Thank you all. Welcome all again to the 2025 Citi Biopharma Conference in Boston. Next on the docket, we have Alnylam. If you could, I guess, introduce us and kind of tell us a little bit about the company for people who haven't heard of you before, and bring us up to speed, that'd be great.
I'm Kevin Fitzgerald, CSO. I'm very high level on the company for five years. Now for the rest of the very productive organic platform for the company we've got.
Great. We've got six products in the market today, four of which that we're marketing ourselves, which came out of our research labs, meaning this guy's labs. And we've got a terrific pipeline of things that we think are going to continue the growth trajectory for the company over the long term. And I know we're going to get into a number of those topics here in the next 40 minutes. I think the big focus right now for investors on the company is clearly the launch in ATTR cardiomyopathy. And we reported strong initial results, which was in Q2 in terms of what we delivered. Again, I know we're going to get into the details on that, but that enabled us to upgrade the guidance for this year pretty substantially.
And I think got people pretty excited about what we were able to say about the initial demand for the product. So we're excited. Yeah.
I guess going way back when, I mean, RNAi has been around theoretically for a long time. And much more recently, you started getting commercial approvals. It's a Nobel Prize. There's a Nobel Prize associated with it. How has RNAi evolved? Obviously, at the beginning, there was a vision of all these different indications that could be approached. How has it evolved from early days to now?
That's definitely, Kevin, one for you.
That's fine. I've been with the company over 20 years. I've been in RNAi probably, I don't know, 27 years. So I think the beauty of RNAi is that it's a naturally occurring mechanism. It's in every cell in the human body. And so the idea that you could take a small RNA and deliver it inside a cell and get it to co-opt the mechanism by which microRNAs, which are these naturally occurring RNAi's, work, was really pie in the sky when we first started. As we moved along, there were really two key things we needed to solve. One was, how do you get a small RNA inside a cell? And how do you keep it stable long enough that it can act? And so over time, we solved that problem first with lipid nanoparticles for patiseran.
And then later on with something called GalNAc, which is really a small molecule that you put on the end and you drag it into the liver, and then stabilizing the molecules themselves. And that really allowed us to have a pharmacology, which is fairly unprecedented. You can do a subcu injection once every six months, maybe once a year as we go forward, and lower a protein that might be involved in human disease. And so we started out in the liver. We've now moved over into the central nervous system and are currently expanding into the muscle and into adipose, heart and other places. We announced at our R&D day that really our goal is to get into every major organ and to then start to go after diseases in that fashion. So it's been a very long journey.
We've had our ups and downs, but the technology just works.
We're going to definitely dig into the outside the liver at some point here. Naturally, people are focusing a lot more on something more recent. And that, of course, is AMVUTTRA. It's strong launch. Now, there's been a certain evolution in ATTR. I think that the expectations for how significant it could be has changed a lot over the last few years. How do you see the ATTR market now versus how you saw it even two or three years ago?
Yeah, I mean, maybe a couple of things. It's a rare disease, but it's a big market, which maybe seems sort of like an oxymoron, but it's the truth based on what we know about it. We think that, talk about the wild-type part of the market for just a second, but then I actually want to pivot to polyneuropathy, which is the place that we've been sort of playing commercially for the last five or six years. We think the wild-type part of the market, which is a cardiomyopathy market, is about 300,000 plus globally in terms of number of patients. And we think that's largely underpenetrated today. Maybe about 20% of the patients are being treated today with cardiomyopathy. We, again, mentioned earlier, we started out in the hereditary polyneuropathy part of the market.
The hereditary part of the market is probably 50,000 patients and about maybe half of that polyneuropathy. So that's the place that we've been playing from a commercial standpoint for the last five years is about 25,000, 30,000 patients. We did $1.2 billion in revenue last year. That was polyneuropathy only. And that was growing more than 30% a year. We're probably somewhere around 5,000 patients on therapy for polyneuropathy. Now we're talking about opening up, obviously, with the label expansion first in the U.S. to what I described in terms of a much, much larger market opportunity. And I think what you've seen in the first two quarters of this year with the second product that launched, which was Bridge's product and then Alnylam's product in the second quarter. And if you watch kind of how Pfizer's business has been evolving, there's a lot of growth here already.
Our expectation is, as you get more voices in the market for a rare disease like this, that drives diagnosis and ultimately treatment rates up. So that's what we're expecting is going to happen over time is you may even see an acceleration of that growth. And it's been a terrific franchise for Pfizer, the CM for Taf. That's a $6 billion franchise. So there's a huge opportunity here, number one. And then the second thing that I would highlight that we're certainly continuing to learn is there's still a lot of unmet need in the market. I mean, the Pfizer franchise has been a great franchise for them, but there's still a lot of patients, as I mentioned, that aren't diagnosed or treated, but the patients that are on drug, they're not all responding adequately to the therapy. And now there's some choices for those patients.
And so, particularly for us with an orthogonal mechanism of action, the first one is orthogonal to the stabilizer mechanism. I think that's a real opportunity for us as well in terms of that second-line setting. So the size and the unmet need are the things that I think that we continue to see here.
Towards that end, I know a few years ago, this kind of view is a zero-sum game. There's going to be winners and there's going to be losers. And maybe that position is starting to shift to a degree. How do you see the coexistence of all the players?
I think we've said that for a long time, that we don't think that this is a one company, one product, take all kind of market opportunity. It's a significant opportunity. So I do think that's the case. I mean, we're obviously very focused on our product and educating and getting it into as many patients' hands as possible. But I do think it's a market that there can be multiple companies and products that are going to do well. I think you're seeing the beginning signs of that already.
In the early run here for you, you're starting to hear of an overall view on how the doctors look at each therapy, what types of patients might go where versus other.
It's probably a little bit early. I mean, I think that right now, because there's really been only one product for these patients, certainly tafamidis, there's getting the majority of the new patients still are going on tafamidis, which is, again, I would say at this point to be expected, but this is a progressive fatal disease, so the physicians and the patients ultimately want to be on the best product they can be on as quickly and as early as they can be on that product, and so it's our responsibility and job now to make sure that we're educating the community as to why we think Amvutra should be the product that they should reach for. Again, it's not a disease that you want to put a patient on a product, see how they do for a period of time.
If they're not doing well, then move them up. So that's really our responsibility. It's probably, again, a little bit too early to say exactly how those choices are being made. I mean, we did talk on the Q2 results call about the patients that came on to therapy. There were about 1,400 patients that started therapy with Amvutra in the U.S. for cardiomyopathy in the second quarter. And the initial patients right out of the approval were probably more second line, some more switches, maybe some add-on, but mostly switches, I would say. But over the course of the quarter, there was really a pretty good balance in terms of first line and second line. So for us, I think the real priority is that first line setting because long term, because of what we talked about, mentioned earlier in terms of the market being underpenetrated.
And that's really what's going to drive growth over time is diagnosis and getting new patients on therapy. That's where we want to win. That's what we're prioritizing. And again, because it's progressive and fatal, you should go on the most potent, effective therapy as early as you can. We think that based on HELIOS-B results, we can make a very persuasive and compelling case that that should be our product. So that's what we're focused on. I think the advantage we've got on the second line side, which I mentioned earlier, is we're the first orthogonal mechanism. So I think we're going to probably get a lot of that business as a result of the way cardiologists make decisions about moving patients around. And we're seeing that early on.
So we're likely going to have two pretty good sources of growth over the long haul here, we think, both in that first and second line setting.
In terms of that initial couple of quarters performance, do you find that the initial prescribers are doctors who used to prescribe under the polyneuropathy label and that there's going to be more of a, it's going to take more time to kind of move into the broader cardiology?
Yeah, I'd say it's pretty broad already in terms of what we're seeing in terms of uptake. It's really balanced: first line, second line, community setting, academic setting. We talked about a pretty significant expansion of new prescribers in the second quarter compared to the first quarter, and so I think it's both physicians that are experienced with it on the polyneuropathy side, but early indications in the second quarter is we were also expanding it to physicians to use it that had never used it before, so I think that's going to continue on a go-forward basis.
I mean, back in the day, I think that there's typically a three to five-year mortality for patients when they're diagnosed with cardiomyopathy. Has there been an evolution in that number since tafamidis was initially approved? And I mean, as it gets longer, obviously, that means patients are going to be on medications longer itself. How should we be viewing that when we try to estimate what the true size of the market opportunity is?
Kevin, you want to talk about that?
I think clearly from the Helios B results and other results, patients are going to live longer. And that's the whole goal of the therapy is to keep them alive all the way till their natural lifespan. So I think you've seen that in this disease over time is that you want to get diagnosed early, and then you want to get on drug early enough that you have a natural lifespan and maybe something else, not this disease, is in the end what.
When looking at what's going on, I guess, with the big initial competition, Pfizer, who's been around for a while, $6 billion, they just recently announced this week that they're basically pulling Vyndaqel. How does that really affect things in your mind?
Yeah, I think I don't know for sure, but I think our belief probably is that's sort of a commercial decision, four pills for Vyndaqel, one pill a day for Vyndamax. And they're competing probably pretty extensively right now with Bridge. And Bridge is twice a day, two pills sort of each setting. So four pills a day for Bridge. So I suspect that it's about convenience for patients. Most of the business was already on Vyndamax. I think it was 80% of the patients, from what I understand, are already on Vyndamax. But that's my suspicion or our suspicion, I should say. We don't think that this changes the IP situation in terms of when we would expect generic entry in the U.S., which I think Pfizer has consistently said end of 2028. And I think that's a view that we share. I don't think this is about that.
Got it. I mean, I guess you had talked about how you're targeting the frontline population. Investors are still kind of asking questions, trying to understand what types of questions are the payers actually asking and try to determine which to use. Obviously, there's a Part B drug versus Part D, so it's two different sides of the payer world. Do these two sides of the world actually talk? What's actually happening?
Yeah, maybe I should. It's a good question. Maybe I should talk a little bit about the second quarter results. And probably the key to that actually was sort of the progress that we made in the quarter on the access front. We had originally guided the market that we thought this was largely going to be a second half of the year story in terms of revenue growth for the company, meaning that we didn't expect a lot in the second quarter. And that's because of what you said. This is a Part B buy and build drug. So there's really two key steps that you have to take to unlock physicians' ability to start using the product and putting patients on therapy and generating revenue. One is on the payer side.
You got to work with the payers to get policies in place that enable utilization of the drug. I mean, patients can get on it without those policies being in place, but it's more work for the physicians in that situation, and so we've been really successful there on the policy side, on the Medicare Advantage and the commercial side of getting most policies in place during the quarter that enable first-line utilization of the product, which I think had been somewhat of a debate about whether or not we were going to be successful with that, so that was one step, but probably the more important step and the one that we thought was going to take longer is the providers, so the ones that are doing the buying and building, the purchasing of the product, administering, and then getting reimbursed for it.
The majority of the providers that are doing the buy-and-build work at health systems. They think of these as networks of hospitals, about 170 of those in the U.S. that are treating the majority of these patients. We got almost all of those, the product on formulary in the second quarter, and I think that's what we thought was going to take a little bit more time and really probably through the end of the year before we were going to reach that level of success, and so that really was the key to the unlock in the quarter of the much quicker revenue uptake, and I think a couple of things contributed to that. One was the fact that a lot of these health systems were familiar with and they had been utilizing Amvutra for polyneuropathy, so there was a familiarity there that certainly helped us.
And then second, I think it was really good commercial execution. You really can't start having these conversations with these providers until you have an approval and you have a label. But the commercial team in the U.S. did everything up to being able to have the meeting to get the product on formulary that they could in advance. And so that really accelerated things when we got the approval. So those are the things that I think really helped. I will say on the payer front in terms of the policies that are in place that enable first line, that's not planting the victory flag. That's not necessarily a forever thing. Payers have the ability on an annual basis to review their policies and make changes.
And so that's something that we're going to have to continue to work on very carefully to make sure that we maintain that kind of access. And we have signaled that we believe that over time that our net price for Amvutra in the U.S. will come down gradually. And that's largely as a result of rebating that we may have to do to maintain the kind of formulary position that we've got in terms of first line over time. But we're off to a very good start and we're encouraged by that.
Towards that end with the buy and build and these systems and the price, kind of the net price being lowered gradually over time. What type of inventory do these systems actually hold? And I mean, is there a theoretical risk they're taking relative to a decrease, or is it in the contracts to kind of make up for inventory?
Yeah, the health systems don't hold a lot of inventory. The inventory is really held by our distribution, vast majority of it with sort of a single distributor that we've got. I mean, this stuff is shipped out on a daily basis, so the systems that are doing the administering don't need to hold a lot of inventory here, and look, I do think that the price reductions that we're talking about are going to be pretty gradual over time, so sort of the risk that you're highlighting is probably a very small risk for the distribution partner that we've got.
Got it. So let's jump on to the follow-on, ALN-TTRsc04. There's obviously two dynamics to this. One is the therapy itself and what its characteristics are. And of course, then we jump over. There's the economic situation with ALN-TTRsc04, which is very, very different. Let's start out on how the therapy itself differs.
Yeah, so Nucresiran is our next generation. We call it Icaria, which is a small Greek island where people live a very long time. So it's a very long-acting drug. And part of what we've done there is to make this drug exceptionally clean in terms of its off-target profile. So you can dose it higher up to we're up to 300 milligrams, which is the go-forward dose. And we also have it's got a much better ability to lower TTR. So TTR is into the high 90s. And so our data over time suggested from the clinical trials we've run that more knockdown is better. And so between the longer-acting, the clean profile, and the ability to get lower TTR, we're very excited about that as a follow-on drug.
I mean, does the data speak to, I guess, to what degree of an improvement in efficacy with knockdown? I know there's been a lot of companies kind of discussing what these percentages mean.
Yeah, it's hard from the trials that we've done to put an exact percentage on it, but I think the trend there is very clear. An 80/70 was not as good as an 80/85, which we don't think will be as good as an 80/95.
What's the status? Where does that sit in the trials, and where could we actually start seeing some data?
We've initiated the phase 3 study in cardiomyopathy, and we will initiate the polyneuropathy phase 3 study by the end of the year as well. So we're off to the races, I would say.
When might we see data for each trial?
I think what we've guided to is CM because it's an outcome. Kevin could talk a little bit more about the study, but it's an outcome study. So it's going to need to run. It's going to be larger and need to run longer than the PN study. We haven't announced the design of the PN study yet, but likely 2030 is what we're talking about with the CM opportunity with ALN-TTRsc04, and the PN opportunity should be a couple of years ahead of that.
Got it. Got it. And how are the economics different for ALN-TTRsc04?
Pretty significantly. I mean, I think the two things I think economically that are important. One is the royalty burden to Sanofi is zero with ALN-TTRsc04, and it's between 15%-30% on Amvutra. So that's one, obviously, fairly significant difference. And then the IP on ALN-TTRsc04 gives us the potential to have the franchise extend out into the 2040s. Amvutra is 2036, 2037 kind of timeframe in terms of when you could see generic entry. So both of those things, obviously, economically are good for the franchise.
Now, if we jump back a little bit and look, the one part we didn't really talk about was combination therapy. I know that it's an expensive drug. It's hard to say right now the extent that combination can get worked in, but over time, there's a possibility it might become easier.
Yeah, we think that because of what you said, putting two expensive therapies together, payers are probably going to make that difficult, which is what we expect. And I think you see most policies on the Medicare Advantage and the commercial side are making that difficult to get two products for the same disease reimbursed. Probably there's some opportunity on the Medicare fee-for-service side, but we think that'll be pretty nominal, frankly, until we get to a generic entry. And we talked about the possibility of Tafamidis being generic in the U.S. by the end of 2028. We do think that will open up the opportunity for combination therapy from a payer standpoint. We're fortunate about that sort of point in time, and you can debate whether it's 2028 or sometime later.
For us, frankly, it doesn't quite matter quite as much because we've got data in the label that shows that the drug was effective in the different subgroups that we studied in HELIOS-B, which included patients that were on a background stabilizer at baseline. And we did show a positive effect across all endpoints in the study when it was used in combination versus a stabilizer alone. And so I think that we're going to be well-positioned when the combination opportunity opens up more broadly. The other thing is the design of the ALN-TTRsc04 study is likely going to be mostly an add-on study because patients that are on a stabilizer will be. There's no cap on that coming into the study. So most patients are very likely going to be on a stabilizer in that study.
And so given the size of that study, that may lead to an actual claim, a combination claim. So I think we're in a good position as the market opens up to combination therapy. There is interest, I would say, from the physicians to use it in combination. Yeah.
So ESC 2024 for you was about Amvutra. ESC 2025 was about zilebesiran. Could you tell us about that drug and what you presented this past weekend?
I'm going to start.
Maybe I'll just start with the size of the opportunity that we're looking at here. Obviously, this is a massive potential opportunity. I think there's over 200 million patients that have hypertension across the seven largest markets and somewhere between a quarter and a third of the patients' high CV risk and uncontrolled hypertension. And that's really the patient population that we're targeting with the CVOT. That's the patient population that we looked at in KARDIA-3. And so this is a significant opportunity for us longer term. This is a program that's in combination with Roche. We did a deal with them a couple of years ago. And so there's a co-development, co-commercialization opportunity there. They're picking up about 60% of the cost to develop the drug. And then as we launch, we would have the opportunity to co-market it alongside them in the U.S.
They'll have full commercialization rights outside the U.S. But I'll let Kevin talk a little bit more about the data that we shared at ESC from KARDIA-3 and then the plan based on some of the learnings there to move this into a CVOT.
Yeah, so I was going to start first with hypertension itself. And really, the most important part about hypertension is keeping your blood pressure low tonically so that you keep it down and it doesn't go up and down. And we've published some papers recently where we've actually looked at across populations where it's those spikes in blood pressure that actually are the most harmful, especially if those spikes occur at night and you don't get the so-called nocturnal dipping where your blood pressure naturally goes down at night. And so really, this is a disease of exposure over time to too high a pressure.
And so the concept here really is to once every six months be able to go in to your practitioner, get a subcu injection, keep your blood pressure low, and you don't have to worry about whether you took your pill every day, whether if you didn't take the pill, your blood pressure is going to spike, whether it spikes after night. And so the data really shows in this, especially with this nocturnal dipping, that leads to bad outcomes if your blood pressure doesn't go down at night. And so that was the whole concept of this drug was to really change how hypertension is treated, which is to go in and have the ability to keep that down tonically. And so we've run a bunch of trials. We were at a phase 1, phase 2, and now you've seen sort of the results come out at the ESC.
And really what we were trying to figure out is within this, all of those trials showed clinically significant lowering of blood pressure on multiple agents. And really what we were trying to learn is if you're going to go into a very large outcome trial, you want to know how to power it. You want to know the right dose, and you also want to know the right patient population to try. And so the data that we presented at ESC really gave us confidence of all three of those things. Which patient population should you enrich for? Which dose should you take? And then we're going to go on into an outcome trial with our partners at Roche.
When you think in terms of the fluctuations throughout the day, is that a function of often people just taking all their pills and these combinations in the morning and they wearing off by the end of the day? Is it something that more appropriate management if they were taking some of the pills in combination in the morning and some at night that might lessen the magnitude of it?
I think it could if you could change human behavior potentially. I don't think it'll take care of all of it. Like the nocturnal dipping is not the same on some of the standard of care that's out there. But I have to say, even looking at our clinical trial where we were measuring whether patients coming in and they're running, we're supposed to be on medications, but we weren't detecting the medications in the system. And so it's just as people get older in particular, if you're on multiple medications, they just don't take the pills regularly. And so I think, and because it is a disease of area under the curve, every time you're not doing that, you're actually putting yourself at greater risk. And so I think that's part of the whole underlying hypothesis.
When talking about this with physicians who have been treating blood pressure for years and they're used to this whole process of titrating, you titrate one drug up, add a second drug on, start titrating that up, then you might add a third on, titrating that up until you find it. And then you bring a therapy that titration isn't a thing. How do they, what's their initial response to that? And how do they compare number one versus the other? And brainstorming how that actually fits into their practice.
Yeah, so I think as they get their head around it, the concept becomes, okay, well, I can use your drug to take the blood pressure down and hold it tonically. And now I can use these other medications to do my little titration and sort of in a narrow band, push it up or down a little bit more as I want to. And I think that's how they start to think about it once they get their head around a novel mechanism.
I know in this trial, actually, the hypotension rates were pretty much in line with placebo. In the trial itself, how does that actually get managed? In the event there is a situation, does the protocol actually have it for downtitrating other therapies?
So you can either downtitrate other therapies. We've shown early in our phase 1s that you can use salt to rescue short term. And then behind this, we don't feel like we'll ever really need to use it, but we do have something called a reverser, which is another drug that can reverse the action of our current medication.
Got it. So let's talk about the pivotal with Roche. I know you certainly gave some outlines of it this past weekend. What would this study look like?
Yeah, so we're looking at somewhere around 11,000 patients, I think it was.
Yeah, that's the right number.
Yeah. And we're looking at. It's an event-driven trial. And so we'll be looking at MACE endpoints. It's a lot like other hypertension trials and cardiovascular outcome trials that have been out there.
How long would it take?
It's event-driven, so it's hard to say an exact timeframe.
I think a minimum two-year follow-up, but we haven't, yeah.
Minimum of 2030.
I think we've sort of set approximately 2030.
We've got a model, so we have.
I think we've set approximately 2030 is what the expectation right now, but it'll obviously depend on enrollment and then how quickly we accrue the events, but that's the best guess at this point.
Yeah, we'll have to double-check ours. So how large of an opportunity is this ultimately in your mind?
Yeah, I think it's a big opportunity. I highlighted previously just the size of the opportunity, even in a subset of the market, which is really what we're talking about is going into hypertension for patients with high CV risk. Even that part of the market is 60 million-plus patients in the seven largest pharma markets around the world. So there's a significant opportunity here. I think given the size of the opportunity and what was going to be needed to be successful commercially, that was one of the main reasons a couple of years ago that we did the deal with Roche. We thought that we needed their experience and, frankly, in the buy-and-bill in a much broader sort of buy-and-bill market, as well as their experience in launching highly innovative therapies into very competitive markets.
I think they had a lot of success in the hemophilia market as an example. We thought that we would really benefit from their experience with this drug. And we do think it's a sizable opportunity.
So we have a little less than 10 minutes left and wanted to drift outside of the liver. For years, it's been about the liver.
We have a few more things coming in the liver.
I know there's a lot of stuff in the liver, but there's also a lot of other stuff coming outside the liver that are kind of just starting to emerge. What is the nature of the challenge outside the liver? And what is the cadence of when we can actually, we already know there's some things going on. Certainly, we have Mivelsiran, and there are other areas, but what is the cadence of actually seeing more of these therapies come out?
Yeah, so where we, our first foray really outside the liver was into the central nervous system where we have our protein that targets APP. That's amyloid precursor protein for Alzheimer's and also a disease called CAA, which is basically Alzheimer's of the vascular system in the brain, as you can think about it. And that drug is an IT injection every six months. We've seen really phenomenal knockdown, 80s, 80s, 90s of APP in CSF. And that program is continuing to go ahead in early onset Alzheimer's patients where we're measuring over time a bunch of different biomarkers, including Aβ40 and 42, which are part of that disease. But separately, we've launched into a phase 2 in this disease called CAA where people get microbleeds to start with in their brain and then eventually strokes. It's probably a very underestimated cause of stroke, especially in elderly patients.
That trial actually has both a sporadic arm, but also there is a genetic population in the Netherlands where they have mutations in this protein called APP that we're knocking down. And those patients on 100% penetrant get this disease. So their family members all eventually succumb to stroke. And so they've been very well studied. And once you get four or five microbleeds, which you can see by imaging, every time you have a microbleed, you leave behind a little bit of iron that can show up on an MRI. And so you can follow these patients over time. And there's a couple of other biomarkers you can follow. And so what we're looking to do there is to really reduce the bleed rate over time in those patients. And so that's very exciting. That's an ongoing trial.
Behind that, we have our Huntington's program in the CNS where we've targeted Exon 1, which is sort of a unique strategy. We had a molecule that targeted just the full length, and we're happy we didn't take that forward as the biology has emerged. A lot of, we think that disease, especially as it progresses, there's these little peptides that come off and aggregate out of this thing called Exon 1. And so we're able to knock that down. That's an ongoing trial. And then behind that, we have our first program in adipose, which will be in the end of the year, targeting ACVR1C. We've shown an KD of 98 plus and a very long-acting adipose delivery. And then behind that, we have several different muscle programs that are coming along quite nicely, as well as we also have a blood-brain technology that we've been working on actively.
What's the challenge when taking RNAi out of the liver? I mean, it was the people who worked on it for the liver for a long time. So we know the liver very, very well, but how does it work? It's different.
So I think the beauty of RNAi is it does work in every cell. However, every cell is not the same. I mean, every organ is not the same. So if you look at the liver, it's predominantly hepatocytes. There are a couple of other cell types, but the hepatocytes drive a lot of biology. As you get into certain other tissues, like obviously in the brain, there's a bunch of different cell types in the brain. And our delivery system actually hits most of the cell types in the brain on purpose because APP that I talked about, Huntington's, they're very broadly expressed. Now, we have some other programs where we'll be looking to hit specific cell types. And a lot of that is just engineering, getting the right ligand receptor pair.
And then there are certain cells that are just a little bit more amenable to RNAi versus others. And so a lot of it is the challenge that we've been tackling the 27 years I've been in it, which is delivery. How do you get specific delivery? How do you make sure it gets in the right part of the cell?
Towards that end, what learnings from the liver? It wasn't always smooth getting to delivering RNAi technologies. Obviously, the biggest headache in the early years of the technology was getting in there, getting it stabilized. How does it vary from tissue to tissue? And what learnings you take from the earlier iterations into these new tissues?
So the good news is we don't have to reinvent everything. So a lot of the learnings about how you make a good molecule for one tissue hold true in other tissues, the longevity, depending on the half-life of the cells in that particular tissue. Adipose is actually a very long-lived cells. You have basically the same adipocytes for a very, very long time. There's not a lot of turnover, so you can expect very long action there. I think there are some other things that you learn as you go cell by cell, how much they tolerate in terms of off-target, how much you have to pay attention to the chemistry. So there are some tricks as you move from tissue to tissue. But a lot of what we've learned can also be applied.
So we got a couple of minutes left here. Any way we should think about the next couple of quarters in terms of beyond what we've already talked about in guidance as far as our expectations for growth?
Yeah, I mean, I think certainly there's still going to be a lot of focus on the quarterly results for Amvutra cardiomyopathy. So as I talked about earlier, what the commercial team is focused on is really continuing to drive positioning-wise first-line demand. And we think we're going to get the second line that's going to come with that. But sort of watching how the demand figures look on a quarter-over-quarter basis, I think it's going to be a big focus for the investment community. And then look, we upgraded the guidance pretty substantially on the Q2 call. So we're very focused on delivery and on that. We know the importance of when we say we're going to do something that we need to follow through and make sure that happens.
So commercially, those are the things that we're very focused on right now to continue to drive strong performance through the balance of the year and have us in a strong position to start next year as well. People will start to look at their models for 2026 soon as well.
Yeah, indeed. We are. Thank you so much for visiting us today. Appreciate it. It was a long drive from Cambridge. And look forward to chatting again soon.
Thanks, David.