TTR Day. I'm Christine Lindenboom, Chief Corporate Communications Officer at Alnylam, and we're very pleased to have everyone join us for our first in-person investor day since post-pandemic. So this is very exciting to have everyone together. Today, you'll hear more about our leadership in ATTR amyloidosis, as well as the efforts we're undertaking to optimize the success of the launch of Amvuttra in ATTR cardiomyopathy. So today you'll hear from our talented leadership team, who's here in the room with us, as well as senior members from our TTR clinical and commercial teams. We're extremely pleased to be joined by Dr. Ahmed Masri, who is the cardiomyopathy section head at the Oregon Health and Science University. Oops! Turning to the agenda, we have a diverse set of presentations scheduled during our time together as we dig into the exciting inflection point for our company.
Specifically, we'll take a closer look at the significant unmet need in ATTR cardiomyopathy. We'll look at the promise of RNAi therapeutics, which rapidly knock down TTR in the liver to address the disease at the source, and we'll look at our commercial leadership and our readiness in ATTR-CM. We'll also provide a brief overview of our robust and high-yielding pipeline of RNAi therapeutics, which is positioned to deliver strong growth and innovation across multiple disease areas and indications. And lastly, you'll have an opportunity to ask questions and hear from Dr. Masri and members of our medical and commercial teams in a moderated live Q&A session today. A few quick reminders before we begin. The event is scheduled to run until about noon, and we've incorporated a break into our agenda.
A replay of today's session will be available on our investor page of our website later today, and the slides are available on Capella as of now if you would like to look at those concurrently. There's a QR code at your place that you could scan to look at those. And then finally, before we dig in, during the course of the meeting, we will be making forward-looking statements. For additional information, I'd encourage you to take a look at the SEC filings posted on the investor page of our website. And with that, I'd like to turn the meeting over to Yvonne. Yvonne?
Well, thanks, Christine, and welcome to everybody. It is so nice to see so many faces with us today. It's been a long time since we held one of these in person, so delighted to be here. And we're very excited to be with you to discuss our leadership in the TTR space and actually Alnylam's role as a leading global biotech. This is an incredibly exciting time for the company as we move towards the launch of Amvuttra in ATTR cardiomyopathy. And assuming regulatory approval, we believe that this milestone reflects a major inflection point in our journey. And we're gonna have a lot of presentations today, but there are a few key points that I'd like you to keep in mind as we go through today's presentations.
First of all, the high unmet need in ATTR cardiomyopathy, and you'll hear directly from an ATTR cardiomyopathy patient and from Dr. Masri that this is a devastating, progressive, and ultimately fatal disease, which early effective treatment is absolutely essential. But unfortunately, many patients continue to progress on current treatment options, or they remain untreated altogether. So it's against this backdrop that Amvuttra is positioned to serve as a new first-line standard of care. We have incredible results in our hands. The results of HELIOS-B demonstrate the profound benefit that Amvuttra has on outcomes, on functional status, on quality of life, and on biomarkers in a population that is reflective of today's TTR patients, the TTR patients that are being seen by physicians in clinic today, and we believe that its unique product profile supports strong adherence and facilitates access.
Now, we're leaders in the hATTR polyneuropathy space, and we've built upon this strong foundation to make sure that we are absolutely ready for a successful launch in cardiomyopathy and for sustainable growth of this franchise for many years to come. Lastly, we're confident that an approval in ATTR cardiomyopathy will allow us to achieve our next significant wave of top-line growth to achieve profitability and importantly, support reinvestment in our highly organic and productive pipeline and platform. As you'll hear today, we're playing to win in this important market for patients and our company. I'd like to start by providing a quick snapshot of Alnylam's profile as a fully integrated biotech company and the leader in RNAi therapeutics. We validated RNAi as an entirely new class of medicines, and we have outstanding R&D productivity, delivering a portfolio of five approved medicines in less than four years.
As Christine mentioned, we have a robust and high-yielding pipeline, and this currently consists of 15 clinical programs, and we expect this to double by the end of 2025. We've also got leading commercial capabilities. We've got a presence in over 60 countries and direct sales in all major markets. And as of our Q2 earnings call, we achieved a 33% year-over-year growth in net product revenues. Finally, we have a strong financial position. We recently increased our guidance to more than $1.5 billion in net product revenues, and we're on a clear path towards near-term profitability. We're on track to deliver our P5x25 goals, while becoming a leading global biotech company, developing and commercializing transformative medicines for patients around the world.
As the immediate next step in unlocking the opportunity in front of us, you'd have heard that we've announced today that we've submitted the sNDA for vutrisiran in ATTR cardiomyopathy to the FDA with a priority review voucher, so that we can look to bring this important medicine to patients as soon as possible. Potential approval could come in early 2025, and we remain on track for additional global regulatory filings later this year. Look, to provide some context, I wanted to share how we're thinking about Amvuttra and TTR leadership as the foundation for Alnylam's future growth. In building a flagship franchise with TTR, we're following a blueprint that's actually proved pretty successful. It's delivered durable growth for established industry leaders like Regeneron, Amgen, and Gilead, and it's enabled them to invest in R&D, in new product development, and portfolio diversification for the long term.
But a key differentiator for us is our homegrown, sustainable drug discovery engine, and this fuels our pipeline, and we've continued to invest in this as we've built our capabilities in TTR. So we're looking ahead to this next phase of growth and our ability to further our commitment to organic innovation with the anticipated inflection in revenues for our TTR franchise. Before we continue with today's agenda, I'd like to take a moment to remind us of why we're here today. Actually, what it is that really, really drives us at Alnylam. The focus on the patients that we serve, and we'll hear from Mark, whose life has been severely impacted by ATTR cardiomyopathy due to a delayed diagnosis and lack of the opportunity for early effective treatment. So Mark's story underscores the critical need for new options for patients with ATTR cardiomyopathy.
Let's go ahead and play the video. Thank you.
The disease is life-changing, there's no doubt about it. I'm not the same person I was. It's affected a lot of my life. I try to keep a good attitude about it. I was so active, my parents used to tell me I was accident prone. I was always getting into some sort of accident or injury. Being so active as a young fella, I was into gymnastics and running. My first surgery was at the age of fifteen, and that was the downfall of my dancing career and my gymnastic career. I've had a total, as of now, of 35 surgeries. Looking back, I attributed the surgeries to the sports, only to find out that most of my surgeries were due to the amyloidosis.
Between my spine and my hands, and the bilateral carpal tunnel, and trigger fingers, and my elbows, and even now my eye, it's all come to light that this disease has been with me for a very long time. I first started to feel symptoms, seeing my local cardiologist. He sent me to a particular doctor for HCM, hypertrophic cardiomyopathy, and for approximately two years I was treated for HCM. The problem was the breathing. The way I describe it to the doctors is that I can't catch a full breath. It would be like someone putting a plastic bag over your head as you try to breathe. For two years, I was treated, and I thought it was getting better, and then it got worse, and I then found out that it wasn't hypertrophic cardiomyopathy, it was amyloidosis. The diagnosis changed our lives instantly.
I went on the internet to find out what this word meant, because I had never heard of it before. The findings on the internet are pretty traumatic. I was told I had somewhere between two and four years to live.
When Mark was first diagnosed, we didn't understand how serious the situation was. We didn't know, moving forward, what our future would look like.
When I saw a doctor in New York, he put me into a treatment plan, which was to slow down the process of the disease. That was five years ago. I'm still having issues. When I was offered the possibility of being part of a test study, I honestly jumped at it because I think it's very important, but I'm hoping that the treatment plan, in the long run, is working. The amyloidosis obviously affects much more than just the heart. The breathing, in particular, is very difficult.
With his breathing, sometimes at night, I look over to make sure his chest is going up and down. But a lot of these situations are things I, as the caregiver, deal with on a day-to-day basis.
I do enjoy the walking with Ruth and Olivia. However, I'm definitely limited in how far I can go. I fall, and I've fallen many times. Unfortunately, the last time was the worst. I fell, hit concrete first, and broke my nose, and from that point on, I had to change my life. I had to change the way I walk, how long I walk, how long I sit. I was to be surgically repaired on my spine. Pre-op testing indicated that I could not have the surgery because of my heart function. Amyloidosis affected my heart to such a point that the pressure in my heart would not withstand being under anesthesia for that length of time. I was told that I have since lost about 36% of the function of my heart because of the amyloidosis. That changed my life. It just changed everything.
My anxiety level has increased tremendously, but I know Mark deals with a lot more than me, so I have to keep that into perspective. I'm just there to help be supportive.
The disease has definitely affected my outlook on life. I'm one of these that, at this point, just go for it. We don't know tomorrow.
He calls me his rock, but actually, he's my rock. I get a lot of strength from him. He hopefully can make some mark in a legacy to other people with the same disease.
When I was diagnosed with ATTR amyloidosis, it was a very frightening time in our life. But life's like a rollercoaster. It's ups and downs, but I'm not ready to get off the ride yet.
Wow, this gets me every time, and I just have to reiterate Yvonne's comments, that these videos and interactions when we're able to actually see the patients, we try to share this as often as we can in venues within the company because it reminds us that at the end of everything we do, there is a patient, and that really is what drives us and gets us up each morning. I'm John Vest, Senior Vice President and the Global Development Lead for the TTR franchise, and I'm going to come back up in a bit to talk to you about our data in ATTR cardiomyopathy. But before I do that, it is my distinct pleasure to welcome Dr.
Ahmed Masri, who is an Associate Professor of Medicine at the Oregon Health and Science University. Dr. Masri obtained his MD from Jordan University of Science and Technology in Jordan, prior to joining the Cleveland Clinic, where he obtained his internal medicine residency training, and then went on to the University of Pittsburgh, where he completed fellowships in both cardiology and cardiac imaging, as well as obtaining advanced degrees in epidemiology and statistics. Dr. Masri has worked in the space of ATTR amyloidosis for over nine years and currently runs the Multidisciplinary Center and Cardiac Amyloid Program at the Oregon Health and Science University, where they treat over 500 patients, half of whom are patients with ATTR amyloidosis. Due to his clinical commitments, Dr.
Masri is not able to be here in person today, but will be joining us by Zoom, and we are absolutely thrilled to welcome him here to give us his perspectives. Dr. Masri?
Thank you, Dr. Vest. Happy to be here. Sorry, I'm not there in person. It's not really easy to follow Mark's story with the presentation, but, hopefully, this will build on the video that you've just seen, that there is significant unmet need in transthyretin amyloidosis, and we actually, as physicians, we have to do better also in terms of finding the disease. You've just heard that Mark was diagnosed with HCM for two years before being diagnosed with transthyretin amyloidosis, and this is a very, very common story. Next slide, please. Those are my disclosures. Next slide. And so many of you are already familiar that in transthyretin amyloidosis, the source of the protein comes from the liver. There is not a single human born without transthyretin.
And the TTR protein itself, once it's secreted from the liver, it gets into a tetramer form, and the tetramer circulates in the body. And if things go wrong, you'll misfold, and that's how we end up with deposits in the heart, the nerves. There is a little bit of different pathophysiology of how things can happen, but transthyretin proteins and fibers are not meant to be directly toxic. However, they could produce toxicity at the organ level, even if they're not directly toxic. Next slide. And so I think this is the crux of it, is that we moved from a disease space. When I first started in amyloid space. Actually, the reason why I started it is the fact that there were these drugs that can go directly to the liver and selectively shut down the production of a protein.
That was the principle that I thought was actually pretty interesting and unusual. And when I first thought about this disease and the space, we had very few patients where I was training at the time. And if you fast forward to now, we have a lot more patients compared to 10 years ago. But part of the reason is this understanding, based on these studies. I'm just showing you three out of many, many studies, where if you look into the prevalence of the disease. If you're being proactive in finding patients, you will find patients. The first example is a study of patients with heart failure being admitted to the hospital, showing you that almost 13% of them got diagnosed with the disease. Obviously, this is an elderly population.
It's not like it's, you know, any patient coming in with heart failure, but still, it's a very significant prevalence of this disease. The second study was done at Hopkins, where they did this research study where they biopsied consecutive patients with HFpEF or heart failure that doesn't have a clear etiology upfront, and found similar prevalence of the disease. And then finally, in aortic stenosis, which is becoming now a very common source of finding patients with transthyretin amyloidosis, those patients who are referred to TAVR, transcatheter aortic valve replacement. 10 years ago, 15 years ago, TAVR wasn't available. These patients would just essentially die within a year or two of the diagnosis, and nowadays, these patients are living because you can replace their valve transcatheter.
And so that allowed us to study these patients more and find out the high prevalence of TTR amyloidosis in these patients as well. Next slide. And so it doesn't matter how good of a clinician you are. Arguably, you know, we have really good systems in place that allow us to find patients and screen for them, correct? But this is, I think, a brilliant study, and it's good because it came out of the Mayo Clinic. So, you know, this discussion of, you know, what are the physicians doing or what not doing, I think becomes less important since Mayo is known for implementing pathways and for implementing screening strategies for certain illnesses. And in this scenario, if you essentially just use your clinical diagnosis and clinical suspicion, you really don't get much in terms of the diagnosis.
We're talking about 1%-2% range. If you employ a systematic strategy, that number gets all the way up to 6% on average, but the confidence interval can go up all the way to 10%. And I think these are the principles. If you look for the disease, you'll find it. Our referring practices who refer to us are always the same, and we can create a map where there are zip codes where there are no patients coming from, where there are zip codes where there are many patients coming from, and you know that this is not real. This is just simply how the physicians who think about TTR amyloidosis find it, and how those who don't, they just simply miss it all the time. Next slide. And so this builds on these principles that the disease is common.
This is a study by some of my colleagues at the Cleveland Clinic, who showed that it is fairly common in orthopedic conditions, in this example, carpal tunnel, beyond a certain age, that is not technically explained by trauma or by rheumatological disorders, that you have 10% of these biopsies had amyloid deposits, and 3% had to be initiated on therapy because they had already systemic disease. We are at a stage where we don't necessarily treat orthopedic disease in isolation, but I think this might change in the future, depending on all these ongoing studies, what they show us. But the principles are, again, the same. This is a common problem. Next slide. And so to build on that, it just not is a common problem only. It does affect individuals in an asymmetric fashion, depending on their background in terms of race and ethnicity.
So while wild-type TTR amyloidosis represents 85%-90% of the current patients with transthyretin amyloid cardiomyopathy, I think this is largely driven by the severe underdiagnosis of transthyretin amyloidosis in patients of West African descent or in African American patients. These, typically, studies focused on patients who self-identify as Black. This is fairly unique because 95% of patients affected by V122I are Black, and so it's highly prevalent, 3.4% or so. There have been many, many studies that came at the exact number, plus, minus, you know, few decimal points. That means you have more than 100,000 patients living carriers above the age of 65 in just the United States.
But if you look at the map of how these drugs that target transthyretin amyloidosis are being used and prescribed, you don't see the highest rate of use and prescribing in neighborhoods where you have Black patients. You actually see lower utilization and use in these neighborhoods. So we have a lot of work to do in this space, and the number of patients, you know, will continue to rise, and I think we gotta do better in finding these patients and identifying them earlier as well. Next slide. Many of you have seen this figure before. It has become kind of a traditional figure used in different presentations. I did modify it because we can't really keep up with the pace of development in this space by just publications.
And so in this figure, I provided you every step that we're trying to target along the pathophysiology of the disease, showing you how TTR silencers, knockdown agents to the left there, patisiran, vutrisiran, eplontersen, inotersen, and NTLA-2001, and then you have TTR stabilizers. The only one that is currently approved by the FDA is tafamidis. Acoramidis is under review, and then diflunisal can be used off-label, but it's not as commonly used as people, you know, think of it. You know, we talk about it during academic meetings probably more than it actually being used in real life. And then, you know, we skip all these steps in between just simply because we have not figured out how to target or if there's a need to target any of these intermediate steps.
And then finally, there is a new wave of these fibril depleters or removers that are currently being trialed in different clinical trials from phase I to phase III. Next slide. So it is essential to find these patients early, and we try to tell every single referring cardiologist that if you get into this, and if you start finding patients, please don't wait too long. And if you wanna work someone up, work them up in a timely fashion, because ultimately, if you can prevent one cardiovascular hospitalization for patients, that's a win. Because every stay in a hospital leads to patients losing time, they lose muscle, they essentially can be set back tremendously, but also it actually interferes with the workup of patients and typically leads to more delay.
I think this is best highlighted by the ATTR-ACT trial, which even in the most rigorous, controlled environment, we've seen that if you have NYHA Class one and two, patients did much better than having NYHA Class three, for example. We haven't learned a lot after this primary publication from ATTR-ACT, what happens to those patients with more advanced disease and what could be the predictors of non-response. But I think we have a pretty good clue clinically, how patients could respond and not respond to the disease, to the treatment that is commercially available. And the principles are, the earlier the presentation is, the much better that patients typically do. Next slide. And so this is a very recent publication. I included it because I was-- you know, I saw it as part of the recent publications in the last month.
You know, I speak about this all the time. Lots of people and colleagues I interact with argue that we're doing such a good job finding amyloidosis, and we're finding it so early, that maybe we can't even recruit easily into clinical trials. That's absolutely not true, and this illustrates that. You know, this was a multicenter study in Italy, looking at 800 patients or so, and looking at how many patients did they find at a very early disease stage, and they defined it as having NAC stage 1A, which is a very subselect group of patients within NAC stage 1, and Columbia stage 1, which is also a subselect group. Don't worry about what Columbia is, what NAC is, what any of this stuff is. The principles are that it is not true that we're finding patients early.
When we say we're finding patients early, it's because we used to find them before they died. That's essentially the principle. Now, we're finding patients with still significant burden of the disease. However, they don't have fairly advanced heart failure lots of the time. That's one. And two, we actually do a decent job in taking care of them. It's not because we suddenly became brilliant five years, you know, after, you know, a certain change in our background information and knowledge. It actually changed because we no longer look at the disease as futile illness. We no longer look at the patients as patients who are just gonna die anyway, who cares? We actually take very good care of these patients, and we have established programs and systems in place that would rescue them every time they're in trouble.
But again, what we wanna achieve is that we wanna achieve the ability to find these patients in these tiny bubbles that you see here, and we wanna reverse the size of these bubbles. We wanna make the advanced patients, symptomatic patients, become the minority of patients, if possible. Next slide. And so this is one of the first systematic evaluations or systematic evaluation of aortic stenosis coexistence with amyloidosis. And don't worry about the numbers. The principles are that across the United States, we used claims data to look at this. There is common coexistence between aortic stenosis and transthyretin or cardiac amyloidosis in this scenario in general, because it's not easy to differentiate, even though we employed a very rigorous algorithm to differentiate transthyretin from other types of amyloid, including light chain amyloidosis. It's not really very reliable, so we call it cardiac amyloidosis in general.
And so you can see how there is increased risk of death and heart failure hospitalization rate compared to having just aortic stenosis, and that's a significant burden for these patients. These patients are largely untreated. This is such a robust space to focus on, and we focus on in our clinical practice. Because interventional cardiologists see these patients with aortic valve stenosis, they treat their aortic valve disease, and then 40% of these patients are either dead or no better by one year after having their transcatheter aortic valve replaced. That's obviously not for the low-risk group, that's for the intermediate and high-risk group patients, but still, we're talking about a treatment, transcatheter treatment, procedural treatment, where 40% of the patients still don't do very well at one year.
The driving force, probably in good chunk of these patients, is having underlying transthyretin amyloidosis. Next slide. I modified this slide again, and so you're not gonna find this necessarily in the publication itself, but this is the open-label extension of ATTR-ACT, showing you good results. Correct? We see the separation between placebo to tafamidis and between ongoing tafamidis. Ongoing tafamidis is the upper or left orange line, and then placebo to tafamidis is the blue line. Then you have an extrapolated placebo there in terms of the outcome, and this up to 72 months of follow-up. But look at the unmet need in terms of death. Flip the term. You know, let's flip what we always look at, which is survival, and look at, you know, the hazards of death and death in this scenario.
50% of the patients almost died, and in this scenario, you know, really, we don't lose patients to follow-up as much as other diseases. And so most patients who fall off the curve are typically patients who died in general, or who ended up being forced to exit certain studies based on how the studies get terminated or get stopped and whatnot. But those are the principles, correct? We still have lots to do in this disease space. Next slide. And so this is a study that we've done. This is not a statistical comparison. This is not essentially head-to-head comparison. These are reconstructed Kaplan-Meier curves. The reason to reconstruct them is not to tell you that one treatment is better than another.
The reason to reconstruct them is to show that in our 600 patients on commercial tafamidis, we got the same rate of survival as we saw in ATTR-ACT study. Granted, these patients were enrolled in 2018 to 2021, so this doesn't include patients who were diagnosed in 2022 to 2024. And then on top of that, you have the first two lines, which are the black and the red. This is the ATTRibute-CM trial, showing you even the placebo, essentially, patients in ATTRibute-CM did better than the treated patients in ATTR-ACT. This is just to put things in context. I know we all like to compare trials to compare different treatments, but these are fairly different patient populations that are at baseline, different.
And if they're at baseline different, trying to understand the outcome have to be put into context with that difference that we're observing in these clinical trials. Next slide. So you can be as extensive as you wanna be or as brief as you want to be when you monitor patients with transthyretin amyloidosis for progression. We have so many tools to do that. You can have hard endpoints. You can have things that we do in clinical trials that we really don't do very well in practice because they have so much variability at the individual level. They work much better at a population average, like KCCQ, six-minute walk test. But some of my favorites on the slides are: How are the patients doing in terms of their hospital stays? Did they have a hospitalization or not on tafamidis or on commercially available drugs?
Did they have an urgent visit? Did they need more diuretics as an outpatient over time? This is one of the best metrics to know that someone is progressing. Is their GFR declining without having any other issues going on? Do they have progression of their NT-proBNP over time, more than 500 or so absolute increase or more than 30% from baseline increase? Troponin and TTR levels without having treatment on board are not as, you know, robust in terms of our progression and monitoring. Cardiopulmonary exercise testing is being evaluated in this scenario. It's not really robustly well established. Imaging is still out there. It's not yet established as a very strong tool to monitor a patient's progression or not.
But we are doing lots of work, others are doing a lot of work, and clinical trials such as HELIOS-B, which you're gonna hear about shortly, providing us with more data and information about imaging, is really vital to allow us to understand how to think about this. Next slide. So what are some of the future goals that we have set in transthyretin cardiac amyloidosis? We need to be to better control the disease. We need to improve survival, decrease hospitalizations. We need to improve function and quality of life. This is really important. You've heard Mark's story. You've heard what he had to talk about. You know, we're being greedy, correct?
We're happy that we can make patients essentially live longer compared to no treatment, for example, and we're happy that we can decrease their hospital stays and their, you know, worsening over time. But we really wanna improve their function and quality of life. This is one of the most important things to patients. And we need to try and figure out a way to address this progressive, unintentional weight loss despite controlling the underlying disease. We don't understand it. We don't know what's going on in some of these patients. And then, you know, kind of a holy grail, can we regress the disease? It has not yet been robustly, essentially established, but we, you know, working very hard to get there. And then there is really an ongoing need for long-term studies.
We need to move away from the timelines of having studies over, you know, one, two, three years or so. We need to start thinking of a longer time horizon since these patients are living longer. Next slide, so to conclude, while transthyretin cardiac amyloidosis is being transformed through earlier recognition, better overall management, and targeted therapy, such as Tafamidis, there remains a significant unmet need. Hopefully, I've shown you that, and there are new diagnostic approaches and new therapies. I think these open the door for us to try and treat our patients better and find them earlier. Thank you, and I look forward to the discussion.
Great. Thank you so much, Dr. Masri. We really are grateful. We know how busy you are, and it is just incredibly important for all of us collectively to hear what you are seeing and physicians caring for these patients in the real world, and how we should be thinking about the unmet need and where we should be focusing our efforts as we try to continually improve the care that we're able to provide for these patients. So I'm gonna talk now about the promise of vutrisiran for TTR patients.
But before I do that, just to kind of put into context the steady stream of data releases that we've done over the past few months that started with our announcement of top-line results at the end of June, where we disclosed that we had achieved a positive result from the HELIOS-B study, and then followed not long after that at the end of August at ESC, where we gave the full details of the HELIOS-B study results, detailing that we had hit 10 out of 10 endpoints, the primary and all secondary endpoints. And in addition to reducing the composite of all-cause mortality and recurrent CV events, had a beneficial impact on a range of measures of disease progression.
We simultaneously published these same results in The New England Journal of Medicine, and then more recently at HFSA, where we discussed the exploratory analyses that we'd done on important cardiac biomarkers and echocardiographic parameters. I'm here today to try to encapsulate all of these key data that we believe outline the clinical benefit that can be achieved with RNAi therapeutics, and specifically vutrisiran, and how we believe that these strongly position vutrisiran to be a first-line choice for these patients, should it be approved. I don't want to belabor this too much because Dr. Masri just did a beautiful job of outlining the pathophysiology of this disease. I do want to make a few key points to put this into context of our therapeutic hypothesis and our mechanism of action.
As we've heard, and as we all know, ATTR amyloidosis is a progressive and fatal disease, and this is caused by deposition of misfolded transthyretin as amyloid fibrils into the wall of the heart, into the myocardium. The heart wall. This continual deposition causes the heart wall to grow thicker and thicker over time. It becomes unable to pump blood effectively, what we call systolic function, and also, very importantly, it's unable to relax to accommodate blood coming back into the heart, what we call diastolic function. This physiology is responsible for everything that we're gonna discuss that happens downstream. So these patients wind up with heart failure, arrhythmias, and progressively, over time, they lose their ability to function. We heard this from Mark. They start to have trouble walking. They can't do the things they enjoy.
Eventually, even just simple activities of daily living become impossible tasks. This, in turn, leads to an increase in hospitalizations and unfortunately, ultimately, death. So with this in mind, our RNA therapeutics, both vutrisiran and patisiran, rapidly knock down transthyretin to decrease the circulating levels of this pathogenic protein, thereby fundamentally and directly targeting the underlying pathophysiology of the disease. So our therapeutic hypothesis holds that, in turn, this will diminish or even halt the clinical manifestations of the disease, which includes the cardiomyopathy, as we've just discussed and heard about in detail, as well as the polyneuropathy of the disease. And indeed, prior to the results of HELIOS-B, we initially validated this therapeutic hypothesis in patients with hereditary ATTR amyloidosis with polyneuropathy, for which both vutrisiran and patisiran are currently approved and marketed around the world.
And now, as everybody is well aware, we, of course, have the results from HELIOS-B that provide us evidence of the benefit in cardiomyopathy. But before I get there, I do want to briefly just highlight the transformational profile that RNAi therapeutics have had in hereditary ATTR polyneuropathy, where both vutrisiran in the HELIOS-A study, as well as patisiran in the original APOLLO study, have yielded highly consistent results of the profile of this drug, which includes a stabilization or improvement in the neuropathy manifestations, stabilization or improvement in patients' quality of life, beneficial effects on functional status, and beneficial effects on nutritional status. And indeed, when we looked at exploratory analyses and post-hoc analyses from the original APOLLO study, as well as the APOLLO-B study of patisiran in patients with ATTR cardiomyopathy, we saw evidence of trends towards improvement of mortality in these patients as well.
Now, these were exploratory analyses, and these data are not part of the established profile of the drug. However, they were very, very important in bolstering our confidence in what we would see with this mechanism of action in the HELIOS-B study. And so I'd now like to turn to that in discussion of vutrisiran and ATTR cardiomyopathy. So by way of reminder, just to briefly look at the study design of HELIOS-B. This was a phase III study in patients with ATTR amyloidosis with cardiomyopathy. Patients were randomized one to one to either vutrisiran or placebo. The primary endpoint of the study was a composite of all-cause mortality and recurrent CV events. And then we had a range of secondary endpoints, including the six minute walk test, Kansas City Cardiomyopathy Questionnaire, and New York Heart Association class.
All of these endpoints were analyzed in two distinct populations: the overall study population and the vutrisiran monotherapy subpopulation. Those were the patients who were not on tafamidis at baseline. There were a total of ten endpoints, two primary and eight secondaries. Now, after completion of the double-blind period of 33-36 months, patients have rolled over into an open-label extension study where all patients are receiving vutrisiran. It's very important to recognize that this study enrolled a population that is reflective of today's patients, who typically have milder disease and are on substantial background therapy, including tafamidis, SGLT2 inhibitors, and more intensive use of diuretics.
And indeed, on the HELIOS-B study, during the double-blind period, over 50% of patients received tafamidis, over 30% of patients were on SGLT2 inhibitors, and 80% of patients were on diuretics at baseline, and then 50% had either initiation or intensification of those diuretics after their first dose of study medication. Now, on the table on the right-hand side of this slide, what we're showing is real-world observational data, where you can see that indeed, over time, based on a number of different important clinical metrics, these patients have gotten milder and milder. So the population in HELIOS-B, where we're which is highlighted on the far right-hand column, are indeed reflective of these real-world trends.
Now, before we leave this slide, I do want to point out that showing a treatment effect on top of this type of intensive background therapy is a very, very high bar across a stringent, a panel of different parameters and assessments. Really hard to do this, and this underscores the profound magnitude of the treatment effect that we saw with vutrisiran on HELIOS-B. So I want to turn to the HELIOS-B data, but first, just to think about it on a high level. HELIOS-B looked at the impact of vutrisiran across a comprehensive series of assessments, with the first clinical impact occurring early and then subsequent clinical benefits cascading over time in a biologically rational manner.
The first thing that we saw was rapid and robust knockdown of TTR, which is characteristic and consistent of the well-recognized mechanism of action of this class of drugs. We then saw impact on cardiac biomarkers, as well as echocardiographic assessments, which reflects the impact on the underlying pathophysiology of the disease. This was then followed by impact on a number of important clinical parameters and disease manifestations. And then lastly, as events accumulate over time in this relatively mild population, we saw profound benefits on outcomes. First here, we're just looking at the TTR knockdown over time on the HELIOS-B study. We can see that TTR was reduced rapidly after the first dose of study medication and achieved durable reduction, a median of 87% at month 30.
This is entirely consistent with the well-established profile of this drug, which was first seen on the HELIOS-A study. And then following on from this rapid TTR knockdown, we see all of the subsequent clinical benefits on the study. So the first key observation is the impact on the exploratory cardiac biomarkers, NT-proBNP, which we're showing in the left-hand panel, and troponin, that we're showing in the right-hand panel. What we can see is that in vutrisiran-treated patients, with both of these biomarkers, we achieved stability over thirty months, compared to the steady increase that's seen and expected in the untreated patients on the placebo arm.
The clinical effect was seen early, as early as six months for both biomarkers, and then the treatment effect grew over time, such that by month 30, there was a 32% reduction in the vutrisiran arm compared to placebo for both biomarkers. Now, this is a very important observation because both NT-proBNP and troponin are well-recognized in the literature as being predictive of outcomes in heart failure and specifically in TTR cardiomyopathy. And in fact, in data that we shared at HFSA, we showed that within the HELIOS-B study, indeed, both of these biomarkers were predictive of the outcomes that we saw on that study. So this underscores the importance of the treatment effect, because the effects that we're seeing early here, we would expect to be predictive of the long-term outcomes for these patients.
So consistent with these biomarker results, we also saw evidence of benefit compared to placebo on a range of echocardiographic assessments of cardiac structure, systolic function, so that's the pumping function of the heart, as well, very importantly, as diastolic function, which is the ability of the heart to relax. So looking at the data here on the far left, you can see that compared to placebo, vutrisiran improved both the mean LV wall thickness as well as the LV mass index. These are both parameters reflective of structure of the heart.... In the middle column, you can see that compared to placebo, vutrisiran improves global longitudinal strain, as well as left ventricular ejection fraction. These are both very important parameters of the heart's ability to squeeze, of that systolic function.
And then on the far right, we can see that vutrisiran improved both the E to E prime ratio, as well as lateral E prime. These are important measures of diastolic function, again, reflecting the heart's ability to relax and accommodate blood. It's really quite profound to us to see this type of improvement and beneficial impact across this range of important parameters. Along with the biomarker data, this tells us that we are having an impact on the underlying pathophysiology of this disease and suggests the potential for a disease-modifying effect.
So now, moving down the cascade of benefit that we talked about, here we are showing the favorable impact that was seen across a number of important measures of disease progression, which included 6-minute walk test, which is reflective of functional capacity of the patients, the Kansas City Cardiomyopathy Questionnaire, which is a well-recognized assessment of health status and quality of life in heart failure, and New York Heart Association class, which is a commonly used clinical assessment of heart failure symptoms, severity, and progression. And what I one of the things I wanna highlight is shown on the right-hand panel, is the observed data with both 6-minute walk test and KCCQ.
This is reflecting what we saw in patients who remained on treatment on the study, and we can see that for both of those assessments, both functional status and quality of life, we provided stability for the patients who were on treatment, as opposed to the clear decline that's seen in patients on the placebo arm. We also see here evidence of early clinical benefit. These are observations that are not only potentially important to patients, but are potential points of differentiation from stabilizers. We also can see on the bottom of the table that compared to placebo, significantly more patients on the vutrisiran arm experienced improvement or stable New York Heart Association class. Again, a potential point of differentiation from the data we've seen with stabilizers. And as Dr.
Masri talked about towards the end of his presentation, we really need to highlight these are critically important observations. These types of assessments, how patients feel, how they function, this is incredibly important, okay? The patients are suffering. We heard from Mark, and this is the type of thing that really does matter, how they feel and function. Now, of course, hard outcomes are of the utmost importance to patients and their physicians. And again, this is an area where vutrisiran had a profound impact on the HELIOS-B study. So, in the right, in the upper right-hand table, we are showing the effect on the primary composite endpoint of all-cause mortality and recurrent CV events, where there was a 28% relative reduction with vutrisiran compared to placebo.
On the top left, we're showing the impact on that primary composite as a time to first event analysis, where we can see the separation occurring and then growing over time. An analysis of time to first event, we saw a highly consistent 28% reduction in that metric as well. Now, back in the table, we're also looking at the component analysis of the primary composite endpoint. What we can see is that overall effect on the composite was driven by similar and consistent effects on the individual components. We can see that for all-cause mortality, as a component during the double-blind period, there was a nominally significant 31% reduction, and for CV events, a nominally significant 27% reduction.
Furthermore, as shown in the table on the bottom right, where we're looking at the secondary endpoint analysis of all-cause mortality through 42 months, a pre-specified endpoint on the study, we observed a highly significant 36% reduction with vutrisiran compared to placebo. So the results of this secondary endpoint of all-cause mortality served to further support that nominally significant effect that we saw during the double-blind period. Highly consistent results. Now, importantly, the effect on the primary composite endpoint, shown in the left-hand panel, as well as that secondary endpoint of all-cause mortality, were highly consistent across every pre-specified subgroup on this study. Now, of particular note, we saw particularly strong trends in greater efficacy in subgroups of patients with evidence of earlier disease.
The subgroup of patients who were less than 75 years of age, and the subgroup of patients with baseline NT-proBNP that was less than 2,000, where we saw reductions in the primary composite endpoint of 46% and 48% respectively, and we saw 45% and 65% reductions of all-cause mortality, respectively. This underscores a very important point that Dr. Masri also highlighted in his presentation, which is these patients need to be identified early and started on effective therapy. Now, we also observed consistent results in patients who were on baseline Tafamidis, as well as patients who were not on baseline Tafamidis... And these two subgroups, the baseline Tafamidis subgroup and the vutrisiran monotherapy subgroup, which again, are the patients not on Tafamidis, are of particular interest. So we'll look at those in more detail on this next slide.
To orient you here, on the top of the slide, we're showing data from the monotherapy population. In the top left-hand panel is data from the primary composite endpoint in those patients who are not on tafamidis at baseline, where we saw a 36% reduction in the primary composite of all-cause mortality and recurrent CV events. We're then showing the data as time to first event, where again, we see the separation occurring and then growing over time. In the top right panel, in the patients on vutrisiran monotherapy, we saw a significant 35% reduction in all-cause mortality. Now, on the bottom of the slide are the data from the patients on baseline tafamidis subgroup, and just by way of reminder, the HELIOS-B was not designed or powered to detect a treatment effect of vutrisiran on top of tafamidis.
However, we saw clear favorable trends in both the primary composite endpoint in the lower left hand panel, where we saw a 22% reduction with vutrisiran compared to placebo in patients who were on baseline tafamidis, and on the bottom right, we see a relative risk reduction in all-cause mortality of 41% with vutrisiran compared to placebo. We are very encouraged by these trends of added benefit, as we believe that they suggest that vutrisiran on top of tafamidis may be more effective than tafamidis alone, and also underscore the potential efficacy that is left on the table with the stabilizer. And again, collectively, this serves as a point of potential differentiation of vutrisiran compared to the stabilizers. The key takeaways.
We saw these results in a population of patients who are reflective of patients that are being seen today, who are in general milder and are on substantial background therapy. The clinical effect was seen early with initial effects on biomarkers that are predictive of outcomes, both in the real world and within the HELIOS-B study. We saw improvements compared to placebo in multiple measures of cardiac structure, systolic function, and diastolic function, which along with the biomarkers speak to the impact that the drug is having on the underlying pathophysiology of the disease. We saw evidence of early benefit on quality of life and an impact on functional status, with preservation of both of these important assessments over thirty months.
This treatment effect we saw on outcomes was consistent across all subgroups on the study, including patients on background tafamidis. And we saw particularly profound effects in patients with evidence of earlier disease. Very importantly, the drug demonstrated an acceptable safety and tolerability profile on the study, which, as had previously been established. So how do we kind of put this all together? When we collectively look at this data, we feel that it solidly positions vutrisiran for first-line use based on several key observations, many of which I've just covered. But to reiterate, these results we're seeing in a population that's reflective of patients today on substantial background therapy. This raises the bar to see a treatment effect, and it underscores that despite this, the magnitude of the benefit that we observed was profound.
Next were the trends of substantial benefit that were observed in patients on background tafamidis. This highlights the unmet need in this patient population and suggests that the stabilizers may be leaving efficacy on the table. We saw an outsized benefit in patients with milder disease. Again, this underscores this critically important point that these patients need to be identified early and started on effective therapy, and then we saw a preserved functional status and quality of life. These are both key measures of disease progression. This is absolutely critical in this type of disease that's progressive. Patients lose their ability to function, and very importantly, what patients lose here, they will never gain back. So collectively, we feel these points were very confident that we're well-positioned for first-line use, and with that, I will invite Pushkal Garg, our Chief Medical Officer.
Fantastic. Thank you, John. For those of you who don't know, John, actually a board-certified cardiologist. He trained here in the city at Columbia. He's been with Alnylam for about ten years. He's actually one of the first people I hired. That was one of the proudest decisions I made. And he's dedicated his last ten years actually to developing therapies for patients with ATTR amyloidosis, and I think hopefully, his passion and his depth of knowledge really just came through. So, I'm Pushkal Garg, I'm the Chief Medical Officer. I oversee development and medical affairs, and, I'm gonna moderate the Q&A session. We'll talk, more about the clinical data. And so we'll have John there, and I wanna invite back Dr. Masri, onto the screen. Dr. Masri, thank you for your presentation.
Really one of the most succinct presentations of the pathophysiology, unmet need, and needs for patients with this really progressive and devastating disease. So with that, we're gonna open it up to Q&A for the 3 of us, and we have folks on either side of the room, so if you raise your hand, someone will come around with a mic, and then we'll just go in turn. We have about 20 minutes for Q&A.
... Hello, can you hear me?
Yes, Kostas, go ahead.
Thanks for the presentation. This is Kostas from BMO Capital Markets. So a couple of questions from me. One is, how could you leverage the existing network you have from Amvuttra in ATTR polyneuropathy to really boost the uptake in ATTR cardiomyopathy? And the second question is, we have heard that some cardiologists may naturally tend to prefer prescribing pills over an injection. So any thoughts around that, and potentially, what benefits, besides the efficacy, do you see from an injection compared to a pill that you will potentially compete with? Thank you.
Great. So two questions. I mean, the first, Kostas, you're asking about our established presence in polyneuropathy and how that's gonna support, the subsequent uptake, launch, et cetera, in cardiomyopathy. I think I'm gonna ask you to actually hold onto that question because we're gonna have my commercial colleagues, who are gonna be speaking actually quite extensively about that, and as well as about the pill versus, sub-Q therapy. But, you know, we do have Dr. Masri, so maybe he can talk a little bit about some of the factors that might, impact his decision-making in terms of including, you know, different routes of administration, et cetera. Dr. Masri, do you want to comment a little bit about those prescribing decisions?
Sure. You know, I think it's actually a good thing to have multiple different options with different routes of administration. What is gonna happen is, you know, based on the patient's factors and circumstances, you do make a decision, with the patient regarding which is the best fit for them. In terms of, your specific question, you know, this is not new in cardiology, correct? Maybe 15 years ago, that would have been the case. But you have essentially the PCSK9 inhibitors, for example, which are a very, you know, so far successful franchise within the preventive care in cardiology, and lots of these, or the majority of them right now, are subcutaneous injections. And so it's not like you're introducing a wholly different, you know, landscape into cardiology.
At the same time, there are, you know, benefits of having subcutaneous injections, sometimes related to, adherence, sometimes related to what patients essentially, you know, think about when they're doing this on day-to-day basis. There is a downside, obviously, which is, the patients, at least in the current circumstances with polyneuropathy, they have to come to the site, once every three months to get the injection, but that's exactly why you would have a discussion with the patient and talk about this. But I don't see necessarily the idea that the route of administration itself, in this patient population... These are very special kind of patients that are committed and motivated to feeling better and getting better. So I don't think that itself is a major issue.
Thanks, Dr. Masri, and again, our commercial colleagues will talk about both of these points a little bit more 'cause these are both important aspects that our team is really thinking about, about how to bring this therapy to patients. Over on this side?
Great. Luca Issi, RBC Capital Markets. Two quick questions. Maybe one, Dr. Masri, as you highlighted on slide 21, lots of innovation going on here across different orthogonal modalities, which is fantastic for patients. But assuming that both Amvuttra and acoramidis get approved during the next few months, how are you thinking about the use in the first-line settings? How are you planning to use tafamidis, acoramidis, and Amvuttra in those settings? How will you pick and choose which drug is best for which patients? So any call there are much appreciated. And then maybe Pushkal, obviously, fantastic data, but, how are you thinking about the risk of an ad com in the context of, the history with APOLLO-B? Thanks so much.
Sure. So two questions there. Maybe I can start with your second question around advisory committee, and then we can turn to Dr. Masri about how he's thinking about these different therapies. Maybe just a bit of context around advisory committees, right? So typically, the FDA convenes an advisory committee when there's questions about benefit-risk around a product, right? You referred to APOLLO-B. There was a question there that the FDA had about in terms of the magnitude of clinical benefit that was conferred with a 6-minute walk test in that study. I think here the circumstances are incredibly different, right? We're talking about a clinical outcomes trial that showed not only benefits on a composite endpoint, but very substantial benefits on mortality alone.
I think the magnitude of benefit and the fact that it is of clinical benefit is really unequivocal, and a safety profile that's well-preserved from a drug that's already on the market. I think along with, as John just highlighted, a set of ancillary benefits across every parameter that we looked at. I think here, the question around benefit-risk doesn't have a lot of uncertainty around it, and so we're quite confident that this is an application that the FDA should be able to review without the addition of an advisory committee. Of course, it's always their prerogative, and we'll support that if that's what they choose to do, but we feel confident that they won't need an ad com to review this application. Maybe I'll turn to Dr. Masri. Dr.
Masri, the question was with potential for Acoramidis to be approved, with Tafamidis already on the market, and assuming Amvuttra gets approved, how would you think about how you would evaluate and talk to a patient about those different choices as a first-line therapy for a newly diagnosed patient?
In the absence of a head-to-head comparison, I think you are left with trying to summarize the data in a patient-friendly way and present it to the patient and talk to them about it. And so, obviously, I fully agree with the presentation that was just given that, you know, vutrisiran is, you know, an option for first-line therapy, the same as tafamidis is an option, and the same as, acoramidis, you know, also might become an option based on the FDA's decision... Same for eplontersen, obviously, because they both are not approved yet. When it comes to this conversation, again, it has to do with the patient characteristics, their underlying disease process. Do they have cardiomyopathy symptoms only? Do they have neuropathy symptoms as well?
And what is their preference in terms of taking an oral medication versus a subcutaneous injection? And so these are all will come into play. I personally don't necessarily see Acoramidis and Tafamidis within exact like, an exact same medication in a way, because they do bind to different sites. They do have different properties and, you know, we have yet to essentially work on seeing more and more data once we're in the commercial space, in the real world, essentially, how these different treatments stack up to the, to each other. But ultimately, you know, I think the decision will really be individualized to the patient, which is, again, a good, good problem to have.
That will lead to our discussions being much longer with these patients, but you know, there are certain rules from HELIOS-B compared to other things from other trials, which will, you know, guide you to how you can talk to patients and how you can discuss these things with them.
Great. Thank you, Dr. Masri.
Hi there, Liisa Bayko from Evercore ISI. We've been getting a lot of different prevalence numbers, and indeed, you gave some today, too. Can you maybe just zero in on how many patients have the disease? How many are diagnosed? How many today are treated? What is gonna improve treatment rates, and why they're so low today? And then also, any comments on future guidance and inclusion of these very important markers of progression? Thanks.
Yeah. So maybe, Liisa, to your question, I think, again, you're gonna hear a little bit more in terms of our perceptions at Alnylam about the size of the opportunity, in terms of the number of patients who are diagnosed and untreated. But maybe, Dr. Masri, you can comment from your perspectives about what you're seeing in your clinic and from your colleagues in terms of diagnosis rates, treatments, and really, particularly, why there are so many patients who aren't currently being diagnosed. You know, you talked about awareness and some of the efforts that might be going on to help identify patients earlier. I think you started to touch on that in your presentation, but what are some of the efforts the academic community is making to identify these patients and improve diagnosis rates?
Yeah, I think, you know, the reason why the feeling that the real prevalence or the real, you know, essentially patient population, all of it, is not being found in this situation is because the disease presents just similar to other diseases. And so we are easily, you know, diagnosing patients with HFpEF, with HCM, with, you know, reduced ejection fraction, without thinking beyond what could be the underlying cause. And I think that's the primary issue. The fact that we can now do cardiac MRIs and bone scintigraphy in these patients has significantly improved that rate of detection, but still there is this significant unmet need that has to do with our lack of easily accessible methods to diagnose.
For example, if you look at the United Kingdom versus the United States, in the United Kingdom, most patients who have left ventricular hypertrophy or heart failure get an MRI, and lots of their patients with amyloidosis get diagnosed with... through the route of getting an MRI. That's actually not the case in the United States. Very few patients end up getting MRIs in the U.S., just simply because of access, because our reimbursement, current reimbursement methodologies, essentially, you lose money on doing cardiac MRIs compared to doing knee MRIs, for example. And so all of these things are related to the problem. So I think the numbers are there.
I think if you look at the growth, even at our single center level, if you look at the growth essentially in the number of ATTR patients over 10 years, we actually went up almost 20 times in terms of the number of patients at the center over these 10 years. And so I expect this to continue to grow, and it will be incumbent upon us to really continue to educate, you know, the communities. And we are seeing patients who have been living with symptoms for 5+ years, who have had progression of disease, and no one has ever looked them up. I think that's where the focus is, education and trying to, you know, get different physicians, practices, and guidelines to focus on the real need for investigating these patients.
Dr. Masri, as I understand it, I mean, there's a lot of work in the community around sort of identifying patients with red flag type symptoms so that they can sort of have more reflexive testing. Is that right?
Yeah, definitely. So, you know, we go around and give many, many talks here locally to try and talk about, you know, thinking about these red flag symptoms. We actually created some SmartSets in, you know, for clinical notes for different physicians to try and think about the orthopedic red flags, you know, carpal tunnel, the neuropathy, the GI symptom. We talk about the fact that you should explain every single left ventricular hypertrophy case and not just blame it on aging or hypertension. And also, there are other, they're early, but there are other efforts, including EKGs and Echos, where you apply AI-based algorithms to try and provide the previous probability for the disease. We ourselves have developed a natural language processing algorithm to try and pick these patients up from the charts, for example, using clinical notes.
There are a lot of different avenues, a lot of different initiatives to do this. And I know I'm coming down hard on some of the physicians and, you know, providers and whatnot, but the reality is we have done so much more than we have, you know, in the last five years, and I think the next five years will probably even be better in terms of identification. Final point is that we need to figure out a way to have a blood test that could increase the rate, you know, the suspicion for having the disease, and there are at least two or three efforts that are being done in different academic labs around the country and worldwide to try and get at this as well.
Thank you, Dr. Masri. Next question?
Hi. Hi, Joohwan Kim, part of Whitney Ijem's team, Canaccord Genuity. This has been touched on a little bit, but I'm gonna ask this maybe in a different way, for Dr. Masri, actually. As you think about the longer-term future, can you provide us with a view of how Vutri, maybe SC04, and then eventually gene editing approaches would fit into the future treatment landscape?
Yeah. So I think you're asking about, you know, with newer modalities coming online. We'll talk a little bit more about SC04 and our plans for that later in the presentation, but we do certainly believe that can offer even greater knockdown and more convenience for patients and follow on the success that we've had for vutrisiran. But maybe, Dr. Masri, you can talk a little bit about how you're thinking about some of the early data and prospects for vutrisiran and how that might be used with depleters or other agents that come forward in the future.
Yeah, definitely. You know, from our perspective, you know, we were very happy with the data that came out of HELIOS-B. You know, I told some of you, and I would repeat that again, I did not expect that, you know, that trial to have these exact results. You know, I expected the trial to be positive, but not to this degree, essentially in terms of the rates and events that you've seen and terms of reduction as well in events. So I'm very happy and satisfied with what I have seen. And when it comes to comparison to other, you know, knockdown agent and combinations, I think, you know, ultimately the point remains that, you know, vutrisiran has sparked the way that, you know, knockdown in transthyretin cardiomyopathy works and works very well.
You know, we'll have to look into the future. You're talking at least, you know, five to 10 years from now. And kind of the approach will not be, is this a better approach or that a better approach? It's gonna really be a patient preference and, you know, a discussion kind of a thing. Because ultimately, if you have multiple drugs that achieve, you know, that work on the same pathway, you're gonna have to have the exact details of the studies, of the outcomes, of what happened to patients, and then patients can make a decision with their physicians. I don't think you can easily just, you know, imagine how things would look like and go from there. The depleters are different, correct?
Because there is not gonna ever be a scenario, or at least a logical scenario, where you would say: I'm gonna deplete someone, and I'm not gonna control the source of the illness. So I don't think the depleters will create any problem or any issues in terms of our, us treating the underlying disease process itself. You're looking more on combination in that scenario and not one or the other whatsoever.
Thanks, Dr. Masri. Next question?
Hi, good morning, Tazeen Ahmad from Bank of America. Thanks for hosting this session. A couple of questions from me, maybe the first one for Dr. Masri. What is the definition that you're going to use to determine if a patient is progressing, if they're currently on tafamidis, in order to be able to recommend a different treatment? And do you think that your definition of progressing will be sufficient for approval from the mindset of the payer? And then secondly, for frontline use, once tafamidis goes generic and cost becomes more of an issue, what do you think could be potential points of differentiation for vutrisiran that would argue putting a patient on vutrisiran frontline, given what we expect to be a big price differential? Thanks.
Great. So two important questions, and maybe I'll turn to Dr. Masri, and then, John, you may wanna add on as well a little bit, bring you into the conversation. But, Dr. Masri, you talked about a number of different parameters that can be used to look at progression in a patient. Maybe you can elaborate a little bit, and we just have a few minutes on, in terms of, how you look for progression in patients. And then, I think the second question was just: what do you think about in terms of potential points of differentiation and the data that you've seen for HELIOS-B, relative to what you understand about, stabilizers and, and what might draw, you know, that would be important in first-line consideration?
Yeah. So essentially, in terms of progression, you know, it's fairly simple. If the patient is unhappy with the current treatment, they need a different treatment, and this is not a small minority of patients. The second point is, if they are requiring more and more diuretics, even if that means just doubling their diuretics as an outpatient, that's a marker that they have progressed. Of course, it has to be sustained, not just one time off. If they're essentially having one heart failure hospitalization, we have shown data before that this is a big differentiator in the outcome on Tafamidis, for example. And so that's, for me, the really important metric. Did they have an emergency room visit, an urgent visit?
Are they having progressive decline in their eGFR, and their creatinine is going up, which is direct measure of the cardiomyopathy stability being, you know, worse essentially. Are they continuing to lose weight? Their blood pressure lower than when I first saw them. So when you put this basket and umbrella of all of these metrics, there are many, many patients who actually progress. You know, you can then get to the second stage, which is looking at NT-proBNP, looking at, you know, NYHA class, quality of life, these things, but all of them, they go hand in hand. And so there are significant number of patients who progress on currently available therapy. So that's why I think it's not really too difficult to pinpoint that down.
There is a group of patients who are stable, and these typically tend to be the ones that you started the treatment very early in the disease process. Now, in terms of the second question, you know, overall, TTR is a progressive disease. It's essentially associated with progressive heart failure. Ultimately, we will use the drug that we all think confers, you know, better benefit and efficacy long term, and so this is the period of time, it's our job in the next four years to generate data and understand which drug is conferring the best benefit for patients, and which drug essentially would lead to longer term benefit for these patients.
The fact that one drug can become very cheap versus another, I think in a specialty and rare disease settings, it has to do more with what is the effect size and what is the benefit, rather than just simply, you know, this price is X, this price is Y.
Thank you, Dr. Masri. And maybe John, I'll turn to you real quick, just in terms of how we're thinking about progression. Dr. Masri talked about diuretic intensification, things like that. You touched a little bit on that. Maybe a little. You could elaborate a little bit on how we're thinking about some of that work.
Yeah. No, this is such an important question. I, you know, I think the first thing that I would look to are the subgroup analyses that we did, and, you know, when we look across every single endpoint that we studied, we see evidence that vutrisiran may be providing benefit on top of tafamidis in that baseline tafamidis subgroup. Again, it was just such a consistent observation. We have to acknowledge the study wasn't designed to look at that, and statistical significance wasn't achieved, but as an observation, that was just so highly consistent, we find that data compelling.
But beyond that, I think I would look at just the entire package of data that we just covered, where when we look at biomarkers, not just NT-proBNP, but troponin as well, when we look at six-minute walk, the observed data with six-minute walk tests as well as KCCQ, we see evidence that these, that there's stabilization in these patients, and to us-
With the biomarkers as well, right?
The NT-proBNP and troponin. Just such a highly consistent observation. To us, that's a potential point of differentiation, which really would be an important thing for somebody to think about when they're facing something like a patient who's progressing on disease.
Thank you. I think we have time for one more question before the break, so we'll go over onto the left side here.
Thank you. David Lebowitz from Citi. When people think of polyneuropathy, they usually think of the hereditary side of the disease. To what extent are there neuropathic symptoms in wild-type patients, and how might that impact treatment decisions going forward?
All right, so the important question is in terms of really concomitant disease, in terms of patients with wild-type cardiomyopathy, and how often there might be polyneuropathy. I know, John, we were involved in some collaborations, but maybe Dr. Masri, you want to start, and then we'll have John speak. If you're, you know, in terms of seeing in your clinical practice, do you see neuropathy symptoms in some of your wild-type patients?
Yeah, we certainly do, and the prevalence depends on how you define the neuropathy, correct? So if you want significant burden of neuropathy and polyneuropathy, I think you're talking about 10-15% of these wild-type patients. They really struggle with significant neuropathy. And as such, you know, you get to a point where you don't have to really struggle too much to prove that the neuropathy is related or not to transthyretin amyloidosis when you have a treatment that can address the underlying pathology and the disease itself. In terms of if you wanna scale it differently, there are lots of patients with autonomic symptoms, and these autonomic symptoms are also seen sometimes as neuropathic symptoms, even in isolation. And so I think we'll have to become a little bit more sophisticated in terms of working up these symptoms because they are very prevalent.
Finally, at least in my practice right now, we don't consider mononeuropathy, you know, like, compressive neuropathy, such as, you know, spinal stenosis and carpal tunnel and whatnot, as essentially markers of neuropathy. This essentially might change in the future. One of the important areas of investigation that no one has focused on yet is what would happen to these compressive and neuropathic, essentially, pathways if you control the production of TTR, for example? Lots to come down the road with this.
That's fantastic. I don't know, John, anything to add?
Yeah, I guess maybe just to go back to the first slides that I presented in my presentation. You know, in the hereditary polyneuropathy of this disease, the data with RNAi therapeutics has been really profound, and you know, would certainly invite everybody to review that. We've clearly established in that hereditary form of polyneuropathy, it's the same pathogenic protein and you know, in a similar pathophysiology. So that's-
In the wild-type as in the hereditary, yeah.
Yeah.
Great. Wonderful. Thank you, John. Thank you, Dr. Masri. I think we're gonna bid you adieu, but thank you so much for your presentation and participating in the Q&A. Hope you have a good rest of the day. Thank you again for joining us so early in the morning. I think we're gonna take a break now. How long is the break?
We will resume at 10:15 A.M.
10:15 A.M. Thanks, everyone.
Your love is rated X. That means you're extra, extra, extra ordinary!
Hello, everyone. We'll be getting started shortly. If you wanna make your way back to your seats, and we will get started in just a moment.
Please welcome Tolga Tanguler.
Good morning, everyone, and welcome to the second part of our TTR Investor Day. It's really great to be here. Dr. Masri's last slide ended with future goals: better disease control, improved survival outcomes, improved function and quality of life. At Alnylam, we often tell ourselves, and it's actually written on our walls in big, bold letters, "Challenge accepted." So today, this part of the day, what I'd like to do is to actually provide you how we're gonna put all this great data, great biomarker outcomes, good quality of life metrics, and outcomes into all together, and make this medicine into the hands of the patients. That's the goal today, and more importantly, what we'd like to be able to touch on is, how we will unlock value that we've already discussed step by step as a long-term flagship franchise.
We already started this discussion around increased improved diagnostic rates. Not too long ago, back in 2018, effectively, this category didn't even exist until the availability of first available, the targeted treatment. And since then, there has been a tremendous increase in disease awareness, both for patients as well as physicians. Dr. Masri also highlighted the introduction of system-level retrospective and prospective red flags, and at the top of that, the invention or introduction of non-invasive scintigraphy versus heart biopsy. If you think about it, ATTR-ACT trial was essentially those patients that were qualified, they were all come in with a heart biopsy. It's really important to understand how this actually category is evolving.
The numbers that you see here is just an evolution in the United States from 2019 to 2023, and we've seen a tenfold increase, granted from a very small base. What we've also seen in other categories, whether it's rheumatoid arthritis, whether it's MS or pulmonary arterial hypertension, with the introduction of new therapies, with the increase of share of voice, disease awareness increases tremendously. So although what we don't know how specific that growth is gonna be, we are confident that this category will continue to be expanding as the patients are found early and treated early. We also know that even though it's a rare orphan disease category, there is a significant large number of patients still being undiagnosed. In fact, in our best estimates, we believe about 20% patients only across the world are diagnosed.
Therefore, this really is, in a way, I'm gonna date myself, a bit of a blue ocean opportunity with some important players, which is only going to actually expand, increase access and availability. Why do we have the right to play in this category? The numbers that you see here today is actually our performance since the inception of Alnylam's first commercial franchise back in 2018 , where we started to launch in 2019 . Since then, we've been able to grow this category nearly $1 billion. The last 24 number is a sell-side analyst consensus number, which actually exceeds that. This is a smaller category, but it's really an important part because essentially, what I really like to highlight is, we are going to, with the cardiomyopathy, not to have a standing start, but a running start.
I also like to peel back a little bit about how we got to this growth, 'cause there are actually two tales of story here. In the U.S., this category didn't exist. When Tafamidis was launched in Europe back in 2011 , in the U.S., they received a complete response letter in polyneuropathy. Therefore, when we actually introduced the first available treatment, we had to build this market. We had to build this category from diagnostics to treatment choices, patient support network, and we've been able to do that in a market that's highly fragmented, where there weren't really many centers of excellence. In Europe and Japan, the story was a little different.
In Europe and Japan, a price-sensitive market against an oral treatment that was available, thanks to APOLLO trial first, and obviously after that HELIOS-A, with great mNIS+7 scores, we've been actually able to convert and switch the market as high as over 80% in Europe and Japan, in all major markets. Today, Amvuttra is the clear market leader in polyneuropathy, with ever-expanding patient and prescriber base. Again, when you look at our performance, it's really important to understand the distinction between those two categories. The goal is, essentially, we need to do the same in a much larger category, but effectively where we know these centers, we understand these patients, and we've been actually involved in cardiomyopathy management for over a decade through our trials. What it takes to be a first line? I think Dr.
John Vest clearly articulated how important it is, get these patients treated early, and treated with the best available medicine. So we believe these patients are desperate for a choice, and they need to be hit hard and hit early with the best available option. That's what I call a market leading profile. And HELIOS-B effectively only increased our confidence in this expanding category. What you will also see today, with my colleagues here, it requires a talented, highly focused team. And we assembled over the last three years, a highly talented team that really knows how to scale an organization, to be able to meet the needs of this ever-growing category. What we'll also discuss, and I can hear some of...
from some of the questions, very specific details about how we're going to commercialize it in such a patient-centric approach. That's really important because those of us who have been in the category or who've been doing this for a while will appreciate that great data is a must, but not enough, and we believe we need to be able to understand the treatment paradigms from centers of excellence to community cardiologists. We need to understand a highly complex and fragmented U.S. care system. We need to understand the advances in key markets like Japan and the rest of Europe, and we also need to make sure that we support those patients, so that patients adhere to the therapy.
Those are all important capabilities that an organization needs to build, and we've been doing that for the last six years and last but not least, which supports every one of that, and I think this puts really Alnylam in a unique position. As Yvonne indicated, this is a transformational moment for Alnylam, and that transformational moment really lies on our success of how we're gonna commercialize Amvuttra for the cardiomyopathy population when approved, so organizationally, we are laser-focused on the success. We've built teams from end to end in all major key markets, that is ready to deploy and start communicating and promoting the product and the last part of the formula is the TTR experience. As I highlighted before, this is gonna be a running start for us. Nonetheless, it's gonna be and we need to continue to run.
We're really not underestimating what it's gonna take us to really build and scale the organization, and today we're really looking forward to discussing that in detail, and if we can do all that, which we absolutely believe we will be able to, when Amvuttra is approved, we believe we're looking at a multi-billion dollar franchise that's not only gonna transform patient care, but also Alnylam, so I mentioned to you about a talented team. Unfortunately, I couldn't have brought all my team here today, but I was able to, we were able to actually showcase some of the very important leaders that's been behind the scenes, getting the the organization ready for this really important launch, and how we actually pick those individuals? How we've been actually building this team? How we assembled our organization? Look at an important mix.
We like to be able to actually attract talent that have established themselves in large pharma, because we wanna make sure that they understand how to scale the organization. But we all know it takes a certain type, an archetype of individual, who can actually operate nimbly and agilely, and be able to attract talent into biotech. And what I like to think is, we've been able to do that. We have individuals with broad therapeutic experience in many large categories that have been successfully launching products in rare specialty as well as prevalence. So we've been able to actually assemble a team that understands the nuances, and more importantly, how to scale an organization. Joining us today, and you'll be hearing from each of them, is John Kennedy, who heads up our broad commercialization efforts across the world.
Mark Sew, head of our U.S. organization, and Jason Gittleson, who have decades of market experience, market access experience, starting from Pfizer, Alexion, and for the last several years at Alnylam. So what I'd like to leave you with, and obviously we're gonna have plenty of time to have a Q&A at the end of the session, is, as Dr. Masri indicated, as you will be hearing from my team, this is a rare disease. It's a severe disease that needs to be diagnosed and treated early. At the end of the day, for a rare disease, this is large and untapped, and continues to grow. We are, we believe, if Amvuttra is approved, poised to become the standard of care for everything that Dr. John Vest so clearly articulated.
Our success in polyneuropathy is a very important marker for all of us to believe that we are ready and be able to expand this category with the cardiomyopathy opportunity. Last but not least, we have a deep focus as an organization in ATTR, and have already scaled for a successful launch. With that, I'm going to invite my partner in crime, John Kennedy.
Thanks so much. All right, good to see everybody. As Tolga said, my name is John Kennedy. I'm the global commercial lead for the TTR franchise. I've been in the industry about 25 years, and most of that in commercial and commercial leadership roles. It's been in the United States, in Europe, and in global roles like this one, and worked across a number of therapeutic categories, and that includes cardiovascular as well as rare diseases. So it's great to be with you today, but really great to be part of such an important launch. So I know that there are some questions about how we see the ATTR cardiomyopathy category, and so we just wanna break that down a little bit, and just to give you a sense of how we see it, let me start by backing up.
This is a large and really, really underserved category, so you saw on Tolga's slides that we estimate it's about 300,000 patients that are affected by ATTR cardiomyopathy today. Majority of those patients are undiagnosed and certainly untreated. The good news is, that is changing very, very quickly, and so we're gonna talk a little bit more about that, but this is a large and really underserved category where there's a lot of opportunity for us to help. Just to break that down a little bit further, we see three different segments of opportunity. We'll go through each of these. The first, and what will be our primary focus at launch, are these new to treatment patients. These are the patients that are coming in on an annual basis, looking for that very first treatment decision.
This is where our goal is to establish Amvuttra as a first-line treatment of choice, and it's likely this is also where physicians will have their first experience using Amvuttra. So doing well here will beget opportunities across the other segments as well. The second segment are stabilizer progressors. So we know there are a lot of patients that are being treated with stabilizers. Some may experience suboptimal response to treatment. The opportunity is switch or could be add-on, for some patients. Now, we have to say that there hasn't been a whole lot of switch behavior in this category because there hasn't been another choice, and so that pattern of behavior will form and will progressively unlock more of this opportunity over time. And then, of course, there's a third segment, which are the undiagnosed patients. This is the largest, but again, it's rapidly changing.
And so the undiagnosed patients of today will eventually become those new to treatment patients tomorrow. That's the hope for the sake of these patients as more and more are diagnosed and eventually given the opportunity of treatment. So you can imagine, with so much changing so quickly, there is a lot of movement in this category, with more and more patients becoming new to treatment patients and a first-line opportunity, that we have an opportunity to establish. So that gives you a general sense of how we look at the category. But again, I do wanna go through each of these segments in turn, just to give you a sense of how we think about the opportunity more specifically. We'll start first with the new to treatment patient. Again, this is our primary focus at the time of launch.
We've seen some of the math and what Tolga has shared. There is significant movement already. But today, we estimate about 18,000 patients globally will present to a physician for that first treatment decision. It's about 18,000 patients per year presenting today. But again, if you look at the growth in the total treated patient population, there's significant growth. So this is very dynamic and will continue to grow year-over-year. The goal is to establish Amvuttra as a first-line treatment choice, and so for us to do that, we have to drive awareness, access, and preference. So in terms of how we'll do that, you'll hear more from Mark, and you'll hear from Jason about our intent for the preparation for launch in the United States.
They'll talk more about how we'll do that, but I do wanna give you a sense of why we're confident that this can happen. What I will say about these patients, though, is, if you look at them, the majority of these patients, the largest segment and the fastest growing segment, are patients that are now milder in disease. We're fortunately for those patients beginning to find more of these patients early in their disease progression. This is remarkably consistent with the HELIOS-B patient population. That's an important point. We also know that many of these patients will experience multisystem manifestations of the disease. So with all that said, why are we confident we can establish Amvuttra as a first-line choice for these patients?...
It goes back to two things: the clinical profile, but also the patient experience that we can provide with Amvuttra once we receive regulatory approval. So just to give you a sense, on the clinical side, you've heard from John Vest what we saw from the HELIOS-B study. First and foremost, again, the patient that was studied in HELIOS-B is very familiar. It looks very consistent with the patients that are presenting to physicians for that first choice today. We also saw that HELIOS-B represented a really high bar to be able to show that treatment benefit. Again, generally speaking, these are milder patients with very substantial background treatment. So it's a high bar to be able to show treatment effect, and yet that's what we saw from HELIOS-B. Very significant, profound, impact on hard outcomes, mortality, and other cardiovascular events.
John shared the impact that we saw in terms of preservation of function and quality of life, as well as an effect on the underlying biology, whether it's biomarkers or some in the imaging data that John was able to share. Again, highly consistent across the endpoints, but also across patient populations in the HELIOS-B study. I think one of the most compelling takeaways from HELIOS-B is it really suggests that the earlier patients start on Amvuttra, the better. So that's the clinical package that HELIOS-B delivered. We also understand that there are very practical considerations, and we've already had questions to Dr. Masri about some of those. But just to talk about the Amvuttra patient experience, we know that it's quarterly dosing, so it only requires four doses per year. That's a good experience for patients. It also can support really, really strong adherence, and we've seen that.
If you look at hereditary ATTR polyneuropathy, we've seen really strong adherence. This is real-world experience. We also know that access matters. Here, too, I'll look at hereditary ATTR polyneuropathy. Patients have broad access to Amvuttra, and the majority of patients in the United States, 70%, have access to Amvuttra with zero-dollar copay. That's in hereditary ATTR polyneuropathy today. What we expect is the cardiomyopathy indication will be very, very similar, and Jason will talk more about that later. All told, when you put this together, the clinical package as well as the patient experience, this is a really compelling package and an opportunity to position Amvuttra for a first-line treatment. So this is what we see. Obviously, what's really, really important is what cardiologists think. So here we have some very early but encouraging indicators.
There's a market research firm called Ipsos, and they conducted an independent study, a poll, so unsolicited by us, they talked to more than 80 cardiologists. They were in the U.S. and in Europe. These were cardiologists that had direct and recent experience treating patients with ATTR cardiomyopathy. And Ipsos asked a couple of very basic, fundamental questions: On the basis of HELIOS-B, do you expect to use Amvuttra? Are you likely to use it in first line, and are you likely to see Amvuttra become a standard of care? What we saw was, resoundingly, the answer was yes from cardiologists that were polled.
Majority said: "Yes, I expect to use Amvuttra, to use Amvuttra as first-line treatment and for Amvuttra to become a standard of care on the basis of the HELIOS-B data." Now, this poll was done in the summer, early July, so this was right after we had announced the top-line results, in late June. Ipsos then went out and repeated the survey, did the poll again after European Society of Cardiology. So you remember, at ESC, we had the full presentation of the data, as well as simultaneous publication in New England Journal of Medicine. So they went back out, same questions, this time to about 150 cardiologists, still in the U.S. and Europe. What do we find? The perceptions held. In fact, they strengthened.
This suggests to us that as cardiologists have more exposure to the data, they gain more confidence in their likelihood to use Amvuttra, use it in first-line specifically, and have Amvuttra become the standard of care. I, I want to be very clear, we're under no illusions. We know we have a lot of work to do. Our medical teams will continue to provide data at future congresses, and once we have approval, we'll start the important work of educating customers. So we have a lot of work to do, but this is a really, really encouraging indicator of how cardiologists see the data coming out of HELIOS-B already. So that gives you a sense of how we see that first-line opportunity in our priority area of focus, which are these new-to-treatment patients. We know that there are other segments of opportunity as well.
If we shift and look at the stabilizer progressors, we estimate there are about 40,000 patients that are actively treating today on a stabilizer. Now, if you look in the literature, you see a wide range of estimates in terms of how many of these patients are progressing. We believe it could be about 50%, based on a recent and robust analysis that was just presented at HFSA and cited here on the slide. Some of these patients may be looking for an alternative treatment option, ideally an orthogonal mechanism of action. We also know from the enrollment in APOLLO-B, but also the Patisiran Early Access Program, physicians are identifying these patients, and patients are looking for an alternative treatment option. We've already seen that. That's happening in the real world.
And then separate from all of this, we know that persistence with a daily oral treatment is far from perfect. And that, that's the case even in really, really significant or conditions that have life-threatening consequences, whether you're looking at oral oncolytics, oral MS treatments, or even here within ATTR cardiomyopathy. When we look at claims data, what we tend to see, it's not uncommon to see about 30% of patients discontinue treatment within that first year alone.
So all of this taken together, these are just different indications that patients are likely looking for alternate treatment options. And then on the basis of the clinical package we talked about, on the basis of that patient experience we talked about, coupled with the fact that this is an orthogonal treatment or mechanism of action, we do think we have a compelling proposition to help some of these patients that are looking for another choice. Of course, that brings us to the third category, which is the largest. These are the undiagnosed or untreated patients, and there are too many of them, frankly. Here, again, I'll say the good news is that there's momentum. Just in the last several years, we've seen a tenfold increase in diagnoses in the United States, granted, from a lower rate, but there's momentum.
We've also seen in analogous underserved specialty categories, more voices in the market help. Whether that's RA or MS, gMG, we've seen it in different categories. As there are more voices in the market, that is helpful for patients who are looking for diagnosis ultimately, and eventually finding their way to treatment. We also know that we have a role in this, and so here I, I'd point to what we're doing in hereditary ATTR polyneuropathy. Again, far and away, we are the market leader in the polyneuropathy space, and so it's incumbent upon us to do that work of raising awareness and helping facilitate diagnosis so those patients can make their way eventually to appropriate treatment. So what does that look like? All sorts of things. It could be general awareness. That's what we're driving.
It could be using advanced analytics as we partner with centers of excellence or IDNs, and they establish care pathways. This is the work that we're already doing today, hereditary ATTR polyneuropathy. It's transferable when we move into the cardiomyopathy space after regulatory approval. If you look at the impact that we're having, obviously, there's a lot more work to do. We've doubled the prescriber base in the PN space. We've driven very, very significant and sustained growth, year-over-year sustained growth in the category. That is good for patients. So all of this is in practice, we're doing that work today, and it is transferable into the cardiomyopathy space, though, of course, we have more work still to do. So just to kind of pull it all together, what do we see when we think about this category?
A large category with a very, very significant unmet need, but a lot of momentum, and we have an opportunity to help. We see multiple categories where there are opportunities. Our primary focus at launch will be in those new to treatment patients, where our goal is to establish Amvuttra as a first-line treatment of choice. Doing that well will beget opportunities across the other segments as they continue to unfold, and this market truly forms. So with that, I do want to turn it over to Mark, who will give you a better sense of how we're thinking about the launch in the United States. So, Mark?
Great. Thank you, John. Appreciate it. Good morning, everyone. I'm Mark Sew. I head our U.S. business. I've been with Alnylam for almost three years now, and actually prior to that, I was at Pfizer for about 20 years in a number of functions, number of therapeutic areas, number of geographies. And actually, in 2019, I launched Vyndamax in the U.S. and could not be more excited to continue to be a part of really growing and advancing the state-of-the-art in ATTR-CM. So today I'm here with Jason Gittleson, our head of U.S. market access, and together we wanna talk to you about unlocking the U.S. opportunity in ATTR-CM. And we wanna do that through a prism, if you will, of really three foundational elements that we think are critical to the success.
First is treatment selection, second is access, and the third will be patient support. And, what we wanna share with you is why we believe that entering the ATTR-CM market is a step up for us, but it's not a giant leap. And we'll talk more about why we're saying that, momentarily. So starting with treatment selection, as we talked about a little bit before, and just to go into a little more detail now for the U.S., we believe there's a prevalence of around 150,000 patients in the U.S., and the Amvuttra opportunity spans really three key patient segments, which John just alluded to.
The first segment is this new to treatment segment, and we think within the U.S., there are anywhere from 5,000-10,000 patients a year that are getting on therapy. And we do think that's gonna increase over time with the entrance of, you know, new companies in the space and the advancement of more awareness and disease education. As we said, we think Amvuttra is really well-positioned to compete in this segment in first line, and we do think that this is the segment where we'll most quickly start to unlock the opportunity for Amvuttra. The second segment is this stabilizer progressor segment. We think there are anywhere from 15,000-20,000 patients in the U.S. today on a stabilizer, and that's actually a relatively large number.
We think, approximately half of those or up to half of those, based on the literature, are potentially progressing. That translates to 8,000-13,000 patients, who we believe, you know, may benefit from an add-on or switch, to Amvuttra. In terms of add-on, we do think that this will take a little longer to unlock, and that probably will happen less frequently before the tafamidis LOE, and that's due to, you know, payer restrictions around combination therapy. In terms of the switch, we really do think that establishing Amvuttra in first line will really facilitate and enhance the comfort physicians have, to, you know, switch patients from a stabilizer, to Amvuttra.
The last category is this undiagnosed, you know, patient category, and we think, you know, more than half of the patients in the U.S., remain undiagnosed, and this is again a large opportunity here. We do think with the increased awareness and education around the disease, that'll happen with all the entrants coming in, this rate of diagnosis should increase, and that will then fuel that new to treatment segment. But to be very clear. Our focus out of the gate is really gonna be on this new-to-treatment segment and really firmly establishing Amvuttra as the standard of care within this segment.
We think that's really gonna help to then drive, switch, and eventually add on, for those physicians, those patients that are really looking for, you know, an orthogonal, MOA that rapidly knocks down the disease-causing protein and delivers, you know, cardiovascular outcomes and functional benefits. It's important to think now. All right, we talked about the patients. Now, you know, who are the physicians treating these patients? Where are they, and what, where are the systems where these patients are being treated? Starting with the top line here, there are around 3,700 patients in the U.S. today, currently treating about 95% of the ATTR-CM patients. And actually today, we're already calling on 65% of those physicians, and that's for our PN business.
And that's because it's very common within the hATTR PN diagnostic pathways to actually have that pathway start in cardiology. Oftentimes, cardiologists will first diagnose the patients with ATTR amyloidosis, will then send them as part of a standard workup to get a genetic test to see if they have hereditary amyloidosis. If they do, then they'll send them for a PN workup to see if they have polyneuropathy. And so we're there today in 65%. We plan to be covering 100% of those physicians, and frankly, even more, at launch. And in fact, we've already hired and expanded, I should say, the field organization. And the idea is to really train them and have them fully prepared for launch.
If you go to the bottom line, and you look at the systems where these patients are being treated, it's about 170 systems across the U.S. And by healthcare system, what I mean is anything from, for example, a large national system like Ascension Health, which has, you know, hospitals across the U.S., to a more regional system like Mayo, which has hospitals in, you know, Minnesota and Florida and Arizona, or an academic system like Stanford, which is more local. And it's important to note, with these systems, they can have large hospitals, but they can also have community hospitals, clinics that are all part of that system. And so today, for our PN business, we're calling on 45% of these systems.
And we're calling on those systems with a dedicated team of account leaders, strategic account leaders, as we call them. And their goal and their sole focus is to call on the non-physician decision-makers within these systems and really focus on care pathways for patients and really optimizing those care pathways. The idea being, we want a physician to be able to prescribe Amvuttra with the knowledge that that patient will easily be able to get that Amvuttra, you know, injected, whether it's in the hospital or it's at an infusion center or it's at home. And so, that's why we're there today, and I think we've been, you know, quite successful there today.
Our goal, again, is to cover 100% of those systems at launch, and of course, we've already hired the expanded team, so that they're trained and ready to go at launch. This is why, or one of the reasons why we say that entering ATTR-CM is a step up; it's not a leap. We already have a footprint in this space, and frankly, this footprint is what has helped us, I think, with our PN business and deliver some of the results that Tolga talked about earlier. And our plan is to expand this footprint. You know, we've got a running start, as Tolga said before, in this space. With that, I'm gonna turn it over to Jason Gittleson now to talk a little more about the access landscape. With that, over to you, Jason.
All right. Thank you. Thank you, Mark, and good morning. My name is Jason Gittleson. I lead the U.S. Market Access team at Alnylam. As Tolga said earlier, I have more than 25 years of market access experience, including several launches in competitive categories across specialty, rare disease, and more prevalent conditions. It's really a pleasure to speak to you today to discuss our expectation that assuming approval in ATTR-CM, patients will have widespread coverage and affordable access to Amvuttra, and let's discuss why. Starting with today, as we spoke about earlier, in hATTR-PN, greater than 99% of patients have coverage to Amvuttra. I'll remind you that hATTR-PN is a competitive market, and this coverage has been consistent since approval. This is across all payer types. Today, approximately 70% of coverage is under Medicare in the hATTR-PN category.
Not only do patients have widespread coverage, but they also have affordable access. As you can see on the slide, approximately 70% of patients have zero dollars in out-of-pocket cost. I wanna say that this coverage comes from several reasons. Two of those, of course, is the value proposition that Amvuttra offers to payers, but I think very importantly, the established payer relationships that Alnylam has, including value-based agreement. This will be important as we move forward in ATTR-CM. Okay, so let's think ahead a little bit to ATTR-CM and as payers think about coverage for Amvuttra. We know that what payers think about first is the clinical impact of a drug, the efficacy and the safety of the medicine. This is particularly important in ATTR-CM, which is a rare, debilitating, and ultimately deadly disease with significant unmet need.
We believe that the HELIOS-B data, as you heard earlier today, has really important clinical outcomes that matter. This includes a mortality benefit, preservation of function, a reduction in hospitalizations, which, as you heard earlier, not only has a clinical impact potentially on patients, but also we know economic considerations. Importantly, these results were delivered in a population that's representative of who payers are covering today. I'd like to provide a little more detail regarding how we expect coverage to look. And a consistent theme here is our experience in hATTR PN. Based on an analysis that we conducted in ATTR CM claims data, we expect the payer mix in ATTR CM to be similar, with about 75% of patients covered by Medicare and the balance being covered by commercial and other government payers. So let's unpack this a little bit.
In ATTR-CM, the approximately 75% covered by Medicare, about half of those will be covered by Medicare fee-for-service. This is Part B that you may be familiar with. Our expectation with Part B coverage is coverage at approval to label without a policy. Now, the other piece of the Medicare business covering Part B is Medicare Advantage, and Medicare Advantage also covers drugs covered by Part B that are reasonable and necessary, which of course, we absolutely believe Amvuttra will be, assuming approval in ATTR-CM. That's the majority of the market. The remaining market, as we think about coverage, as I've spoken about, we expect that to be based on the clinical efficacy and safety of our medicine, and of course, we will continue to work with payers to ensure appropriate coverage. Okay.
The other important dynamic are out-of-pocket costs, and as we spoke about today, approximately 70% of patients have zero dollars out-of-pocket cost. So when you consider a similar payer mix in ATTR CM and the benefit design of those payers, we expect the same, that most patients will have zero dollars out-of-pocket cost. A large segment within the ATTR CM space is, again, Medicare fee-for-service, where patients, through additional coverage, such as Medigap, have zero dollars out-of-pocket cost. In the commercial segment, Alnylam offers co-pay support that can bring patients, again, down to zero dollars out-of-pocket cost. And for the other government payers, representing about 5% with medical benefit, again, many of those patients have zero dollars out-of-pocket cost.
In Medicare Advantage, where Medigap is not available and we cannot provide co-pay support, we expect the median out-of-pocket cost to be about $3,500. But overall, a majority of patients will have zero dollars out-of-pocket cost, as approximately 70% of patients do today in hATTR PN. I can speak from experience that we receive questions regarding the implications of the Inflation Reduction Act, specifically to how we're thinking about ATTR CM and the potential approval of Amvuttra, so I'm gonna start at a high level and just remind you that we believe that in ATTR CM, approximately 75% of patients will be covered by Medicare. In the case of Amvuttra, an HCP-administered medicine, that coverage will come under Medicare Part B.
The IRA, as it pertains to ATTR CM, really had minimal, or we say, no changes to both the payer liability and the patient out-of-pocket in ATTR CM. On the Part D side, that's different. While Medicare Part D, the Inflation Reduction Act capped the patient out-of-pocket cost at $2,000, it increased the liability to the plan almost fourfold, from 15% of drug cost to 60% of drug cost in Medicare Part D. So the question is: What does this mean? Well, what does that mean?
We know from publicly available market research that along with this change, payers are considering increased utilization management, and this can include formulary exclusions. Now, again, as we've discussed, ATTR CM is a rare disease, a deadly disease, a progressive disease. We expect patients to have coverage, and in Medicare Part B, as we discussed, that coverage will be to label in a fee-for-service side of the business and will also be covered by Medicare Advantage with a policy. Okay. Moving on to a discussion that occurred earlier.
So we talked about the widespread coverage, the greater than 99% of coverage patients have today, and our expectation that that coverage will continue to be widespread, the affordability of access, about 70% having zero out-of-pocket costs today, and our expectation that due to a similar benefit design and payer mix, most patients will continue to have zero dollars in out-of-pocket cost. Now let's talk about site of care access and administration. Two important concepts that aren't necessarily the easiest to understand. The first is buy and bill. That's the framework by which HCP-administered medicines, at least most of them, are acquired and reimbursed in the United States. So what does that mean? It means a healthcare practitioner, an office, a clinic first purchases an HCP-administered medicine.
They then administer that medicine to a patient, and then they bill the payer based on the cost of the medicine and any associated services. That's the buy, and that's the bill. Hopefully, that's straightforward. The second concept that's important to understand is that today, in hATTR-PN, really only 5% of the time when a patient is prescribed Amvuttra in the clinic or group practice setting, is that HCP office also the provider of the medicine, or they also administer the medicine. 95% of the time, when a patient is diagnosed or prescribed in a clinic or group practice setting, that patient receives their administration somewhere else. So what we say is the prescriber is usually not the actual HCP that provides the treatment, that injects Amvuttra. So let's talk about that 95% where patients receive their administration. It can be in multiple sites.
You know, I think Amvuttra is unique in that we have site of care optionality under the care of a healthcare provider, which we believe is important in such a deadly, rare, and debilitating disease. About 25% of patients actually receive their Amvuttra in the home. Another 25% of patients can receive their care in the community setting. So these specialty infusion providers, they specialize in specialty diseases, rare diseases. They're spaced throughout the community setting. They have a healthcare practitioner on site to make sure that a patient's receiving appropriate treatment. Now, the balance, they receive their treatment in a health system, and I think Mark did a great job of giving several examples of those health systems where a patient can receive treatment. Now, the HCP may or may not be affiliated with those health systems. So what does this mean in the entirety?
We believe patients have convenient access to Amvuttra. As we were completing this presentation, there were approximately 900 sites where we knew that Amvuttra was available to patients. You know, we heard yesterday from the team that that number just increased over 1,100 sites, with approximately 200 new sites where we've confirmed that treatment is available to patients. The net-net of all this is that about 90% of patients receive their Amvuttra treatment within 20 mi of a treatment site, and that's our commitment to continue to grow the sites of care for patients and increase that convenience. It's a process that is well understood, the buy and bill process for Amvuttra.
Amvuttra has a J-code, for those of you who maybe get a bit more technical, and that's the J-code that they'll continue to be able to use for Amvuttra, assuming approval in ATTRCM. So that was quite a bit in a short period of time, but in summary, we expect to continue widespread coverage for Amvuttra as greater than 99% of patients have today. We expect patients to have affordable access, with today about 70% of patients paying zero dollars out of pocket, and most patients expected to pay zero dollars out of pocket, assuming approval in ATTRCM. And we expect convenient access, with about 90% of patients today being treated within 20 mi of a treatment site. So with that, we'll turn it back over to Mark, who's gonna talk about patient support.
Thank you, Jason. Okay, so we'll take a look at the last foundation element in our launch planning, which is patient support. And I'm really proud to say that since Alnylam's first commercial launch in 2018, we've built a really robust patient services organization. Today we have a team of dedicated colleagues within patient services that are supporting around 2,000 patients across the U.S. today, and they're supporting patients across things like benefits verification and navigating the insurance process to financial assistance and helping patients that are in need, to providing disease and product education to patients and to their caregivers.
And I we're proud to say, I think, because of this, this great organization, and of course, augmented by a product like Amvuttra, that's, you know, dosed once a quarter by HCPs, we have an approximately 95% adherence rate today. You know, looking ahead to ATTRCM, we will continue to optimize and augment our offerings for these patients and make sure that we're addressing their needs. So again, this is why we say, you know, entering ATTRCM is a step up. It's not a giant leap. We already have a footprint here, and we're gonna expand on that footprint, knowing that we still have work to do. That leads us to sort of the last recap of what Tolga had shared earlier, which is that we really think we're uniquely positioned to lead in ATTRCM.
As we said, ATTRCM is a disease where there is a significant unmet needs. We think Amvuttra is really well positioned to actually help to meet that need. We have a track record of success with PN and being competitive, and we plan to continue building on that, and I will tell you, we have this intense end-to-end focus from top to bottom within the company on TTR and being successful there, so we really think this sets us up really for the next phase of growth for Alnylam and to really have an impact on this devastating disease. With that, we're gonna move into the Q&A, and I would just invite my colleagues to join us back up here.
Thank you, team, and I hope it was evident, the level of preparation we have and how we see this market. So I see a lot of questions. Why don't we go in the back? Yeah, go ahead.
Hey, guys, Eliana Merle, UBS. Thanks so much for hosting this. Maybe just in terms of the number of patients, just trying to reconcile the 5,000-10,000 a year starting treatment, but only 15,000-25,000 on stabilizers in the U.S. Can you maybe just give a bit more color on the dynamics there, maybe what the current adherence rate is on stabilizers today? And then just a question on the diagnosis. So you've mentioned that the diagnosis is getting earlier and earlier. I think you had the stat that 10% of people with carpal tunnel surgeries have TTR.
I guess, at what point is the disease too early to treat, and how are you thinking about how that could change the dynamics in terms of who the prescribers are and what the centers are that are receiving these patients? Thanks.
... Thank you. So it's a two-parter question. The first part is more about the specific U.S. numbers that we talked about in terms of who is on tafamidis right now, and the market is also evolving in terms of new patients. And then the second part of the question is more about diagnosis and how we actually anticipate that to be accelerated through a number of different symptomatic signaling, like spinal stenosis and bilateral carpal tunnel. So maybe the first question, I'll turn it over to Mark.
Yeah.
You can talk a little bit about how we see those dynamics.
Yeah. No, thank you for the question, Ellie. So, as we said before, you know, first and foremost, our priority is gonna be on really establishing Amvuttra in the first line, right? And for those new to treatment, patients. To your question around that, that group we said of maybe 15,000-25,000 patients on stabilizers today, and how adherent are they? What we do know is that within daily orals, in general, it's hard for patients to stay adherent for the long term. And so I think what you're probably teasing out there and seeing there is a dynamic where patients do not necessarily stay on their therapies for the long term. And so this is where we think we're uniquely positioned, frankly, with Amvuttra, given that it's once a quarter, it's HCP administered.
We see very high rates of adherence today with the PN market. We think we're in a unique position to really tap into, you know, supporting those patients longer term, especially those new to treatment patients that'll be coming in. I don't know if you want to add to that, John.
No, I think well said. In terms of the second question, you know, I don't want to weigh into a clinical domain in terms of what is too early, but what I would say is if you just look at the landscape, I don't think that's the biggest concern at this point when there are so many patients that just are undiagnosed and untreated altogether. So I do acknowledge there's definitely a trend that's in the right direction. More mild or earlier in disease stage, patients are presenting to physicians, but that's a good thing, and there's just so much missed today that I don't think we're at a point where we're concerned about too early treatment.
Again, I'm not trying to get into the clinical parameters per se, but I just think that there's such an untapped opportunity for patients that can benefit from treatment today, very, very clearly, based on what we've learned from studies like HELIOS-B.
Yeah, I mean, if I were to recap, you will be seeing a lot of different numbers from various sources, and the reason is there is no one definitive epidemiological study in this category. There are a number of things we're all trying to triangulate and try to provide ourselves and obviously to the investors, how this market is gonna evolve. The key point is, what we see from a volume of patients that are coming into the system through the claims data, that's increasing. You've heard from Dr. Masri, more and more centers are actually incorporating system-level diagnostic tools to be able to incorporate that. We also see a number of things like MRI, with the help of AI and machine learning, to be able to accelerate that diagnosis.
Rather than actually try to be super specific about these diagnostic numbers, it's really important to understand the directional, you know, volume and how that's actually increasing. Next question. Yes.
Let's do rock, paper, scissors.
Yeah, rock, paper, scissors.
Me?
All right. Yeah, go ahead, Gena.
Okay. Gena Wang from Barclays.
Hi, Gena.
So two questions. The first one is maybe wanted to know, what is the latest thoughts regarding the pricing? I know you put a list, the number one is efficacy, then safety, and then the price, but then we don't have a head-to-head comparison, right, across all different drugs. So, you know, do you think it was your current price, it will be a little bit at a disadvantage? And the second question is regarding, basically, how do you transform study in 2026? If we saw there is a substudy for the Tafamidis add-on group, would that be a disadvantage for you in terms of, say, in the future, that Tafamidis go generic? Would that be a disadvantage for you?
That's helpful. So let me take the first question, and I'll turn it over to John and Pushkal, if you wanna also comment on that. Look, we look at our pricing throughout the years through the lens of Alnylam's patient access philosophy. And that philosophy actually has two arms. The first piece is actually the value, and I think to what you alluded, we're incredibly pleased with the HELIOS-B results and how that value can actually be interpreted first for the patients as well as the systems. And we will be obviously communicating that and already engaging with various payers, especially U.S., but as well as ex-U.S. It is too soon for us to provide you any specific guidance right now on pricing, but we will obviously...
We don't have our label yet in our hands, but as soon as we have a clearer picture, we'll obviously communicate that. Now, in terms of how the market is gonna evolve, if you know there are more silencers that are actually gonna be making more data available, and with that, maybe I'll turn it over to John first.
Yeah, yeah, thank you. So I think the first thing I would say is I'd go back to HELIOS-B, and what HELIOS-B showed us is that you had profound and very, very consistent effect on outcomes, on progression, and that was consistent across patient populations, with and without background tafamidis, as in terms of just the consistency of effect. So I feel very, very good about that data set. I also think that we're in a really good position in terms of our anticipated time to market entry. So there may be other competitors out there. We have to wait and see how that plays out, but we're in a really good position in terms of our time to entry.
Maybe the last thing I'd point out is if you look at hereditary ATTR polyneuropathy today, different market, of course, but it's also competitive. And so I think that underscores that we have a value proposition clinically and in terms of the patient experience, coupled with the access that does resonate even in a competitive context. So I think all of these things really position us well to establish Amvuttra as a first-line treatment choice and to sustain that differentiation over time.
... Great. Thank you. Oh, yeah, Pushkal, you want to add?
I don't have a lot to add maybe, but just, since you called me up, I think, you know. Look, I think, we're incredibly excited about the results we've seen. I think we expect that the data really support, you know, full use of Amvuttra across the full range of patients that we treated, including both patients on monotherapy as well as on background tafamidis. And so we would expect that the data support such a label. Obviously, the FDA is reviewing that right now. And as John Vest said, the additive benefits on top of tafamidis were seen actually across a full spectrum of patients. So I think, look, we'll have to see what eplontersen's data shows. They may have, because they have a larger study, perhaps some tighter confidence intervals in certain parameters.
But we don't expect that the treatment effects are necessarily gonna be any better than what we've already seen with HELIOS-B.
Yeah.
And it's possible we'll have to see. You know, we have very rapid knockdown of TTR. We know that with Eplontersen, based on some of those data, there's perhaps a little bit longer time to that knockdown, whether that has a clinical effect. So I think there's a lot to see. As you've heard it from our colleagues, I think we're really well positioned to bring this forward, this medicine forward, in the near future.
Thank you, Pushkal.
Great, thanks. Jessica Fye, JP Morgan. Two questions. One thing we hear debate on among investors is whether it's favorable or unfavorable for Amvuttra use once taf goes generic, i.e., does it unlock more budget for combination use, or does it incentivize payers to try and force patients to step through generic taf? And the second question, maybe for Pushkal, if he comes back. How are you guys thinking about executing on the most optimized trial design for TTRsc04? Is there possibility of approval based on TTR knockdown? Is that on the table on the back of HELIOS-B validating the link between this biomarker and outcomes, or should we anticipate another outcomes trial? And maybe you can't answer that just yet. So in that case, I'm sure you've at least thought through those scenarios.
Can you talk about the scenario in which you might have to run an outcomes trial? How would you execute on that with Amvuttra approved and on the market?
Okay, shall we go with the first question? John, why don't you take that?
Yeah, a good question. In terms of tafamidis and loss of exclusivity, there are kinda two phases of market evolution that we anticipate. And so prior to tafamidis' loss of exclusivity, we think it's predominantly a monotherapy market. And so really all those dynamics that we talked about today will hold. So we see an opportunity to establish Amvuttra as a first-line treatment, especially for those new to treatment patients, and then subsequently unlock opportunities over time. And so we have multiple years for physicians to gain that experience, for patients to gain that experience, and I think we're really well positioned to establish Amvuttra in that market prior to tafamidis' loss of exclusivity. Now, what happens after that? I think it presumably could unlock more add-on use.
Here again, I think I'll just refer to what Pushkal talked about the data set that we have. Highly consistent in terms of the outcomes benefit across patient populations, with or without Tafamidis and background. So I think we're really well positioned even for that phase after Tafamidis' loss of exclusivity, if that does unlock combination use.
Actually, if I may just add one last point, Dr. Masri articulated really well. This is a rare, quickly progressing, and deadly disease. So in this category, I think most physicians will attest to the fact that they do get access. Now, there might be some additional barriers, but what we've seen in PN, as well as in other categories, that when it's rare, when it's deadly, when it's disease progressing, doctors wanna use their best alternative option first and early, and we believe this will continue pre-TAF LOE or post-TAF LOE. Pushkal, I'm sorry, I guess I started a trend here, but I think it's a good, relevant question.
Yvonne is gonna actually talk-
Get him a chair.
... more about it. See, too many questions. You should save your questions for me. Yvonne's gonna talk a little bit more about SC04 in her presentation in a couple of minutes. Obviously, we're very excited about these data. They validate the therapeutic hypothesis that RNAi silencing can be of benefit. We wanna continue to innovate on behalf of patients, and so we think beyond Amvuttra, SC04 can offer not only deeper knockdown, which we think is gonna lead to better efficacy, as well as more convenience. In terms of the actual details, in terms of how we'll develop that medicine, you know, we'll be giving a further update. We needed the HELIOS-B results that we got just not that long ago. Obviously, our team's very focused in getting the filing out, which we just announced this morning.
And so we'll be giving further updates on the study design, early next year, in terms of how we're thinking about the development plan for that. So we'll have to give you some more updates. Some of the considerations you highlighted are very much the ones that we're thinking through in terms of, you know, how do we sort of bring this as quickly as possible to patients because of benefits that it may offer. But also, we wanna make sure that this ensures a very durable franchise, right, for years to come. We think that we can do that and make sure that that's sort of the definitive, standard of care for patients, in the, in the future. So we'll give further updates on that, as time comes. Sorry.
Mani, for taking the question. I guess this is for Mark and the whole team. You talk about the current population treated with Amvuttra for polyneuropathy, as well as some of your assumptions derived from hard data about what's currently happening in ATTR-CM, which is at the moment, a stabilizer market, but that's gonna change very quickly into a multi-asset market. But the longer-term opportunity in cardiomyopathy for all companies involved is in the undiagnosed pool of patients. So help paint a picture about sort of what information can be drawn from that negative space of the patients that are not yet diagnosed? Are they more rural, more urban, different socioeconomic status than the early adopters, who sort of by definition are who is on Tafamidis now, the more severe, more early adopters, and what are differences in those patient populations?
So let me maybe take a stab at it, and John, after that, and Mark. I think the biggest opportunity right now and in the midterm is going to be actually really establishing ourselves as the first-line treatment, because that patient population that's walking in the door is ever-increasing, and that's precisely because what you have articulated, meaning there are more undiagnosed patients getting diagnosed, and that's accelerating. Now, when it comes to the type, archetype of those patients, and why those patients are not being diagnosed, our hypothesis is actually nothing to do with whether it's demographics or whether it's age. It's more of a question of how they're showing up in different centers and whether actually they are being triaged into quickly into the scintigraphy and subsequent diagnostic tests.
The more expansion that we see in clinical centers, the more we see increase in diagnosis. But maybe, John, you can further articulate that.
I was going to go in the same direction. I think in some ways, we heard the answer from Dr. Masri, where he said there are zip codes where you have prevalence and zip codes where you don't. That doesn't make sense. It's more a reflection of are the centers really set up to identify those patients and move them from diagnosis to treatment quickly? And that's why the fact that we are engaged with so many centers today is really, really important. It's about making sure that they have care pathways that are established, and so they aren't missing these patients more consistently. I don't know if you want to add to that.
Yeah. The last thing I'll add here is that I speak with a large number of physicians across the U.S. Every single time I speak with them, the one question I ask is: What can we do to help, you know, once we enter ATTR-CM, help support the work you're doing? And the number one response I always get is, "Help us drive awareness of this disease." And I always ask, "Awareness with patients? Awareness with physicians?" It's both, but especially with physicians. And so I think this is still a relatively... I mean, it's a rare disease, right?
And so it's still a relatively unknown disease, and so I think a lot of what, you know, we see in terms of this undiagnosed population is simply physicians that are less familiar with the disease, seeing signs and symptoms earlier on and not really correlating those into saying, "Oh, this may be a patient that needs to get worked up for ATTR-CM." So, this is where we think, you know, there's gonna be a big opportunity, and with more players in the market, that should expand.
Just to build on that, a very quick example of how basic we are in some certain categories. In the Midwest, I met a physician who's a cardiologist, who's really excited and passionate about cardiomyopathy. He decided to send a snail letter, snail mail, to a couple thousand primary care physicians. He has one of the largest diagnostics now. So the issue is more awareness and passion and making sure that we're actually establishing the right ecosystem for these physicians, which I think not just only us, but other players will certainly contribute that, too.
Could I say one last thing?
Go ahead.
The last thing I'll say, though, is I wanna double down, though. Our focus at launch is really going to be on establishing ourselves as that first-line standard of care for those patients that are coming into the market. That's gonna be our big focus, and that will then allow us to really tap into then those newly diagnosed patients.
Well said. Well said.
I know this is a largely U.S.-centric team, but with a lot of global experience. Now that the somewhat limited amount of revenue that tafamidis generated in polyneuropathy, given the label approved abroad, has largely been washed out by Onpattro and vutrisiran's dominance in the polyneuropathy segment. So the remaining tafamidis revenue reported by Pfizer is essentially entirely cardiomyopathy at this point, and that represents a pretty small slice of the tafamidis pie. The OUS market, Japan, Europe, et cetera, rest of world, collectively is pretty small compared to the U.S., even adjusting for price. How do you think about the revenue mix for Amvuttra in cardiomyopathy, U.S. versus EU? Should we think of that as looking more like polyneuropathy? Is that your expectation, or more like the current TTR cardiomyopathy mix that we're seeing for the high-dose Vyndaqel/Vyndamax market?
We certainly look at the big picture. I mean, if you think about our current success, as you pointed out, through different dynamics, we've been able to establish relatively healthy and equal contribution of different regions into the franchise. When it comes to cardiomyopathy and the opportunity, we're thinking big, across Japan, as well as all major European markets, and that's why we're resourcing ourselves, and that's how we're gonna position the product across the globe. Now, the good news is, unlike in the U.S., where you see a lot of fragmentation in terms of treatment centers, similar to polyneuropathy, in cardiomyopathy, we see a lot of central management of this disease, particularly like in France and in Japan. You see a lot of centers of excellence that are driving this.
Therefore, we believe, actually, with profound data set that we have, our compelling argument is gonna be probably more effective in running this in the centers of excellence that exist in ex-U.S. markets. John, anything to add?
Yeah, I'll just underscore. So today we announced that we filed the sNDA in the U.S., but obviously, and you heard from Yvonne, that we are pursuing regulatory filings in Europe and in Japan, because we do have a commercial presence in about 60 markets today, so that's our footprint. And so, you know, our goal is to make sure that we can bring Amvuttra to as many patients as we can, as quickly as we can.
Hi there.
First, just following up on the prior question a little bit, how aggressive will you be in terms of targeting the patient to try and activate the patient in terms of driving awareness? Talk about some of the initiatives that you're gonna have on that front, 'cause sounds like you're gonna focus more on the HCPs, but that will be an important component going forward. And then with the 3,700 HCPs that you're currently targeting, I was surprised to see that you have 65% coverage already. So talk about the breakdown in terms of neurologists versus cardiologists, and how many additional reps are you gonna need to get to the 100% coverage?
So let me break down that in two components. Are we actually going to focus on the patients and their caregivers? The answer is yes. I mean, we're gonna do this in varying degrees, and as I mentioned, we look at the overall value chain and where we believe actually is going to help and support in terms of awareness of these patients, so that they can actually come and be able to to visit the physicians. Or as Dr. Masri pointed out, are they gonna be aware of the differences, the nuances of available options? Now, we can do this in many different ways. And we'll obviously, you know, look at those options and see what's the most effective way of reaching out to those patients.
So that's for sure is something that we would look in terms of our promotional mix. Now, the second question, Mark, why don't you?
Yeah. So the second question around that mix, right? Of the 65% of those 3,700 that we're calling on today, what percentage of those are cardiologists? Vast majority. The exact percentage is probably, like, 95% +, because those are the physicians that are writing for Tafamidis. And so we're calling on more than those physicians, more than that 65%. Obviously, we're also calling on many neurologists today, right? Because that is obviously core to the product. But in terms of that 65%, that you know of cardiologists, those are mainly cardiologists. In terms of, I think, the second part of your question, which was: How many representatives do we need to hire in order to be ready? We're not sharing specifics.
What I will say, though, is that we will be competitive, if you think about the overall market and what other companies are doing, and so our goal is to, you know, leave no stone unturned and be out there with a, you know, very competitive organization that can really cover all the physicians and the centers across the U.S.
Yeah, I mean, let me just also add some more color on that. The reason why we call on those 3,500 only right now, or 3,700, is because those offices, they prescribe obviously polyneuropathy as well, and that's been our indication, and we are absolutely compliant in making sure that we're not, you know, investing in resourcing areas where there is no real opportunity for polyneuropathy. Now, having said that, the way we scale this organization has the ability to actually expand in a larger, larger target cardiologists. Because what we shared with you is we've increased our prescriber base for polyneuropathy by 50% in two years. We certainly would anticipate be able to actually have more coverage as the expansion of the cardiologists and the treatment of cardiomyopathy. So this is something we are...
It's well within our reach, and how we did our plan and resource planning, we were able to set our goals accordingly.
Thank you.
Hi there. Sorry, a little too loud. Hi there, Julian Harrison with Stifel, Paul Matteis's team. So quick question, I guess. To begin, how confident are you in getting a specific mortality claim on the label for vutrisiran, like tafamidis? And I guess in the context of how you set up for the commercial opportunity, how important is that specific claim in vutrisiran's ability to compete in first line?
Look, I mean, I'll just start, and John, feel free to allude on that. We met all our primary and secondary endpoints, and all of our endpoints were actually statistically pre-specified, including all-cause mortality. So we feel confident about how we're gonna be able to translate into label. Now, as always, it is FDA's decision, and how that's gonna be reflected in the label is gonna be up to them. But the data is our data, and it's also published in peer-reviewed journals in the exact way that we would expect to see in our label. John, anything else to add?
Well said. I'll just underscore what John Vest had shared, which is it's comforting also that you have a pre-specified second endpoint that is consistent with what we saw in the component of the composite primary. So again, as a function of the data set that we're filing to FDA, we feel very good about that data package.
Yeah.
Hi, this is Farzin from Jefferies. Maybe for Mark, can you talk more about the experience with the tafamidis launch, and what can be applied to vutri launch, and what are some of the key differences? Then maybe for Tolga is, what is the split expected between academic and community settings, and how do you expect the uptake to be even-
Yeah
... greater in the community settings, in the treatment clinics also?
Let me take that on, so you don't get into trouble. I mean, look, I was also involved in the tafamidis launch, and obviously, those two are very different dynamics, given that it was one was about a new category and making it a treatment available first time. And here we have very importantly data that actually is established based on today's patient population, which is vastly different than what we've seen six, seven years ago, and this is an area where obviously we're going to communicate. And the other good news is thanks to the availability of an available product, there are more established clinical centers that understand this disease. We shared with you how actually diagnosis rates went from 2% to 20% in a short amount of years.
So that's really important, and obviously, the market is incredibly different. The category is very different than what it is there today. And the big thing I can tell you on Alnylam's side is the fact that we are laser focused on the success of this. This is a transformational moment for our company, and the data also suggest that. So that to me is probably the key difference, I would say, in how we really see things. Can you repeat your second question? Academic and community. Oh, academic and community centers. Mark-
Yeah.
Maybe you can take that.
Yeah, yeah, sure. So if we look at the sort of source of business today for Tafamidis, if I recall the number, something like 60% or so, something in that range is coming from academic. And that means the balance is coming from non-academic. Recall what I said earlier, non-academic can be large hospitals, it can be small community hospitals, et cetera. So, you know, that's kind of the mix today, and I think we think of it as, let's say, roughly half-half, right? And so the goal with the organization we're bringing to market, and that we're expanding to, to call on this is, we'll call on physicians that are in academic settings and large hospitals. We'll also call on the physicians that are in the smaller setting, and similarly, you know, with the systems, right?
The large national systems as well as more of the academic systems.
What I would also highlight is, even though we're talking about this sort of expansion of this category, I just want to underline that this is still remains a rare disease. It's orphan disease, and therefore, when you think of the broader, you know, hypercholesterolemia, hypertension, we're talking about 25,000-30,000 cardiologists and many internal medicine, and primary care physicians. This is not the case. Yes, it is expanding. Yes, it will be primarily driven by academic centers and maybe some community centers, but those community centers will remain specialized. These are multidisciplinary treatment approaches where patients are followed through a long time. So I think Dr. Masri really highlighted that.
We're excited, it's gonna expand, but the expansion is not gonna be at a level where you would see, you know, a more prevalent disease or even in, even a specialized, a specialty care disease. These, I think... Oh.
Hey, Trevor Allred from Oppenheimer. Just want to ask a little bit on pricing. Can you discuss some of the dynamics that go into pricing considerations, particularly within Medicare? Is there any advantage to pricing below competitors? Given the fact that Medicare won't negotiate on orphan pricing, what limits the price ceiling, as the balance of the commercial payer-
Can you repeat that last sentence?
Yeah, given the fact that Medicare won't negotiate on orphan pricing, what limits that price ceiling, and is it the balance of the commercial payer segment?
Yeah, I mean, look, again, I think, I'm gonna repeat what I said in terms of the decision and how we're thinking about it is not something we're gonna be disclosing today. Having said that, our patient access philosophy has withstood a lot of scrutiny in terms of how we've been able to articulate the value of our medicines and how patients have been able to access those medicines. Those are going to be our North Star. Obviously, we'll provide more updates as you know we understand our label better and our engagements with various stakeholders, including CMS.
Hello, Kostas here from BMO. Thanks again for all the data. So maybe one technical question first. In the survey you showed, the physician survey, do you correct for the number of patients that each physician sees, or you consider all physicians equally? Because I know other companies actually correct for this factor.
You are you referring to the market research that we shared with you?
Yeah, right.
- Ipsos data?
Right.
Yeah.
Yeah, so-
Go ahead.
I'm sorry. Yeah, so the survey that I showed was among cardiologists. It was conducted by a company called Ipsos. It was an independent survey. It was unsolicited by us, and so it's really up to them, the methodology that they applied. What we do know is in that first wave, they went to, I think it was 82, just above 80 cardiologists in the U.S. and in Europe. The second wave, they went to 150. And so it's really up to them to determine that methodology.
I mean, look, I recognize that we have a lot of PhDs with biostats degree. I wouldn't necessarily read too much into all the specifics. I think what's really important is the direction of travel that you see from these cardiologists who are experienced in management of ATTR-CM. And this was an independent study. We didn't, you know, solicit this. And looking at pre-data, which was, I think, quite significantly favorable, and then see that actually with the broader data points, that only their confidence increased, is an important sort of signal. But it's a signal that's directional, and obviously, Alnylam has work to do to make sure that everybody feels that way.
Maybe, and maybe one follow-up. Some patients that are under tafamidis do not go to the physician that often, so it may take some time to see a potential switch to Amvuttra. Based on your estimation, how long do you think it will take to start seeing material revenues from these switches after you launch? Thank you.
Yeah. So, Kostas, I think it's really important to highlight that, as my colleagues also alluded to, we are really positioning this important medicine, if approved, for first line. There is clearly an opportunity with the hemophiliacs that are stabilized, yet they are progressing as high as 50%. But that's not gonna be our primary focus. Now, in terms of the duration of time that it's gonna take, it will depend on the physician who actually have a good, rigorous understanding of how progression happens, and in some cases, they will do that switch very quickly because they follow up those patients. But as John, I think, highlighted, there are no real sort of standardized approaches of how and when the switch happens. So what we'll see is actually a dispersed behavior in the short period.
Over time, we believe we're gonna be able to get to a lot of those patients that are progressing. John, do you have anything to add?
I think that, that's well said. I mean, this is a category where there isn't a pattern of switch behavior because it hasn't been an option. So I do think it will take some time for that behavior to fully unlock, but I would agree. We've already seen evidence from enrollment in the APOLLO B and in the patisiran EAP, that physicians are identifying these patients, but for it to fully unlock, I think it will just become from awareness and experience with Amvuttra, which will likely take place in the first line setting first.
We're out of time.
Tommy, GS, thanks for taking our question. So just to follow up on the comment about the 60% payer liability under Part D redesign and potential for increased utilization management, what's the liability for Amvuttra to the payer under Part B, and are the Part B and Part D groups able to cross-manage?
Jason, this is firmly on your end.
Yeah. Well, thank you for the question. And, you know, as we think about coverage dynamics for ATTR-CM, you know, we first started by talking about the fact that 75% of coverage is under Medicare. And as you pointed out, the change in the benefit design due to IRA is within the Part D segment. So if payers are thinking about it just from their liability perspective, and they're thinking about the payments they receive and what they'll have to pay, that's really the important change as they consider costs, as they think about their full cost. As far as benefit management goes within Medicare Part B, which is about half the Medicare population, you know, that is coverage to label without a policy.
So the Part D plan would be offered separately, and as I said, we would expect our coverage to be to label. Within Medicare Advantage as well, they cover Part B medicines as are reasonable and necessary. As they think about coverage criteria, it's gonna be exactly as we discussed earlier, that there's an understanding that it's a rare disease, that it's progressive and deadly. There'll be an appreciation of the Amvuttra data, and ultimately, you know, first, they're gonna consider the clinical impact. You know, beyond that, they'll make coverage decisions. We'll be prepared to support all patients. But really beyond that, you know, there's not much more we can say about it.
Very good. Liisa?
Thanks. Hi, guys. Thanks again for having this event, and maybe the last question from me is to Tolga. You've talked about the PN launch for Amvuttra a few times now while being on stage. So would it be wise for the investment community to think of the launch of PN as a read-through to how the launch in CM will go? If not, can you talk about some of the differences in the dynamics of those two populations and access points and things like that? And then secondly, you do have a new competitor, relatively new competitor in the PN space. Can you talk about what impact, if any, you're seeing to your own market share as a result of that new entrant?
Yeah. So let me start with your last question, and I'll turn it over to my colleagues as well. Look, as we've actually reported in our second quarter earnings, we've been very pleased with the growth that we've been able to post in the U.S., which, where we have now a competitor. In other markets, we have yet to have a plan. And we've been very pleased with the growth rates that we've been able to post. So we haven't really skipped a beat in terms of how we've been able to reach out to the patients. So that's very encouraging. I think that tells two things.
One is obviously the merit of our product and the data that we have on polyneuropathy, but also in our ability to be able to make sure that we're actually continuing that growth rate with a good commercial capability. So those are very encouraging. When it comes to how we're gonna actually signal our launch, that's a little too early for us to provide you guys the specific, you know, details about how we're gonna keep the investor community up to date. We know that this is a very important launch, not only for us, but also for the investor community, and we'll obviously provide additional color as soon as we decide how to do that.
So that's probably gonna be the best way to determine how cardiomyopathy is going to be launching. But as we all said, we're excited because this is a running start, not a standing start, and I think we will have considerable advantages in terms of how we focused our capabilities on making the product available to a larger category in CM. One last question.
Two more.
Luca and Liisa.
Luca and Liisa. Okay, good.
All right, great. Thanks again for taking the question. Maybe one, Jason, following up with you on the IRA impact. I think your slide 74 makes a good argument that payers may increase scrutiny for Medicare Part D drugs versus Part B, given they're not responsible for 60% of the cost and not 15% of the cost.
... Just curious, are you already seeing that dynamic playing out in the field? I think the imperfect comp here with the PCSK9 or the siRNA, obviously, the Part B drug versus monoclonal antibodies are Part D drugs. Are you already seeing payers favoring the former versus the latter, or is it maybe too early to tell? So any color there would be much appreciated. And then maybe big picture, Yvonne, if I may. I think Alnylam has a long history of out licensing drug on favorable economics, and zilebesiran is probably a good example of that. However, you can make an argument that Alnylam is now in a different position. So wondering if there's any appetite to actually in-license drug to either strengthen the pipeline or maybe extend the durability of the franchise.
I don't know, maybe in-licensing the platforms or whatever is the next modality that you think can protect the franchise longer term. Thanks so much.
Yvonne, do you want to take that on first? Yeah.
No, that's a great question. Look, I think one of the advantages that we have at Alnylam is, you know, we obviously now have this flagship franchise, which is going to drive the revenue trajectory for the company. But we also have this incredibly rich pipeline. I'll be coming onto some of the aspects of that shortly, which gives us an awful lot to deliver for patients within the organization. And we have a priority of trying to make sure that we're going to progress Alnylam-led substrates going forward. We also have committed to being leaders in the TTR space, and we will be open to opportunities that there might be for us to ensure that we maintain that leadership.
With respect to, you know, other opportunities that we might, you know, in-license, I think it's important for us to recognize that we are in this period, I call it the golden period of biotech innovation, if you like. And so we're going to be very watchful of what's happening in our ecosystem and, you know, be prepared to be open to opportunities that we think significantly drive our business and will be opportunities for patients. That being said, we have an awful lot of work to do to make sure that we're able to deliver a successful launch here, and that's going to be really our number one focus for the next period. Thanks for the question.
Thank you, Yvonne. And if I may, just one quick point. I'm glad you brought up the Zilebesiran example. That's not a straight out licensing opportunity. We're actually building our U.S. capabilities with that very exciting future asset as well. So, that's really important to highlight how we're actually thinking about our commercial capabilities as well. So going back to your question around inclisiran and the experience with the PCSK9s. Look, I mean, I know it's very tempting to compare an siRNA and a cardiology asset, but those are very different, I think, markets. And it also goes back to sort of. You know, we like to provide a little bit nuance around Part D and Part B, but the bottom line is, this is a rare disease, very fast progressing and deadly.
So I think, the community, the payers, and us, we're fully cognizant of that, and therefore, we're going to actually make sure that these, these products, broadly speaking, will be covered. And there are going to be some nuances, and we'll make sure that we are, you know, managing that and navigating that appropriately. That's the, that's the goal, but comparing inclisiran dynamics is probably not the best analog, when it comes to, to Onpattro. Liisa, finally.
Yes, two questions for me. First of all, as a follow-up to some of the questions on the Medicare Part B versus Part D, can you give us a sense of how you expect long-term gross-to-nets to look like, considering you're going to be a Medicare Part B drug? And then I just wanted to ask about manufacturing, where you stand with that in-house versus CDMO, et cetera. Thank you.
Right. So, great question. I mean, I think one of the points that we haven't articulated on Part D IRA changes is also the manufacturer liability that also has increased in the Part B case that hasn't been impacted. So that, I think, is an area where you will probably find some gross-to-net dynamics that are going to be different. And the other question you had?
Can you be specific about gross-to-nets that you'd expect? And the other one was manufacturing.
I mean, we expect similar gross-to-net ranges. And obviously, if there are differences in terms of rebate and so forth, we would appropriately update the market on that. In terms of manufacturing, look, we've been able to, you know, drive down. First of all, in terms of volume, we're well prepared for that. We are absolutely anticipating with our launch, and our forecast is according to that. And in terms of cost, we always drive our costs down, and, you know, we're pleased with where we are right now, and we're obviously progressing in manufacturing and even more optimally. Okay. Well, with that, I'm going to turn it over to our CEO, Yvonne Greenstreet.
Thank you.
Let's, uh-
Thank you.
Round of applause for the commercial team. Thank you, Yvonne. You're welcome. So look, I think a terrific set of presentations, and I hope that you've all now got a little bit more insight into, you know, how we're thinking about our TTR franchise. So what have you heard about today? So, I think you've heard quite a lot about Amvuttra's market-leading profile. You've heard about the compelling HELIOS-B data that we've generated to the convenient quarterly dosing and broad access, which we believe positions Amvuttra for first-line use in ATTR cardiomyopathy.
And, we've demonstrated, I think, quite successfully over the last six years since we launched in ATTR polyneuropathy, that we truly have a leadership position in this market. And this gives us an optimal foundation, which we're gonna build on ATTR cardiomyopathy. We're launch-ready. We've got all the capabilities in place, to execute and win in this key market. And, looking beyond the transformative moment that the launch of Amvuttra, provides Alnylam, we're also very confident in the long-term growth prospects of our TTR franchise in the large and growing ATTR cardiomyopathy market. And, there's some great questions about TTRsc04. And I think it's important to highlight that we're continuing to innovate for patients with TTR amyloidosis, 'cause we're progressing this next generation, clinical stage, asset called TTRsc04.
And as Pushkal highlighted, what this does is deliver very high levels of TTR knockdown, and we believe this could translate into increased efficacy, together with a very convenient biannual or annual dosing regimen. And furthermore, there are no third-party royalties due associated with TTRsc04. So all in all, I think we're very excited about moving forward TTRsc04. And many of you are probably familiar with this data, the phase I data for TTRsc04. You can see here that with a single dose, we're able to achieve rapid, deep, and durable knockdown of TTR of more than 90% at day 15 and 97% at day 29. And these levels of TTR reduction are sustained for 180 days after administration of just a single dose.
TTRsc04 has also been well tolerated across all the doses study. We talked about the fact that, you know, we'll be sharing additional information on our phase III development plan in the first quarter of 2025, and there'll be some more data from our phase I study as well towards the end of this year. We're very excited about TTRsc04. I think this is a demonstration of the level of commitment that we have to patients with TTR amyloidosis. Now, what about the breadth of opportunity that we have beyond TTR and with our RNAi platform? Many of you, again, have seen, you know, the quantity and quality of the clinical programs that we have in the pipeline.
Currently, fifteen clinical programs across a range of disease areas, and we plan to double the size of this pipeline by the end of 2025. There are some highlights, I think, maybe to draw your attention to. We recently communicated the initiation of our phase II KARDIA-3 study, evaluating zilebesiran in patients with hypertension. We're also very excited about mivelsiran. I see my colleagues looking at me because it's one of the things that's a bit of a tongue twister for me, but I think I might have that right. Mivelsiran, formerly ALN-APP, and this is our first CNS program, and this has the potential to address unmet needs in two really important CNS diseases, cerebral amyloid angiopathy and Alzheimer's disease.
We're actually so pleased to have initiated dosing in the CAPRICORN-1 phase II study of mivelsiran in cerebral amyloid angiopathy. This is the second most common cause of intracerebral hemorrhage, and it remains highly undiagnosed. We can deliver clinical benefit for this disease. We're going to help a lot of, a lot of patients. And in Alzheimer's disease, we plan to start a phase II study at or around the end of this year. Our partners also continue to make progress. Sanofi submitted regulatory filings for fitusiran for hemophilia in China, Brazil, and the U.S., and the FDA have set a target action date of March the 28th, 2025. So lots happening with our partners as well.
Now, beyond all of these programs, we continue to focus on platform innovation, and we're progressing a large multi-organ pipeline to the clinic by the end of 2025. One of the things that we do at Alnylam is set ourselves some pretty broad and bold goals. So in addition to multiple INDs in the liver and the CNS, we expect to file our first INDs for both adipose and muscle targets next year. We've also got preclinical data for some additional tissues. INDs are still to be determined, and we'll come back with more information on those over the course of the next several months.
So really, look, if you take a step back, the possibilities with RNAi are unparalleled, and they've driven what we believe to be one of the most exciting pipelines in the industry, with programs across multiple tissue types and therapy areas, so we're very excited about the future, but before concluding, I think it probably is worth taking just a moment to underscore why we believe that we are so well positioned for leadership in the ATTR amyloidosis market, as well as in progressing the next frontier of RNAi therapeutic innovation. We've touched on many of these points. Our established position in ATTR polyneuropathy, combined with a durable flagship franchise. Our focused team, you've had the opportunity to meet some of them today.
We've got core capabilities in place and a track record of commercial success across our portfolio. Look, these are some of the factors that we believe are gonna be critical to win in this marketplace, and as I've said before, we are playing to win, and in parallel, our robust pipeline, our sustainable innovation engine, this will drive future growth for the company. Just to wrap up then, we believe that we're well on our way to achieving our latest five-year goals, P5x25, really establishing Alnylam as a leading global biotech company. We're gonna be closing out the final quarter of 2024 soon, and as we approach the next period and we look into 2025 and beyond, we have many exciting milestones.
These are all gonna propel us in our quest to realize the exciting vision that we have at Alnylam. So with that, I'd like to thank you all very much for your attention, and I've enjoyed this so much. I hope that we'll have another opportunity to meet face-to-face over the next several months. Thank you so much for your participation and attention. Thank you.