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

Good morning, and welcome to Intellia Therapeutics' Investor Event. My name is Drew, 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 Lina Li, Senior Director of Investor Relations and Corporate Communications at Intellia. Please proceed.

Thank you, operator, and good morning, everyone. Welcome to today's call to discuss updated clinical data from the Phase I study of nex-z in development for the treatment of ATTR amyloidosis. Earlier this morning, we issued a press release detailing the interim results from our ongoing study. This release and the accompanying slide 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 Intellia's website. Before we get started, I would 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 nex-z has not been approved by any health authority. Joining me on today's webcast are Dr. John Leonard, our Chief Executive Officer; Dr. David Lebwohl, our Chief Medical Officer; and Dr. Marianna Fontana, Professor of Cardiology at the University College London Centre for Amyloidosis and Honorary Consultant Cardiologist at the National Amyloidosis Centre, and a clinical investigator on our nex-z Phase I trial. Also on the call and available for Q&A is Dr. Liron Walsh, our Head of In Vivo Pipeline Development. As outlined on the slide, John will begin with introductory remarks. Next, Dr. Fontana will review the clinical data from the cardiomyopathy arm presented just a few hours ago at the American Heart Association Scientific Sessions here in Chicago. Then David will discuss the implications of these data for the ongoing MAGNITUDE Phase III trial and provide an update on the polyneuropathy arm and the MAGNITUDE-2 Phase III trial, before we open up the call for questions. With that, I'll now turn the call over to John.

Thank you, Lina, and welcome, everyone. Today we're very pleased to be sharing new findings from the ongoing Phase I study of nex-z, our investigational in vivo CRISPR gene editing therapy for the treatment of ATTR amyloidosis, both cardiomyopathy and polyneuropathy. We're equally pleased to be joined by one of the experts in the field, Dr. Marianna Fontana, to walk through the updated results and to provide her perspective on the data. Before I turn it over to Dr. Fontana, let me start by reflecting on the significance of today's update. Over the past few years, we've demonstrated with a growing body of clinical evidence the power of CRISPR-based therapies as a potential new therapeutic modality for the treatment of ATTR amyloidosis and other life-threatening diseases. By targeting the TTR gene responsible for production of the disease-causing protein, nex-z achieved consistently rapid, deep and durable TTR reduction in all patients. Now with our collaborators at Regeneron, we are presenting the first clinical evidence that deep and persistently low levels of TTR reduction, achieved with a simple onetime infusion of nex-z, may have important disease-modifying activity. The data across multiple measures of disease progression, both for patients with cardiomyopathy and polyneuropathy, indicate a benefit in the form of disease stability or improvement for most patients when compared to patients baseline. These are remarkable results in any patient population, but especially within our Phase I study in which half the ATTR-CM population had NYHA Class III heart failure and 31% had the hereditary form of the disease, which is often more severe and difficult to treat. Moreover, these data shed light on our hypothesis that deeper and more consistent TTR reductions are important for changing the clinical course of ATTR amyloidosis. We are highly encouraged by these results, including the favorable safety and tolerability observed to date. These results give us even greater confidence in the designs of our 2 Phase III trials, and we continue to believe that the probability of technical and regulatory success remains high. We are rapidly advancing the pivotal studies, MAGNITUDE for ATTR-CM and MAGNITUDE 2 for ATTR-PN, for what we believe will be a best-in-class onetime treatment capable of resetting the standard of care for ATTR amyloidosis. With that, I'm honored to turn the call over to Dr. Marianna Fontana.

Thank you, John. Good morning, everyone. On behalf of my fellow authors, it is my pleasure to present the results of the interim report of the Phase I study of nex-z in patients with ATTR cardiomyopathy. Here is my disclosure. ATTR cardiomyopathy is a disease caused by disruption in the dynamics of myocardial deposition and clearance of misfolded transthyretin in the form of amyloid fibrils depositioned within the myocardium, with resulting pathologic cardiac remodeling and, ultimately, organ dysfunction. ATTR cardiomyopathy is a progressive and fatal disease and characterized by deterioration in functional capacity and quality of life, symptomatic heart failure, frequent hospitalization, and death. It is emerging as an under-diagnosed cause of heart failure, especially in the elderly. And although the true prevalence is unknown, it is estimated to affect 200,000 to 500,000 individuals worldwide. Current treatment focused on either stabilization of the TTR protein or inhibition of the TTR protein synthesis by means of degradation of the TTR messenger RNA. However, results from recent trials indicate that these treatments only slow disease progression, while quality of life and functional capacity continue to decline on these treatments. Additionally, these therapies require lifelong administration, adding to the overall disease burden for patients. The disease is particularly aggressive in patients with hereditary disease or those in NYHA functional Class III, which have much greater mortality rates. Recently, markers of disease progression had been established. Indeed, in recent analysis in a large population of patients with ATTR cardiomyopathy, the majority of which were in NYHA functional Class I or II, worsening in NT-proBNP, troponin and 6-minute walking test was common, occurring in 35%, 50% and 40% of patients, respectively, reflecting the relentlessly progressive nature of the disease. The threshold for the 3 markers used to define progression were clinically meaningful and strongly predictive for mortality, with only 25% to 30% of worsening patients surviving at 5 years. In patients with ATTR cardiomyopathy, vutrisiran, a TTR gene silencer, led to a lower risk of death and cardiovascular events. This result was achieved with a TTR reduction of about 80% at 6 months, with patients achieving a main absolute TTR level at 30 months of about 50 microgram per milliliter. Greater suppression in amyloid precursor protein in amyloid AA and amyloid AL amyloidosis is associated with better outcome. Deeper reduction in TTR levels was correlated with increased clinical benefit in patients with ATTR polyneuropathy. Overall, based on this observation, it is likely that achieving the lowest possible level of circulating TTR may be important to disrupt the dynamics of myocardial deposition and clearance to maximally impact disease progression in ATTR cardiomyopathy. Nexiguran ziclumeran, nex-z, is a single-dose investigational therapy designed to permanently inactivate the TTR gene in liver cells, the main source of circulating transthyretin, with the goal to consistently knock down circulating TTR levels long term. Nex-z is a CRISPR/Cas9-based in vivo gene editing therapy. It consists of a single guide-RNA molecule that precisely targets the human TTR and an mRNA sequencer Streptococcus pyogenes Cas9 protein encapsulated in a lipid nanoparticle delivery system with liver tropism. Following intravenous administration of nex-z, the therapy is transported directly to the liver and taken up via the LDL receptor on hepatocyte. The Cas9 mRNA is translated, producing the Cas9 enzyme, which interacts with single guide-RNA to form a complex. The complex binds to the TTR gene and leads to precise cleavage in the targeted TTR gene sequence, permanently inactivating the production of the TTR protein. This ongoing Phase I trial is a 2-part open-label study in 36 patients with wild-type and hereditary ATTR cardiomyopathy. In the part one dose-finding portion of the study, patients received a dose of either 0.7 milligram per kilo, 9 patients; or 1 milligram per kilo, 3 patients. Following this, in the part two dose expansion of the study, patients received treatment with nex-z at a dose of 55 milligrams, 24 patients, the fixed dose equivalent of 0.7 milligram per kilo. The primary objectives were to evaluate the safety, tolerability and PD, i.e. TTR level. The secondary objectives were to evaluate efficacy on clinical measures of cardiac disease with biomarkers: 6-minute walking test, cardiopulmonary exercise test, cardiac imaging, and KCCQ score. The baseline characteristics are reported here. The population enrolled had a high proportion of patients with severe disease, with a median NT-proBNP of 2,000 and up to 20,000 nanograms per milliliter; a severe reduction of functional capacity with a median peak VO2 of 12.7 milliliter per kilo/minute; a very high level of cardiac infiltration as demonstrated by a baseline extracellular volume of 58%; and a high proportion of variant patients, of which 2 were V142I homozygous, which commonly present with a very aggressive form of disease. 50% of patients had NYHA functional Class III at baseline. And notably, there was no concurrent use of other disease-modifying therapy. For the primary endpoint, following a single IV infusion of nex-z, we observed a deep, rapid and durable reduction in serum TTR, with every patient treated demonstrating similar TTR reductions regardless of the baseline TTR level or patient's genotype. Indeed, serum TTR protein concentrations rapidly declined from baseline, reaching a mean percent reduction of 89% at day 28, with a mean absolute serum TTR level of 18.9 micrograms liter. Importantly, these deep reductions were well maintained over time, with TTR levels remaining low and virtually unchanged throughout 24 months of follow-up. Secondary endpoints, which included cardiac biomarkers, functional capacity and cardiac imaging were assessed at 12 months, a time point which was reached by all patients in this ongoing Phase I study. The reduction in TTR levels with nex-z treatment was associated with evidence of disease stabilization at 12 months based on 3 markers of disease progression. Indeed, stability throughout the 12 months was observed on NT-proBNP on the left, Troponin T in the middle, and functional capacity as assessed by 6-minute walking test on the right panel. When a responder analysis was performed at an individual patient level using the validated disease progression criteria for NT-proBNP, Troponin T and 6-minute walking test, stability or improvement in these biomarkers was observed in nearly 80% of patients at 12 months. Notably, 83% of NYHA functional Class I and II patients, and even 47% of NYHA functional Class III patients, showed no worsening in any of these 3 markets at 12 months. Evidence of stability or improvement in patients and quality of life following nex-z treatment was also confirmed by evaluating the changes in NYHA functional class and KCCQ overall score. Indeed, 92% of patients demonstrated either no change or improvement in NYHA class at 12 months, including improvement in 72% of patients with NYHA functional Class III. And although these observations were made in a single arm open-label study, the findings are consistent with the results observed in other markers of disease progression. Moreover, despite the severity of the disease in the population enrolled, stability in functional capacity was also confirmed with cardiopulmonary exercise testing where the 2 key prognostic markers, peak oxygen consumption and ventilatory efficiency remained stable throughout the initial 12 months. Stability was also confirmed across a wide range of structural functional parameters evaluated by either echocardiography or CMR. There was evidence of stability on systolic/diastolic function as well as cardiac amyloid load. Regarding the safety observed with nex-z treatment, we observed a favorable safety and tolerability profile. Infusion-related reaction was the most common treatment-related adverse event. These reactions were predominantly mild, self-limiting, and did not require permanent discontinuation of the infusion in any patient. Liver enzyme elevations were mild and not indicative of liver injury. In addition, the rate of cardiac hospitalization, 0.16 patient years, appeared to be low in this population. In summary, administration of a single dose of nex-z demonstrated several safety and tolerability profile and resulted in deep, durable and rapid reduction in serum TTR, with very low variability among the patients in the study. Reductions in TTR were associated with stability or improvement of several disease markers in an ATTR cardiomyopathy population with advanced disease who would have been expected to have rapid disease progression and high mortality rates. As for the limitations, the observations in this study with nex-z treatment were obtained in a Phase I single-arm open-label study. Therefore, these results will need to be confirmed in randomized placebo-controlled trials. These results represent the first clinical evidence of in vivo CRISPR/Cas9 gene editing in cardiomyopathy, showing that targeted inactivation of the TTR gene may favorably impact disease progression in ATTR cardiomyopathy. These results also support the hypothesis that rapid, deep and durable reduction in serum TTR results in meaningful clinical benefit. The effects of nex-z on clinical outcomes are being evaluated in MAGNITUDE, a Phase III global, randomized, placebo-controlled trial in patients with ATTR cardiomyopathy. We wish to extend our regards to patients, their caregivers, their families, study site coordinators, and staff. Finally, we are excited to invite you all to read the paper published today in the New England Journal of Medicine. I will now turn over the call to David.

Thank you, Dr. Fontana. We appreciate your being with us today to share your expert insights. Let me start by saying we are delighted with these updated results in which all 36 patients with ATTR-CM have been followed for at least 12 months. From the beginning, we have hypothesized that inactivating the TTR gene with CRISPR gene editing would achieve rapid, deep and durable reduction in levels of a damaging TTR protein, and in turn would lead to greater clinical benefit for patients. This relationship between greater TTR reduction and better subsequent control of disease has been observed in ATTR-PN and in patients with AL amyloidosis. We now believe that we're seeing the same trend emerging for ATTR-CM. As Dr. Fontana highlighted, all patients achieved deep and durable TTR reduction after a onetime infusion. Notably, the TTR reduction occurred rapidly with nadir reach at 28 days, which is particularly important for a condition with high mortality. With TTR silencers, the reported mean reduction was approximately 80%, which is not reached until 6 months after starting chronic treatment. Now we have observed positive trends that the very low levels of circulating TTR seen with nex-z are associated with disease stabilization or improvement across several markers of cardiac progression at month 12 compared to baseline. These favorable results were observed even though half the patients were Class III and about 30% had a mutated TTR gene, both characteristics of patients with more rapidly worsening disease. This is a significant insight because when patients are untreated, disease progression as measured by these markers is typically evident within 12 months. We see this graphically on the next slide. Despite earlier diagnosis and currently available therapies, ATTR-CM remains a progressive and ultimately fatal disease with significant unmet need. In 2 recent ATTR-CM studies, the placebo arms exhibited rapid disease progression when patients didn't receive a TTR-directed therapy. As presented on this slide, the natural history of the disease is marked by a high incidence of cardiovascular events and significant morbidity by month 12. Although each of these clinical trials had distinct enrollment criteria and methodologies, the trajectories of the clinical outcomes for untreated patients were similar in both studies, indicating the consistently poor prognosis of these patients, even though the baseline characteristics in these 2 studies were much better than the cohort in our Phase I. Only 5% to 11% were NYHA Class III and 10% to 12% had variant disease in the 2 Phase IIIs. The reported rate of CV hospitalizations per year in ATTRibute-CM was high at 0.45. In addition to the favorable trends across markers of disease progression, we have also observed a low rate of cardiac events, 0.16 per patient year thus far in our Phase I study, despite the more advanced patient population treated with nex-z. These data, while from a relatively small open-label study, are informative for our assessment of the ongoing magnitude Phase III trial design and its potential clinical outcomes. Here on this slide, we have plotted the nex-z Phase I data as an estimated Kaplan-Meier curve of time to first cardiovascular event or death. Because the patient population in the Phase I was 31% variant ATTR-CM, we have reweighted the data to be more reflective of the patient population we anticipate enrolling in the Phase III study based on the most recent ATTR-CM pivotal study, specifically with 12% variant patients. The resulting curve is compelling relative to the otherwise short time to first event expected if the patients did not receive nex-z. This finding reaffirms our assumptions in our pivotal trial and gives us confidence based on the Phase I results that the magnitude study is well designed, both adequately sized, and sufficiently powered to meet its objectives. Turning now to the ongoing Phase III study, MAGNITUDE, where we're making strong progress in enrollment. The broad interest in the trial from patients and physicians has enabled us to enroll patients more quickly than our internal projections. With these data presented today supporting a benefit from nex-z treatment, we anticipate that interest in nex-z will increase even further, and the robust enrollment momentum will continue. Switching to ATTR-PN. As a reminder, this multisystem disease also manifests in polyneuropathy through the progressive accumulation of protein deposits in the peripheral nerves. In the Phase I trial, we also evaluated nex-z in patients with hereditary ATTR amyloidosis with polyneuropathy. Please refer to the appendix included in the slides made available for download with today's call for the detailed data update on the polyneuropathy arm. Consistent with the observations in ATTR-CM, the rapid, deep and durable reduction in serum TTR observed in all patients was accompanied by evidence of disease stabilization or improvement across multiple clinical measures of neuropathy. Across NIS, mNIS+7 and mBMI, there were favorable trends of clinical benefit at month 12 compared to baseline levels, with further improvements noted in NIS and mBMI in the part one patients where 24 months of follow-up was available. These results were observed in patients with both early-stage disease and in patients with severe neurologic impairment previously treated with patisiran. In patients with early-stage disease, we know from the well-characterized natural history of the disease that these patients would normally experience progression and significant impairment without a disease-modifying treatment. For patients previously treated with patisiran, these patients now appear to be showing stability in their neuropathy as measured by mNIS+7. This suggests that nex-z can potentially benefit patients throughout the spectrum of disease. And finally, nex-z has demonstrated a favorable safety and tolerability profile to date. Taken together, these data support our belief that nex-z can halt and potentially reverse the disease, which we will evaluate within the MAGNITUDE-2 Phase III trial. As previously announced, the FDA cleared our IND application for MAGNITUDE-2, a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of nex-z. The study will enroll 50 patients with ATTR-PN, and be conducted in ex U.S. region with limited or no access to TTR silencers. Patients will be randomized 1-to-1 to receive a single 55-milligram infusion of nex-z or placebo. Patients randomized to the placebo arm will be eligible for crossover to receive nex-z. The primary endpoints are the change from baseline in mNIS+7 at month 18 and serum TTR at day 29. We are very pleased to share today that we have initiated the study and are actively enrolling patients at our first site in New Zealand. This represents our third active Phase III study for an in vivo CRISPR-based gene editing therapy, an important milestone for the company that puts us in a position to achieve a key pillar of our 2026 strategic priorities. In summary, based on the excellent Phase I results reviewed today, we're highly encouraged by the potential benefit nex-z could bring to people living with ATTR amyloidosis. Looking ahead, we are focused on rapidly enrolling both MAGNITUDE and MAGNITUDE-2 where we will be testing our hypothesis that greater TTR knockdown has the potential to modify this debilitating disease and change the treatment landscape in meaningful ways. We believe today's data bode well for what we'll see in the future for the Phase III studies. Assuming success, we anticipate that nex-z will be a welcome addition to the treatment choices for patients and physicians, one that has the potential to reset the standard of care as the best-in-class TTR-lowering drug. With that, we will now open the call for your questions. To do our best to address as many questions as possible, we will only be able to take 1 question per caller. Operator, you may now open the call for Q&A.

[Operator Instructions] The first question comes from Mani Foroohar with Leerink Partners.

I guess, congrats on the data and thanks for taking the questions. I guess, 2 quick ones. First and foremost, when we think about the universe of these patients, and maybe this is for the doctor more than anyone, how should we think about the level of demand and interest in a onetime therapy amongst patients in a world where silencers are available? And I guess this is sort of a separate question for cardiomyopathy versus polyneuropathy patients. But just trying to get a sense of the interest amongst patients in this therapy versus existing options. And I have a follow-up afterwards.

Thanks, Mani. Maybe we can direct that question to Dr. Fontana. You've treated many, many of these patients. So how are patients thinking about this? What do you think the demand is in your clinic and investigators that you interact with?

Yes. So there is a lot of enthusiasm in this treatment. And the reason why this population is so interested in a 1 infusion and then done with the treatment is that the first thing the patients ask once they come to our clinic is, "Doctor, I'm on 10, 15 pills. Can you get rid of some of them?" So the last thing they want to know is that you're adding a pill on top of their already very complex polypharmacy they have. And that's why patients are really queuing up for this. And also, they see this as something that is going to fix their problems with just 1 single infusion. So there is a huge of enthusiasm and patients are queuing up to get into the trial.

That's very helpful. John and team, I guess the other question I have is on, based on what you've seen in enrollment today, more MAGNITUDE-1, obviously, how do you think about the portion of patients that we should reasonably expect to be on baseline tafamidis? And is this sort of a tafamidis proportion half that we should think about? I know that's been discussed about some of the other competitor studies. So if you can help us think about that population and what proportion have been on tafamidis thus far, up to what percentage we should expect to be on baseline tafamidis, et cetera, that would be really helpful.

Thanks, Mani. The estimate is 50% to 60%. And with respect to tafamidis and the other forms of therapy, we think this is going to be a very good test of what is the current standard. And as the study is designed, we expect to see not only the favorable outcome overall, but we think we'll have very illuminating data with respect to the drug on top of tafamidis.

That's really helpful. Congrats again on the data. And I know you have a lot of other analysts in line, so I'll hop off.

The next question comes from Dae Gon Ha with Stifel.

Question for Dr. Fontana. I'll stick to 1. Table 3 in the New England Journal, but also included in, I think, Slide 13 of your AHA presentation. I was hoping if you can delve into a little bit more on the improvement, no change and worsening of the NYHA Class I/II and the III subjects. Specifically, what have you noticed about the Class I/II that have worsened? I mean, is it just something minor and somewhat of a subjective assessment that led them to worsen? Just kind of curious, if their robust TTR is translating to functional benefit, why they would show this kind of effects.

Dr. Fontana, can you tell us why some of the Class I and IIs may have progressed and we've seen such robust results overall, especially with the Class III?

I mean, I think that going into individual patient level analysis is extremely difficult because we are talking only about 36 patients. However, from a clinical perspective, I was really -- I really welcome this data because we are used to see patients progressing on the current available treatment. And actually seeing stabilization in a high proportion of patients with very severe disease, and actually improvement in a good proportion of those patients, was absolutely remarkable. I think it's a bit -- in drawing more conclusions on why more number of patients worsened, I think, is a bit difficult considering the low patient number. But for me, the key message was, with, of course, an extremely severe patient population, I mean 50% of the patients are NYHA functional Class III, and you can also see that by the peak VO2, they had severe reduction in the functional capacity, but in spite of that, overall, they did extremely well. And not just about disease stability, but actually bringing about improvement. So that's what -- how I interpret these results.

I mean one of the points you made in your presentation was that if you look across all of the indicators, that biomarkers, the physiologic measurements, et cetera, overall, all of them moved in the same direction.

Yes. Absolutely. It's about not just the individual results on each marker of the progression, but it's the consistency of the results across a wide range of metrics used, ranging from flat biomarkers to functional capacity. I mean this one is the first trial reporting the cardiopulmonary exercise test, which is really the gold standard to assess functional capacity, which provides way more information than just the 6-minute walking test. And then echocardiography and CMR with T1 mapping. So it's about the consistency of the results, with a strong signal of not only stability but actually improvement across all markers used.

Okay. Congrats on the data, guys.

The next question comes from Joon Lee with Truist Securities.

Congrats on the great data. I have a question for Dr. Fontana. The absolute TTR achieved with vutrisiran at month 6 was around 50 milligrams -- 50 micrograms per liter as you presented in one of your slides, versus less than 24, nex-z. Can you quantify or qualify what that means in terms of what you would expect eventually in terms of clinical outcome?

Absolutely. I mean I've got a strong belief on this, which comes from the last 25 years of research in systemic AL and AA amyloidosis. So just to give you an example, going back to the absolute levels. In AA amyloidosis, when there is inflammation, the SAA levels go in the range of 200, 300, 400. Then you give treatment and you bring it down to, let's say, 5 or 6, which is just outside the normal range which is 4. Just and so you think "I've done a good job, 400 to 6," but actually an elevation of SAA from 4 to 8 is associated with a 3x higher risk of overall mortality. So bringing it down from just outside the normal range to completely normal range reduces the mortality risk of 3x. We have seen exactly the same in systemic AL amyloidosis. Initially, we were happy with a 50% knockdown, in 2001. Then we realized that 70% was better than 50 %, then that 90% was better than 70%. And now we want 100% in all patients. But the goal is to achieve at least 90% in every single patient. So 80% in systemic AL amyloidosis cardiac involvement wouldn't be good enough. So I'm absolutely certain that exactly the same will be seen in TTR amyloidosis where actually we already see that in polyneuropathy, there is a correlation, a tight correlation between level of knockdown and clinical outcome. So it's just a matter of waiting another couple of years, getting more data, and you will see exactly the same. So what we are doing with nex-z is just anticipating the unmet clinical need that will be extremely clear in a couple of years. It actually surprises me that this is not clear to the scientific community because we've got 25 years of research in AA and AL amyloidosis that we have to look at.

Great. And congrats on the great results.

The next question comes from Maury Raycroft with Jefferies.

I'll add my congrats on the results. I was wondering, for the Kaplan-Meier analysis on Slide 31, wondering if that's reweighted based on the NYHA class accounting for a higher rate of Class III patients as it relates to your Phase III. And for this analysis, did you run it versus silencer and stabilizer data available? And what insights do you get from that?

David, maybe you can tell us how you approached the weighting of the Kaplan-Meier plot that you showed in that, how we use that information as we think about MAGNITUDE?

Yes. First, you have some measure of this just by the event rate. I just want you to pay notion to that, that 0.16 compared to the 0.45 placebo rate in ATTRibute would come out will be a hazard ratio of 0.36. This is already astounding, even though the 0.16 is with patients who are much sicker. The curve that you see there is not reweighted for the Class IIIs. It's a much more complicated analysis to reweight it for both the variant population and for the Class II. So this is, I guess, a little bit worse than it might be if we were able to correct for that as well. To compare to silencer data, we haven't put that directly on here. The result does look quite good. I think this is work maybe some of the analysts might be doing. But we do think that this shows that not only we have a positive trial, but this is possibly the best-in-class drug for this disease.

So you tried to synthesize something that would look like our MAGNITUDE patient population in terms of what we would expect to see.

That's right, yes. The reason we did is, of course, is because we do expect to have more like 12% variant patients in our Phase III as all the other Phase IIIs have been.

The next question comes from Gena Wang with Barclays.

I will also ask 1 question regarding the ATTR cardiomyopathy program. So how would you -- when we look at this curve you projected, what would be the impact of the silencer dropping for the Phase III studies? Related question for Dr. Fontana, so how would you -- I know we talk about the baseline, the absolute serum TTR level differences between, say, a neutral HELIOS-B study, 50 microgram per mL versus here 20 microgram per mL. What could be the -- when we look at the -- let me see which slide, the proBNP and Troponin, 6-minute walk test at the 12 months, how do you compare that to HELIOS-B data?

Maybe before we get to that, we could address the question of vutrisiran drop-ins. David, do you expect to see many of those? And how do you think about that for the trial?

Yes. As we designed this trial, we did anticipate that there would be some silencer drop-ins, and the statistics of that account for that. We should say though, what we're hearing is that patients are not going to be able to get both tafamidis and vutrisiran. That's what we're hearing from investigators around the world, partly because tafamidis is quite expensive now and the data coming from HELIOS does not support that this should be done for all patients. So that we do think the rate of silencer drop-in will be relatively low. We may see patients changing from tafamidis to vutrisiran. And from what we see in the results of the 2 trials, that would have no effect on our trial because they seem to have very similar efficacy.

Dr. Fontana, I think Gena was asking us about baseline values of proBNP and -- proBNP for the HELIOS-B study and this patient population, and whatever conclusions you might be able to draw from the 12-month data.

Yes. So as discussed in the presentation, this patient population is a patient population with significantly more severe disease. I mean if you think about it, NYHA III, 50% of the patients. The BNP was -- the median is 2,000, in this cohort of patients went up to 20,000. As you know, actually, both the acoramidis trial, the vutrisiran trial has an upper limit of -- upper limit of 8,500. So those patients wouldn't have been included in those Phase III trials. There was also a severe reduction in functional capacity. And as I said, not just looking at the 6-minute walking test, but also the cardiopulmonary exercise test, which is a much more precise way to look at it. So we have to look at the parameters of disease progression in the context of a significantly more severe disease compared to the even recent Phase III trial. So for me, when I look at the markers of disease progression, especially in this context, very severe disease, there was a remarkable stability, and improvement in a proportion, which was almost an unexpected finding. Because in such a severe population, seeing even improvement was not something that wasn't entirely expected. And as I mentioned, with the consistency across all the results. I mean the paradigm, the treatment paradigm, of the lowest, the better in the reduction of the amyloid precursor protein, as I said, is not new. It's 25 years of research in AA and AL amyloidosis, just that, as cardiologists, we've remained kind of confined in the cardiology field and we actually don't look and don't learn very much from other fields where actually 25 years of research has established this treatment paradigm, which works across all types of amyloids. So for me is whatever can give you the lowest level, durably and permanently, because also fluctuations we know from other types of amyloids are a problem, would become the first choice.

David, do you want to make a point?

Yes, just wanted to add one point to that. I think if you do -- you're asking about the HELIOS trial, the vutrisiran curve, same is true for acoramidis, but for both proBNP and for 6-minute walk, they both get worse in the active arms. It doesn't get worse as quickly as the placebo, so that's why they're positive trials. But if you look at it, they are deteriorating over time, and you see that at 1 year. We did not see that in our trial, any of that worsening.

The next question comes from Liisa Bayko with Evercore ISI.

Can you just remind us of any tafamidis drop-ins in the study? And then also, was there any intensification of diuretics?

Dr. Fontana, do you know -- or maybe, Liron, you could speak to any tafamidis drop-ins in the study.

Yes. Basically, there was no concurrent use of disease-modifying treatment just because tafamidis was not available during the time frame of the study. There was 1 patient who started tafamidis at day, I think, 350-something...

Almost 1 year. Yes.

Yes. Just a few days before 1 year. So fundamentally, there was no disease-modifying treatment. And as concerned the diuretic intensification, we haven't looked at the data yet, but this is something that definitely we will look into.

Thanks a lot and congratulations on the data.

The next question comes from Brian Cheng with JPMorgan.

Congrats on the data. I guess just more of a broad-picture question, how confident are you in the durability of the stability and the improvement that you're seeing here, especially related to the cardiac and the 6-minute walk distance measures?

Brian, we have terrible audio. Could you try that again and maybe slow it down a little bit so we can get the words?

Yes. Curious how confident you are in terms of the durability of the stability and the improvement you're seeing here in the cardiac and the 6-minute walk distance measures.

I think we can speak with great confidence about the durability of the actual edit that we introduced. And that's something that we talked about preclinically with very active studies where we've tried to accelerate turnover and we've, of course, passively followed animals and now human beings. So I think from the standpoint of knowing the edit, as time goes on, we've seen no change from where we started. But maybe Dr. Fontana can say a word about, do you expect these clinical findings to be durable as time goes on? Or would more of the patient perhaps improve even?

I mean what we've seen from data in AL amyloidosis and also AA amyloidosis is that if you can keep stably the low levels of knockdown, so you can keep the levels down in a -- like to a deep response marker durably over time, what you're going to see is not only stability but actually disease regression. So ATTR amyloidosis is not just a disease of misfolding but clearance, of course, a very important role as well. And so if you can reduce enough the amyloid precursor protein, then you will start to see regression as well. And that's the key step forward that a deep reduction in the amyloid production could actually lead to, where you're not going to just see stability, but you will actually see clearance of amyloid with improvement in the patients. And this is what that marginal increase, which is not actually marginal, it's very significant in reduction in the percentage and absolute levels, could actually lead to.

I mean one of the things that, in conversations with you, that you've taught us, is with respect to those concentrations, thinking about it as an area under the curve is a useful way to interpret or think about the disease, where if you take the data that we presented and what we've seen in the recent HELIOS-B study, it's about a threefold difference in terms of concentration, which, preserved over the many months or even years ultimately, seems to be an important contributor. Would you agree?

Yes, absolutely. So again, from AL, we have seen that it's not just the lowest level to achieve, but it's the area and the curve. Any fluctuation in the level of the amyloid precursor protein will be associated with worse prognosis. So it's really the durability over time, over the follow-up of the deep reduction, so it's how much it's sustained that is going to be key.

One final point. If you look in the appendix of the HELIOS study, they do show the curve of TTR on vutrisiran. And it takes about 6 to 9 months to reach that 50-microgram per mL level. And we think that is possibly also a significant issue in terms of treating the patients rapidly.

The next question comes from Kostas Biliouris with BMO.

Congrats on the data. One question from us on mortality, which is something that a lot of investors and physicians focus on. So if we're focusing the Class III patients because, I guess, for Class I and Class II is a little early for mortality assessment, it seems that, in the results you presented, you only had 1 death. So I'm not sure if it's from Class III or not. But this would suggest that your Class III survival rate is either 95% or 100% at 12 months. And in natural history, we've seen that the survival rate in Class III is 80%. So is this the right way to think about the mortality benefit early on? And the follow-up on that is, would you expect the gene editing, given the results, to give earlier effects on mortality compared to other silencers and stabilizers that we have seen so far?

Liron, do you want to address the...

Sure. Yes, you're correct that that single death was in a Class III patient. That was -- occurred at day 505. So even though this patient has baseline significantly elevated risk of morbidity and mortality, was able to live 505 days. This bodes quite well for MAGNITUDE, in particular, as we enroll Class I and Class II, but also obviously, the Class III patients as well.

One other point is that the patients coming into the trial had a proBNP of 19,600. This patient would not be entered into the Phase III under the current rules coming in. So this patient is really extraordinary, and the fact that they -- so they lived 1.5 years. And the survival, you have to think that it doesn't actually go beyond a year. We're not just showing the death that might have occurred with the year. It's about an -- the patients are on average about 18 months at this point. So that you have a much longer -- you have a group of patients getting all the way out as you saw it to 24 and even longer.

Yes. And you can see in terms of the natural history Dr. Fontana had presented in the AHA presentation, those survival curves with respect to variant population and New York Heart Association class, and you could see the significant reduction in survival for those Class III patients, as well as the variant patients.

Yes. I mean from a clinical point of view, I interpret that death, that single death, as actually a great success, because you wouldn't have expected that patient to live longer than 6 months. So the fact that the patient reached 1.5 years is absolutely incredible.

The next question comes from Luca Issi with RBC Capital.

Great. Congrats on this data. Maybe a super quick follow-up on Liisa's prior questions on diuretic intensification. Wondering if there was any use of SGLT2 drop-in here in the trial. Again, just trying to figure out whether there were other factors here that may have contributed to the benefits. And then maybe second, David or Liron, how are you thinking about actually proving that your therapy can be potentially better than siRNA? What's your appetite to maybe run a small head-to-head trial versus siRNA where you maybe look at proBNP or Troponin or maybe imaging? Is that something that you're contemplating?

Liron, do you -- can you speak to the SGLT use in the study and I can come back to...

Yes. So at baseline, 9 patients were in SGLT2s, and then by the 12-month follow-up, there were 13. Actually, several of those were related to type 2 diabetes as opposed to due to heart failure. We don't think that these additional patients that started SGLT2s would have any meaningful impact really on what we've observed as it relates to the clinical stability or improvement that we've seen in the study to date.

I think with the head-to-head study that you're proposing, it's probably a little premature. We've got a lot of work underway with our Phase III trial, which is a top priority for us. And as you've heard from David, the enrollment is going very briskly. And we would expect that as the cardiology community understands these data, that it will be even brisker. I think Dr. Fontana's comments in terms of level of reduction of TTR by itself is already informative. And my suspicion is that that will influence how cardiologists think about using these drugs.

The next question comes from Joseph Thome with TD Cowen.

Congrats on the data. Maybe for the Phase III, can you remind us on the potential of an interim analysis? I know patients will be followed up for at least 18 months. But how are you thinking about that? And maybe on the flip side, any blinded analyses to adjust for the overall enrollment size of the study if -- those related, and maybe how you'll be making those decisions?

David, do you want to speak to the interim analysis plans?

Yes. So the study design does have the potential for an interim analysis. We've actually been saying for a while, because of our deeper reductions in TTR, there is real potential for this to turn positive at an interim analysis. So we'll be watching that very carefully, and we do think that would be a way of getting this to patients more quickly.

The part two question was how do we think about the study size and the effect size of the drug, et cetera. Do we think that we need to tweak in any way the study as it goes on?

Yes. Right now, based on the results we're seeing and the kind of curve you saw on the time to first event, we don't need to adjust it at this point. But we will be looking -- we'll be continuing to follow these 36 patients to see the consistency of this good result. And we can also follow the number of events in the trial to see if we're reaching a number of events to get to the final analysis in the appropriate time frame, or the interim analysis.

The next question comes from Ry Forseth with Guggenheim.

A question for Dr. Fontana. If we see recapitulation of the nex-z Phase I performance in the MAGNITUDE study, how are you thinking about switching from silencers or stabilizers given what may be a stronger biomarker efficacy signal in the NYHA Class III patients?

I mean for me, it's not really about NYHA III or I, II. A drug that gives you the lowest level of knockdown is going to be the first in class across all patients because it's not just that there is greater benefit in NYHA III, you would expect the greatest benefit to be across the wide range of disease. So it's really not about subgroup, but greatest level of knockdown for me would be the best class in all patients.

So a preemptive switch is kind of what you're saying?

Yes. I mean this is exactly what we do in AA and AL amyloidosis. It doesn't mean how you get the protein down, but the compounds that give you the lowest level of protein, that's what you're going to choose in that patient.

The next question comes from Alec Stranahan with Bank of America.

It's Matthew on for Alec here. Just a brief one for us. Curious on choosing the time point for the MAGNITUDE-2 study for mNIS+7. Why 18 months versus 12 versus 24 that you saw in Phase I?

David, can you speak -- or Liron, maybe you can speak to the MAGNITUDE study, which, again, is the polyneuropathy study, why 18 months, and speak to the size of the trial?

So as you've seen, it's a small study of 50 patients that will be enrolled predominantly in regions without access to silencers. The 18 months, as we did our statistical work, gives us the best power in order to assure a favorable benefit and obviously a statistical win. We're thinking about ways to perhaps bring that earlier in with interim analyses or other approaches to accelerate that development.

The next question comes from Jay Olson with Oppenheimer.

Congrats on these impressive results, and thank you for providing the update here today. We have a question for Dr. Fontana. Based on the totality of evidence, which seems overwhelming, is it fair to conclude that nex-z can reverse this terrible disease? And if not, what additional evidence would you need to see before you could reach that conclusion?

I mean even from the Phase I trial, and we are talking just about 12-month observation, we see that actually in some patients there is improvement and there is reduction in the cardiac amyloid load. So I'm absolutely convinced that this very low level of knockdown sustained over time will lead to regression in a proportion of patients for exactly the same concept I mentioned before, it's really not just about misfolding, but it's misfolding and clearance. So if you can knock down to very low levels the misfolding, we will see clearance. So I'm absolutely certain that that's going to happen. And you can already see that from these very early 12 months data from the Phase I.

The next question comes from Yanan Zhu with Wells Fargo Securities.

Great. I wanted to dig into a little more about NT-proBNP and 6-minute walk comparison with available therapy. I think vutrisiran and acoramidis both showed a 1.1x to 1.2x change at month 12 on NT-proBNP. Obviously, you showed a 1.0, roughly. But I'm not sure if that's a dramatic difference given how much lower during the first few months your TTR levels is compared with these other modalities. On 6-minute walk, I think vutrisiran had a median of 5-meter decline at 12 months. You have roughly maybe a little bit of improvement. But still a 5-meter decline is not a dramatic worsening at that time point yet. So given these differences, I was wondering, recognizing you have a more severe population, is it possible to do a reweight on the severity of patients and perhaps show the data in another way? And I have a quick follow-up also, I'll wait for the answer.

Maybe you can put the NT-proBNP changes into perspective for this study versus the Phase III data that's been presented, as well as 6-minute walk test.

Yes, absolutely. As you mentioned, it's all about the disease which was treated. I mean 50% NYHA III, high proportion of variant patients. The peak VO2 was 12.7, which is a severe reduction in functional capacity. And whilst you may think, okay, the median NT-proBNP is not so different, you have to look at the distribution here. Because in the Phase III studies, both acoramidis and HELIOS-B, there was an upper limit of 8,500. So a good proportion of patients that were included in here wouldn't have been included because they would have been excluded from the Phase III trial. So you are comparing a degree of stability with a much more severe population, which was expected to progress much faster. And so that's, I think, really the key. I think that doing a reweighting analysis on 36 patients is probably going to be quite challenging. But the key of interpreting these results is really thinking about how severe this population was. I mean we didn't mention it, but even 2 patients had B142I homozygous mutation, which basically is one of the most aggressive phenotypes that we've ever seen in TTR amyloidosis. And these patients were part of -- were 2 out of 36. So again, just to point out how severe this population was.

That's great. That's it from...

I actually want to put some additional numbers onto it. So vutrisiran went up about 20% at 1 year. So this is looking different from that. The 6-minute walk, the median did -- went down 5 meters, but the mean went down quite a bit more, if you look at the vutrisiran. We also have looked at our mean, and there's no change at 1 year. So this is becoming a big difference. Now we do know it's hard to say what this -- how this translates into the MAGNITUDE trial, so that's why we tried to give you some additional context. One is that the event rate is low in this and quite low for this group of patients. And then even translating it into a time to first event curve, which is available for all of these studies, we do see that we have a very striking result that isn't seen in the other studies, and that the hazard ratio relative to placebo, as you look at the events, would be about 0.36. So we do think there is distinguishing characteristics already.

Nonetheless, MAGNITUDE is underway, and we will conduct a study, and we look forward to the results. But as you made the points earlier, David, we've taken these results and tried to estimate what that means for the MAGNITUDE study. So we're quite excited about the progress of that study. We very much look forward to the results.

The next question comes from Myles Minter with William Blair.

Congrats on the data. Just wanted to ask about the serious infusion reaction, whether you had any more color on that, that occurred in 1 patient. Did they have to stop the infusion or have a pause there? And I guess, what does the TTR knockdown and various parameters look like? I know it's only 1 patient, but anything you could tell us there would be great.

Liron, can you tell us about, I mean, generally speaking, the safety profile around the infusion, and there was 1 and there's some interest in that.

So generally speaking, the infusion-related reactions have been quite mild. All patients received the full intended dose. This individual patient was a Class III patient with severe autonomic dysfunction, as well as having significant heart failure. So did have a reduction in blood pressure following the infusion. This individual was able to complete the infusion. And the treatment was just administration of normal saline. They kept him overnight in the clinic in order for observation and was sent home the next day, and is otherwise doing well. His knockdown is within the same range as the other patients, 90-plus percent.

The next question comes from David Lebowitz with Citi.

Understanding that the patient numbers could limit the ability to do this, what do the curves and the various endpoints look like when you compare the wild-type patients to the mutant patients, in the cardiomyopathy trial?

Do you want to speak to that, David?

Yes. So as you might expect, the patients with variant disease have more hospitalizations than the patients with wild-type disease. So the trial, when we do our Phase III, of course, 90% of the patients will be wild type. So the curve is going to look, obviously, on the good side of things. And you see that a bit in the curve that I presented, that -- where it has estimated 12% wild-type patients as we might see in Phase III.

And as a reminder, 31% of the patients in this study had the heritable form. And I think Dr. Fontana has made the point that some of these patients have a very, very aggressive form of the disease.

The next question comes from Salveen Richter with Goldman Sachs.

This is Mark on for Salveen. Just wanted to kind of follow up. You said that all patients we saw a significant reduction in TTR levels, but only 80% of patients saw a stability or improvement of their disease. And I was wondering if there's anything special about those 20% that didn't see stability or improvement. Were those like, at baseline, the worst patients? Or were those the patients that potentially didn't see as strong of a reduction in TTR levels?

Dr. Fontana, is it reasonable to expect every patient who's had these significant knockdowns to necessarily improve their disease?

I mean, again, these are very advanced patients, so it is very -- it's not possible to expect 100% patient stability in such advanced population. I mean one would wonder, could you see it in another population? That's entirely possible. But in these populations, I don't think it's possible to expect 100% stability even if you fully knock down to similar levels the TTR. And again, the key here is that every single patient had a similar knockdown to the deep and durable level. So there were really no variations there. But of course, when a patient is extremely advanced, you will see some progression.

It may be an overestimate to say that 20% of the patients had progression. It's on various markers, and that's really telling you essentially what that individual patient is experiencing. Also make the point, if a patient does progress in a year's period, it may be that they -- we've really delayed their progression, where some of these patients were getting -- deteriorating very rapidly as they came into the trial. And as mentioned, at least for the patient who did die, they lived much longer than you would have expected.

The next question comes from Rick Bienkowski with Cancer Fitzgerald.

Congrats on the impressive data. I just wanted to follow up on the potential interim analysis in MAGNITUDE. Would this interim be triggered by a prespecified number of events, number of patient years in the study, or specific time point?

David, how are we thinking about what triggers IA?

Yes. We haven't given the details of that, but it would involve both time frame and number of events before we do an interim analysis.

The next question comes from Andy Chen with Wolfe Research.

Possibly for Dr. Fontana. So it's not just proBNP, but also the other endpoints, 6-minute walk, KCCQ, all of them look favorable versus competition. So if you have to guess, is nex-z faster-acting clinically? And therefore, in the Intellia Phase III study, do you think curve separation on the primary endpoint from placebo, do you think that's going to happen more quickly compared to other trials such as HELIOS-B, especially given that there's a stabilizer washout in the protocol?

I mean as I've seen, there was a very rapid decline of the TTR levels down to 89% at only 28 days, which is absolutely remarkable. So is it possible that that would translate into earlier onset of the treatment effect on clinical markers? I think it's absolutely possible.

Just want to mention, there isn't a tafamidis washout in the trial. Patients are, if they're coming on -- not on tafamidis and it becomes available, they are able to get tafamidis later. If they come, they had been started on tafamidis, there is a short waiting period before they can join the trial. But there is no -- we don't have people stopping tafamidis for this trial.

Dr. Fontana, do you think that with TTR amyloid, it's a damaging process on a daily basis where short intervals actually matter for these patients?

I mean, absolutely. What we see, again, going back to AL amyloidosis, that achieving what we say complete response or very good partial response -- very good partial response in 90%, achieving at 1 month, 3 months or 6 months matters because that's translating a significant decline in mortality. So again, we need to learn from 25 years of research on other types amyloids.

You made the point that you think this is a very dynamic disease. Maybe that's the way that we should be thinking about, those things actually change and move.

Absolutely, yes. Because it's all about the equilibrium between clearance and production. And here, what you do, you switch off completely the production and then you give the body the ability to clear the amyloid, positive remodel, and so bring about, actually, improvement.

The next question comes from Silvan Tuerkcan with Citizens JMP.

Congrats on the great data. Just on Slide 31 on your time to progression plot, Kaplan-Meier curve that you presented here. I know the patient numbers are very small here, but is there anything you can say about the difference in CV events that were observed in this Phase I trial versus stabilizers or silencers overall?

David, maybe we can ask you, what can we read into the data and the curve that you shared, what's the makeup of events? And is there any qualitative difference that we see with what's been reported elsewhere?

Yes. So of course, it is a small trial. But if you compare this curve to some of the existing trials, including with active agents, it does look very favorable. As was also mentioned, only a single death, so that the survival coming out to 24 months would also be very high, in the 95% or higher rate. So looking at those 2 things, we haven't put up the curves of the other drugs, but that's work that you can do. And we do think this is extremely promising for these patients. And we do think that we want to get to these patients as soon as possible. By the way, there are about 25,000 to 50,000 new patients with this every year. And we think it's extremely important to treat them with the best therapy.

This concludes our question-and-answer session. I would like to turn the conference back over to Lina Li for any closing remarks.

Thanks, Drew. And thank you all for joining us today and for your continued interest and support of Intellia. I hope everyone has a great rest of your weekend. Take care.

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