All right. Good morning, everyone. Thanks for joining us for our next session. My name's Derek Archila. I'm one of the Senior Biotech Analysts here at Wells. With us today is Alnylam Pharmaceuticals, and from the company, we have John Kennedy, Head of Commercial, as well as Pushkal Garg, the Chief of R&D. Gentlemen, thank you so much for joining us, and look forward to the discussion here.
Thanks for having us.
Excellent. Maybe the first place to start here would be the TTR revenue outlook for 2026. John, during the quarter, we learned there were some things that maybe were not really reflected in the guidance, and you gave us a little bit of a reset. I guess the question now becomes, what's the confidence level in the reset guidance and ultimately, how should we be thinking about future growth, not only for 2026, but beyond?
Yeah. Thank you for that. Maybe I'll just start by characterizing the launch, what we see when we look back, and then what that means going forward. We'll talk about the guidance along the way. First and foremost, we're about 18 months into this launch for cardiomyopathy. AMVUTTRA was already approved for hereditary polyneuropathy. We added cardiomyopathy in March of 2025. We're about 18 months in, and the launch has gone exceptionally well. Just a single headline, if you think about the last quarter, we passed a billion-dollar quarter for the TTR franchise. This is very, very strong. Now, when we look back, there are several things that we were really focused on to make sure that this had the fundamentals in place for sustainable growth, and they're there. Generally speaking, the first area of focus for us has been access.
That is both provider access but also payer access, and the access is very, very strong. Generally unencumbered access to AMVUTTRA, particularly in first-line, with the majority of patients paying $0 in out-of-pocket cost. That has allowed us to focus on demand. Now if we look at physician experience and demand, since the launch of the cardiomyopathy indication through the end of last quarter, we have seen more than 1,700 physicians have a first experience with AMVUTTRA. There is tremendous uptake, especially in a rapidly growing category where more physicians are coming in. Now what we look for is what is that experience, and a great indicator of that experience is if we look at those physicians that have experience, we have north of 50% share of new starts with those physicians. In other words, trial results in a favorable experience and in preference for AMVUTTRA.
That is all very, very strong and encouraging. Of course, this is in a category that has grown. It has grown for the last six, seven years. It will continue to grow when you think that the majority of patients, unfortunately, are still untreated. So those are all the fundamentals that we are very, very confident in and give us quite a bit of runway for opportunity moving ahead. Now, as it relates to the guidance, one of the things that we talked about was just the learning in terms of the contribution of the AMVUTTRA source of business. To back up a little bit, there is a first-line segment and a second line. First line are these newly diagnosed patients. They are looking for that very first treatment choice. First line has, from the very beginning, been our strategic area of focus.
We want to establish AMVUTTRA as a first-line choice, knowing that, again, the vast majority of patients in this category are untreated. They will come in and seek that first-line treatment choice. So long term, that is a significant part of the opportunity, and that has gone very well. There is a second component, which is second line.
What we have seen from real-world evidence data sources is that patients treated with stabilizer unfortunately continue to progress. There was one analysis that looked at more than 800 patients treated on a stabilizer, mostly tafamidis, and what we saw was that within about a year on average, about half of those patients experienced cardiac worsening. So these patients continue to progress, and they will be looking for another treatment choice. Now, we are the first and only alternate mechanism of action in cardiomyopathy, and so we are a natural option for those patients.
Going back to the guidance, what we saw early on the launch is we had many of these high-volume prescribers start using AMVUTTRA, which is a good thing. With those higher volume physicians, they had more of these patients that had been treated with a stabilizer for some period of time. As you can imagine, many of those patients were progressing. So what we saw in the first several quarters of launch is those physicians moved more of those patients to AMVUTTRA in a second-line opportunity, and that was a robust part of the opportunity. So early on, it was relatively balanced where our source of business was coming from that first line and the second line. Now take a step back if you look at the category at large, this is more of a first-line category.
Now, part of that is because there hadn't been another option for a long time, but switching behavior is a relatively new behavior. That will take some time to really form and unlock. When we look at the category, generally about 80% of new treatment initiations are first-line treatment initiation. It's the minority, it's about 20%, that are second line. As you can see, when we started, we have more of a balanced contribution across both lines of therapy, but with those higher volume physicians that were earlier adopters, they moved more of those patients to AMVUTTRA, and what we saw is that second-line inflow has normalized. There's still robust inflow of second-line starts. It's still an opportunity, but it is normalized so that it's less of a contribution in terms of the AMVUTTRA source of business.
Now, the good news is our volume has continued to grow, and it just means that a greater proportion of our volume is now in first line, which strategically was the priority for us. The guidance is to reflect this change where there's a normalized volume of second-line inflow. It is different than what we saw in the first several quarters, and that was a learning for us. We had to adjust the guidance to reflect that normalized flow of second-line volume starts. That's on us in terms of the guidance, but again, just the context is prior to us, there really wasn't a second-line market. That was the newest part of this category where we had to observe and just see how that would play out.
Got it. No, very helpful. As we think about, again, first-line is where you're seeing the majority of the new starts, how do you think about the split between community and centers of excellence for AMVUTTRA usage, and how much does the 340B kind of incentive play a role there?
Yeah. What we're looking at for the initiations of AMVUTTRA, what we're seeing is it is still very balanced across these centers of excellence and the community. Just to step back, this is a category that is growing. It's growing very, very rapidly in terms of patient volume, in terms of RX volume, but also in terms of physicians that are active in the category, meaning they're diagnosing and they're initiating treatment. There's an expansion of the physician growth. About half of that growth is coming from these more community centers as opposed to the centers of excellence. We still have a robust business in the centers of excellence. We continue to see depth of penetration. That's a good thing. But in terms of the growth, we're also seeing quite a bit come from the community. Again, we're seeing balanced utilization of AMVUTTRA.
The reason for that is because AMVUTTRA is very widely accessible. I talked about the beginning. Access is a function of both provider and payer. On the provider side, if a community cardiologist chooses to engage in buy and bill, that's fine. That is a relatively well-tried and easy experience. By the way, we're not the only ones that are engaged in that space. Think of Leqvio in the lipid-lowering category. There are more experiences that cardiologists are having engaging in buy and bill. But if there's a physician that says, I don't want to get involved for some reason, that's okay, too.
Because we've established a very, very broad network of buy and bill alternate sites of care, such that about 90% of patients anywhere in the U.S., about 90% of patients can receive AMVUTTRA within about 10 mi of their home, whether that's in the physician's office, in a site of care that's part of a large integrated network that the physician is part of, or one of these clinics that is often down the street from where the patient lives.
Got it. Going back to the first line. I guess, where do you think you guys can peak out, or what's the aspirational share in that first line, and how much of the growth is really about share gains versus stabilizers versus just overall category growth?
Yeah. Moving forward, what matters is both share and category growth both, just to be very clear. What we're seeing in terms of first line is very encouraging. Again, within the first couple quarters, in terms of share of new starts, we had surpassed one competitor that launched just before us, and we were challenging, at the time, six-year incumbent in the category for share of new patient starts. We saw that within the first couple quarters of launch, and we continue to work towards that ambition today. We've got a tremendous data set. Again, physician experience tends to be favorable and drive greater utilization. Then on top of it, what we haven't talked about is just the dosing experience, where we are a quarterly physician-administered dose.
That is part of the value proposition of the product, which contributes, again, to the patient and the physician experience. All of that allows us to compete aggressively for first-line choice. Let's also not forget that after CARDIO-TTRansform, presumably, there's one less competitor that we have to contemplate in the future. Then moving forward in terms of category growth, I think it's informative for me to look back before looking forward. Looking back, we have about now seven years of category experience. You can look at tafamidis volume as a proxy of category volume for the last several years. What you see is for years, this was stable and robust growth, in excess of about, I think, 40% volume growth year over year for the last several years. Looking forward, the majority of these patients continue to be untreated.
I would expect that you will continue to have robust growth in the patient inflow, especially with more voices in the market driving greater awareness, more suspicion, diagnosis, and we will continue to play our part to facilitate that. We can talk about it if helpful, but we have several initiatives, partnerships with others that are focused on driving even greater diagnosis and category growth also.
Got it. Maybe one of the things that post ESC, post CARDIO-TTRansform, a lot of us are trying to work out, is there going to be an impact to AMVUTTRA usage? Is there kind of a ceiling in that first line in terms of share? I guess, how do you think about the overall value prop for AMVUTTRA relative to stabilizers and kind of point to some of the differentiating data maybe that the doctors are really pulling and being like, hey, this is why I want to prescribe it first line?
Yeah. I think first and foremost, in the aftermath of CARDIO-TTRansform, which is a competitor trial, one thing is true. Nothing has changed with regards to our data. HELIOS-B is a tremendous data set. It has been part of what has driven the initial uptake and demand for AMVUTTRA, and so that continues to be true. What we saw on that was a very robust impact on cardiovascular outcomes, about 40% reduction in all-cause mortality over four years. By the way, this is on top of aggressive standard of care background treatments. That's remarkable in terms of what you expect to see in categories like this or in heart failure or in cardiology categories at large. That is a really, really remarkable finding.
On top of it, to have had the impact on functional capacity with this, again, quarterly physician-administered dose, which is not just a convenience thing. I'll go back to what we've seen in this category, we've seen in many categories. Daily oral treatments, as much as we'd like to believe patients are adherent and persistent, they're not. What we see is after about a year, about 30% of patients on a daily oral treatment stop taking their medicine. By the end of the next year, another 30%. It's a very real dynamic that we see with daily oral treatment. Again, that's all part of the value proposition. What I've talked about is what we saw from the HELIOS-B primary results. But since then, we've also had additional analyses drawing from HELIOS-B, and we have other data generation initiatives that continue in the background.
Other things that we've seen is that AMVUTTRA appears to have very remarkable impact or the potential for impact on cardiac structure and function. There are multiple ways to look at it, but we have some MRI data that has now not just been presented, but published in a peer-reviewed journal that showed that there is a very serious signal with the potential of showing an improvement versus baseline on some parameters of cardiac structure and function. We also know that this disease affects multiple systems of the body, and what we've seen is that not only are we having an impact on the cardiovascular manifestations, but there are some signals that suggest extra cardiac manifestation impact.
To give you an example, we have a post hoc safety analysis that suggests that about half of patients, or there was a halving of the incidence of GI issues or manifestations. It all suggests that this is a very, very potent drug that is having a tremendous efficacy signal for these patients. That matters quite a bit for sure.
Understood. I guess we were talking about the second line, smaller part of the AMVUTTRA business, but I guess what are the kind of the pushes and pulls on that business in terms of stabilizer use being used earlier, so longer duration versus maybe less complacency around physicians looking for progression?
Yeah, I think there are multiple dynamics at play. For sure, as there are more voices in the market, there's better awareness, better understanding of the disease. We expect that diagnosis will happen more consistently and earlier, and that's a good thing. In fact, we intend to continue to facilitate that. But unfortunately, it's not like these patients are at the very earliest stages of manifestation, unfortunately. These patients are still recognized later than they should.
There are many pieces of data you can look at to get a sense of how the market is behaving, but there's one analysis that was done by the National Amyloidosis Centre in the U.K. that looked at cohorts of patients over time, and it generally showed that yes, diagnosis is in fact happening earlier, but the majority of these patients are still stage two, three in terms of NYHA staging or just I'll say, progressed in the disease. So there's still ample opportunity for us to help these patients. What we know from the HELIOS-B data set is the earlier you intervene with AMVUTTRA, the better. That is clear, and we continue to communicate that. For patients that have started on a stabilizer, we've seen in real-world data sets that unfortunately those patients do continue to progress. They will be looking for something else.
We are the first and only product approved in cardiomyopathy that is in a different mechanism of action, and so whether it's an add-on or a switch, we are really well positioned for that. I do think that with increased awareness, there is greater opportunity to identify those patients that could benefit from more aggressive or more intensive treatment options, again, whether that's a switch or add. So that's all helpful. In terms of duration of time on treatment, again, the earlier you help patients, it is likely those patients will remain on treatment for longer.
I think that's particularly helpful for us because we have quarterly HCP-administered dosing. Whether that benefit accrues to the stabilizers, it remains to be seen, but I would go back to what we've observed in this category and others, where again, by the end of the first year, about 30% stop taking their medicine. That repeats again. So ample opportunity.
Understood. We have talked a lot about the U.S., but maybe you can kind of give us a sense of how AMVUTTRA ramp in ex-U.S., and we had a little bit of lumpiness earlier this year with some pricing resets in some countries, but what should we kind of expect out of that business?
Yeah. For outside the United States, we are launching in several countries. Our goal is to bring AMVUTTRA to as many patients as we can, as fast as we can around the world. One of the things that you have heard us talk about in the earnings is that in Q1, we are expecting a reduction or a decline in the revenue, but then sequentially that would improve over time. Just to give you a sense for the why. One of the earlier countries we had launched in was Germany. It is a relatively higher volume country, and when I say higher volume, do not forget that we had approval for AMVUTTRA in the hereditary polyneuropathy before adding cardiomyopathy. Outside the U.S., the pricing reimbursement system is different from country to country, but generally, and in a country like Germany, we have a negotiated price for cardiomyopathy.
That negotiated price for cardiomyopathy is lower than polyneuropathy. The reason for that is prevalence. Cardiomyopathy is about tenfold greater prevalence than polyneuropathy, and so what that means is the legacy volume of polyneuropathy business has a correction as you reset the price for cardiomyopathy. That results in a transition where in the first quarter you have a reduction in your revenue, but then sequentially the volume grows past that and there is ample volume to grow. That is kind of the dynamics that we saw in the first quarter, and so what we have said is you saw that in Q1, but we expect quarter-over-quarter improvement in that ex-U.S. contribution.
In absolute terms, the revenue growth for 2026 outside the U.S. will be very similar to the absolute revenue growth we saw outside the U.S. for 2025. But again, that is just a function of countries launching progressively throughout the course of the year. Many of them will have that kind of transitional adjustment at the beginning of the launch, and then because the cardiomyopathy volume is so much bigger, will continue to grow through that.
Got you. Just a question that we get frequently is around 340B and the potential impact of some future legislation here. Maybe talk through what you guys are thinking about and how things could be mitigated depending on if that advances.
Yeah. So in terms of the proposed rule, there has been a proposed rule. It remains to be seen what happens, if it happens, and in what form. We just went through a comment period, so we haven't seen the conclusion of that. What I do know is that there are many voices that likely participate in the comment period that have some strong feelings about this, particularly on the provider side with regards to reimbursement rates. So I think it remains to be seen what will play out. What I can tell you is that we have secured broad access for AMVUTTRA across sites of care, and if you look at utilization, we're seeing broad utilization across sites of care. We are very focused on maintaining that access, and we expect that there will demand.
Again, what actually happens with this proposed rule, I think remains to be seen, and if something like that goes through, what happens in terms of provider behavior remains to be seen. But there is quite a bit of optionality on the provider behavior side, whether they participate, whether they go outside of 340B or we have alternate sites of care. So we have a broad network, broad access and broad utilization, again, across sites of care.
Got you. We were talking earlier at the breakfast in terms of we've had a lot of new developments with more clarity around tafamidis generic, obviously CARDIO-TTRansform.
Yeah.
And all that stuff. I guess, how do you envision that both on price mix and volume mix for AMVUTTRA in the future?
Yeah. What we are referring to is there have been a couple events in the marketplace that I think lend a little bit more certainty. Number one, we saw that the tafamidis loss of exclusivity according to Pfizer, we now expect later in 2031. That does two things in my opinion. Number one, it removes some of this pricing risk or pricing pressure in the midterm. Number two, it just gives us more of this time to continue to compete for first-line preference. A net good thing. The second event is CARDIO-TTRansform from Ionis Pharmaceuticals and AstraZeneca, which unfortunately was a failed study.
Again, I think that has two implications. One is that likely also removes some potential for pricing pressure in that midterm. That is a net good thing for us, and then presumably removes a competitor from the mix. A net good thing on share. I think if you were to just look at where we are today in terms of what we are capturing for new patient starts, you take more certainty in the midterm in terms of the pricing dynamics in a category that continues to grow. I think there is quite a bit of reason for optimism here.
Yeah. I guess in terms of generic tafamidis, how much do you think that is either a headwind neutral or tailwind for the AMVUTTRA business? In light of CARDIO-TTRansform, the push to potentially use combo, is that still on the table, or do you think that is going to be more modest than maybe the original kind of assumptions?
Yeah. One of the things that we've said really since launch is that until you have loss of exclusivity for tafamidis, we expected this category to be more of a monotherapy market, and generally that's what we see. We do see some combination treatment. There are physicians and there are also patients who are looking for the most intensive treatment regimen that they can have, just knowing that this is functional capacity at stake, not to mention, obviously, morbidity and mortality. We do see combination therapy, but the majority of this market has been monotherapy. I can put that into context for you. At the beginning, we were talking about this first line, second line. Most combination treatment tends to be in that second line.
Again, if about 80% of new starts in the category first line, then you have about 20% that are second line, some portion of that is combo. That gives you a sense. I expect that you'll continue to see some of that. The reason for it is HELIOS-B. It's a tremendous study, and what that showed is that you had consistency of treatment effect with AMVUTTRA, with or without background tafamidis. That's in the label, it's in the dataset. There's substantiation for those physicians and/or patients that pursue that, so I think it will persist, but the real unlocking event would likely be tafamidis generic. By that point, though, we expect that we'll have mivelsiran. So another dataset with another tremendous asset, with a different dosing frequency that I think would make it a wonderful foundational treatment option.
Incredible segue. Maybe we can talk to TRITON with Pushkal here. Coming out of ESC and CARDIO-TTRansform, a lot of questions around TRITON and what could be done around that trial, or what needs potentially to be done to that trial, if anything, to make sure and ensure it's successful. Maybe just talk about the key learnings from the more detailed dataset at ESC, what else you might want to know prior to making any sort of modifications that would help the probability of success for mivelsiran.
Yeah. Thanks, Derek. Look, I think the ESC presentations around CARDIO-TTRansform were quite informative, right? I think a number of things that we think really point, unfortunately, to why the trial didn't succeed as anticipated. I think one, probably the biggest surprise was the knockdown levels, right? That they saw 70% knockdown as a mean level with nucresiran. With vutrisiran, we're at 81%, 87%, depending on mean and median. So pretty sizable difference in terms of that knockdown. I think you saw that really play out, even if you look across the data, you saw benefits of that drug in monotherapy, and even when you look at across the endpoints, you saw some benefits in combination across a variety of endpoints, not the top-line one, but a variety of other endpoints suggesting there was really an example of basically a dose-response effect.
Less knockdown, less effect, more knockdown, greater effect compared to HELIOS-B and the AMVUTTRA dataset. I think the second thing was patient selection. I think we've seen coming out of HELIOS-B as a learning and actually even earlier studies, that with the silencing mechanism, when you're turning off production, you actually really want to get in upstream, you want to get in before patients accumulate a lot of irreversible damage to their heart. That's harder to change if you're turning off the spigot in production. It's not to say you can't change it just may take longer, beyond what you can do in a short-term clinical trial. We saw there again that the greatest benefits of that drug really occurred in the earliest patients.
The most noteworthy example of that was, if you look at the NAC stage one, which is largely defined by BNP under 3,000, we know BNP is probably the strongest predictive factor in heart failure. In 900 patients, they actually would've seen a stat sig effect, and that's including all the patients who are on combo, which was 60% on the onset, another pretty much 20%, 25% who dropped in. In 140-week trial in that earlier patient population, that's where they would've seen a stat sig effect. Then the third was around endpoint selection, and there again, I think they focused on CV mortality and CV events. We've tended to focus on all-cause mortality because this is a systemic disease, and we think that captures the totality of what happens to a patient and tends to be more sensitive.
I think those were the kind of the key learnings coming out of CARDIO-TTRansform that really tended to point to why the study didn't succeed, and really said, look, not all silencers are created equal, and ASO is different from an RNAi. Importantly, that as we design TRITON-CM, these were actually learnings that we'd carried forward from HELIOS-B and we had incorporated. So A, we've got a molecule with the deepest knockdown ever studied, vutrisiran, median knockdown of 95%. It gets everybody more or less to deep levels of knockdown. Two, we focused on the earlier patient population. We have compared to the eplontersen study, real caps on BNP, not only at the higher level, but even at intermediate levels within the study. Then we focused on endpoints that we think are most sensitive.
Lastly, we have an event-driven study as opposed to a fixed time study. We think there's a lot of tailwinds and frankly what we learned corroborated a lot of the design choices we made for TRITON-CM. You'll recall that we recently upsized the study early in the year from 1,250- 1,750, recognizing, as we had intended, that we were getting an earlier patient population. This just increased the probability of getting more events, accruing events earlier. We feel like we're in a good position, but look, we just got the data this last weekend. Our teams are going through it. There was a lot there, and we're doing a lot of simulation work, et cetera, to think about if there's anything more that we need to do in terms of optimizing TRITON-CM. It's obviously a very important study. Those probably fall into two main categories.
One could be things that relate to enrollment, whether we enrich or further accrue more patients, et cetera, in certain segments. That is something if we decide to do, we have to do this year. The other would be something that could be more in the analytics category, endpoints, et cetera, like we did with HELIOS-B. That would happen farther down the line after we have kind of accrued the patients and seen what their trajectory is over time.
I guess, what is your confidence level based on kind of what you have already talked about in terms of stratifying those patients, and BNP levels that these patients would be kind of earlier stage relative to CARDIO-TTRansform?
Oh, no, I think we feel quite confident that the way we have designed the study and what we are accruing, these are going to be milder patients or earlier patients than that in CARDIO-TTRansform. We even did this in HELIOS-B, right? If you compare the eplontersen study to HELIOS-B based on the way that we designed it and the caps we had put in place, there were twice as many NYHA Class III patients in CARDIO-TTRansform. There were twice as many NAC stage three patients in CARDIO-TTRansform. The median BNP level was higher. There was a number of things that really pushed them a little bit towards a more advanced population that we had purposely avoided in HELIOS-B, and we have further exploited those learnings in the way that we have designed TRITON.
Got it. I think you alluded to this, but we also talked about it at breakfast this morning, but you do not really view this as like monotherapy versus combo. It is more about kind of the advanced patient population. I guess if you were to look at the mix and make any changes, would that mean more of like changing those caps that you talked about, or would it be more about looking for mono, or what would be kind of the mix that you would want to change?
Yeah. What I would say is there's a number of different things we can pull. Again, we want to develop the medicine ultimately to have a label that's going to be most supportive of what John does in terms of getting this medicine out to patients, right? And to the broadest mix of patients that we possibly can, and where it's going to have the greatest benefit risk for patients. As we've said, we always think this drug should be used early and as first line. That's been our objective with AMVUTTRA and with [inaudible]. We're seeking a broad label, both as mono and combo. There's a number of levers you can kind of pull, but again, we want to support the label that we're trying to get that we think is going to help patients. Mono combo has been kind of an incessant focus.
I get why based on what the top line release is, but I think it misses the forest for the trees a little bit, that there are multiple other important levers that really help, and that's again, proper patient selection, high levels of knockdown. We put out some clinical trial simulation work that we'd done that really showed that with high levels of knockdown, we expect to see benefit both as mono and as combo, which is what the biology would suggest very strongly and existing clinical trial data supports. That's where we're focused.
Is it fair to say, regardless if you make changes this year to kind of like enrollment criteria or SAP design, which we would find out later, that you're not going to sacrifice a broad label, that's like first and foremost?
We think it is important as we kind of think about where the field is going and how patient care is going to evolve, and so we're committed to showing the benefit as therapy in both settings.
Very helpful. Maybe with the last couple minutes here, it would be great to talk beyond TTR, and maybe talk about some of the pipelines. Near term, you are going to talk about some Huntington's disease data from one of the programs. I think that is coming out late October, so maybe talk about that and give us a little bit of context of what would constitute a good update there.
Yeah, I mean look, I do not think we have to do a lot of educating about Huntington's disease. Really incredibly devastating disease with no approved therapies, been likened to having Parkinson's, Alzheimer's, and ALS all at the same time. We are excited about the molecule we have brought forward. It is a siRNA that is now built upon the platform that we have developed that really allows us to usually dose about twice a year.
It is intrathecal dosing that actually has deep knockdown and broad biodistribution in the brain. That is really important in this disease, where you are really trying to get into the deeper brain structures like the caudate nucleus. We also have a unique targeting approach, so we are not only targeting mutant huntingtin, which has been tried before, but we are specifically targeting a segment of the gene that includes something called Exon 1 that codes for a protein called HTT1A.
We know that small fragment is really critical in terms of the biology of this disease, in terms of nucleating the tangles that happen in Huntington's disease. Very exciting approach. I will note that uniQure actually, where they have shown some benefits compared to natural history, is the one other approach that actually specifically targets Exon 1. So, that is in a phase I study. We will have some data out in October at EHDN. What we are looking for there is, A, what is the safety and tolerability? B, can we get to deep levels of knockdown? This will be single-dose data. I will remind you that previously, Roche, Ionis had brought forward tominersen, which had about a 25% knockdown and had some tolerability issues in terms of NfL increases, ventricular enlargement, et cetera.
We think that is largely ASO related, but it will be important that we can hopefully get a well-tolerated level of deeper knockdown than that. We would love to see 50% or greater. I think if we can get to that, then we think we will be able to move this program quite rapidly. It is also encouraging to see that there may be some regulatory flexibility in the Huntington space as well. All of that we will stay tuned for, but we are excited.
Got you. Then maybe just quickly on ALN-6400. Looking at development in a couple bleeding disorders. What should we kind of expect from the data later this year? I guess maybe sketch out for us a little bit about the opportunity in von Willebrand disease.
Yeah. ALN-6400 targets a protein called plasminogen, which is a liver-derived protein that's involved in fibrinolysis or clot breakdown. By silencing it, we can stabilize clots. Think of it like a Band-Aid. Beauty of the Band-Aid is it can be used across a variety of bleeding disorders. We believe based on very strong genetic evidence from patients with plasminogen deficiency, that it will not be associated with thrombosis. A lot of times we worry about drugs that help with bleeding, that they promote thrombosis. Here we think we can dissociate those two phenomenon. Very interesting program. We'll have later this year some phase I data, which will have evidence of knockdown and safety. Then we'll also have data later this year in our first indication, which is hereditary hemorrhagic telangiectasia. Really devastating disease, affects about 70,000 patients in the United States.
They are affected by telangiectasia, which are small arteriovenous malformations at the capillary level. They can affect the gut, really impact the nasal mucosa, so these patients can have incessant bleeding hours at a time, several days out of the week. Half these patients are anemic, require blood transfusions. Our hope is that we can actually start to reduce the bleeding in a prophylactic way for these patients, giving this several times a year to prevent bleeding. Our second, so we'll have data in HHT later this year. Then next year we expect to bring forward, we're bringing forward data in von Willebrand disease, which is more of a platelet type of disorder, again, to highlight the impact of this drug across a variety of bleeding disorders.
Got it. Well, I think we'll leave it there. Gentlemen, thank you so much for the conversation.
Thanks, Derek.
Thank you.