Good day, everyone, and welcome to today's Alnylam Pharmaceuticals conference call to discuss the results from the HELIOS-B Phase Three study. At this time, all participants are in a listen-only mode. Later, you will have an opportunity to ask questions during the question and answer session. You may register to ask a question at any time by pressing star one on your telephone keypad. Please note that this call will be recorded and I will be standing by should you need any assistance. It is now my pleasure to turn today's call over to the company. Please go ahead.
Hello, I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer, and Pushkal Garg, Chief Medical Officer. We are also pleased to be joined by Dr. Scott Solomon, Professor of Medicine at Harvard Medical School, who will be providing his perspective on the results of HELIOS-B and will be available for Q&A.
Also joining us and available for Q&A are Jeff Poulton, Chief Financial Officer, Tolga Tanguler, Chief Commercial Officer, and John Vest, Senior Vice President of Clinical Research. For those of you participating via conference call, the slides we have made available via webcast can also be accessed by going to the investors page of our website, alnylam.com/events. Now turning to today's call, as outlined in slide two, Yvonne will provide some opening comments.
Pushkal will provide an overview of ATTR amyloidosis with cardiomyopathy and discuss the HELIOS-B study and full results in more detail. Dr. Solomon will share some perspectives on HELIOS-B, and we will then open the call to your questions. Before we begin, I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans, and prospects, which constitute forward-looking statements for the purposes of the Safe Harbor provision under the Private Securities Litigation Reform Act of 1995.
Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent quarterly report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date.
We specifically disclaim any obligation to update such statements. With that, I'll turn the call over to Yvonne. Yvonne?
Thanks, Christine, and thank you everyone for joining the call today. My colleagues and I are excited to be speaking to you from the European Society of Cardiology Congress in London, where earlier this morning we presented detailed results from the HELIOS-B phase 3 trial for vutrisiran, our investigational RNAi therapeutic that was evaluated in patients with ATTR amyloidosis with cardiomyopathy.
Back in June, we shared our positive top-line results from the study, and today we reveal the full breadth of these data that we believe clearly demonstrate vutrisiran's transformative potential and the profound impact it could have for patients living with ATTR amyloidosis with cardiomyopathy, their families and caregivers, physicians, and the ATTR amyloidosis community at large. In addition, this is a landmark moment for Alnylam. It's been a remarkable journey in our quest to address this major unmet medical need.
Indeed, it's been over ten years since we first began to explore the potential of RNAi-mediated knockdown of TTR to achieve transformative therapeutic benefit in patients with ATTR amyloidosis with cardiomyopathy. And as Pushkal will show you in a moment, we now have hard outcomes-based evidence that rapid knockdown of toxic TTR can significantly improve cardiovascular outcomes in these patients.
But before he does that, I'd like to start with some overall context. First, as I said earlier, we view the HELIOS-B results as very impressive. Vutrisiran met every primary and secondary endpoint in both the overall and monotherapy populations. Ten out of ten with highly statistically significant and clinically meaningful results.
This included the primary endpoint, the composite of all-cause mortality and recurrent CV events at thirty-three to thirty-six months, with each of the components of the composite endpoint in the overall population also achieving robust and statistically significant results, and all secondary endpoints, including a pre-specified analysis of all-cause mortality and evidence of stabilization of functional capacity, health status, and quality of life.
Vutrisiran also demonstrated encouraging safety and tolerability consistent with its established profile. Second, we believe that, if approved, vutrisiran has the potential to become the new standard of care in ATTR cardiomyopathy. HELIOS-B is the most contemporary ATTR cardiomyopathy study completed to date, with many patients on effective background therapies.
And yet, against the incredibly high bar of this contemporary therapeutic backdrop, vutrisiran showed a profound impact over and above progressive background standards of care and on the most important endpoints, mortality and CV events, while also stabilizing disease as measured by functional and quality of life measures.
Furthermore, vutrisiran offers an attractive dosing schedule with quarterly dosing that aligns with doctor visits, supports strong adherence, and provides the flexibility of in-office or at-home dose administration by a healthcare professional. Therefore, we expect favorable payer dynamics with medical benefit coverage. The third point I'd like to make is that we're also now focused on preparing for the launch of vutrisiran in ATTR cardiomyopathy, assuming regulatory approval....
We remain on track to initiate global regulatory filings later this year, beginning with the submission of a supplemental NDA with the U.S. FDA, using a priority review voucher that could enable U.S. approval in the first half of 2025. Medical and commercial investments are planned to support a strong launch, and we plan to leverage and scale up our well-established commercial infrastructure for ATTR cardiomyopathy.
We believe vutrisiran is well positioned to address the significant unmet need in ATTR amyloidosis with cardiomyopathy, given the large and growing population of those untreated, and for those whose treatment could be optimized beyond what background treatments alone provide. We could not be more excited about the prospect of launching vutrisiran and ATTR-CM based on our HELIOS-B data.
Given these results, we believe regulators, payers, and prescribers will recognize the strong profile of vutrisiran in ATTR amyloidosis with cardiomyopathy and its potential to help patients living with this serious, debilitating, and progressive disease. There's really nothing more important than strong clinical evidence in bringing a new medicine to the market, and we believe we've got wind in our sails with the HELIOS-B results.
A nd finally, we believe the HELIOS-B results support the potential for vutrisiran to become an anchor commercial franchise for Alnylam that will secure our next wave of significant top-line growth and allow us to achieve sustainable non-GAAP profitability. This will provide the capacity for us to strategically reinvest in our highly productive organic R&D platform and pursue other high-value therapeutic opportunities like obesity, diabetes, neurological diseases.
So with these HELIOS-B results now in hand, we're closer than ever towards realizing our vision of becoming a leading global biotech company. With that, I will now turn it over to Pushkal to review the full scope of the HELIOS-B results in more detail. Pushkal?
Thanks, Yvonne, and welcome everybody. I am really excited to be able to share the highly positive results from our HELIOS-B phase 3 study, which Dr. Fontana presented just a few hours ago at the ESC Congress here in London. Now, as most of you know, ATTR cardiomyopathy is a progressive and debilitating disease caused by misfolded transthyretin protein, which forms amyloid fibrils that deposit in the heart, resulting in thickening and stiffening of the myocardium.
This reduces the heart's ability to pump blood, resulting in heart failure as well as arrhythmias. As amyloid deposition increases, shortness of breath and fatigue worsen and exercise tolerance declines. It becomes more and more difficult for patients to walk and perform activities of daily living. Cardiovascular hospitalizations become longer and more frequent, and the disease is ultimately fatal.
The median survival of ATTR cardiomyopathy ranges from two and a half to five and a half years, a natural history that is worse than some cancers. Over the past few years, we've witnessed an evolution towards earlier diagnosis and improved heart failure management, and as a result, contemporary patients have less advanced disease, and many patients are managed with effective treatments such as tafamidis, SGLT2 inhibitors, and diuretics.
We estimate that there's approximately two hundred to three hundred thousand patients worldwide with ATTR cardiomyopathy, with the majority of patients having the wild-type form of the disease. Now, by rapidly knocking down TTR in the liver, RNAi therapeutics lower circulating levels of the pathogenic protein, which we believe offers the potential to halt or even improve patients' heart failure manifestations and reduce the risk of hospitalization and death.
Let me now turn to the HELIOS-B study itself, but before I walk you through the detailed results, I thought it'd be helpful to outline our key takeaways from the data. First, vutrisiran demonstrated profound and unequivocal reductions of mortality and cardiovascular hospitalization in patients with ATTR cardiomyopathy. And of note, this was in a contemporary cohort of patients who were diagnosed non-invasively with substantial concomitant use of other effective therapies, including tafamidis, SGLT2 inhibitors, and diuretics.
Patients given vutrisiran also experienced benefits on functional capacity, health status, and quality of life, NYHA class, and NT-proBNP. These are all key measures of disease progression. Importantly, consistent efficacy was seen across all patient subgroups. This includes patients who received vutrisiran monotherapy and patients on baseline tafamidis, where we saw evidence of additive efficacy.
We also saw particularly large effects in patients with characteristics of early disease, highlighting the importance of initiating effective treatment as early as possible. Finally, vutrisiran demonstrated encouraging safety and tolerability profile, consistent with its established profile. Taken together, we believe these data support vutrisiran, if approved, as a new standard of care for patients with ATTR-CM, which can be used as first line and as a switch or add-on therapy.
Now, let's turn to the detailed results. HELIOS-B enrolled 655 patients with ATTR cardiomyopathy, either the wild type or hereditary forms of the disease. Patients had to have clinical symptoms of established heart failure, as assessed by a physician. As we've discussed, 40% of patients were already on an active drug, tafamidis, at baseline, and others were able to start stabilizers during the study.
Patients were randomized one-to-one to receive a 25 milligram dose of vutrisiran or placebo, administered subcutaneously once every three months during a double-blind treatment period of 33 to 36 months. The primary endpoint was a composite outcome of all-cause mortality and recurrent CV events assessed in two populations: the overall population and the monotherapy population, defined as the subset of those patients who were not on tafamidis at baseline.
In addition, the study included a number of secondary endpoints, which were also tested in both populations. These secondary endpoints focused on important clinical measures that we believed could best highlight vutrisiran's potentially differentiated profile and its impact on disease progression. The first secondary endpoint was a change from baseline, the six-minute walk test, a measure of functional capacity.
Next was a change from baseline in the Kansas City Cardiomyopathy Questionnaire, a validated measure of health status and quality of life in patients with heart failure. Third was all-cause mortality as a standalone endpoint, which is recognized as the most stringent measure of efficacy in this disease. And last was New York Heart Association Classification, which is a common assessment that physicians use to monitor disease progression in their patients.
The patients we enrolled in the study were representative of the ATTR-CM population in the modern era. The average age was seventy-six to seventy-seven years, and the large majority were men, had wild-type disease, and were NYHA Class II. Importantly, baseline characteristics in the overall population were balanced in the vutrisiran and placebo arms. Further reflecting the modern era, there was substantial use of other effective therapies.
As I mentioned, 40% of the enrolled patients were on background tafamidis at study entry. These patients in the combo arm were generally healthier than those who were not on tafamidis, i.e., the monotherapy arm, based on multiple measures of baseline disease severity. Baseline tafamidis was a key stratification factor, so it was balanced between the placebo and vutrisiran arms.
In those patients not on tafamidis at baseline, a little over 20% began tafamidis over the course of the double-blind period. In addition, about a third of patients in the overall study started taking SGLT2 inhibitors during the double-blind period. Moreover, about 80% of patients in each treatment arm were on baseline diuretics, and we saw diuretic intensification in 56% and 48% of patients in the placebo and vutrisiran arms, respectively. Turning now to the results.
Let me begin with the primary endpoint in the overall population, where vutrisiran reduced the risk of the composite of all-cause mortality and recurrent CV events by 28%, with a p-value of zero point zero one one eight. The effects are shown here as a time to first event curve, where you can see the separation growing over time.
The impact on time to first event was very similar to the primary analysis, with a 28% reduction. We next look at the contributions of the individual components to the primary composite outcome during the double-blind period. Here you can see that the results were driven by similar effects of vutrisiran on mortality, as well as recurrent CV events.
In fact, in the overall population, the study achieved statistically significant effects on both components, with a 31% reduction in all-cause mortality and a 27% reduction in CV events during the double-blind period. In the pre-specified secondary endpoint of all-cause mortality in the overall population, the hazard ratio was 0.645, corresponding to a relative risk reduction of 36%, with a p-value of 0.0098.
As we've previously described, in this analysis, we included up to six months of data from the open-label extension period to increase the exposure time for up to 42 months, given the understanding that targeted therapies for ATTR-CM don't immediately impact mortality.
This pre-specified ICT analysis therefore compares the experience of patients who were randomized to vutrisiran against those who received placebo during the double-blind period and then crossed over to receive active drug during the open-label extension. Thus, this positive result further corroborates the significant effects on mortality that we observed during the double-blind period.
It's also important to assess the consistency of treatment effect across key patient subgroups enrolled in HELIOS-B. Particularly, we assessed the consistency of effect in patients receiving baseline tafamidis, wild-type and hereditary disease, and multiple measures of disease severity, and we were very pleased to see that the effects of vutrisiran on the primary composite endpoint, as well as the secondary endpoint of all-cause mortality, were robust across all key subgroups, indicating the strength of the data and that vutrisiran may be effective across a broad spectrum of patients.
That said, I'd like to draw your attention to two notable observations. First, we saw trends towards particularly large effects in patients with characteristics indicative of early disease, such as age less than seventy-five or NT-proBNP less than two thousand. In these subgroups, we saw reductions of all-cause mortality and recurrent cardiovascular events of 46% and 48%, respectively.
We saw 45% and 65% reductions of all-cause mortality alone in these two subgroups. These results highlight the importance of early treatment. Second, we also saw consistent benefits of vutrisiran as a monotherapy and in patients on background tafamidis. Let me review those data in the next two slides. Here we show the effects of vutrisiran on the primary composite and secondary endpoint of all-cause mortality in the monotherapy population.
On the primary composite endpoint, the hazard ratio was 0.672, corresponding to a relative risk reduction of 33%, with a p-value of 0.0162. For the secondary endpoint of all-cause mortality, the hazard ratio was 0.655, corresponding to a relative risk reduction of 35%, with a p-value of 0.0454.
Next, let's turn to the results in the subgroup of patients who were on tafamidis at baseline, which comprised 40% of the overall population. As a reminder, the HELIOS-B study wasn't designed or powered to assess the additive effects of vutrisiran on top of tafamidis. Nonetheless, we were delighted to see favorable trends in the baseline TAF group in both the primary composite endpoint and in all-cause mortality.
Specifically, on the composite of all-cause mortality and recurrence of events, the hazard ratio was 0.785, corresponding to a relative risk reduction of 22%, with a p-value of 0.2701. And on all-cause mortality, the hazard ratio in the tafamidis subgroup was 0.588, corresponding to a relative risk reduction of 41%, with a p-value of 0.0983....
We find these trends of added benefit on both of these endpoints in the tafamidis subgroup to be encouraging, as they suggest that adding vutrisiran on top of tafamidis may be more effective in reducing and improving CV outcomes than tafamidis alone. Now, in addition to heart outcomes of death and hospitalizations, patients and physicians care about how patients feel and function with this disease when they're alive.
So we were pleased to see benefits of vutrisiran on multiple measures of disease progression, six-minute walk test, KCCQ, and NYHA class, as shown on the left side of this slide in the overall population. We saw similar benefits on each of these endpoints in the monotherapy population. One important caveat to the calculations for the six-minute walk test and KCCQ results on the left is that they impute results for patients who died, assuming them to be at the worst tenth percentile or nearly zero.
Now, this makes sense for a statistical endpoint, as you don't want to declare a win on either of these measures if the drug also increases mortality. But now that we see favorable impacts of vutrisiran on mortality, what's of greatest interest to patients is: how much will my disease progress while I'm alive?
The curves on the right, which show observed data without that worst-case imputation for death, help to answer that question. And what's encouraging is that the median values for both six-minute walk tests and KCCQ are relatively stable over thirty months for patients on vutrisiran, similar to what we saw with patisiran in the APOLLO-B study, and in contrast to the steady decline seen in placebo-treated patients.
Another important measure of disease progression used by clinicians is NT-proBNP, which is a well-established cardio biomarker, prognostic of mortality in ATTR cardiomyopathy. In HELIOS-B, NT-proBNP steadily increased in placebo patients, where it was much flatter in patients treated with vutrisiran, both in the overall population and monotherapy populations. And both of these results were highly statistically significant.
Thus, these biomarker results further corroborate the clinical data on the prior slide and indicate that vutrisiran treatment appears to significantly delay disease progression in ATTR-CM. Turning to safety, in the HELIOS-B study, vutrisiran demonstrated an encouraging safety and tolerability profile, consistent with the established profile of the drug.
Rates of adverse events, serious AEs, severe AEs, and AEs leading to study drug discontinuation were similar between the vutrisiran and placebo arms. The majority of AEs were mild or moderate, and none were seen 3% or more frequently in the vutrisiran arm compared to the placebo arm. Rates of cardiac AEs were similar or lower in the vutrisiran arm compared to placebo. In conclusion, we are thrilled with these results.
HELIOS-B met the primary and all secondary endpoints in both the overall and monotherapy populations, with highly statistically significant and clinically meaningful results in a contemporary patient population, many of whom were concurrently treated with other effective therapies. Specifically, vutrisiran demonstrated profound and unequivocal clinical benefits on mortality and cardiovascular hospitalization in patients with ATTR-CM.
Patients treated with vutrisiran also experienced benefits on multiple clinical and laboratory measures of disease progression, including functional capacity, health status, quality of life, NYHA class, and NT-proBNP. Importantly, consistent efficacy was seen across all patient subgroups. This includes patients who received vutrisiran monotherapy and patients who were on baseline tafamidis, where we saw evidence of additive efficacy.
We also saw particularly large effects in patients with characteristics of early disease, highlighting the importance of initiating treatment as early as possible. Importantly, vutrisiran demonstrated an encouraging safety and tolerability profile.
We're also delighted that the HELIOS-B results have simultaneously been published in the New England Journal of Medicine and are available online. This marks Alnylam's thirteenth publication in this prestigious journal, and we're proud to continue our legacy of scientific innovation. Looking ahead, we plan to continue sharing detailed results from HELIOS-B at upcoming medical conferences, including HFSA later in September.
Also, as we announced on our Q2 earnings call, we'll be hosting a TTR Investor Day on October ninth in New York City. And importantly, as Yvonne mentioned, and consistent with our previous guidance, we remain on track to submit a supplemental NDA filing for vutrisiran in the U.S. in late 2024, with additional global regulatory filings thereafter. In the U.S., we plan to use our priority review voucher to accelerate the regulatory review in hopes of bringing this medicine to patients as quickly as possible.
Before I wrap up, I'd like to extend my thanks and admiration to my many Alnylam colleagues, who always maintain their belief in our mission and sweated every detail to deliver a high-quality study. Likewise, I'm grateful to the investigators, site staff, and partners and vendors who worked with us and most of all, I want to extend my heartfelt thanks to the patients who volunteered to participate in this study, which we hope will allow us to bring this medicine to ATTR-CM patients around the world who need additional therapies for this devastating disease.
It's now my pleasure to welcome Dr. Scott Solomon of Harvard Medical School to provide some additional reflections on the HELIOS-B data set. As many of you know, Dr. Solomon is the Edward Frohlich Distinguished Chair and Professor of Medicine at Harvard Medical School and the Brigham and Women's Hospital.
He directs the Clinical Trials Outcome Center and the Cardiac Imaging Core Laboratory. His research interests have focused on understanding the effects of heart failure on cardiac structure and function, modifiers of risk and outcomes in heart failure, and therapeutics for heart failure.
He's a well-renowned clinical trialist, having led numerous phase II and phase III clinical trials in heart failure, including in patients with heart failure with reduced ejection fraction, mild reduced and preserved ejection fractions, amyloidosis, and hypertrophic cardiomyopathy. And his work has led to the introduction of several key therapeutics in heart failure. So I think his opinions here will be very helpful. Dr. Solomon?
... Thanks. And, there's very little for me to add actually to what has been really an extraordinary morning. These results truly speak for themselves. When I reflect on the fact that just a decade ago, we really had virtually no therapy, certainly no targeted therapies for patients with ATTR cardiomyopathy, and how that has changed, and how today, I think, has really moved the field even further. I'll just make a couple of comments.
First of all, I can't stress how important it is to realize that this is a progressive disease. If you don't treat it, these patients are going to develop heart failure, they're going to be hospitalized for heart failure, and they're going to die.
And you see that in even the treatment arms that you see in the results of this trial, that there is progression in this disease, and what new therapies can do sometimes is to attenuate progression. I think that the robustness of these results need to be considered in light of the fact that in heart failure, we rarely see relative risk reductions of the magnitude that was seen in the HELIOS-B trial.
And the fact that this was the case, not just in the overall population, in the monotherapy population, but also that there was consistency in every single subgroup, importantly, in the subgroup that received tafamidis, makes us think that there's actually incremental value here in the mechanism of action of the silencer on top of tafamidis.
It's a small subgroup that's important to recognize of those patients, but the data suggests that there's consistency of those results, so I'm extremely excited about these results. I think that you're gonna learn a lot more that will come out over the next year or so, or even sooner, including other mechanistic data and additional data that's gonna support this overall the magnitude of this outcomes result that you saw today, so I congratulate the sponsor for doing an incredibly well performed trial that's gonna clearly change the way people practice.
Thank you, Scott.
Thanks, Dr. Solomon. Operator, we will now open the call to your questions. As a reminder to those dialed in, we would like to emphasize that we will be fielding only one question from each analyst. We ask you, please get back in the queue if you have additional questions.
Certainly. At this time, if you would like to ask a question, please press star one on your telephone keypad. You may withdraw your questions at any time by pressing star two. Once again, that is star and one. We will take our first question from Eliana Merle with UBS. Please go ahead.
Hi, guys. Thanks so much for taking the question. Can you give us a little bit more color on how you think the month 30 all-cause mortality results compare to the stabilizers? So specifically, the discussant slide showing the relative risk reduction on all-cause mortality at month 30 was 13.8%. Is that correct? We're just trying to reconcile this with the 31% all-cause mortality benefit in the overall population at the 33- to 36-month time point. Thanks.
Yeah. Thanks, Ellie. Look, I think, obviously, cross-study comparisons are always hazardous. First of all, these are different populations at different points in time. And I think what Dr. Cuddy was actually trying to convey there was how treatments actually have been benefiting patients and over time, and we're seeing sequentially greater improvements in treatment outcomes. We've been in touch with Dr. Cuddy. I think there was actually a calculation error on the slide. So the hazard ratio that's shown is point six nine. If you just do the simple math, the relative risk reduction would be 31%. So I think there was just a typo on the slide.
It was about a 31%, which is in line with the 30%-36% reductions that we've cited in terms of relative risk reduction across all the hard outcomes in the study.
Great. Thanks.
Thank you. We'll take our next question from Maury Raycroft with Jefferies. Please go ahead.
Hi, congrats on the data, and thanks for taking my question. I'm just wondering if you can contextualize your patient baseline data as well as the extensive background meds in HELIOS-B versus the acoramidis and tafamidis phase 3s, and how this contributes to the timing of curve separation for HELIOS-B outcomes versus the other studies?
Yeah, that's a great question, and I'm glad you've noted the baseline characteristics. And I think this really continues to underscore the point that Dr. Solomon made about how patients are being diagnosed earlier and being treated with many, many therapies for this condition. So I think the fact that we were able to demonstrate such impressive results of the treatment in this context, I think is remarkable. Scott?
Yeah, Maury, thanks. You know, look, I get why looking at sort of timing of curve separation is an appealing concept, but maybe there's two problems I would just sort of highlight. I mean, first of all, it's a somewhat subjective parameter, right? It's kind of an eyeball test. It's two versus one event or eleven versus nine events is that separation? And it's very event dependent.
You just need to have enough events over time for curves to separate. Now, in this study, we purposely enrolled an earlier population that's gonna lead to a lower event rate. We also allowed patients in a modern setting to be on many medicines. Over half were on tafamidis at one point or another, 30% were on SGLT2 inhibitor, so that also leads to lower event rates.
So the curves here are actually what we expected as we designed the study. And I'll point out, as Dr. Fontana did, that there are many parameters that show an early treatment effect. When you look at BNP, six-minute walk test, etc., all of which suggest the quick manifestation of the rapid knockdown that vutrisiran offers.
So I would really just focus on more robust measures of efficacy, and I think here in this contemporary population, to see reductions in mortality and hospitalization, which, as Dr. Solomon pointed out, are sort of on the high end of what's typically seen in heart failure studies to date, impact on progression and consistent data that seem to be applicable across a broad spectrum of patients, we think is fairly unprecedented and quite remarkable.
Thanks, Pushkar.
Thank you.
Thanks.
Thank you. We'll take our next question from Paul Matteis with Stifel. Please go ahead.
Hi, this is James on for Paul. Thanks for taking our question, and congrats on the data. You know, maybe just a quick question, if you know, you could remind us in terms of, you know, when you made the changes to the Alnylam, you know, the stats plan, kind of exactly what and when the discussions took place with the FDA, and you know, just your confidence that they're 100% on board with the changes as you kind of, you know, now approach a filing and potential regulatory approval. Thanks so much.
Yeah, thanks, James. So as we've talked about, we were in discussions with FDA and other regulators and other health authorities, you know, after we saw the APOLLO-B results, last fall, the two-year data, really looking to strengthen the endpoint structure so that we could, you know, demonstrate outcomes benefits. We recognized the higher bar. We wanted to demonstrate a mortality benefit, and focus on clinically relevant endpoints.
And also to highlight benefits both as a monotherapy and in the overall population. All of those changes were made and discussed with the health authorities, and codified in a pre-specified statistical analysis plan. And I'll point out that analysis plan, the protocol, and the results go through a pretty rigorous review by editors of the New England Journal of Medicine, and all those were published online, today.
So you can look at those as well. So we feel good this study was designed to show, to demonstrate a mortality and hospitalization benefit, and we think it's convincingly done that.
Thanks, Pushkal. Next question.
Thank you. We'll take our next question from Kostas Biliouris with BMO Capital Markets. Please go ahead.
Hello, everyone. Thanks for taking our question, and congrats on the detailed data. Would you be able to break down for us the CV versus non-CV deaths under the all-cause mortality? As I know, this is important for some people, and sorry if it's somewhere and we missed it, but, I'm wondering whether you are planning to present it or you can break it down for us here. Thank you.
Thanks, Kostas. That's a great question. We'll ask John Vest to respond to your question.
Yeah, thanks for the question, and certainly understand why you're asking, but I think we should back up. First of all, death is death. Okay? And if anything, we would consider all-cause mortality to be the highest possible bar. Now, that said, all-cause mortality, of course, encompasses CV mortality. And what we can say is that, as we would expect, the vast majority of deaths on the study were indeed CV. And when we look at the results, considering CV mortality, the results are entirely consistent.
Thanks, John.
Thank you. We'll take our next question from Gina Wang with Barclays. Please go ahead.
Thank you. I have one question for Dr. Solomon. So which, you know, data point is more important when we look at the tafamidis monotherapy group and when we look at the vutrisiran monotherapy group, this baseline, if we back calculate, for tafamidis, proBNP is one thousand seven hundred. For vutrisiran, actually, it's very high, it's two thousand four hundred. I know the NYHA Class three, you know, group vutrisiran is only 5%, but for tafamidis monotherapy group is 13%. So which data point is more important to determining patient are more severe?
That's a great question. Gina, I have to say, it's a little difficult to understand you, that the lines are not terribly good, but we'll do our best. Maybe, Pushkal, you can start off. I think it's around which data points are the most convincing in the study. Perhaps if you start and then, Dr. Solomon.
Yeah, why don't I start? Gina, I think you were trying to look across the baseline severities of the TAF patients and the vutrisiran patients. And look, I certainly get the nature, but it's, this is, they're really quite different. This wasn't a head-to-head study of TAF versus vutrisiran. In fact, the TAF patients were primarily US patients.
They were healthier, and I think we put on the baseline demographic slide across a variety of parameters. NT-proBNP, six-minute walk test, KCCQ, troponin, all of those sort of suggested it was a somewhat healthier population. And they'd been on drug for a median of about eleven months before they entered the study, as opposed to the vutrisiran patients, who were de novo.
So in trying to do that comparison, you're kind of trying to compare U.S. patients versus ex-U.S. patients or healthier versus sicker patients, those who started on drug versus those who'd been on drug. So you can't really do that. I think maybe the couple of takeaways, before I turn it over to Dr. Solomon, are that, you know, this, this drug was studied in the modern era, on patients on multiple background medicines.
And what we see is actually, as Dr. Solomon was pointing out, we're seeing benefits both in mono and, and evidence of benefits on top of tafamidis. And that suggests that tafamidis, TTR stabilizers may be leaving some efficacy on the table, that Vutri is able to address. But Dr. Solomon, maybe you may have some other points to add.
Yes, and, you know, you may want to make some more general comments about, you know, the insights that you believe the medical community will take away from the study results.
Yeah. So first of all, to answer the, or at least to address this question, I look at this as, you know, the only comparison that is valid in a trial like this is the randomized comparison, it's vutrisiran versus placebo, whether patients are on tafamidis or not, whether they're on SGLT2 inhibitors or not, whatever they're on.
What you can do, of course, is to look at the consistency of that result, and we do this statistically by looking at the interaction, the formal interaction, between the subgroups in the therapeutic arms. And here, there was no evidence whatsoever of an interaction suggesting that there was no heterogeneity, that patients had similar benefit, whether they were on the tafamidis, in the tafamidis group or in the monotherapy group.
I think, we are loath to make comparisons of tafamidis monotherapy with vutrisiran monotherapy because then you're breaking the randomization. You know, as we've mentioned before, these are still relatively small subgroups, but the data are suggestive that there should be, as Pushkal said, incremental value when we add a silencer to a stabilizer.
Thank you.
Thank you, Dr. Solomon.
Thank you. We'll take our next question from Mike Ulz with Morgan Stanley. Please go ahead.
Good morning. Thanks for taking the question. Maybe just more of a follow-up on the TAF subgroup benefit, and maybe to get a little bit more of context from Dr. Solomon as well. In terms of the benefit and what's meaningful, and in that context, you know, what percentage of your patients would you consider putting on the combo? Thanks.
Yeah. So look, Mike, I think, I mean, first of all, it's important to remember, we're talking about mortality and hospitalization. And so there is sort of no minimum, no floor for that. We want to improve those outcomes as much as possible. And what we're seeing overall, I just point out, is a pretty substantial effect if you just look in aggregate at what we're seeing in terms of relative risk reduction.
We're talking about 30-35% if you look across a variety of the hard endpoints. So this is quite sizable. We actually put some of the absolute risk reductions, which are on the order of 10-20%, which leads to actually very small numbers needed to treat if you kind of do the calculation there. So these are pretty substantial.
You know, again, not to draw too much from small, small subgroups, but in that TAF subgroup, we saw 41% relative risk reduction in mortality. In patients with evidence of earlier disease, we saw 65%. We can look across this, but I think what you're seeing is remarkably consistent results across a broad range of patients. But maybe, Dr. Solomon, you want to speak a little bit more in terms of what you consider meaningful.
Let me just provide some context here. In the general heart failure field, we've been using multiple therapies for many years. We now put patients on beta blockers and ACE inhibitors and ARNIs and SGLT2 inhibitors. We have literally four pillars of therapy.
I think what these results show is that vutrisiran alone reduces morbidity and mortality in these patients, but they are very suggestive that in combination with therapies like stabilizers, tafamidis, they would also reduce morbidity and mortality incrementally. Obviously, there are gonna be other challenges to getting patients on both of these drugs, but scientifically, it makes sense. There's nothing in these data that would suggest there would not be incremental benefit.
That's great.
Very helpful. Thank you.
Thank you. We'll take our next question from David Lebowitz with Citi. Please go ahead.
Thank you very much for taking my question. I guess two things. One, could you just comment on the nature of the censored data in the charts and just what that exactly is? And also, could you characterize the functional data? I know certainly the mortality is, and the outcomes are more of a focus, but how would you characterize the functional data, vis-à-vis stabilizers?
You know, those are two great questions. Clearly, with respect to the functional data, I mean, we're really impressed by what we've been able to see here in terms of stabilizing disease, and we believe this is gonna be really important to patients. As Pushkal said, you know, first of all, you're concerned about, you know, mortality, CV outcomes, and then obviously, how you function and feel is incredibly important. I think what we're seeing here is actually the, you know, power of the RNAi mechanism in terms of, you know, rapid knockdown and pretty early impacts on both quality of life and six-minute walk test. Pushkal, perhaps you'd like to comment a little bit on the censored data or John?
I can start, and then, John, you can add in. Look, the censoring, Dave, is just because as a reminder, we actually locked the database when the last patient got to month thirty-three, right? And so there are gonna be some patients, with all patients reaching month thirty-three to thirty-six, so you see some censoring that happens in the primary endpoint after that. And then for the month forty-two analysis, that was somewhat opportunistic, right?
So we actually, again, locked when people were at thirty-three to thirty-six months when they'd completed the double-blind period. Not all patients have made it to forty-two months up to that point. In fact, about 20% of the patients had gotten to month forty-two. Other patients were in that spread of data time points between thirty-three and forty-two months, and so you see that censoring there.
What's important is that you see that curve steadily separating over time, and they continue to separate.
Got it. Thank you.
Dr. Solomon wanted to add something.
I just want to add something about the functional data, because as a clinician, I would say that patients will thank you when they feel better, and when they can do more, and I can tell you that in most heart failure therapies do not have the magnitude of improvement that we saw in this trial.
We've looked at this with SGLT2 inhibitors, we looked at this with the angiotensin receptor neprilysin inhibitor, and we never see an improvement in six-minute walk, so that alone is impressive, but the magnitude of the Kansas City Cardiomyopathy Questionnaire score is way bigger than we typically see in our traditional heart failure trials, and this is the kind of thing that patients will come back and say, "Thank you, doctor, for putting me on this medicine.
Excellent. Got it. Thank you. Comments, guys.
Thank you. We'll take our next question from Luca Issi with RBC Capital. Please go ahead.
Oh, great, thanks so much for taking my question, and obviously, congrats on the data. Maybe Pushkal, at high level, you know, obviously, one of the challenges here is that you, Pfizer, BridgeBio, obviously have run trials in different eras, and so not only the baseline characteristics are very different, but obviously, you have a much higher rates of drop-in of both tafamidis as well as the SGLT2.
However, I think you did mention during your top-line data that you believe HELIOS-B will be established on vutrisiran as a first-line therapy. Can you just maybe articulate why you think docs should actually pick this therapy over tafamidis or acoramidis for newly diagnosed patients? Any call there much appreciated. Thanks so much.
Sure, Luca. Let me start, and then Tolga may have something he wants to add as well. Look, I think there's a couple of points here. First of all, I do think we should just step back and recognize that there's a tremendous unmet need in this disease. The majority of patients are not treated. If not, they're not even diagnosed, some don't respond, and many progress on current therapy.
And so there's a sore need for new therapies in this progressive and ultimately fatal disease. The study we did here was in the modern era. This was a really stringent test of efficacy. I think you heard that from the podium as well today. To be able to show efficacy in a modest-sized study on top of rigorous and effective background therapies is actually quite remarkable.
And in that context, the drug hit ten out of ten. Now, when you look in the data set itself, what you see is pretty strong results as a monotherapy. You know, 35%-36% reductions in mortality, which Dr. Solomon has commented on, is on the high end of what's typically seen in heart failure studies. So that, in and of itself, is quite remarkable. Now, the other thing that we see is some evidence of additive benefits on top of TAF.
This, I think, suggests two things. One, I think it suggests just again, the possibility that there's additive effects, but also that the stabilizers may be leaving some efficacy on the table that vutrisiran is able to fulfill. And so that, I think, is a pretty remarkable finding as well.
And so what we also then see is benefits in terms of disease progression, which Dr. Solomon's pointed out, is really important to clinicians. They wanna be able to start to feel better. They don't wanna lose that function that allows them to go to their kid's ball game or their grandkid's ball game, or do other activities. And so that's very important.
So look, physicians and patients will have additional choices now, and we think that's a good thing, given the unmet need that's here. But we do think that when you look at these data in totality, they stand up quite well to what's available, and will make this drug suitable both for first-line use as well as for patients who may be progressing on another therapy.
Yeah. Just to add on a few points that Pushkal highlighted, and I know these will be maybe a little repetitive, but I think it's really important to underline. We do believe upon approval, vutrisiran will have a clear opportunity to be a first-line in standard care. And when the dust settles, these are the key drivers that will really matter. One, as Pushkal highlighted, this remains an underdiagnosed, undertreated category.
There's a significant amount of patient need that's out there. And as you heard from Dr. Solomon, for a disease where the median survival is two and a half to five and a half years, physicians and patients, they wanna really hit this disease hard, and they wanna hit fast. And the disease-causing protein that's showing a clear impact on mortality in a contemporary patient population, including data on top of TAF, is really compelling.
And you also wanna see the benefits on preservation of function and quality of life, and we've delivered on all those results in all trial subgroups. It's really critical that we underline this. And last but not least, in a crowded category, Amvuttra, which is a unique and highly differentiated mechanism of action that works upstream, enabling rapid knockdown of TTR at the source that is deep and durable.
So with an attractive quarterly dosing schedule that aligns with physician visits, supporting strong adherence with site-of-care flexibility, favorable payer dynamics, we believe all those elements will enable us to position this important medicine upon approval as a first-line standard of care.
Thanks, Tolga. Okay.
Thank you so much.
Thank you. We'll take our next question from Gary Nachman with Raymond James. Please go ahead.
All right, great, and thanks for taking my question. So how early are patients typically getting diagnosed now with ATTR-CM? And what's the likelihood you can get these patients on treatment as early as possible? That's clearly where you saw the best results in the study. And do you think physicians would think differently about how they'll use vutrisiran later on in more severe patients, given that dynamic?
It'd be great for Dr. Solomon to start answering that question, then Tolga, you may have some perspective.
Yeah. Let me start. I mean, I think one of the remarkable things we've seen over the past decade is that as we have realized that there are now therapies for this disease, we're starting to make this diagnosis earlier and earlier. We're thinking about it more. The estimates in the typical heart failure with preserved ejection fraction group of patients that I study tends to be between 5% and about 15% might actually have ATTR CM. And this is something that was completely unrecognized until several years ago.
So we're starting to think about it more, but we're not thinking about it enough. We certainly need to pay more attention to this disease because this is really one of the first truly targeted therapies in heart failure.
And one of the reasons I think we are seeing such a profound risk reduction here is because most of the therapies we use in heart failure are not targeted to the molecular problem, but this one is. But I think your point is that we are beginning to diagnose these patients earlier in the course of disease. As we do that, of course, their event rates are lower. They will live longer, and the benefit that they're going to see accrue from treatments like this are going to extend to longer years of considerably longer years of life, the earlier we catch them.
And that's terrific, Dr. Solomon. I think, you know, what we believe we have in our hands is actually a game changer for these patients with ATTR cardiomyopathy. Anything to add, Tolga?
Two quick points, completely aligned with Dr. Solomon's view. Since the approval of the first stabilizer, the diagnostic rates went up tenfold in a quick, short amount of time of six years, and it continues to grow. So that's a very encouraging sign because of the uniqueness of scintigraphy and other, you know, diagnostic tools. So that's number one. Number two is about the how we want to be able to actually position this product. What HELIOS-B has provided us is that we've been actually able to demonstrate consistent benefit across all severity of patients.
Of course, despite the fact that the bar is much higher for moderate patient severity, we've still been able to demonstrate that, and we believe we're going to be well positioned first line, but we also have data available for more severe patients. In combination of all these, you know, elements enables us to position the product first line, but if patients want, if patients wants to be switched off of other products, I think we're well positioned to do that.
Maybe just one last point. And just I think it's important because what you're asking about in terms of early treatment is just such a critical aspect of moving the needle for these patients, and I think it's such a key finding from this study, and where the field is going. I think, you know, recognizing this is a targeted therapy and a disease that can be treated early, I think what you're seeing also beyond technetium scanning is pilot work that's going on in terms of red flag symptoms, right?
So patients presenting with bilateral carpal tunnel syndrome often have underlying amyloid, or patients who have spinal stenosis. So these are all clinically. These diseases present, they can. These patients can then be screened. We're seeing the pilot programs like that that are happening around the world so l ook for earlier diagnosis to continue.
Great. Thank you.
Next question?
Thank you. We will move next to Whitney Ijem with CGF. Please go ahead.
Hey, guys. Thanks for taking the question. Just to follow up on the diagnosis rate question. I guess, can you remind us or talk about kind of the existing efforts from a screening or genetic testing perspective? And in particular, I think I'm remembering a partnership with 23andMe. Can you, I guess, talk about what you're seeing with some of the genetic screening efforts and maybe any acceleration in terms of patient identification or early screening efforts in that regard from a genetic perspective that are planned or ongoing?
So, Tolga?
Yeah, I mean, it obviously, any genetic testing efforts that we've had were very appropriate for polyneuropathy and mixed phenotype patients, and that's actually been able to, I think, you know, you can see from our earnings results, we've been very successful about getting more patients treated in polyneuropathy. Now, when it comes to cardiomyopathy, I think Pushkal highlighted a number of important points.
Given that scintigraphy is easily accessible and relatively inexpensive, education of community cardiologists, and most importantly, as Pushkal highlighted, having red flag symptoms through electronic medical records, system integration of these so that these patients can be actually diagnosed just by early symptoms beyond cardiac biomarkers, is something I think we are working on, we're going to be working on. Obviously, other competitors will be working on, which is a great thing for the patients.
Thank you. So clearly, one of our advantages is having been in the ATTR market for some years now, and that has allowed us to, you know, really understand some of the dynamics here, and we're obviously looking forward to getting the vutrisiran approved so we can turn our efforts to helping patients with ATTR cardiomyopathy. Next question.
... Thank you. We will move next to Ritu Baral with TD Cowen. Please go ahead.
Hi, everyone, from the Wi-Fi black hole of the London Conference Center. Thanks for taking my question and fitting me in. Oh, my God. Well, now that we've seen that you guys have actually hit statistical significance on the double-blind portion mortality, how should we think about mortality as explained in your label, and the potential for that? And will that be impacted at any point, or could that be impacted by that little, I guess, blip that we saw in the monotherapy curves, where the curves crossed and then uncrossed, sort of early on? Thanks.
Yeah, thanks, Ritu. Look, I you know, I'm not going to prognosticate the details of the label by any stretch, but what I can say is it's a, I agree with your general premise here, which is not only did we hit the mortality at the month 42, which is the pre-specified standalone endpoint, but obviously the rigor and strength of the data are only compounded by hitting mortality during the double-blind period with statistical significance.
And so this study was designed for an indication of reducing mortality and hospitalization in patients with ATTR-CM, and we think it's convincingly done that. Now, as you see, we have multiple data points on mortality alone that show the rigor of the data and the strength of the data. So we feel good about that.
Thank you. Certainly, we'll take our next question from Salveen Richter with Goldman Sachs. Please go ahead.
Thank you. This question is for Dr. Solomon. In the context of the data set presented, you know, what is your view on event rate separation and mortality being a few months after acoramidis? Is this meaningful for practice? And, you know, as you think now with this armamentarium that you're going to have here, you know, help us understand how your treatment paradigm may change within your practice.
First of all, I think you need to be very careful when we look at the separation of curves in general, when the number of events are very small. And I think, Pushkal, you already made that comment. It really depends on the patient populations. If you look at the other endpoints in this trial, for example, the cardiovascular event endpoints or even the functional endpoints, you really see separation occurring much earlier.
There's no question in my mind that biologically, this drug is working early. But if you don't have events, you can't show a difference until a certain point in time. And that is dependent on the ambient event rate and the overall health or degree of sickness of the population, among other things.
So I wouldn't try to compare across trials. In terms of practice, when this drug is approved, I think that it becomes another weapon in our armamentarium for the treatment of this disease. And I'm very pleased that it is really apparent, as I've said a few times, that there's going to be potentially incremental value because I'm a strong believer that we probably do need to combine mechanisms. This mechanism absolutely works. We know that stabilization also works, but I think that what we have to think about is getting the best overall results for our patients.
Thank you.
Thank you.
We will move next. Sorry. We'll move next to Tazeen Ahmad with Bank of America. Please go ahead.
Hey, guys, this is Daniel on for Tazeen. Thanks for taking our question. I just had a question on these functional endpoints. I was wondering if you could help us frame sort of the magnitude of effect you saw on the six-minute walk test and the KCCQ, and how clinically relevant those are. And maybe comment on how relevant that is versus just looking at the stabilization in the vutrisiran arm. And if you could also comment on what additional analysis you're planning to present about HFSA.
Yeah. So maybe I can start on the functional endpoints and HFSA, and then, Dr. Solomon may have another few words to say about the functional endpoints from a clinical relevance perspective. Look, I think, you know, on the functional endpoints, we were really pleased to see... You know, if you'll recall back in APOLLO-B days, we looked and talked about these functional endpoints being relatively stable over an extended period of time when we looked at the two-year data.
In this study, we now have the opportunity to look at patients randomized over three years, and again, in the context of this deadly progressive disease, to see what looks like, you know, relative stabilization on these endpoints over such an extended period of time, in contrast to what you're seeing in the placebo patients, I think is really, quite impressive.
That's obviously after you subtract out any amputation. You just look at the observed patients who are surviving on this drug and how they're doing. It's quite impressive, and it's corroborated by even more sensitive biomarkers of clinical progression, which is the NT-proBNP, which, you know, again, Dr. Solomon has a lot of experience, and he can comment on, having seen these data, you know, that's a parameter across a lot of studies.
It is quite remarkable, actually, to see what we're seeing there over an extended period of time. So all of this, I think, points to hopefully, you know, patients who get on this drug, not only surviving longer, avoiding the hospital, but actually maintaining their ability to function and their quality of life for an extended period of time.
... As it relates to HFSA, you know, we will be presenting some more data, particularly from exploratory endpoints at HFSA, and we'll look forward to sharing that in a few weeks, but Dr. Solomon?
Yeah, well, just a brief comment. I mean, with respect to the biomarker endpoints, you know, the fact that you see the magnitude of reduction of NT-proBNP is substantially more than we see with Entresto, for example, in typical heart failure. It's substantially more than we see with SGLT2 inhibitors in typical heart failure. Again, getting to the fact that we have a targeted mechanism here, I think.
In addition to that, when you look at the KCCQ and the six-minute walk benefits, remember, you're looking at means. What we really care about is what percentage of patients - and you will probably see more of this data as they are analyzed - what percentage of patients cross specific thresholds?
These means are of such a substantial magnitude that we expect that we will see that there is a very high percentage of patients who have substantial increases in their measures of quality of life, and that's what they care about very much.
Thank you.
Thank you.
Thank you. We'll take our next question from Lisa Bayko with Evercore ISI. Please go ahead.
Hi. Thanks for taking my question. A question for Dr. Solomon. As you look at this data and sort of think about some of the other treatment options, tafamidis, acoramidis, maybe available soon, there may be another silencer as well. Like, what attributes are you gonna consider when you're kinda choosing which therapy to put a patient on? And then, how do you think it will ultimately break down between sort of tafamidis, vutrisiran, acoramidis, and how many do you think you'd put on combination therapy? Thank you.
Yeah, so that's a difficult question. Why don't we wait and see after the approval of this drug? I mean, I think that this as I said before, the fact that clinicians are gonna have options for these patients, we will obviously consider options in patients who are already not on anything. Getting somebody on a therapy is gonna be incredibly important from my perspective, and then I think there is gonna be room for, as I've said before, combination therapy in this disease.
Yeah, Tolga's been thinking about this question quite hard as well, so maybe, Tolga, you've got some-
Yeah, and obviously, we have an inherent bias here. But maybe what I can defer to is, we've actually looked at a third-party market research by Ipsos. They've done their own cardiology research across U.S. as well as Europe and Japan. And there, you know, based on the available information, and I completely agree with Dr. Solomon, I mean, at the end of the day, the label of what's gonna really define and determine how we can actually promote this product, but based on the available data, more than two-thirds of the physicians do see vutrisiran as a standard of care and first-line product, which essentially confirms what we've been seeing in our own research and our own discussions.
Thank you, Tolga. I think we've got time for one last question.
Yes, certainly. We will take our final question from Jessica Fye with J.P. Morgan. Please go ahead.
Hey, guys. Good morning. Thanks for taking my question. Curious if you could speak to how the six-minute walk and KCCQ results look in the monotherapy population TAF subgroup. Was there consistency there? I think we saw those for the overall population. Curious if you could shine any light on the subgroups. And then I did just have a housekeeping one, which was, can you just confirm what percent of patients were on background TAF by the end of the trial? I think you mentioned earlier, more than half. So it was about 40% at baseline, and then just where did it land at the end after all those TAF drop-in? Thank you.
Oh, I think you could take those last two questions.
Yeah, thanks. So I think the first part of the question was about the effects on six-minute walk test and KCCQ in the monotherapy population. And the short answer is that the results were entirely consistent. We shared this, I believe, in the press release. It was about 32 meters, was the LS mean difference in six-minute walk test and around 9 points on the KCCQ. And similar stability in the median changes over time, reflecting the results in the patient surviving on the trial. So highly consistent results there, and likewise, as we saw in every endpoint that we looked at, the results in the background tafamidis subgroup were similarly consistent.
Good. Okay, well, I think that brings our call to a close, and-
Oh, there was a question on background TAF. Sorry.
Or total TAF.
Total TAF.
Total.
Yes, I apologize. Yes. So there was 40% at baseline, and then 20% in the monotherapy group dropped in. So and that's sort of... So if you add it all up, you kinda get to about 50, 52%.
Yeah.
in the overall population by the end of the study.
Good.
Sorry to interrupt.
Great. No, that's fine. I just wanted to end by saying thanks to everyone for joining us. You've heard on the call that we're absolutely delighted with these results from HELIOS-B. We're looking forward to rapidly moving the regulatory filings forward and assuming regulatory approval, bringing vutrisiran to patients with ATTR amyloidosis with cardiomyopathy. Thank you, everybody, and have a great day.
Thank you. This does conclude today's program. Thank you for your participation. You may disconnect at any time.