Alnylam Pharmaceuticals, Inc. (ALNY) Earnings Call Transcript

Ladies and gentlemen, thank you for standing by, and welcome to the Alnylam Pharmaceuticals conference call to discuss the 18-month results from the HELIOS-A Phase III study. There will be a question-and-answer session to follow. Please be advised that this call is being [ recorded ] at the company's request. I would now like to turn the call over to the company.

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, Chief Executive Officer; Akshay Vaishnaw, President; Pushkal Garg, Chief Medical Officer; and Rena Denoncourt, Vice President, TTR Franchise lease. Also, on the line and available for Q&A is John Vest, VP of Clinical Research. For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, alnylam.com/events. During today's call, as outlined on Page -- Slide 2, Yvonne and Akshay will provide some introductory remarks. Pushkal will discuss the HELIOS-A data and the 18-month results in more detail. Rena will give an update on next steps for vutrisiran, and we will then open the call for your questions. I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent annual and quarterly reports 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 reliant upon as representing our views as of any subsequent dates. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over now to Yvonne. Yvonne?

Thanks, Christine, and good morning, everyone. Today, we are pleased to be presenting full 18-month results from our HELIOS-A Phase III study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis. These results are being presented at the Annual Meeting of the Société Francophone du Nerf Périphérique in Paris. Pushkal will go to the results in a moment. But let me start by saying, we're thrilled with these 18-month results in hATTR amyloidosis patients with polyneuropathy, which further reinforce the positive 9-month results that we previously reported. Given these data and considering that vutrisiran is administered as a once-quarterly subcutaneous injection, we believe that vutrisiran has the potential to be a very welcome treatment option for patients with hATTR amyloidosis with polyneuropathy, if approved by regulatory authorities. These positive HELIOS-A data help lay the foundation for the planned expansion of our TTR franchise, into what we believe could represent a multibillion-dollar opportunity for Alnylam over time. And if approved, we expect the launch of vutrisiran will drive significant growth of our hATTR amyloidosis with polyneuropathy opportunity beginning this year. We also believe that the ongoing clinical studies with both patisiran and vutrisiran in ATTR amyloidosis with cardiomyopathy, if positive, will open up a significantly broader opportunity for Alnylam. This includes the APOLLO-B Phase III study of patisiran, expected to read out top line results in mid-2022; followed by the HELIOS-B Phase III study of vutrisiran in early 2024. We also anticipate vutrisiran's application to an entirely new space, an important rare disease called Stargardt disease, with a Phase III study in that population to potentially begin in late 2022. And ultimately, the franchise is expected to also include ALN-TTRsc04, which comes from our IKARIA platform and provides the potential for once-annual subcutaneous dosing regimen and is expected to enter the clinic this year as well. In the meantime, we look forward to the potential launch of our fifth RNAi therapeutic in the U.S., assuming FDA approval of vutrisiran by the PDUFA date of April 14. Vutrisiran's approval would 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 and, at the same time, delivering exceptional financial performance. Before turning it over to Akshay, I'd like to take just a moment to acknowledge the many people across the globe who participated in HELIOS-A and made this important medical advance possible. It shouldn't go unmentioned that a significant portion of these study results were generated during the COVID-19 pandemic, where our entire development organization, especially our clinical operations team, our CRO partners and most importantly, our dedicated investigators and study site staff successfully enabled study continuity and integrity. And of course, we are particularly indebted to and inspired by all the patients participating in HELIOS-A and other vutrisiran studies. Without their participation, we could never have generated the evidence needed to seek approval for vutrisiran and, if approved, bring an impactful treatment option to patients with polyneuropathy in the ATTR amyloidosis community. With that, I'll now turn it over to Akshay to provide more context. Akshay?

Thanks, Yvonne, and welcome, everybody. We're indeed thrilled with these results from our HELIOS-A Phase III study. I'll briefly review the program and then turn it over to Pushkal, who will share the results with you in more detail. As most of you are aware, hereditary ATTR amyloidosis is a multisystem orphan disease caused by mutations in the transthyretin or TTR gene that leads to aggregation of misfolded TTR monomers into amyloid fibrils depositing in a range of tissues. This pathogenic process results in a multisystem disorder that typically includes polyneuropathy due to amyloid deposition in the nerves or cardiomyopathy due to deposition in the heart. Most patients, however, exhibit a mixed phenotype, including both polyneuropathy and cardiomyopathy. As indicated by the term polyneuropathy, all classes of nerves are involved, leading to disabling sensory, motor and autonomic symptoms. Regardless of the clinical presentation, hATTR amyloidosis is a rapidly progressive debilitating disease that is often unfortunately fatal. ATTR amyloidosis has a common pathogenic mechanism related to wild-type or mutant TTR production and amyloid deposition 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 reduced the production of the disease-causing TTR protein in the liver, thereby reducing continued amyloid deposition, and thus halting or improving the manifestations of disease. This concept was first demonstrated in the polyneuropathy with ONPATTRO or patisiran, then later shown with vutrisiran 9-month results from the HELIOS-A study that we presented last year and has now been further supported by today's 18-month data. As you know, we have 3 RNAi therapeutics in development for the treatment of ATTR amyloidosis. On the left, you see ONPATTRO or patisiran, which was the first-ever approved RNAi therapeutic. It's administered every 3 weeks via the infusion and is now being marketed around the world for the treatment of the polyneuropathy of hATTR amyloidosis. Patisiran is also currently in further clinical development in our APOLLO-B Phase III study. Vutrisiran, which is the focus of today's call, is an investigational RNAi therapeutic, which, in addition to HELIOS-A, is also being evaluated in the HELIOS-B Phase III outcome study in patients with ATTR cardiomyopathy. We believe vutrisiran has a very compelling product profile with subcutaneous administration of a 25-milligram dose once every 3 months. We're also evaluating a potential additional dosing regimen of 50 milligrams once every 6 months. And finally, ALN-TTRsc04 is the newest program within our franchise. It utilizes our new IKARIA platform chemistry in its design, and we believe has the potential for once annual dosing and greater than 90% serum TTR reduction. Collectively, it's our belief that these 3 programs will support Alnylam's development of the leading ATTR amyloidosis franchise. With that, I'll now hand it over to Pushkal to take you through the exciting HELIOS-A study design and the new 18-month data in more detailed. Pushkal?

Thanks, Akshay, and good morning, everyone. I'm delighted to share these exciting results from the HELIOS-A study with you this morning. Let me start by reminding you of the design of the HELIOS-A study. HELIOS-A is a randomized open-label study in patients with hereditary ATTR amyloidosis with polyneuropathy. The study enrolled 164 patients who are randomized 3:1 to receive vutrisiran at a dose of 25 milligrams subcutaneously once every 3 months or patisiran intravenously once every 3 weeks at a dose of 0.3 milligrams per kilogram as a reference comparator. The study compared vutrisiran to the placebo arm of the APOLLO Phase III study as an external control for the primary and most secondary endpoints. The primary endpoint was measured at 9 months and with a change from baseline in the modified neuropathy impairment score, or mNIS+7, is compared to the external placebo. Now early in 2021, we presented positive 9 months results from the study, which showed the study met its primary and secondary endpoints set at 9 months. These data form the basis for our regulatory submissions to the FDA and EMA and as well as the Brazilian and Japanese regulatory authorities in 2021. The study was designed to continue patient dosing past than the 9-month mark, and a series of secondary endpoints were evaluated at 18 months to evaluate the impact of vutrisiran on polyneuropathy manifestations and TTR reduction. Study also included exploratory endpoints to better understand vutrisiran's potential impact on cardiac manifestations of the disease, including the cardiac biomarker, NT-proBNP, echocardiographic parameters and cardiac amyloid burden through the use of technetium scans. Let me now review the baseline demographics on Slide 13. The patient population enrolled in HELIOS-A included a wide range of disease severity and was representative of the global population with this disease, with patients enrolled across 57 sites in 22 countries. Baseline characteristics were generally well-balanced between the vutrisiran and patisiran reference arm with HELIOS-A and the external placebo arm from APOLLO. And the populations were clinically comparable. Further, just as we did with APOLLO, we predefined a cardiac subpopulation as those patients with thickened heart walls and without a history of hypertension or aortic valve disease. Turning now to Slide 14. Serum TTR reduction in the vutrisiran group was rapid and sustained over a period of 18 months. Specifically, vutrisiran achieved a mean steady-state serum TTR reduction from baseline of 88%. We're also very pleased to see low inter-patient variability in TTR reduction over the same time period. As expected, the TTR reduction achieved with vutrisiran was statistically noninferior to that observed in the patisiran reference arm. It is important, as we would expect that a comparable level of TTR reduction by vutrisiran and patisiran should result in a comparable level of clinical impact. I'll further elaborate on this point in a few moments. Let's now turn to the clinical efficacy results at 18 months, and I'll start with the impact on neuropathy impairment and quality of life. At 18 months, vutrisiran treatment resulted in a 29-point mean treatment benefit on mNIS+7 and 21-point mean treatment benefit on Norfolk Quality of Life relative to the external placebo group. These effects were highly significant with p-values of 6.5x10-20 and 1.8x10-10, respectively, highlighting the robustness of the treatment effects. In contrast to the control group that demonstrate rapid and marked worsening in neuropathy, the mean change in mNIS+7 relative to baseline for vutrisiran-treated patients was a negative value, indicating an improvement in the overall score on average. In fact, 48% and 57% of patients, respectively, demonstrated improvements in neuropathy impairment and quality of life compared with baseline at month 18. Improvements were seen across all components of the mNIS+7 score and also across all prespecified subgroups, such as age, sex, race, geography and prior TTR stabilizer use. Further, consistent treatment effects were seen in the within-study patisiran reference arm as are being shown here for the vutrisiran arm. Moving now to Slide 16. We see that at 18 months, vutrisiran achieved statistically significant improvement relative to the external placebo group on a range of additional secondary endpoints, including 10-meter walk test, measure of gait speed, modified body mass index, a measure of nutritional status and the Rasch-built Overall Disability Scale, or R-ODS, a measure of disability. Each of these results was highly statistically significant. Particular importance is the results on the 10-meter walk test. Gait speed is an important and clinically meaningful measure of patient function. It's often referred to as the functional vital sign. In contrast to the placebo group that demonstrate continual and steady worsening in gait speed over the 18-month assessment period, the vutrisiran patients remained relatively stable. Let me now turn to a review of the exploratory endpoints, beginning on Slide 17, which looks at the biomarker NT-proBNP, a measure of cardiac stress. On this endpoint, higher values indicate a greater level of cardiac stress. Here, we see that at month 18, vutrisiran led to a relative improvement in NT-proBNP. Specifically, while the external placebo group showed an approximately doubling or worsening in NT-proBNP over 18 months, levels in the vutrisiran group remained stable. Next, over the next 2 slides, let me turn to 2 additional exploratory endpoints focused on imaging. The study included assessments of echocardiographic parameters relative to the external placebo group as well as technetium scintigraphy imaging, which was a comparison relative to baseline. Let's start with the echo results, which provide information on cardiac structure and function. Here, you can see that compared to external placebo, vutrisiran-treated patients demonstrated a trend towards improvement in left ventricular wall thickness, longitudinal strain, cardiac output and left ventricular end diastolic volume. And finally, on Slide 19, you see technetium results from a planned cohort of patients at select site. Treatment with vutristan was associated with an improvement in technetium uptake that has reduced to tracer uptake in the heart relative to baseline in a majority of patients. Specifically, about 2/3 of patients showed a reduction in uptake as assessed by 2 measures: technetium normalized left ventricular total uptake as well as technetium heart-to-contralateral lung ratio. Next, we looked at the 18-month change from baseline in Perugini grade, which is a visual assessment of technetium uptake in the heart that is now commonly used in clinical practice as the basis for making a diagnosis of ATTR amyloidosis with cardiomyopathy in lieu of biopsy. In this analysis, over 95% of patients either remain stable or improved. And notably, 28% of patients experienced an improvement in Perugini grade, meaning they moved, for example, from Grade 3 to Grade 2 or Grade 2 to Grade 1 or Grade 0. To our knowledge, this is the largest study conducted to date using technetium imaging to characterize the potential impact of a TTR silencer on cardiac amyloid. Now it's important to recognize that these are exploratory data and these patients had predominant polyneuropathy. We believe these results are encouraging with respect to providing potential evidence that vutrisiran treatment may reduce cardiac amyloid burden. Considering the totality efficacy data, an important question was to understand how the 18-month efficacy of vutrisiran in HELIOS-A compare to that seen with patisiran in APOLLO. Given that there are no statistically powered head-to-head studies, we looked at the treatment effects of both drugs compared to placebo across the full spectrum of endpoints using standardized effect size calculations. This analysis is shown here on Slide 20. On the left is a pair of 4 plots showing results for the primary and secondary endpoints from each study as assessed in the modified ITT populations, vutrisiran in the top panel and patisiran in the bottom. In the center, you can see the exploratory cardiac measures, including echo parameters and NT-proBNP, again, across the mITT populations in both studies. And finally, on the far right, we're again showing the exploratory cardiac endpoints, but we're focusing on the results from the cardiac subpopulations in both studies. What you can readily see from these standardized effect size plots is that across this broad and comprehensive range of both neurologic and cardiac assessments, the results with vutrisiran and patisiran are strikingly consistent. The 18-month results with vutrisiran in HELIOS-A appear to line up well with what we saw with patisiran in APOLLO. In accordance with the similar levels of TTR knockdown caused by these 2 medicines, it's true for the neurologic endpoints as well as for the cardiac exploratory endpoints where we see great consistency across NT-proBNP and echo parameters. Let me now turn to the safety results during the 18-month treatment period. Vutrisiran demonstrated an encouraging safety and tolerability profile. By month 18, 3 patients on the vutrisiran arm, or 2.5%, discontinued the study due to adverse events. The single new discontinuation since month 9 was an event of cardiac failure considered unrelated to study drug by the investigator. By month 18, there were 2 deaths, neither of which was considered related to study drug. There were 2 serious adverse events deemed related to vutrisiran by the investigator consisting of dyslipidemia and urinary tract infection. These 2 deaths and related SAEs, all occurred by month 9 and have been previously reported. Treatment-emergent adverse events occurring in 10% or more of patients included fall, pain in extremity, diarrhea, peripheral edema, urinary tract infection, arthralgia and dizziness, the exception of pain in extremity and arthralgia. Each of these events occurred at a similar or lower rate as compared with external placebo. Injection of site reactions were reported in 5 patients or 4.1%, and all were mild and transient, and there were no hepatic safety concerns. In summary, we're very pleased that vutrisiran met all secondary endpoints at 18 months in the HELIOS-A study, with improvements compared to external placebo in neuropathy impairment, quality of life, gait speed, nutritional status and disability in hereditary ATTR patients with polyneuropathy. Vutrisiran also demonstrated improvement relative to external placebo, and the exploratory cardiac endpoint NT-proBNP trends towards improvement in echocardiographic parameters, an improvement compared to baseline and cardiac uptake of technetium on scintigraphy imaging. All these data collectively provide evidence to suggest that vutrisiran treatment may potentially result in improvement of the cardiac manifestations of the disease. Looked at in aggregate and as expected, we were delighted to see that the treatment effect of vutrisiran in 18 months across an array of endpoints is quite similar to that observed with patisiran. Finally, vutrisiran demonstrated an acceptable and encouraging safety profile. Going forward, patients in the HELIOS-A study continue to be treated in the open-label extension period, which now includes a randomized treatment extension. In this extension, patients from the study will be randomized to receive vutrisiran at a dose of either 25 milligrams every 3 months or 50 milligrams every 6 months. These data, which were intended to demonstrate the safety and efficacy of the 50-milligram biannual regimen, are expected in late 2022. We're very excited about the potential opportunity for a biannual dosing regimen with vutrisiran and believe that advancing this alternative regimen has the potential to further reduce the burden of care and provide additional optionality for patients and physicians. In closing, let me also thank the patients, patient families, investigators, study staff and collaborators for their participation in the HELIOS-A Phase III study. We could not have achieved this remarkable milestone without the hard work and dedication of countless people, not the least, by Alnylam colleagues. With that, let me turn the call over to Rena. Rena?

Thanks, Pushkal, and hello, everyone. I, too, am thrilled to be at this stage in vutrisiran's journey. Based on the positive data from HELIOS-A, we believe that vutrisiran, if approved, will present an exciting commercial opportunity, providing an attractive treatment option for patients with hATTR amyloidosis with polyneuropathy around the world. For its initial market opportunity, we believe that vutrisiran could address unmet needs for 20,000 to 30,000 hATTR amyloidosis patients with polyneuropathy, including those with a mixed phenotype. As a once-quarterly subcutaneous injection, we expect to see strong uptake starting this year. We believe that vutrisiran, based on HELIOS-A alone, has the potential to expand Alnylam's overall share of the hATTR amyloidosis polyneuropathy market in many ways. First, similar to what we've forged with ONPATTRO, we aim to secure broad patient access across the globe for vutrisiran with proactive and innovative access approaches. We also expect that with the quarterly subcutaneous dosing, vutrisiran has the potential to be a particularly well-suited treatment option for those patients who may otherwise have been in a watch-and-wait holding pattern before committing to treatment or other patients who wish to switch therapy. We also anticipate increased use by HCPs to treat hATTR amyloidosis patients with a mixed phenotype given the simplicity of the dosing regimen. Importantly, vutrisiran, if approved, would provide greater patient choice with the availability of 2 RNAi therapeutic treatment options. In short, we believe the HELIOS-A study results and safety at 18 months will make vutrisiran, if approved, a very attractive option for patients and their HCP. In summary, we are extremely excited by the prospect of bringing vutrisiran to the market, if approved, and believe that it has the potential to make a meaningful difference in our overall ATTR amyloidosis franchise. In closing, I'd also like to thank our patients, caregivers, patient advocacy groups and study investigators and staff who continue to work extraordinarily hard for the ATTR amyloidosis community. With that, I'll now turn the call back to Christine to coordinate Q&A. Christine?

Thanks, Rena. Operator, we will now open the call for questions. [Operator Instructions]

[Operator Instructions] First question comes from Alethia Young with Cantor Fitzgerald.

Congrats on this data. I just want to talk a little bit about, I think, Rena's comment at the end on the mixed phenotype. Just can you help us think about like kind of maybe what the context lies over around what's going on with patisiran now? And how this can actually maybe having the subcu and having the quarterly dosing actually be more attractive and also the preponderance of more cardio-related data to this mixed phenotype?

Sorry, Alethia. Certainly, it was a bit broken up. I think just to recap your question, was it how are things going in the mixed phenotype with patisiran? And what are the prospects for vutrisiran? Is that in a nutshell?

Yes, essentially. I mean -- and just like since you have a lot of cardiac data with this vutrisiran data and that's a subcu, so just talk about how that could broaden out the market and what you've learned from being in the market so far.

Yes. Sure. Rena, do you want to take that?

Sure. I think what we are seeing with ONPATTRO is continued expansion of the HCP footprint. More and more physicians, both on the neurologists and cardiologists side are interested in ONPATTRO, and we certainly expect that, with the potential introduction of vutrisiran, that would continue to expand given the simplicity of the dosing regimen.

Yes. And I would just add to that, Alethia, that in Europe, where we have certain cardiac data for ONPATTRO in the label, we clearly see doctors prescribing ONPATTRO for patients with mixed phenotype, often, patients not doing well in parameters. And so the prospects, I think, for vutrisiran are very good in light of the continuing consolidation of cardiac data, with the addition to that of these very encouraging technetium data that we've seen. So does that help you?

Yes. Actually, can I just add just one other comment? I think it's important to recognize that we really are at the very early stages of the opportunity in hATTR polyneuropathy. We shared in our pre-revenue at JPMorgan that we have about 2,050 patients now on ONPATTRO. And if we think about the size of the opportunity that Rena shared of 30,000 to 40,000 patients, we really have a lot of growth to go actually in the hATTR polyneuropathy opportunity.

Your next question comes from Maury Raycroft from Jefferies. Our next question comes from Salveen Richter with Goldman Sachs.

In light of the amount of cardiac data here and recent competitor data, how does this impact your thoughts about APOLLO-B in any way? And generally, how do you want to approach the cardiomyopathy label?

Yes. Let me just start, and then I'm sure Pushkal and John will want to follow up. We find that today's data extremely encouraging overall. Obviously, for the polyneuropathy, we've shown data recapitulating the improvement we saw with patisiran and vutrisiran, ONPATTRO and APOLLO. So that's very exciting. On the cardiac side, we also see very encouraging data that look similar to what we found in the cardiac subgroup in APOLLO. And this very exciting observation that in some patients, we're in fact, beginning to see reduction on technetium scanning, which suggests that TTR is being mobilized from the heart. So if you add up these various observations across multiple studies now, BNPs, stabilizing and improving 10-meter walk, total functional work has stabilized or improved and the encouraging echo and technetium findings, I think this bodes very well for the prospects of RNAi-based mechanisms in this disease. But Pushkal, do you want to speak to prospects for APOLLO-B?

Yes. Salveen, I agree with everything that Akshay said. I think this only highlights and strengthens our conviction in terms of the hypothesis that we're testing and the potential impact of the silencer mechanism to be effective in the cardiac aspects of the disease. I think as you said, we're consolidating -- we're seeing consolidation and the consistency of data across the APOLLO study; across now HELIOS-A out to 18 months; external data that have come from a couple of reports, including the large U.K. National Amyloidosis Center; and really not only consistency across studies, but also internal consistency in terms of a variety of endpoints, right? And when you're dealing with an upstream mechanism to see that kind of tightness in terms of results, across neuropathy indication manifestations, cardiac manifestations, multiple data sets, multiple points in time, internal and external consistency, just strengthens our conviction. So we're very much looking forward to the results of the APOLLO-B study in the middle of this year.

Our next question comes from Ritu Baral with Cowen.

I wanted to ask you about the sort of relative importance of the exploratory echo measures. I think it's your Slide 18. First, it looks like especially how to look at global longitudinal strain because it's the only thing that did look like it was still worsening and not stable versus everything else that looked stable. And then as we think about these 4 measures on this slide, what's the best one to sort of put together with gait speed to give you a better idea of what a 6-minute walk represents, which is sort of like exercise capacity, cardiac capacity, et cetera.

Yes. Thanks, Ritu. I'll comment at a high level, and then John, who's a cardiologist, I'm sure, has impressions on the details of these echo data and what they mean as well, these are exploratory endpoints, we should keep that in mind. And at the highest level, what we're struck by is the remarkable similarity of these findings relative to APOLLO. And so for such a small sample size across 2 studies separated in space and time with 2 different drugs, to see this kind of recapitulation of data to our eyes is wonderful, actually. And as we were discussing earlier consolidated our belief that ultimately, we'll, through APOLLO-B and HELIOS-B, hope to show a great impact on the cardiac aspects of the disease. As you've seen with other drugs recently with -- we've discussed BridgeBio data, many of us, not always easy to replicate data across studies. And so we're delighted that with our RNAi's silencing mechanism between APOLLO and now HELIOS-A, we see this wonderful repetition of the cardiac data. Now John, do you have any impressions on the importance of LV strain or what that means?

Yes. Thanks, Akshay, and thanks for the question. I really think we need to look at the totality of the data here. When we compare to the external placebo, all of these parameters, including the longitudinal strain, trend towards improvement in the vutrisiran arm, again, consists, as actually as highlighted in Pushkal in his presentation, very consistent with what we saw on APOLLO. In terms of -- I think you asked which of these specific parameters would we put the most weight behind. I really think we need to look at the totality of the data here. That includes NT-proBNP, where we've again recapitulated strong treatment effect, highly significant. The trend we're seeing towards improvement across all of the echocardiographic parameters and now it's very exciting data with technetium, where we're seeing improvement in cardiac uptake of technetium across the majority of patients. So I really think we have to think about the totality of the data as opposed to pointing to any 1 specific echocardiographic parameter.

And ultimately, to patients, functional outcomes matter. And when we look at the 10-meter walk test data, we show stabilization relative to the decline in the control group, that's very encouraging indeed for patients. So does that help, Ritu?

Yes.

Our next question comes from Gena Wang with Barclays.

So I have one question regarding your Slide 15. When we look at the 2 scores, the measurement, it seems like it did not maintain the magnitude of benefit. It was very impressive, the opposite direction, but the magnitude did not maintain at 18 months compared to the month 9. And when we look at the knockdown level, it seems serum TTR level maintained very well through the 21 months. Just wondering what could be the reason causing that? And then very quickly on Slide 17, just wondering if you can remind us the baseline score for vutrisiran arm and the placebo arm for NT-proBNP?

Yes, I have just one very brief comment that I know Pushkal is very excited about these data and want to show why they're an important replication of APOLLO-A. But I'll restate what I just said to Ritu. We've had remarkable replication of data across different studies. And minor difference is here or there, when you look at the overall picture, it's striking, and patients have improved in their neuropathy both at the level you see on Slide 15 and also the proportion who improved relative to the control group. So I think we're very, very pleased with these data. Pushkal, your thoughts on any minor differences you see.

Yes. On -- thanks, Gena, for your question. Look, talking about Slide 15, I guess I have to do have to highlight what Akshay said. These are remarkably consistent. I mean, we're talking about a data set of less than a couple of hundred people. And looking at this over a period of 18 months, these are overlapping clinical effects. The treatment effect is about 29 points on the mNIS+7. That's a remarkably large difference there. And 20 points or so -- 21 points on the Norfolk Quality of Life. And I'll also remind you that we've seen -- now we have data of patients on patisiran from our open-label extension, 5-plus years. We have patients in the marketplace who've been on a silencer drug. So I really would sort of telescope out a little bit and say this is really evidence of halting and reversal of disease, and it's very consistent over time.

Thank you, Pushkal. Gena, does that help?

Yes. And also the Slide 17, the proBNP baseline for both vutrisiran and placebo.

John, do you want to take that?

Sorry, the question is -- what was it?

BNP baseline for -- in HELIOS-A and then in the control arm in APOLLO?

Yes. So the baseline NT-proBNPs are relatively consistent between the 2 studies.

And I think, Gena, you may have been in conversations that many of us had at JPMorgan, where we said the BNP is around 800, 900 in both APOLLO and HELIOS-A.

Next question comes from Anupam Rama with JPMorgan.

I just have a quick logistical question. Have any portions of the 18-month update been shared with regulators given the PDUFA is just a couple of months away? Or any updates beyond the 9-month update that have been shared with the regulators?

Yes. Pushkal?

Yes. So thanks for your question, Anupam. Yes, as appropriate, as we've said, we've got ongoing regulatory reviews in multiple territories. And as appropriate, we've been submitting the 18-month data.

Thank you, Pushkal. Does that help, Anupam?

Yes.

Our next question comes from Tazeen Ahmad with Bank of America.

How do you think we should be thinking about this cardiac subpopulation? How severe is the disease that was enrolled versus, say, what you were seeing for HELIOS-B? And then going back to NT-proBNP for a second, how would just compare the baseline values of the study to what BridgeBio had enrolled?

Yes. Let me just start, and then Pushkal, John, you guys may want to fill in. Many of these points were disclosed at JPMorgan, of course. And what we would highlight is that the population here, they all have neuropathy, a significant proportion of coexistent cardiomyopathy. The -- generally speaking, the patients coming into the study have Class I or Class II New York Heart Association disease. So they're at the earlier end of the spectrum. And I think one of the recent debating points has been, in fact, that can you ameliorate disease that when it's at the heart -- New York Heart Association 1, 2 stage and, in fact, both in APOLLO and here. We just discussed the BNP, which was about 800 in these studies relative to 2,800 or 3,000 when in the more advanced studies like ATTRACT. And even with these earlier-stage patients, we see the striking effect. So we're excited that we can impact Class I, Class II disease. And in more detailed analysis in APOLLO, we were able to show that, in fact, patisiran was impacting at all grades of disease in quartile of the patients with disease parity at baseline. Then both from the very early to the most advanced, we were able to have similar impacts. But Pushkal, anything else to add to that?

I think you really have covered it. I think you've hit all the key points. Tazeen, I think we're seeing efficacy. These are from a cardiac perspective, have lower BNPs than you might see than the BridgeBio folks reported from their study. But we see efficacy across the full range based on all the parameters that we've looked at even within subdivisions of patients in APOLLO and HELIOS-A.

And I mean, just to add and, Pushkal, I'm sure you agree that, this study was to address the primary endpoint of polyneuropathy. Patients had some coexisting cardiac disease. But of course, APOLLO-B and HELIOS-B, these are patients with established and unfortunately, much worse baseline numbers than these, I imagine. And so there, we'll be testing the full range of patients, Class I, Class II, Class III New York Heart Association.

Okay. I just wanted to squeeze in one more, if I could, about what are your expectations on patient switching once this gets approved from the approved indication in ONPATTRO in presumably a peripheral neuropathy indication for vutrisiran?