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. At this time, all participants are in listen-only mode. Following the formal remarks, we will open up the call for your questions. If anyone requires operator assistance during the conference, please press star then zero on your telephone keypad. I will now turn the conference over to Lina Lee, 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 and media section of Intellia's website at intelliatx.com. As a reminder, this call is being broadcast live, and a replay of the event will be archived on Intellia's website. Before we 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 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 Nexi 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. Mariano Fontana, Professor of Cardiology at the University College London Center for Amyloidosis, an honorary consultant cardiologist at the National Amyloidosis Center and a clinical investigator on our Nexi phase one 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's scientific sessions here in Chicago.
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 one study of Nexi, 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. Mariano 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 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, Nexi achieved consistently rapid, deep, and durable TTR reduction in all patients.
Now, with our collaborators at Regeneron, we're presenting the first clinical evidence that deep and persistently low levels of TTR reduction achieved with a simple one-time infusion of Nexi 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 one 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're highly encouraged by these results, including the favorable safety and tolerability observed today. These results give us even greater confidence in the designs of our two phase three 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 AMPLITUDE for ATTR-PN for what we believe will be a best-in-class I time treatment capable of resetting the standard of care for ATTR amyloidosis. With that, I'm honored to turn the call over to Dr. Mariano 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 Nexi in patients with ATTR cardiomyopathy. Here's 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 deposition within the myocardium, with resulting pathologic cardiac remodeling and ultimately organ dysfunction. ATTR cardiomyopathy is a progressive and fatal disease characterized by deterioration in functional capacity and quality of life, symptomatic heart failure, frequent hospitalization, and death. It is emerging as an underdiagnosed cause of heart failure, especially in the elderly, and although the true prevalence is unknown, it is estimated to affect 200,000-500,000 individuals worldwide.
Current treatment focuses 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 this treatment only slows 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 function class three, which have much greater mortality rates. Recently, markers of disease progression have been established. Indeed, in recent analysis in a large population of patients with ATTR cardiomyopathy, the majority of which were in NYHA function class one or two, worsening in NT-proBNP, troponin, and six-minute walking test was common, occurring in 35%, 50%, and 40% of patients, respectively, reflecting the relentlessly progressive nature of the disease.
The thresholds for the three markers used to define progression were clinically meaningful and strongly predictive of mortality, with only 25%-30% of worsening patients surviving at five 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 six months, with patients achieving a mean absolute TTR level at 30 months of about 50 micrograms 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, Nexi, 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. Nexi 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 mRNA sequence of Streptococcus pyogenes Cas9 protein encapsulated in a lipid nanoparticle delivery system with liver tropism. Following intravenous administration of Nexi, 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 one trial is a two-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 milligrams per kilo, nine patients, or one milligram per kilo, three patients. Following these, in the part two dose expansion of the study, patients received treatment with Nexi at a dose of 55 milligrams, 24 patients, the fixed dose equivalent of 0.7 milligrams 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, six-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 milliliters per kilogram per minute, a very high level of cardiac infiltration as demonstrated by a baseline extracellular volume of 58%, and a high proportion of ATTR patients, of which two were V142I homozygous, which commonly present with a very aggressive form of disease. 50% of patients had NYHA function class three at baseline, and notably, there was no concurrent use of other disease-modifying therapy.
For the primary endpoint, following a single IV infusion of Nexi, 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% day 28, with a mean absolute serum TTR level of 18.9 micrograms per liter. Importantly, these deep reductions were well maintained over time, with TTR levels remaining low and virtually unchanged throughout 24 months of follow-up. The 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 one study. The reduction in TTR levels with Nexi treatment was associated with evidence of disease stabilization at 12 months, based on three markers of disease progression.
Indeed, stability throughout the 12 months was observed on the NT-proBNP on the left, troponin T in the middle, and functional capacity as assessed by six-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 six-minute walking test, stability or improvement in these biomarkers was observed in nearly 80% of patients at 12 months. Notably, 83% of NYHA function class one and two patients, and even 47% of NYHA function class three patients, showed no worsening in any of these three markers at 12 months. Evidence of stability or improvement in patients' quality of life following Nexi 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 function class three, 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 two 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 and diastolic function, as well as cardiac amyloid load. Regarding the safety observed with Nexi 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 Nexi demonstrated a favorable 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 Nexi treatment were obtained in a phase 1 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 Nexi on clinical outcome are being evaluated in MAGNITUDE, a phase three global randomized placebo-controlled trial in patients with ATTR cardiomyopathy. We wish to extend our gratitude 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 you 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 the 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 one-time infusion. Notably, the TTR reduction occurred rapidly, with nadir reached 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 six months after starting chronic treatment. Now, we have observed positive trends that the very low levels of circulating TTR seen with Nexi 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 three 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 two 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 two studies were much better than the cohort in our phase one. Only 5%-11% were NYHA class three, and 10%-12% had variant disease in the two phase threes. 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 one study, despite the more advanced patient population treated with Nexi. These data, while from a relatively small open-label study, are informative for our assessment of the ongoing MAGNITUDE phase three trial design and its potential clinical outcomes. Here on this slide, we have plotted the Nexi phase one data as an estimated Kaplan-Meier curve of time to first cardiovascular event or death. Because the patient population in the phase one was 31% variant ATTR-CM, we have reweighted the data to be more reflective of the patient population we anticipate enrolling in the phase three 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 Nexi. This finding reaffirms our assumptions in our pivotal trial and gives us confidence, based on the phase one results, that the MAGNITUDE study is well designed, both adequately sized and sufficiently powered to meet its objectives. Turning now to the ongoing phase three study, MAGNITUDE, we are 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 Nexi treatment, we anticipate that interest in Nexi will increase even further as the robust enrollment momentum will continue. Switching to ATTR-PN, as a reminder, this multisystem disease also manifests as polyneuropathy through the progressive accumulation of protein deposits in the peripheral nerves.
In the phase I trial, we also evaluated Nexi 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 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 Nexi can potentially benefit patients throughout the spectrum of disease. And finally, Nexi has demonstrated a favorable safety and tolerability profile to date. Taken together, these data support our belief that Nexi 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 Nexi.
The study will enroll 50 patients with ATTR-PN and be conducted in ex-US region with limited or no access to TTR silencers. Patients will be randomized one-to-one to receive a single 55 milligram infusion of Nexi or placebo. Patients randomized to the placebo arm will be eligible for crossover to receive Nexi. 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 three 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 one results reviewed today, we're highly encouraged by the potential benefit Nexi 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 three studies. Assuming success, we anticipate that Nexi 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 one question per caller. Operator, you may now open the call for Q&A.
We will now begin the question and answer session. To ask a question, you may press star then one on your touch-tone phone. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star then two. Again, please limit yourself to one question. At this time, we will pause momentarily to assemble our roster. The first question comes from Mani Foroohar with Leerink Partners. Please go ahead.
Hey, guys. Congrats on the data, and thanks for taking the question. I guess two 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 one-time 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?
Yeah. So there is a lot of enthusiasm in this treatment.
The reason why this population is so interested in one infusion and then done with the treatment is that the first thing the patients ask once you 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 the already very complex polypharmacy they have. And that's why patients are really queuing up for these. And also, they see these as something that is going to fix the problems with just one single infusion. So there is a huge amount of enthusiasm, and patients are queuing up to get into the trial.
Thanks. That's very helpful.
John and team, I guess the other question I have is on, based on what you've seen in enrollment to date in MAGNITUDE-1, obviously, how do you think about the proportion of patients that we should reasonably expect to be on baseline tafamidis? And is there sort of a tafamidis proportion cap 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's 50%-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.
As the study's 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 t op of Tafamidis.
Thanks. 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.
Thank you.
The next question comes from Dae Gon Ha with Stifel. Please go ahead.
Great. Good morning. Thanks for taking our questions. Question for Dr. Fontana. I'll stick to one. Table three 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 one, two, and the three subjects. Specifically, what have you noticed about the class one, two 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 the robust TTR is translating to functional benefit, why they would show this kind of effect. Thanks so much.
Dr. Fontana, can you tell us why some of the class one and twos may have progressed and we've seen such robust results overall, and especially with the class three?
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 really welcome this data because we are used to seeing 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 a small number of patients worsen. I think it is a bit difficult considering the low patient number. But for me, the key message was we're accruing an extremely severe patient population. I mean, 50% of the patients are NYHA functional class three. And you can also see that by the peak VO2 of the cohort that there's a 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 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 are in the same direction.
Absolutely.
It's about not just the individual results on each marker of disease progression, but it's the consistency of the results across a wide range of metrics used, ranging from blood 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 a six-minute walk test. And then echocardiography and CMR with T1 mapping. So it's about the consistency of the results, so with a strong signal of not only stability, but actually improvement across all markers used.
Right. Okay. Congrats on the data, guys. Thanks so much.
The next question comes from Joon Lee with Truist Securities. Please go ahead.
Hey, congrats on the great data, and thanks for taking our questions. I have a question for Dr. Fontana.
The absolute TTR achieved with vutrisiran at month six was around 50 micrograms per liter as you present in one of your slots versus less than 24 Nexi. 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 strong belief on these, which come 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, five or six, which is just outside the normal range, which is four. Just until you think, "I've done a good job," 400 to six.
But actually, an elevation of SAA from four to eight is associated with a three-times higher risk of overall mortality. So bringing it down from just outside the normal range to completely normal range reduces the mortality risk of three times. 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 Nexi is just anticipating the unmet clinical need that will be extremely clear in a couple of years. And actually, it 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. Thank you, and congrats on the great results.
The next question comes from Maury Raycroft with Jefferies. Please go ahead.
Hi. I'll add my congrats on the results, and thanks for taking my question. 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 three patients as it relates to your phase three?
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 approach the weighting of the Kaplan-Meier plot that you showed, and how we use that information as we think about MAGNITUDE.
Yeah. First, you have some measure of this just by the event rate. I just want you to pay attention to that, that 0.16 compared to the 0.45 placebo rate and 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 threes. 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 will 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.
Yeah. The reason we did this, 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.
Got it. Okay. Thank you for that. Thanks for taking my question.
The next question comes from Gena Wang with Barclays. Please go ahead.
Thank you. I will also ask one question regarding the ATTR cardiomyopathy programs. So how would you, when we look at this curve you projected, what would be the impact of the silencer dropping for the phase three studies? Related question for Dr. Fontana. So how would you, and we talk about the baseline, the absolute serum TTR level differences between the HELIOS-B study, 50 micrograms per ml versus here, 20 micrograms per ml. What could be the, when we look at the, let me see which slides, or the proBNP and troponin six-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 the TTR drop-ins.
David, do you expect to see many of those, and how do you think about that for the trial?
Yeah. 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 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 of the results of the two 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 NT-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 three, 50% of the patients. The NT-proBNP, one SD median in 2000 in these patients went up to 20,000. As you know, actually, both the acoramidis trial, the vutrisiran trial has an upper limit of 1,500. 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 six-minute walk 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 trials. So for me, when I look at the markers of disease progression, especially in this context with very severe disease, there was a remarkable stability and improvement in that proportion, which was almost an unexpected finding because in such a severe population, seeing even improvement was not something that wasn't highly expected. And as I mentioned, was 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. It's just that as cardiologists, we remain kind of confined to the cardiology field, and we actually don't look and don't learn very much for other fields. We're actually 25 years of research that established this treatment paradigm, which works across all types of amyloid. So for me, it was that I can give you the lowest level durably and permanently because also fluctuations we know from other types of amyloid are a problem would become the first choice.
David, do you want to make a point? I just wanted to add one point to that.
I think if you do, you're asking about in HELIOS-B trial, the letrozone curve, same is true for acoramidis, but for both proBNP and for six-minute walk, they both get worse in the active arms. It doesn't get worse as quickly as a 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 one year. We did not see that in our trial, any of that worsening.
Thank you.
The next question comes from Lisa Bayko with Evercore ISI.
Please go ahead. Hi. Can you just remind us of any Tafamidis drop-ins in this study? And then also, was there any intensification of diuretics?
Dr. Fontana, Gina, or maybe Liron, you could speak to any Tafamidis drop-ins in the study. Yeah. Yes. I can speak. Oh, go ahead.
Basically, there was no concurrent use of disease-modifying treatment just because tafamidis was not available during the timeframe of the study. There was one patient who started tafamidis at, I think, 350-something. Almost one year. Yeah. Just a few days before one year. So fundamentally, there was no disease-modifying treatment. And as concerning the diuretic intensification, so we haven't looked at those data yet, but this is something that definitely we're looking into.
Okay. Thanks a lot, and congratulations on the data.
The next question comes from Brian Cheng with JP Morgan. Please go ahead.
Great. Thanks for taking our questions and concerns on the data. And I guess just more of a broad-picture question, how confident are you in the durability and also stability and the improvement that you are seeing here, especially related to the cardiac and the six-minute walk distance measure?
Thanks. Brian, we have terrible audio.
Could you try that again and maybe slow it down a little bit so we can get the words?
Yeah. I'm curious how confident you are in terms of the durability of the stability and improvement you are seeing here in the cardiac and the six-minute walk distance measures. I think we can speak with great confidence about the durability of the actual edit that we introduce. And that's something that we've talked about preclinically with very active studies where we've tried to accelerate mature 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 patients 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 to a deep response marker durably over time, what you're going to see is not only stability, but actually disease progression, so ATTR amyloidosis is not just a disease of misfolding, but clearance has got 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 kind of keep 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, is very significant in reduction in the percentage and absolute level 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 studies, 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?
Yeah. Absolutely. So again, from AL, we have seen that it's not just the lowest level that you achieve, but it's the area under curve.
Any fluctuation in the level of the amyloid precursor protein will be associated with disease progression. So it's really the durability over time, over the follow-up of the deep reduction. So it's how much is sustained that is going to be key.
Yeah. One final point. If you look in the appendix of the HELIOS-B study, they do show the curve of TTR on vutrisiran, and it takes about six to nine 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.
Thank you, sir.
The next question comes from Kostas Biliouris with BMO. Please go ahead.
Hello. Thanks for taking our question and 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 focus in the class three patients, because I guess for class one and class two is a little early for mortality assessment, it seems that in the results you presented, you only had one death. So I'm not sure if it's from class three or not, but these would suggest that your class three survival rate is either 95% or 100% at 12 months. In natural history, it seems that the survival rate in class three is 80%. Is this the right way to think about the mortality benefit early on? The follow-up on that is, would you expect the gene editing, given the results, to give an earlier effect on mortality compared to other silencers and stabilizers that we have seen so far?
Thank you. Leron, do you want to address? Sure. Yeah.
You're correct that that single death was in a Class III patient that occurred at day 505. So even though this patient has baseline significantly elevated risk of morbidity and mortality, was able to live 505 days. That's both 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 patient 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 lived a year and a half, and the survival, you have to think that it does actually go beyond a year. We're not just showing the deaths that might have occurred within a year.
The patients are on average about 18 months at this point, so that you have a much longer group of patients getting all the way out, as you saw, to 24 and even longer.
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. You could see the significant reduction in survival for those class three patients as well as the variant patients.
Yeah. 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 less than six months. So the fact that patients reach one and a half years is absolutely incredible.
The next question comes from Luca Issi with RBC Capital. Please go ahead.
Oh, great. Thanks so much for taking my question and congrats on the statement. Maybe super quick follow-up on Lisa'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 it out whether there were other factors here that may have contributed to the benefit. And then maybe second, David or Leron, 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? Thanks so much.
Leron, can you speak to the SGLT2 use in the study and that background?
Yeah. So at baseline, nine patients were on 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 heart failure. We don't think that these additional patients that started SGLT2s would have had 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 three trial, which is top priority for us. And as you've heard from David, the enrollment's going very briskly. And we would expect that as the cardiology community understands these data, 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.
Got it.
Thanks so much.
The next question comes from Joseph Thome with TD Cowen. Please go ahead.
Hi there. Good morning. Congrats on the data, and thank you for taking my question. Maybe for the phase III, can you remind us on the potential of an interim analysis? I know patients have to be followed 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 there's those related, and maybe how you'll be making those decisions?
David, do you want to speak to the interim analysis plans?
Yeah. 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 a 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, etc.? Or do we think that we need to tweak in any way the study as it goes on?
Yeah. Right now, based on the results we're seeing and the kind of curve you saw in 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 the number of events to get to the final analysis in the appropriate timeframe or the interim analysis.
The next question comes from Rai Forseth with Guggenheim. Please go ahead.
Thanks for taking our question. A question for Dr. Fontana. If we see recapitulation of the Nexi phase I performance in the MAGNITUDE study, how are you thinking about switching from silencers or stabilizers, given what may be a stronger biomarker or efficacy signal in the NYHA class three patients?
I mean, for me, it's not really about NYHA 3 or 1, 2. 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 3. I 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.
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.
Thank you.
The next question comes from Alec Stranahan with Bank of America. Please go ahead.
Hi guys. Matthew on for Alec here. Thanks for taking our question. 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 one?
David, can you speak or Leron, 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?
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. Please go ahead.
Oh, hey. 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 Nexi can reverse this terrible disease? And if not, what additional evidence would you need to see before you could reach that conclusion? Thank you.
I mean, even from the phase one trial, and we are talking just about 12 months 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 these very low levels of knockdown, just sustained over time, will lead to regression in a proportion of patients for exactly the same cause that 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 one.
The next question comes from Yanan Zhu with Wells Fargo Securities. Please go ahead.
Great. Thanks for taking the questions.
I wanted to dig into a little more about NT-proBNP and six-minute walk comparison with available therapy. I think Tafamidis and Acoramidis both showed a 1.1x-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 six-minute walk, I think Tafamidis had a median of five-meter decline at 12 months. You have roughly maybe a little bit of an even improvement, but still a five-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 3 data that's been presented as well as the six-minute walk test.
Yeah, absolutely. As you mentioned, it's all about the disease that was retreated. I mean, 50% NYHA 3, high proportion of variant patients. The peak VO2 was 12.7, which is a severe reduction in functional capacity. And while you may think, "Okay, the median and difference is not so different," you have to look at the distribution here because in the phase 3 studies, both Acoramidis and HELIOS-B was an upper limit of 8,500. So a good proportion of the patients that were included here wouldn't have been included because they would have been excluded from the phase 3 trials.
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 reweighting analysis on 36 patients is probably going to be quite challenging. But the key of interpreting these results is really thinking about how the baseline these populations was. I mean, we didn't mention it, but even two patients had the V142I homozygous mutation, which basically is one of the most aggressive phenotypes that we ever see in TTR amyloidosis. And these patients were two out of 36. So again, just to point out how severe this population was. Great. That's super helpful. I actually want to put some additional numbers onto it. So NT-proBNP went up about 20% at one year.
So this is looking different from that.
The six-minute walk, the median went down five meters, but the mean went down quite a bit more if you look at the vutrisiran. And we also have looked at our mean, and there's no change at one year. So this is becoming a big difference. Now, we do know it's hard to say 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, you 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 a distinguishing characteristic already.
Nonetheless, Magnitude is underway, and we will conduct the 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. Please go ahead.
Hi. Thanks for sticking me in here. And congrats on the data. Just wanted to ask about the serious infusion reaction, whether you had any more color on that that occurred in one 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?
No, it's only one patient, but anything you could tell us there would be great. Thanks very much.
Leron, can you tell us about, I mean, generally speaking, the safety profile around the infusion and if there was one that there's some interest in? So generally speaking, the infusion-related reactions have been quite mild. All patients received the full intended dose. This individual patient was a class three 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+%.
The next question comes from David Lebowitz with Citi. Please go ahead.
Thank you very much for taking my question. 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?
Yeah. 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 3, 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 where it has estimated 12% wild-type patients, as we might see in phase III.
As a reminder, 31% of the patients in this study had the heritable form. I think Dr. Fontana's made the point that some of these patients have a very, very aggressive form of the disease.
Thank you for taking my question.
The next question comes from Salveen Richter with Goldman Sachs. Please go ahead.
Hey, guys. Thanks for taking our question. This is Marc on for Salveen. Just wanted to kind of follow up. You said that all patients that we saw a significant reduction in TTR levels, but only 80% of patients saw stability or improvement of their disease. I was wondering if there's anything special about those 20% that didn't see stability or improvement. Were those at baseline the worst patients, or were those the patients that potentially didn't see a stronger reduction in TTR levels? Thanks. Dr.
Fontana's, 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 not possible to expect 100% patient stability in such advanced populations. 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 with 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 we've really delayed their progression where some of these patients were deteriorating very rapidly as they came into the trial. And as mentioned, at least for the patients who did die, they lived much longer than you would have expected.
That's helpful. Thank you.
The next question comes from Rick Bienkowski with Cantor Fitzgerald. Please go ahead. Hi. Congrats on the impressive data, and thanks for taking the question. I just wanted to follow up on the potential interim analysis and MAGNITUDE. Would this interim be triggered by a pre-specified number of events, number of patient years in the study, or a specific time point? David, how are we thinking about what triggers the IA? Yeah.
We haven't given the details of that, but it would involve both timeframe and number of events before we were doing an interim analysis. All right. Thank you. The next question comes from Andy Chen with Wolfe Research. Please go ahead. Hey, thank you for taking the question, possibly for Dr. Fontana. So it's not just NT-proBNP, but also the other endpoints, six-minute walk, KCCQ, all of them look favorable versus competition. So if you have to guess, is Nexi faster acting clinically? And therefore, in the Intellia phase three 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? Thank you.
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, if they're coming on not on Tafamidis and it becomes available, they are able to get Tafamidis later. If they had been started on Tafamidis, there is a short waiting period before they can join the trial. But 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 one month, three months, or six months matters. That's translating a significant difference in mortality. So again, we need to learn from 25 years of research on other types of amyloid. You made the point that you think this is a very dynamic disease. Maybe that's the way that we should be thinking about this. Things actually change and move. Absolutely. Yeah. 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 actual improvement.
The next question comes from Silvan Tuerkcan with Citizens JMP. Please go ahead. Thank you.
Congrats on the great data, and thanks for taking my question. Just on slide 31, on your time to progression, plot a couple of my curves that you presented here. And 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? Thank you.
David, maybe we can ask you, what can we read into the data in the curve that you've shared? What's the makeup of events, and is there any qualitative difference that we see with what's been reported elsewhere? Yeah. 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, there's 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 two 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 the patients as soon as possible. By the way, there are about 25-50,000 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 in Intellia.
We 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.