Welcome, everyone. Glad to have you here at HFSA. This is Alnylam's first in-person investor event post-pandemic, so we're really extra pleased to have you here as well. I'm Christine Regan Lindenboom. I am the Senior Vice President of Investor Relations and Corporate Communications at Alnylam, and we've got a great panel with us today. So we'll have Pushkal Garg, our Chief Medical Officer, give some opening remarks. Mathew Maurer is joining us from Columbia University, and he will review the data that was presented earlier today, and then we'll go through some summary and next steps. We'll then have Tolga Tanguler, our Chief Commercial Officer, join us for a Q&A, as well as John Vest, our Vice President of Clinical Research as well. Before we start, I wanted to share some forward-looking statements. Please review those at your leisure. Thank you.
Then we will take Q&A both from the room as well as from the webcast. If you're on the webcast and you have a question, feel free to type it in the Ask a Question box, and we'll try to get to as many as we can. With that, I'm going to turn it over to Pushkal to lead us off.
Oh, you don't need that.
I don't need that, yeah.
Thanks, Christine, and thank you all for choosing to spend your Friday evening with us. We really appreciate that. It's really exciting to be here at HFSA sharing additional data from the APOLLO-B clinical trial of patisiran in ATTR cardiomyopathy. I'm going to turn it over to Dr. Maurer in just a few moments to actually walk through the data that were presented today. But maybe at a high level, I just want to give the perspective that we couldn't be more excited by the results. Building on the top-line data that were presented at ISA about three and a half weeks ago that showed statistically significant and clinically relevant benefits of patisiran on six-minute walk tests and KCCQ, the results today look at those data across a number of pre-specified subgroups and show general consistency of effect across all of the pre-specified subgroups.
In addition, important data from exploratory analyses indicate benefits or favorable effects on measures of cardiac stress, cardiac injury, cardiac structure, and cardiac function coming from biomarkers and imaging modalities. So all very exciting and building upon corroborating the top-line results that were presented a few weeks ago. And that, along with an encouraging safety profile, together really fuels our belief that patisiran and RNA therapeutic agents in general that target TTR can be effective therapeutics for patients with ATTR cardiomyopathy. So that's important, as at Alnylam, we are looking to build an industry-leading TTR franchise. If APOLLO-B, we will be submitting it for an sNDA at the end of the year, and if that's successful and meets regulatory approval, it may be on the market at the end of 2023.
It builds upon our already two commercialized products, Onpattro and Amvutra, for the polyneuropathy of hereditary ATTR amyloidosis. And beyond that, we're looking forward to the HELIOS-B trial of vutrisiran in ATTR cardiomyopathy. We're kicking off a program with ALN-TTRSC04, which has the potential to be a once-annual therapy for patients with ATTR amyloidosis, as well as exploring the potential of TTR silencing to be a therapeutic for Stargardt disease, an inherited retinal disease. So together, we think we have the potential to build a franchise that may offer tremendous benefit to patients and also, as well as be a big source of growth and value creation for the company.
And all of that feeds into our aspirations for our P to the fifth by 25 strategy, which is a vision to actually have a top-tier biotech that is delivering medicines for rare and prevalent diseases to patients all around the world, advancing the clinical development of innovative therapeutics that can transform the lives of patients built upon our organic product engine, and as well as deliver strong financial performance. So with that, I'm going to turn it over to Dr. Maurer, who's going to walk you through some of the data that were shared today. Matt?
Oh, it's really a pleasure to be with everybody. I must say, these data look better and better all the time, I have to say. The more endpoints we look at, the better they look. So just to review, I think you're all aware, transthyretin cardiac amyloidosis is a pretty terrible disease. It's rapidly progressive, and it results from misfolded monomers or oligomers of the transthyretin protein that can deposit in many organs, but the heart is one of the main ones. And patients can either have hereditary disease inherited in an autosomal dominant fashion or wild-type disease. It results typically in a restrictive cardiomyopathy with heart failure as a manifestation. Obviously, in heart failure, patients have declines in functional capacity and quality of life. They have increased hospitalizations and, unfortunately, pretty shortened survival.
Patisiran, which we've been leveraging for patients with transthyretin amyloid polyneuropathy for several years since its approval in 2018, is IV-administered RNAi therapeutic. Prior data that we analyzed with Scott Solomon and others, and we published several years ago, showed that in patients with polyneuropathy who have concomitant cardiomyopathy, there were demonstrable effects of patisiran on important cardiac endpoints, biomarkers, and echocardiography. I would say parenthetically, if I had one thing to do over in the field, I probably have a few. I might have not let us to dichotomize into neuropathy and cardiomyopathy because many patients have both. Apollo-B, as you, I think, know, is a phase three randomized double-blind international placebo-controlled clinical trial in patients now with transthyretin amyloid cardiomyopathy. There were 360 patients enrolled in this trial. They either had wild-type or variant disease. They had symptomatic heart failure.
There were key entry inclusions related to biomarkers I mentioned previously. Their NT-proBNP had to be above 300. If they're in sinus rhythm or greater than 600, there was an upper limit of 8,500 for certain patients. And they had to have a minimum walking distance. And up to 30% of the patients were allowed to be on background tafamidis therapy for at least six months and, in the opinion of the investigator, were progressing. Subjects were randomized one-to-one to either patisiran, which was given IV every three weeks, along with concomitant medications to prevent infusion reactions, or placebo. The placebo group also received those concomitant medicines. And randomization, as you see at the bottom here, was stratified based on several variables.
Importantly, whether they're taken tafamidis, yes or no, did they have hereditary or wild-type disease because progression is very different, and did they have New York Heart Association Class I or II disease, and were they less than 75 versus all others. The primary pre-specified endpoint was the change in the six-minute walk distance from baseline to 12 months. Key secondary endpoints are shown here. The KCCQ is the universally used in cardiomyopathy trials, and we used the overall summary score, and it's changed from baseline to 12 months as a measure of health status or some people say quality of life. And we looked as well at death and hospitalization outcomes over the 12-month study period. And at the meeting here, my colleagues presented data on the cardiac biomarkers and very intriguing and positive effects on imaging. And the patients are now in an open-label extension, which is fantastic.
These are the high-level, if you will, table one data that demonstrate randomization works. The groups were well-balanced across all the parameters. As you can see, the average age of these patients is 76. It's a male-dominated disease, which we've always struggled with a little bit, but it's still borne out even in our clinics. 80% had wild-type. You can see down that they're average NYHA class II. Baseline tafamidis use was 25% in each group. The Gillmore staging system that we talked about earlier, using NT-proBNP above 3,000 or an eGFR less than 45, is used to rate patients into stage one, two, or three disease. You can see most patients had stage one or two disease. Six-minute walk distance, about 360 meters, compatible with class II symptoms.
And so was the KCCQ overall score, about 70, with median NT-proBNP levels across both groups about 1,900. I say picograms per mL, but here it's nanograms per liter, same units, but depending upon whether you're in the States or across the pond, as they say. So patisiran is really very effective at its therapeutic goal of lowering TTR. And you can see here rapid reductions within three weeks. At month 12, there was an 86.8% reduction in serum TTR in the full cohort. And you can see that there were comparable serum reductions in TTR irrespective of whether you received tafamidis at baseline or not or were taking it through the duration of the trial. So that's important. This is the data from the primary endpoint. So it demonstrated a significant clinical benefit.
As you can see, the kind of group in red, if you will, is the placebo group, and they have a steady and progressive decline measured first at sixth and nine and twelve months with a change in their six-minute walk distance on average of 21 meters declining. And the group on patisiran is quite stable. And the absolute, or I should say the median difference, was 14, 15 meters and statistically significant. And we showed, I think, at the ISA in Heidelberg that the pre-specified sensitivity analysis using the MMRN confirmed these findings with similar statistics, a slightly greater effect size. These are the data for the secondary pre-specified endpoint. That was the quality of life of patients for their KCCQ.
Again, I think you can see remarkably stable self-reported quality of life based on the overall summary score over the 12 months that, unfortunately, doesn't occur in patients who were taking placebo. These differences were nearly four points with, again, a statistically significant p-value. These are the new data that we've presented, I think, here. This is a forest plot showing the effect size across many clinically relevant cohorts. As you can see, overall, the point estimates and the confidence intervals in some are wider, but the point estimates always favor essentially patisiran, both for the 6-minute walk distance and for the KCCQ overall summary score. Very, very, very consistent benefits across multiple different subgroups. This is the time to first event. These events include kind of harder things, if you will, all-cause hospitalization, urgent heart failure visits, or deaths.
You can see for the full analysis set, a hazard ratio that's not statistically significant. HR is 1 but favors patisiran as opposed to placebo. Subgroups divided by whether they were taking baseline tafamidis or not on tafamidis. Someone asked in the previous about these differences, and I think these are very small subgroups, so I would interpret them with a lot of caution. I think there are 91 people in the entire cohort that are taking tafamidis that gets divided up into little groups. All-cause mortality over the 12-month double-blind period is shown here. Again, in this trial, as in others, when patients progress and are sick enough to, God forbid, need and are eligible for a heart transplant, or rarely if they're sick enough and they're eligible for an LVAD, we equate that to equivalent to death.
That's been the standard in the field. And you can see here that in patients on placebo, there were unfortunately 10 "deaths" and only four in the patients on patisiran. Two of the subjects got a heart transplant on placebo and none on patisiran, and the CV deaths were five and two. You can see, again, in favor of patisiran. The hazard ratio estimate, again, crosses one, but it's certainly way in favor of the drug with a point estimate here of 0.355. And the data here doesn't differ whether someone is taking baseline tafamidis or not. Numerically, in all circumstances, patisiran has a more favorable hazard ratio than placebo in the subgroups, as you can see. These are also, I think, new and somewhat complementary data. This is just the geometric fold change in NT-proBNP, a marker of cardiac stress. This rises quite a bit in patients.
Recall back to our natural history study years ago. People's NT-proBNP went up 1,800 picograms per mL in the ATTR-ATTR study years ago that defined the natural history in six months. So it's a pretty bad disease. We've obviously identified people now who have an earlier phenotype, but the increase you can see in NT-proBNP over a year in the placebo arm was, on average, from baseline 518 picograms per mL or nanograms per liter, pretty significant increases, and you can see that the patients on patisiran really had very minor increases, probably not at all clinically significant, and here, the statistics aren't even close to being borderline. They're highly statistically significant. This is similar data for another cardiac, if you will, stress marker. These are patients who have often what we call colloquially troponinemia. They come into an emergency room. They have a troponin elevation.
They often get inappropriate catheterizations because people think in the absence of a coronary syndrome they're having coronary disease, but this is a marker of the disease. And here, we're using high-sensitivity troponins. And you can see, again, the mean fold change much lower in those on patisiran than those who were taking placebo. Did I do something? Nope. Looks. And you can see the baseline data was well-matched for the high-sensitivity troponin I and the changes there. These are also new data that are presented at the meeting just recently and I think are beyond encouraging, really amazing at such a short period of time that we can see these, I'd say personally, highly significant and dramatic effects on cardiac structure and function. So you can see global longitudinal strain, which is a measure of myocardial shortening, is getting significantly worse in those on placebo.
That's attenuated by treatment with patisiran. LV mass, which is composed, ideally, the heart is composed only of muscle and some intracellular tissue, but in this case, a lot of amyloid is very stable, or if not slightly better, declines in LV mass in those on patisiran while those on placebo progress. Over time, the ventricle with this disease usually gets smaller, less capacious, if you will. The end-diastolic volume usually goes down. You can see that happening in the placebo group, which is not happening with the blue, the patisiran. As a result, if the ventricle is a little bigger and it can generate a little better stroke volume, then cardiac output is maintained, which is one of the central physiological responsibilities of the heart. I'm not touching a thing. I think it's just the.
The wall thickness also, which has been kind of an old-fashioned and I would say not very robust measure from years ago, basically also shows trends in the right direction, as does what's called the relative wall thickness. Okay. Looks like we need some duct tape. These are also new and I would say pretty provocative data. As you all know, the diagnosis of transthyretin cardiac amyloidosis has also undergone a revolution. We used to have to stick people under a cath lab table and do an endomyocardial biopsy. We use technetium-labeled agents, different ones in the U.S. versus Europe, PYP in the U.S., HMDP also in the U.S., I recently learned. It is approved, by the way. Both are available. I used to tell people in lectures there's only one in the U.S., but I turned out to be wrong.
That's because we just had a shortage of PYP, so we all found out that HMDP was also approved. And we started using it. It works great. And also DPD scintigraphy. So these are used to diagnose the condition. There's emerging data about quantification using CT scans. In this particular subgroup, there were 37 patients who had serial scans with patisiran and 28 in placebo. So it's not the entire cohort. But as you can see in the chart, if you will, on the upper right, almost everyone's a grade two or three. That makes the diagnosis. Almost everyone's grade three to start. And there are patients who go from grade two to grade one or grade zero. And that's not something we expected to see, to be frank, in the world of amyloid. And I've never seen that with any stabilizer therapy.
So with all the caveats of we've never known what technetium's binding to begin with, this certainly suggests that something important and demonstrable is happening in the heart in a very good way. And there was essentially no one who got placebo who got any better or had a change. You can see all the red, in fact, patients on placebo. Probably, if anything, one of them got worse. So this is, I'd say, one of the more provocative things to come from this study, especially as someone who years ago said scintigraphy is good for diagnosis but is never good to follow patients. So I've said a few things that are probably wrong, but at least I admit them. So these are the safety data. I think mistakenly people were worried about this drug in the past, but you'll see there's nothing to worry about.
Majority of AEs were mild to moderate in severity. AEs that occurred more often in the patisiran group than the placebo were what everyone expected, right? An infusion reaction, arthralgias, or muscle spasms, and oof, this is sorry. Okay, but numerically, you'll see the AEs, including the important ones we mentioned at the bottom, deaths, were numerically in favor, and they change a little bit because death related to COVID, which I would note was only one person in the whole trial, which is kind of unbelievable in the midst of COVID, that this entire trial was conducted by Alnylam and the sponsors in a fashion, I would just say, that is probably better than any clinical trial I've ever seen with regard to fidelity and to the proposed intervention is just a mind-boggling phenomenon.
I mean, never mind that it's wildly successful and met every endpoint. [What matters] is that it was conducted in a way that allowed patients to get access to the therapy and get it at times at their home, so it was convenient and not be at risk for developing COVID. [That] is really a testament to not only the sponsor and everyone they work with, but also, I'd say, the patients. This is the cardiac safety data that just uses standard MedDRA queries that clinicians provide. And as you can see, everything is less on patisiran than placebo. Overall cardiac disorders, cardiac failure, arrhythmias. I would note no one had Torsades. That's just a reflection of the nomenclature that is used in this, but certainly no safety signal and, if anything, a trend toward benefit. You may just want to hang out there at that little spot. Okay. I'll keep going.
I'd say, in summary, this is a really short-term trial. I mean, it's 12 months. I can recall times where KOL sat in a room, and obviously, sponsors always want to try to develop their drug as quickly as possible. And we all said neuropathic effects at 18 months, you'll be lucky, and cardiac, you need to take a long time, so I think it's just amazing that these changes are seen in this relatively short time period. And it definitely supports the hypothesis that RNAi therapeutics to reduce TTR, they nicely say potential treatment because that's probably the right thing to say, but I think they're going to be a treatment for patients, in my opinion. It met every primary and first secondary endpoint. There were consistent benefits, as we show now, across all pre-specified subgroups.
Time to first event, including important ones of all-cause hospitalization, urgent heart failure visits, and God forbid, death, and even all-cause mortality directionally really strongly favored patisiran. And that was, again, only over a short period of time. And the exploratory endpoints that are presented here, as I said, are just more icing on the cake. Cardiac stress measured by NT-proBNP and troponin are all beneficial with patisiran compared to placebo. Most echocardiographic parameters move in the right direction. Those that don't are probably just derived and have higher variance. And amazingly, scintigraphy seems to, at least preliminary data, suggest that things might be getting even a little better, certainly are stable. It has a very acceptable safety profile. There's been no emergent cardiac safety concerns. And thankfully, I've had the privilege of caring for my cohort, and they're still getting access to the drug.
And now they're all open label in an extension trial. So congrats to the patients, most importantly, and to Alnylam. My pleasure.
Thanks, Dr. Maurer, for that fantastic summary and presentation. We'll take some questions in just a moment. But maybe what I wanted to do, sorry, was just very briefly just summarize next steps. So we are obviously very encouraged by these data. We are intending to file an sNDA with the U.S. FDA by the end of this year, hopefully for approval. We are also looking into other geographies and regions where there may be regulatory submissions subsequently. If this is approved by the FDA, we would anticipate being able to commercialize patisiran, Onpattro, for ATTR cardiomyopathy towards the end of 2023.
And then, as we've talked about at the beginning of this, we're also eagerly anticipating the vutrisiran study in this same patient population, which is expected to read out in early 2024. And certainly, the results that we've seen here across the whole range of endpoints that Dr. Maurer just highlighted really give us further encouragement in the probability of success of that study, which is a larger and longer study. So with that, I do want to just close by building on what Dr. Maurer said, which is that this study couldn't have been successful without the 360 people and their families who volunteered. It's a sizable commitment and a matter of trust that those patients volunteered for the study. We're very appreciative to them. We're appreciative to all the investigators, site staff, study coordinators, and colleagues at vendors, CROs, and Alnylam colleagues who made this study possible.
Thanks to all of them. We will open it up for Q&A. I'm going to invite up Dr. Maurer. I'm going to invite up Tolga Tanguler, who's our Chief Commercial Officer, and John Vest, who's the Senior Vice President and leads our clinical TTR franchise. Am I supposed to sit up here too? All right. Okay. I don't think I need this. Maybe we'll start. We've got a number of people in the room, and we also have people on the webcast. We'll start with some questions in the room. If everyone could just introduce themselves, that would be great.
Hi, guys. Ritu Baral from Cowen. Thanks for taking the question. I want to zero in on that figure seven, Dr. Maurer, from your poster, the one with the subgroups and time to first event.
Is there any biochemical rationale as to why one of those subgroups looked different than the other? Any biochemical rationale for synergy? And if you looked at those two, I know they're small numbers, but it seemed like the separation in the background TAF occurred in the second six months versus the separation in the without TAF group against patisiran was in the first six months. So the delta was sort of in the first half versus the second half. And I believe you guys in your last call said that that was sort of a cluster of hospitalizations that occurred in the tafamidis group early on. Is there any sort of rationale for that, biochemical rationale? Because that seems to be the only figure that didn't align with most of the other figures presented across both posters today.
So maybe thanks, Ritu.
So, I think just for the folks who are in the audience, I think the questions really are around the time to first event on the composite endpoint. The Figure 7. And really just trying to understand if there's differences, potentially biologic reasons that might explain why there might be different trajectories. But maybe what we could start is, Dr. Maurer, if you just want to start with just your overall gestalt as you look at that and if there is any biologic reason why you would think there would be. How do you interpret those time to event curves in the subgroups? You started to talk about it in your presentation.
Yeah. I mean, I think the data is very robust, as I said, across a lot of pre-specified endpoints. Everything is in favor of drug.
I think you can get into the weeds, and I think we're really getting into weeds that are uninterpretable, and I don't know of any biological reason why one group that you're mentioning would do worse. I mean, broadly in the field, one of the questions out there is, will combination therapy be something that will be useful in some regard? There are debates about that. To be frank, if you knock out 90% of your TTR, I'm not sure what the role per se of a stabilizer would be in those particular circumstances. But my general belief is I think you're asking too much of these data. We're talking about n's that are really, really, really tiny, not only in the number of people we're looking at, but also in the events. And so we all know this. Things can flip one way or the other, so.
Okay.
So my next question is going to annoy you. It's about an even smaller end subgroup. This was the New York Heart Association Class III on the Whisker plot. That was the one that sort of deviated versus the others. Do you think that Class III patients are just sort of beyond saving, or how should we think of them as far as treatment benefit?
Yeah. I mean, I think your question kind of goes a little bit to the old ATTR-ACT data in which we showed across multiple pre-specified endpoints everything was consistent, but there was one that was not consistent and was highly statistically different, right? And it wasn't just a little bit. It was that the patients who lived longer with NYHA Class III disease spent more time in the hospital. And that's predictable. This is a disease in which it's very hard to clinically manage.
And if you pass the point of no return, you then, God forbid, have some dietary indiscretion. You develop an atrial arrhythmia. It doesn't take much to tip those people over the edge. I would just parenthetically say, probably back in the day when we were doing ATTR-ACT, some of the patients who investigators claimed were Class III probably may have even had Class IIIB or IV disease because we're not unbiased as investigators. We really, really like our patients, and we do everything we can to try to get them into the trial. So that's the bias.
I don't think that subgroups that you're talking about, again, I think we've all come to the conclusion that it's quite possible that silencer therapy will be favorable for people who have more advanced disease because the siRNAs, as you see from these data, it looks like it's stabilizing patients as opposed to allowing them to progress. And I don't want to read too much into the echocardiographic or PYP data or scintigraphy data, but I don't think stabilizers reverse this disease at all, as their name implies, whereas there's the potential for silencers to really stop the disease in its tracks or potentially even, in the long term, as Dr. Hanna was saying at the meeting today, maybe even reverse things, so.
Maybe just on this point, I think that subgroup that you're talking about is, I think if I recall, 28 patients, I believe, right?
It's 14 and 14. Maybe, John, do you want to just speak about some of the other indicators in terms of severity of disease, like baseline six-minute walk test and BNP and what that might tell us also?
Yeah. Thanks. As Pushkal's pointing out, that NYHA Class III group that you're talking about is 28 patients. If we look at the other metrics in that forest plot that would be markers of advanced disease, so NT-proBNP is greater than 3,000, baseline six-minute walk tests that are less than 150 meters, those are still small groups, but they're bigger than 28 patients, okay? They're more adequately sized. There we see clear evidence of a treatment effect that's consistent with what we're seeing in the overall population.
So when we look at that, at least, that gives us confidence that this is a fairly consistent effect across this entire population, including the full range of disease severity.
One last quick one for Pushkal. What are your plans currently for releasing the 18-month open label data?
Yeah. So right now, these patients just crossed the 12-month time frame in the middle of the summer. So we're continuing to follow them. As Dr. Maurer said, we've got them in an open label extension. All patients are on drug. And we're going to continue to collect the data. And as is our practice, we will release those data at the appropriate time. But we haven't made a specific determination when that will be. We'll talk with the investigators and do that in due course.
I'll speak out and say I'm following patients who've been on drug for more than two years now, and they're all doing perfectly fine, right? That's my own clinical. That's not all 360 who are randomized and left over. But long term, the patients are doing really, really well.
That you would use both silencers and stabilizers together in a patient population that you would treat. If so, what subset of the patient population do you think would be ideal for that? And then a couple of questions for the Alnylam team. Just on HELIOS-B, have you made a decision as to whether or not you will take an interim read on that? Because you did seem to reiterate on the slide just now that the data sets due in the early part of 2024. And then last question related topic.
You did make changes from APOLLO- B to HELIOS-B in terms of letting 50% of patients be on background TAF versus the 30%. And you also took away the language that patients be required to advance while on TAF. Can you explain what led to that decision to make that criteria different in the two studies? Thanks. All right. So a couple of questions. I guess the first, Matt, if you could just speak about, based on these data, that gives you any perspective in terms of whether you think combination use would be appropriate or not appropriate or how you think about that.
Yeah. I don't think these data provide, unfortunately, to us clinicians, any insight about that. And that's going to be a holy grail, lest you think that doctors make decisions about healthcare.
No offense, you're going to have a hard time convincing the insurance company without hardcore data to give someone $750,000 potentially of therapy every year. So I follow currently more than 700 people on tafamidis and lots of people on patisiran. I'm nowhere near the same numbers clinically, but I can tell you that I have less than five people who are on expensive combination therapy. That doesn't mean we don't often try to leverage diflunisal in patients who are currently taking patisiran. It's much cheaper. But I don't think these data, and that's one of the struggles that I just say as a doc we're all going to be faced with in the amyloid world is how to decide which therapies people should get and when they should get them and so forth. We anxiously await more information, but we're not running to prescribe combination therapy. Yeah.
Tolga, do you want to just speak from how you've been thinking about the potential places where something like patisiran may be used?
Obviously, subject to regulatory approval and what the label looks like.
Yeah. I mean, as Dr. Maurer indicated, the label really defines how we're going to be able to communicate the benefits of this product once it's approved. Look, what we know based on the research that we've done and the advisory boards that we conducted is that there is a need, right? That's confirmed by the ATTR-ACT study. We know that there are patients who are progressing, and they're inadequately responding, a group of patients that are inadequately responding. So that's one group that we believe is actually going to be eligible or we would actually position based on the label that we would get.
The second one is, again, this is based on what Pfizer communicates, particularly in the United States: those patients that get the prescription, but they don't end up actually getting the product due to a number of financial reasons. Part of that, we believe, is driven by Part B, where the copay burden is directly on the patient. And in our case, as you know, we are physician-administered. Therefore, it's Part B. And the burden, especially those patients that are on Medicare, which mostly are, the supplemental insurance actually removes that burden for those patients. So that would be a benefit as well. And more importantly, obviously, we see this not just a sprint, but a marathon. And the fact that we have the HELIOS-B data coming out relatively soon, and with the outcomes data, that will obviously have, I believe, a different position. But we're excited.
I mean, look, you don't have a lot of products in this highly devastating disease. As Dr. Maurer indicated, that sort of you have great clinical benefit, and you have good quality outcomes, and cardiac outcomes all moving in the right direction. A lot of good signals. So these patients do need alternative treatments. And because of that, we're really excited about that.
Thanks, Tolga. Maybe I'll handle your IA question, Tazeen. And then, John, maybe in a second, you can address the third question that Tazeen had about the population enrolled in HELIOS-B. Look, with regard to the interim analysis, as we've said, HELIOS-B does allow us to do an interim analysis. And that is something that we'll be deciding in the near future for the study. And we'll make that announcement when we're ready to do it. And obviously, we'll be discussing that with regulators as well.
As we've also said, the time frame, because of how quickly HELIOS-B enrolled, the time gap between the two studies has become narrower, which is a good thing. That would be a consideration in terms of not doing the interim analysis. But certainly, we want to. These data are very encouraging. We want to make sure that we can bring forward an appropriate medicine as quickly as possible. So those are the considerations. We'll get back, and we'll be clear about that at the appropriate time. John, do you want to speak a little bit about? Tazeen was asking about the entry criteria for HELIOS-B and the number of patients who might enter on baseline TAF and whether there's any implications to that in terms of the powering of the study and the success of the study?
Yeah.
Look, both of these studies, when we designed them, what we're trying to do is to bring in a population of patients that's going to be reflective of the global population with this disease. And that's what we did. So at a high level, I just want to say that these two trials really are enrolling a very, very similar patient population. You've pointed out a couple of subtle differences in the inclusion-exclusion criteria, which are both accurate. But that really is reflective of the very different goals we have with these two studies, right? The APOLLO-B study was intended to, as rapidly as possible, try to demonstrate the benefits of RNAi therapeutics in this disease by looking at functional status and quality of life. HELIOS-B, on the other hand, is twice as large and three times as long. It's designed to look at outcomes.
And so these subtle differences in these inclusion-exclusion criteria are simply reflective of those very, very different goals of the two studies. But the population of patients we brought into these two studies really is very similar and, again, intended in both cases just to be reflective of the population with this disease around the world.
Thanks, John.
Great. Thank you. Hi. I'm Z. Shu from Berenberg. Thanks for taking the questions. The first one, just look at the subgroups. If we compare the six-minute walk and the first time to CV event, if you look at the TAF at baseline versus no TAF at baseline, it looks like six-minute walk. It shows there seems no benefit in the TAF baseline patients. I know it's a small group. But then on the first time to event, it shows the opposite.
Maybe you can help me understand the kind of how should we reconcile that? That's the first question.
Yeah. I mean, maybe I can start, and then Dr. Maurer, you might like to build on it. I think actually you're pointing out the challenges of actually interpreting small subgroups, which is this is a, again, I think, as Dr. Maurer said, in the overall scheme of heart failure studies, it's a pretty modestly sized study. The subgroups are even then smaller than that. And then you've got endpoints which have this inherent amount of variability in them, particularly six-minute walk test or low event rates in a short study for outcome variables. And so I think you're just seeing noise around that that's creating these patterns. And I think I would encourage you to maybe take a step back and look at the totality of it.
If you look at those forest plots for KCCQ next to six-minute walk test as Dr. Maurer presented, you kind of see just a holistic picture that really there's a very strong consistency of benefit across all those potential subgroups, all those subgroups that are listed there. But I don't know, Dr. Maurer, is there anything you'd add?
No, I agree. I mean, I think you're just crazy to start getting involved and looking at all these little individuals that I can counter by saying, yes, the point estimate for the six-minute walk on the TAF group was slightly different, but the confidence intervals are usually wide. And we all know how to interpret statistics, which means that you can't conclude one group is different than the other. I don't know.
My grandmother used to say, "You're getting involved in mishigas." So I mean, really, it's just I just wouldn't go there. I just urge you, if that's what you want to do, have a good time. But you can't convince anyone one way or the other, I think. You have to look at the totality of the evidence. And basically, on the primary endpoint, the key secondary, all the exploratory endpoints, this drug is effective, right? And what I hope personally is that it will be not only as effective as it is now, but I think that probably, unfortunately, over time, it's going to become more and more effective. I made this point, but taking care of these patients, this idea that we're going to reverse amyloid and make everything all better is, I think, selling patients a bill of goods, and early treatment is really important.
We've learned that. We try to identify people a lot earlier. That's one of the successes. And we try to institute therapy. So my concern, I guess, is about the effect size that people start talking about. It's kind of small. It's going to accrue a lot over years. And these people are going to be waiting for a few years to get access to the next level therapy. It could be a dramatic change in how they're doing. This is not a slowly progressive disease. This is a rapidly progressive disorder. So those are some thoughts.
Thanks, Matt. Yeah. Well, thank you. Maybe just kind of to your last point, Dr. Maurer, on the reversal of disease, obviously, within 12 months, we didn't see that.
I guess, do you have any data or imaging data to show any remodeling of the heart that can maybe in a few years' time that those patients might have a reversal of disease? Any thoughts on that?
I personally don't have data, but I would just point out there are other amyloid diseases, not the focus of today's discussion, but in light chain amyloidosis that we've been treating with anti-plasma cell therapy for a long, long, long time. The name of the game is I can't do anything to the heart until the hematologists get the light chains back to normal. And when they do that, there are many, many, many papers demonstrating that patients' hearts, not quickly, but over time, can get better. And there are some dramatic examples that have been described and delineated.
I mean, it's public knowledge, but Isabelle Lousada, who runs the Amyloid Research Consortium, had multisystem AL amyloid years ago, and 20 years later, we barely can find it. So that's the hope is the body does have a natural mechanism to remove amyloid, and as Dr. Hanna was saying at tonight's meeting, we hope that by shifting the balance, getting rid of the precursor protein that's causing the problem, we'll put things in a favorable light. At the same time, I spend a lot of my time at the patient's bedside and with them in the office, and you have to set expectations clearly because this is not a short disease. It's a long haul. Thankfully, people are living a lot longer thanks to all the efforts by all these companies, which is great.
Thanks very much. And maybe just a quick follow-up. I want to ask a question.
On the class three, I know it's only 20-something patients. I know it's very small. We make a rule that anyone under 100, we're not going to talk about anymore tonight. That means all the tafamidis patients.
Okay. I just want to confirm those were patients on baseline tafamidis, or they're a mix of no? The class three patients, you're saying? Yes. I don't know the details. That's the level of detail I don't know. Oh, yeah. I'm not sure, but there we'd be getting into. Yeah. I mean, even smaller subgroups. I think the point I would come back to you as is when you look at a small subgroup, then you'd have to redo the baseline characteristics in that subgroup. And there's so many other things that drive stuff. Example, in this disease, black race is tightly tied to the V122 mutation. And those people do much worse.
You can interpret a lot of things from just race, but it's tied to the genotype and so forth. More often, patients with advanced disease have a genotype that's positive. So there are a lot of confounders in all of this. Overall, the groups are well-matched at baseline. But if you start looking at subgroups, I have no idea whether they're going to be so well-matched. Yeah. And just to be clear, there's no necessity that those class three patients were necessarily on TAF or not on TAF. We don't know.
Yeah. Thank you.
Myles Minter from William Blair. You did have at least a handful of patients that reduced their Perugini grade by two, right? Two grades. That's pretty impressive. Did you see that across the biomarkers like NT-proBNP and troponin, that they were the greatest responders there? That's a drastic difference.
So, just wondering whether in those patients, did you see clear evidence of cardiac remodeling or biomarkers that could point you that way?
John, do you want to maybe comment on whether there were any associations between those and the people who reversed their Perugini scores or reduced their Perugini scores?
Yeah. And I mean, look, it's a really important question. It's a very interesting question. We don't have that level of individual patient data to correlate biomarkers with the Perugini scores at this point in time. It's certainly something that we might be interested in looking into in the future.
Okay. I'll tell you a quick story is that I have one patient who was in HELIOS-A, who he has a genetic variant. He and his brother have it. His mother had a heart, unfortunately, liver transplant at Columbia years ago. And he was in the trial.
At the end of the trial, I ordered another PYP scan. The lab called me to say, "Why are you ordering a repeat PYP scan?", and what the hell happened to this guy is PYP was a grade three, and now it's literally a grade half. So I don't know what's going on, but that was with vutrisiran. It was made for a lot of discourse in the halls of Columbia for the day, so very, very, very provocative. And like I said before, I used to think there's no reason to repeat these scans, but clearly, there will be. One of the holy grails in amyloid is patients ask all the time, "How do you know how I'm doing?
How much amyloid do I have?" And I'm not an imager, but I think those kind of things, MRI, PET scans with novel isotopes, and maybe even PYP scanning will seriously be very useful in this particular regard. I mean, to that point, I didn't actually know that anecdote, so thanks for sharing it. But I mean, we did, John, maybe you want to speak. I mean, it's not the first time we've seen this sort of pattern with technetium scans in patients treated with a silencer. And so John, I don't know if you want to speak in general about HELIOS-A. And also, maybe you want to mention there has been a little bit of work through an IST on cardiac MRI that sort of gets to this point.
Yeah.
So I mean, the pattern that we're seeing here with the technetium, the echo parameters, this is very, very consistent with what we saw on HELIOS-A, including the technetium where we also saw substantial regression in the technetium uptake in the patients who were treated with vutrisiran on that experience. And Pushkal's alluding to an investigator-initiated study, post-marketing data from the Julian Gillmore and Marianna Fontana's group at the National Amyloidosis Centre in London, where they have also published data that has shown regression in technetium uptake in patients who are receiving patisiran. And in those cases, they also, in the same cohort of patients, have shown decreases in extracellular volume, which is probably the most sensitive measure there is to suggest actual regression of amyloid from the heart.
Most patients also demonstrated in that cohort improvements in six-minute walk test and NT-proBNP and some of the other types of things that we looked at on APOLLO-B. So again, it's a small study, but it's coming from people who are taking care of these patients in the real world. And we certainly find it very consistent with what we're seeing on APOLLO-B.
Last one from me is just we've heard about this taking tafamidis progression. That's the clinician's judgment in APOLLO-B. What's your specific definition of clinical progression that would have enrolled a patient in this trial, Dr. Maurer?
Yeah. So I think it's a good question. I mean, declines in functional capacity, worsening NYHA class would be one, and intercurrent hospitalization, the development of an atrial arrhythmia that really decompensates the patient. Those are kind of the high-level things.
I believe in the trial, there were checkboxes that clinicians were asked to complete, but it was in the eyes of the beholder. As a selfless plug, sorry, I'm going to also just speaking of surrogate markers and other things, Alnylam was nice enough a long time ago to give us the original Apollo data. One day, hopefully in the next 10 years of my life, we'll actually get this paper published. But we've only submitted it to like 12 different journals. John knows. But we did cardiac mechanics on the original Apollo data using the available echo data. You can recapitulate cardiac contractility, chamber stiffness. You can do Starling curves. And what was amazing in the original Apollo data was, A, a lot more patients have cardiac amyloid than everyone believes. Most cardiologists think if you don't have an NT-proBNP over 2000, you can't have amyloid.
But the average wall thickness in Apollo, the original trial with neuropathy, was 15 millimeters. And I can tell you that wasn't caused by hypertension because their blood pressures were like 110. So in our estimate, like 85% or 90% of the patients in the trial had, and we showed pretty elegantly, one of our fellows, that after only nine months of patisiran therapy in the original Apollo trial, there were demonstrable effects. So we tried to tell everyone, "Look at these great data. We're predicting APOLLO- B will be positive." And people couldn't see the message. Maybe now they will, or now they'll tell us it's too old and boring. We wanted to see the other side. Maybe I'll promise the editor that we'll submit the paper to him.
But it's kind of unbelievable that we don't see that kind of stuff with other therapies that are available right now, so. I'll make the point that I think what's kind of remarkable from the drug development perspective is to see across patisiran and across vutrisiran, across studies that we've done and across investigator studies, post-marketing, and across a whole series of endpoints, no matter how you look at it, there's a remarkable consistent pattern that's sort of emerging. It really highlights potentially the potency of this mechanism at addressing the underlying cause of disease. Because otherwise, how do you see so many parameters lining up? And I think that's very exciting as a drug developer to see that pattern.
John. A couple of questions that came through on the webcast.
So why don't I start with a question about clarity on how heart transplant is defined as it relates to the mortality efficacy analysis. So the question reads, "For these patients that went for heart transplant, were they due to disease progression or the availability of donor organ?"
Disease progression. I can tell you because I transplanted two of them. They were dying. So in a trial, we don't know, but they were I don't know what they were on. Turns out they were both on placebo, but they were literally they had reduced ejection fractions, worsening renal function. They had a cardiorenal syndrome. One was wild type, and one had hereditary disease, one of whom the hereditary patient ended up getting not at my institution. So I referred him back to his provider. He got a heart and kidney transplant, so. Thank you. Great.
Another one here for Tolga. It's early days, but anything you can comment on how you're thinking about pricing, given there's a drug on the market that's priced at $225,000 and is administered orally and has mortality on the label? Anything we can comment on that?
I think we should look into this in a couple of different ways. When Dr. Maurer was highlighting that he didn't get the scintigraphy evolution right, he did get one thing right. Back in my former life, we were discussing with him about the prevalence of this disease. He insisted that actually this is a disease the more you look, the more you will find.
And therefore, I think one of the exciting parts about being able to provide a really viable option, first obviously with patisiran and then hopefully with also vutrisiran, is this is a devastating disease, and this category continues to grow. And what we know is the diagnostic rates went up by tenfold in the U.S., yet 80% of those patients are still not treated. So it's clearly not going to be a zero-sum game. And the modality and how we actually administer those things, we do know that there are going to be some hurdles for infusion patients. But if you look at our ability to actually provide the right level of support for reimbursement, site of care, home infusion, we will be able to scale those up in the category that we're going to be going in as soon as we're obviously, hopefully when we are approved.
In terms of the specific pricing, I mean, look, we always look for long-term value. We also, we've been able to demonstrate that we really minimize the impact on patients in terms of their copay burden. At the end of the day, though, the price question is, as the person indicated, it's too soon. It's a competitive market. We don't want to be able to right now reveal. We obviously have plans. When we get the label, obviously, we'll communicate that effectively. But again, we're very much also aware of our responsibility as a company. And with a number of ways, with our patient access philosophy, we've been able to show that we make sure that those patients who need the access will get access. That's our commitment.
Thanks, Tolga. Jeff, any more questions? And then we've got one more here, which is another clarifying question.
Maybe John has some color here. What proportion of the patients on background tafamidis were on for the full 12-month trial, and what proportion came off tafamidis during the trial?
That's a very detailed question, and I'm going to give a very high-level answer. The patients who were on tafamidis were encouraged to remain on tafamidis. We did not want anybody to come off of tafamidis who entered. And I can honestly say that I'm not 100% certain, but I do not think that any of those patients came off of tafamidis to my knowledge. And that was certainly the way that the study was designed and intended to run.
Great. Thank you, John. Any other questions in the room or on the webcast? Myles.
We've seen plenty of data, but when are we getting the hereditary versus wild-type or full breakout of that data?
Yeah.
So there were some of them on the forest plots that Dr. Maurer presented, there were some breakouts of the hereditary versus wild-type population. I don't know if it matters, John, if you want to speak to that.
Yeah. No, I mean, that's what we've shared so far. You're asking when are we going to show you? When, where, what? I mean, look, again, the message here across both the key endpoints on those breakdowns of various subgroups is one, in our view, of general consistency. And we'll, of course, continue to dig in and present more data over time. But I really think that's the take-home message here from our perspective. Consistent with the Maurer rule, there's only 20% who have variant disease. And so you can do the math. There's 72 people. We can't talk about anyone less than 100.
So we could look, but I think we're going to, again, make a mountain out of them alone. Don't do the Dr. Maurer rule. Sorry. There you go.
Yeah. All right. So why don't we hand it back to Pushkal for some closing remarks?
No. First of all, I just want to thank Dr. Maurer today for presenting the data and being available to answer all the questions. It's unparalleled to have someone who actually takes care of so many patients and has had the experience across multiple therapies and clinical trials. So we're grateful for your commitment to the patient community, but also for taking time today to speak to everyone and put the results in context. And thank Tolga and John as well for answering questions. And thank you all for all of your interest.
Again, we appreciate you coming and spending time on a Friday night with us to talk about these results. We think they're really important. We're glad you think they're important too, and we look forward to sharing more in due course, but thank you. Thank you. Thank you.