Alnylam Pharmaceuticals, Inc. (ALNY) September 2026 Conference Transcript

All right.

Good morning, everyone. Thanks for joining us for our next session. My name is Derek Garcilla. I'm one of the senior biotech analysts here at Wells. With us today is Al Nylum, pharmaceuticals. And from the company, we have John Kennedy, head of commercial, as well as Pushkal Garg, the chief of R&D. So, gentlemen, thank you so much for joining us and look forward to the discussion here. thanks for having us excellent so you maybe you know the first place to start here would be kind of the the TTR revenue outlook for 2026 so you know John during the quarter you know we learned you know there were some things that maybe we're not really reflected in the guidance and you kind of give us a little bit of a reset so I guess the question now becomes you know what's the confidence level in in kind of the reset guidance and you know ultimately how should we be thinking about future growth not only for 2026 but you know kind of beyond yeah thank you for that so maybe I'll just start by characterizing launch what we see when we look back and then what that means going forward and

we'll talk about the guidance along the way so first and foremost we're about 18 months into this launch for cardiomyopathy so which was already approved for polyneuropathy the hereditary polyneuropathy we added cardiomyopathy in March of 25 so we're about 18 months in and the launch is gone exceptionally well. Just a single headline. If you think about the last quarter, we passed a billion dollar quarter for the TTR franchise. So this is very, very strong. Now, when we look back, there are several things that we weren't 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's both provider access, but also payer access. And the access is very very strong generally unencumbered access to Amvutra particularly in first line with the majority of patients paying zero dollar and out-of-pocket cost that has allowed us to focus on demand and now if we look at physician experience and demand since the launch of the cardiomyopathy indication through the end of last quarter we had we've seen more than seventeen hundred physicians have a first experience with Amvutra so there's 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. So in other words, trial results in a favorable experience and preference for Amvutra. So that's all very, very strong and encouraging. And of course, this isn't a category that has grown. It's 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're very very confident in and give us quite a bit of runway for 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 Amvrucha source of business so to back up a little bit there's a first line segment and the second line so first line are these newly diagnosed patients they're looking for that very first treatment choice first line has from the very beginning been our strategic area focus we want to establish and which is a first line choice knowing that again the vast majority of patients in this category on untreated they will come in and seek that first line treatment choice so that's long term that's a significant part of the opportunity and that has gone very well there's a second component which is second line what we've 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 to feminists 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're a natural option for those patients so going back to the guidance what we saw early on the launch is we had many of these high volume prescribers start using Amvutra which is a good thing and with those higher volume physicians they had more of these patients that had been treated with a stabilizer for some period of time and as you can imagine many of those patients were progressing so what we saw in the first several quarters of launch is those physicians move more of those patients to Amvutra 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 you know switching behavior is a relatively new behavior that will take some time to to really form and unlock and so when we look at the category generally about 80% of new treatment initiations are first line treatment initiation it's the minorities about 20% that are second line so 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 Amvutra and so what we saw is that second line inflow has normalized so they're 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 in which a source of business now the good news is our volume has continued to grow and so it just means that a greater proportion of our volume is now in first line which strategically was the priority for us so the guidance is to reflect this change where there's a normalized volume of second line inflow it is different than than what we saw in the first several quarters. And that was a learning for us. And so we had to adjust the guidance to reflect that normalized flow of second line volume starts. And 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. So that was the newest part of this category where we had to observe and just see how that would play out.

Got it, very helpful. So 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 AmVutra usage and how much does kind of the 340B kind of incentive play a role there?

Yeah, for what we're looking at for the initiations of AmVutra, what we're seeing is it is still very balanced across these centers of excellence and the community. So 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. So there is 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. Now, 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. Now, again, we're seeing balanced utilization of Amvutra. The reason for that is because Ambusha is very widely accessible. So 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. And by the way, we're not the only ones that are engaged in that space. Think of Lectio 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-build alternate sites of care such that about 90% of patients anywhere in the United States about 90% of patients can receive amfuture within about 10 miles 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 so going back to kind of the the first line so i guess where you know where do you think you guys can peek out or what's the aspirational share in that first line and you know how much of the growth is really about share gains versus stabilizers versus just overall category growth yeah i'm moving forward you know what matters is is both uh share and category growth both uh just to be clear. So, you know, what we're seeing in terms of first line is very encouraging. So 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 the six at the time, six-year incumbent in the category for share of new patient starts. And so we saw that within the first couple quarters 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 and then on top of it what we haven't talked about is just the the dosing experience where we are quarterly physician administered dose that is part of the value proposition of the product which contributes again to the patient and the physician experience so all of that allows us to compete aggressively for first-line choice let's also not forget that after cardio transform presumably there's one less competitor that we have to contemplate in the future and then moving forward in terms of category growth i think i it's informative for me to look back before looking forward so looking back we have about now seven years of category experience you can look at to feminist volume as a proxy of category volume for the last several years and what you see is for years this was stable and robust growth in in excess of about i think 40 volume growth year of a year for the last several years looking forward the majority of these patients continue to be untreated. So 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. And 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. So maybe, you know, one of the things that, you know, post-ESC, post-cardio transform, you know a lot of us are trying to work out you know is there going to be an impact to Amvutra usage and you know is there kind of a ceiling in that first line in terms of share so I guess like how do you think about the overall value prop for Amvutra relative to stabilizers and you know kind of point to some of the differentiating data maybe that the doctors are really you know 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 transform which is a competitor trial.

One thing is true, nothing has changed with regards to our data. So Helios B is a tremendous data set. It has been part of what has driven the initial uptake and demand for Amphutra, and so that continues to be true. What we saw in that was a very robust impact on cardiovascular outcomes, about 40% reduction in all-cause mortality over four years. And by the way, this is on top of aggressive standard of care background treatments. And so 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. And then 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% so that is it's a very real dynamic that we see with daily oral treatment so again that's all part of the value proposition now 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 as initiatives that continue in the background other things that we've seen is that in Vutra appears to have very remarkable impact or the potential for impact on cardiac structure and function and there are multiple ways to look at it but we have some MRI data that has now not just been presented but published in peer-review journal that showed that there is a very serious signal of with the potential of showing an improvement, improvement versus baseline, on some parameter of the cardiac structure and function. We also know that this disease affects multiple systems, 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. So 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 so so that matters quite a bit for sure understood I guess you know we were talking about the second line smaller part of the Ambutra business but I guess you know what are the kind of the push and pulls you know on that business in terms of stabilizer use being used earlier so longer duration versus you know maybe less complacency around physicians you know 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 and 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 so 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 is one analysis that was done by the National Amyloidosis Center in the UK 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 max staging, or just, you know, I'll say progressed in the disease. So there's still ample opportunity for us to help these patients. What we know from the Helos-B data set is the earlier you intervene with Avutra, 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. And so we are the first and only product approved in cardiomyopathy that is a different mechanism of action. And so whether it's an add-on or a switch, we are really well positioned for that. And I do think that with increased awareness, there is greater opportunity to identify those patients that could benefit benefit for more aggressive or more intensive treatment options, whether, again, whether that's a switch or add. So that's all helpful. In terms of, you know, 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. So whether that benefit accrues to the stabilizers, you know, 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. So we've talked a lot about the U.S., but maybe you can kind of give us a sense of how Amvutra ramped 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, so for outside the United States, we're launching in several countries. Our goal is to bring Amvutra to as many patients as we can, as fast as we can around the world. One of the things that you've heard us talk about in the earnings is that in q1 we're expecting a reduction or a decline in the revenue but then sequentially that would improve over time so just to give you a sense for the why one of the earlier countries we had launched in was Germany it's a relatively higher volume country and when I say higher volume don't forget that we had approval for rambutra in the hereditary polyneuropathy before adding cardiomyopathy now outside the US 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 volume the legacy volume of polyneuropathy business has a correction as you reset the price for cardiomyopathy and so 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's ample volume to grow and so that's 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-US contribution and then in absolute terms the revenue growth for 2026 outside the US will be very similar to the absolute revenue growth we saw outside the u.s for 2025 but again that's 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 we'll continue to grow through that gotcha and then just you know a question that we get frequently is around kind of 340b and kind of the potential impact of some future legislation here so maybe kind of talk through you know what you guys are thinking about and and how things could be mitigated you know depending on if that advances yeah so in terms of the proposed rule that there has been a proposed rule uh you know 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 you know there are many voices that likely participate in the comment period that 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 Amputra across sites of care and if you look at utilization we're seeing broad utilization across sites of care and so we are very focused on maintaining that access and we expect that they 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.

And we were talking earlier at the breakfast in terms of, like, we've had a lot of new developments with kind of more clarity around Tafamish Generic, obviously Cardio Transform, and all that stuff. So I guess how do you kind of envision that, both on kind of price mix and volume mix for Ambutra in the future?

Yeah, so what we're referring to is there have been a couple events in the marketplace that I think lend a little bit more certainty. So number one, we saw that the tefaminous 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. And number two, it just gives us more of this time to continue to compete for first line preference. So a net good thing. The second event is Cartier Transform from Ionis 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's a net good thing for us. And then presumably removes a competitor from the mix. So a net good thing on share.

So I think if you were to just look at where we are today in terms of what we're capturing for new patient starts, you take more certainty in the the midterm in terms of the pricing dynamics in a category that continues to grow I think there's quite a bit of reason for optimism here yeah I mean I guess in terms of you know generic to famously how much do you think that is either headwind neutral or tailwind for the M Vutra business and it kind of in light of cardio transform it kind of the the push to potentially use combo is that still on the table or do you think that's kind of going to be more modest than maybe the original kind of assumptions.

One of the things that we've said really since launch is that until you have loss of exclusivity for tefaminis, we expected this category to be more of a monotherapy market. And generally, that's what we see. So 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. And so we do see combination therapy, but the majority of this market has been monotherapy. I can put that into context for you. So at the beginning, we were talking about this first line, second line. Most combination treatment tends to be in that second line. So 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. So that gives you kind of 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 Amvutra, with or without background tefeminis. That's in the label, it's in the data set. So 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 tefeminis generic. By that point though, we expect that we'll have new crecer in. So another data set with another tremendous asset with a different dosing frequency that I think would make it a wonderful foundational treatment option.

Incredible segue. So maybe we can talk to Triton with Pushkal here. So, you know, coming out of ESC and kind of Cardiotransform, a lot of questions around kind of Triton and, you know, what could be done around that trial or what needs potentially be done to that trial, if anything, to make sure and ensure it's, you know, successful. So maybe just talk about, you know, kind of the key learnings, you know, from kind of the more detailed data set at ESC. What else you might want to know, you know, prior to making any sort of modifications that, you know, would help the probability of success for Nucrecerin?

Yeah, thanks, Derek. So, look, I think the ESC presentations around Cardiac Transform 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 vitriceran, I mean, with vitriceran, we're at 81%, 87%, depending on mean and median, so pretty sizable difference in terms of that knockdown, and 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 in the Amvutra data set. I think the second thing was patient selection. You know, 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 right that's harder to change if you're turning off the spigot in production it's not to say you can't change it it just may take longer beyond what you can do in a short-term clinical trial and so we saw there again that the greatest benefits of that drug really occurred in the earliest patients and the most noteworthy example that was you know if you look at the next 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 have seen a stat sig effect and that's including all the patients who are on combo right which was 60% on the onset another pretty much 20% 25% who dropped in and so in a 140 week trial and those at the earlier patient population that's where they would have seen a stat sig effect and 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 systemic disease and we think that captures the totality of what happens to a patient tends to be more sensitive so I think those were the kind of the key learnings coming out of cardio transform 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. But importantly, that as we designed Triton-CM, these were actually learnings that we carried forward from Helios B and we had incorporated. So, A, we've got a molecule with the deepest knockdown ever studied, Nucre-Saran, 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 eplontersin study, real caps on BNP, not only at the higher level but even at intermediate levels within the study and then we focused on endpoints that we think are most sensitive and then lastly we have an event driven study as opposed to a fixed time study so 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 1250 to 1750 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 so so 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 and we're doing a lot of simulation work etc 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 etc in certain segments that's something if we decide to do we have to do this year and then the other would be something that could be more in the analytics category end points etc like we did with Helios B that would happen farther down the line after we've kind of accrued the patients and and seen what their trajectory is over time.

I guess what's your confidence level you know based on kind of what you've already talked about in terms of stratifying those patients and BMP levels that you know these patients would be kind of earlier stage relative to cardio transform?

Oh no I think we feel quite confident that the way we've designed the study and what we're accruing these are going to be milder patients or earlier patients than that in cardio transform. We already are you know and we even did this in Helios B right if you compare the Eplon-Tursin study to Helios B based on the way that we designed it in the caps we put in place you know there were twice as many NYHA class 3 patients in cardiac transform there were twice as many NAC stage 3 patients in cardiac transform the median BNP level was higher so 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 further exploited those learnings in the way that we've designed triton yeah and And I think you alluded to this, but we also talked about at the breakfast this morning, but you don't really view this as like monotherapy versus combo.

It's more about kind of the advanced patient population. So I guess if you were to look at the mix and make any changes, would that be 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'd 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, you know, benefit risk for patients. As we've said, we always think this drug should be used early and, you know, as first line. That's been our objective with Amvutra and with Nucresan. 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. Monocombo has been kind of an incessant focus. I get why, based on what the top line releases, 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, you know, 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. So that's where we're focused.

So is it fair to say, regardless if you make changes this year to enrollment criteria or SAP design, which we would find out later, that you're not going to sacrifice a broad label? That's 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. So maybe with the last couple of minutes here, it'd be great to kind of talk beyond TTR. And maybe talk about some of the pipelines. So near term, you're going to talk about some Huntington's disease data from one of the programs. I think that's 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 don't 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. and we're you know excited about the molecule we've brought forward it's a sRNA that's now built upon the platform that we've developed that really allows us to usually dose about twice a year it's intrathecal dosing that actually has deep knockdown and broad bio distribution in the brain and that's really important in this disease where you're really trying to get into the deeper brain structures like the caudate nucleus we also have a unique targeting And so we're not only targeting mutant Huntington's, which has been tried before, but we're specifically targeting a segment of the gene that includes something called exon 1 that codes for protein called HTT1A. And we know that 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. And so very exciting approach. I'll note that Unicure, actually, where they've shown some benefits compared to natural history, is the one other approach that actually specifically targets Exxon 1. So that's in a Phase I study. We'll have some data out in October at EHDN. And what we'll be looking for there is, you know, A, what's the safety and tolerability? B, can we get to deep levels of knockdown? This will be single-dose data. I'll remind you that, you know, previously Roche Ionis had brought forward Tominerson, which had about a 25 percent knockdown and had some tolerability issues in terms of NFL increases, ventricular enlargement, et cetera. We think that's largely ASO related, but it'll be important that we can hopefully get a well tolerated level of deeper knockdown than that. And so we'd love to see 50% or greater, and so that's, and then I think if we can get to that, then, you know, we think we'll be off, be able to move this program quite rapidly. It's also encouraging to see that there may be some regulatory flexibility in the Huntington space as well. So all of that we'll, you know, stay tuned for, but we're excited.

Gotcha. And then maybe just quickly on 6,400, so, you know, looking at development in a couple bleeding disorders, so what should we kind of expect from the data later this year? and I guess maybe sketch out for us a little bit about the opportunity in Von Willebrand's.

So ALN6400 targets a protein called plasminogen, which is a liver-derived protein that's involved in fibromyalysis or clot breakdown. By silencing it, we can stabilize clots. So think of it like a Band-Aid. The beauty of the Band-Aid is it can be used across a variety of bleeding disorders. And two, 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 phenomena. So very interesting program. We'll have later this year some phase one data, which will have evidence of knockdown and safety. And 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 is 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, and so 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 and so we'll have data in HHT later this year and then next year we expect to bring forward we're bringing forward data in von Willebrand's disease which is more of a platelet type of disorder and again to highlight the impact of this drug across a variety of bleeding disorders yeah well I think we'll leave it there gentlemen THANK YOU SO MUCH FOR THE CONVERSATION.