Welcome to the Alnylam Pharmaceuticals conference call to discuss results from the APOLLO-B phase III study. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session.
Thank you.
Yes, we are going to have quite a bit.
This conference is being recorded. I would now like to hand the conference over to the company. Please go ahead.
Good morning. I'm Christine Lindenboom, Senior Vice President of Investor Relations and Corporate Communications at Alnylam. With me today on the phone are Yvonne Greenstreet, our Chief Executive Officer, Akshay Vaishnaw, our President, Pushkal Garg, our Chief Medical Officer, and Tolga Tanguler, our Chief Commercial Officer. Also joining us on the line and available for Q&A are Jeff Poulton, our Chief Financial Officer, Rena Denoncourt, Vice President, TTR Franchise Lead, 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 investor page of our website, alnylam.com/events. Now, turning to today's call, as outlined in slide two, Yvonne and Akshay will provide some opening comments. Pushkal will discuss the APOLLO-B study and results in more detail.
Tolga will give an update on next steps with the TTR and ATTR amyloidosis with cardiomyopathy. We will then open the call for your questions. Before we begin, I would like to remind you that this call will contain remarks concerning Alnylam's future actions, 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 filing 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'd like to turn the call over to Yvonne. Yvonne?
Thanks, Christine, and thank you all for joining us. Earlier today, we presented results from our APOLLO-B phase III study of patisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis with cardiomyopathy. These results were presented during a late-breaker session at the 18th International Symposium on Amyloidosis in Heidelberg, Germany. Pushkal will provide an overview of the results shortly. But at a high level, patisiran achieved a statistically significant and clinically meaningful benefit relative to placebo in the six-minute walk test at 12 months, the primary endpoint of the APOLLO-B phase III trial. It also achieved a statistically significant and clinically meaningful benefit on the Kansas City Cardiomyopathy Questionnaire, the study's first secondary endpoint, and a key measure of patients' health status and quality of life.
Collectively, we believe these efficacy results validate the therapeutic hypothesis that RNAi-mediated silencing of TTR has the potential to result in a disease-modifying impact on the cardiac manifestations of ATTR amyloidosis. Further, the patisiran demonstrated an acceptable tolerability profile. In our view, these results strongly support advancing the patisiran towards a supplemental NDA filing, which we remain on track to submit in late 2022, with the goal of obtaining regulatory approval and making this medicine available to patients with ATTR amyloidosis with cardiomyopathy as rapidly as possible. This represents a major step forward in advancing our TTR franchise towards what we believe could represent a multi-billion-dollar opportunity for Alnylam over time, and where we aim to become the global leader in delivering impactful and highly differentiated medicines to patients with all forms of ATTR amyloidosis.
Assuming regulatory approval, we expect the launch of patisiran for ATTR amyloidosis with cardiomyopathy in the US in 2023. Thereafter, we see the potential for further expansion of the TTR franchise. Namely, we look forward to outcomes data from HELIOS-B and the potential approval of vutrisiran for ATTR amyloidosis with cardiomyopathy as well. The positive results of this study of vutrisiran give us further confidence in the potential of vutrisiran to show a positive benefit in the HELIOS-B study in ATTR amyloidosis with cardiomyopathy. And we also anticipate the potential for vutrisiran to address an important rare disease called Stargardt. And ultimately, we look forward to advancing ALN-TTRsc04, which provides the potential for a once-annual dosing regimen.
The bottom line here is that with our leadership, innovation, and commitment to help patients, we believe we have a compelling roadmap to enable impact for patients, substantial growth for Alnylam, and significant value creation for years to come. It's important to emphasize that these positive APOLLO-B results underscore the power of our organic, reproducible, and modular platform and an R&D strategy anchored on human genetics. And as we've discussed before, these elements combine to create an overall probability of clinical success for our programs that greatly exceed historical industry norms. Moreover, we believe this achievement highlights Alnylam's expertise in innovative clinical trial design, a deep track record of conducting trials in the ATTR space, a thoughtful approach to patient selection, conservative pairing of our pivotal studies, and a rigorous approach to implementation, training, and oversight of clinical assessments such as the six-minute walk test.
This is all driven by a corporate culture devoted to a passion for excellence. When it comes to drug development, we pay a lot of attention to thoughtful study design and careful execution. We believe these positive APOLLO-B results also move us further along our path towards achieving our Alnylam P5x25 goals. Alnylam P5x25 is aimed at bringing transformative medicines for rare and prevalent diseases to patients around the world while advancing a robust and high-yielding pipeline of first and/or best-in-class clinical programs from our organic product engine, as well as delivering exceptional financial performance.
As we now advance on patisiran towards an sNDA filing to expand its label, we also look forward to many other near-term growth drivers that can help build Alnylam into a top-tier biotech company, including our expansion into prevalent diseases, as well as our expansion into extrahepatic tissues. In closing, I'd like to take a moment to acknowledge the patients, their families, and caregivers, and the investigators and study staff across the globe who participated in APOLLO-B and made this important medical advance possible. I'd also like to acknowledge all my Alnylam colleagues that went above and beyond and poured over every little detail to ensure trial success. All the details matter. In this case, the team executed flawlessly. With that, I will now turn it over to Akshay to provide some additional context.
Thanks, Yvonne, and welcome, everybody. As most of you are aware, ATTR amyloidosis is a rare, progressive, debilitating, and fatal disease. It occurs when misfolded transthyretin leads to aggregation of TTR monomers into amyloid fibrils that deposit in multiple tissues, including the heart, nerves, and gastrointestinal tract. This pathogenic process often results in multi-system disease manifestations. And today, we'll focus on the cardiomyopathy that occurs in the vast majority of ATTR amyloidosis patients across both the wild-type and hereditary forms of the disease. Let me review again what exactly happens in ATTR amyloidosis patients with cardiomyopathy. On the left-hand side of this slide, you see an illustration of a normal heart. On the right of the slide, an illustration of important changes in the heart when you have extensive amyloid deposits.
As shown in the illustration, cardiac amyloid deposition results in marked thickening of the myocardium, or the muscular walls of the heart, which is in turn accompanied by a reduction in the volume of the heart chambers, which are the cavities that accommodate the blood flowing into and out of the heart. As you can imagine, this thickening of the myocardium results in a heart that is stiff and non-compliant with reduced myocardial elasticity. Accordingly, the heart is unable to relax properly, limiting its ability to fill with blood flowing into the heart. This is known as diastolic dysfunction and is also unable to contract properly, limiting its ability to effectively squeeze blood out of the heart, known as systolic dysfunction. Amyloid deposition in the heart can also impact the conduction system responsible for maintaining a normal heartbeat. The resulting conduction defects frequently manifest in abnormal heart rhythm.
What does a patient experience with this disease? As a consequence of all these pathological changes in the heart, patients experience progressive heart failure, which commonly results in clinical manifestations, including poor exercise tolerance. They can't walk as far. They get breathless, and that can be measured in a clinical trial via the six-minute walk test. However, in turn, the impaired exercise tolerance also reduces the patient's quality of life, which can be assessed by quality-of-life tools such as KCCQ. Furthermore, defects in the conduction system can lead to cardiac arrhythmias, including heart rates that are either excessively slow or dangerously fast. As the disease continues, progressive dysfunction, known as cardiomyopathy, leads to continuously increased symptoms, as I've described, and an increased risk of hospitalization and ultimately death.
It should be noted that the pathophysiology and clinical manifestations of ATTR amyloidosis with cardiomyopathy I've just described are reflected in abnormal findings on laboratory tests that physicians often follow, such as echocardiograms and NT-proBNP, a biomarker of cardiac stress. As you will hear from Pushkal in a moment, the APOLLO-B results with the TTR demonstrate remarkable consistency across the full breadth of cardiomyopathy endpoints assessed. ATTR amyloidosis is a common pathogenic mechanism related to wild-type or mutant TTR production and deposition as amyloid in a range of tissues. It's a single disease caused by TTR that results in a spectrum of clinical manifestations. Alnylam's RNAi therapeutics reduce the production of the disease-causing TTR protein in the liver, thereby reducing continued amyloid deposition and thus halting or possibly improving manifestations of disease.
The concept was first demonstrated in the polyneuropathy of ATTR amyloidosis with ONPATTRO or patisiran, then later with AMVUTTRA or vutrisiran. And the APOLLO-B results have now demonstrated that this is also the case in the cardiomyopathy of ATTR amyloidosis as well. Other treatment modalities interfere with the disease cascade at later points after the TTR protein has been made and is circulating throughout the body. We strongly believe that suppressing the production of both variant and wild-type TTR protein in a highly potent and reversible manner may prove to be the best approach to treating this disease. And we've designed our TTR-targeting RNAi therapeutics to do just that. I'll now hand it over to Pushkal to review the APOLLO-B study design and results in more detail. Pushkal.
Thanks, Akshay. And greetings to all of you from Heidelberg, Germany. I want to apologize in advance because we have been having some technical difficulties in case those of us from Heidelberg drop off. We'll reconnect as quickly as possible. Let me begin by saying it is a real joy and honor for all of us to be sharing these positive results with you. I want to add my thanks to the patients, to the investigators, study staff, and my Alnylam colleagues who all contributed to this successful study. Let me start by reminding you of the design of the APOLLO-B study. The study enrolled 360 patients with ATTR amyloidosis with cardiomyopathy, either the wild-type or hereditary forms of the disease. Patients had to have clinical symptoms or established heart failure as assessed by a physician, and up to 30% of patients were allowed to enter on baseline tafamidis.
Patients were randomized one-to-one to patisiran or placebo with stratification for hereditary versus wild-type ATTR, use of baseline tafamidis, and baseline clinical severity. The primary endpoint was the change from baseline to 12 months in the six-minute walk test, a validated test of a patient's functional capacity. This test is a recognized measure of clinical benefit in heart failure, and we identified this as an endpoint that could allow us to bring patisiran and the potential benefits of an RNAi therapeutic to this patient population as rapidly as possible. The use of six-minute walk test as the primary endpoint was aligned with the FDA. In addition, the study included a number of secondary endpoints to further assess the impact of patisiran on the disease.
These included the Kansas City Cardiomyopathy Questionnaire, which measures health status and quality of life in patients with heart failure, as well as three composite outcome endpoints. The first is a composite of all-cause mortality, frequency of CV events, and change from baseline and six-minute walk test. Next is a composite of all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in patients not on TTR stabilizers at baseline. And the last is a composite of all-cause mortality and all-cause hospitalizations and heart failure visits in the overall population. We also evaluated a variety of exploratory endpoints such as cardiac biomarkers and cardiac imaging. Let's start with a review of enrollment and disposition. A total of 360 patients were randomized one-to-one to receive patisiran or placebo, with 181 receiving patisiran and 178 receiving placebo.
Over 93% of patients in each of these two study arms completed the study, and importantly, we had vital status follow-up on 100% of the patients who entered the study. I'll now turn to the demographics on slide 16. The median age was 76 years, and nearly 90% of the patients were male. 80% of patients had wild-type ATTR, and 20% had hereditary ATTR. 25% of patients were on baseline tafamidis upon entry into the study. Approximately 85% of the patients were NYHA Class 2. You can see the baseline six-minute walk test, KCCQ, and BNP values presented here. Overall, the two study arms were generally matched. Turning to slide 17, you can see that patisiran robustly knocked down serum TTR in patients randomized to the treatment arm.
Specifically, vutrisiran achieved rapid and deep TTR knockdown seen as early as week three, with a mean 86.8% reduction from baseline in serum TTR at month 12. This slide now shows the clinical efficacy results reported in this study on the primary endpoint, specifically the median change from baseline in the six-minute walk test at month 12. As shown here on slide 18, we are very pleased to report that vutrisiran treatment resulted in a 14.693 m median benefit relative to placebo at 12 months using the Hodges-Lehmann estimate of median difference. The median difference between vutrisiran and placebo was statistically significant with a p-value of 0.0162. At 12 months, there was a 21 m decline in placebo patients and an approximately 8 m decline in vutrisiran patients.
Interestingly, this 8 m decline is in the range of the approximately 5 m decline that is normally experienced by normal healthy adults, as documented in multiple research studies. We also ran a sensitivity analysis using a mixed model of repeated measures, or MMRM model, where we looked at the least-squares mean changes. Here, we confirmed the robustness of the primary six-minute walk test results, with patisiran achieving an 18.1 m LS mean benefit relative to placebo at 12 months, with a nominal p-value of 0.0234. Now, turning to slide 20, where I'll review the results of the first secondary endpoint, the change from baseline in the Kansas City Cardiomyopathy Questionnaire overall summary at 12 months.
Here, vutrisiran demonstrated a statistically significant and clinically meaningful benefit in health status and quality of life as assessed by the KCCQ, with a 3.7-point least-square mean difference relative to placebo at 12 months and a p-value of 0.0397. Just as with the six-minute walk test, you see a steady decline in the placebo arm over 12 months. In contrast, the vutrisiran arm shows relatively stable, underscoring the clinical importance of the treatment effect that was observed. Let me now turn to slide 21 to review the results of the secondary composite outcome endpoints at 12 months. Here, it's important to note that while the study was designed and powered for the six-minute walk test and KCCQ endpoints, the size and 12-month duration of the study were not optimized to demonstrate an outcome's benefit, which would require a substantially larger sample size and a longer study.
The first of these outcome endpoints was a composite of all-cause mortality, frequency of CV events, and change from baseline and six-minute walk test. patisiran achieved a non-significant result, demonstrating a patisiran to placebo win ratio of 1.27, with a p-value of 0.0574. Based on the hierarchical testing procedure, formal statistical testing was not performed on the final two composite endpoints. However, the nominal p-values shown here indicate that patisiran would not have achieved a statistically significant benefit relative to placebo on these two endpoints at 12 months. One way to illustrate the potential impact of patisiran on cardiac outcomes is to look at the Kaplan-Meier curve for time to first event of either all-cause hospitalizations, urgent heart failure visits, or death.
As you can see, over the 12 months, the endpoint directionally favored patisiran with a non-significant hazard ratio of 0.839 and a crossover of the curve suggesting a possible flattening of the patisiran hazard rate for these events. Next, we looked at all-cause mortality during the 12-month double-blind period. This endpoint also numerically favored patisiran, with all-cause death observed in 10 placebo patients, or 5.6%, and 4 patisiran patients, or 2.2%, with a nominal hazard ratio of 0.355. Note that for the pre-specified statistical analysis plan, in this efficacy analysis, patients who underwent heart transplantation and/or had ventricular-assist device placement were handled in the same manner as death. Furthermore, deaths due to COVID-19 were excluded from the mortality calculations in the efficacy analysis. Of interest, we also conducted an exploratory assessment of levels of NT-proBNP, a marker of cardiac stress.
We were very pleased to see that at 12 months, vutrisiran demonstrated a benefit in the change in NT-proBNP levels from baseline relative to placebo. Specifically, the adjusted geometric fold change from baseline for NT-proBNP was lower in the vutrisiran group at 1.11 versus 1.38 for the placebo group, indicating a 20% reduction in favor of vutrisiran with a nominal p-value of 1.825 x 10 to the - 5. Now, let me turn to the overall safety summary shown here on slide 25. We were very encouraged by the overall safety profile of vutrisiran in this population of patients with ATTR amyloidosis with cardiomyopathy. The vutrisiran and placebo arms had similar frequencies of adverse events and serious adverse events. AEs reported in 5% or more of vutrisiran patients and seen at least 3% more frequently with vutrisiran compared to placebo were infusion-related reactions, arthralgia, and muscle spasms.
No SAEs occurred 2% more frequently in patisiran versus placebo-treated patients. Now, turning to the mortality data. I've already described for you the efficacy analysis on mortality with 4 in the patisiran arm and 10 in the placebo arm. The results of the safety analysis are consistent. During the study's safety analysis, deaths were reported in 5 patients on patisiran, 2.8%, and 8 patients on placebo, or 4.5%. The safety analysis includes the deaths due to COVID-19 and excludes the two cases of cardiac transplant that occurred in the placebo arm. Now, on slide 26, we'll take a closer look at cardiac safety. Obviously, this is an area of great interest as we're evaluating patisiran in an older population with heart failure. We were pleased to see that the cardiac safety across a number of categories of adverse events numerically favored patisiran.
Specifically, the number of patients who reported any cardiac AE or AEs in the categories of arrhythmias, including atrial or ventricular arrhythmias or conduction defects, or heart failure events were all lower in the patisiran than the placebo arm, which is very encouraging to see. So, in summary, we couldn't be more pleased with the positive results of the APOLLO-B study. patisiran demonstrated a statistically significant and clinically meaningful benefit on functional capacity, as measured by the six-minute walk test, and on health status and quality of life, as measured by the KCCQ, both at 12 months. Further, while the composite outcome endpoints did not achieve significance at 12 months, as was expected due to the short study duration and small sample size, we're encouraged to see that the mortality rates trended in favor of patisiran.
In addition, vutrisiran demonstrated a benefit on the exploratory endpoint NT-proBNP, a biomarker of cardiac stress compared to placebo at 12 months. vutrisiran also demonstrated an acceptable safety profile in APOLLO-B, including no cardiac safety concerns. In fact, the cardiac safety data suggested somewhat lower rates of multiple cardiac AEs in patients who received vutrisiran versus those who received placebo. We believe that the totality of these data firmly validates the hypothesis that TTR silencing by an RNAi therapeutic has the potential to be an effective and safe medicine for treating the cardiomyopathy of ATTR amyloidosis. Moreover, we believe that the fact that the benefits across so many endpoints and assessments were seen to emerge as early as 12 months in a disease as complex as heart failure speaks to the power of vutrisiran's underlying mechanism.
Overall, we believe these results will provide a suitable data package to support consideration for label expansion in the United States pending regulatory review, and the efficacy and safety of patisiran will continue to be investigated in the ongoing APOLLO-B open label extension. I'd also like to announce today that additional data from the 12-month double-blind period of APOLLO-B will be presented at the upcoming Heart Failure Society of America meeting, being held in Washington, D.C., on September 30th through October 3rd. As part of this presentation, we plan to present additional data analyses, including exploratory assessments of echocardiographic parameters, as well as various subgroup analyses, including results in patients with wild-type versus hereditary ATTR and in patients on versus not on tafamidis at baseline.
Let me close by once again thanking the patients, patient families, investigators, study staff, and collaborators for their participation in the APOLLO-B phase III study. We could not have achieved this remarkable milestone without the hard work and dedication of countless people, not the least, my Alnylam colleagues. With that, I will now turn it over to Tolga, who joins me here in Heidelberg. Tolga.
Thanks, Pushkal, and greetings from the ISA. These are indeed exciting times for patients living with ATTR amyloidosis with cardiomyopathy, whom we hope will have the opportunity to potentially benefit from vutrisiran in the future. As Yvonne mentioned, and consistent with our previous guidance, we now plan to engage with the FDA and advance ONPATTRO toward a supplemental NDA filing in the U.S. by year-end while evaluating filings in other regions.
Assuming approval of the sNDA, we expect to launch ONPATTRO into the cardiomyopathy setting in the U.S. in 2023. Treatment of this disease provides the potential for a significant and growing commercial opportunity for Alnylam. Over 250,000 patients globally are living with ATTR amyloidosis with cardiomyopathy, and patients continue to experience significant unmet medical needs, including decline in functional capacity and quality of life, as well as hospitalizations and death. Given the advancements made in the last decade, there has been a growing disease awareness among physicians and patients and wider utilization of diagnostic tools, including less invasive methods. We are encouraged that this has increased the diagnosis of this devastating disease. However, we believe there continues to be significant room for growth and improvement in diagnosis, as well as many patients even today experience a long journey from the time of initial symptom onset to confirmative diagnosis.
Importantly, our market research suggests there is a significant unmet need remaining among patients who are experiencing an inadequate response to currently available treatments and among patients who cannot access available treatments. We believe patients need additional treatment options that offer the potential for an improvement in functional capacity and quality of life. Improved disease awareness and diagnosis, as well as the availability of new treatment options like vutrisiran for this patient population pending regulatory approval, are greatly needed and will be key factors in driving the potential commercial opportunity in this space. We have been and continue to be deeply committed to succeed in ATTR amyloidosis and understanding the unique needs of this community. We established market leadership in hATTR amyloidosis with polyneuropathy by building scalable capabilities that we intend to leverage as we expand into the potential treatment of a significantly larger patient population.
We have and will continue to implement a strong patient-centric approach in serving the growing patient needs. We believe Alnylam is well-positioned to make this potential therapy option available to patients as we've built our footprint and capabilities and been engaging with physicians, patient advocacy organizations, healthcare systems for many years to understand the disease and have gained insights that are helpful for engagement, advocacy, education, and for aiding speed and accuracy of diagnosis. We believe we are also well-prepared with our manufacturing and supply chain to meet the needs of this expanded patient population. Assuming label expansion, we are working with the payer community to ensure the patients can achieve rapid and affordable access following approval based on our patient access philosophy, including potential value-based agreements to ensure good clinical value for reimbursement is provided for ONPATTRO in ATTR amyloidosis with cardiomyopathy.
As we think about the full picture of the ATTR franchise as it stands today, over the past four years, we've established a strong foundation in ATTR amyloidosis with polyneuropathy based on the landmark APOLLO study with patisiran and the more recent HELIOS-A study with vutrisiran, resulting in our U.S. launch of AMVUTTRA in June. Today, we are potentially on the cusp of entering the ATTR amyloidosis with cardiomyopathy population pending regulatory review of today's APOLLO-B results and subsequent approval in the U.S. Given the existing unmet need we see every day in ATTR amyloidosis, this urgency has been important to enable us to provide a viable treatment option for patients. The APOLLO-B study represents the potential for a swift path to entering this segment of the market with the very first RNAi therapeutic to show potential benefit across a spectrum of clinically impactful disease manifestations.
Ultimately, we envision the HELIOS-B study of vutrisiran expected to demonstrate a robust efficacy and safety profile with outcomes data and a highly attractive product profile will potentially provide a transformative treatment option for patients assuming positive results and regulatory approvals. With the positive APOLLO-B results and our ongoing HELIOS-B trial, we believe Alnylam is well-positioned to make potentially two transformative medicines for the treatment of ATTR amyloidosis with cardiomyopathy available. I could not be more excited about the opportunity in front of us. With that, I will now turn it over back to Christine to coordinate the Q&A. Christine.
Thank you, Tolga. Operator, we will now open up questions. As a reminder to those dialed in, we would like you to emphasize that we will be fielding one question each from each analyst. We would ask you to please get back in the queue if you have additional questions.
As a reminder to ask a question, please press star one one on your telephone. Please stand by while we compile the Q&A roster. Our first question comes from David Lebowitz with Citi. Your line is now open.
Thank you very much for taking my question. I guess the main question I have is regarding how to view the data in context of the competition. People will look at the 14.7 m improvement versus placebo on six-minute walk. They'll also look at the outcomes curve, which at this point shows a slight but seemingly clear separation. How does that mean as far as implications for how ONPATTRO might compete with tafamidis in addition with the follow-on AMVUTTRA, what that data might mean for that therapy?
Thanks, David. That's a great question. Look, we're clearly very pleased with the results from APOLLO-B, and vutrisiran is clearly providing a clinically meaningful benefit, and we believe the totality of the data that we have delivered creates a compelling profile for vutrisiran in patients with TTR amyloidosis with cardiomyopathy. Maybe I'll ask Pushkal just to provide some additional color on his perspective of the data, and then I'll turn it over to Tolga to respond to the question with respect to the marketplace. Pushkal?
Thanks, Yvonne, and thanks, Dave, for your question. Look, maybe I think what you're getting at is what's the clinical meaningfulness of these data, so let me maybe try and give a little perspective on that based on what we're hearing from investigators here at the ISA conference. What people care about, what patients and physicians care about, is how they feel, function, and survive.
And if you were a placebo patient in this study, in the course of just 12 months, your walking distance would have declined by over 20 meters. Your quality of life would have declined by three and a half points. You would have had about a 40% increase in your NT-proBNP. You would have experienced a 5.6% rate of mortality, and you would have had about a 27% rate of cardiac arrhythmias. That's what was observed in placebo-treated patients in this study. And I think what is striking is that, in contrast, and what the investigators have noted, is within a relatively short period of time of 12 months, we are seeing that the six-minute walk test has been substantially ameliorated with that decline so that it approximates the decline that's seen in healthy adults, which is about a five-meter decline per year.
You're seeing that the KCCQ has been flattened such that quality of life and health status has been preserved in these patients. We're seeing numerical trends in terms of a favorable impact on mortality. And we are seeing that the rate of cardiac arrhythmias, among other cardiac adverse events, is being reduced, and we're seeing NT-proBNP reduced by about 20%. So I think what we're seeing looks to be a very clinically important benefit and clinically meaningful benefit, and that's what the investigators that we've been talking to here at the ISA have been noting as well in their comments, and I think what Dr. Maurer was elaborating on in his plenary presentation. So I'll turn it over to Tolga to maybe expand on the commercial implications.
Yeah, thanks, Pushkal. Just to build on what Pushkal said, first of all, I would caveat what I'm about to say with the fact that we don't have a label yet. But here's how I would really think about vutrisiran's potential in several dimensions. First of all, this is not a zero-sum game. Cardiomyopathy is a large unmet market, and with many patients yet to be diagnosed and treated, and the prevalence is several-fold larger than polyneuropathy. It's also a growing market, especially if you were to consider the evolution of this category in the U.S. since 2018.
The diagnoses have improved by tenfold, yet 80% of CM patients remain untreated. Therefore, there is a significant unmet patient need. Secondly, we know that in the ATTR-ACT study, patients still showed progression across multiple measures, including six-minute walk test and outcomes. And therefore, we certainly see room for multiple therapeutics in this space.
Not to mention, based on our research, we know and therefore we certainly see room for multiple therapeutics in this space. Not to mention, based on our research, we know that patients who are on this treatment experience inadequate response, some patients, to currently available treatments. Also, there's a group of patients who cannot access the available treatment options. Lastly, focusing on patisiran, we really believe the totality of the APOLLO-B data and will be very attractive options for both patients and physicians. We have a compelling product profile with statistically significant differences, as Pushkal indicated, and clinically meaningful impact on primary endpoint as well as preservation of quality of life as measured by KCCQ. We're very excited about the space that it could create.
Now, to answer your other question, obviously, we are running the HELIOS-B trial, a longer and a larger study looking at the outcomes, and we're excited about vutrisiran, which is our first foray into this very important segment.
Thank you very much for taking the question.
Thanks. Next question, please.
Please stand by for our next question. Our next question comes from Ritu Baral with Cowen. Your line is now open.
Hello, everybody. Good morning. Hi, good morning, guys. Thanks for taking the question. I just wanted to ask a little bit more about more detail around patient demographics. There's been a lot of discussion about what the background hATTR patients look like versus, I guess, the untreated patients. Can you talk a little bit about six-minute walk in these patient populations at baseline, not the response data that may be at HFSA?
Do the ATTR background patients, do they end up being relatively sicker or really in line with the other population? And how might that affect interpretation of data? Thanks.
Thanks, Ritu. I mean, clearly, as you pointed out, we're going to be presenting further data to provide more information around the various endpoints. But perhaps, Pushkal, you could answer the question about patient demographics and just provide some of your perspective on the patients that we've enrolled into the APOLLO-B study.
Sure. Thanks, Yvonne. Thanks, Ritu, for your question. Look, I think in general, I think the patient population that we enrolled in the overall study is really what we were targeting. As you know, we purposely learned from the ATTR-ACT study and sought to enroll a population, excluding the sickest of the sick, who may not have a chance to benefit in the course of a 12-month study.
And we're really pleased that we were able to see, unfortunately, the decline in the placebo patients, but that there was a substantial treatment effect across all the measures, as I just mentioned. I don't have. We'll be presenting more data on the subgroups at the HFSA meeting, Ritu, and you'll probably get a little bit more. I would say, in general, you're going to find that those patients weren't dramatically different, although obviously, patients may have had diagnosis a bit earlier if they've already tried tafamidis before they entered the study.
Thanks, Pushkal. And Ritu, probably just worth reminding everybody that actually it's kind of less than five weeks since we presented top-line data. And clearly, we're continuing to kind of work through the very rich data set that we have. But thanks for the question, Ritu. Next question.
Please stand by for our next question. Our next question comes from Paul Matteis with Stifel. Your line is now open.
Hi, this is James on for Paul. Thanks for taking our question and congrats on the full data. Maybe just a quick one on the hazard ratios. The hazard ratio for all-cause mortality and hospitalizations was higher than the hazard ratio just for mortality. So can you provide any color on kind of the directionality of the hospitalization data there? Was there any trend in favor of drug? Any color on the kind of discrepancy between those two hazard ratios would be great. Thanks so much.
And Pushkal, I think we can hand that one right over to you.
Thanks, Yvonne. Yeah, James, look, in response to your question, I guess just a reminder that APOLLO-B wasn't designed for outcomes. It was focused on the six-minute walk test and the KCCQ. It would be a mistake to overinterpret some of those hazard ratios, particularly when we start looking at subgroups, etc., and making inferences. I think what I would say is we're really encouraged when we look at a couple of different parameters that get to the broader aspect of your question, which is A, the numerical trends in mortality.
B, when you look at those time-to-event curves. Again, to be borne out with longer and larger studies, but the fact that you see a steady hazard rate in the placebo arm and potentially some flattening in the patisiran arm with the crossover is encouraging. And third, when you look at the cardiac safety events, right, those are all types of events that ultimately lead to hospitalization and poor outcomes for patients.
And when you see numerical trends favoring the drug in terms of arrhythmias, heart failure events, etc., I think that's encouraging. So I think all of this is quite encouraging in terms of validating the hypothesis and the potential beyond what we're seeing today in terms of favorable impacts on quality of life and functional status to actually portend favorable outcomes in the future to be borne out with longer and larger studies.
Makes sense. Thanks so much.
Please stand by for our next question. Our next question comes from Salveen Richter with Goldman Sachs. Your line is now open.
Good morning. Thanks for taking my question. Could you just speak to the curves here and why we're seeing the separation occurring at about six months on six-minute walk test?
So could you repeat your question, Salveen? I heard something about curves separating the six-minute walk test, but I didn't hear the first part of your question.
Sure. Sorry about that. Just the time period that it takes for separation, just the fact that it takes about six months before you're seeing the separation and what that means here, just overall why that's playing out.
Got it. Pushkal, I think did you hear the question?
I did, Yvonne. Thanks. Yeah. And thanks, Salveen. Look, six months was the first time point that we assessed. And so I think we're again, Salveen, I think this is the fact that we were able to demonstrate this result in the course of the 12 months and the separations occurring as it is, I think is really quite positive. But six months was the first time point.
Okay. Thanks, Salveen. Next question, please.
Please stand by for our next question. The next question comes from Maury Raycroft with Jefferies. Your line is now open.
Hi, good morning. Thanks for taking my question and congrats on the update. I'm wondering if you can talk more about how FDA views the NT-proBNP data and how much weight those data are going to carry in FDA's review of the 12-month data that you have. Do you plan on submitting a cut of the proBNP data from the open label extension crossover population in your filing?
Yeah. Thanks for that question, Maury. I mean, clearly, we believe that the results and their totality support us moving forward with the sNDA, and as Pushkal said, we're moving expeditiously to try to get this medicine to patients as soon as possible, and of course, we aligned with the FDA on study design and endpoints, and we now believe we've got a very robust package.
But Pushkal, maybe you would like to take the specific question about the importance of NT-proBNP.
Yeah. Thanks, Yvonne, and thanks, Maury. I think not much to elaborate based on what Yvonne has said. We're going to present the totality of these data to the regulators, and they will review all of them. And I'm sure that they will look across the totality of all that, not just the efficacy, but the safety data to make their assessment in terms of benefit-risk. They certainly, I think, NT-proBNP is certainly recognized as an important marker for clinical severity. It's followed by clinicians, and I'm sure the regulators will pay attention to that. But I think they'll be looking at the totality of the data as they make their assessment.
Got it. Thank you.
Next question.
Please stand by for the next question. Our next question comes from Luca Issi with RBC Capital Markets. Your line is now open.
Oh, great. Thanks so much for taking my question and then congrats on the update here. Maybe a quick one, Pushkal, if I may. I think six-minute walk on page 18. I think in the footnotes, you're actually imputing some data when there's some patient dropout. Is this the way the FDA look at it? How does the p-value look like if you do not impute data for dropouts? Does the p-value remain static? Any color there would be great. Thanks so much.
Luca, so thanks for your question. Look, I guess what I would say is that my staff colleagues are going to keep me honest here, but we've pre-specified a statistical analysis plan that's inordinately detailed. It goes through the analytic methods as well as the imputation methods for missing data.
Obviously, how you handle missing data is a very, very important and complex part of trial analytics. The statistical analysis plan here, both for the primary analytic method, the Wilcoxon rank-sum, as well as the MMRM that was done as a sensitivity, all of that was pre-specified in the SAP, which was reviewed by the FDA and the health authorities. So this is kind of the robust data package. And so this was all pre-specified, and you're seeing the results that come from that.
And Pushkal, I'd just add to that, as you described earlier in the call, that we did a sensitivity analysis, and the MMRM also is highly supportive. So I think, Luca, it's not a question of imputation. These are very deep and consistent data.
And we should also remember that it's not the first time that either patisiran or vutrisiran have shown impacts on walking tests. I mean, we have prior data on 10-metre walk tests, for example, for those two drugs. So this is on the backdrop of a lot of support for the hypothesis now, in this case, now randomized double-blind placebo-controlled study that reduction of TTR with TTR RNAi therapeutics has very important effects in ATTR.
That's excellent. Actually, thank you.
Next question, please.
Please stand by for our next question. The next question comes from Gena Wang with Barclays. Your line is now open.
Thank you for taking my questions. I have one question regarding slide 22. When we look at the curve, it seems like the curve before month six seems to be in the opposite direction. Any thought there?
I do understand it's a very small event and early phase, but any thoughts there why the curve is on the opposite direction? And then for this slide, if we exclude DASSs, how's the curve look like?
Yeah.
I think that's yeah.
Sorry, Yvonne. Go ahead.
No, no. So I think that's another one for you with providing some more color on slide 22.
Yeah. And maybe I can turn that over to John Vest, actually, who's here, who's overseeing the program. John?
Yeah. Thanks so much for the question. The short answer is we believe this is likely a chance occurrence. We've looked very carefully at all of these events. This is a small number of hospitalizations in the patisiran arm that were the majority of which were related to heart failure, the expected type of events that we see in this patient population.
And I think what's important, as you've alluded to, as we look at these curves over time and the events begin to accumulate, we see what appears to be a flattening of the curve in the patisiran arm, whereas in the placebo arm, we see steady decline.
Thanks, John.
Very helpful.
Very good. Next question, please.
Please stand by for our next question. The next question comes from Jessica Fye with JP Morgan. Your line is now open.
Hey, guys. Good morning. Thanks for taking my question. Thinking about those event curves for all-cause death and all-cause hospitalizations and urgent heart failure visits, can you talk about what those curves look like in the tafamidis progressor population? And if you don't want to speak to that ahead of HFSA, can you talk about how you think about the clinical relevance of the magnitude of separation you saw on NT-proBNP?
It looks like that delta is widening over time. If we were to project forward, would you expect that pattern to continue?
Did you get all of that?
I did. I did. Thanks, Yvonne. So maybe I'll handle the first part, and then I'll turn it over to John, who's a cardiologist and can speak to the NT-proBNP. But on the curves, yeah, Jessica, look, at this point, we have a limited amount of time, so we really focus on the high-level primary outcomes, etc., from the study. We'll be presenting more data at HFSA, including some of the subgroups, and so maybe we'll hold your question till then, and we can readdress it then, but John, do you want to talk about the clinical significance of the NT-proBNP?
Yeah. Thanks for that, for the question. Look, we really are very excited about this NT-proBNP data, and we do think it's certainly meaningful. As you can see in the curves in the placebo arm, these patients are clearly steadily progressing with regard to NT-proBNP, and that's been largely mitigated in the patisiran arm. We know that this is an important predictor. This has been shown in numerous studies in heart failure and specifically in TTR amyloidosis, and NT-proBNP indeed is a part of multiple recognized staging systems that are used in the field. So we really are very encouraged about this and certainly found it to be very meaningful. I don't know, Pushkal, if you have anything you want to add.
No, I'd just add that we've shared these data with the investigators as well in the last couple of days, and I think all of them have commented on the importance and the significance of the NT-proBNP data. So another data. And John, just to add to what you're saying about BNP, these changes we anticipate would be durable because of the data we saw at 18 months in the cardiac subsets of the original APOLLO study, in the cardiac subset of the HELIOS-A study. So I don't know whether you want to elaborate further, but these are exciting changes, and we do expect them to be durable.
Absolutely.
I think we can go on to the next question.
Please stand by for our next question. The next question comes from Joseph Stringer with Needham & Company. Your line is now open.
Hi. Thanks for taking our questions. We have one on KCCQ. Just curious if you can comment on the clinical meaningfulness of the 3.7 difference there. And what's been the initial feedback from physicians and the relevance of that treatment difference relative to, say, some of the endpoints such as six-minute walk tests? Thank you.
That's a great question. I mean, maybe we'll start with Pushkal and the clinical meaningfulness of the improvements that we saw with vutrisiran and the KCCQ compared to placebo, and then get some perspectives from Tolga on the relevance to physicians of what we believe is an important endpoint here. And then actually, I don't know if you want to put things into perspective at the end, particularly when we think about the data that we've seen with vutrisiran from a comparative perspective. So Pushkal, do you want to start?
Sure. Thanks for the question. I think maybe a couple of points. I'll probably reiterate a little bit of what I said in the first response, which is what we've noted and what I think the investigators here have noted is when you look at the totality of the data and what the placebo patients are experiencing, they're experiencing a decline in functional capacity, a decline in quality of life. They're experiencing an increase in NT-proBNP, elevated mortality, and fairly frequent occurrence of cardiac arrhythmias and other cardiac adverse events. And all of those with patisiran are being ameliorated. You're seeing six-minute walk tests returning close to the age-related decline that's experienced in healthy individuals. And to your point around KCCQ, you're actually seeing a full preservation of quality of life without a decline in that treated population over the course of 12 months.
Likewise, favorable impacts on NT-proBNP, trends favoring the drug in mortality and in cardiac adverse events. The other point I'd mention is that if you look at other drugs that are developed in heart failure, actually, this effect size is larger than many of those other drugs that we've seen, for example, with Entresto, dapagliflozin, and ivabradine in much larger studies. So I think that also points to the clinical significance of what we're seeing here, both specifically on KCCQ and the totality of data that we're seeing across a whole series of endpoints that point to the impact of patisiran. Tolga?
Yeah. I mean, just to add, Pushkal summarized it perfectly. Specific to the KCCQ, the potential of preservation of quality of life really matters to patients. And based on our research, also a clinical cardiologist, because these patients really do suffer for years before they get their diagnosis. And throughout their treatment, the quality of life and feeling better is a huge driver of both adherence and success of treatment, and obviously, combined with other related endpoints, makes a big difference. So we're really excited at the fact that we actually have the potential of preserving the quality of life per the KCCQ.
Yeah. And Pushkal, I thought you summarized the totality of the data very well, which fleshed out the importance of KCCQ observation. I've also emphasized across our various studies with RNAi therapeutics for TTR, the consistency of the data we see across various endpoints. And I think that, as you said, then strengthens the hypothesis of TTR reduction helping patients.
The other thing I would add, and comparing across studies, of course, is fraught with difficulty, but if we look at other studies in the ATTR space, I'm really encouraged by the proportionate change in six-minute walk tests with patisiran relative to placebo. In this study, it's a 62% improvement at 12 months. I'm really pleased with the stabilization. I mean, the line looks flat for KCCQ for patisiran versus the decline in placebo. And I think within this study, these points really stand out in terms of the impact this drug is likely having on patients and also compares very favorably to other drugs, we think. Although difficult to compare across studies, and this was not a head-to-head study, but I'm just trying to understand the perspectives on the data in different ways.
Really helpful. So I think we're getting to our last question.
Please stand by for our next question. The next question comes from Matthew Harrison with Morgan Stanley. Your line is now open.
Great. Good morning. Thanks for fitting us in. I just wanted to follow up. Obviously, you had previously talked about potentially conducting an interim analysis on HELIOS-B. I'm just curious, now that you've had some more time with the APOLLO-B data, how you're thinking about that potential interim and thoughts around that interim. Thanks.
Thanks. That's great. I mean, clearly, as I said earlier, we only got these data five weeks ago, so we're continuing to consider our approach with respect to an interim analysis. We'll inform you on that decision in due course. But I think worth emphasizing that we're really pleased with the enrollment in HELIOS-B, and obviously, we'll be getting those results sooner than anticipated.
And that does reduce the benefits that we see by any potential interim analysis. Good. So I think we've come to the end of the call, and I just want to thank everybody once again for joining us today. As you've heard from everybody on the call, we could not be happier with these results on APOLLO-B, and we look forward to advancing vutrisiran and sNDA filing, as well as sharing further study results of the HFSA meeting at the end of this month. So thank you, everybody, and have a great day.
This concludes today's conversation. You may now disconnect.