Welcome to the Alnylam Pharmaceuticals conference call to discuss the positive top-line results from the APOLLO-B Phase 3 study. At this time, all participants are on a listen-only mode. After the speaker presentation, there will be a question-and-answer session. To ask a question during the session, you need to press star 11 on your telephone. Please be advised that today's conference is being recorded, and when I'd 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 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, Vice President of Clinical Research. For those of you participating via conference call, the slides we've made available via webcast can also be accessed by going to the investment 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. First, we'll discuss the Apollo B study and top-line results in more detail.
Tolga will give an update on next steps with KeySprint and ATTR amyloidosis with cardiomyopathy, and 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 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 the 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 cannot be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I will now turn the call over to Yvonne.
Yvonne?
Thanks, Christine, and thank you, everyone, for joining us this morning. As you saw in our press release, we're announcing positive top-line results from our APOLLO-B Phase 3 trial of patisiran in patients with ATTR amyloidosis with cardiomyopathy. Pushkal will go through our results in a minute, but let me start by saying that we could not be happier with these results and what they mean for patients, physicians, families, caregivers, everyone in the ATTR amyloidosis community. Moreover, we believe these results show the true power of the RNAi mechanism of action by using a natural process to silence the production of the disease-causing TTR protein. We have achieved a disease-modifying impact on the cardiac manifestations of ATTR amyloidosis.
Patisiran met the primary endpoint of change from baseline to month 12 in the six-minute walk test relative to placebo, as well as the key secondary endpoint of change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire overall score . In addition, the patisiran demonstrated an encouraging safety profile. Pushkal will be providing more data on the secondary endpoints later in this presentation. And as Tolga will touch on later, the APOLLO-B data support the potential for Onpattro, assuming regulatory approval of supplemental NDA, to become a welcome treatment option for patients living with ATTR amyloidosis with cardiomyopathy. As you know, over the past few years, we have observed the emergence of a growing body of clinical evidence supporting the potential of RNAi therapeutics as a highly impactful therapeutic modality for the treatment of ATTR amyloidosis with cardiomyopathy.
Now we have the first results from a randomized placebo-controlled Phase 3 study of an RNAi therapeutic in this disease setting, along with a recent FDA approval and U.S. launch of Amvuttra for patients with hATTR amyloidosis with polyneuropathy. These APOLLO-B results provide further support for the expansion of Alnylam's TTR franchise into what we believe could represent a multi-billion-dollar opportunity for Alnylam over time. Consistent with our previous guidance, we now plan to engage with regulators and advance Onpattro towards a supplemental NDA filing by year-end. Assuming regulatory approval, we expect the launch of Onpattro in ATTR amyloidosis with cardiomyopathy in the U.S. in 2023. Thereafter, we see the potential for further expansion of the TTR franchise. Namely, we look forward to outcomes data from the HELIOS-B study and the potential approval of patisiran for ATTR amyloidosis with cardiomyopathy as well.
Certainly, the positive results of this study of the patisiran give us further confidence in the potential of the vutrisiran to show a positive benefit in the HELIOS-B study in ATTR amyloidosis with cardiomyopathy, and we also anticipate the potential for the vutrisiran to address an important rare disease called Stargardt and ultimately ALN-TTR-SC04, 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 plan to enable impact for patients, substantial growth for the company, and significant value creation for years to come. With that, I will now turn it over to Akshay to provide some additional context on today's news.
Thanks, Yvonne, and welcome, everybody. We're indeed thrilled with these top-line results from our APOLLO-B Phase 3 study. As most of you are aware, ATTR amyloidosis is a rare, progressive, debilitating, and often fatal disease. It occurs when misfolded transthyretin leads to aggregation of transthyretin amyloid fibrils that deposit in multiple tissues, including the heart, nerves, and GI tract. This pathogenic process often results in multi-system disease manifestation. And today, we will focus on the cardiomyopathy that occurs in the vast majority of ATTR amyloidosis patients across both the wild type and inherited forms of the disease. What exactly happens in ATTR cardiomyopathy? On the left-hand side of this slide, you see an illustration of a normal heart, and on the right, 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 in turn is 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, which is known as diastolic dysfunction, and is also unable to contract properly, limiting its ability to effectively squeeze blood out of the heart, which is known as systolic dysfunction. Amyloid deposition in the heart can also impact the conducting system responsible for maintaining a normal heartbeat.
The resulting conduction defects frequently manifest as an 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 with a validated assay, 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 excessively slow or dangerously fast. As the disease continues, progressive heart dysfunction, known as cardiomyopathy, leads to continuously increasing 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 that I've just described are reflected in abnormal findings on laboratory test tools that physicians often follow, such as echocardiograms and NT-proBNP, with the latter being a biomarker of cardiac stress. 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 improving the manifestations of the disease. This concept was first demonstrated in the polyneuropathy of hATTR amyloidosis with Onpattro or patisiran, and then later with Amvuttra or vutrisiran, and has now been demonstrated in 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 of treating the disease, and we've designed our TTR-targeting RNAi therapeutics just to do just that. I'll now hand it over to Pushkal to take you through the APOLLO-B study design and top-line results in more detail. Pushkal.
Thanks, Akshay, and good morning, everyone. It is a real joy and an honor to be sharing these positive top-line results with all of you. I want to add my thanks to the patients, and to the investigators, study staff, and my Alnylam colleagues who all contributed to the successful Phase 3 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. They were randomized one-to-one to patisiran or placebo. The primary endpoint was the change from baseline to 12 months in the six-minute walk test, a clinically validated assessment 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.
In addition, the study included a number of secondary endpoints, which I will describe in more detail in a moment, and exploratory endpoints such as cardiac biomarkers and cardiac imaging. Let me now turn to reviewing the top-line results from the study. Please note that we are sharing top-line data only today, and as is our practice, we will share the full data at a medical meeting. In this case, I'm happy to announce that the complete results will be shared at the upcoming meeting of the International Symposium on Amyloidosis in Heidelberg, Germany, on September 8th. This table shows the pre-specified primary and secondary endpoints for the APOLLO-B study. In addition to the primary endpoint of the six-minute walk test, we included several secondary endpoints encompassing several clinically meaningful readouts to further assess the impact of patisiran on this disease. These are all listed here.
The first secondary endpoint was the Kansas City Cardiomyopathy Questionnaire, a validated measure of quality of life in patients with heart failure. After the KCCQ, we included three composite endpoints of cardiovascular outcomes. The first is a composite of all-cause mortality, frequency of CV events, and change from baseline for the 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. This endpoint was added to the statistical analysis plan prior to database lock, as it was hypothesized that this larger subgroup might have had the potential to demonstrate an outcomes benefit in this relatively short study. The last is a composite of all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in the overall population.
Now, it's important to note the study was designed and powered for the six-minute walk test and KCCQ endpoints. However, the size and 12-month duration of the study were not optimized to demonstrate an outcome's benefit, which would have required a significantly larger sample size in a longer study. As such, we had insufficient power for these outcome endpoints. I am very pleased to report positive results from APOLLO-B, which did meet its primary endpoint. Indeed, patients who received patisiran showed a significant improvement in change from baseline in the six-minute walk test at 12 months relative to patients who received placebo with a P of 0.0162. Patisiran-treated patients also demonstrated improvement in quality of life relative to their placebo-treated counterparts, as measured by the KCCQ with a P value of 0.0397.
The next secondary endpoint in the hierarchy is a composite of all-cause mortality, frequency of CV events, and change from baseline in the six-minute walk test. Patisiran achieved a non-significant result relative to placebo on this endpoint with a P value of 0.0574. As a result, and based on the pre-specified 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 endpoints. Now, let me turn to the top-line safety results. We're also very encouraged by the overall safety profile of patisiran in this population of patients with ATTR amyloidosis with cardiomyopathy. The patisiran and placebo arms had similar frequencies of adverse events and serious adverse events.
Adverse events reported in 5% or more of patisiran patients and seen at least 3% more frequently with patisiran compared to placebo for infusion-related reactions, arthralgia, and muscle spasms. No serious adverse events occurred 2% more frequently in patisiran versus placebo-treated patients. Now, turning to the mortality data. In the safety analysis, death was reported in five patients on patisiran for 2.8% and eight patients on placebo for 4.5% during the 12-month double-blind period. In addition, an all-cause mortality efficacy analysis was performed in accordance with the predefined statistical analysis plan. That analysis plan excluded death due to COVID-19 and also treated cardiac transplant as a death event consistent with other studies in the field. In this all-cause mortality efficacy analysis, the number of deaths also trended in favor of patisiran-treated patients, with four in the patisiran arm for 2.2% and 10 in the placebo arm for 5.6%.
In sum, we are very pleased to see the positive and clinically meaningful results on the six-minute walk test and KCCQ and an encouraging safety profile. We believe this will provide a suitable data package to support consideration for label expansion in the U.S. pending regulatory review. We're also very excited for patients who appear to have benefited from patisiran in the study and for the rest of the community of patients with ATTR amyloidosis with cardiomyopathy. We hope we'll have the opportunity to potentially benefit from this medicine in the future. As Yvonne mentioned, and consistent with our previous guidance, we now plan to engage with regulators and advance Onpattro towards a supplemental NDA filing in the U.S. by year-end and evaluate filings in other regions thereafter. Assuming approval of the sNDA, we expect to launch Onpattro into the cardiomyopathy setting beginning in 2023.
In the meantime, we look forward to presenting detailed results from the APOLLO-B study at the 18th meeting of the International Symposium on Amyloidosis in Heidelberg, Germany, on September 8th. In addition, we continue to advance vutrisiran in the HELIOS-B outcome study, with top-line results expected in early 2024. We also believe these positive data from APOLLO-B add further support for continued confidence in HELIOS-B as we build towards the future of our TTR franchise with vutrisiran, and with that, I'll now turn the call over to Tolga.
Tolga, thanks, Pushkal. We are excited about the positive results observed in APOLLO-B and what this potentially represents for patients with ATTR amyloidosis with cardiomyopathy. Treatment of this disease provides 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 a decline in functional capacity and quality of life, as well as hospitalization 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 confirmatory diagnosis. Importantly, our market research suggests that there is a significant unmet need remaining among patients who are experiencing an inadequate response to currently available treatment and among patients who cannot access the available treatment option. 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 patisiran 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 deeply committed to succeeding 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 patients' needs. Alnylam is well-positioned to make this potential therapy option available to patients as we have built our footprint and capabilities and been engaging with physicians, patient advocacy organizations, and healthcare systems for many years to understand this disease, have gained insights that are helpful for engagement, advocacy, education, and for aiding speed and accuracy of diagnosis. We believe we are 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 that patients can achieve rapid and affordable access following approval based on our patient access philosophy, including potential value-based agreements to ensure good value for reimbursement is provided for Onpattro in ATTR amyloidosis with cardiomyopathy. As we think about the full picture of the TTR franchise as it stands today, over the past four years, we've established a strong foundation in hATTR amyloidosis with polyneuropathy based on the landmark APOLLO study with patisiran and the more recent HELIOS-B 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.
Given the existing unmet need we see every day in ATTR amyloidosis, this need has been an important part for patients to provide a viable treatment option. 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. Finally, I'd like to join my colleagues in expressing how excited I am about the APOLLO-B results. It is truly a remarkable achievement for Alnylam, for RNAi therapeutics, and most importantly, for the ATTR patient community.
With these exciting top-line 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. With that, I will now turn the call back to Yvonne for additional remarks. Yvonne?
Thanks, Tolga. An important point to make is that these positive APOLLO-B results underscore the power of an organic, reproducible, and modular platform and an R&D strategy anchored on human genetics. As we've discussed before, these elements combine to create an overall probability of clinical success for our programs that greatly exceeds historical industry norms. Moreover, this achievement highlights Alnylam's expertise in 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 assessments such as the 6-minute walk test. This is all driven by a corporate culture that is devoted to a passion for excellence. When it comes to Phase 3 trial design and drug development in general, we sweat the small stuff.
These positive APOLLO-B results 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 all best-in-class clinical programs from our organic product engine, as well as delivering exceptional financial performance. As we now advance Onpattro towards an sNDA filing to expand its label, we also look forward to many other near-term growth drivers that could help build Alnylam into a top-tier biotech company, including our expansion into prevalent diseases as well as our expansion into extrahepatic tissues. In fact, these growth drivers are associated with many catalysts we're expecting later this year.
These include clinical data readouts from our prevalent disease programs in NASH and gout, as well as initial human data from our first CNS program, ALN-APP, which, if positive, could unlock significant value potential not just in Alzheimer's disease, but in other neurodegenerative diseases as well. 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. It shouldn't go unmentioned that the majority of the study results we're reporting today were generated during the COVID-19 pandemic, where our entire development organization and our clinical operations team, our CRO partners, and study sites successfully enabled study continuity and integrity.
In that spirit, I'd like to acknowledge all my Alnylam colleagues that went above and beyond and pored over every little detail to ensure trial success. Commitment to people, passion for excellence, and innovation and discovery are at the heart of what we do at Alnylam. In fact, this was illustrated just yesterday by Alnylam's ranking number one on Fast Company's fourth annual list of best workplaces for innovators. I could not be prouder of the team. And when it comes to clinical trial design, all the details matter. And in this case, the team led by Pushkal executed flawlessly. I'll now turn it back to Christine to coordinate Q&A. Christine?
Thanks, Yvonne. Operator, we will now open the call for questions. As a reminder, for those dialed in, we would like to emphasize that we will be fielding one question from each analyst. We ask that you please get back in the queue if you have any additional questions. Also, as a reminder, since we are sharing top-line data only today, we intend to share more full results of the upcoming ISA meeting on September 8th. There are certain results that will not be able to be communicated or commented on today.
Thank you. Our first question will come from Salveen Richter from Goldman Sachs. One moment, please.
Good morning. Thank you for taking my question and congratulations. Quick question here on how you're thinking about the read-through to HELIOS-B's mortality and hospitalization endpoint at 30 months and the potential to conduct the optional interim analysis. Just to remind us here on the filing, is there a specific p-value that was required in order to file? Thank you.
Thank you, Salveen. Look, we're delighted by these results, which really validate the hypothesis that TTR silencing by an RNAi therapeutic is effective in treating the cardiomyopathy of ATTR amyloidosis and, as such, strengthen our confidence in the HELIOS-B study, which was specifically designed to assess outcomes. It's a much longer study, much larger study, and we're very confident as we continue to execute on that study. Now I'm going to turn it over to Pushkal to provide some additional perspectives that underscore our level of confidence in the HELIOS-B study and also touch on how we're thinking about the interim analysis.
Thanks, Yvonne, and thanks, Salveen, for your question. Look, a couple of points, I think, with regard to HELIOS-B, I think we should just step back. There's been an accumulation of data over several years, as you know, about the potential role of a TTR silencing by an RNAi mechanism in ATTR cardiomyopathy that comes from our own studies, comes from investigator-sponsored studies, etc. And what's really critical today is that we've established, we believe, with the positive results from APOLLO-B, that this mechanism does have the potential to have a meaningful impact on the lives of patients with ATTR cardiomyopathy and validating that therapeutic hypothesis.
When you look at the totality of data coming out of this study, including the efficacy data on orthogonal endpoints, the safety data, including, as you'll see at the upcoming ISA meeting, cardiovascular safety, when you look at the numerical trends in terms of mortality favoring the drug, all of this only further our confidence about the HELIOS-B study, so we remain steadfastly confident and only enhance the study. With regards to the interim analysis, as we've mentioned, it is something that we've considered. We've, just as you can imagine, just received these results in the last few days, so we're going to take a little bit more time to look at that and make those considerations. Obviously, our decision will be impacted as we've always said.
Obviously, our decision will be impacted, as we've always said, by the rapidity of enrollment in HELIOS-B and the timeframes there, as well as regulatory feedback on that strategy. So we'll take all of those inputs together and make a decision. And when we've got to that point, we'll certainly be updating all of you in terms of our decision.
Akshay?
Yeah. I mean, thanks, Yvonne, and I agree with everything Pushkal said, of course. But Pushkal, the way that the team has designed these two studies, of course, HELIOS-B is a bigger, longer study. And so the exciting data we have in hand today bode well for an even stronger readout, I hope, in HELIOS-B. So exciting data to come there too, I suspect.
Thanks, actually. And just a reminder, those dates were not that far off now, beginning of 2024. So next question, please.
Thank you. One moment. Our next question comes from Paul Matteis from Stifel. Your line is open.
Hey, let me add my congratulations on the data. I actually wanted to just clarify because I thought the last question from Salveen was a good one on the p-value threshold for filing, if there's anything you could just kind of comment there on your confidence. And then on the mortality CV events, just from looking at the p-values disclosed in the press release, it seems like the preponderance of events came in patients who were on tafamidis who may have been sicker. Can you just comment at all if that's the case and that's where you seem to have seen this preliminary trend? Thanks so much.
Thanks for your question. Pushkal, perhaps we'll take the first question. We're trying to not have multi-part questions so that we can get through as many analysts and interested people as possible. So could you just comment perhaps on how we're thinking about what's required for filing and approval, particularly with respect to the P-value?
Yeah, absolutely. Thanks, Paul. With regard to the P-value and just the general considerations for filing, look, it's not our place to speak for the FDA, and they will certainly make their own determination. But we have aligned with them on the overall design of the study. There is no sort of specific one point around any of this. I think they're going to look at the totality of data with regard to the endpoints, and we'll be presenting data on the six-minute walk test. Again, it's also helpful here that we saw positive results on the secondary endpoint of the KCCQ. The clinical meaningfulness of the data as well are going to be important, along with the safety profile. Importantly, we have also, while this is not an outcome study, we've ruled out harm as well.
And so, I think the totality of all that data, I think, will be very important for the regulators and will take the data to them and hopefully be submitting an sNDA by the end of the year.
Yes, and of course, we'll be presenting more full data really just around the corner, four weeks from now, so we all look forward to that. Next question, please.
Thank you. Our next question comes from Ritu Baral from Cowen. Your line is open.
Good morning, guys. Congratulations as well. But Yvonne, this doesn't mean I hate 6-minute walk any less as an endpoint. Thank you for taking the question. We're all kind of back into what your effect size might be. Can you comment at all about the standard deviation that you saw in your data set versus ATTR versus the Bridge study? Was it along your expectations, or was it sort of more historical?
That's a great question, Ritu, and we can always kind of look for you to answer some great questions on our call. So thank you very much. But I think, Pushkal, can you provide some commentary, perhaps, on how we're thinking about effect sizes with the study compared to tafamidis and Amvuttra? Obviously, difficult to make cross-study comparisons.
Yeah, that's what I was going to say, Yvonne. Thanks. And thanks for your question, Ritu. I think, look, there'll be more data that will be presented at ISA. At this point, we're focusing on top-line results. What I'll say is that we, as we've been talking about for months and months, we designed the study to account for a range of endpoints and variability, recognizing sort of the nuances of these endpoints. And we're really pleased with the results, which are not only statistically significant but clinically significant. And we think, so that's what I can say at this point.
Pushkal, that's a great answer. Akshay, anything to add?
No. No.
Pushkal's covered it.
Pushkal's covered it.
Next question.
One moment. Our next question comes from David Lebowitz from Citi. Your line is open.
Thank you very much for taking my question. When you look forward to eventual approval, how do you market Onpattro, given that it's being approved based on six-minute walk test and ultimately it's being compared by physicians to other drugs on outcomes?
Thank you, David, for that question. I'd just like to emphasize that with these data, we really are building kind of a leading TTR franchise. And as we move forward, we'll obviously be able to leverage our existing commercial capability and scale that up, as Tolga described in his introductory remarks. I'm going to hand this question to Tolga. How are we thinking of marketing Onpattro with the profile that we've delivered in this study for patisiran?
Thanks, Yvonne. Good morning, David. This is a good day for patients, a good day for Alnylam. We see a significant opportunity for patisiran and view its potential profile in the disease as very meaningful. Within this vein, it's important to recognize patisiran is the first RNAi therapeutic with supportive data across the full spectrum of ATTR amyloidosis. As I highlighted in my slides, we're looking at a growing market, higher diagnosis and treatment rates, and more patients coming in over the course of their treatment pattern. Therefore, we believe this is not going to be a zero-sum game, and there will be plenty of opportunities both for naive patients and those patients that are currently inadequately getting a treatment response.
That's great, Tolga. Next question.
Thank you. Our next question comes from Tazeen Ahmad from Bank of America. Your line is open.
Hi, guys. Good morning, and also a big congratulations for the terrific results. I just wanted to ask a question on the HELIOS-B trial in that you're allowing, I believe, up to 50% of patients to have advanced onto tafamidis to enter the study. Did you define what advancing onto tafamidis means differently in that study relative to how you define the parameters for APOLLO-B?
That's a very specific question, which I'm going to hand over to John Vest. How do we define the tafamidis progressives in this study?
Yeah, thanks. On the APOLLO-B study, it was at the discretion of the investigator whether or not they felt the patient was advancing onto tafamidis. I believe the question was asking if there's a difference in how that was approached in HELIOS-B. The answer is that we did not include that element in HELIOS-B. HELIOS-B, as you pointed out, will include both patients who are on baseline to tafamidis and patients who are not on baseline to tafamidis. But we don't have a requirement in that study that they be progressing onto tafamidis to come into the study.
Okay. And then.
No. I think we'll go on to the next question, please.
Thank you. Our next question comes from Gena Wang from Barclays. One moment, please. Your line is open now.
Thank you. This is truly a great day for Alnylam and also for Biotech. Congratulations. So, I maybe just follow up Tazeen's questions. So, based on, since you have a different enrollment criteria, do you actually see similar patient population on tafamidis between APOLLO-B and HELIOS-B? And regarding the interim analysis for HELIOS-B, I know you cannot comment specifically, but what are the data points you are looking for?
So I'll take the question on interim analysis and then pass the question on enrollment over to Pushkal. Look, we only received this data a very short while ago. And obviously, we're continuing to review, reflect on the data. As we've always said, we would wait till we have a full understanding of this data set and then decide on the appropriateness of interim analysis. And we're not in that position at this point in time. Pushkal?
And Gena, thank you for your kind words. I think in terms of the patient population, again, I think we feel very good about how HELIOS-B is designed overall. I think that's really maybe the key take home I can share with you at this point. That study was specifically designed for outcomes, includes a mix, as you've said, of patients on baseline tafamidis and not on baseline tafamidis. Most importantly, the study is about twice as large as APOLLO-B and about three times as long as APOLLO-B. It's been optimized to deliver clinical outcomes.
All of the data that we've seen to date for RNAi-based or RNA interference therapeutics in this disease, as well as all the data looking at patients treated for these diseases who have cardiomyopathy, whether it's in post-hoc analysis, exploratory analysis, and now coming out of this study, all give us additional confidence in the design and execution and hopefully a successful outcome with a positive safety and efficacy profile coming out of HELIOS-B.
Next question, please.
Thank you. Our next question comes from Maury Raycroft from Jefferies. Your line is open.
Hi. I'll add my congrats and thanks for taking my question. I was just wondering if you can comment on whether the outcomes data are taking into account all patients at longer-term follow-up at data cutoff, and will FDA get to look at a more mature cut prior to approval?
Pushkal, why don't I hand those two questions straight over to you?
Yeah, thanks for your question, Maury. The data that we presented today really focused on the 12-month double-blind period of the study. There is an open-label extension where all patients cross over to receive active drug, and we will be looking at those data over time. We haven't made specific plans on when exactly we'll be presenting those data, but certainly, those are being collected and we'll share those with you, of course. I mean, just to add, this was the analysis we presented to them with 12 months of the study, and that's the formal analysis per the protocol, per the statistical analysis plan. Exactly.
Good. Next question, please.
Our next question comes from Anupam Rama from J.P. Morgan. Your line is open.
Hey, guys. Thanks so much for taking the question and congratulations on the update, so at the medical conference presentation at the International Symposium on Amyloidosis here next month, what are the additional analyses and data that we could see beyond the top-line release given it's only a month or so away? Thanks so much.
Great question. Will that provide us an opportunity to present data on the primary and secondary endpoints and, of course, more information on safety as well as patient characteristics and baseline demographics? Next question.
Thank you. Our next question comes from Patrick Trucchio from H.C. Wainwright. Your line is open.
Hi, good morning, and congrats on the data. I'm just wondering if you can discuss more specifically how the APOLLO-B data will contribute to the achievement of the goals outlined in the P5x25 plan, particularly on the revenue guidance and as well as the implication for pivot to profitability over the timeframe.
Thank you. Well, clearly, positive APOLLO-B data is great for Alnylam and great for patients. And as I said, it takes us one step closer to delivering on our P5x25 goals. We remain committed to those, both the product pipeline goals as well as the revenue goals. So yeah, we're committed to delivering those. We're confident about delivering them, and we're on track to deliver them.
Our next question comes from Luca Issi from RBC Capital Markets. Your line is open.
Oh, great. Thanks so much for taking my question. And again, congrats on the data. Maybe any directional color on how patients and tafamidis perform in the study? I know you can't comment on the specifics, but obviously, tafamidis and Onpattro have complementary mechanisms of action, potentially a non-overlapping toxicity. So wondering if you're seeing a synergistic effect between the two drugs or if the benefit here is simply driven by patients not on tafamidis. Any color would be great.
Thanks, Luca, for your question. Look, I certainly get the reason. Again, these are top-line results presented. We're focusing on really what the study was designed for, which is to demonstrate overall whether the drug was effective on improving patients' functional capacities measured by six-minute walk test and their quality of life, and the study absolutely met its primary objective. It's not powered to look at subgroups, etc. That's not what it was designed for. Certainly, in future medical presentations, you'll see more and more of those data as we look at forest plots, etc., of subgroups, but that's not what it was essentially designed for. Overall, we're very pleased with what we've seen in terms of the overall effect of the drug in this study.
Absolutely. This study delivered exactly what we set out to do here. So we're obviously very pleased. Next question, please.
Thank you. Our next question comes from Joseph Stringer from Needham. Your line is open.
Oh, hey, good morning. Thanks for taking our question and congrats on the data. Ours is related to a question that was asked earlier, but do you believe that there's a certain subset of cardiologists with TTR cardiomyopathy patients who would be sort of waiting for the HELIOS-B outcomes data to come out to consider using the treatment in their patients? How do you think that was before APOLLO-B results? And do you think that how do you think things could change post-APOLLO-B results here? Thank you.
Yeah, no, that's a really good question. I mean, clearly, there are significant unmet medical needs in these patients who I think would benefit from the introduction of an additional treatment option, assuming successful regulatory approval of Onpattro. Perhaps, Tolga, you might want to comment a little bit more on how you think about the color with respect to how cardiologists might view these data.
Yeah, good morning, Joseph. It's obviously difficult for us to comment specifically on positioning and how cardiologists will perceive this as we haven't discussed yet these data with regulators or gone through regulatory review, and obviously, our label is unknown. Having said that, obviously, there is an unmet medical need. Some patients are getting inadequate treatment. And based on our research, there is a group of physicians and patients who are looking for different options. And couple that with increased diagnosis and treatment rates, we believe patisiran will play an important role in the treatment of ATTR cardiomyopathy.
Thanks, Tolga. Next question.
Our next question comes from Leland Gershell from Oppenheimer. Your line is open.
Hi, let me add my congratulations as well on the data.
My question is actually sort of an extension of the prior one. Even though the official label expansion may not happen until sometime next year, these data will be disseminated to the broader treating physician population. Wondering if you may expect any benefit to current Onpattro use, particularly in those patients with mixed phenotype or toward kind of the cardiomyopathy end who may either be considered for stabilizer and may now just have one therapy which could address both aspects of the disorder. Perhaps a question for Tolga in terms of you can help us understand what the near-term benefit to Onpattro may be, if any. Thank you.
So, Tolga, that question goes straight to you.
Yeah, I mean, it's a pretty clear answer to that. We don't promote off-label. We're very thoughtful about making sure that we're actually consistent with our promotion with our existing label. So we wouldn't foresee any benefit from the halo effect of this data. And frankly, we would be very careful about that we have the right guardrails to make sure that we're actually promoting effectively.
Thanks, Tolga. Next question.
Our next question comes from Eliana Merle from UBS. Your line is open.
Hey, guys. Congrats on the data. Just also on the commercial front, I guess for Tolga, maybe just as you think for your commercial preparation from a payer perspective, how you're thinking about sort of the willingness to pay for a combination versus a monotherapy phase switch from tafamidis? And maybe from your commercial checks so far, I guess, of the patients on tafamidis, what would you estimate are the proportion of these patients that are kind of currently progressing and could either benefit from combination or, say, a pure switch to patisiran? Thanks.
Yeah, I'll just start off by making general points and we'll pass over to Tolga. Look, we have had really no headwinds from a payer perspective as we've launched multiple products now. And I think that is driven by our patient access philosophy as well as our use of value-based agreements. And so we're confident that as we move forward, assuming positive regulatory review and approval of Onpattro and cardiomyopathy, we will again be successful. Tolga, perhaps you would want to add some color to.
Yeah, just some additional perspective. First of all, we're really well-positioned to promote this label extension if approved, given that we have years of experience not only on the access side, as you pointed out, but overall in the customer-facing side and other capabilities like patient services and adherence. So we're really thrilled about that. Those are good scalable capabilities. In regards to our access play, obviously, we don't have the label yet. But as Yvonne indicated, we always focus on our patient access philosophy and, of course, always consider managing our building long-term value proposition for the company. So again, we're excited about this, but it's a little too soon for us to give further color on this based on these top-line results.
Thank you, Tolga. Next question, please.
Thank you. Our next question comes from Myles Minter from William Blair. Your line is open.
Hi, everyone. Congrats on the data again. Just wondering if you can run us through just rate-limiting steps ahead of the sNDA filing by year-end and if you expect an AdCom. I only asked that last part because of the prior FDA comments on the APOLLO study review about cardiac safety and if you have any more data here to overcome those comments. Thanks.
Thank you, Myles, for that question. Pushkal, that's one for you. Next steps.
Yeah, thanks, Myles. Look, our team has been anticipating these results and has already been working towards preparing for a potential sNDA. And they're all being mobilized quickly as of today to start work on that. We're very excited about this drug and these data, and we're going to be moving expeditiously to get the data in front of the regulators. And so we'll be meeting with them, we hope, shortly to share the data. We have a track record of moving very quickly in terms of getting NDAs out the door. And this one is an incredibly high priority for our team and for our company and for patients. And so we'll be moving expeditiously to move forward.
Akshay?
Yeah, I mean, I would just add that obviously, we can't comment on how the FDA will review all this. They're the deciders of whether there are outcomes or not, but these data are incredibly promising. Obviously, we're excited about the positive nature of the study and the overall totality of the data, including the safety data that we've reviewed, really wonderful profile for this drug, we believe, and so we're looking forward to discussions with the FDA, but we move forward with great confidence in the mechanism of action and RNAi therapeutics for the TTR space.
Next question, please.
Thank you. Our next question comes from Liisa Bayko from Evercore ISI. Your line is open.
Hi there. Congratulations on the data, and thanks for taking the question. Mine was just regarding tafamidis. Could you comment on the percentage of patients that were on tafamidis? I know you had an upper cap, and was it evenly balanced? I know you're not sharing baseline right now, but if you could just comment if it was even across both arms. Thank you very much.
Pushkal, another question on the Tafamidis subgroup in the study.
Yeah, Liisa, thanks. Your question, as we've said, we targeted approximately 30% of patients to come in on the study on baseline tafamidis, and while we're not speaking to specifics of the enrollment criteria, I can tell you that we were on track and in that range in terms of the final numbers in the study. It was a stratification variable, so it was certainly balanced across the study arms.
Thanks, Pushkal.
Thank you. Our next question comes from Gary Nachman from BMO Capital Markets. Your line is open.
Hi, good morning. This is Dennis on for Gary. Thank you for taking our question. Congrats on the positive results. We were just wondering if you plan on increasing your commercial sales force to help with the potential launch and to what scale that might be at. Thanks again.
Thanks for that question, Gary. I think this is one of the benefits of having a franchise. We've actually built a robust commercial capability which we can look to scale and leverage as we bring forth additional products to market. And Tolga, maybe you want to say a few words about how you're thinking about.
Sure, absolutely. Again, we're well-positioned to launch and promote this product when it's approved. 2023. The critical capabilities that we have already established, that includes our advocacy organization, patient support system, our access organization, those will really play a very important and synergistic role. In terms of our customer-facing, we will look at the label. We'll think about how to best serve the needs of the physicians. And obviously, our goal is to make sure that we maximize the value of this asset and make sure that every right patient is put on treatment. And we'll do what's necessary to make sure we do that.
Thanks, Tolga.
Thank you. And our last question for today will come from Olivia Brayer from Cantor . Your line is open.
Hey, good morning. Thank you for the question and my congrats as well on the data. I have a quick follow-up on the longer-term mortality and CV data cut from the OLE. So is the strategy there to announce some of those data at or around the time of approval? Just trying to think of ways to help drive commercial uptake in that initial launch period. Thank you.
Sorry, Olivia, could you clarify the question? We didn't quite understand it fully.
Yeah, so in terms of the open label extension, when you think about the longer-term data cut for mortality and CV benefit, is there an opportunity to present longer-term follow-up data there around the time of a potential approval next year to help with initial commercial adoption?
Okay, so it's whether there'll be an opportunity to present any early data at the time of launch.
Yeah, thanks for your question, Olivia. Look, we still are. We've just got these data. We're having patients roll into the OLE as they cross the 12-month period. So we haven't finalized our plans, but certainly, we think that the OLE data will be really informative in terms of elaborating both the safety and potentially elements of the efficacy of this drug. Obviously, it won't be a randomized comparison, but I think it'll be very informative as we think about the emerging profile of the patisiran in ATTR cardiomyopathy. Certainly, we'll want to make those data available to the broader community of physicians out there through medical conferences, etc. We'll do that, but the specific timing of those is not. We don't know yet.
No, I mean, I just wanted to add very shortly that patisiran, which is powered for outcome data, will hopefully be available, which should actually further help us to position the product. Great point, Tolga.
Lots of exciting data to come. So look, I'd just like to thank everyone again for joining us today. As you've heard on the call, we could not be happier with these results from APOLLO-B. And we look forward to sharing further details at the upcoming ISA meeting in September. So thank you, everybody, and have a wonderful day.
Goodbye. This concludes today's conference call. Thank you for participating. You may now disconnect, everyone. Have a great day.