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 taped 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 Lead. 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 slide two, 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 relied upon as representing our views as of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'll turn the call over now to Yvonne. Yvonne?
Thanks, Christine, and good morning, everyone. Today, we're 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 through 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 nine-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 multi-billion 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 3 study in that population to potentially begin in late 2022.
Ultimately, the franchise is expected to also include ALN-TTRsc04, which comes from our IKARIA platform and provides the potential for a 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've 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're 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 is a single disease caused by TTR that results in a spectrum of clinical manifestations. Alnylam's RNAi therapeutics reduce the production of the disease-causing TTR protein in the liver, thereby reducing continued amyloid deposition and thus halting or improving the manifestations of disease. This concept was first demonstrated in the polyneuropathy of the disease with Onpattro or patisiran, then later shown with vutrisiran nine-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 three 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 is administered every three 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 three months. We're also evaluating a potential additional dosing regimen of 50 milligrams once every six months. 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 three 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 detail. 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 were randomized three to one to receive vutrisiran at a dose of 25 milligrams subcutaneously once every three months, or patisiran intravenously once every three 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 nine months, the change from baseline in the modified neuropathy impairment score, or mNIS+7, compared to the external placebo.
Now, early in 2021, we presented positive nine-month results from the study, which showed the study met its primary and secondary endpoints at nine months. These data formed the basis for our regulatory submissions to the FDA and EMA, as well as the Brazilian and Japanese regulatory authorities in 2021. The study was designed to continue patient dosing past the nine-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. The 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 patients enrolled across 57 sites in 22 countries. Baseline characteristics were generally well-balanced between the vutrisiran and patisiran reference arm in 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 interpatient variability in TTR reduction over the same time period.
As expected, the TTR reduction achieved with vutrisiran was statistically non-inferior to that observed in the patisiran reference arm. This 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 a 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 6.5 times 10 to the minus 20 and 1.8 times 10 to the minus 10, respectively, highlighting the robustness of the treatment effects.
In contrast to the control group that demonstrated 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 pre-specified 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, a measure of gait speed, modified body mass index, a measure of nutritional status, and the Rasch-built Overall Disability Scale, or RODS, 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 demonstrated 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 two slides, let me turn to two 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 sites. Treatment with vutrisiran was associated with an improvement in technetium uptake that has reduced tracer uptake in the heart relative to baseline in a majority of patients. Specifically, about two-thirds of patients showed a reduction in uptake as assessed by two 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 remained 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. While 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 of the efficacy data, an important question was to understand how the 18-month efficacy of vutrisiran and HELIOS-A compared to that seen with patisiran and 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 Forest 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. 18-month results with vutrisiran and HELIOS-A appear to line up well with what we saw with patisiran and APOLLO, in accordance with the similar levels of TTR knockdown caused by these two medicines. This is 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, three patients on the vutrisiran arm, or 2.5%, discontinued the study due to adverse events.
A 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 two deaths, neither of which was considered related to study drug. There were two serious adverse events deemed related to vutrisiran by the investigator, consisting of dyslipidemia and urinary tract infection. These two 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 site reactions were reported in five 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 in the exploratory cardiac endpoint NT-proBNP, trends towards improvement in echocardiographic parameters, and improvement compared to baseline in 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 at 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 three months or 50 milligrams every six months. These data, which are 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 my 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 therapies. 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 two 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 HCPs. 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. As a reminder to those dialed in, we would like to ask you to limit your questions to one each and then get back in the queue for any additional questions.
Ladies and gentlemen, if you have a question or a comment at this time, please press the star, then the one key on your touch-tone telephone. If your question has been answered or you wish to move yourself into the queue, please press the pound key. Our first question comes from Alethia Young with Cantor Fitzgerald.
Hey, guys. Thanks for taking my question and congrats on this data. I just wanted to talk a little bit about, I think, Rena's comments at the end on the mixed phenotype. Just can you help us think about kind of maybe what the contextualize around what's going on with vutrisiran now and how this connects to maybe having this subgroup and having the quarterly dosing actually be more attractive and also the preponderance of more cardio-related data to this mixed phenotype?
Thanks. Sorry, Alethia. At this time, it was a bit broken up.
I think just to recap your question, was it how's things going in the mixed phenotype with patisiran and what are the prospects for vutrisiran? Is that in a nutshell?
Yeah, essentially. I mean, and just since you have a lot of cardiac data with this vutrisiran data set and it's a subgroup, so just talk about how that could broaden out the market and what you've learned from being in the market so far. Thanks.
Yeah, sure. Rena, 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 neurologist and cardiologist 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.
Yeah.
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 on tafamidis. And so the prospects, I think, for Vutrisiran are very good in light of the continuing consolidation of cardiac data with the addition today of these very encouraging technetium data that we've seen. So does that help you?
Yeah. 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 presentation at J.P. Morgan that we have about 2,050 patients now on Onpattro.
If we think about the size of the opportunity that Rena shared of 30,000-40,000 patients, we really have a lot of growth to go, actually, in the hATTR polyneuropathy opportunity.
Awesome, guys. Thank you.
Thanks, Alethia.
The next question comes from Maury Raycroft with Jefferies. Maury, your line is open. You can ask your question. Good morning. I'm Rena. Okay.
Our next question comes from Salveen Richter with Goldman Sachs.
Good morning. Thanks for taking my question. In light of the amount of cardiac data here and recent competitor data, how does this impact your thoughts about APOLLO-B, if in any way? And generally, how do you want to approach the cardiomyopathy label?
Yeah. Let me just start, and then I'm sure Pushkal and John will want to follow up. We find that today's data is extremely encouraging overall.
Obviously, for the polyneuropathy, we've shown data recapitulating the improvement we saw with patisiran on Onpattro and APOLLO. So that's very exciting. On the cardiac side, we also see very encouraging data that looks similar to what we found in the cardiac subgroups 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 test, a functional walk test stabilizer improved, and the encouraging echo and technetium findings, I think this bodes very well for the prospect of RNAi-based mechanisms in this disease. But Pushkal, you want to speak to prospects for APOLLO-B?
Yeah. 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 seeing consolidation and a 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 Centre, 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 manifestations, cardiac manifestations, multiple data sets, multiple points in time, internal and external consistency, it just strengthens our conviction.
We're very much looking forward to the results of the APOLLO-B study in the middle of this year. Great. Thank you.
Our next question comes from Ritu Baral with Cowen.
Hi, guys. Thanks for taking the question. I wanted to ask you about the sort of relative importance of the exploratory echo measures. And 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 four 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 six-minute walk represents, which is sort of like exercise capacity, cardiac capacity, etc.?
Yeah. 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. First of all, these are, of course, exploratory endpoints, and 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 two studies separated in space and time with two different drugs, to see this kind of recapitulation of data to our eyes is wonderful, actually. And as we were discussing earlier, consolidates that 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, 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 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?
Yeah. 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 within the vutrisiran arm. Again, consistent, as Akshay has highlighted and Pushkal in this 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 there'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 one 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? Yeah. Thanks.
Yeah. Thank you so much.
Our next question comes from Gena Wang with Barclays.
Thank you for taking my questions. So I have one question regarding slide 15.
When we look at the two 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 the 18 months compared to the month nine. 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. 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.
Yeah. Now, just one very brief comment that I know Pushkal is very excited about these data and will want to share why they're an important replication of APOLLO. But I'll restate what I just said to Ritu. These are remarkable replications of data across different studies.
And minor differences here or there, when you look at the overall picture, it's striking. 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?
Yeah. Thanks, Gena, for your question. Look, talking about slide 15, I guess I 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 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 on patients on patisiran from our open label extension, five-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 NT-proBNP baseline for both vutrisiran and the placebo arm. John, you want to take that?
Sorry. The question is, what was the BNP baseline in HELIOS- A and then in the control arm in APOLLO?
Yeah. So the baseline NT-proBNPs are relatively consistent between the two studies.
And I think, Gena, you may have been in conversations that many of us had at J.P. Morgan where we said the BNPs were around 800, 900 in both APOLLO and HELIOS-A.
Thank you very much.
Our next question comes from Anupam Rama with J.P. Morgan.
Hi, guys. Thanks so much for taking the question. I just have a quick logistical question. Have any portions of the 18-month update been shared with regulators, given that PDUFA is just a couple months away, or any updates beyond the nine-month update that have been shared with the regulators? Thanks so much.
Yeah. Pushkal?
Yeah. So thanks for your question, Anupam. Yeah. 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?
Yep. Good.
Our next question comes from Tazeen Ahmad with Bank of America.
Hi. Good morning, guys. Thanks for taking my questions. 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 you compare the baseline values of the study to what BridgeBio had enrolled?
Thanks. Yeah. Let me just start, and then Pushkal, John, you guys may want to fill in. Many of these points were discussed at JP Morgan, of course. And what we would highlight is that the population here, they all have neuropathy. A significant proportion have coexisting cardiomyopathy. 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.
I think one of the recent debating points has been, in fact, that can you ameliorate disease when it's at the New York Heart Association one-two stage? 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 in the more advanced studies like ATTR. Even with these earlier stage patients, we're able to see these striking effects. We're excited that we can impact Class I and Class II disease. In more detailed analysis in APOLLO, we were able to show that, in fact, patisiran was impacting at all grades of disease. We quartiled the patients for disease severity at baseline, then both from the very early to the most advanced, we were able to have similar impacts. 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 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 will be testing the full range of patients, Class I, Class II, Class III New York Heart Association.
Okay. Thanks, and can I just? Yeah.
I just wanted to squeeze in one more, if I could, about what are your expectations around patient switching once this gets approved from the approved indication in Onpattro, presumably a peripheral neuropathy indication for vutrisiran?
Yeah. I think the prospects with Onpattro being on the market and so well embraced by the community and then an option once every three months really presents an opportunity for us to sort of grow the base of patients that can be helped by our drugs. But Rena, what would you say?
Right. There will be both patients who are on Onpattro who will really want to stay on Onpattro. They're happy with that treatment and do not want to switch. There will be some who do want to switch, but it's also really about identifying those new patients and providing vutrisiran as a growth opportunity.
There will also be patients outside of the U.S., certainly, who will be switching from other therapies, not Onpattro, but perhaps other silencers or stabilizers who will find Vutrisiran as an attractive option.
Thank you, Rena.
Thank you.
Our next question comes from Paul Matteis with Stifel.
Great. Thanks so much for taking the question. I wanted to ask one question about the NT-proBNP analysis. From the footnote, it looks like you presented the data for Vutrisiran for all patients where the baseline is less than 300. Am I reading that right, just based on the sample sizes? And if I am, does the data look the same in the cardiac subgroup in this trial?
And then separately, going back to your point, Akshay, regarding the ability of a TTR silencer to impact heart failure in early-stage patients, I'm wondering, now that you have a lot of experience tracking NYHA Class I and Class II patients, do you see in your trials that at a time point like nine months or 12 months, that these patients show a trend towards getting functionally worse, or are you really just seeing worsening of biomarkers in these populations? I guess when you kind of just think about it in terms of placebo arms. Thanks so much.
Yeah. So I think there were two questions. One is a question around baseline BNPs and the footnote. And the second is worsening at nine months. Do I have that right, Paul?
Yeah.
Well, so it looks like if you look at slide 17, it looks like the BNP data for vutrisiran are for all patients, not the cardiac subgroup. And the baseline for all patients is really low. I think it's below 300. So I was just kind of curious why you presented the data that way.
Yeah. Well, of course, it's the most conservative way to present the data for the MITT analysis. I think regulators would certainly applaud that. But John, do you have anything to say on what would you expect of the BNPs in the cardiac subpopulation relative to the overall population?
Yeah. Thanks. You're correct. What we've shown here today, again, these are the overall study results, and we've shown the NT-proBNP in the overall study populations.
You're pointing out, as I think we've illustrated on the slide that's comparing across the studies, we saw a very consistent result in the cardiac subpopulation as well with regard to NT-proBNP.
And Paul, the second part of your question on the progression of disease, I mean, the cardiac disease progresses inexorably, unfortunately, in these patients, both in the hereditary setting and the wild-type setting. And even at nine months, you see not just the deterioration in biomarkers and imaging parameters, but you also see functional deterioration in many patients. So our further studies, APOLLO-B and HELIOS-B, will go out to longer time points, but we're confident that, for example, at one year in APOLLO-B, we'll see a difference in an important functional test such as six-minute walk distance between patisiran and placebo. Hope that helps.
Okay. Yeah, it does.
Even in Class I patients, you think they're still likely to show a decline based on your experience running these different endpoints.
Yeah. I mean, if you look at the current data in this HELIOS- study, these patients have Class I or Class II disease. And look at the 10-meter walk. Rather, you'd have to look in the control arm, but look at the 10-meter walk or look at the other parameters in the control arm. And they show deterioration in Class I and Class II. Pushkal, you think? Yeah. I mean, Paul, to that point, right? We saw that in HELIOS- A. We saw that in APOLLO, as Akshay mentioned, the ATTR study. The NYHA Class I and II patients progressed.
When we did the quartiles analysis on BNP, we saw even people below the median in the first quartile of low BNPs continue to progress. And the U.K. NAC study also enrolled patients who were polyneuropathy predominant, and those patients continued to progress.
Yeah. I just want to make one other point back to your question about NT-proBNP and what we've presented. I just want to make sure it's clear that what we're showing in the placebo arm in that slide is also in the overall placebo population from APOLLO. And you can see that marked worsening of NT-proBNP in those patients who also were less severe, of course, than the cardiac subpopulation from that study.
Thank you, John. Good point.
Thank you.
Thank you, Paul.
Our next question comes from Ellie Merle with UBS.
Hey, guys. Thanks so much for taking the question and congrats on the update.
I guess just in light of the cardiac subgroup data here, can you help us understand a little bit sort of bigger picture how you're thinking about differences in efficacy in the hereditary versus wild-type cardiomyopathy patients? And I guess maybe even within this cardiac subgroup, looking at some of these endpoints like technetium uptake and echocardiograms, any learnings in terms of how maybe different genetic subgroups within the cardiac subgroup performed in terms of thinking about potential efficacy in the wild-type cardiac population? Thanks.
Yeah. Thanks for the question, Ellie. So these data focus, of course, on the hereditary population. Generally speaking, I think most people would say that's the most stringent test of drugs in the TTR space. We're delighted with these findings showing improvement in neuropathy and the extensive exploratory cardiac data we've discussed today, including improvement in technetium in many patients.
Given the common pathogenic mechanism, which I discussed in the commentary of TTR being misfolded and depositing in the heart, is the common thing, whether you've got hereditary cardiomyopathy or the wild-type, we would expect that these data all go well for what we will see in the wild-type patient population when we get the data from APOLLO-B and HELIOS-B eventually. So we're excited about that. Pushkal, anything to add?
Yeah. I think, obviously, concur with everything you've said. I think this is a stringent test for the mechanism looking at these patients with hereditary ATTR, Ellie. I would also just point out that we've looked across the range of genotypes, for instance, that have been in these studies, and we've seen consistent efficacy across the full range of genotypes, including very aggressive genotypes like T60A and others, and so V122I, etc.
So I think all of that portends well for the role of this mechanism. And then the last point I would just make is probably the most robust data that we have to compare across hereditary and wild-type comes from the ATTR-ACT study where they did see in that study fairly consistent progression and treatment effects across the two populations.
Thank you, Pushkal. Thanks, Ellie.
That's great. Thanks.
Our next question comes from Patrick Trucchio with H.C. Wainwright.
Hi. Good morning. I'm wondering if you have the data on slide 19 and 20 broken down by patients with prior stabilizer use, and if so, if there's any difference between the treatment naive versus prior treated patients. And then secondly, just to what extent can we expect these exploratory CM endpoints to be included in the initial vutrisiran label, and how important would that be for the launch this year?
Yeah.
Both the findings from APOLLO and the current study clearly show that whether patients were on prior to tafamidis or not, they do well in these studies with patisiran in the APOLLO study and with vutrisiran here. We're impressed by the extent of efficacy in patients that were previously on tafamidis. I don't know whether we've broken down these current data you speak to, but we're getting to very small subgroups or subgroups once we start doing that. Generally speaking, that's not something we'd do. Pushkal, anything to add?
No. I would just say, as you said, we're seeing consistent results with this across the full array of endpoints that we've looked at in patients who have been or have not been exposed to stabilizers in the past.
And so that's, again, a good indicator of the efficacy, the potential efficacy of this in other studies as well. And then you asked a question about the label, and this is under regulatory review, so we can't really comment on what the ultimate label will look like. That's for the FDA to decide.
Thank you, Pushkal. Thanks, Patrick.
Thank you.
Our next question comes from Luca Issi with RBC Capital.
Paul, great. Thanks so much for taking my question and congrats on the data. Two quick ones. The first, maybe on page 20 on the right side of the page, it looks like the benefit in left ventricular wall thickness is actually a little bit more modest for vutrisiran in HELIOS-A versus patisiran in APOLLO-B. So wondering if you can comment on what's potentially driving that. And then second, maybe on 10-meter walk test.
I don't think I saw the 10-meter walk test for the cardiac subgroup. So can you provide any color on what you've seen there? And then maybe bigger picture, whether you think that the 10-meter walk test is a good proxy for six-minute walk test or not. Any color there would be great. Thanks so much.
Yeah. Several questions there. Let's go one by one, and I know my colleagues will want to jump in as well. So with respect to your comment on, I think, slide 20 and LV wall thickness, let's use the phrase that Pushkal used about standing back and telescoping back. I think it's very, very important, Luca, that to see this kind of replication across studies is surprising. And to our eyes, it's a wonderful replication of the overall data set, neuropathy, some of these exploratory cardiac endpoints.
Nothing's going to be exactly the same across two studies, and I caution about a recent example with a stabilizer and the BridgeBio experience, so to see the kind of reproduction of data that we're seeing here, if you speak to drug developers, I think, generally speaking, people will be very encouraged, so when you speak of a small subgroup of a small subgroup in a small sample size and look at one aspect like the LV thickness, I think we have to look at the overall picture, and the overall picture, as I think we've all noted, is very encouraging indeed in terms of consistency of the mechanism of action. The second point you made is that: have we got the cardiac subgroup 10-meter walk data? Again, I think that's such a small subgroup of a subgroup. I don't think we've done that.
Certainly, regulators wouldn't expect us to do that. And then what, sorry, what was your last question?
I was wondering if 10- meters walk test.
Insights from the 10-meter walk test. Yeah. Sorry. Yeah. Look, the 10-meter walk test is an important functional walk test. It's especially favored by neurologists, but you can appreciate it focuses on speed over a period of time as opposed to distance walked over a period of time. And clearly, it's integrating both neurological and cardiac aspects. Both would be involved. But we think it's a very important functional measure. We think it bodes well for what we ultimately hope to find with six-minute walk distance in APOLLO-B . If you look at, Pushkal brought up earlier the National Amyloidosis Centre study, the Fontana paper where they showed stabilization of six-minute walk distance with patisiran. So it was formally measured relative to their historic controls.
So we're looking forward eagerly to the APOLLO-B data later in the year, but I think the 10-meter walk test bodes well. It's an important functional walk test. Does that help, Luca?
Yes. Thanks. Super helpful. Thank you, Akshay. Thank you.
Our next question comes from Mani Foroohar with SVB Leerink.
Hey, guys. Thanks for taking the question. Following up on Paul's question around slide 17, obviously, these are both all common regarding cardiac subgroup, but the gap in NT-proBNP at baseline is quite substantial from below 300 in the vutrisiran group versus the APOLLO placebo rolling up to 500. So I'm not really sure how meaningful this comparison is, but does that change in terms of baseline? Is that reflective of the experience of progressively more mild patients enrolling across your TTR franchise?
And how do you think that might be reflected in what we'll see in APOLLO-B and HELIOS-B? Should we also expect progressively milder, earlier patients with lower event rates in those studies as we saw in ATTRibute-CM?
Yeah. So let's recall this is an hATTR amyloidosis peripheral neuropathy study. So all patients were expected to have peripheral neuropathy at baseline, and some may have had cardiomyopathy, and we've demonstrated that today. And we specifically restricted the entry of patients with cardiomyopathy coexisting to New York Heart Association I or II. So by design, they would have early-stage disease. We were attempting to reproduce what was in APOLLO, and in fact, there's a wonderful reproduction both in terms of the baseline disease characteristics as well as the results from APOLLO, we believe.
Earlier, we discussed that this mechanism of action is impactful across all grades of baseline BNP and these other cardiac features. But Pushkal, do you want to add anything to that?
Yeah. The only thing I would just add to all the things that you expressed, Akshay, is, Manny, you questioned the interpretability of the data. I guess I'd have to disagree. The analysis actually adjusts for the baseline NT-proBNP. So these are, we think, quite robust analyses. Again, they indicate that everything that we've seen suggests that there is progression across the full range of baseline NT-proBNPs that we've evaluated in these studies, and that the silencer mechanism appears to have a meaningful effect across that full range as well.
Yeah. I do see the adjustment for baseline, and that makes sense.
Although the absolute relevance of a single point difference for a 500 versus a sub-300 baseline might be different. Let's approach from a different perspective. When looking at the patients that did see signs of improvement in this study on these cardiac endpoints that were exploratory, but you clearly collected in a very disciplined fashion, obviously very well in study, were there differences in baseline characteristics from the patients that saw improvement on cardiac exploratory endpoints versus those who did not? And what were those differences that you saw in this study?
Yeah. I mean, I think just to answer at a high level, we showed clearly in APOLLO that the RNAi mechanism of action, whether it's patisiran and now here with vutrisiran in HELIOS- A, works through all grades of disease. The cardiac subgroups in both studies will necessarily have more severe baseline disease.
Their BNPs will be worse than the overall population. Their LV thickness will be worse. Their LV strain will be worse, etc. And whichever way you cut the data, we showed the impact on the disease in a consistent fashion, albeit these are exploratory endpoints. And so I think that that's really very exciting. And the important thing for us is to be able to help all grades of patients, whether they're at an early stage or a more advanced stage. And if you look at the totality of data across APOLLO and here in HELIOS- A, we clearly can do that. And if you're concerned that can we help early-stage patients, I think these data attest that we can. And that's great. We hope patients do get diagnosed earlier, and we can help them.
But across the two studies, we're building a very robust picture of the ability of our drugs, both patisiran and vutrisiran, to help patients with cardiomyopathy. And of course, the ultimate data will come out now with APOLLO-B and then HELIOS-B. But these are very encouraging and support confidence for those studies. Thanks.
Great. Thanks, guys. Take care.
Our last question comes from Gary Nachman with BMO Capital Markets.
Hi. Thanks for squeezing me in. So across the data sets you showed, patisiran and vutrisiran seem to be pretty similar. So outside of dosing benefit from vutrisiran, is there any other notable benefit for vutrisiran versus patisiran across the different endpoints? Should they be viewed pretty interchangeably from an efficacy standpoint from the data that we've seen thus far? Thank you.
Yeah.
I'll just agree with an important comment you made, Gary, that the data indeed are very similar, and the two drugs with a similar mechanism of action with similar degrees of TTR knockdown are delivering these remarkably consistent neuropathy and exploratory cardiac outcomes across two different studies. Rena, what would you say to the expansion of our offerings with now patisiran and hopefully soon vutrisiran?
Yes. I think it is an exciting opportunity and an exciting time to expand the franchise. Really, there's a heterogeneous patient population, and we want to ensure that the patients and their physicians have that optionality to choose a treatment option that best meets their needs. I think regarding the data packages of both products, so far, they are quite similar.
As we look at the B studies, right, they will be slightly more differentiated in what the data package readouts of APOLLO-B and the HELIOS-B studies are anticipated to yield over the coming years. So that's where you will see further expansion of the data available on both agents.
Thanks, Rena. And thanks, Gary. Over to you, Pushkal. Thank you. Yvonne.
Thanks again to everyone for joining today. We're really excited by the prospect of making vutrisiran available to patients and look forward to the potential FDA approval in April and later this year in Europe and other markets, which, if positive, will lead to the launch of our fifth commercial RNAi therapeutic, which is wonderful. So have a great day, everybody. Thank you.
Thank you.
Goodbye.
Goodbye.
That concludes today's presentation. You may now disconnect and have a wonderful day.