have been missing some of the additional specification from the site. You know, the safety is done at a regular intervals. The patients are being followed initially for two years at regular intervals, and then all patients will go into a long-term follow-up study, like for all gene and cell therapies. Currently, regulators are interested in asking about 15 years of follow-up for these patients. We will have very extensive follow-up of the safety and perhaps some aspects of activity as well in these patients.
David, you might want to add when TTR collection's going forward, how that changes over.
Oh, okay. Oh, yes. The TTR. Yeah. After 12 months, there'll be a collection at 18 months, and then at the end of this trial is two years. We're actually, you know, going to start talking about the long-term follow-up analysis, but we'll tell you in the future.
Thanks, David. Thanks so much.
The next question comes from Silvan Tuerkcan from JMP Securities. Please go ahead.
Great. Thank you so much for taking my questions and congrats on this data. Considering the source of TTR is the same in cardiomyopathy versus polyneuropathy patients, how can we triangulate what TTR reductions we can get to in these cardiomyopathy patients? Do these patients you hope to enroll differ in any important baseline characteristics that you know would lead to changes here? Thank you.
Maybe I can take a first crack at that. The underlying biology of TTR production is identical in you know the two manifestations two primary manifestations of TTR amyloidosis. It just turns out that certain patients for a variety of reasons have either primarily a polyneuropathy or primarily a cardiomyopathy, but in fact most of these patients have some mixed phenotype. That's really the regulatory process that drives us to think more about one or the other extreme because of the types of endpoints which have been some of the questions that have been asked about today. You know in terms of demonstrating a clinical effect for a polyneuropathy versus cardiomyopathy you're just measuring different things.
The way the study is designed is to confirm that the presumption here, the hypothesis of the underlying biology is the same, is in fact correct, and that the same dose will lead to the same TTR knockdown benefit. That really, you know, lays the foundation for collecting a dose that we take forward into subsequent trials, where we apply the relevant, you know, clinical standards and clinical endpoints to determine the extent of the effect. That's what you're seeing here, and that's the design of the study and that's, you know, the basic plan.
Great. Thank you, sir, very much. The bar will be basically the high bar that you've already set.
Yeah. There's little reason to believe that it'll behave differently. Remember that when we started the study, we offset the polyneuropathic patients from the cardiomyopathy patients. We began in, you know, the PN patients, and that was really just, you know, an abundance of caution. Those patients tend to be more stable physiologically than some of the patients with cardiomyopathy, particularly those with advanced CM. We started in that patient population to get a good understanding of what the safety profile would be with the various doses that we were testing, and then moved into the CM patient population. That's what we're doing. In terms of the expected effect, in terms of TTR knockdown, we'll be surprised if there's any differences in terms of these doses and how far the TTR goes down.
Great. Thank you so much, and congrats again.
Thank you.
As a reminder, please limit yourself to one question. Our next question comes from Tony Butler from Roth Capital. Please go ahead.
Thanks very much. I wanted to go back to the single patient with vomiting, which was characterized as gastroparesis. I think you've addressed this with the backdrop of a very relatively clean side effect profile, but it may also manifest, I guess, as nausea in the earlier doses. I'm just thinking though, if in fact you had a reduction, and let's just say it's a fairly rapid reduction in a variety of aggregate structures or amyloid fibrils, that in any one patient may be, especially in those who have low weight, could manifest as, you know, additional nausea. At the fixed dose of 80, I'm just curious to what degree, if any, does the issue of nausea or vomiting concern you? Thanks.
David, can you find any clues to nausea besides the preexisting gastroparesis in this patient or across the population?
Yeah, we don't think there's any direct relationship with the, you know, the reduction in TTR, which as you see from the charts, actually occurs over a month period. So it's not something that's, you know, happening immediately, the decrease in that protein. What we do think is any of the, you know, nausea, everything was essentially grade one other than that patient. So it isn't a significant clinical issue for this treatment. And, you know, at this, even those grade ones, it's where everything was really very transient. So we feel good about the GI profile. And of course this, you know, except for this one patient who had preexisting gastroparesis, which made it more complicated.
Thank you, David.
The next question comes from Raju Prasad from William Blair. Please go ahead.
Thanks, taking the question. Just want to get your commentary on the FDA draft guidance on genome editing, specifically on the sentence on development of genome editing products for diseases with approved FDA therapies. In your slide, I think you said that you're in conversations with the FDA on a potential pivotal trial design. Can you just clarify that? Would the plan be to dose U.S. patients in a pivotal trial, or do you think you'd have to run a phase 1 with U.S. patients prior to dosing those patients in a pivotal trial? Thanks.
Well, we're working on our regulatory strategy with the FDA and other agencies. I think that by and large, the draft guidance is very helpful and I think makes good sense and is a standard that, you know, we've either already worked to or assumed was going to be in place, because it just makes good sense and frankly is an extension from some of the other work that has been done. In terms of starting with patients with approved therapy, first of all, for cardiomyopathy, you know, patients have unsatisfied, or I should say incompletely satisfied clinical benefit, and it's a mortal illness, which absolutely, you know, is in the spirit of what the FDA guidance is.
We, with all the work that we do, we think about the benefit that can be brought to patients, and we think about, you know, the underlying morbidity and mortality of those conditions. That guides our thinking in terms of even what we pursue from a research point of view and then from a development point of view. The various diseases that we've been working with all fall into that category. We'll give you more information as that regulatory strategy in the U.S. plays out. We're confident we will be working in the U.S. and we'll be doing pivotal work in the U.S. at the appropriate time.
The next question comes from Jay Olson from Oppenheimer. Please go ahead.
Hi, good morning. This is Cheng. I'm calling for Jay. Thanks for taking the question and congrats on progress. Just wondering, can you elaborate a little bit more on the decision moving to a fixed dose regimen, just because NTLA-2001 is a one-time treatment, so changing to a fixed dose doesn't seem to significantly simplify the process or procedure. Also wondering, do cardiomyopathy patients have a similar weight distribution as polyneuropathy patients? Thank you.
I'll let David speak to the weight aspect of cardiomyopathy. I'm not aware of much difference unless you have very, very advanced disease in both of those conditions. With respect to the fixed dose, well, you're correct in pointing out that this would be presumably a single application. It certainly appears to be shaping up that way. There are still complexities in terms of weighing patients, measuring it out in the pharmacy, and applying the drug. I think not only has this been studied in the academic setting, but generally speaking, you know, if you ask physicians, patients, pharmacists, payers, et cetera. A single dose is far preferred, or I should say a fixed flat dose is far preferred to anything that's weight-based.
From an efficacy point of view, as we're seeing here thus far, we don't see any discernible difference. You know, we emphasize safety and you know, the safe application of these products for patients. You know, taking as many steps out of the process is in everybody's best interest. Now, as I said earlier, you know, we continue to collect data as the study goes on, and if we learn that at an extreme of weight, you know, on the low or high side, none that we've seen thus far, but if we learn that, we will adjust. I mean, that's why we're doing a phase 1 study to collect ongoing information that we can choose the right dose for subsequent work. David, any thoughts on, you know, patient weights in terms of the underlying, you know, manifestations of the disease?
Yeah. We won't see significantly different weights in patients with cardiomyopathy, except as John mentioned, until the very advanced stages. Of course, you know, the weight, what you're seeing from our analysis doesn't affect the exposures. Whatever weight the patients come in with cardiomyopathy, they would be appropriate weight. Of course, we will be confirming that fixed dose in our studies of the patients with cardiomyopathy. We're collecting the same pharmacokinetic data that's and pharmacodynamic information that's important for choosing, making sure the dose choice in cardiomyopathy is, you know, is either the same or not as polyneuropathy, can we fully expect the dose to be the same in those patients.
The next question comes from Jack Allen from Baird. Please go ahead.
Hi. Thank you so much for taking the questions, and congratulations on the data. My question was around the 0.7 milligram per kilogram cohort. I see that you have partial data from the 1 milligram per kilogram cohort at 9 months, presented on slide 12, and I was wondering if you had any color from the 0.7 milligram per kilogram cohort. If you could just remind us as to the chronology at which the 0.7 was enrolled and the 1 milligram were enrolled.
David, you'll remind us about the size of the cohorts and go for it.
Yeah. Just to remind you that originally the way the trial was designed was to go from 0.1 to 0.3 to 1 milligram. Recall that we were seeing very good results at 1 milligram, but it was sort of a jump from 0.3 to 1. We wanted to look at an intermediate dose of 0.7 to fill that out. That data is coming in later. You can see so far it's completely consistent in terms of durability, deep reductions, that we're seeing at 1 milligram.
Great. Thank you so much.
The next question comes from Greg Harrison from Bank of America. Please go ahead.
Good morning. This is Mary Kate on for Greg. Thanks for taking our question. You mentioned the reductions in TTR could be associated with better outcomes. Maybe what would you consider to be clinically meaningful to these patients? Thank you.
David, what? You want to speak to that?
Yeah. What you're measuring for the patients with cardiomyopathy would be reduced number of hospitalizations, improved mortality. Those are what we see ultimately as the really important things we're going to be able to see for these patients because we're able to get deeper reductions. That's what's been seen in light chain disease. You know, hopefully the same relationships will be revealed soon from reducing TTR. Of course, in the area of polyneuropathy, patients functioning better, walking better, those are the things that we're looking for in improvements.
Yeah. Just to add to that, I mean, if what was behind the question is what are the TTR levels that lead to those improved clinical benefits, you know, the data that's been presented by others in the field show that the measurable clinical benefit, those improve the lower you go. You know, the presumption here is that, you know, you want to get to levels that are literally as low as you can possibly go, which is what we've been attempting to do here, as long as you can do that safely. Thus far, the safety profile, you know, corroborates our early optimism.
You know, as you look at things like MS, et cetera, from published work, posters that have been presented, et cetera, we see that there's a very significant improvement the further you go below 80. Whether or not that same sort of improvement will take place in cardiomyopathy space awaits clinical study. I think there's little reason to believe that the underlying hypothesis will be very different.
Our last question comes from Kostas Biliouris from BMO Capital Markets. Please go ahead.
Hi, everyone. Congrats on the data. I have a quick question on the equivalence between the dosing regimens. Have you looked into the Cmax, how it is different between the two dosing regimens? Because usually bioequivalent studies will include both Cmax and AUC analysis. Thank you.
David, you want to speak to Cmax? Obviously we're relating. This is not a formal bioequivalence study. We're just looking at some of the attributes that we think are key in terms of determining effect. Any comments you want to make on Cmax at different weights?
Yeah, I guess we can't say much about it. You know, the Cmax obviously in this range is fairly narrow and we don't think has a clinical import. The important factor we do think is the exposure of the liver cells to the LNPs, which is expressed as an AUC.
Right. Have you done the analysis for Cmax or not?
We'll be doing some more extensive discussions of this, clinical pharmacology upcoming.
Okay, perfect. Thank you so much.
You'll look for some more details. Thanks.
Thank you.
This concludes our question and answer session, and the conference has now concluded. Thank you for attending today's presentation. You may now disconnect.