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

Good morning, and welcome to Intellia's Therapeutics Investor event to discuss the updated interim clinical data from the Phase I 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. [Operator Instructions] 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 morning, everyone. I'm pleased to welcome you to Intellia's investor event featuring updated interim data from the Phase I 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 & 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 a discussion of potential risks and uncertainties. All information presented on this call is current as of today, and Intellia undertakes no duty to update this information unless required by law. 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 I 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 Siplorenzino, 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 I 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 help support one of our core scientific hypotheses, namely that deep reductions in a disease causing protein achieved by a onetime genome editing treatment are, in fact, durable over time. With clinical data now out of full year for all patients receiving 0.1 and 0.3 mg per kg dose and a 6 to 9 months for patients receiving the 0.7 and 1.0 mg per 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 onetime 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 2001 trial design. Our ongoing Phase I trial is an open-label, multicenter, 2-part study of 2001 in adults with either hereditary ATTR amyloidosis with polyneuropathy or ATTR amyloidosis with cardiomyopathy. Today's update includes all the patients from part 1 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 objective from this first-in-human study are to evaluate safety, tolerability, pharmacokinetics and pharmacodynamics following a single intravenous infusion of 2001. Following the positive interim results previously announced in February, we initiated part 2 of the study, an open-label single dose expansion cohort in patients with polyneuropathy. Part 2 further characterizes the activity of 2001 at the selected dose of 80 milligrams, fixed dose equivalent of 1 milligram per kilogram. Starting with safety, 2001 continues to be generally well tolerated across all 4 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 event 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 milligram per kilogram cohort to 6 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 a 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 4 cohorts at 28 days post treatment. A single administration of 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 4 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 milligram per kilogram, which was the lowest dose administered to evaluate safety, we observed moderate serum TTR reduction with sustained effects through 12 months. Consistent with our preclinical model, 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 that is all 3 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 3 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 to 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 remain 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 3 of these 6 patients who have reached the 9-month measurement point and the mean reduction also remains at 93% at this time point. While we await the results in the other 3 patients, we are pleased to share the preliminary data for the fixed dose equivalent being evaluated in part 2. In totality, we believe these data strongly support 2001's potential to provide a permanent reduction in the disease-causing protein after a onetime treatment. Now given the favorable adverse event data and maximum pharmacodynamic effect observed, the 80-milligram dose or fixed dose equivalent of 1 milligram per kilogram dose is currently being studied in Part 2 in the expansion cohort. The Part 1 data combined with pharmacokinetic modeling and simulation data suggests that an 80-milligram dose would provide similar exposure to the 1 milligram per kilogram dose, where we observed the 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 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 provide early confirmation that a single systemic administration of 2001 resulted in deep, consistent and notably durable reductions of serum TTR. Mean TTR reductions were sustained between 6 and 12 months at all dose levels without a loss in TTR reduction over time. Further, 2001 continues to be generally well tolerated through the latest follow-up. This growing body of data, which includes unprecedented levels of mean TTR reductions sustained over time, support 2001 potential as a onetime treatment that could hold and possibly reverse the disease. Further, this reflects the promise of systemically administered CRISPR-based in vivo gene editing in humans. And 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 amyloidosis. We look forward to sharing additional program updates as we continue to advance clinical development across both patients with polyneuropathy as well as 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 and 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 preclinical 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.

[Operator Instructions] Our first question comes from Luca Issi from RBC.

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 would be helpful. And then maybe for Phase 3, how are you thinking about the study design, particularly in TTR cardiomyopathy? Can you still run a placebo-controlled study? Or do you need to run a trial as add-on to extend this?

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 III thinking.

Yes, sure. What we're seeing in the lowest dose group is that there is what we saw in the preclinical picture, which is variability if the preclinical setting where the monkeys were either not edited or just had partial editing. And the way you can think about that variability is these patients still have a lot of their liver still intact, 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, includes inflammation. It includes 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 get that natural, you don't see the natural variability that you see at the higher doses.

Luca is also asking about the Phase III thinking. Maybe you could share some of the early thoughts as we progress our thinking here, David?

Yes. We are, obviously, with the Phase I well underway, thinking carefully about what the next studies will be. And as you know, there are no 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. But the -- 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.

The next question comes from Joon Lee from Truist.

Congrats on the data. Following the modeling studies showing the equivalence of 80 milligrams flat dosing to 20-milligram per kilo rate-based dosing. Have you also modeled how knocking down with your NTLA-2001 compares to patisiran every 3-week dosing.

Maybe I can take an attempt at that, Jim. Thanks for the question. We're taking 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. It just goes back to maybe 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. And so for us, what we're trying to do is get a very consistent effect, which we think we're seeing now. That is as substantial as possible with that. And we're very, very pleased with the depth of the reductions that we're seeing at these highest doses. And I'd just point out that if you look across a body of work here, I mean essentially, all these patients are well below 80%, and most of them are below 90%. And that effect once achieved at these low doses doesn't vary. We think that, that's what's going to drive 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 slightly, but it continues to show improved knockdown over time. Is there any survival advantage of the results that have been knocked out with the toxic protein? And if that's the case, I think the FDA might actually ask you to study a lower dose of the 80-milligram flat dose, right?

Yes. So first of all, TTR protein 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. And 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, and this is an ongoing study. But thus far, we think the higher doses are clearly the ones that will be preferred.

[Operator Instructions] The next question will come from Mani Foroohar from SVB Securities.

I guess I want to circle back on something that you and every other company in TTR has been asked about 40 times. As you think about what we've learned for TTR cardiomyopathy from various studies attribute, 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 either on interim or on a longer-term basis that looks more like a track. And then secondarily, I know this was touched on earlier, what should we expect to see [indiscernible] see that first plug of cardiomyopathy data from you guys, just knockdown, some early clinical endpoints, help us get our expectations right.

Maybe I'll take a shot at the first one, then I would point out, Mani, if it's been 40 times, this will be 41, but thanks for the question, nonetheless. We think the 6-minute walk test has utility, although somewhat limited. It's not a particularly discerning end point. the far and away preferred end points 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, make sure ranging from death to hospitalizations, exacerbations of the underlying disease. And I would expect that, that will be the centerpiece of the work that we do. And I think that if you step back and consider the progression of the disease and 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, if you want to amend that or head to that, feel free to do it and maybe you could just say a word or 2 about what we hope to present later this year for the ongoing cardiomyopathy early work.

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. So obviously, we'll be watching that very closely as the new trials come forward. What we'll be able to show this fall or beginning of winter, for patients with cardiomyopathy will be the -- really the knockdowns 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 of cardiomyopathy don't change that quickly. I think you can see that from the ATTRACT trial and other trials, so that we're obviously measuring these things afar we go along. But with this first report, I wouldn't expect to have information on that. But what we do know from other types of cardiomyopathy, of course, and they soon now from trials of TTR silencers is that deeper reductions lead to better efficacy in these patients. So if we can achieve the kind of deep reductions we've achieved in the Phase I 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.

Congrats on the data. So one on the ALT elevation, if you look at day 28, one patient went beyond the upper limit of normal. So 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?

Yes. So this is a different patient from the one with vomiting. The patient was completely asymptomatic. As you can see that it was an elevation at day 28 that came back to normal completely at day 56. So we can't say there's any clinical significance to this finding, but of course, we are keeping this in mind as we go forward.

The next question comes from Maurice Raycroft from Jefferies.

I'll add my congrats. Just wondering if you've collected any functional measures for the Part 1 patients that have completed at least 9 months post dosing. And can you talk about what you're seeing there? And maybe when we'll see data from Part 2.

David, that's for you.

Yes, we don't have clinical data to report yet from Part 1. As you mentioned, it takes -- we really measure the -- in this case, we don't even have mNIS+7, that's part of Part 2 of the study. And 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 clearly from the data with other agents that getting those deep reductions is associated with better outcomes for patients. So as we go forward to future trials and Part 2 of the study, we do hope to be able to talk more about that.

Got it. That's helpful. And do you guys plan on having a data update from Part 2 this year? Or is that more of a 2023 event?

I'd say stay tuned, Maury. It really comes down to how the data accumulates. And as you know, there's accrual and collecting the observations, et cetera. We tried to be very, very consistent with these principles that we've espoused from the beginning about having information that's complete and interpretable, meaningful, and we'll continue to apply that as we go on.

The next question comes from [Salveen Adair ] from Goldman Sachs.

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 use for the predictions for AEC for the fixed dose? And then just on the NIS and the mNIS measures, if you could, it kind of helps that expectations for what we should expect from the Part 2 data on that.

David, do you want to speak to how we approach the pharmacokinetics of this?

Yes. If you look at that slide, what we're doing is taking the information we have about the patients on the trial with their rates, of course, not chosen by us but randomly coming into the trial and the exposures that are exhibited and put it into a model in which you can actually predict, you do 1,000 reiterations of this thing and predict what the expected exposure is in the various weight quartiles. And you see on the left slide, you recall that no matter what the way, the exposures are very similar in all the quartiles. You do the same model with saying, well, what if we gave these patients 80 mg 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. So 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. And it also, of course, ultimately, it will be easier drug packaging and delivery to patients.

I think it's fair to point out that there is a weight minimum to come into the study. So when you think about the lower bounds of this, there's a cutoff in terms of what patients need the weight to be in the study in the first place. So 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 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. And at the limits of this, either the extremes that we're testing in all the different dose groups, you're very close to being a bioequivalent in terms of the exposure, which we think is a really good thing for patients. And as David said, it really simplifies how to think about this. But as the study goes on, we're continuing to accumulate data. We'll continue to test those assumptions. And this is obviously an ongoing Phase I study, and it's very much about data collection. David, I think there's a second part of this thing, but just again, the mNIS piece, I just want people understand and mNIS+7 only comes from the second part of the study, people should not look 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 consequence. Again, in small numbers of patients only in part 2, I don't know, is there something to add to that, David, that might be illuminated here.

Yes. No, that's completely right.

The next question comes from [Richard Law] from Credit Suisse.

Congrats on the data. [indiscernible] received approval earlier this month. Was there anything surprising in the label that stood out to you like [indiscernible] participant in the study, but the data were not mentioned in the label. And then is there anything that you've learned from the label that kind of applies to 2001 approval pathway? So for someone looking at a 9-month endpoint, do you think for 2001, would you -- can you use a 9 months? Or would it be longer because of gene therapy?

I don't think we learned that much incremental new information. And I think it was helpful that the effect was formalized when the FDA looked at the data, see knockdown of about low 80s percent, which is what the silencer has been running previously. I think that that's helpful to make it clear, which is what we've seen in other presentations. But 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.

So I wanted to go back to Slide 8, and try to understand the durability more. I think it's very important for both a scientific perspective and a clinical perspective. So I know you mentioned a few hypothesis. Just wondering, have you thought about or have you tested the editing efficiency that you mentioned, but specifically, have you tested biallelic editing versus monolithic editing means like cutting -- like when you edit cells, how complete you edit? Like both copy of genes did you knock out or only single copy? And could that explain the low dose why we'll have a rebound if you have a residual cells like say, like a meaningful percentage of cells has a monolithic editing. So that's the first question and the comparison of a low dose versus high dose. My second question is regarding the status of R&D filing. Just wondering what will be included in the R&D package? I understand you have tons of the clinical data now, ex U.S. for the next step. Can you just lay out the data package will be included for the global clinical trials next step?

Yes. I mean, just before we start, I would point out that the study is ongoing. So I appreciate you're referring to it as tons of data, and we think we're collecting a lot of information, but we're not done. And 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. And that's why we call these updates interim, because we continue to collect that information, which we will continue to do, and that will be part of ongoing regulatory filings. Laura, do you want to say a word about any -- even the relevance of thinking about different editing profiles. It's just to address Gena's question.

Yes. Yes, thank you for the question. So in the 0.1, the [indiscernible] number of hepatocytes that are edited, and that results in these partial [indiscernible] TTR, you move higher, right, where you're achieving 93% as a mean and maximum of 98%, that means that we're getting to almost all of the hepatocytes and that were achieving biallelic edits. That's the only way you would be able to achieve these really profound knockout in TTR.

All right. When you say 98%, was that biallelic editing ?

It has to be.

Yes. And then when we go back to the 0.1, like lower dose, what is the editing efficiency if only focusing on the biallelic editing?

So for the humans, we don't have that data. Obviously, we're not doing any biopsies, right? So when there is partial knockout at the lower doses, it's a combination of cells that are unedited, cells that are mono -- allelic edited and biallelic editing. And anyway, the end result at those lower doses [indiscernible] you still have residual TTR and that's [indiscernible] that we're going to be moving forward, right? So that's -- I think that that's important for us to consider. And that's why it's important that pending regulatory approval that we will be able to redose those patients, so we can achieve the profound TTR knockout that we believe is going to be efficacious for DCC.

The next question comes from Joseph Thome from Cowen and Company.

Historically, you indicated that you would go forward with both cardiomyopathy and polyneuropathy, but the 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 end points? And maybe when would you be in a place, do you think, to make those conversations.

David, do you want to speak to data collection and what we hope to take to regulatory agencies?

I think what you can see, we have a growing body of data not only from the patients with cardiomyopathy, but also polyneuropathy. So this is important when you're bringing safety data to the FDA. Obviously, they are interested in seeing follow-up of 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 1-year point at this moment, including at the higher doses. So this will be valuable to support the safety. Another aspect to the safety is, of course, we're only giving this drug once. So unlike drugs that you're continuing to give, that might have cumulative safety issues, that won't happen. This is just a onetime therapy and then you're following out. And so far, what we're seeing is 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.

The next question comes from Steve Seedhouse from Raymond James.

I just wanted to go back to the discussion on the functional data because you mentioned mNIS+7 as only being measured in Part 2, but there are obviously other assessments, whether it's polyneuropathy 10-meter walk test. I think just NIS in both parts. And it's -- I guess, it is just not clear why you aren't measuring mNIS+7 in Part 1. And if that's always been the case, it seems like a new detail at least that I wasn't aware of. And it couldn't be a function of end because you have more patients in aggregate in Part 1 than you do in Part 2. So, I'm 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 1 and when we'll see that.

David, do you want to address that?

Yes. So the protocol has not changed, and you could have seen at clintrials.gov that we've always had NIS as the first part on mNIS+7 as the second part. And the main reason for that is, when you're especially at low doses, you're not going to learn very much. And it's actually very -- it's actually complicated for sites to carry out mNIS+7. It's a whole training program and things that we wanted to get ready for them to reach that. So 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 is also measured first at 1 year. So we're just reaching the first people at the higher doses having any data about NIS. So, we will obviously be now from now on, hopefully, have some of that, but it's not -- none of that or the walk tests are very sensitive relative to the standard here, which is the mNIS+7. Again, though, in terms of going to future studies, we don't feel we need that data. This data is best collected in randomized studies in any case. And the -- and really the -- what we know from prior studies is that when you reduce the TTR, when you reduce it more, you get better effects. And 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 in a better direction from mNIS+7. So we feel very confident about that our TTR reductions will translate into good clinical benefit, but it will -- it takes a rigorous study to do that, and we're getting ready for that.

Very helpful. And 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. And if redosing is a strategy that you're planning to incorporate into a pivotal study and eventual label.

Yes. Thank you for that. Yes, this is really being offered to the patients at the lowest doses because as part of our commitment to them as 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 the recommended dose of 80 milligrams. As you can see, all the patients above the lowest dose have had very good results really as good or better than any of the standard agents. So we're very happy that patients joining this Phase I trial have actually received what looks like a potential for important benefits. So we feel good about that, and we won't be offering them additional drug. It's unlikely they can get additional editing, getting a similar dose a second time.

The next question comes from Dae Gon Ha from Stifel.

Congrats on the update. I have a couple of clarification questions on safety. So if we looked at your slide deck that I'm looking at on the safety table. It does have a little bit of a footnote. So for the Grade 3 COVID-19, which was also seen in February, that patient now has a chest pain at day 296. So 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. So maybe can you clarify that for me? And going forward, the draft guidance does include a long-term follow-up. So just wondering how frequently are you getting those patients monitored for any kind of safety updates.

Yes. Let me start with the chest pain and the COVID. So there is no apparent relationship between those 2 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. So it's an event that they evaluated. And as far as we know it, there's no relation to the COVID or, of course, to the drug as well. For the patient with the vomiting, the sites always put a rating of either possibly, probably, definitely related to study drug, basically. And the rating that the site gave was possibly related. So if you had heard just related in the past, it might have been missing some of the additional specification from the site. The safety is done at regular intervals. The patients are being followed initially for 2 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. So 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 TTR collections going forward, how that changes overtime.

Okay. TTR, yes. So after 12 months, there'll be a collection at 18 months. And then at the end of this trial is 2 years, and we're actually talking about the long-term follow-up analysis that we'll tell you in the future.

The next question comes from Silvan Tuerkcan from JMP Securities.

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? And do these patients you hope to enroll differ in any important baseline characteristics that would lead to changes here?

Maybe I can take a first crack at that. The underlying biology of TTR production is identical in the 2 manifestations, 2 primary manifestations to TTR amyloidosis. It just turns out that certain patients for a variety of reasons have either primarily a polyneuropathic or primarily a cardiomyopathic but in fact, most of these patients have some mixed phenotype. And 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 in terms of demonstrating a clinical effect for polyneuropathy versus cardiomyopathy, you're just measuring different things. But the way the study is designed is to confirm that the presumption here, the hypothesis of the underlying biology time is, in fact, correct. And at the same dose will lead to the same TTR knockdown benefit. And that really lays the foundation for collecting a dose that we take forward into subsequent trials where we apply the relevant clinical standards and clinical endpoints to determine the extent of the effect. And so that's what you're seeing here, and that's the design of the study, and that's the basic plan.

So the bar will be basically the same bar you've already -- the high bar that you've already set?

Yes. And there's little reason to believe that it will behave differently. Remember that when we started the study, we offset the polyneuropathic patients from the cardiomyopathic patients. We began in the PN patients. And that was really just an abundance of caution. Those patients tend to be more stable physiologically than some of the patients with cardiomyopathy, particularly those with advanced CM. And so 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. So that's what we're doing. But in terms of the expected effect in terms of TTR knockdown, we will be surprised if there's any differences in terms of these doses and how far the TTR goes down.

[Operator Instructions] Our next question comes from Tony Butler from ROTH Capital.

I wanted to go back to the single patient with vomiting, which was characterized as gastroparesis. And 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. And 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 additional nausea. And so at the fixed dose of 80, I'm just curious to what degree, if any, does the issue of nausea, vomiting concern?

David, can you find any clues to nausea besides the pre-existing gastroparesis in this patient or across the population?

Yes. We don't think there's any direct relationship with the reduction in TTR, which as you see from the charts actually occurs over a month period. So it's not something that's happening immediately, the decrease in that protein. What we do think is any of the nausea, everything is essentially Grade 1 other than that patient. So it isn't a significant clinical issue for this treatment. And at this -- even those Grade 1 where everything was really very transient. So we feel good about the GI profile. And of course, this -- except for this 1 patient who had preexisting gastroparesis, which made it more complicated.

Next question comes from Raju Prasad from William Blair.

I 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 as would the plan be to dose U.S. patients in a pivotal trial? Or do you think you'd have to run a Phase I with U.S. patients prior to dosing those patients in the pivotal trial?

Well, we're working on our regulatory strategy with the FDA and other agencies. I think that with -- by and large, the draft guidance is very helpful and I think makes good sense. And as a standard that we've either already worked to or assumed it's going to be in place because it just makes good sense. And frankly, it's 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, patients have unsatisfied or I should say, incompletely satisfied clinical benefit, and it's an illness, which absolutely is in the spirit of what the FDA guidance is. So with all the work that we do, we think about the benefit that can be brought to patients and we think about the underlying morbidity and mortality of those conditions. And 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 and the various diseases that we've been working with all fall into that category. So we'll give you more information as that regulatory strategy in the U.S. plays out, but 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.

This is Cheng on the line for Jay. Congrats on progress. Just wondering, can you elaborate a little bit more on the decision moving to a fixed dose regimen just because 2001 is a onetime treatment. So changing to a fixed dose doesn't seem to significantly simplify the progress or procedure. And also wondering, do cardiomyopathy patients have similar weight distribution as polymyopathy patients?

I'll let David speak to the weight aspect of cardiomyopathy. I'm not aware of much difference unless you have a 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 is still complexities in terms of weighing patients, measuring it out in the pharmacy and applying the drug. And I think not only has this been studied in the academic setting, but generally speaking, 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. And from an efficacy point of view, as we're seeing here thus far, we don't see any discernible difference. And we emphasize safety and the safe application of these products for patients. So taking as many steps out of the process is in everybody's best interest. Now as I said earlier, we continue to collect data as the study goes on. And if we learn that at an extreme of late 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 I study to collect the ongoing information that we can choose to write those for subsequent work. David, any thoughts on patient weight in terms of the underlying manifestation of disease?

Yes. We won't see significantly different weights in patients with cardiomyopathy, except as John mentioned, until the very advanced stages. But of course, the weight what you're seeing from our analysis doesn't affect the exposures. So whatever way the patients come in with cardiomyopathy, they would be appropriate weight. And of course, we will be confirming that fixed dose in our studies with 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 and cardiomyopathy 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.

Congratulations on the data. My question was around the 0.7 milligram per kilogram cohort. Do you have partial data from the 1 milligram per kg 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. Maybe 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.

Yes. Just to remind you that originally, the way the trial was designed was to go from 0.1 to 0.3 to 1 milligram. And then recall that we are seeing very good results at 1 milligram, but it was sort of a jump from 0.3 to 1. So we wanted to look at an intermediate dose of 0.7 to fill that out. So that data is coming in later. And you can see so far it's completely consistent in terms of durability, deep reductions that we're seeing at 1 milligram.

The next question comes from Greg Harrison from Bank of America.

This is Mary Kate on for Greg. So you mentioned the reductions in TTR could be associated with better outcomes. Maybe what would you consider to be clinically meaningful to these patients.

David, what -- can you speak to that?

Yes. So what you're measuring for the patients with cardiomyopathy would be reduced number of hospitalizations, improved mortality. Those are what we see ultimately is the really important things we're going to be able to see for these patients because we're able to get deeper reductions. And that's what's been seen in light chain disease and hopefully, will the same relationships will be revealed soon from reducing TTR. And of course, in the area of polyneuropathy patients functioning better, walking better, those are the things that we're looking for in improvements.

And just to add to that, I mean, what was behind the question is what are the TTR levels that lead to those improved clinical benefits. The data that's been presented by others in the field show that the measurable clinical benefit does improve the lower you go. And the presumption here is that 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. And thus far, the safety profile corroborates our early optimism. And if 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. And whether or not that same sort of improvement will take place in cardiomyopathy space, awaits clinical study. But 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.

I have a quick question on the equivalents between the dosing regimens. Have you looked into the Cmax. How it is different between the 2 dosing regimens because usually bioequivalent studies will include both Cmax and AUC analysis.

David, do you want to speak to Cmax. I mean, 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 the effect. But any comments you want to make on Cmax at different weights.

Yes, I can't say much about it. The Cmax, obviously, in this range is fairly narrow, and we don't think has a clinical -- the important factor we do think is the exposure of the liver cells to the LNPs, which is expressed as an AUC.

Right, but have you done the analysis for Cmax or not?

We'll be doing some more extensive discussions of the clinical pharmacology upcoming and we'll give you more details.

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