Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript & Summary

Welcome to the Alnylam Pharmaceuticals Conference Call to discuss the Positive Topline Results from the APOLLO-B Phase 3 study. [Operator Instructions] 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 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 Investors page of our website, alnylam.com/events. Now turning to today's call as outlined in Slide 2, Yvonne and Akshay will provide some opening comments, Pushkal will discuss the APOLLO-B study and topline results in more detail, Tolga will give an update on next steps with patisiran 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 these forward-looking statements as a result of various important factors, including those discussed in our most recently quarterly report on file with the SEC. In addition, any forward-looking statements represent our views 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 data. With that, I would now like to 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 are announcing positive topline results from our APOLLO-B Phase 3 trial for 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 6-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 result score. In addition, 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 a 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 of this disease setting. Along with the 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 multibillion-dollar opportunity for Alnylam over time. Consistent with our previous guidance, we now plan to engage with regulators and advance ONPATTRO towards a supplementary NDA filing by year-end. And 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. Mainly, we look forward to outcomes data from the HELIOS-B study and the potential approval of vutrisiran for ATTR amyloidosis with cardiomyopathy as well. Certainly, the positive results of this study of patisiran 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, 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 path to enable impact for patients, substantial growth of 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 of today's news.

Thanks, Yvonne, and welcome, everybody. We're indeed thrilled with these topline 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 monomers into amyloid fibrils that deposit in multiple tissues, including the heart, nerves and GI tract. This pathogenic process often results in multisystem 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 the slide, you see an illustration of the 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 in the muscular walls of the heart, which in turn is accompanied by a reduction of volume for 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 the heart that is stiff for noncompliant 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 the patient experience with this disease? As a consequence of all these pathological changes in the heart, patients experience progressive heart failure, which commonly results from 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 of the 6-minute walk test. However, in turn, the impaired exercise tolerance also reduces the patient's quality of life, which can be assessed by a quality of life tool such as KCCQ. Furthermore, defects in the conduction system can lead to cardiac arrhythmias, including heart rate 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 just described are reflected in abnormal findings on laboratory tests too 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 to treat the disease. And we've designed our TTR targeting RNAi therapy just to do just that. I'll now hand it over to Pushkal to take you through the APOLLO-B study design and topline results in more detail. Pushkal?

Thanks, Akshay, and good morning, everyone. It is a real joy and an honor to be sharing these positive topline results. I'm going to add my thanks to 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 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 1:1 to patisiran or placebo. The primary endpoint was the change from baseline to 12 months in the 6-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 topline results from the study. Please note that we are sharing topline 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 8. This table shows the prespecified primary and secondary endpoints for the APOLLO-B study. In addition to the primary endpoint of 6-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. And after the KCCQ, we included 3 composite endpoints of cardiovascular outcomes. The first is a composite of all-cause mortality, frequency of CV events and change from baseline in 6-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. And the last is a composite of all-cause mortality and frequency of all-cause hospitalization and urgent heart failure visits in the overall population. Now it's important to note, the study was designed and powered for the 6-minute walk test and KCCQ endpoints. However, the size and 12-month duration of the study were not optimized to demonstrate an outcomes benefit, which would have required a significantly larger sample size in a longer study. And 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 6-minute walk test to 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 the composite of all-cause mortality, frequency of CV events and change from baseline in 6-minute walk test. Patisiran achieved a nonsignificant result relative to placebo in this endpoint with a p-value of 0.0574. As a result, and based on the prespecified hierarchical testing procedure, formal statistical testing was not performed on the final 2 composite endpoints. However, the nominal p-value 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 topline safety results. We're also very encouraged by the overall safety profile of patisiran in this population of patients with ATTR amyloidosis for 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 5 patients on patisiran, or 2.8%, and 8 patients in placebo, or 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 4 in the patisiran arm, or 2.2%, and 10 in the placebo arm, 5.6%. In sum, we are very pleased to see the positive and clinically meaningful results of 6-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 cardiomyopathy. 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 supplementary 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 8. In addition, we continue to advance vutrisiran in the HELIOS-B outcome study, with topline results expected in early 2024. We also believe these positive data from APOLLO-B adds 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 declining 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 [indiscernible] as we have built our footprint and capabilities and been engaging with physicians, patient advocacy organizations and health care 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 [indiscernible] value for reimbursement is provided for ONPATTRO in ATTR amyloidosis with cardiomyopathy. And as we think about the full picture of the TTR franchise as it stands today, over the past 4 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-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 view of today's APOLLO-B results and subsequent approval. Given the existing unmet needs we see every day in ATTR amyloidosis, this 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 transformative treatment options 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 topline results and our ongoing HELIOS-B trial, we believe Alnylam is well positioned to make potentially 2 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 with 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, deep track record of conducting trials in the ATTR space, a thoughtful approach to patient selection, conservative powering 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, [indiscernible] the small stuff. These positive APOLLO-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 for 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 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 that were expected 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 is 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 and listen to 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 was generated during the COVID-19 pandemic, where our entire development organization and our clinical operations teams, 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 poured over every little detail to ensure trial's success. Commitment to people, passion for excellence and innovation in discovery are at the heart of what we do at Alnylam. In fact, this is illustrated just yesterday by Alnylam's ranking #1 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, 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, we're sharing topline data only today and we intend to share more full results at the upcoming ISA meeting on September 8, there are certain results that will not be able to be communicated or commented on today.

Our first question will come from the line of Salveen Richter from Goldman Sachs.

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. And just a reminder here on the filing, is there a specific p-value that was required in order to file?

Look, we're delighted by these results, which really validates the hypothesis of TTR silencing by an RNAi therapy 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 with 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 took a step back. There has 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, et cetera. 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 in the lives of patients with 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, as you'll see at the upcoming ISA meeting cardiovascular safety. When you look at the numerical trends in terms of mortality favor the drug, all of this only further our confidence about the HELIOS-B study. So we remain steadfastly confident and only enhance [indiscernible]. With regards to the interim analysis, as we've mentioned, it is something that we 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, by the rapidity of enrollments in HELIOS-B and the time frames 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 got to that point, we'll certainly be updating all of you in terms of our decision.

Yes. I mean, I agree with everything Pushkal said, of course. But, Pushkal, the way that the team has designed these 2 studies, of course, HELIOS-B is a bigger, longer study. And so the exciting data we have in hand today bode well for even stronger read-out about -- in HELIOS-B. So exciting data compared to [indiscernible].

Just a reminder, those days were not that far off now, beginning of 2024. So next question, please.

Our next question comes from the line of Paul Matteis from Stifel.

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 as disclosed in the press release, it seems like the preponderance of events came in patients who are 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?

Pushkal perhaps will take the first question. We're trying to not have a multi-part question 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 p-value?

Yes, absolutely. With regard to the p-value and just the general considerations for filings, 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 6-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 we'll 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 wholesome data really just around [ performance ] 4 weeks from now.

So we all look forward to that.

Next question, please.

Our next question will come from the line of Ritu Baral from Cowen.

Congratulations as well. But Yvonne, this doesn't mean I hate 6-minute walk any less as an endpoint. We're all kind of back into what your effect size might be. Can you comment at all about the standard deviation that we saw in your data set versus ATTRACT versus 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 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 [ ATTRACT ]. Obviously difficult to make cross-study comparisons.

Yes. That's what I was going to say, Yvonne. I think -- look, there will be more data that will be presented at ISA. At this point, we're focusing on topline results. What I'll say is that, as we've been talking about for months and months, we've designed the study to account for a range of endpoints and variability, recognizing for 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 that?

No, nothing.

Pushkal covered it. Next question?

Our next question will come from the line of David Lebowitz from Citi.

When you look forward to eventual approval, how do you market ONPATTRO given that it's approved based on 6-minute walk test? And ultimately it's being compared by physicians to other drugs on outcomes.

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 at scale, as Tolga described in his introductory remarks. And then, I hand this question to Tolga. How are we thinking of marketing ONPATTRO with the profile that we've delivered in the study.to patisiran?

This is a good day for patients, a good day for Alnylam. We see 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 which supported 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 0 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?

Our next question comes from the line of Tazeen Ahmad from Bank of America.

And also a big congratulations for the terrific results. I just wanted to ask a question on [indiscernible]. In that, you're allowing, I believe, up to 50% of patients to have advance on tafamidis to enter the study. Did you define what advancing on tafamidis means differently in that study relative to how you define the parameters for APOLLO-B?

I think that's a very specific question, which I'm going to hand over to John Vest. How do we define tafamidis progressive in the study?

Yes. On the APOLLO-B study, it was at the discretion of the investigator whether or not they felt patient was advancing on 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 tafamidis and patients who are not on baseline tafamidis. But we don't have a requirement in that study that they'd be progressing on tafamidis to come into the study.

I think we'll go on to the next question, please.

And our next question comes from Gena Wang from Barclays.

This is truly a great day for Alnylam then 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 [ CBOC ], 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 the data very short while ago. And obviously we're continuing to review reflect on the data. As we've always said, we would wait to -- 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 taf and not on baseline taf. Most importantly, the study is about twice as large as APOLLO-B and about 3x as long as APOLLO-B. It's been optimized to deliver clinical outcomes. And all of the data that we've seen to-date for RNA [indiscernible] -- or RNA interference therapeutics in this disease as well as all the data looking at patients with -- treated with these disease who have cardiomyopathy, whether it's a post-hoc analysis, exploratory analysis and now coming out of this study, all give us additional confidence in the design and execution and hopefully actual outcome with a positive safety and efficacy profile coming out of HELIOS-B.

Next question, please.

Our next question comes from the line of Maury Raycroft from Jefferies.

I'll add my congrats. 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 prior to approval?

Pushkal, why don't I hand those 2 questions straight over to you?

Yes. 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 in due course.

I think -- I mean just to add, this was analysis we presented with 12 months of the study. And that's the formal analysis per the protocol per the [indiscernible].

Exactly.