Great. Good morning, everyone. Welcome. My name's Jessica Fye. I'm a biotech analyst at J.P. Morgan, and we're continuing the 43rd Annual Healthcare Conference this morning with Alnylam. In a moment, I'm going to pass it over to the company CEO, Yvonne Greenstreet, to present. She's going to give a presentation, then we're going to go into some Q&A. If you want to ask a question, raise your hand. Someone will bring you a microphone, or you can send one to me on the iPad up here, and I can ask it for you. So with that, let me pass it over to Yvonne.
Thanks, Jessica. It's really a pleasure to be here once again, presenting on behalf of Alnylam. We've actually been presenting at this conference for over 20 years now, but I have to say that this year feels particularly special because this is the year that, with the pending approval of vutrisiran and ATTR cardiomyopathy, we will establish a flagship franchise for our company and cement Alnylam's position as a top-tier biotech. We truly are on the precipice of a new and exciting chapter in Alnylam's history. And as Jessica mentioned, I'm Yvonne Greenstreet, CEO of Alnylam, and I'm delighted to be joined up here on stage by my colleagues, Tolga Tanguler, Chief Commercial Officer, Jeff Poulton, Chief Financial Officer, and Pushkal Garg, Chief Medical Officer. So clearly, during my presentation today, I'll be making some forward-looking statements.
I'd like to start by just framing where we are as a company. Alnylam is the leader in RNAi therapeutics, and this holds true across many dimensions. We've got tangible results as proof points for this: our outstanding R&D productivity, where we validated an entirely new class of medicines. We've produced an outsized probability of clinical success relative to the rest of the industry, and we've delivered a commercial portfolio of five medicines. We have a rich pipeline with numerous multi-billion dollar opportunities, and we expect over 25 high-value programs across diverse indications by the end of 2025. We've got leading commercial capabilities. Tolga leads this part of the organization, generating over $1.6 billion in annual product sales in 2024.
We have a strong financial position, and we believe that we're firmly on the path towards meeting our Alnylam P5x25 goals, financial goals, including achieving sustainable non-GAAP profitability. I'd like to start by just quickly reflecting on some of our notable accomplishments in 2024, where we delivered strong progress across the business. Now, this included the highly positive results from the landmark HELIOS-B Phase III study, and this led to the submission of global regulatory filings for vutrisiran in ATTR cardiomyopathy. And we advanced continued innovation for ATTR patients with positive Phase I data with nucresiran, supporting the potential for annual or biannual dosing. We also continue to advance mivelsiran, including multi-dose results in patients with early-onset Alzheimer's disease and the initiation of the KAPricorn-1 Phase II study in cerebral amyloid angiopathy.
We're also pleased with our progress with zilebesiran in hypertension, including positive results from the KARDIA-2 Phase II study showing significant additive blood pressure lowering, and we expanded our clinical pipeline with four proprietary CTAs and some additional CTAs filed by our partners. We also continue to demonstrate exemplary financial performance, achieving combined net product revenues of over $1.6 billion with a global footprint serving patients in over 60 countries around the world. We ended the year with $2.7 billion in cash on the balance sheet, and furthermore, we maintained our award-winning culture, which we believe has been a critical enabler of our success, so yesterday, we pre-announced our fourth quarter and full year 2024 global net product revenues. Our transformational medicines delivered $1.646 billion in combined net product revenue, and this is at the high end of our revised guidance range, representing growth of 33% compared to 2023.
Since 2019, which was our first full year of being a commercial company, we've seen impressive revenue growth with a 58% CAGR over this time period. We believe that our strong commercial performance and the solid capabilities behind it position Alnylam well for exceptional future growth. Let's turn to the year ahead. 2025 promises to be a landmark year for Alnylam. We believe that there are three core elements of our business that are going to drive sustainable growth and value creation, not just in 2025, but for years to come, and that will take Alnylam into its next exciting chapter. The first, not surprisingly, is TTR leadership, where vutrisiran, if approved, has the potential to become a new standard of care in ATTR cardiomyopathy and will establish an ATTR franchise for our company, along with the advancement of our next generation TTR asset, nucresiran.
The next pillar is growth through innovation, including a pipeline with numerous multi-billion-dollar opportunities and an R&D engine that is set up to deliver sustainable innovation and value creation. The third pillar is strong financial performance, where we project that our robust commercial delivery and disciplined approach to capital allocation will enable us to become sustainably profitable beginning this year. And all of this is underpinned by a best-in-class team and our award-winning culture. So to start, I want to share how we're thinking about Amvutra and TTR leadership as a fundamental pillar for Alnylam's future growth. As most of you know, ATTR amyloidosis is a rapidly progressive, debilitating, and often fatal disease, where misfolding of the TTR protein accumulates in and damages a wide range of tissues, including the nerves, the heart, the gut, causing irreversible damage and premature death if untreated in patients.
RNAi therapeutics address the root cause of ATTR amyloidosis by providing rapid knockdown of the disease-causing TTR protein, and in ATTR cardiomyopathy, significant unmet medical need remains, so we estimate that there are over 300,000 patients globally who are living with ATTR cardiomyopathy, but approximately 80% of them remain undiagnosed, and of the 20% that are diagnosed and treated, a large portion of them continue to progress in the course of their disease, so all of this creates a substantial opportunity for Amvutra in this underserved market, and as recently as 2018, there's actually very little recognition of this category. It wasn't until the availability of the first approved treatment in 2019 and the availability of non-invasive diagnostic tools like scintigraphy that we began to see a tremendous increase in diagnosis rates, and in the U.S., we saw an approximate tenfold increase from 2019 to 2023.
Furthermore, just like other undiagnosed and undertreated disease categories, we anticipate that this diagnosis rate will continue to increase, driven by the introduction of new products over the next several years. With the only product that would be approved in the U.S. to treat both ATTR polyneuropathy and ATTR cardiomyopathy, we believe that we are built for unmatched leadership and longevity in the ATTR space. Our confidence stems from the success of the HELIOS-B study, which demonstrated a therapeutic profile for Amvutra that is supportive of first-line potential. Specifically, rapid knockdown of the disease-causing TTR protein led to a profound benefit on CV outcomes, including up to a 36% reduction in the risk of all-cause mortality, as well as broad effects on multiple measures of disease progression, very important to patients, and clinical effects that were seen early.
Importantly, these results were demonstrated in a population that's reflective of today's patients who are on substantial background therapy, and finally, vutrisiran offers an attractive quarterly dosing schedule that aligns well with doctor visits and supports strong adherence, as demonstrated by the roughly 95% adherence rates that we've seen with Amvutra in hATTR with polyneuropathy, so we've developed a focused strategy to grow Amvutra over time, and specifically, we see three different segments of opportunity. The first, and what will be our primary focus at launch, are those patients who are new to treatment, so these are the patients that are coming in to see physicians on an annual basis looking for that very first treatment decision, and this is where our goal is to establish Amvutra as a first-line treatment of choice. It's also likely that this is where physicians will have their initial experience using Amvutra.
Doing well in this segment gives rise to opportunities across the other segments as well. The second segment that you can see on this slide is stabilizer progressors. We know there are a lot of patients that are being treated with stabilizers, and many continue to experience disease worsening. With AMVUTTRA being the first and only orthogonal treatment option, we also plan to capture the switch or add-on opportunity. It's worth noting that until now, there's not been a lot of switch behavior in this category because there haven't been multiple therapeutic options. Going forward, we anticipate that treatment patterns that involve switching will evolve over time, which will progressively unlock this opportunity for AMVUTTRA. Then, of course, the third segment is the undiagnosed patients.
Clearly, this is the largest patient segment, but it will rapidly change as the undiagnosed patients of today become those new-to-treatment patients tomorrow. We're in a unique position to build on the leadership that we have established in hereditary ATTR polyneuropathy to drive a successful launch in ATTR cardiomyopathy. Since we've launched into hATTR polyneuropathy, we've grown the category, we've expanded the prescriber base, and we've established over 80% estimated share in competitive markets. We've already expanded and trained our field teams, and I can tell you they are absolutely prepared for launch. We have a significant footprint in the space, which has helped us deliver the impressive commercial performance that we've seen to date. We truly feel that we're going to be starting from a position of strength as we prepare for vutrisiran's approval in cardiomyopathy.
Assuming approval, we anticipate favorable market access dynamics. Today, over 99% of eligible patients have coverage for Amvutra. Not only do they have widespread coverage, but they also have affordable access, with approximately 70% of patients having $0 in out-of-pocket costs. Now, this strong coverage is due in part to the value proposition that Amvutra offers to payers, as well as the established payer relationships that Alnylam has developed over time, including through the use of value-based agreements. We expect that the payer mix in cardiomyopathy is going to be very similar to that which we have in polyneuropathy, which we anticipate will yield similar dynamics in terms of broad access and low patient out-of-pocket costs. Now we're looking forward to the multiple global ATTR cardiomyopathy launches expected in 2025.
As you know, our sNDA was accepted by the FDA, and with our priority review voucher, we expect a regulatory decision by the PDUFA action date of March 23rd, progressing very well. At the same time, we're pursuing ex-US launches with urgency. We've submitted parallel filings in all major regions, including Europe and Japan. We expect accelerated reimbursement with launches in Germany and Japan anticipated in the second half of this year, so our goal is to bring this new and important therapeutic option to patients around the world as quickly as possible. Beyond what we've achieved with vutrisiran, we continue to innovate to optimize outcomes for patients, and a biannual or annual therapeutic offering that reversibly suppresses TTR could represent a significant new opportunity for patients. To that end, we're expanding our TTR franchise with nucresiran, formerly known as ALN-TTR-SC04, our latest generation TTR targeting RNAi therapeutic.
Updated Phase I results were recently presented at the AHA, and they show rapid knockdown of serum TTR that was robust and highly durable. It was greater than 90% at six months, and this supports the dosing regimen that I just described, as well as an encouraging safety profile, which in addition offers convenience for patients and enables broad payer coverage, so together, we believe that these data support a potential best-in-class profile. The Phase I study is ongoing, and we plan to advance nucresiran to a Phase III study in ATTR amyloidosis with cardiomyopathy that is expected to start in the first half of 2025, and we'll provide additional details regarding the study design at our upcoming R&D day in February in New York.
So in summary, we have a therapeutic that offers first-line potential, a focused strategy to expand Amvutra's penetration over time, leadership that we've established in polyneuropathy that we can leverage for successful launch in cardiomyopathy, favorable market access dynamics, and all of this positions us well for multiple global ATTR cardiomyopathy launches that we expect in 2025. And our next generation therapeutic, nucresiran, offers continued innovation to patients. So these core elements will establish a flagship franchise for Alnylam that will catalyze future growth for the company and cement our leadership in TTR. The next pillar is growth through innovation. Now, this includes a pipeline of numerous multi-billion dollar opportunities and an R&D engine that can deliver sustainable innovation and value creation.
Our R&D efforts have enabled us to build one of the most robust pipelines in the biotech industry today, positioned to deliver strong growth and innovation across a broad range of disease areas and indications at all stages of development. This is a pipeline that is truly spring-loaded for growth, so I've highlighted here three programs in our growing portfolio of potentially transformative investigational medicines: zilebesiran for hypertension, mivelsiran for cerebral amyloid angiopathy and Alzheimer's disease, and ALN-HTT02 for Huntington's disease, and each of these programs represent multi-billion-dollar opportunities, and importantly, they're addressing critical disease areas, so we look forward to advancing these programs over the course of 2025 and plan to share additional updates at our upcoming R&D day in February.
Now, to maintain continuous innovation that can deliver transformative medicines, we truly are privileged to have a robust and sustainable innovation engine and a modular drug discovery platform that can catalyze long-term growth. So specifically, we aim to deliver RNAi therapeutics to all major tissues by leveraging our advances in extra hepatic delivery. We'll continue to invest in platform advances to enhance the fundamental designs of siRNAs to make them yet more efficacious, safe, and convenient. We really are in the early innings of what this technology can deliver. And we plan to harness the power of human genetics for access to large databases to continue to identify novel genetically validated targets. And at the center of all of this is the Nobel Prize-winning science of RNAi.
With this approach, we expect to deliver over 25 programs in clinical development by the end of 2025 across four tissue types: liver, CNS, muscle, and adipose tissue, with four or more CTAs expected per year. By continuing to reinvest in our organic product engine, we believe that we're going to sustain long-term innovation, drive growth, and value creation for years to come. The third pillar is strong financial performance. As I highlighted earlier, we delivered strong commercial performance in 2024. In our press release yesterday, we also provided 2025 net product revenue guidance. We're guiding towards total combined product sales between $2.05 billion and $2.25 billion. This represents over $500 million in annual growth at the midpoint of this guidance.
If we're successful in meeting this product revenue guidance, which we absolutely have every intention to achieve, we anticipate that we will achieve non-GAAP profitability this year. Wrapping up, I wanted to share with you our full list of company goals for 2025. These capture the key elements of the exciting year ahead. I won't walk through all of these, but at a high level, this is what we look forward to: six commercial products, four of which are wholly owned, vutrisiran launch, as I've touched on already, KARDIA-3 Phase II results, two Phase III study starts, four or more new INDs, and obviously, as I've said already, achieving sustainable non-GAAP profitability. All of this, in summary, represents tremendous progress against the ambitious five-year goals that we set for ourselves in 2021. Alnylam P5x25.
And I really believe that we are now on the cusp of turning these goals into reality. And importantly, the progress that we make in 2025 will set us up for the next half of the decade and our next era of significant growth. So in closing, I hope I've been able to convey to you the excitement and dedication that drives us at Alnylam as we aim to become a top-tier biopharmaceutical company. We're unwavering in our commitment to deliver innovation to benefit patients. And we believe that we are well positioned to achieve remarkable growth and create significant value for our shareholders. Our vision is bold. The roadmap is clear and actionable. So I'd like to thank you for your attention and your continued support. And we're now going to transition to the Q&A session. Jessica, back to you for Q&A.
Thank you. Thanks for the presentation. So we're in 2025, and the company had laid out the P5x25 goals. Where do you stand on delivering on those targets?
As I said, look, we're really on the cusp of delivering P5x25. We feel confident that we're going to achieve it. Now, you know, back in 2021, we set out some very bold goals for the company with respect to both R&D productivity and financial performance. Now, I think 2024 has provided us real momentum. You know, talked about our commercial performance, over $1.6 billion of global net product revenues. And the revenue goal in P5x25 was to achieve a 40% or more CAGR over the five-year period. And this really sets us up to be able to achieve that. With respect to pipeline progress, and this has been, I think 2024 was an incredible year for the company, delivering HELIOS-B really enables us to achieve P5x25.
We're also going to have, you know, in excess of 20 clinical programs in the pipeline. And I'm really excited by a number of these because they're addressing important disease areas, but also have the potential to be multi-billion dollar opportunities. And I touched on some of these in the presentation: nucresiran, zilebesiran, mivelsiran, and actually a new program that's moving forward really quite swiftly for Huntington's disease. So pipeline, I think, incredible progress, and we will meet that R&D productivity target. And then finally, profitability. You know, we're committed to achieving sustainable non-GAAP profitability by the end of this year, and we intend to do that. And I think the guidance that we issued actually gives confidence in our ability to be able to do that.
In sum, I know the goals were very bold, but I feel confident that we're absolutely on track to deliver against what we promised.
Great. So, I mean, turning to the 2025 guidance that you put out there, it looks like it came in ahead of consensus. You're reflecting contribution from cardiomyopathy. You've already established Amvutra in polyneuropathy. Anything you can share on how you're thinking about growth this year in polyneuropathy specifically?
Sure. I mean, just to remind folks that the guidance that we put out for 2025, $2.02 billion-$2.25 billion, I think is, you know, demonstrates our confidence in the business across cardiomyopathy, polyneuropathy, and our rare disease portfolio. And I think it's important to note the incremental value that this delivers, you know, $500 million at the midpoint. But Jeff, you may want to give some color to how we've thought about guidance.
Yeah, maybe just I'll talk about guidance for just a second. We chose to do it a little bit differently this year for, I think, the primary reason being that we understand the importance of managing market expectations this year on the top line given the CM launch. So we did two things differently with the guidance. We did it earlier. Typically, we would do the product sales and the rest of the guidance on the year-end call. So we chose to do it yesterday with the issuance of the press release. And we also chose to break out a little bit of detail on the product sales. Historically, we've just given combined product sales guidance, but this year we broke out TTR and rare separately.
And you know, the aim of both of these was to provide clarity to the sell side as they're updating their models for 2025. And I think we've done that. Yvonne commented on the TTR guidance in particular that at the midpoint, we see that about $120 million above where consensus was coming into the conference. So we do think that speaks to the confidence that we've got in the upcoming launch.
Do you want to add anything to that?
Yeah, maybe I can add. I mean, look, if you look at the history of 2024, we were facing in the U.S., first time in polyneuropathy with another competitor. And what you've seen in the 2024 results is the fact that we've been able to actually not skip a beat in terms of our growth and continue to that growth. And in ex-U.S. markets where we've been actually competing with the stabilizer, we have actually over 80% market share. So we really like the kind of momentum we've been able to build on PN, which obviously we expect that to translate into CM.
Terrific. Thanks, Tolga.
So maybe sticking with PN for just one more moment. You know, you've had Wainua now in the market competing for, what, I guess, about a year. What are you seeing there? You know, what defines the patients who opt to go on Wainua versus Amvuttra?
I mean, maybe I can just start off by saying I think the important thing to recognize this market, and I touched on it. It's a large and growing market. Actually, kind of new entrants that are coming into the market are only going to grow the disease category. Think about those, you know, those, you know, 80% of those 300,000 or more patients that are yet to be diagnosed. We really see this opportunity as a market growth opportunity and not so much a market share story. Tolga, you may want to add something.
No, nicely laid out. I mean, look, we have a very compelling product profile that provides rapid knockdown within as early as the first dose, and the fact that we're administered four times a day, and with a copay burden of, you know, 70% of patients have zero copay. So that, in combination with the fact that actually this is really a growth market, it's not so much of a market share market. We really like what we see in terms of our growth. We've just posted 34% growth year over year in our TTR franchise, and if we haven't disclosed the regional breakdown, but we can assure you the U.S. growth has been very much consistent. So it's a very nice picture in terms of our ability to actually compete with a product that just came into the market.
That's great.
And then sticking with the guidance and the contribution from cardiomyopathy, how would you characterize the degree of conservatism that's embedded in the assumptions on the CM aspect of the guidance?
Jeff, do you want to take that one?
Yeah, I mean, we didn't break out CM and PN separately in the guidance, right? It's total TTR expectations. But again, the midpoint of that guidance is 36% growth. We grew 34% this year. And if you go all the way to the upper end of that, of the guidance, it would be 41% growth, again, compared to 34% that we delivered this year. So I don't know that I would characterize it as conservative. I think we're confident in our ability to achieve somewhere in the range. But again, we're not breaking out PN and CM separately. We won't actually be able to report revenue that way. It's the same product. So we'll report total TTR revenues. Obviously, from an operational perspective, we'll try to provide as much color as we can between PN and CM.
But from a reporting standpoint, it'll be TTR revenue, which is the way we've guided.
And maybe Michael.
Actually, if I could just add, I mean, I think really just to underscore, we feel pretty good about this guidance. Otherwise, we wouldn't have put it out there. And I think it's important to remember that we are in a launch year, you know, with respect to vutrisiran and TTR cardiomyopathy. And therefore, yeah, there is some uncertainty as exactly how the year is going to go. But we feel we have, as Tolga said, a strong profile. We have a, you know, humming commercial organization. And we feel very confident about the guidance range that we have issued. Tolga, did you want to add anything?
No, all I was going to add was actually our consensus is going to be $100 million above the consensus for 2025. So it's, I think we guided relatively aggressively.
One question we get a lot from investors as it relates to this product, Amvutra, broadening into a larger patient population, the cardiomyopathy setting from polyneuropathy is how to think about the evolution of net price. Any kind of color or context you can share for folks? I keep hearing from investors that people are like all over the place on this.
Yeah. So look, I mean, you know, it wouldn't surprise you that we're not going to be providing details of our pricing approach at this point in time. But we will, of course, when assuming, you know, regulatory approval when we launch AMVUTTRA for cardiomyopathy. And, you know, we're a company that feels very strongly about the patient access principles that we've come up with. And so we'll be guided by two main factors. I mean, the first is the value that a medicine is offering the healthcare ecosystem. We believe that with the HELIOS-B results, we have a compelling proposition for patients, for physicians, for payers, for society. And therefore, we'll be thinking about the value that we're providing with AMVUTTRA. And the second thing that's really important to us is ensuring that patients can get access and, you know, it's affordable for patients.
And I think the results that we've delivered in the polyneuropathy indication, I think, speak very well to our ability to do this in terms of, you know, 99% of covered lives in the U.S. and really 70% of patients having zero out-of-pocket costs. So the plan is to replicate this as much as we can in cardiomyopathy as well. But Jeff, I don't know if there's anything you want to add in terms of any more detail.
I think you've covered it.
Yeah. Thanks, Jeff.
Is there any update to your expectation for an AdCom for Amvuttra in cardiomyopathy?
I mean, I think I can answer that very quickly. I mean, we were calculating how many weeks there were until our PDUFA date, March 23rd. It really is just around the corner. The review's going well. We're not anticipating an advisory committee at this point in time.
Maybe switching to the pipeline and zilebesiran, where I think you've talked about the back half of the year for the next Phase IIb study. What would represent a win? What do you want to see on top of multiple background agents?
That's a great question. I think it's good to start with what we're aiming to do with zilebesiran. What we're aiming to do is actually to reimagine the treatment of hypertension, it's a huge global issue. We believe that we have a very exciting profile in our hands, demonstrated really by the results we got from our two earlier studies, KARDIA-1 and KARDIA-2, which showed substantial blood pressure lowering and nocturnal control. Now, what we're doing with KARDIA-3 is actually assessing zilebesiran in a higher risk patient population. Patients that are high risk of CV disease, they are on two or more antihypertensives. Really to demonstrate that we can deliver, you know, kind of the magnitude of impact on both quantitative measures as well as qualitative measures. Safety is very important.
And the reason why KARDIA-3 is important is because it'll set us up to be able to design our CV outcomes trial because we'll be looking at exactly the same patient population in that CV outcome study. So success for us is having the information that allows us to design a great CVOT, power that study appropriately. So we'll get the results from KARDIA-3 second half of 2025. And then we plan to start the CVOT also in the second half of 2025. And that's obviously going to be a large study, right, with several thousand patients, going to be a global study. And the sort of primary endpoint that we would consider for that trial would be based on a MACE composite endpoint. So that's really the plan for our zilebesiran program.
Yeah, and I would just add, not only I think everything agreed with everything you said, Yvonne. I think the only thing I'd add is that it's also a dose-finding study. So this is really in that pivotal trial population that we'll be going into with the cardiovascular outcomes trial. But we are studying multiple doses. And we're looking at a couple of, you know, a variety of risk-type patients in that study. So it's going to give us a lot of insights in terms of how to sort of refine the inclusion-exclusion criteria, the specific dose, et cetera. And as Yvonne said, it'll be a very large outcome study with a MACE type of endpoint. So we're very excited to move that program forward. This could be, you know, hypertension is the number one addressable cause of cardiovascular disease. And we have a real chance to make an impact.
We have already something that'll be a twice-a-year dosing regimen for this disease. Very excited about it.
The program's moving along very nicely.
I guess recognizing that the ultimate goal is to have the information to power the cardiovascular outcomes trial, just to kind of set investor expectations a little bit, should we expect kind of a similar number of millimeters of mercury delta when we have multiple background agents in the mix? Or should we expect something different than what we've seen from the prior studies?
Yeah, look, in general, we know that as you add on drugs on top of multiple, right, as a monotherapy, we're seeing 15 millimeters plus blood pressure reduction. As you're looking at combinations, that inherently gets to be a smaller effect. But overall, remember, we're looking at a short-term period of time where this is going to be a chronic therapy. And so we expect those benefits to magnify over time.
But, you know, I think generally people believe anything over five millimeters of mercury leads to a pretty substantial impact in terms of mortality in this disease.
I'd just like to add that it's not just about kind of blood pressure lowering. That's obviously important. But I think what's unique about the zilebesiran approach is actually really providing patients with, you know, tonic control. That's, I think, an important unmet need that we believe that we'll be able to address.
So maybe switching to mivelsiran, what data thus far for that asset is most exciting to you?
Actually, so before we get into it, I can't help myself. Before we get into the details around mivelsiran, I'll ask Pushkal to comment. But you know, what this program really does for us is open up the opportunity for RNAi therapeutics for CNS diseases. And so mivelsiran is our first program. And obviously, we're evaluating in both patients with Alzheimer's disease as well as cerebral amyloid angiopathy. But as I mentioned in my remarks, we're also moving forward another CNS program, Huntington's. It's a program that we should be able to move through development, you know, in a very purposeful fashion. So for me, it's actually opening up the whole CNS opportunity to help patients with devastating neurodegenerative diseases. But Pushkal, why don't you say a few specific words around mivelsiran?
Yeah, I mean, mivelsiran really works very upstream in this amyloid cascade by turning off amyloid production at its source, right? So you can see parallels actually to the TTR approach that we've taken as opposed to having an antibody approach that's acting in the parenchyma or acting upstream to turn it off all the different amyloidogenic peptides that are actually produced off of that we can reduce. We've already been dosing patients with early onset Alzheimer's disease for over a year, and it's actually been very well tolerated. We're seeing reductions as we've reported previously in A- beta 40 and A- beta 42, which are the critical peptides involved in both Alzheimer's disease and cerebral amyloid angiopathy. We saw with actually repeat dosing on a q6 monthly frequency that we can actually get up to 90% knockdown, so we're really excited about that.
That early onset Alzheimer's disease program is ongoing. We announced today that we'll be starting a Phase II in Alzheimer's disease in the second half of this year, and we've already kicked off a Phase II study in cerebral amyloid angiopathy, which really is, I think, an under-recognized opportunity here. It's the second leading cause of intracerebral hemorrhage. The United States' intracerebral hemorrhage affects about 60,000-80,000 patients in a year, so we're talking about a lot of patients, and this is an area where actually the antibodies can't be as effectively used because of the contraindication around ARIA-H, and so this may be a unique opportunity, a differentiated opportunity for this drug, so look forward to sharing more at R&D Day in February and then some updates later in the year as well.
Terrific. Thanks, Pushkal.
Great. And maybe with just the last kind of minute here, I guess a little bit bigger question with the pipeline. But what kind of targets and diseases do you see as most attractive as you kind of take this platform forward?
Yeah, that's a great question, and you know, clearly we've achieved delivery, as I said, in outside the liver and obviously the CNS, but also in adipose and muscle, and we have quite a lot of interesting information to share with respect to our progress there, but we're going to save that for R&D Day in February. It's just around the corner, so hope that you'll tune in February in New York.
Great. Thank you.